Thiochroman esters of phenols and terephthalates having retinoid-like activity

Abstract: Compounds of formula I in which: the R groups are independently hydrogen or lower alkyl; one of A and B is O or S and the other is -C(O)-, A being attached to the thiochroman ring at the 6 or 7-position; n is 0-5; and Z is H, an acid or acid derivative, an alcohol or alcohol derivative, acetal or acetal derivative or ketone or ketone derivative, or a pharmaceutically acceptable salt, have retinoid-like activity.

Description: This invention relates to novel compounds having retinoid-like activity. These compounds are esters containing a thiochroman group. The compound 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthoylamino)benzoic acid is disclosed in Sporn et al., J. Amer. Acad. Derm. 15:756-764 (1986). See also the several compounds disclosed in Shudo et al., Chem. Pharm. Bull. 33:404-407 (1985). LU-A-86 259 describes aromatic amide compounds derived from 4,4-dimethyl-6-chromanoic or 4,4-dimethyl-6-thiochromanoic acid and para amino benzoic acid or its esters, as compounds having retinoid-like activity. This invention relates to the following compounds: in which: the R groups are independently hydrogen or C₁₋₆ alkyl; one of A and B is O or S and the other is -C(O)-, A being attached to the thiochroman ring at the 6 or 7-position; n is 0-5; and Z is H, or Z is -COD where D is -OH or a pharmaceutically acceptable salt, or D is -OR₁ where R₁ is an ester-forming group, or D is -N(R₄)₂ where R₄ is hydrogen or an aliphatic or substituted aliphatic group, or Z is -OE where E is hydrogen or an ether-forming group or an acyl ester forming group, or Z is -CHO or an acetal derivative thereof, or Z is -COR₃ where R₃ is -(CH₂) m CH₃ where m is 0-4 and the sum of n and m does not exceed 4 or a ketal derivative thereof. This invention also relates to a pharmaceutical composition comprising a compound of formula I in admixture with a pharmaceutically acceptable excipient. In addition, this invention relates to compounds of formula I for use in medicine and in particular for treating dermatoses, such as acne, Darier's disease, psoriasis, icthyosis, eczema, atopic dermatitis and epithelial cancers. These compounds are also useful in the treatment of arthritic diseases and other immunological disorders (e.g., lupus erythematosus), in promoting wound healing, in treating the dry eye syndrome, and in preventing and/or reversing the effects of sun induced skin aging and damage. In another aspect, this invention relates to the process for making a compound of formula I which process comprises reacting a compound where the A' or B' of formula II or III is an acid or acid derivative which can form an ester with the corresponding formula II or III where A' or B' is -OH or -SH, preferably in the presence of an ester-forming catalyst. Here, R, n and Z are defined above, with the proviso that if Z is an acid or alcohol function, it is preferred that it be protected. Where Z is an aldehyde or ketone, such functional groups need not be protected in order to effect this reaction. Secondly, deprotecting a protected compound obtained by the foregoing ester-forming reaction using deprotecting means gives the corresponding acid, alcohol, aldehyde or ketone, of Formula I, as appropriate if such protected compound has been prepared and is to be converted to the parent functional group. Acids of formula I may be converted to their salts by treating them with the appropriate base under mild conditions. An acid of formula I can also be converted to an ester. Alcohols of formula I may be made from the corresponding aldehydes by reducing means. To synthesize compounds where n is 1 or greater, and the corresponding formula III form is not commercially available, the acid formula of formula III (Z is COOH) can be homologated to insert the desired number of methylene groups. This homologation product, the acid, can then be reduced to give the corresponding aldehyde or alcohol. Aldehydes can be converted to their ketone analogues. Such compounds can then be coupled with the corresponding formula II compound, the functional group represented by Z being protected as necessary. Definitions The nomenclature employed herein is exemplified by the following molecular structure of a thiochroman moiety. The term "ester" as used here refers to and covers any compound falling within the definition of that term as classically used in organic chemistry. It includes organic and inorganic esters. Where Z is -COOH, this term covers the products derived from treatment of this function with alcohols or thiols. Where the ester is derived from compounds where Z is -OH, this terms covers compounds derived from organic acids capable of forming esters including phosphorous-based and sulfur-based acids. Preferred esters are derived from the saturated aliphatic alcohols or acids of ten or fewer carbon atoms or the cyclic or saturated aliphatic cyclic alcohols and acids of 5 to 10 carbon atoms. Particularly preferred aliphatic esters are those derived from C₁₋₆ alkyl acids and alcohols. Also preferred are the phenyl or C₁₋₆ alkylphenyl esters. The term "lower alkyl" as used herein means an alkyl radical of 1 to 6 carbon atoms. Ether derivatives may be prepared for any of the compounds where Z is -OH. Preferred ethers are those derived from an aliphatic radical of 1 to 20 carbon atoms, phenyl or aliphatic-phenyl radical where the aliphatic group has up to 20 carbon atoms. In this last instance, the phenyl group can be on the omega position of the aliphatic chain or at another position on that chain. Also cyclic radicals of 5-7 carbons and aliphatic-cyclic radicals of up to 20 carbons are preferred. Amides has the meaning classically accorded that term in organic chemistry. In this instance it particularly includes the unsubstituted amides and all aliphatic and aromatic mono- and di-substituted amides. Preferred amides are the mono- and di-substituted amides derived from the saturated aliphatic radicals of ten or fewer carbon atoms or the cyclic or saturated aliphatic-cyclic radicals of 5 to 10 carbon atoms. Particularly preferred amides are those derived from substituted and unsubstituted C₁₋₆ alkyl amines. Also preferred are mono- and di-substituted amides derived from the substituted and unsubstituted phenyl or C₁₋₆ alkylphenyl amines. Unsubstituted amides are also preferred. Acetals and ketals includes radicals of the formula -CK where K is (-OR)₂. Here, R is lower alkyl. Also, K may be -OR₃O-where R₃ is C₁₋₆ alkyl of 2-5 carbon atoms, straight chain or branched. In preferred compounds of formula I, A is attached to the thiochroman ring at the 6- or 7-position. Also preferred are those of formula I where the (CH₂) n -Z substituent is para to the ester function on the phenyl ring; n is 0, 1 or 2; and Z is -COOH, an alkali metal salt or organic amine salt, or a C₁₋₆ alkyl ester, or -OH and the C₁₋₆ alkyl esters and ethers thereof. Particularly preferred compounds are: ethyl 4-(2,2,4,4,7-pentamethyl-6-thiochromanoyloxy)benzoate, 4-(2,2,4,4,7-pentamethyl-6-thiochromanoyloxy)benzoic acid, 4-(4,4,7-trimethyl-6-thiochromanoyloxy)benzoic acid, ethyl 4-(2,2,4,4-tetramethyl-7-thiochromanoyloxy)benzoate, ethyl 4-(4,4,7-trimethyl-6-thiochromanoyloxy)benzoate; ethyl 4-(4,4-dimethyl-6-thiochromanoyloxy)benzoate; 4-(4,4-dimethyl-6-thiochromanoyloxy)benzoic acid; 4-(4,4-dimethyl-7-thiochromanoyloxy)benzoic acid; ethyl 4-(4,4-dimethyl-7-thiochromanoyloxy)benzoate; ethyl 4-(2,2,4,4-tetramethyl-6-thiochromanoyloxy)benzoate; and 4-(2,2,4,4-tetramethyl-6-thiochromanoyloxy)benzoic