DISUBSTITUTED ACETYLENES BEARING HETEROAROMATIC AND HETEROBICYCLIC GROUPS HAVING RETINOID-LIKE ACTIVITY

Abstract: Retinoid-like activity is exhibited by compounds of formula (I) where X is S, O, or NR' where R' is hydrogen or lower alkyl; R is hydrogen or lower alkyl; A is pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl or pyrazinyl; n is 0-4; and B is H, -COOH or a pharmaceutically acceptable salt, ester or amide thereof, -CH2OH or an ether or ester derivative, or -CHO or an acetal derivative, or -COR1 or a ketal derivative where R1 is -(CH2)mCH3 where m is 0-4, or a pharmaceutically acceptable salt thereof.

Description: DISUBSTITUTED ACETYLENES BEARING HETEROAROMATIC AND HETEROBICYCLIC GROUPS HAVING RETINOID-LIKE ACTIVITY 1. Cross-reference to Related Application. The present application is a continuation-in-part of application serial number 08/027,627, filed on March 8, 1993, which is a divisional of application serial number 07/792,832 filed on November 15, 1991, now U.S. Patent No. 5,234,926, which is a divisional of application serial number 07/326,191, filed on March 20, 1989 now U.S. Patent No. 5,089,509, which is a continuation-in-part of application serial number 07/246,037 filed on September 15, 1988, now abandoned, which is a continuation of application serial number 07/028,279 filed on March 20, 1987, now abandoned. 2. Background This invention relates to novel compounds having retinoid-like activity. More specifically, the invention relates to compounds having an ethynylheteroaromatic acid portion and a second portion which is a tetrahydroquinolinyl, thiocromanyl, or chromanyl group. The acid function may also be converted to an alcohol, aldehyde or ketone or derivatives thereof, or may be reduced to -CH 3 . The invention also relates to using the compounds as therapeutic agents. 3. Related Art Carboxylic acid derivatives useful for inhibiting the degeneration of cartilage of the general formula 4- (2-(4,4-dimethyl-6-X)-2-methylvinyl)benzoic acid where X is tetrahydroquinolinyl, chromanyl or thiochromanyl are disclosed in European Patent Application 0133795 published January 9, 1985. See also European Patent Application 176034A published April 2, 1986 where tetrahydronaphthalene compounds having an ethynylbenzoic acid group are disclosed. Several issued patents, and pending patent applications assigned to the same assignee as the present application, and other U.S. and foreign patents and publications disclose compounds having retinoid-like biological activity and therapeutic utility. Summary of the Invention This invention covers compounds of formula I wherein X is S, 0, or NR 1 where R 1 is hydrogen or lower alkyl; R is hydrogen or lower alkyl A is pyridinyl, thienyl, furyl, pyridazinyl, pyrimidinyl or pyrazinyl; n is 0-4; and B is H, -C00H or a pharmaceutically acceptable salt, ester or amide thereof, -CH 2 OH or an ether or ester derivative, or -CHO or an acetal derivative, or -CORη ^ or a ketal derivative where R- j^ is -(CH2) m CH 3 where m is 0-4. In a second aspect, this invention relates to the use of the compounds of formula I as therapeutic agents in treatment of numerous diseases and conditions which are described below in detail, and which are, generally speaking capable of being treated with retinoid-like compounds. This invention also relates to a pharmaceutical formulation comprising a compound of formula I in admixture with a pharmaceutically acceptable excipient. In another aspect, this invention relates to the process for making a compound of formula I which process comprises reacting a compound of formula II with a compound of formula III in the presence of cuprous iodide and Pd(PQ 3 ) 2 Cl 2 or a similar complex where the two formulas are represented by graphics II and III $ αr r-A-ζCHj B m where X 1 is a halogen, preferably I; n and A are the same as defined above; and B is H, or a protected acid, alcohol, aldehyde or ketone, giving the corresponding compound of formula I; or to the process of making a compound of formula I which consists of reacting a zinc salt of formula IV with a compound of formula III in the presence of Pd(PQ 3 ) 4 (Q is phenyl) or a similar complex. IV giving the corresponding compound of formula I; or homologating a compound of the formula . A -(CH 2 VB where n is 0-1 to give an acid of formula I; or converging an acid of formula I to a salt; or forming an acid addition salt; converting an acid of formula I to an ester; or converting an acid of formula I to an amide; or reducing an acid or formula I to an alcohol or aldehyde; or converting an alcohol of formula I to an ether or ester; or oxidizing an alcohol of formula I to an aldehyde; or converting an aldehyde of formula I to an acetal; or converting a ketone of formula I to a ketal. General Embodiments Definitions 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. Where A is -COOH, this term covers the products derived from treatment of this function with alcohols. Where the ester is derived from compounds where A is -CH 2 0H, this term covers compounds of the formula -CH 2 00CR where R is any substituted or unsubstituted aliphatic, aromatic or aliphatic-aromatic group. Preferred esters are derived form 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 lower alkyl acids and alcohols. Here, and where ever else used, lower alkyl means having 1-6 carbon atoms. Also preferred are the phenyl or lower alkylphenyl esters. Amide has the meaning classically accorded that term in organic chemistry. In this instance it 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 lower alkyl amines. Also preferred are mono-and di-substituted amides derived from the phenyl or lower alkylphenyl amines. Unsubstituted amides are also preferred. Acetals and ketals includes the radicals of the formula -CK where K is (-OR) 2 - Here, R is lower alkyl. Also, K may be -OR-^O- where R*- ^ is lower alkyl of 2-5 carbon atoms, straight chain or branched. A pharmaceutically acceptable salt may be prepared for any compound of this invention having a functionality capable of forming such salt, for examle an acid or an amine functionality. A pharmaceutically acceptable salt may be 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. Such a salt may be derived from any organic or inorganic acid or base. The salt may be a mono or polyvalent ion. Of particular interest where the acid function is concerned are the inorganic ions, sodium, potassium, calcium, and magnesium. Organic amine salts may be made with amines, particularly ammonium slats such as mono-, di- and trialkyl amines or ethanol amines. Salts may also be formed with caffeine, tromethamine and similar molecules. Where there is a nitrogen sufficiently basic as to be capable of forming acid addition salts, such may be formed with any inorganic or organic acids or alkylating agent such as methyl iodide. Preferred salts are those formed with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid. Any of a number of simple organic acids such as mono-, di- or tir-acid may also be used. The preferred compounds of this invention are those where the ethynyl group and the B group are attached to the 2 and 5 positoins respectively of a pyridine ring (the 6 and 3 positions in the nicotinic acid nomenclature being equivalent to the 2/5 designation in the pyridine nomenclature) or the 5 and 2 positions respectively of a thiophene group respectively; n is 0; and B is -COOH, an alkali metal salt or organic amine salt, or a lower alkyl ester, or -CH 2 OH and the lower alkyl esters and ethers thereof, or -CHO and acetal derivatives thereof. The most preferred compounds are: ethyl 6-(2-(4,4-dimethylthiochroman-6- yl)ethynyl)nicotinate; 6-(2-(4,4-dimethylthiochroman-6- yl)ethynyl)nicotinic acid; 6-(2-(4,4-dimethylchroman-6-yl)ethynyl)nicotinic acid; ethyl 6-(2-(4,4-dimethylchroman-6- y1)ethynyl)nicotinate; ethyl 6-(2-(4,4,7-trimethylthiochroman-6-yl)- ethynyl)nicotinate; ethyl 6-(2-(4,4-dimethyl-l,2,3,4- tetrahydroquinolin-6-yl)-ethynyl)nicotinate; ethyl 5-(2-(4,4-dimethylthiochroman-6-yl)ethynyl)- thiophene-2-carboxylate. 6-(2-(4 ,4-dimethylthiochroman-6-yl)ethynyl)-3- pyridyl ethanol; and 2-(2-(4,4-dimethylthiochroman-6-yl)-ethynyl)-5- pyridinecarboxaldehyde. The compounds of the present invention have retinoid-like biological activity. The compounds of the present invention are particularly useful in the treatment of skin-related diseases, including, without limitation, actinic keratoses, arsenic keratoses, inflammatory and non-inflammatory acne, psoriasis, ichthyoses and other keratinization and hyperproliferative disorders of the skin, eczema, atopic dermatitis, Darriers disease, lichen planus, prevention and reversal of glucocorticoid damage (steroid atrophy), as a topical anti-microbial, as skin anti-pigmentation agents and to treat and reverse the effects of age and photo damage to the skin. The compounds are also useful for the prevention and treatment of cancerous and precancerous conditions, including, premalignant and malignant hyperproliferative diseases such as cancers of the breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood and lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias and papillomas of the mucous membranes and in the treatment of Kaposi's sarcoma. In addition, the present compounds can be used as agents to treat diseases of the eye, including, without limitation, proliferative vitreoretinopathy (PVR) , retinal detachment, dry eye and other corneopathies, as well as in the treatment and prevention of various cardiovascular diseases, including, without limitation, diseases