acid. A pharmaceutically acceptable salt may be prepared for any compounds in this invention having a functionality capable of forming such salt, for example an acid functionality. A pharmaceutically acceptable salt is any salt which retains the activity of the parent compound and does not impart any deleterious or untoward effect on the subject to which it is administered and in the context in which it is administered. Pharmaceutically acceptable salts may be derived from organic or inorganic bases. The salt may be a mono or polyvalent ion. Of particular interest are the inorganic ions, sodium, potassium, calcium, and magnesium. Organic salts may be made with amines, particularly ammonium salts from mono-, di- and trialkyl amines or ethanol amines. Salts may also be formed with caffeine, tromethamine and similar molecules. The compounds of this invention may be administered systemically or topically, depending on such considerations as the condition to be treated, need for site-specific treatment, quantity of drug to be administered, and numerous other considerations. In the treatment of dermatoses, it will generally be preferred to administer the drug topically, though in certain cases such as treatment of severe cystic acne or psoriasis, oral administration may also be used. Any common topical formulation such as a solution, suspension, gel, ointment, or salve and the like may be used. Preparation of such topical formulations are well described in the art of pharmaceutical formulations as exemplified, for example, Remington's Pharmaceutical Science, Edition 17, Mack Publishing Company, Easton, Pennsylvania. For topical application, these compounds could also be administered as a power or spray, particularly in aerosol form. If the drug is to be administered systemically, it may be confected as a powder, pill, tablet or the like, or as a syrup or elixir suitable for oral administration. For intravenous or intraperitoneal administration, the compound will be prepared as a solution or suspension capable of being administered by injection. In certain cases, it may be useful to formulate these compounds in suppository form or as an extended release formulation for deposit under the skin or intramuscular injection. Other medicaments can be added to such topical formulation for such secondary purposes as treating skin dryness; providing protection against light; other medications for treating dermatoses; medicaments for preventing infection, reducing irritation, inflammation and the like. Treatment of dermatoses or any other indications known or discovered to be susceptible to treatment by retinoic acid-like compounds will be effected by administration of the therapeutically effective dose of one or more compounds of the instant invention. A therapeutic concentration will be that concentration which effects reduction of the particular condition, or retards its expansion. In certain instances, the compound potentially may be used in a prophylactic manner to prevent onset of a particular condition. A useful therapeutic or prophylactic concentration will vary from condition to condition and in certain instances may vary with the severity of the condition being treated and the patient's susceptibility to treatment. Accordingly, no single concentration will be uniformly useful, but will require modification depending on the particularities of the disease being treated. Such concentrations can be arrived at through routine experimentation. However, it is anticipated that in the treatment of, for example, acne, or similar dermatoses, that a formulation containing between 0.1 and 1.0 milligrams per milliliter of formulation will constitute a therapeutically effective concentration for topical application. If administered systemically, an amount between 0.01 and 5 mg per kg per day of body weight would be expected to effect a therapeutic result in the treatment of many diseases for which these compounds are useful. The retinoic acid-like activity of these compounds is confirmed through the classic measure of retinoic acid activity involving the effects of retinoic acid on ornithine decarboxylase. The original work on the correlation between retinoic acid and decrease in cell proliferation was done by Verma & Boutwell, Cancer Research , 1977 , 37 , 2196-2201. That reference discloses that ornithine decarboxylase (ODC) activity increased precedent to polyamine biosynthesis. It has been established elsewhere that increases in polyamine synthesis can be correlated or associated with cellular proliferation. Thus, if ODC activity could be inhibited, cell hyperproliferation could be modulated. Although all causes for ODC activity increase are unknown, it is known that 12-O-tetradecanoylphorbol-13-acetate (TPA) induces ODC activity. Retinoic acid inhibits this induction of ODC activity by TPA. The compounds of this invention also inhibit TPA induction of ODC as demonstrated by an assay essentially following the procedure set out in Cancer Res .: 1662-1670, 1975. It is anticipated that the compounds of this invention can be made by a number of different synthetic chemical pathways. To illustrate this invention, there is here laid out a series of steps which will provide the compounds of formula I. The synthetic chemist will readily appreciate that the conditions set out here are specific embodiments which can be generalized to any and all of the compounds represented by formula I. Compounds of formula I where A is -(O)C- and B is O are prepared as follows: The definitions of R and n are those given herein above. Z is H, an ester or amide of COOH, -OH or an ether or ester derivative, -CHO or an acetal derivative or -C(O)- or a ketal derivative. Those compounds having the reverse connectivity, that is where A is O and B is -C(O)- can be made in the manner illustrated in Reaction Scheme II. Compounds having two methyl groups at the 2 position of the thiochroman ring can be made by the sequence of steps outlined in Reaction Scheme III. Where there is only one methyl at the 2 position of the thiochroman ring, those compounds can be made by modifying the reaction requence set out in Reaction Scheme III, as illustrated in Reaction Scheme IV. A general description of the chemistry for making compounds where the substituents at the 2-position of the thiochroman ring are hydrogen is recited as follows, or can be gotten from a reading of the Examples. The 4-bromothiophenol of formula 1 is first treated with approximately an equimolar amount of a strong base such as an alkali metal hydroxide, preferably sodium hydroxide, in a solvent such as acetone at reflux. Refluxing is carried out for between 1 and 4 hours, preferably 2.5 hours, after which the solution is treated with an equimolar amount of formula 2, available from Aldrich Chemical Co. of St. Louis, MO, USA, dissolved in the selected solvent. Refluxing is continued for an extended time, up to 2 days, after which the solution is stirred for another extended period, for example 24 hours, at room temperature. Product 3 is isolated by conventional means. Ring closure is effected by adding the sulfide (compound 3) to a solution of phosphorous pentoxide and a strong acid such as methanesulfonic acid under an inert atmosphere to effect formation of the thiochroman of formula 4. The solution stirred under an inert gas such as argon or nitrogen for a short period, 10 minutes to 2 hours, at about ambient temperature. This mixture is then diluted with water, heated to a moderate temperature, 30° to 50° C. and extracted with an appropriate solvent, ether for example. The product is further recovered and purified by conventional means. The acid function of formula 5 is introduced by means of tert-butyl lithium or a similar base at reduced temperature under an inert atmosphere. The reaction is carried out in an ether-type of solvent such as a dialkyl ether or a cyclic ether, for example tetrahydrofuran, pyran or the like. More specifically, a solution of the bromo compound is dissolved in an ether-type solvent. This solution is cooled, preferably to between -70° and -50°C. An equimolar amount of an alkyl-lithium compound such as tert-butyl lithium in an appropriate solvent (an alkane or the like) is then added in portions at the reduced temperature and mixed for an appropriate time. Between 30 minutes and 5 hours will effect the reaction. The reaction mixture is then treated with solid carbon dioxide and warmed to room temperature, the solution acidified and the product recovered by conventional means. Coupling this acid, or its analoges, with the appropriate phenol or thiophenol gives compounds of formula I. Most means for esterification or thioesterification wil provide the desired compounds of formula I. In these cases, esterification was effected by treating the appropriate acid and phenol with 1,3-dicyclohexylcarbodiimide and 4-dimethylaminopyridine. Preparation of compounds with the reverse connectivity, that is where B is -C(O)-, is achieved by preparing the thiochroman compounds illustrated in Reaction Scheme II. The 4-mercaptophenol (formula 6) is reacted with 1-bromo-3-methyl-2-butene under essentially the same conditions as recited above in the discussion of Scheme I chemistry. Protecting the free OH group of formula 7 by some means makes it possible to form the thiochroman by cyclization using the same means as described above in the discussion of the chemistries of Scheme I. Base hydrolysis of the OH protecting group during work-up results in a free OH group at position 6 on the resulting thiochroman of formual 9. This compound is then reacted with a terephthalate to give a compound with the desired core structure. Terephthalic acids used in Scheme II are readily available from most chemical supply houses. Their esterification and selective hydrolysis to the mono-acid is illustrated for the para-substituted compound, but can be used for the general case of the terephthalates. The coupling reaction used to make the final product is the same or an obvious variation of the generalized reaction sequence and conditions given for Reaction Scheme I. If the Z group is an alcohol, aldehyde or ketone, it can first be converted to an ether or ester, acetal or ketal respectively before being used in the foregoing coupling reaction. Alcohols may be protected as ethers or esters and aldehydes and ketones as acetals or ketals by known methods such as those described in McOmie , Plenum Publishing Press, 1973 and Protecting Groups , Ed. Greene, John Wiley & Sons, 1981. These same procedures can be used to make ethers, acetals and ketals at some other point in the synthetic process. Alcohols are made by converting the corresponding acids of formula I to the acid chloride as described above, then reducing the acid chloride with sodium borohydride (March, Ibid, pg. 1124). Alternatively, the aldehydes of formula I can be reduced to the corresponding alcohols using sodium borohydride. Also, before effecting the coupling of formula II and formula III compounds, aldehydes of formula III can be reduced to the alcohol using sodium borohydride. Alkylating formula I or formula III alcohols with appropriate alkyl halides under Williamson reaction conditions (March, Ibid, pg. 357) gives the corresponding ethers. Esterification may be accomplished by reacting the acid with the appropriate alcohol in the presence of coupling reagents such as 1,3-dicyclohexylcarbodiimide and 4-dimethylaminopyridine. The ester is recovered and purified by conventional means. Amides may be formed by any appropriate amidation means known to the art. One way to prepare such compounds is to first make an acid chloride and then treat that compound with ammonium hydroxide or an appropriate amine. For example, the acid is treated with an alcoholic solution of base such as ethanolic KOH (about one equivalent) and reacted at room temperature for 1/2 hour. The solvent is removed and the residue taken up in an organic solvent such as ether, treated with a dialkyl formamide and then a 10-fold excess of oxalyl chloride. This is all effected at a reduced temperature between -10° and +10°C. The last mentioned solution is then stirred at the reduced temperature for 1-4 hours, preferably 2 hours. Solvent removal provides a residue of the acid chloride which is taken up in an inert inorganic solvent such as benzene, cooled to 0°C and treated with concentrated ammonium hydroxide. The resulting mixture is stirred at a reduced temperature for 1-4 hours. The product is recovered by conventional means. Aldehydes can be prepared from the corresponding primary alcohols using mild oxidizing agents such as exemplified by pyridinium dichromate in methylene chloride (Corey, E.J., Schmidt, G., Tet. Lett., 399, 1979 ) Acetals can be prepared from the corresponding aldehyde by the method described in March, Ibid, p 810. These can then be reacted with formula II compounds to give acetals of formula IV. The acids of formula I can be obtained from the esters of formula I. The terminal benzyl ester can be selectively cleaved using boron tribromide. For example, the ester in an inert solvent such as methylene chloride is cooled to low temperatures, -10°C, under an inert gas. The cold solution is treated slowly with boron tribromide in methylene chloride and the mixture stirred at low temperatures for 1-4 hours. The mixture is quenched and the product recovered by conventional means. The salts are prepared by reacting the acid with an appropriate base under standard conditions. Compounds of formula III where n is 1-5 may be prepared from compounds in which n is 0-4 and Z is COOH by homologation by successive treatment under Arndt-Eistert conditions and subsequent manipulation of the resulting acid as described above. These can be used to prepare compounds of formula I where n is 1-5 and Z is an alcohol, aldehyde or ketone or derivatives thereof. The following examples are set out to illustrate the invention, Example 1 4-bromophenyl-3-methylbut-2-enylsulfide A solution of 25 g (0.132 mmol) of 4-bromothiophenol and 5.56 g (0.139 mmol) of sodium hydroxide in 100 ml of acetone was heated at reflux for 0.5 hours. To the refluxing mixture was then added dropwise a solution of 19.7 g (0.132 mmol) of 1-bromo-3-methyl-2-butene in 30 ml of acetone. The reaction mixture was heated at reflux for a further 1.5 hours, cooled and the solvent then removed in-vacuo . The residue was taken up in water and extracted with ether. The ether extracts were combined and washed successively with dilute sodium hydroxide, water and saturated sodium chloride and then dried (calcium chloride). The solution was filtered and the filtrate concentrated in-vacuo. The residue was then fractionally distilled (124-128°C; 0.5 mm) to give the title compound as a colorless oil. PMR (CDCl₃): δ 1.57 (3H, s), 1.69 (3H, s), 3.49 (2H, d, J ∼ 7.7 Hz), 5.25 (1H, m), 7.15 (2H, d, J . 