associated with lipid metabolism such as dyslipidemias, prevention of post-angioplasty restenosis and as an agent to increase the level of circulating tissue plasminogen activator (TPA) . Other uses for the compounds of the present invention include the prevention and treatment of conditions and diseases associated with Human papilloma virus (HPV) , including warts and genital warts, various inflammatory diseases such as pulmonary fibrosis, ileitis, colitis and Krohn's disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and stroke, improper pituitary function, including insufficient production of growth hormone, modulation of apoptosis, including both the induction of apoptosis and inhibition of T-Cell activated apoptosis, restoration of hair growth, including combination therapies with the present compounds and other agents such as Minoxidil R , diseases associated with the immune system, including use of the present compounds as immunosuppressants and immunostimulants, modulation of organ transplant rejection and facilitation of wound healing, including modulation of chelosis. The compounds of the this invention may be administered > systemically or topically, depending on such considerations as the 2 condition to be treated, need for site-specific treatment, quantity of 1 drug to be administered, and similar considerations. In the treatment of dermatoses, it will generally be preferred to 5 administer the drug topically, though in certain cases such as • treatment of severe cystic acne, oral administration may also be used. 7 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 10 formulations as exemplified, for example, Remington 's Pharmaceutical 11 Science. Edition 17, Mack Publishing Company, Easton, Pennsylvania. u For topical application, these compounds could also be administered as u a powder or spray, particularly in aerosol form. 14 If the drug is to be administered systemically, it may be u confected as a powder, pill, tablet or the like, or as a syrup or elixir for •* oral administration. For intravenous or intraperitoneal administration, 17 the compound will be prepared as a solution or suspension capable of 11 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 intermuscular a injection. 22 Other medicaments can be added to such topical formulation for 25 such secondary purposes as treatin g skin dryness, providing protection 24 against light; other medications for treating dermatoses, preventing 23 infection, reducing irritation, inflammation and the like. * Treatment of dermatoses or any other indications known or 27 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 30 therapeutic concentration will be that concentration which effects " reduction of the particular condition, or retards its expansion. In 1 certain instances, the drug potentially could be used in a prophylactic 2 manner to prevent onset of a particular condition. A given therapeuti 1 concentration will vary from condition to condition and in certain 4 instances may vary with the severity of the condition being treated 5 and the patient's susceptibility to treatment. Accordingly, a given * therapeutic concentration will be best determined at the time and place through routine experimentation. However, it is anticipated that * in the treatment of, for example, acne, or other such dermatoses, that * formulation containing between 0.001 and 5 percent by weight, 10 preferably about 0.01 to 1 %, will usually constitute a therapeutically 11 effective concentration. If administered systemically, an amount 12 between 0.01 and 100 mg per kg body weight per day, but preferabl u about 0.1 to 10 mg/kg, will effect a therapeutic result in most 1 instances. u The retinoic acid like activity of these compounds was confirmed " through the classic measure of retinoic acid activity involving the 17 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. 20 37. 2196-2201. That reference discloses that ornithine decarboxylase 21 (ODC) activity increased precedent to polyamine biosynthesis. It has 22 been established elsewhere that increases in polyamine synthesis can s be correlated or associated with cellular proliferation. Thus, if ODC 24 activity could be inhibited, cell hyperproliferation could be modulated. 21 Although all causes for ODC activity increase are unknown, it is known » that 12-0-tetradecanoyl- 27 phorbol- 13-acetate (TPA) induces ODC activity. Retinoic acid inhibits ■ this induction of ODC activity by TPA. The compounds of this inventio * also inhibit TPA induction of ODC as demonstrated by an assay » essentially following the procedure set out in Cancer Res. : 1662- 1670, » 1975. 1 Specific Embodiments 2 The compounds of this invention can be made by a number of 4 different synthetic chemical pathways. To illustrate this invention, 1 there is here outlined a series of steps which have been proven to • provide the compounds of formula I when such synthesis is followed in 7 fact and in spirit. The synthetic chemist will readily appreciate that 1 the conditions set out here are specific embodiments which can be * generalized to any and all of the compounds represented by formula I. ιo Compounds of formula I where X is -S- are prepared as per •• Reaction Scheme I. u Homologues & Derivatives >« Here, R is hydrogen or a lower alkyl group, A is defined above, n is 0-2 1 and B is H, or a protected acid, alcohol, aldehyde or ketone. X' is Cl, B 2 or I when n is 0 but preferably is Br or I when n is lor 2. 2 Alternatively, compounds of formula I where X is -S- are prepared as per Reaction Scheme II Reaction Scheme II I The definitions of R, n. A, B and X' are the same here as in Reaction * Scheme I. » Compounds of formula I where X is oxygen are prepared as per II Reaction Scheme III. » Reaction Scheme III (QOfePOCl + 12 Homologues & Derivatives J 4 The definitions of R, n, A, B and X' are the same here as in Scheme I. J Compounds of formula I where X is N-R' where R * is hydrogen or • alkyl are prepared as per Reaction Scheme IV. 7 Reaction Scheme IV Homologues & Derivatives - The definitions of R\ n, A, B and X' are the same here as in Scheme I. 5 Alternatively, the sequence of steps outlined in Reaction Schem < V will serve to make such compounds where X is N-R' and R' is H or 7 lower alkyl. « Reaction Scheme V Homologs and Analogs A general description for making each of the compounds recited I in the foregoing Reaction-Schemes follows. * In Reaction Scheme I, the following generalized reaction 7 conditions are applicable. The thiophenol 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 acetone at M reflux. Refluxing is carried out for between 1 and 4 hours, preferably II 2.5 hours, after which the solution is treated with an equimolar u amount of formula 2, l -bromo-3-methyl- 2-butene (Aldrich), u dissolved in acetone. Refluxing is continued for about 2 days after 1 which the solution is stirred for another 24 hours at about room a temperature effecting formation of formula 3. It is isolated by 2 conventional means. Ring closure is effected by treating the sulfide (compound 3), 2 whose formation is described above, with phosphorous pentoxide in * the presence of phosphoric acid under an inert atmosphere to give the 7 thiochroman of formula 4. The sulfide is first dissolved in an inert * solvent such as benzene, toluene, or the like, and then treated with a * small excess of phosphorous pentoxide along with concentrated 10 phosphoric acid. The solution is heated at reflux with stirring under a 11 inert gas such as argon or nitrogen for up to 24 hours. The product is u then recovered and purified by conventional means. ° The ketone of formula 5 is obtained by treating the thiochroman 14 with acetyl chloride in the presence of aluminum chloride. A u suspension of the aluminum chloride in a polar inert solvent is 14 prepared under an inert atmosphere and at reduced temperature, i.e. , 17 - 10 to 10 β C. The inert atmosphere may be argon or nitrogen, " preferably argon. The reaction is conveniently carried out in a solven " such as methylene chloride. To the aluminum chloride suspension is 20 added the throchroman and acetyl chloride via a dropping funnel or 21 similar device. About a 5% molar excess of acetyl chloride and 10% 22 molar excess of aluminum chloride, relative to the thiochroman 23 material, is used. The reaction is effected with agitation (stirring) ov 2 0.5-4 hours at a temperature between 10-50°C. Preferably the B reaction is effected in about 2 hours at room temperature. Then the 4 reaction is quenched with water and/or ice, the product extracted and 27 further purified by distillation or some other appropriate means. 21 The acetylenic function of formula 6 is introduced by means of * lithium diisopropylamide or a similar base at reduced temperature 10 under an inert atmosphere. The reaction is carried out in an 21 ether-type of solvent such as a dialkyl ether or a cyclic ether, for 1 example, tetrahydrofuran, pyran or the like. 2 More specifically, lithium diisopropylamide is generated in situ 1 by mixing diisopropylamine in a dry solvent such as tetrahydrofuran, 4 which is then cooled, to between -70° and -50°C under an inert - atmosphere. An equimolar amount of an alkylithium compound such * as n-butyl lithium in an appropriate solvent is then added at the 7 reduced temperature and mixed for an appropriate time to permit * formation of lithium diisopropylamide (LDA). The ketone of formula 5 * (at least a 10% molar excess) is dissolved in the reaction solvent, the >° solution cooled to that of the LDA mixture, and added to that solution. M After brief mixing, the solution is then treated with a dialkyl a chlorophosphate, preferably diethyl chlorophosphate in about a 20% υ molar excess. The reaction solution is then gradually brought to room 1 temperature. This solution is then added to a second lithium u diisopropylamide solution which is prepared in situ using dry solvent " all under an inert atmosphere, preferably argon, at reduced " temperature (eg. -78°C). Thereafter, the reaction mixture is again 11 warmed to room temperature where it is stirred for an extended " period of time, preferably between 10 and 20 hours, most preferably 20 about 15 hours. The solution is then acidified and the product 21 recovered by conventional means. 22 Formula 7 compounds are prepared under conditions which a exclude water and oxygen. A dry, ether-type solvent such as dialkyl 2 ether or a cyclic ether such as a furan or pyran, particularly a 2 tetrahydrofuran, may be used as the solvent. A solution of formula 6 * is first prepared under an inert atmosphere such as argon or nitrogen, 27 and then a strong base such as n-butyl lithium is added (in about a 21 10% molar excess). This reaction is begun at a reduced temperature of » between -10° and +10 β C, preferably about 0°C. The reaction mixture is 20 stirred for a short period, between 30 minutes and 2 hours, and then 21 treated with about a 10% molar excess of fused zinc chloride dissolved 1 in the reaction solvent. This mixture is stirred for an additional 1 -3 2 hours at about the starting temperature, then the temperature is 2 increased to about ambient temperature for 10-40 minutes. Where a protected heteroaromatic compound is needed to coupl 2 with formula 7 compounds, such may be prepared from their * corresponding acids, alcohols, ketones or aldehydes. These starting 7 materials, the protected acids, alcohols, aldehydes or ketones, are all 1 available from chemical manufacturers or can be prepared by ' published methods. Acids are esterified by refluxing the acid in a 10 solution of the appropriate alcohol in the presence of thionyl chloride. 11 Refluxing for 2-5 hours provides the desired ester. Alternatively, the 12 acid can be condensed with the appropriate alcohol in the presence of a dicyclohexylcarbodiimide and dimethylaminopyridine. The ester is 14 recovered and purified by conventional means. Acetals and ketals ar u readily made by the method described in March, "Advanced Organic w Chemistry," 2nd Edition, McGraw-Hill Book Company, p 810). Alcohol 1 aldehydes and ketones all may be protected by forming respectively, ■ ' ethers and esters, acetals or ketals by known methods such as those u described in McOmie, Plenum Publishing Press, 1973 and Protectin g 6 Groups. Ed. Greene, John Wiley & Sons, 1981. 21 To increase the value of n before effecting a coupling reaction, 22 where such compounds are not available from a commercial source, t 22 heteroaromatics where B is -COOH are subjected to homologation by 24 successive treatment under Arndt-Ei stert conditions or other 21 homologation procedures. These acids are then esterified by the 1 general procedure outlined in the preceding paragraph. Alternatively 7 heteroaromatics where B is a different functional may also be 1 homologated by appropriate procedures. 1 To effect the coupling of the thiochroman moiety with those of 0 formula III, the halo-substituted heteroaromatic compound is 1 dissolved in a dry reaction solvent. The heteromatic compound is use 1 in an amount approximating the molar concentration of formula 7. 2 This solution is introduced into a suspension of tetrakis-triphenylphosphine palladium (about a 5 to 10% molar amount relative to the reactants) in the reaction solvent at a 2 temperature of between about - 10° and +10°C. This mixture is stirred * briefly, for about 15 minutes. To this just prepared mixture is then 7 added the pre-prepared solution of formula 7, the addition being * made at about room temperature. This solution is stirred for an * extended period, between about 15 and 25 hours at room 10 temperature. The reaction is then quenched with acid and the product 11 separated and purified by conventional means to give the compounds a of formula I. u An alternative means for making compounds where n is 1 or 2 is 1 to subject the compounds of formula I where B is an acid or other u function to homologation using the Arndt-Eistert method referred to • « above or other homologation procedures. 17 The acids and salts derived from formula I are readily obtainable 11 from the corresponding esters. Basic saponification with an alkali • » metal base will provide the acid. For example, an ester of formula I 20 may be dissolved in a polar solvent such as an alkanol, preferably 21 under an inert atmosphere at room temperature, with about a three 22 molar excess of base, for example, potassium hydroxide. The solution 22 is stirred for an extended period of time, between 15 and 20 hours, 24 cooled, acidified and the hydrolysate recovered by conventional means. 29 The amide may be formed by any appropriate amidation means * known in the art. One way to prepare such compounds is to convert an 27 acid to an acid chloride and then treat that compound with ammonium 1 hydroxide or an appropriate amine. For example, the acid is treated » with an alcoholic base solution such as ethanolic KOH (in approximately 0 a 10% molar excess) at room temperature for about 30 minutes. The 1 solvent is removed and the residue taken up in an organic solvent such • as diethyl ether, treated with a dialkyl formamide and then a 10-fold 2 excess of oxalyl chloride. This is all effected at a moderately reduced temperature between about - 10° and + 10°C. The last mentioned 4 solution is then stirred at the reduced temperature for 1-4 hours, 2 preferably 2 hours. Solvent removal provides a residue which is 4 taken up in an inert inorganic solvent such as benzene, cooled to abou 7 0°C and treated with concentrated ammonium hydroxide. The 1 resulting mixture is stirred at a reduced temperature for 1 -4 hours. » The product is recovered by conventional means. >° Alcohols are made by converting the corresponding acids to the 11 acid chloride with thionyl chloride or other means (J. March, 12 "Advanced Organic Chemistry", 2nd Edition, McGraw-Hill Book υ Company), then reducing the acid chloride with sodium borohydride 14 (March, Ibid, pg. 1 124), which gives the corresponding alcohols. u Alternatively, esters may be reduced with lithium aluminum hydride >' at reduced temperatures. Alkylating these alcohols with appropriate 17 alkyl halides under Williamson reaction conditions (March, Ibid, 11 pg. 357) gives the corresponding ethers. These alcohols can be " converted to esters by reacting them with appropriate acids in the 20 presence of acid catalysts or dicyclohexylcarbodiimide and 21 dimethylaminopyridine. 22 Aldehydes can be prepared from the corresponding primary 22 alcohols using mild oxidizing agents such as pyridinium dichromate in 24 methylene chloride (Corey, E.J., Schmidt, G.. Tet. Lett.. 399. 1979V or 21 dimethyl sulfoxide/oxalyl chloride in methylene chloride (Omura, K., * Swern. P.. Tetrahedron. 1978. 34. 1651). 7 Ketones can be prepared from an appropriate aldehyde by 21 treating the aldehyde with an alkyl Grignard reagent or similar reage » followed by oxidation. 9 Acetals or ketals can be prepared from the corresponding 21 aldehyde or ketone by the method described in March, Ibid, p 810. i Compounds where B is H are prepared from the corresponding 2 halo-heterocyclic entity preferably where the halogen is I. This haloheterocyclic compound is reacted with the ethynyl entity or the 4 ethynyl zinc chloride entity as represented in Reaction Scheme I and as 3 illustrated in the Examples. Halo-substituted heterocyclic compounds ' where B is H are commercially available or can be prepared by 7 methods in the literature. * Compounds where X is oxygen are prepared by the steps ' outlined in Reaction Scheme III. The phosphate of formula 14 is 10 prepared from the corresponding diphenyl chlorophosphate and » 3-methyl-3-butene- l -ol available from Aldrich or which may be u prepared by means known in the art. It is preferred to prepare for- a mula 14 by dissolving the alcohol of formula 13 in about a 10% excess 14 of pyridine in a polar inert solvent under an inert atmosphere cooled u to approximately - 10 to 10°C. This solution is then added drop-wise, 14 under an inert atmosphere, to a solution of cooled diphenyl 17 chlorophosphate in about an equal amount of the reaction solvent. 11 About a 2-5% molar excess of diphenyl chlorophosphate relative to the " alcohol is employed. The atmosphere may be argon, nitrogen, or 20 another inert gas. The mixture is heated at reflux for between 1 and 21 5 hours, preferably about 3, to effect the reaction. The product is then 22 recovered by conventional means. 22 The diphenyl phosphate ester from the preceding paragraph 24 (formula 14) is then reacted with phenol or 3-alkylphenol to effect 21 formation of compound 16. For example, phenol is added to a flask 24 already containing stannic chloride under argon which has been cooled 27 to between - 10 to 10°C. After thorough mixing of this combination for 21 about 15 minutes to an hour at the reduced temperature, the • » phosphate is added at the reduced temperature. Both of these steps 0 are carried out under an inert atmosphere such as argon or nitrogen. 21 When the addition of the phosphate is completed, the mixture is 1 stirred at about ambient temperature for up to 24 hours. Then the 2 reaction is quenched with a dilute solution of aqueous alkali metal ba 2 or the like. The product is recovered by extraction and other conventional means. 