8.6 Hz), 7.35 (2H, d, J ∼ 8.6 Hz). Example 2 4,4-dimethyl-6-bromothiochroman To 10 ml of 1:10 (w/w) mixture of phosphorus pentoxide and methanesulfonic acid was added slowly with stirring 1.0 g (3.89 mmol) of 4-bromophenyl-3-methylbut-2-enylsulfide. The mixture was stirred at room temperature for 0.5h and then poured into 150 ml water. The resultant mixture was heated up to 50°C, cooled to room temperature and extracted with two portions of ether. The ether extracts were combined and washed successively with water and saturated NaCl solution and then dried (MgSO₄). The solution was filtered and the solvent removed in-vacuo to give the title compound as pale yellow crystals. PMR (CDCl₃): δ1.30 (6H, s), 1.92 (2H, m), 3.01 (2H, m), 6.94 (1H, d, J∼8.8 Hz), 7.13 (1H, dd, J ∼ 8.8 Hz, 2.2 Hz), 7.45 (1H, d, J∼2.2Hz). Example 3 4,4-dimethyl-6-carboxythiochroman To a stirred solution of 5.14 g (0.02 mmol) of 4,4-dimethyl-6-bromothiochroman in 40 ml of dry ether at -78°C was added dropwise 28.2 ml of 1.7 M (0.048 mmol) tert-butyllithium in pentane. The mixture was stirred at -78°C for 2.5 hours and then treated with an excess of solid carbon dioxide. The mixture was warmed to room temperature and treated with sufficient water to dissolve the solids. The aqueous layer was then separated, acidified with dilute sulfuric acid and extracted with three portions of ether. The ether extracts were combined and washed successively with water and saturated NaCl solution and then dried (MgSO₄). The solution was filtered and the solvent removed in-vacuo and the residue recrystallized from ethyl acetate and hexane to give the title compound as a white solid. PMR (CDCl₃): δ 1.37 (6H, s), 1.97 (2H, m), 3.08 (2H, m), 7.17 (1H, d, J ∼8.0 Hz), 7.74 (1H dd, J ∼ 8.0, 1.9 Hz), 8.11 (1H, d, J ∼ 1.9 Hz). Example 4 Ethyl 4-(4,4-dimethyl-6-thiochromanoyloxy)benzoate A solution of 280 mg (1.26 mmol) of 4,4-dimethyl-6-carboxythiochroman and 252 mg (2.52 mmol) of triethylamine in 15 ml of chloroform was stirred at room temperature for 0.5 hours and then treated with 481 mg (1.26 mmol) of bis (2-oxo-3-oxazolidinyl)phosphinic chloride. The reaction mixture was stirred for 0.5h, treated with 209 mg (1.26 mmol) of ethyl 4-hydroxybenzoate and then stirred at room temperature for a further 12 hours. The reaction mixture was washed successively with dilute HCl and saturated sodium bicarbonate solutions. The organic layer was concentrated in-vacuo and the resultant crude product purified by flash chromatography (silica; 10% ethyl acetate in hexane) followed by reversed-phase high pressure liquid chromatography (Whatman Partisil M20 10/50 ODS-2; 10% water in acetonitrile) to give the title compound as a colorless oil. PMR (CDCl₃): δ 1.38 (6H, s), 1.42 (3H, t, J∼7.0 Hz), 1.98 (2H, m), 3.07 (2H, m), 4.39 (2H, q, J∼7.0 Hz), 7.20 (1H, d, J∼9.0 Hz), 7.28 (2H, d, J∼8.1 Hz), 7.82 (1H, dd, J∼9.0, 1.8 Hz), 8.12 (2H, d, J∼8.1 Hz), 8.17 (1H, d, J∼1.8 Hz). Example 5 Benzyl 4-(4,4-dimethyl-6-thiochromanoyloxy)benzoate A solution of 786 mg (3.54 mmol) of 4,4-dimethyl-6-carboxythiochroman, 804 mg (3.53 mmol) of benzyl 4-hydroxybenzoate, 800 mg (3.88 mmol) of 1, 3-dicyclohexylcarbodiimide and 60 mg (0.49 mmol) of 4-dimethylaminopyridine in 50 ml of methylene chloride was stirred at room temperature for 2 hours. The reaction mixture was then filtered and the residue washed with 20 ml of methylene chloride. The filtrate was concentrated in-vacuo and the resultant crude product was purified by flash chromatography (silica, 20% ethyl acetate in hexanes) followed by recrystallization from a mixture of hexanes and ethyl acetate to give the title compound as a white, crystalline solid. PMR (CDCl₃): δ 1.39 (6H, s), 1.98 (2H, m), 3.08 (2H, m), 5.37 (2H, s), 7.20 (1H, d, J∼8.3 Hz), 7.28 (2H, d, J∼8.0 Hz), 7.34-7.48 (5H, m), 7.82 (1H, dd, J∼8.3, 2.0 Hz), 8.14 (2H, d, J∼8.0 Hz), 8.16 (1H, d, J∼2.0 Hz). Using this procedure, or the one described in Example 4, but substituting the appropriate precursors, the following compounds can be prepared: butyl 4- (4,4-dimethyl-6-thiochromanoyloxy) benzoate; cyclohexyl 4-((4,4-dimethyl-6-thiochromanoyloxy) benzoate; ethyl 3- (4,4-dimethyl-6-thiochromanoyloxy )benzoate; ethyl 2- (4,4-dimethyl-6-thiochromanoyloxy )benzoate; ethyl 4- (2,2,4,4-tetramethyl-6-thiochromanoyloxy )benzoate; ethyl 3- (2,2,4,4-tetramethyl-6-thiochromanoyloxy )benzoate; and ethyl 2- (2,2,4,4-tetramethyl-6-thiochromanoyloxy )benzoate. Example 6 4- (4,4-dimethyl-6-thiochromanoyloxy)benzoic acid To a stirred solution of 580 mg (1.34) of benzyl 4-(4,4-dimethyl-6-thiochromanoyloxy)benzoate in 12 ml of methylene chloride at -10°C under nitrogen was added slowly 1.24 ml of a 1.0 M (1.24 mmol) solution of boron tribromide in methylene chloride. The reaction mixture was stirred at -10°C for a further 2h and then was quenched by the addition of ice. The organic layer was separated and the aqueous layer extracted with 2 x 25 ml methylene chloride. The organic extracts were combined and then washed with water and dried (MgSO₄). The solution was then filtered and the solvent removed in-vacuo . The resultant residue was purified by flash chromatography (silica; 20% ethyl acetate in hexane followed by 100% ethyl acetate) and then recrystallization from a mixture of ethyl acetate and ethanol to give the title compound as a white solid. PMR (CDCl₃): δ 1.39 (6H, s), 2.10 (2H, m), 3.10 (2H, m), 7.21 (1H, d, J∼8.4 Hz), 7.28 (2H, d, J∼8.7 Hz), 7.82 (1H, dd, J∼8.4, 2.1 Hz), 8.14 (2H, d, J∼8.7 Hz), 8.16 (1H, d, J∼2.1 Hz). Proceeding in the same or a similar manner, but substituting the appropriate ester prepared by Example 5, the following representative acids can be prepared: 3- (4,4-dimethyl-6-thiochromanoyloxy)-benzoic acid; 2- (4,4-dimethyl-6-thiochromanoyloxy)-benzoic acid; 4- (2,2,4,4-tetramethyl-6-thiochromanoyloxy)-benzoic acid; 3- (2,2,4,4-tetramethyl-6-thiochromanoyloxy)-benzoic acid; and 2- (2,2,4,4-tetramethyl-6-thiochromanoyloxy)-benzoic acid. Example 7 4-Hydroxyphenyl-3-methylbut-2-enylsulfide A mixture of 2.11 g (52.7 mmol) of powdered sodium hydroxide and 7.38 g (52.7 mmol) of 4-hydroxythiophenol (90%) in 25 ml acetone was heated at reflux for 10 min. and then treated dropwise with a solution of 8.35 g (50.4 mmol) of 1-bromo-3-methyl -2-butene (90%) in 10 ml acetone over a period of 15 min. The mixture was heated at reflux for a further 1 hour, cooled to room temperature and the solvent then removed in-vacuo . The resultant residue was treated with water and extracted with 2 x 50 ml ether. The ether extracts were combined and washed successively with water and saturated NaCl solution and then dried (calcium chloride). The solution was filtered and concentrated in-vacuo and the resultant residue purified by flash chromatography (silica; 10% ethyl acetate in hexanes followed by 20% ethyl acetate in hexanes) to give the title compound as a pale yellow liquid. PMR (CDCl₃): δ 1.45 (3H, s), 1.68 (3H, m), 3.42 (2H, d, J∼7.9 Hz), 5.10 (1H, broad s), 5.26 (1H, t, J∼7.9 Hz), 6.76 (2H, d, J∼8.9 Hz), 7.29 (2H, d, J∼8.9 Hz). Example 8 4-Acetoxyphenyl-3-methylbut-2-enylsulfide A mixture of 6.87 g (35.4 mmol) of 4-hydroxyphenyl-3-methylbut-2-enylsulfide, 12.96 g (126 mmol) of acetic anhydride and 10 ml of pyridine was heated at reflux for 1.5 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, poured into water and extracted with 2 x 50 ml ether. The ether extracts were combined and washed successively with water and saturated NaCl solution and then dried (MgSO₄). The solution was filtered and the solvent removed in-vacuo to give the title compound as a pale yellow oil. PMR (CDCl₃): δ 1.55 (3H, s), 1.71 (3H, s), 2.29 (3H, s), 3.51 (2H, d, J∼7.6 Hz), 5.28 (1H, m), 7.00 (2H, d, J∼8.8 Hz), 7.35 (2H, d, J∼8.8 Hz). Example 9 4,4-dimethyl-6-hydroxythiochroman A mixture of 6.8 g (0.029 mmol) of 4-acetoxyphenyl-3-methylbut-2-enylsulfide and 17 g of 1:10 (w/w) phosphorus pentoxide in phosphoric acid was stirred at room temperature under nitrogen for 15hours. The reaction mixture was then treated with water and stirred for 40 min. The mixture was then extracted with 2 x 50 ml ether. The ether extracts were combined and the solvent removed in-vacuo . The residue was then stirred under nitrogen with a solution of 1.93 g (0.034 mmol) of potassium hydroxide in 6 ml of water and 12 ml of ethanol for 1 hour. The ethanol was then removed from the mixture on the rotary evaporator and the aqueous solution then acidified to pH∼2 with sulfuric acid. The acidified solution was extracted with 2 x 50 ml ether. The ether extracts were combined and washed successively with water and saturated NaCl solution and then dried (MgSO₄). The ether solution was then filtered and the solvent removed in-vacuo . The resultant crude product was purified by flash chromatography (silica; 20% ethyl acetate in hexanes) to give the title compound as a colorless, low-melting solid. PMR (CDCl₃): δ 1.25 (6H, s), 1.90 (2H, m), 2.97 (2H, m), 6.57 (1H, dd, J∼8.6, 2.7 Hz), 6.88 (1H, d, J∼2.7 Hz), 6.90 (1H, d, J∼8.6 Hz). Example 10 Diethyl terephthalate Hydrochloric acid gas was bubbled through 100 ml of absolute ethanol until the increase in weight of the ethanol was approximately 5 g. Then 16.6 g (0.1 mmol) of terephthalic acid was then added to the acidified ethanol and the mixture heated at reflux for 31 hours. The reaction mixture was cooled, then filtered and the residue washed with ethanol. The filtrate was concentrated in-vacuo and then poured into a mixture of water and 100 ml ether. After extraction, the ether layer was separated and washed successively with water and saturated sodium bicarbonate solution and then dried (MgSO₄). The ether solution was filtered and the solvent removed in-vacuo to give the title compound as a white solid. PMR (CDCl₃): δ 1.42 (6H, t, J∼7.0 Hz), 4.40 (4H, q, J∼7.0 Hz), 8.10 (4H, s). Example 11 Ethyl hydrogenterephthalate A Soxhlet extractor was charged with 3.83g (0.022 mol) of anhydrous barium hydroxide and continuously extracted for 10 hours with hot ethanol into a refluxing mixture of 10g (0.045 mmol) of diethyl terephthalate in 100 ml of absolute ethanol. The resultant white precipitate was filtered and then washed with ethanol. The precipitate was suspended in 100 ml ether and treated with excess dilute HCl. After extraction, the ether layer was separated and washed successively with water and saturated NaCl solution and then dried (MgSO₄). The ether solution was filtered and the solvent removed in-vacuo . The resultant residue was recrystallized from acetonitrile to give the title compound as a white solid. PMR (CDCl₃): δ 1.40 (3H, t, J∼7.0 Hz), 4.40 (2H, q, J∼7.0 Hz), 8.10 (4H, s), 9.1 (1H, broad s). Example 12 Dibenzyl terephthalate An amount equal to 48.5 g (0.25 mmol) of dimethyl terephthalate, 108 g (1.0 mmol) of benzyl alcohol and 0.5 g of potassium tert-butoxide were placed in a 500 ml, 3-necked round bottom flask fitted with a magnetic stir bar, a thermometer, a nitrogen inlet and an air condenser. The stirred mixture was heated at 140°C for 15 hours while a rapid stream of nitrogen was passed over the surface of the mixture. Most of the excess benzyl alcohol was removed from the mixture by fractional distillation. The residue was dissolved in a mixture of ether and methylene chloride and silica was then added to the solution. The solution was then filtered and the solvent removed in-vacuo . The residual crude product was recrystallized from a mixture of hexanes and tert-butyl methyl ether to give the title compound as colorless crystals. PMR (CDCl₃): δ 5.38 (4H, s), 7.35-7.50 (10H, m), 8.13 (4H, s). Example 13 Benzyl hydrogenterephthalate To a heated mixture of 9.1 g (26 mmol) of dibenzyl terephthalate in 90 ml acetone and 30 ml water was added dropwise a solution of 1.05 g (25 mmol) of lithium hydroxide monohydrate in 10 ml of water and 10 ml of acetone. The reaction mixture was heated at reflux for a further 0.5 hours with vigorous stirring. The reaction mixture was allowed to cool and the aqueous solution was washed with 2 x 10 ml of ether. The aqueous layer was then acidified with glacial acetic acid and the resultant white precipitate extracted with 3 x 25 ml of ether. The ether extracts were combined and washed successively with water and saturated NaCl solution and then dried (MgSO₄). The ether solution was then filtered and the solvent removed in-vacuo . The resultant residue was recrystallized from a mixture of acetone and water to give the title compound as colorless crystals. PMR (CDCl₃): δ 5.40 (2H, s), 7.36-7.49 (5H, m), 8.18 (4H, s). Example 14 Ethyl-4-(4,4-dimethyl-6-thiochromanoxyoyl)benzoate A solution of 550 mg (2.8308 mmol of 4,4-dimethyl-6-hydroxythiochroman, 556.1 mg (2.8637 mmol) of ethyl hydrogenterephthalate, 588.8 mg (2.8583 mmol) of 1,3-dicyclohexylcarbodiimide and 97.2 mg (0.7956 mmol) of 4-dimethylaminopyridine in 40 ml of methylene chloride was stirred at room temperature for 50 hours. The reaction mixture was then filtered and residue washed with 20 ml of methylene chloride. The filtrate was concentrated in-vacuo and the resultant crude product was purified by flash chromatography (silica 5% ethyl acetate in hexanes) to give the title compound as a white solid. PMR (CDCl₃): δ 1.36 (6H, s) 1.45 (3H, t, J∼7.0Hz), 1.99 (2H, m), 3.06 (2H, m) 4.45 (2H, q, J∼7.0 Hz), 6.95 (1H, dd, J∼8.7, 2.4 Hz) 7.14 (1H, d, J∼8.7 Hz), 7.22 (1H, d, J∼2.4 Hz), 8.16 (2H, d, J∼8.1 Hz), 8.26 (2H, d, J∼8.1 Hz). Example 15 Benzyl 4,4-dimethyl-6-thiochromanyl terephthalate A solution of 760 mg (3.9117 mmol) of 4,4-dimethyl-6-hydroxythiochroman, 1.0095 g (3.9394 mmol) of benzyl hydrogenterephthalate, 809.6 mg (3.9301 mmol) of 1,3-dicyclohexylcarbodiimide and 133.8 g (1.0952 mmol) of 4-dimethylaminopyridine in 40 ml of methylene chloride was stirred at room temperature for 70 hours. The reaction mixture was then filtered and residue washed with 20 ml of methylene chloride. The filtrate was concentrated in-vacuo and the resultant crude product was purified by flash chromatography (silica, 6% ethyl acetate in hexanes) to give the title compound as a pale yellow oil. PMR (CDCl₃): δ 1.33 (6H, s), 1.96 (2H, m), 3.03 (2H, m), 5.40 (2H, s), 6.92 (1H, dd, J∼9.0, 2.4 Hz), 7.13 (1H, d, J∼9.0 Hz), 7.20 (1H, d, J∼2.4 Hz) 7.35-7.50 (5H, m), 8.19 (2H, d, J∼8.1 Hz), 8.25 (2H, d, J∼8.1 Hz). Using the same or similar reagents and conditions, but substituting the appropriate starting materials, the following representative compounds can be made: butyl 4,4-dimethyl-6-thiochromanyl -terephthalate; cyclohexyl 4,4-dimethyl-6-thiochromanyl-terephthalate; ethyl 4,4-dimethyl-6-thiochromanyl-isophthalate; ethyl 4,4-dimethyl-6-thiochromanyl-phthalate; ethyl 2,2,4,4-tetramethyl-6-thiochromanyl-terephthalate; ethyl 2,2,4,4-tetramethyl-6-thiochromanyl-isophthalate; and ethyl 2,2,4,4-tetramethyl-6-thiochromanyl-phthalate. Example 16 4,4-dimethyl-6-thiochromanyl hydrogen terephthalate To a stirred solution of 480 mg (1.11 mmol) of benzyl (4,4-dimethyl-6-thiochromanyl)terephthalate in 8 ml of anhydrous methylene chloride at -78°C was added under nitrogen 4.5 ml of 1M (4.5 mmol) boron tribromide in methylene chloride over 15 min. This reaction mixture was stirred at -78°C for 1 hour and then poured into aqueous potassium acetate. The reaction mixture was acidified (pH∼3) with dilute HCl and extracted with 3 x 10 of methylene chloride. The organic extracts were combined, washed with water and saturated NaCl and then dried (MgSO₄). The