2 Formula 16 is then acetylated, converted to the acetylene and * either the acetylene or the corresponding alkynyl zinc chloride salt 7 coupled with the appropriate heterocycle by the steps outlined in 1 Reaction Scheme I. ' The tetrahydroquinoline moiety, that is where X is nitrogen, ca 10 be made by the steps outlined in Reaction Scheme IV in part by the " method described in European Patent Application 0130795 publishe 12 September 1 , 1985. First, 3-methylcrotonoyl chloride is reacted with u aniline to obtain the amide. This amide is then cyclized using 14 aluminum chloride in the absence of solvent. Lithium aluminum u hydride or another acceptable reducing agent of similar type is then 14 used to reduce the 2-oxo- l ,2,3,4-tetrahydroquinoline, preferably in a 17 inert solvent such as diethyl ether. This amine is then acetylated usi 11 acetyl chloride in a polar solvent such as pyridine. This protected " amine is then acetylated in the presence of aluminum chloride. The 20 acetyl function on the nitrogen may then be removed by base 21 hydrolysis. Then the acetylated compound is converted to the 22 acetylene and ZnCl salt as outlined in Reaction Scheme I. The 22 acetylene or the salt is then coupled with an appropriate compound o 24 formula III as described before to give compounds of formula I. 29 Reaction Scheme V sets out an alternative method for making t 24 tetrahydroquinoline compounds illustrated in Reaction Scheme IV. 27 The following Examples are set out to illustrate the invention, n 21 to limit its scope. a EXAMPLE 1 » Phenvl - 3-methvlbut-2-envlsulfide * A mixture of 14.91 g (135.324 mmol) of thiophenol and 5.5 g 2 (137.5 mmol) of NaOH in 100 ml acetone was heated at reflux for 2.5 hours and then treated dropwise with a solution of 20 g (134.19 4 mmol) of l -bromo-3-methyl-2-butene in 20 ml acetone. This solution 2 was refluxed for 40 hours and then stirred at room temperature for * 24 hours. Solvent was then removed in vacuo. the residue taken up in 7 water, and extracted with 3x50 ml ether. Ether extracts were * combined and washed with 3x30 ml of 5% NaOH solution, then water, » saturated NaCl solution and dried (MgSO4). Solvent was then removed » in vacuo and the residue further purified by kugelrohr distillation a (80°C, 0.75 mm) to give the title compound as a pale yellow oil. « PMR (CDCI3): 5 1.57 (3H, s), 1.69 (3H, s), 3.52 (2H, d, J-7.7 Hz), 2 5.29 (IH, t, J-7.7 Hz), 7.14 (IH, t, J-7.0 Hz), 7.24 (2H, t, J-7.0 Hz), 7.32 • 4 (2H, d, J-7.0 Hz). u EXAMPLE 2 17 4.4-Dimethvlthiochroman >< To a solution of 15.48 g (86.824 mmol) of » phenyl-3-methylbut-2-enylsulfide (from Example 1 ) in 160 ml 20 benzene were added successively 12.6 g (88.767 mmol) of phosphorus 21 pentoxide and 11 ml of 85% phosphoric acid. This solution was 22 refluxed with vigorous stirring under argon for 20 hours, then cooled 2 to room temperature. The supernatant organic layer was decanted and 24 the syrupy residue extracted with 3x50 ml ether. Organic fractions 22 were combined and washed with water, saturated NaHCO3 and 24 saturated NaCl solution and then dried (MgS04). Solvent was removed 7 in vacuo and the residue purified by kugelrohr distillation (80°C, 21 0.5 mm) to give the title compound as a pale yellow oil. » PMR (CDCI3): δ 1.30 (6H, s), 1.90- 1.95 (2H, m), 2.95-3.00 (2H, m). » 6.96-7.00 (2H, m), 7.04-7.07 (IH, m), 7.30-7.33 (IH, m). 21 This method can be used to make 7-position alkyl analogues as exemplified by the following compounds: 4,4,7-trimethylthiochroman; 4, 4-dimethy 1-7 -ethyl thiochroman; 4,4-dimethyl-7-propylthiochroman; 4, 4 -dime thy 1-7 -butyl thiochroman; and 4, 4-di me thy 1-7 -he xyl thiochroman. EXAMPLE 3 4.4 Dimethvl-6-acetvlthiochroman A solution of 14.3 g (80.21 mmol) of 4,4-dimethyl thiochroma (from Example 2) and 6.76 g (86.12 mmol) of acetyl chloride in 65 12 benzene was cooled in an ice bath and treated dropwise with 26.712 1 ( 102.54 mmol) of stannic chloride. The mixture was stirred at room 14 temperature for 12 hours, then treated with 65 ml water and 33 ml u cone, hydrogen chloride and heated at reflux for 0.5 hours. After 14 bein g cooled to room temperature, the organic layer was separated a 17 the aqueous layer extracted with 5x50 ml benzene. The recovered 11 organic fractions were combined and washed with 5% sodium » carbonate solution, water, saturated NaCl solution and then dried 20 (MgSO4) . The solvent was removed in vacuo and the residue purifie 21 by flash chromatography (silica; 5% ethyl acetate in hexanes) followe 2 by kugelrohr distillation ( 150°C, 0.7 mm) to give the title compound 2 a pale yellow oil. 4 PMR (CDCI3): δ 1.35 (6H, s), 1.92-1.98 (2H, m) 2.54 (3H, s), 22 3.02-3.08 (2H, m), 7.13 (IH, d, J-8.6 Hz), 7.58 ( IH, dd, J-8.6 Hz, 2 Hz * 7.99 (IH, d, J-2 Hz). 27 This same method may be used to acetylate all compounds ma 1 as per Example 2. a EXAMPLE 4 » 4.4-Dimethvl- 6-ethvnvlthiochroman ■ To a solution of 1.441 g ( 14.2405 mmol) of diisopropylamine in 2 30 ml dry tetrahydrofuran under argon at -78°C was added dropwise 9 ml of 1.6 M ( 14.4 mmol) n-butyllithium in hexane. After stirring this solution at -78°C for 1 hour, it was treated dropwise with a 2 solution of 2.95 g ( 13.389 mmol) of * 4,4-dimethyl-6-acetylthiochroman in 5 ml of dry tetrahydrofuran. 7 After another hour of stirring at -78°C, the solution was treated with 1 2.507 g ( 14.53 mmol) of diethyl chlorophosphate and brou ght to room ' temperature, where it was stirred for 3.75 hours. This solution was 10 then transferred using a double ended needle to a solution of lithium 11 diisopropylamide (prepared as above using 2.882 g (28.481 mmol) of 1 diisopropylamine and 1 8 ml of 1.6 M (28.8 mmol) n-butyllithium in u hexane) in 60 ml dry tetrahydrofuran at -78°C. The cooling bath was 14 removed and the solution stirred at room temperature for 15 hours, u then quenched wi th water and acidified to pH 1 with 3N hydrogen 14 chloride. The mixture was stirred at room temperature for 12 hours, 17 then treated with 65 ml water and 33 ml cone, hydrogen chloride and " heated at reflux for 0.5 hours. After being cooled to room " temperature the organic layer was separated and the aqueous layer 29 extracted with 5x50 ml benzene. The recovered organic fractions 21 were combined and washed with 5% sodium carbonate solution, water, 2 saturated NaCl solution and then dried (MgSO4). The solvent was 2 removed in vacuo and the residue purified by flash chromatography 24 (silica; 5% ethyl acetate in hexanes) followed by kugelrohr distillation 21 ( 150°C, 0.7 mm) to give the captioned compound as a pale yellow oil. 4 PMR (CDCI3 ): δ 1.35 (6H, s), 1.92- 1.98 (2H, m) 2.54 (3H, s), 7 3.02-3.08 (2H, m), 7.13 (IH, d, J-8.6 Hz), 7.58 (IH, dd, J-8.6 Hz, 2 Hz). » 7.99 ( IH, d, J-2 Hz). * In the same manner, all acetyl-containing compounds prepared 20 under Example 3 may be converted to their corresponding ethynyl 1 analogues. EXAMPLE 5 Ethyl 6-chlgrpnicPtinate 4 A mixture of 15.75 g (0.1 mol) 6-chloronicotinic acid, 6.9 g 2 (0.15 mol) ethanol, 22.7 g (0.1 1 mol) dicyclohexylcarbodiimide and * 3.7 g dimethylaminopyridine in 200 ml methylene chloride was 7 heated at reflux for 2 hours. The mixture was allowed to cool, solve * removed in vacuo and residue subjected to flash chromatography to * give the title compound as a low-melting white solid. w PMR (CDCI3): δ 1.44 (3H, t, J-6.2 Hz) 4.44 (2H, q, J-4.4 Hz), 7.44 » (IH, d, J-8.1 Hz), 8.27 (IH, dd, J-8.1 Hz, 3 Hz), 9.02 (IH, d, J-3 Hz). u This procedure may be used to esterify any of the other u halo-substituted acids employed in the making of these compounds 14 such as 15 ethyl 2-(2-chloropyrid-5-yl)acetate; " ethyl 5-(2-chloropyrid-5-yl)pentanoate; " ethyl 2-(2-iodofur-5-yl)acetate; " ethyl 5-(2-iodofur-5-yl)pentanoate; » ethyl 2-(2-iodothien-5-yl)acetate; » ethyl 5-(2-iodothien-5-yl)pentanoate; 21 ethyl 2-(3-chloropyridazin-6-yl)acetate; 2 ethyl 5-(3-chloropyridazin-6-yl)pentanoate; and the 2 corresponding chloro, or other halo, substituted pyrimidinyl or 24 pyrazinyl analogues of such esters. a EXAMPLE v v Ethvl 6-r2-(4.4-diτncthvlthiochτoτnan-6-vn- * ethynvllnicotinate * Reaction vessels used in this procedure were flame dried unde so vacuum and all operations carried out in an oxygen-free, argon or 1 nitrogen atmosphere. To a solution of 465.7 mg (2.3019 mmol) of 1 4,4-dimethyl-6-ethynyl-thiochroman in 4 ml of dry tetrahydrofuran 2 at 0°C was added dropwise 1.5 ml of 1.6 M (2.4 mmol) n-butyllithium in hexane. This was stirred at 0°C for 10 minutes and at room temperature for 10 minutes, cooled again to 0°C and then 2 treated with a solution of 330 mg (2.4215 mmol) of fused ZnCl2 in • 4 ml dry tetrahydrofuran using a double ended needle. Thereafter 7 the solution was stirred at 0°C for 30 minutes, then at room ' temperature for 10 minutes. A solution of 426.3 mg (2.2967 mmol) * of ethyl 6-chloronicotinoate (from Example 5) in 4 ml dry 10 tetrahydrofuran was transferred by double ended needle into a 11 suspension of 430 mg (0.37 mmol) of tetrakistriphenylphosphine 12 palladium in 4 ml dry tetrahydrofuran and stirred at room a temperature for 10 minutes, then treated by double ended needle 14 with the solution of the alkynylzinc prepared above. This mixture was u stirred at room temperature for 18 hours, then quenched with 100 ml 14 water. Product was recovered by extraction with 3x75 ml ether. 17 Ether fractions were combined and washed with saturated NaCl " solutions and dried (mgSO4). Solvent was removed in vacuo and the " residue purified by flash chromatography (silica; 5% ethyl acetate in 20 hexane) followed by HPLC (Whatman Partisil M-9 10/50; 4% ethyl 21 acetate in hexane) to give the title compound as a white solid. 2 PMR (CDCI3 ): δ 1.36 (6H, s), 1.45 (3H, t, J-7 Hz), 1.96-2.00 (2H, 2 m), 3.05-3.09 (2H, m), 4.45 (2H, q, J-7 Hz), 7.1 1 (IH, d, J-8.4 Hz), 7.29 4 (IH, dd, J-8.4 Hz, 2.2 Hz), 7.59 ( IH, d, J-7.8 Hz), 7.66 ( IH, d, J-2.2 Hz), » 8.30 (IH, dd, J-7.8 Hz, 2.3 Hz), 9.22 (IH, d, J-2.3 Hz). 24 Using this method, but substituting the appropriate 27 ethynylthiochroman from Example 4 and the appropriate 22 halo-substituted heteroaromatic ester from Example 5, the following 22 compounds may be prepared: » ethyl 6-(2(4,4,7-trimethylthiochroman-6-yl)- ethynyl)nicotinate; 1 ethyl 6-(2-4,4-dimethyl-7-ethylthiochroman-6-yl)- > ethynyl)nicotinate; ethyl 6-(2-(4,4-dimethyl-7-propylthiochroman-6-yl)- 2 ethynyl)nicotinate; 4 ethyl 6-(2-(4,4-dimethyl-7-hexylthiochroman-6-yl)- 2 ethynyl)nicotinate; « ethyl (2-((4,4-dimethylthiochroman-6-yl)ethynyl)- 7 pyrid-5-yl)acetate; » ethyl (2-((4,4,7 -trimethylthiochroman-6-yl)ethynyl)- * pyrid-5-yl)acetate; 10 ethyl (2-((4,4-dimethyl-7-ethylthiochroman-6-yl)- " ethynyl)pyrid-5 -yl)acetate; a ethyl (2-((4,4-dimethyl-7-hexylthiochroman-6-yl)- u ethynyl)pyrid-5-yl)acetate; 14 ethyl 3-(2-((4 ,4-dimethylthiochrom-2-yl)- u ethynyl)pyrid-5 -yl)propionate; 14 ethyl 3-(2-((4,4,7-trimethylthiochroman- 6-yl)- 17 ethynyl)pyrid-5-yl)propionate; » ethyl 3-(2((4,4-dimethyl-7-ethylthiochroman-6-yl)- • » ethynyl)pyrid-5-yl)propionate; 28 ethyl 3-(2((4,4-dimethyl-7-hexylthiochroman-6-yl)- 21 ethynyl)pyrid-5-yl)propionate; 22 ethyl 5-(2- ((4,4-dimethylthiochroman-6-yl)ethynyl)- 22 pyrid-5-yl)pentanoate; 24 ethyl 5-(2-((4,4,7-trimethylthiochroman-6-yl)- 25 ethynyl)pyrid-5-yl)pentanoate; 24 ethyl 5-(2-((4,4-dimethyl-7-ethylthiochroman-6-yl)- 27 ethynyl)pyrid-5-yl)pentanoate; 22 ethyl (5-((4,4-dimethylthiochroman-6-yl)ethynyl)- » fur-2-yl)acetate; 0 ethyl (5 - ((4,4,7 -trimethylthiochroman-6-yl)ethynyl)- » fur-2-yl)acetate; ethyl (5-((4,4-dimethyl-7-ethylthiochroman-6-yl)- ethynyl)fur-2-yl)acetate; ethyl (5-((4, 4-dimethy 1-7-hexyl thiochroman- 6-yl)- ethynyl)fur-2-yl)acetate; ethyl 5-(5- ((4, 4-dime thy lthiochroman-6-yl)ethy nyl)- fur-2-yl)pentanoate; ethyl 5-(5-((4,4,7-trimethylthiochroman- 6-yl)- ethynyl)fur-2-yl)pentanoate; ethyl 5-(5-((4,4-dimethyl-7-ethylthiochroman-6-yl)- ethynyl)fur-2-yl)pentanoate; ethyl 5-(5- ((4, 4-dimethy l-7-hexylthiochroman-6-yl)- a ethynyl)fur-2-yl)pentanoate; u ethyl (5- ((4,4-dimethylthiochroman-6-yl)ethynyl)- 1 thien-2-yl)acetate; « ethyl (5-((4,4,7 -trimethylthiochroman-6-yl)ethynyl)- 1 thien-2-yl)acetate; 17 ethyl (5-((4,4-dimethyl-7-ethylthiochroman-6-yl)- » ethynyl)thien-2-yl)acetate; » ethyl (5-((4 ,4-dimethyl-7-hexylthiochroman-6-yl)- 20 ethynyl)thien-2-yl)acetate; » ethyl 5-(5-((4,4-dimethylthiochroman-6-yl)ethynyl)- 2 thien-2-yl)pentanoate; 2 ethyl 5- (5- ((4,4,7-trimethylthiochroman-6-yl)- 24 ethynyl)thien-2-yl)pentanoate; » ethyl 5-(5-((4,4-dimethyl-7-ethylthiochroman-6-yl)- * ethynyl)thien-2-yl)pentanoate; s ethyl 5-(5-((4,4-dimethyl-7-hexylthiochroman-6-yl)- 22 ethynyl)thien-2-yl)pentanoate; » ethyl (6-((4 ,4-dimethylthiochroman-6-yl)ethynyl)- " pyridazin-3-yl)acetate; 1 ethyl (6- ((4,4,7-trimethylthiochroman-6-yl)ethynyl)- pyridazin-3-yl)acetate; ethyl (6-((4,4-dimethyl-7-ethylthiochroman-6-yl)- ethynyl)pyridazin-3-yl)acetate; ethyl (6- ((4, 4-dimethy l-7-hexylthiochroman-6-y 1)- ethynyl)pyridazin-3-yl)acetate; ethyl 5-(6-((4,4-dimethylthiochroman-6-yl)ethynyl)- pyridazin-3-yl)pentanoate; ethyl 5-(6-((4,4,7-trimethylthiochroman-6-yl)- ethynyl)pyridazin-3-yl)pentanoate; ethyl 5-(6-((4,4-dimethyl-7-ethylthiochroman-6-yl)- ethynyl)pyridazin-3-yl)pentanoate; a ethyl 5-(6-((4,4-dimethyl-7-hexylthiochroman-6-yl)- a ethynyl)pyridazin- 3-yl)pentanoate; 1 ethyl (5-((4,4-dimethylthiochroman-6-yl)ethynyl)- u pyrimidin-2-yl)acetate; ■• ethyl (5-((4 ,4,7-trimethylthiochroman-6-yl)ethynyl)- 17 pyrimidin-2-yl)acetate; « » ethyl (5-((4,4-dimethyl-7-ethylthiochroman-6-yl)- » ethynyl)pyrimidin-2-yl)acetate; 20 ethyl (5-((4 ,4-dimethyl-7-hexylthiochroman-6-yl)- 21 ethynyl)pyrimidin-2-yl)acetate; 22 ethyl 5-(5 -((4,4-dimethylthiochroman-6-yl)ethynyl)- 22 pyrimidin-2-yl)pentanoate; 1 ethyl 5-(5-((4,4,7-trimethylthiochroman- 6-yl)- 22 ethynyl)pyrimidin-2-yl)pentanoate; 24 ethyl 5-(5-((4,4-dimethyl-7-ethylthiochroman- 6-yl)- 27 ethynyl)pyrimidin-2-yl)pentanoate; ■ ethyl 5-(5-((4,4-dimethyl-7-hexylthiochroman-6-yl)- 22 ethynyl)pyrimidin-2-yl)pentanoate; 20 ethyl (5- ((4,4-dimethylthiochroman-6-yl)ethynyl)- - pyrazin-2-yl)acetate; » ethyl (5-((4,4,7-trimethylthiochroman-6-yl)ethynyl)- 2 pyrazin-2-yl)acetate; 2 ethyl (5-((4,4-dimethyl-7-ethylthiochroman-6-yl)- 4 ethynyl)pyrazin-2-yl)acetate; 2 ethyl (5-((4,4-dimethyl-7-hexylthiochroman-6-yl)- 4 ethynyl)pyrazin-2-yl)acetate; 7 ethyl 5)5-((4,4-dimethylthiochroman-6-yl)ethynyI)- 1 pyrazin-2-yl)pentanoate; » ethyl 5-(5- ((4,4,7 -trimethylthiochroman-6-yl)- lβ ethynyl)pyrazin-2-yI)pentanoate; » ethyl 5- (5-((4,4-dimethyl-7-ethylthiochroman-6-yl)- 12 ethynyl)pyrazin-2-yl)pentanoate; and u ethyl 5-(5-((4,4-dimethyl-7-hexylthiochroman-6-yl)- 1 ethynyl)pyrazin-2-yl)pentanoate. u Altern ative synth esi s : The title compound of Example 6, ethyl " 6-[2-(4,4-dimethylthiochroman-6-yl)ethynyl]nicotinate, was also 17 prepared as follows. » A solution of 15.4 g (76.2 mmol) of 4,4-dimethyl-6-ethynyl- " thiochroman and 14.0 g (75.5 mmol) of ethyl-6-chloronicotinate in 20 35 ml of freshly distilled triethylamine was degassed and then treated 21 under nitrogen with a finely powdered mixture of 1 g (5.25 mmol) of 22 high purity cuprous iodide and 2 g (2.85 mmol) of 22 bis(triphenylphosphine) palladium (II) chloride. The mixture was » heated under nitrogen at 55°C for 20 hours and then cooled to room a temperature. The triethylamine was then removed under vacuum and 24 the residue was diluted with 200 ml of a 1 :4 mixture of ethyl acetate 27 and hexanes. This mixture was filtered through silica and the filtrate 22 concentrated in vacuo. The resultant residue was purified by flash 22 chromatography (silica gel; 15 % ethyl acetate in hexanes) and recrys- 20 tallized from a mixture of ethyl acetate and hexanes to give the title 21 compound as a pale yellow solid. 1 Example 7 2 (3-Methvl-4-bromo-phenvn-3-methvlbut-2-envlsulfidc 2 To a stirred solution of 9.52 g (68 mmol) of 3-methyl-4-bro- mothiophenol in 80 ml of acetone was added 2.86 g (68 mmol) of 2 powdered sodium hydroxide. This mixture was stirred until the com ponents were dissolved. The reaction mixture was then heated to 7 reflux, and then treated with a solution of 11.26 g (68 mmol) of * 4-bromo-2-methyl-2-butene in 20 ml of acetone. The mixture was * heated at reflux for a further 0.5 hour, cooled to room temperature a » the solvent removed in vacuo. The residue was taken up in 35 ml of 11 water and extracted with ether. The ether extracts were combined a 12 washed successively with water and saturated NaCl solution and the u dried (MgSO4). The solvent was removed in vacuo and the residue «4 kugelrohr distilled ( 140 - 145°C, 0.2 mm) to give the title compound u a colorless oil. " PMR (CDCI3 ): δ 1.58 (3H, s), 1.70 (3H, s), 2.33 (3H, s), 3.49 (2H, d » J-7.8 Hz), 5.26 (IH, t, J-7.8 Hz), 6.98 (IH, dd, J-8.3 Hz, 2.3 Hz), 7.17 (I « d J-2.3 Hz), 7.38 (IH, d, J-8.3 Hz). » 20 Example 8 a 4.4.7 -Trimethvl- 6-bromothiochroman 2 To 40 g of a vigorously stirred mixture of 10% phosphorous 22 pentoxide in methanesulfonic acid was added slowly 6.0 g (28.8 mmo 24 of (3-methyl-4- bromophenyl)-3-methylbut-2-enylsulfide. The 21 mixture was stirred at room temperature for a further 2 hours and 2 was then poured onto ice. The mixture was extracted with 2 x 40 ml 27 ether and the combined ether extracts were washed successively wit 21 water and saturated NaCl solution and then dried. The solvent was •» removed in vacuo and the residue distilled using a kugelrohr appara 0 tus (130°C; 0.07 mm) to give the title compound as a viscous oil. * PMR (CDCI3 ): δ 1.28 (6H, s) 1.84- 1.93 (2H, m), 2.26 (3H, s), « 2.95-3.03 (2H, m), 6.94 (IH, s), 7.46 (IH, s). 2 2 Example 9 4 4.4.7-Trimethvl-6-trimethvlsilvlethvnvlthiochroman 2 A mixture of 624 mg (3.0 mmol) of 4,4,7-trimethyl-6- * bromothiochroman, 314 mg (3.2 mmol) of trimethylsilylacetylene, 40 7 mg (0.21 mmol) of cuprous iodide, 80 mg (0.1 1 mmol) of bis-(triphe- * nylphosphine) palladium (II) chloride and 1 ml of triethylamine was * degassed under nitrogen and heated in a sealed tube at 85°C for 15 10 hours. The mixture was then treated with a further 20 mg (0.1 1 ii mmol) of cuprous iodide and 40 mg (0.06 mmol) of the palladium (II) 12 catalyst. The mixture was then heated under a nitrogen atmosphere in 1 the sealed tube at 100°C for a further 64 hours. The triethylamine was 1 then removed under vacuum and the residue purified by flash u chromatography (silica; hexanes) to give the title compound as a yellow » oil. " PMR (CDC1 3 ): δ 0.28 (9H, s), 1.30 (6H, s), 1.88- 1.97 (2H, m), 2.33 » (3H, s), 2.97-3.05 (2H, m), 6.92 (IH, s), 7.43 ( IH, s). l» " Example 10 a 4.4.7-Trimeth vl- 6-ethvnvlthiochroman 22 A mixture of 380 mg ( 1.69 mmol) of 4.4.7-trimethy-6- 21 trimethylsilylethynylthiochroman, 4 ml of isopropanol and 2.5 ml of a aqueous I N potassium hydroxide was degassed under nitrogen and 22 stirred at room temperature for 16 hours. The mixture was 21 concentrated under vacuum and extracted with 2 x 10 ml of ether. 