solution was filtered and the solvent removed in-vacuo . The residue was recrystallized from a mixture of acetone and hexanes to give the title compound as white crystals. PMR (CDCl₃): δ1.34 (6H, s), 1.97 (2H, m), 3.05 (2H, m), 6.94 (1H, dd, J∼8.1 Hz, 2.5 Hz), 7.14 (1H, d, J∼8.1Hz), 7.25 (1H, d, J∼2.5 Hz), 8.25 (2H, A of AB, J∼8.1 Hz), 8.31 (2H, B of AB, J∼8.1 Hz). This method, with appropriate substitution of starting materials, can be used to prepare the acids of this particular isomeric form, as illustrated by the following compounds: 4,4-dimethyl-6-thiochromanyl hydrogen isophthalate; 4,4-dimethyl-6-thiochromanyl hydrogen phthalate; 2,2,4,4-tetramethyl-6-thiochromanyl-hydrogenterephthalate; 2,2,4,4-tetramethyl-6-thiochromanyl-hydrogenisophthalate; and 2,2,4,4-tetramethyl-6-thiochromanyl-hydrogenphthalate. Example 17 3-bromophenyl-3-methylbut-2-enylsulfide A mixture of 12.6 g (67 mmol) of 3-bromothiophenol and 4.1 g (102.5 mmol) of powdered NaOH in 50 ml of acetone was heated at reflux for 10 min. To the refluxing mixture was then added dropwise a solution of 10.9 g (73.2 mmol) of 1-bromo-3-methyl-2-butene in 20 ml of acetone. The reaction mixture was heated at reflux for 1 hour, cooled and the solvent removed in-vacuo . The residue was purified by flash chromatography (silica; 5% ethyl acetate in hexane) to give the captioned compound as a clear, yellow oil. PMR (CDCl₃): δ 1.62 (3H, s), 1.73 (3H, s), 3.54 (2H, d, J∼8.1 Hz), 5.28 (1H, t, J∼8.1 Hz), 7.12 (1H, t, J∼7.8 Hz), 7.23 (1H, d, J∼7.8 Hz), 7.29 (1H, d, J∼7.8 Hz), 7.45 (1H, s). Example 18 4,4-Dimethyl-7-bromothiochroman and 4,4-dimethyl-5-bromothiochroman To 45 ml of a 1:10 (w/w) mixture of phosphorus pentoxide and methanesulfonic acid was added slowly with stirring 7.0 g (27.24 mmol) of 3-bromophenyl-3-methylbut-2- enylsulfide. The mixture was stirred at room temperature for 15 minutes and then poured onto ice. The mixture was extracted with 2 x 30 ml ether. The ether extracts were combined and washed with water and saturated NaCl solution and then dried (MgSO₄). The solution was filtered and the solvent removed in-vacuo to give an approximately 85:15 mixture of the title isomers 4,4-dimethyl-7-bromothiochroman and 4,4-dimethyl-5-bromothiochroman as a pale yellow oil. The mixture of isomers was used without further purification in the next step. Example 19 4,4-Dimethyl-7-carboxythiochroman To a stirred solution of 1.0 g (3.9 mmol) of the 4,4-dimethyl-7-bromothiochroman and 4,4-dimethyl-5-bromothiochroman mixture in 12 ml of anhydrous ether at -78°C was added, dropwise under nitrogen, 6.0 ml of 1.7 M (10.2 mmol) tert-butyllithium in pentane. The reaction mixture was stirred at -78°C for 1 hour and then a rapid stream of dry carbon dioxide gas was passed through it with vigorous stirring. The reaction mixture was warmed to -20°C and then quenched with water. The mixture was warmed to room temperature and is pH adjusted to 10 with ammonium hydroxide. The basic solution was washed with 2 x 10 ml ether and then acidified with dilute HCl. The mixture was extracted with 3 x 20 ml of ether. The ether extracts were combined and washed with water and saturated NaCl solution and then dried (MgSO₄). The ether solution was filtered and the solvent removed in-vacuo . The residue was recrystallized from a mixture of ethyl acetate and hexane to give the captioned compound as a white solid. PMR (CDCl₃): δ 1.33 (6H, s), 1.96 (2H, s), 3.04 (2H, m), 7.42 (1H, d, J∼8.1 Hz), 7.66 (1H, dd, J∼8.1 Hz, 1.8 Hz), 7.77 (1H, d, J∼1.8 Hz). Example 20 Ethyl 4-(4,4-dimethyl-7-thiochromanoyloxy)benzoate A solution of 103.5 mg (0.466 mmol) of 4,4-dimethyl-7-carboxythiochroman and 77.8 mg (0.468 mmol) of ethyl 4-hydroxybenzoate in 10 ml of methylene chloride was treated sequentially with 14.2 mg (0.116 mmol) of 4-dimethylaminopyridine and 96.9 mg (0.47 mmol) of 1,3-dicyclohexylcarbodiimide. The reaction mixture was stirred at room temperature for 120 hours and then filtered and the residue washed with 10 ml of methylene chloride. The filtrate was concentrated in-vacuo and the residue purified by flash chromatography (silica; 5% ethyl acetate in hexanes) to give the title compound as a colorless oil. PMR (CDCl₃): δ 1.38 (6H, s), 1.42 (3H, t, J∼7.1 Hz), 2.02 (2H, m), 3.08 (2H, m), 4.41 (2H, q, J∼7.1 Hz), 7.29 (2H, d, J∼8.7 Hz), 7.51 (1H, d, J∼8.3 Hz), 7.81 (1H, dd, J∼8.3 Hz, 1.9 Hz), 7.95 (1H, d, J∼1.9 Hz), 8.14 (2H, d, J∼8.7 Hz). This same procedure can be used to make other compounds of this invention where A is C(O) and is at the 7-position on the thiochroman moiety. Example 21 S-(4-bromophenyl)-3,3-dimethylthioacrylate . To an ice-bath cooled solution of 1.92 g (80 mmol) of NaH (obtained from a 60% suspension in mineral oil by 3 x 15 ml hexane wash) in 30 ml of dry tetrahydrofuran (THF) was added slowly under argon a solution of 15.1 g (80 mmol) of 4-bromothiophenol in 60 ml of dry THF over 1h. The mixture was stirred at 0°C for a further 30 minutes and then treated with a solution of 10.1g (85 mmol) of dimethylacryloyl chloride in 30 ml of dry THF. The cooling bath was then removed and the mixture then stirred at room temperature for 40h. The reaction mixture was poured into 200ml of water containing 2ml of glacial acetic acid and the organic layer was separated. The organic layer was washed with 2 x 75 ml of water and then dried (MgSO₄). The solvent was removed in-vacuo to give the title compound as a yellow oil. PMR (CDCl₃):δ1.91 (3H, s), 2.14 (3H, s), 6.03-6.06 (1H, m), 7.28 (2H, d, J∼8.6H z ), 7.53(2H, d, J∼8.6Hz). Example 22 4,4-Dimethyl-6-bromo-2-oxothiochroman To a stirred, ice-cooled suspension of 15.9 g (119 mmol) of aluminum chloride in 140 ml of methylene chloride was added under nitrogen a solution of 21.64g (79.9 mmol) of S-(4-bromophenyl)-3,3-dimethylthioacrylate in 100 ml of methylene chloride. The mixture was then stirred at room temperature for 2h and then poured into 250 g of an ice and brine mixture. The mixture was extracted with methylene chloride and the combined organic extracts were washed with saturated NaCl solution and then dried (MgSO₄). The solvent was removed in-vacuo and the residue recrystallized from hexanes to give the title compound as white crystals. PMR (CDCl₃): δ 1.40 (6H, s), 2.67 (2H, s), 7.31-7.40(3H, m). Example 23 +-Bromo-2-(1,1,3-trimethyl-3-hydroxybutyl)thiophenol To a solution of 3.0g (11 mmol) of 4,4-dimethyl-6-bromo-2-oxothiochroman in 30 ml of dry ether was added under nitrogen 37 ml of 3.0M (111 mmol) methyl magnesium chloride in THF. The reaction mixture was stirred at reflux temperature for 40h and then at room temperature for 24h. The reaction mixture was then poured onto a mixture of 100 g of ice and 8ml of concentrated H₂SO₄. The mixture was extracted with ether, the ether extracts were combined and washed successively with saturated NaHCO₃; water and saturated NaCl and then dried (MgSO₄). The solvent was removed in-vacuo and the residue purified by flash chromatography (silica; 15% ethyl acetate in hexanes) to give the title compound as a pale yellow oil. PMR (CDCl₃): δ1.05(6H, s), 1.52(6H, s), 2.30(2H, s), 3.71(1H, s), 7.22(1H, dd,J∼8.5Hz, 2.1Hz), 7.28(1H, d, J∼8.5Hz), 7.35 (1H, d, J∼2.1Hz). Example 24 2,2,4,4-Tetramethyl-6-bromothiochroman. A mixture of 500mg (1.49 mmol) of 4-bromo-2-(1,1,3-trimethyl-3-hydroxybutyl thiophenol and 8ml of 20% aqueous H₂SO₄ was heated at reflux for 24h. The mixture was extracted with hexanes, the organic extracts were combined and washed successively with water, saturated NaHCO₃, water again, saturated NaCl and then dried (MgSO₄). The solvent was removed in-vacuo