27 The ether extracts were combined and washed successively with water 21 and saturated NaCl solution and then dried (MgSO4). The solvent was 22 removed in vacuo to give the title compound as a yellow oil. » PMR (CDCl3): δ 1.31 (6H, s), 1.88- 1.96 (2H, m), 2.35 (3H, s), » 3.00-3.08 (2H, m), 3.25 ( IH, s), 6.94 ( IH, s), 7.47 (IH, s). i 2 Example 11 Ethyl -f2-(^,^,7-tπmethylthiPchrpmaπ-6-yl)ethyτιynπicpύπaιe A mixture of 86 mg (0.4 mmol) of 4,4,7-trimethyl-6-ethynyl- 2 thiochroman, 85 mg (0.46 mmol) of ethyl 6-chloronicotinate and 0.8 * of triethylamine was degassed under nitrogen and then treated with 7 mixture of 10 mg (0.05 mmol) of cuprous iodide and 20 mg (0.03 * mmol) of bis(triphenylphosphine) palladium (II) chloride. The reacti * mixture was heated at 55°C under a nitrogen atmosphere for 18 hour 10 The mixture was then extracted with 1.5 ml of 40% ethyl acetate in 11 hexanes and purified by flash chromatography (silica; 10% ethyl u acetate in hexanes) to give the title compound as a yellow solid. " PMR (CDCI3 ): δ 1.32 (6H, s), 1.43 (3H, t, J-7.2 Hz), 2.44 (3H, s), • 4 3.01-3.05 (2H, m), 4.42 (2H, q, J-7.2 Hz), 6.98 ( IH, s), 7.54-7.63 (2H, " 8.27 (IH, dd, J-8.3 Hz, 2.3 Hz), 9.21 (IH, d, J-2.3 Hz). It " Example 12 » Ethvl 5-(2-f4.4-di methvl-thiochroman-6-vnethvnvn- » thipphcnc-2-carboxylate 20 Using the same general procedure described in the preceeding 21 Example 11 , but using instead 4,4-dimethyl-6-ethynylthiochroman a 22 ethyl 5-bromothiophene-2-carboxylate, the title compound was syn- thesized. 4 PMR (CDCI3): δ 1.31 (6H, s), 1.36 (3H, t, J-7.5 Hz), 1.90-1.94 (2H » m), 2.99-3.03 (2H, m), 4.33 (2H, q, J-7.5 Hz), 7.04 (IH, d, J-8.1 Hz), 24 7.13-7.18 (2H, m), 7.50 ( IH, s), 7.65 ( IH, d, J-3.9 Hz). V » Example 13 » Ethvl-5-f2-(4.4-dimethv\thiochroman-6-vnethvnvn-2-furoate 20 Again using the general procedure of Example 1 1 , but using 1 instead 4,4-dimethyl-6-ethynylthiochroman and ethyl 5-bromo-2-fu 1 rate, the title compound was synthesized. 2 PMR (CDCI3): δ 1.24 (6H, s), 1.31 (3H, t, J-7.0 Hz), 1.83-1.87 (2H, m), 2.93-2.97 (2H, m), 4.30 (2H, q, J-7.0 Hz), 6.60 (IH, d, J-3.4 Hz), 6.98 4 (IH, d, J-8.1 Hz), 7.09-7.11 (2H, m), 7.46 (IH, d, J-1.7 Hz). EXAMPLE H 7 Di ph envl-3 - ethvl -3- bu ten- l-vl phosph ate • To an ice-cooled solution of 12.2 g ( 141.65 mmol) of » 3-methyl-3-buten- l -ol (Aldrich) and 1 1.9 g ( 150.44 mmol) of pyridine 10 in 100 ml of tetrahydrofuran was added dropwise under argon a 11 solution of 38.5 g ( 143.21 mmol) of diphenyl chlorophosphate 93 in 12 100 ml of tetrahydrofuran. The mixture was heated at reflux for 3 a hours and then cooled and filtered. The filtrate was concentrated in. 1 vacuo and the residue dissolved in 400 ml of 1 : 1 ether and hexane and » then washed with 2 x 200 ml water, 75 ml saturated NaCl solution and 14 dried (MgSO4 ). The solvent was removed i n vacuo to give the 17 captioned compound as a pale yellow oil. « • PMR (CDCI3 ): δ 1.69 (3H, M), 2.37 (2H, t, J N7 Hz), 4.32 (2H, q, J-7 » Hz), 4.72 ( IH, M). 7.10-7.35 ( 10H, m). » EXAMPLE 15 22 4.4-Dimethvlchroman 2 To a dry, ice-cooled flask containing 34.95 g (0.134 mol) of 24 stannic chloride was added quickly under argon 63.0 g (0.669 mol) of 2 phenol. The mixture was stirred at 0°C for 0.5 hour and then treated 24 with 43.0 g (0. 135 mol) of diphenyl-3-methyl- 7 3-buten- l -yl phosphate, followed by a 5 ml carbon disulfide rinse. 21 The mixture was stirred at room temperature for 21 hours and then 2 quenched by pouring onto 700 g ice and 1 liter of 1.5N NaOH. The 0 mixture was extracted with 1 x 600 ml and 2 x 300 ml ether. The 1 combined ether fractions were washed with 2N NaOH, saturated NaCl 1 and dried (MgSO4). Solvent was removed in vacuo and the residue 2 purified by flash chromatography (silica; 2% ether in hexane) to give the title compound as a colorless oil. PMR (CDCl3): δ 1.34 (6H, M), 1.80-1.85 (2H, m), 4.15-4.20 (2H, m 2 6.80 (IH, dd, J-8.1 Hz, 1.5 Hz), 6.87 (IH, td, J-8.1 Hz, 1.5 Hz), 7.07 (IH, td, J-8.1 Hz, 1.5 Hz), 7.26 (IH, dd, J-8.1 Hz, 1.5 Hz). 7 This method also serves to prepare the corresponding 7-alkylchroman compounds, starting with the appropriate 3-alkylphe * nol, for example: »° 4,4,7-trimethylchroman; n 4,4-dimethyl-7-ethylchroman; 12 4,4-dimethyl-7-propylchroman; u 4,4-dimethyl-7-butylchroman; 14 4,4-dimethyl-7-pentylchroman; and " 4,4-dimethyl-7-hexylchroman. M EXAMPLE lv » 4.4-Dimethvl-6-acetvlchroman » To a stirred solution of 7.94 g (48.9425 mmol) of 20 4,4-dimethylchroman in 70 ml of nitromethane was added under 21 argon 4.0 g (50.96 mmol) of acetyl chloride followed by 6.8 g (51 22 mmol) of aluminum chloride. This was stirred at room temperature f 32 5.5 hours and then cooled in an ice bath and treated slowly with 70 4 6N hydrogen chloride. The resultant mixture was stirred at room 22 temperature for 10 minutes, then treated with 100 ml ether and the 26 organic layer separated. The organic layer was washed with water, 27 saturated NaHCO3 and saturated NaCl solutions and dried (MgSO4). * Solvent was removed in vacuo and the residue purified by flash 22 chromatography (silica; 10% ethyl acetate in hexanes). This was » followed by kugelrohr distillation (95- 100 β C; 0.15 mm) to give the tit » compound as a colorless oil. • PMR (CDCI3): δ 1.40 (6H, M), 1.95-2.00 (2H, m), 2.58 (3H, M), 2 4.25-4.30 (2H, m), 6.83 (IH, d, J-8.0 Hz), 7.62 (IH, dd, J-8.0 Hz, 1.5 Hz), 2 8.00 (IH, d, J-1.5 HZ). 4 Following the same procedure and using the compounds of 2 Example 15, the following compounds can be prepared: 4, 4-dimethy 1- 6- acety 1-7 -methylchroman; 7 4, 4-dime thyl-6-acetyl-7-ethylchroman; » 4, 4-dimethy 1-6- acety 1-7 -propylchroman; » 4,4-dimethyl-6-acetyl-7-butylchroman; » 4,4-dimethyl-6-acetyl-7-pentylchroman; and » 4, 4-dime thyl-6-acety 1-7 -hexylchroman. n EXAMPLE 17 • 4 4.4-Dimethvl-6-ethvn v1chroττ_an " To a solution of 2.47 g (24.41 mmol) of diisopropylamine in 40 » ml dry tetrahydrofuran under argon at -78 β C was added dropwise 15.2 17 ml of 1.6 M (24.32 mmol) n-butyl lithium in hexane. Mixture was 11 stirred at -78 β C for 1 hour and then treated dropwise with a solution of »» 4.98 g (24.3 , 8 mmol) of 4,4-dimethyl-6-acetylchroman in 4 ml of dry 20 tetrahydrofuran. After stirring at -78°C for 1 hour, the solution was 21 treated with 4.2 g (24.36 mmol) of diethyl chlorophosphate. The 22 cooling bath was then removed and mixture stirred at room a temperature for 2.75 hours. This solution was then transferred using a 24 double ended needle to a solution of lithium diisopropyl amide 22 (prepared as per Example 4) using 4.95 g (48.92 mmol) of diisopropylamine and 30.5 ml of 1.6 M (48.8 mmol) n-butyl lithium in 7 hexane in 80 ml dry tetrahydrofuran at -78°C. The cooling bath was 21 removed and mixture stirred at room temperature for 18 hours and > then quenched with 50 ml water and 25 ml of 3N hydrogen chloride. 20 The mixture was extracted with 2 x 100 ml and 3 x 50 ml of pentane 21 and the combined organic fractions washed with 3N hydrogen chloride. > water, saturated NaHCO3 and saturated NaCl solution and then dried 2 (MgSO4). Solvent was then removed in vacuo and the residue purified 2 by flash chromatography (silica; 10% ethyl acetate in hexane) followed 4 by kugelrohr distillation (70°C; 0.35 mm) to give the title compound as 2 a colorless crystalline solid. PMR (CDCI3): δ 1.33 (6H, s), 1.81- 1.86 (2H, m), 3.00 (IH, s), 7 4.19-4.24 (2H, m), 6.75 (IH, d, J-8.5 Hz), 7.22 (IH, dd, J-8.5 Hz, 2.3 Hz), 2 7.44 ( IH, d, J-2.3 Hz). * This procedure serves to convert all acetyl-containing 10 compounds prepared as per Example 16 to their corresponding 11 ethynyl-containing compounds, u EXAMPLE 18 14 Ethvl 6- r2-( , 4.4-dimethvlchroman-6-vnethvnvn nicotin ate u Reaction vessels used in thi s procedure were flame dried under 14 vacuum and all operations were carried out in an oxygen-free, argon o 17 nitrogen atmosphere. To a solution of 509.4 mg (2.74 mmol) of ■« 4,4-dimethyl-6- ethynylchroman in 4 ml of dry tetrahydrofuran at 0° » was added dropwise 1.72 ml of 1.6 M (2.75 mmol) of n-butyl lithium 20 in hexane. Stirring was commenced at 0°C for 30 minutes and at room 21 temperature for 15 minutes, after which the solution was cooled again 22 to 0°C and then treated with a solution of 380 mg (2.79 mmol) of 32 fused zinc chloride in 5 ml of dry tetrahydrofuran using a double 24 ended needle. The resulting solution was stirred at 0°C for 1 hour an 29 then at room temperature for 15 minutes. A solution of 628.6 mg 24 (2.74 mmol) of ethyl 6-chloronicotinate in 4 ml of dry 27 tetrahydrofuran was transferred by double ended needle into a 1 suspension of 380 mg (0.33 mmol) of tetrakistriphenylphosphine 22 palladium in 5 ml dry tetrahydrofuran and mixture stirred at room 0 temperature for 15 minutes and then treated by double ended needl 1 with the solution of alkynylzinc prepared above. The mixture was • stirred at room temperature for 20 hours and then quenched with ice 2 and 30 ml of 3N hydrogen chloride. The mixture was extracted with 2 3x75 ml ether and ether extracts were combined and washed successively with saturated NaHCO3 and saturated NaCl and then dried 2 (MgSO4). Solvent was removed in vacuo and the residue further purified by flash chromatography (silica; 10% ethyl acetate in hexane) 7 to give the * title compound as a yellow solid. » PMR (CDCI3): δ 1.36 (6H, s), 1.44 (3H, t, J-7.1 Hz), 1.83- 1.87 (2H, •0 m), 4.22-4.26 (2H, ), 4.44 (2H, q, J-7.1 Hz), 6.80 (IH, d, J-7.6 Hz), » 7.35 ( IH, d, J-8.9 Hz), 7.58 ( IH, d, J-7.6 Hz), 7.60 (IH, M), 8.28 ( IH, d, » J-8.9 Hz), 9.21 (IH, s). u By this method, using the appropriate precursors, the following 1 compounds are prepared: " ethyl 6-(2(4,4,7-trimethylchroman-6-yl)-ethynyl)nicotinate; " ethyl 6- (2- (4,4-dimethyl-7-ethylchroman-6-yl)- » ethynyl)nicotinate; 1 ethyl 6-(2- (4,4-dimethyl-7-propylchroman-6-yl)- • » ethynyl)nicotinate; 29 ethyl 6-(2-(4,4-dimethyl-7-hexylchroman-6-yl)- 21 ethynyl)nicotinatc; 22 ethyl (2-((4 ,4-dimethylchroman-6-yl)ethynyl)- 22 pyrid-5-yl)acetate; 4 ethyl (2-((4,4,7-trimethylchroman- 6-yl)ethynyl)- 22 pyrid-5-yl)acetate; 4 ethyl (2-((4,4-dimethyl-7-ethylchroman-6-yl)- 7 ethynyl)pyrid-5-yl)acetate; 2 ethyl (2- ((4,4-dimethyl-7-hexylchroman-6-yl)- 2 ethynyl)pyrid-5-yl)acetate; 0 ethyl 3- (2-((4,4-dimethylchroman-2-yl)- 1 ethynyl)pyrid-5-yl)propionate; ethyl 3-(2-((4,4,7-trimethylchroman-6-yl)-ethynyl)- pyrid-5-yl)propionate; ethyl 3-(2( (4, 4-dimethy 1-7-ethy lchroman-6-yl)- ethynyl)pyrid-5-yl)propionate; ethyl 3-(2((4,4-dimethyl-7-hexylchroman-6-yl)- eth nyl)pyrid-5-yl)propionate; ethyl 5-(2-((4,4-dimethylchroman-6-yl)ethynyl)- pyrid-5-yl)pentanoate; ethyl 5-(2-((4,4,7-trimethylchroman-6-yl)- ethynyl)pyrid-5-yl)pentanoate; ethyl 5- (2- ((4, 4-dime thy 1-7-ethy lchroman-6-y 1)- ethynyl)pyrid-5-yl)pentanoate; ethyl 5-(2-(4,4-dimethyl-7-hexylchroman-6-yl-ethynyl) pyrid-5- l)pentanoate; ethyl 5-(2-((4,4-dimethylchroman-6-yl)ethynyl)- fur-2-yl)acetate; ethyl (5-((4,4,7-trimethylchroman-6-yl)ethynyl)- fur-2-yl)acetate; ethyl (S-( (4, 4-dime thyl-7-e thy lchroman-6-yl)- ethynyl)fur-2-yl)acetate; ethyl (5-((4,4-dimethyl-7-hexylchroman-6-yl)- ethynyl)fur-2-yl)acetate; ethyl 5-(5-((4,4-dimethylchroman-6-yl)ethynyl)- fur-2-yl)pentanoate; ethyl 5-(5-((4,4,7-trimethylchroman-6-yl)- ethynyl)fur-2-yl)pentanoate; ethyl 5-(5-((4,4-dimethyl-7-ethylchroman-6-yl)- ethynyl)fur-2-yl)pentanoate; ethyl 5-(5-((4,4-dimethyl-7-hexylchroman-6-yl)- ethynyl)fur-2-yl)pentanoate; ethyl (5-((4,4-dimethylchroman-6-yl)ethynyl)- • thien-2-yl)acetate; 2 ethyl (5-((4,4,7-trimethylchroman-6-yl)ethynyl)- 2 thien-2-yl)acetate; 4 ethyl (5-((4,4-dimethyl-7-ethylchroman-6-yl)- 2 ethynyl)thien-2-yl)acetate; 4 ethyl (5-((4,4-dimethyl-7-hexylchroman-6-yl)- 7 ethynyl)thien-2-yl)acetate; ethyl 5-(5-((4,4-dimethylchroman-6-yl)ethynyl)- * thien-2-yl)pentanoate; » ethyl 5-(5-((4,4,7-trimethylchroman-6-yl)-ethynyl)- " thien-2-yl)pentanoate; » ethyl 5-(5-((4,4-dimethyl-7-ethylchroman-6-yl)- 1 ethy nyl)thien-2-y l)pen tan oate; 14 ethyl 5-(5-((4,4-dimethyl-7-hexylchroman-6-yl)- u ethynyl)thien-2-yl)pentanoate; >« ethyl (6-((4,4-dimethylchroman-6-yl)ethynyl)- 17 pyridazin-3-yl)acetate; 12 ethyl (6-((4,4,7-trimethylchroman-6-yl)ethynyl)- w pyridazin-3-yl)acetate; 20 ethyl (6-((4,4-dimethyl-7-ethylchroman-6-yl)- 21 ethynyl)pyridazin-3-yl)acetate; 22 ethyl (6-((4,4-dimethyl-7-hexylchroman-6-yl)- 2 ethynyl)pyridazin- 3- yl) acetate; 4 ethyl 5-(6-((4,4-dimethylchroman-6-yl)ethynyl)- 25 pyridazin-3-yl)pentanoate; 24 ethyl 5-(6-((4,4,7-trimethylchroman-6-yl)-ethynyl)- 27 pyridazin-3-yl)pentanoate; » ethyl 5-(6-((4,4-dimethyl-7-ethylchroman-6-yl)- » ethynyl)pyridazin-3-yl)pentanoate; 0 ethyl 5-(6-((4,4-dimethyl-7-hexylchroman-6-yl)- 21 ethynyl)pyridazin-3-yl)pentanoate; i ethyl (5-((4 ,4-dimethylchroman-6-yl)ethynyl)- pyrimidin-2-yl)acetate; 2 ethyl (5-((4,4,7-trimethylchroman-6-yl)ethynyl)- 4 pyrimidin-2-yl)acetate; ethyl (5-((4,4-dimethyl-7-ethylchroman-6-yl)- * ethynyl)pyrimidin-2-yl) acetate; ethyl (5- ((4,4-dimethyl-7-hexylchroman-6-yl)- • ethynyl)pyrimidin-2-yl)acetate; » ethyl 5-(5-((4,4-dimethylchroman-6-yl)ethynyl)- ιo pyrimidin-2-yl)pentanoate; » ethyl 5-(5-((4,4,7-trimethylchroman-6-yl)-ethynyl)- 12 pyrimidin-2-yl)pentanoate; 1 ethyl 5 - (5 -((4,4-dimethyl-7-ethylchroman-6-yl)- 14 ethynyl)pyrimidin-2-yl)pentanoate ; u ethyl 5- (5 - ((4 ,4-dimethyl-7-hexylchroman-6-yl)- 14 ethynyl)pyrimidin-2-yl)pentanoate; 1 ethyl (5-((4,4-dimethylchroman-6-yl)ethynyl)- 11 pyrazin-2-yl)acetate; » ethyl (5-( (4,4,7 -triraethylchroman-6-yl)ethynyl)- 20 pyrazin-2-yOacetate; 21 ethyl (5- ((4,4-dimethyl-7-ethylchroman-6-yl)- 22 ethynyl)pyrazin-2-yl)acetate; a ethyl (5- ((4,4-dimethyl-7-hexylchroman-6-yl)- 24 eth ynyl)pyrazin-2-yl)acetate; 22 ethyl 5 )(5-((4,4-dimethylchroman-6-yl)ethynyl)- 24 pyrazin-2-yl)pentanoate; 27 ethyl 5-(5- ((4,4,7-trimethylchroman-6-yl)-ethynyl)- 21 pyrazin-2-yl)pentanoate; » ethyl 5-(5- ((4,4-dimethyl-7-ethylchroman-6-yl)- 20 ethynyl)pyrazin-2-yl)pentanoate; and 21 eth yl 5- (5- ( (4,4-dimethyl-7-hexylchroman-6-yl)- ■ ethynyl)pyrazin-2-yl)pentanoate. 3 2 Example 19 4 N-r4-Bromophenvn-3.3-dimethvl aervlamide 2 To a solution of 9.48 g (80 mmol) of 3,3-dimethylacryloyl 4 chloride in 200 ml of dry tetrahydrofuran (THF) was added with vigorous shaking a solution of 13.76 g (80 mmol) of 4-bromoaniline in * 300 ml of dry THF. The mixture stood at room temperature for 2 * hours and was then treated with 80 g of ice followed by 200 ml of 10 hexane. The organic layer was separated and the aqueous layer was " extracted with 2x50 ml o f hexanes. The organic layers were combined u and washed successively with 30 ml of water and 2x30 ml of saturated u NaCl solution and then dried (MgSO4). The solvent was removed in. 14 vacuo and the residue purified by recrystallization from an ethyl u acetate and hexanes mixture to give the title compound as colorless 14 crystals. » PMR (CDCI3 ): δ 1.91 (3H, s), 2.23 (3H, s), 5.73 ( IH, broad s), » 7.38-7.55 (5H, m). If " Example 20 21 4.4-Dimethvl-6-bromo-2-oxo- 1 .2.3.4-tetrahvdroquinoli ne 22 To 6.7 g (26.02 mmol) of molten N-(4-bromophenyl)3,3- a dimethylacrylamide (heated to 135°C) was added 4.15 g (31.09) of 24 aluminum chloride over 25 minutes. The reaction mixture was stirred 22 at 130°C for 16 hopurs and then treated with a further 1 g of 24 aluminum chloride. The reaction mixture was heated at 130°C for a 27 further 9 hours and then cooled to room temperature. The reaction 21 was then quenched by the slow addition of 100 ml of ice cold water 22 with slight warming of flask to facilitate mixing. The mixture was 0 extracted with 1 x 100 ml and 4x50 ml of ether. The organic extracts 1 were combined and washed with 25 ml of saturated NaCl solution and 1 then dried (MgSO4). The solvent was removed in vacuo and the 2 residue purified by flash chromatography (silica; 30% ethyl acetate in 2 hexanes) to give the title compound as a pale yellow solid. PMR (CDCI3 ): δ 1.37 (6H, s), 2.53 (2H, s), 6.85 (IH, d, J-8.4 Hz), 2 7.32 (IH, dd, J-8.4 Hz, 2.1 Hz), 7.43 (IH, d, J-2.1 Hz), 10.12 (IH, broad • s). 7 • Example 21 * 4_4-Dimethvl-6-broπ,o- 1 .2.3 _4-tctrahvdroquinoline 10 To 23.5 ml of 1.0 M (23.5 mmol) lithium aluminum hydride in 11 THF, heated to reflux under nitrogen, was added a solution of 4.95 g » ( 19.48 mmol) of 4,4-dimethyl-6-bromo-2-oxo- l ,2,3,4- 12 tetrahydroquinoline in 50 ml of dry THF and 100 ml of dry diethyl 1 ether via a double-ended needle. The mixture was heated at reflux f 15 2 hours and then cooled to room temperature. The reaction mixture 14 was then quenched by the slow addition of 25 ml of water followed b 17 50 ml of 5 % NaOH solution. The mixture was extracted with 2x25 ml « ether, the organic extracts were combined and washed successively 12 with 25 ml each of water and saturated NaCl solution and then dried 20 (MgSO4 ). The solvent was removed i n vacuo and the residue purified 21 by flash chromatography (silica; 15% ethyl acetate in hexanes) to giv 22 the title compound as a brown oil. = PMR (CDCl3): δ 1.27 (6H, s), 1.67- 1.74 (2H, m), 3.23-3.32 (2H, m 24 3.90 (IH, broad s), 6.33 (IH, d, J-8.4 Hz), 7.10 (IH, dd, J-8.4 Hz, 2.3 Hz 2 7.25 ( IH, d, J-2.3 Hz). a * Example 2? ■ 4.4-Dimethvl-6-trimethvl sMvlcthvn vl- 1 .2.3 _4-tetrahvriroq u inoline 22 A solution of 1.608 g (6.7 mmol) of 4,4-dimethyl-6-bromo- 20 1 ,2,3 ,4-tetrahydroquinoline in 1.5 ml of triethylamine in a 21 heavy-walled tube was degassed under argon and then treated with 1 75 mg (0.39 mmol) of cuprous iodide and 150 mg (0.21 mmol) of 2 bis(triphenylphosphine) palladium (II) chloride. The mixture was 2 degassed again under argon, treated with 2.09 g (21.2 mmol) of trimethylsilylacetylene and the tube was sealed. The mixture was 1 heated at 50°C for 48 hours. After cooling to room temperature 4 methylene chloride was added to the reaction mixture and the mixture 7 filtered. The filtrate was concentrated in vacuo and the residue 1 purified by flash chromatography (silica; 10% ethyl acetate in hexanes) * to give the title compound as a yellow oil. » PMR (CDCI3 ): δ 0.20 (9H, s), 1.20 (6H, s), 1.57- 1.63 (2H, m), » 3.16-3.25 (2H, m), 4.02 (I H, broad s), 6.24 ( IH, d, J-8.2 Hz), 7.00 ( IH, » dd, J-8.2 Hz, 1.8 Hz), 7.26 (IH, d, J-1.8 Hz), u « * Example 23 u 4.4-Dimeth vl-6-ethvπvl - 1 .2.3.4-tetrahvdroq uinoli ne 14 To a solution of 569 mg (2.21 mmol) of 4,4-dimethyl-6- 17 trimethylsilylethynyl- l ,2,3 ,4-tetrahydroquinoline in 3 ml of " isopropanol was added, under argon, 1 ml of IN aqueous KOH solution. " The reaction mix ture was stirred at room temperature for 36 hours 0 and the isopropanol was removed u nder vacuum. The residue was 21 extracted with ether and the ether extract was washed successively 22 with water and saturated NaCl solution and then dried (MgSO4). The 2 solvent was removed i n vacuo and the residue was purified by flash 24 chromatography (silica; 10% ethyl acetate in hexanes) to give the title » compound as a brown oil. 4 PMR (CDCl3 ): δ 1.26 (6H, s), 1.65- 1.72 (2H, m), 2.96 ( IH, s), 7 3.27-3.34 (2H, m), 6.34 ( IH, d, J-8.3 Hz), 7.08 (IH, dd, J-8.3 Hz, 1.6 Hz), 22 7.33 (IH, d, J-1.6 Hz). EXAMPLE 24 0 6-(2-(4.4-dimethvlchroτnan-6-vncthvnvnnicotinic acid 1 The absolute ethanol used in this experiment was degassed by 1 applying a vacuum while simultaneously