and the residue purified by flash chromatography (silica; hexanes) to give the title compound as a colorless oil. PMR (CDCl₃): δ 1.35(6H, s), 1.40(6H, s), 1.93(2H, s), 7.17(1H, dd, J ∼ 8.4Hz, 2.1Hz) 7.23(1H, d, J∼8.4Hz), 7.26 (1H, d, J∼2.1Hz). Example 25 2,2,4,4-Tetramethyl-6-carboxythiochroman To a stirred solution of 240mg (0.84 mmol) of 2,2,4,4-tetramethyl-6-bromothiochroman in 1ml of dry ether at -78°C was added, dropwise under nitrogen, 1ml of 1.7M (1.7 mmol) tert-butyl lithium in pentane. The reaction mixture was stirred at -78°C for a further 2h and then treated quickly with an excess of dry ice. The reaction mixture was warmed to room temperature and treated with 1ml of water and 1ml of ether. The aqueous layer was separated and the organic layer was extracted with 4x5ml of water. The aqueous extracts were combined, acidified with HCl to a pH of 2 and then extracted with 2x15ml of ether. The ether extracts were combined, washed with water and saturated NaCl solution and then dried (MgSO₄). The ether solution was filtered and the solvent removed in-vacuo to give the title compound as a white solid. PMR (CDCl₃): δ 1.42(6H, s), 1.43(6H,s), 2.03(2H,s), 7.50(1H, d, J∼8.4Hz), 7.81 (1H, dd, J∼8.4Hz, 1.8Hz), 7.89(1H, d, J∼1.8Hz). Example 26 Ethyl 4-(2,2,4,4-tetramethyl-6-thiochromanoyloxy)benzoate A solution of 90mg (0.36 mmol) of 2,2,4,4-tetramethyl-6-carboxythiochroman and 60 mg (0.36 mmol) of ethyl 4-hydroxybenzoate in 2 ml of methylene chloride was treated with a solution of 1,3-dicyclohexylcarbodiimide 74.4mg (0.36 mmol) and 11 mg (0.09mmol) of 4-dimethylaminopyridine in 1ml of methylene chloride. The reaction mixture was stirred under nitrogen for 22h and then filtered. The filtrate was concentrated in-vacuo and the residue purified by flash chromatography (silica, 10% ethyl acetate in hexane) to give the title compound as a colorless oil. PMR (CDCl₃): δ 1,43 (3H, t, J∼7.2Hz), 1,46 (6H, s), 1,47 (6H, s), 2.03 (2H, s), 4.42 (2H, q, J∼7.2 Hz), 7.29 (2H, d, J∼8.8Hz), 7.54 (2H, d, J∼8.3Hz), 7.89 (1H, dd, J∼8.3Hz, 1,8hZ), 7.99 (1H, d, J∼1.8 Hz), 8.15 (2H, d, J∼8.8Hz) Example 27 2-Hydroxy-2,4,4-trimethyl-6-bromothiochroman To 30 ml of 3.0M (90 mmol) of methyl magnesium chloride, cooled in an ice bath, was added under nitrogen a solution of 8g(29.63 mmol) of 4,4-dimethyl-6-bromo-2-oxothiochroman in 60 ml of dry ether over a period of 30 min. The cooling bath was then removed and the mixture stirred for 13h. The reaction mixture was then poured onto a mixture of 200g of ice and 6 ml of concentrated H₂SO₄. The organic layer was separated and the aqueous layer extracted with ether. The organic layers were combined and washed successively with water, saturated NaHCO₃ and saturated NaCl solutions and then dried (MgSO₄). The solvent was removed in vacuo and the residue purified by flash chromatography (silica; 9% ethyl acetate in hexane ) to give the title compound as a white solid. PMR (CDCl₃): δ 1.35 (3H, s), 1.47 (3H, s), 1.71 (3H, s), 2.02-2.17 (2H, m), 2.42 (1H, s), 7.17-7.28 (3H, m). Example 28 2,4,4-Trimethyl-6-bromo-2,3-dehydrothiochroman. A mixture of 300mg (0.99 mmol) of 2-hydroxy-2,4,4-trimethyl-6-bromothiochroman and 4ml of 20% aqueous H₂SO₄ was heated at reflux for 15h. The mixture was then cooled, diluted with water and extracted with hexane. The organic extract was washed with water and saturated NaCl solution and then dried (MgSO₄). The ether solution was filtered and concentrated in vacuo to give the title compound as a pale yellow oil. PMR (CDCl₃): δ1.33 (6H, s), 1:99 (3H, d, J∼1.4 Hz), 5.45 (1H, broad, s), 7.19 (1H ,d, J∼8.4 H z ), 7.27(1H, dd, J ∼ 8.4Hz, 2.0 Hz), 7.30(1H,d,J ∼ 2.0Hz). Example 29 2,4,4-Trimethyl-6-bromothiochroman. A solution of 2.69g (10 mmol) of 2,4,4-trimethyl-6-bromo-2,3-dehydrothiochroman in 100ml of 1:1 ethanol/benzene was degassed under argon and then treated with 280mg (0.3 mmol) of tris(triphenylphosphine) rhodium (I) chloride. The mixture was shaken in a Parr Hydrogenation apparatus under 50 psi hydrogen pressure for 18h. The solvent was removed in-vacuo and the residue was purified by flash chromatography (silica; hexane) to give the title compound. Example 30 (3-Methyl-4-bromo-phenyl)-3-methylbut-2-enyl sulfide To a stirred solution of 9.52g (68 mmol) of 3-methyl-4-bromothiophenol in 80ml of acetone was added 2.86g (68 mmol) of powdered sodium hydroxide and mixture stirred until dissolution was complete. The reaction mixture was then heated to reflux and then treated with a solution of 11.26g (68 m mol) of 4-bromo-2-methyl-2-butene in 20ml of acetone. The mixture was heated at reflux for a further 0.5h, cooled to room temperature and the solvent removed in-vacuo . The residue was taken up in 35ml of water and extracted with ether. The ether extracts were combined and washed successively with water and saturated NaCl solution and then dried (MgSO₄). The solvent was removed in-vacuo and the residue kugelrohr distilled (140-145°C,0.2mm) (mm Hg) to give the title compound as a colorless oil. PMR (CDCl₃) : δ 1.58 (3H, s), 1.70 (3H, s), 2.33(3H, s), 3.49(2H,d,J∼7.8Hz), 5.26(1H,t,J∼7.8Hz), 6.98(1H,dd,J∼8.3Hz, 2.3Hz), 7.17(1H,d,J∼2.3Hz), 7.38(1H,d,J∼8.3Hz) Example 31 4,4,7-Trimethyl-6-bromothiochroman To 40g of a vigorously stirred mixture of 10% phosphorus pentoxide in methanesulfonic acid was added slowly 6.0 g (28.8 mmol) of (3-methyl-4-bromophenyl)-3-methylbut-2-enyl-sulfide. The mixture was stirred at room temperature for a further 2h and was then poured onto ice. The mixture was extracted with 2x40ml of ether and the combined ether extracts were washed successively with water and saturated NaCl solution and then dried. The solvent was removed in-vacuo and the residue kugelrohr distilled (130°C; 0.07mm (mm Hg)) to give the title compound as a viscous oil. PMR(CDCl₃): δ 1.28(6H,s) 1.84 - 1.93(2H,m), 2.26(3H,s), 2.95-3.03(2H,m) 6.94(1H,s), 7.46(1H,s). Example 32 4,4,7-Trimethyl-6-Carboxythiochroman A solution of 500mg (1.85 mmol) of 4,4,7-trimethyl-6-bromothiochroman in 2.3ml of dry ether was cooled to -78°C under nitrogen and then treated dropwise with 2.2ml of 1.7M (3.74 mmol) tert-butyllithium in pentane. The reaction mixture was stirred at 78°C for a further 3h and then a stream of dry carbon dioxide gas was bubbled through the mixture for 10 min. The mixture was allowed to warm to room temperature and then treated with 1ml of ether and 5ml of water. The aqueous layer was separated, acidified with dilute HCl and then extracted with 3x20ml of ether. The ether extractions were combined and dried (MgSO₄). The ether solution was filtered and the solvant removed in-vacuo to give the title compound as a white solid. PMR(CDCl₃): δ 1.35(6H,s), 1.91-2.00(2H,m), 2.55(3H,s), 3.00-3.09(2H,m), 6.99(1H,s), 8.11(1H,s). Example 33 Ethyl 4-(4,4,7-trimethyl-6-thiochromanoyloxy)benzoate A solution of 83.7mg (0.35 mmol) of 4,4,7-trimethyl-6-carboxythiochroman and 59.1mg (0.35 mmol) of ethyl-4-hydroxybenzoate in 2ml of methylene chloride was treated sequentially with 74.5mg (0.36 mmol) of 1,3-dicyclohexylcarbodiimide and 11.1mg (0.09 mmol) of 4-dimethylaminopyridine.. The mixture was stirred under nitrogen for 24h and then filtered. The filtrate was concentrated in-vacuo and the residue purified by flash chromatography (silica; 15% ethyl acetate in hexane) to give the title compound as a pale yellow oil. PMR(CDCl₃) : δ 1.37(6H, s), 1.41(3H,t,J∼7.1Hz), 1.92-2.00(2H,m), 2.56(3H,s), 3.02-3.10(2H,m), 4.40(2H,q,J∼7.1Hz), 7.03(1H,s), 7.29(2H,d,J∼8.7Hz), 8.13(2H,d,J∼8.7Hz), 8.18(1H,s). Example 34 Preferably, these compounds may be administered topically using various formulations. Such formulation may be as follows. Ingredient Weight/Percent Solution Compound 0.1 BHT 0.1 Alcohol USP 58.0 Polyethylene Glycol 400 41.8 Gel Compound 0.1 BHT* 0.1 Alcohol USP 97.8 Hydroxypropyl Cellulose 2.0

Claims: Claims for the following Contracting States : AT, BE, CH, DE, FR, GB, IT, LI, LU, NL, SE A compound of the formula: in which: the R groups are independently hydrogen or C₁₋₆ alkyl; one of A and B is O or S and the other is -C(0)-, A being attached to the thiochroman ring at the 6 or 7 position; n is 0-5; and Z is H, or Z is -COD where D is -OH or -OM where M is a pharmaceutically acceptable cation, or D is OR₁ where R¹ is an ester-forming group, or D is -N(R₄)₂ where R₄ is hydrogen or an aliphatic or substituted aliphatic group, or Z is -OE where E is hydrogen or an ether-forming group or an acyl ester-forming group, or Z is -CHO or an acetal derivative thereof, or Z is -COR₃ where R₃ is -(CH₂) m CH₃ where m is 0-4 and the sum of n and m does not exceed 4 or a ketal derivative thereof. The compound of claim 1 where n is 0 or 1 or 2. A compound according to either of claims 1 or 2, wherein A is 0 and is attached to the thiochroman ring at the 6 position and Z is -COOH or an ester or amide thereof; or a pharmaceutically acceptable salt thereof. A compound of claim 3 which is ethyl 4,4-dimethyl-6-thiochromanyl terephthalate or 4,4-dimethyl-6-thiochromanyl hydrogen-terephthalate or a pharmaceutically acceptable salt thereof. A compound of either of claims 1 or 2, where A is 0 and is attached to the thiochroman ring at the 7 position and Z is -COOH or pharmaceutically acceptable salt thereof or an ester or amide thereof. A compound of either of claims 1 or 2, where A is -C(0)- and is attached to the thiochroman ring at the 6 position and Z is -COOH or a pharmaceutically acceptable salt thereof or an ester or amide thereof. A compound of claim 6 which is ethyl 4-(4,4-dimethyl-6-thiochromanoyloxy)benzoate, ethyl 4-(4,4,7-trimethyl-6-thiochromanoyloxy)benzoate, 4-(4,4-dimethyl-6-thiochromanoyloxy)benzoic acid, 4-(4,4,7-trimethyl-6-thiochromanoyloxy)benzoic acid, ethyl 4-(2,2,4,4-tetramethyl-6-thiochromanoyloxy)benzoate, ethyl 4-(2,2,4,4,7-pentamethyl-6-thiochromanoyloxy)benzoate, 4-(2,2,4,4-tetramethyl-6-thiochromanoyloxy)benzoic acid, 4-(2,2,4,4,7-pentamethyl-6-thiochromanoyloxy)benzoic acid or a pharmaceutically acceptable salt thereof. A compound of either of claims 1 or 2, where A is -C(0)- and is attached to the thiochroman ring at the 7 position and Z is -COOH or an ester or amide; or a pharmaceutically acceptable salt thereof. A compound of claim 8, which is ethyl 4-(4,4-dimethyl-7-thiochromanoyloxy)benzoate or 4-(4,4-dimethyl-7-thiochromanoyloxy)benzoic acid or a pharmaceutically acceptable salt thereof. A compound of any one of claims 1-9 for use in medicine. A compound of claim 10 for use in treating dermatoses A pharmaceutical composition comprising a compound as defined in any one of claims 1-9 and a pharmaceutically acceptable carrier. A compound according to claim 11 for use in treating psoriasis. The use of a compound of any one of claims 1 to 9 for the manufacture of a medicament for treating dermatoses. Claims for the following Contracting States : ES, GR A process for making a compound for the formula I: where: the R groups are independently hydrogen or C₁₋₆ alkyl; one of A and B is O or S and the other is -C(O)-, A being attached to the thiochroman ring at the 6 or 7 position; n is 0-5; and Z is H, or Z is -COD where D -OH or D is OR₁ where R₁ is an ester forming group, or D is -N(R₄)₂ where R₄ is hydrogen or an aliphatic or substituted aliphatic group, or Z is -OE where E is hydrogen or an ether-forming group or an acyl ester-forming group, or Z is -CHO or an acetal derivative thereof, or Z is -COR₃ where R₃ is -(CH₂) m CH₃ where m is 0-4 and the sum of n and m does not exceed 4 or a ketal derivative thereof, which process comprises reacting a compound of formula II with a compound of formula III wherein formula II and III are where one of A' and B' is -OH or -SH when the other is - COL, where L is -OH, Cl or another leaving group and R, n and Z are as defined above, in such a manner as to form an ester, for example by employing an ester-forming catalyst. The process of claim 1, wherein n is 0, 1, or 2, A' is -OH which is attached to the thiochroman ring at the 6 position and Z is -COOR₁ where R₁ is C₁₋₆ alkyl or C₁₋₆ alkylphenyl. The process of claim 2, where the resulting compound is ethyl 4,4-dimethyl-6-thiochromanyl terephthalate or benzyl 4,4-dimethyl-6-thiochromanyl terephthalate. The process of claim 1, where n is 0, 1, or 2 and A' is -OH and is attached to the thiochroman ring at the 7 position and Z is COOR₁ where R₁ is C₁₋₆ alkyl or C₁₋₆ alkylphenyl. The process of claim 1, where n is 0, 1, or 2, A' is -COOH and is attached to the thiochroman ring at the 6 position and Z is COOR₁ where R₁ is C₁₋₆ alkyl or C₁₋₆ alkylphenyl. The process of claim 5, where the resulting compound is ethyl 4-(4,4-dimethyl-6-thiochromanoyloxy)benzoate, ethyl 4-(4,4,7-trimethyl-6-thiochromanoyloxy)benzoate, ethyl 4-(2,2,4,4-tetramethyl-6-thiochromanoyloxy)benzoate, ethyl 4-(2,2,4,4,7-pentamethyl-6-thiochromanoyloxy)benzoate, benzyl 4-(4,4-dimethyl-6-thiochromanoyloxy)benzoate or benzyl 4-(2,2,4,4-tetramethyl-6-thiochromanoyloxy)benzoate. The process of claim 1, where n is 0, 1, or 2, A' is -COOH and is attached to the thiochroman ring at the 7 position and Z is COOR₁ where R₁ is C₁₋₆ alkyl or C₁₋₆ alkylphenyl. The process of claim 7, where the resulting compound is ethyl 4-(4,4-dimethyl-7-thiochromanoyloxy) benzoate or ethyl 4-(2,2,4,4-tetramethyl-7-thiochromanoyloxy)benzoate. A process for making a compound of the formula where the R groups are independently hydrogen or C₁₋₆ alkyl; one of A and B is O or S and the other is -C(O)-, A being attached to the thiochroman ring at the 6 or 7 position; n is 0-5; and Z is H or Z is -COD where D is - OH, or Z is -OE where E is hydrogen, or Z is -CHO, or Z is -COR₃ where R₃ is -(CH₂) m CH₃ where m is 0-4 and the sum of n and m does not exceed 4, which process comprises deprotecting a compound of the formula where R, A, B and n are defined above and Z is -COD where D is -OR₁ where R₁ is an ester-forming group, or Z is -OE where E is an ether-forming group or an acyl ester-forming group, or Z is an acetal derivative of CHO, or Z is a ketal derivative of -COR₃ where R₃ is as hereinbefore defined. The process of claim 9, which gives 4,4-dimethyl-6-thiochromanyl hydrogenterephthalate, 4-(4,4-dimethyl-6-thiochromanoyloxy)benzoic acid, 4-(2,2,4,4-tetramethyl-7-thiochromanoyloxy)benzoic acid, or 4-(4,4-dimethyl-7-thiochromanoyloxy)benzoic acid. A process for making a pharmaceutically acceptable salt of a compound of the formula where R, A, B and n are defined above and Z is -COOH or -COD where D is -OR₁ where -OR₁ is an ester-forming group, which process comprises treating said compound with a base under mild conditions. A process for the preparation of a pharmaceutical composition containing a compound of the formula I as defined in any of the preceding claims, which process comprises bringing the compound into association with a pharmaceutically acceptable carrier. The use of a compound of the formula I, as defined in any one of claims 1 to 11, for the manufacture of medicament for the treatment of dermatoses.

Inventors: CHANDRARATNA ROSHANTHA A S, CHANDRARATNA, ROSHANTHA A.S.
Applicants: ALLERGAN INC, ALLERGAN, INC
Application year: 1989
Main classification: C07D335
IPC codes: A61K31, C07D335, A61P31, A61P17, A61P35