bubbling nitrogen through i 2 A solution of 101.1 mg (0.30 mmol) of ethyl 6-(2-4,4-dimethylchroman-6-yl)ethylyl)-nicotinoate in 2 ml ethanol 4 was treated under argon with 0.7 ml of a 1.81 M (1.27 mmol) solutio 2 of potassium hydroxide in ethanol and water. This mixture was stirr 4 at room temperature for 60 hours and then solvent removed in vacu 7 The residue was dissolved in 25 ml of water and extracted with 25 m 2 of ether. The aqueous layer was acidified with glacial acetic acid and 2 extracted with 4x50ml of ether. Ether extracts were combined and 10 washed with water, then saturated NaCl and dried (MgSO4). Solvent " was then removed in vacuo to give the title compound. PMR » ((CD3 )2CO): δ 1.40 (6H. s) 1.88- 1.92 (2H, m), 4.26-4.30 (2H, m), 6.82 » (IH, d, J-8.7 Hz), 7.37 (IH, dd, J-7.6 Hz, 2.2 Hz), 7.62 (IH, M), 7.63 (IH > 4 d, J-8.7 Hz), 8.37 (IH, dd, J-7.6 Hz, 2.2 Hz), 9.27 (IH, d, J-2.2 Hz). a Proceeding in the same manner 6-(2-(4,4-dimethyl- 14 thiochroman-6-yl)ethynyl)nicotinic acid was prepared from ethyl 17 6-(2-(4,4-dimethylthiochroman-6-yl)-ethynyl)nicotinoate. » PMR (CDCI3 CD3 )2 CO): δ 1.37 (6H, M), 1.99 (2H, m), 3.09 (2H, » m), 7.10 ( IH, d, J-8.1 Hz), 7.28 (IH, dd J-8.1 Hz), 2.1 Hz), 7.64 (IH, dd » J-7.8 Hz), 1.8 Hz), 7.65 (IH, d, J-7.8 Hz, 1.5 Hz), 9.24 ( IH, m). a Proceeding in the same manner, the esters prepared as per the 22 preceeding Examples may be converted to their corresponding acid. a 24 Example 25 * 6-(2-(4.4-Dimeth vl-thiochroman-6-v1Vcthvnvn-3 -pvridvlmeth ano 24 To 3.0 ml of 1 M lithium aluminum hydride (3.0 mmol) in THF, 27 cooled to -78°C, was added dropwise over 5 min a solution of 2.0 g (5 21 mmol) of ethyl 6-(2-(4 ,4-dimethylιhiochroman- 22 6-yl)-ethynyl)nicotinate in 5 ml of THF. The reaction mixture was 20 stirred at -78 β C for 40 min and then treated with 2 ml of water. The 1 mixture was warmed to room temperature and the organic layer was 1 separated. The aqueous layer was extracted with 3x 10 ml of ether. 2 The organic extracts were combined and washed successively with 2 1 x 10 ml of dilute HCl, 3x 10 ml of water and 1x15 ml of saturated NaCl 4 solution and then dried (MgSO4). The solvent was removed in vacuo 2 and the residue purified by flash chromatography (silica; 50% ethyl 4 acetate in hexanes) to give the title compound as a pale yellow solid. 7 PMR (CDCI3 ): δ 1.33 (6H, s), 1.91 - 1.98 (2H, m), • 3.01 -3.07 (2H, m), 4.75 (2H, s), 7.08 ( IH, d, J-8.2 Hz), 7.23 (IH, dd, » J-8.2 Hz, 1.7 Hz), 7.46 (IH, d, J-7.9 Hz), 7.60 (IH, d, J-1.2 Hz), 7.71 (IH, » dd, J-7.9 Hz, 1.2 Hz), 8.51 (IH, broad s). u " Example 26 2 2-f4.4-dimethvl -thiochroman- 6-vnethvnvn-5-bromopvridine 14 A mixture of 6.36 g (31.5 mmol) of 4,4-dimethyl-6-ethynyl- u thiochroman, 7.46 g (3 1.5 mmol) of 2,5-dibromopyridine, 122 mg (0.64 14 mmol) of cuprous iodide, 224 mg (0.32 mmol) of 17 bis(triphenylphosphine) palladium (II) chloride and 70 ml of freshly 1 distilled triethylamine was degassed under nitrogen and stirred at » room temperature for 1 hour. The mixture was then treated with 180 20 ml of ether and 40 ml of water and the organic layer was separated. 21 The aqueous layer was extracted with ether, the organic layers were 22 combined and then washed with 2x40 ml of water, 2x40 ml of 22 saturated NaCl solution and then dried (K2 CO3). The solvent was 2 removed in vacuo and the residue purified by flash chromatography 29 (silica; 5% ethyl acetate in hexanes) and recrystallization from ethyl 24 acetate and hexane to give the title compound as a pale brown solid. 2 PMR (CDCl3): δ 1.34 (6H, s), 1.94- 1.98 (2H, m), 3.04-3.08 (2H, m), » 7.08 (IH, d, J-8.4 Hz), 7.23 (IH, dd, J-8.4 Hz, 1.8 Hz), 7.38 (IH, J-8.4 Hz), » 7.60 ( IH, d, J-1.8 Hz), 7.78 (IH, dd, J-8.4, 2.3 Hz), 8.66 ( IH, d, J-2.3 Hz). X » Ex ample 27 > 2-(2-(4.4-dimethvlthiochτomaτ.-6-vn-cthvnvn- 5-Pvridinecarboxaldehvde To a cooled (-78°C) solution of 358 mg (1.0 mmol) of 2-(4,4-dimethylthiochroman-6-yl)ethynyl-5-bromopyridine in 5 ml 2 anhydrous ether was added slowly under nitrogen 1.3 ml of 1.7 M (2.21 mmol) tert-butyl lithium in pentane. The mixture was stirred 7 -78°C for 1 h and th en treated with 95 mg ( 1.3 mmol) of anhydrous 1 dimethylformamide. The mixture was stirred at -78 β C for a further 2 hours, then warmed to 0°C and treated with 5 ml of saturated NH4C 10 solution followed by 5 ml of ether. The organic layer was separated 11 and the aqueous layer was extracted with ether. The organic layers •i were combined, washed successively with water and saturated NaCl a solution and then dried (MgSO4). The solvent was then removed in. • « vacuo and the residue purified by flash chromatography (silica; 15% " ethyl acetate in hexanes) followed by high pressure liquid 14 chromatography (Whatman M-9 Partisil 10/50 column, 15% ethyl 17 acetate in hexanes) to give the title compound as a pale yellow solid. » PMR (CDCl3 ): δ 1.33 (6H, s), 1.93- 1.97 (2H, m), 3.03-3.07 (2H, » 7.08 ( IH, d, J-8.2 Hz), 7.26 (IH, dd, J-8.2 Hz, 1.8 Hz), 7.63-7.65 (2H, 9 8.14 (2H, dd; J-8.0 Hz, 2.3 Hz) 9.05 ( IH, d, J-2.3 Hz), 10.1 ( IH. s). u EXAMPLE 28 2 2- r2- r4.4-Di methvlchroman -6-vnethvnvl1- 5-hvdrox vmethvl- 24 pyridine 29 A 250 ml 3-necked flask is fitted with a stirrer, a dropping 22 funnel, a nitrogen inlet and a thermometer. In the flask is placed a 17 solution of 379.5 mg ( 10 mmol) of lithium aluminum hydride in 30 22 of dry diethyl ether. The solution is cooled to -65°C under nitrogen 22 and a solution of 3.2343 g ( 10 mmol) of ethyl 9 6-[2-(4,4-dimethylchroman-6-yl)ethylyl]nicotinate in 15 ml of dry 1 ether is added dropwise at a rate such that the temperature does no 1 exceed -60°C. The mixture is stirred at -30°C for 1 hour and the excess hydride is then destroyed by the addition of 300 mg (3.4 mmol) of 2 ethyl acetate. The reaction mixture is then hydrolyzed by adding 3 ml of saturated ammonium chloride solution and allowing the 2 temperature to rise to room temperature. The mixture is then filtered and the residue washed with ether. The ether layer is then washed 7 with saturated sodium chloride solution, dried (M S O4) and then I concentrated in vacuo. The residue is purified by chromatography > followed by recrystallization to give the title compound. 10 B y the same process, acids or esters of this invention may be II converted to their corresponding primary alcohol, u u Example 29 14 2- r2-(4.4-Dimcthvlchroman-6- vnethvn vn -5- acetoxvmethvl- u ri di ne 14 A solution of 2.81 g ( 10 mmol) of 2-[2-(4,4-dimethylchroman-6- 17 yl)ethynyl]-5-hydromymethylpyridine, 600 mg ( 10 mmol) of glacial » acetic acid, 2.06 g (10 mmol) of dicyclohexylcarbodiimide and 460 mg " (3.765 mmol) of 4-dimethylaminopyridine in 150 ml methylene chloride is stirred at room temperature for 48 hours. The reaction 21 mixture is then filtered and the residue washed with 50 ml of 21 methylene chloride. The filtrate is then concentrated in vacuo and the 25 residue is purified by chromatography followed by recrystallization to 24 give the title compound. 29 Proceeding in the same manner, other alcohols of this invention 24 may be esterified. a 32 Example 30. » 2- f 2 -(4.4-Dimethvlchroman -6-vnethvnvn- 9 Pvridine-5 -carboxaldehvde 21 A solution of 1.396 g ( 1 1 mmol) of freshly distilled oxalyl 1 chloride in 25 ml of methylene chloride is placed in a 4-necked flask 2 equipped with a stirrer, a thermometer and two pressure- equalizing 2 addition funnels fitted with drying tubes. The solution is cooled to -60°C and then treated dropwise with a solution of 1.875 g (24 mmol) 2 of dimethyl sulfoxide (distilled from calcium hydride) in 5 ml of 4 methylene chloride over a five minute period. The reaction mixture i 7 then stirred at -60°C for an additional 10 minutes. A solution of 2.82 • ( 10 mmol) of 2-[2- (4 ,4-dimethylchroman- 6-yl)ethynyl]-5 -hydromy » ethylpyridine in 10 ml of methylene chloride is then added to the 10 reaction mixture over a period of 5 minutes. The mixture is stirred f 11 a further 15 minutes and is then treated with 5.06 g (50 mmol) of 12 triethylamine. The cooling bath is then removed and the mixture is 12 allowed to warm to room temperature. Thirty ml of water is then 14 added to the mixture and stirring is continued for a further 10 12 minutes. The organic layer is then separated and the aqueous layer i 14 extracted with 20 ml of methylene chloride. The organic layers are 17 then combined and washed successively with dilute HCl, water and 12 dilute Na2θθ3 solution and then dried (MgSO4). The solution is then • » filtered and concentrated in vacuo and the residue is purified by 20 chromatography followed by recrystallization to give the title 21 compound. 22 Primary alcohols of this invention may be oxidized to their 22 corre sponding aldeh yde by this method. a 29 Example 31 9 2- f2-f4.4-Di methylchroman -6-yl'. ethvnvn-5 - » π -hydrpxypTPpyUpyridinc a Four ml of a 3 M ( 12 mmol) solution of ethylmagnesium bromid 22 in ether is placed in a 3-necked flask fitted with a mechanical stirrer, 9 reflux condenser protected by a drying tube and a pressure-equalizin 3i dropping funnel protected by a drying tube. The flask is cooled in an i ice bath and a solution of 2.8 g (10 mmol) of 2 2-(2-(4,4-Dimethylchroman-6-yl) ethynyl)- pryidine-5-carboxaldehyde in 10 ml of dry ether is added slowly with vigorous stirring. The cooling bath is then removed and the mixture 2 heated at reflux for 3 hours. The mixture is then cooled in an ice-salt * bath and 5 ml of saturated ammonium chloride solution added. The 7 mixture is stirred for a further 1 hour and then filtered and the * residue washed with two 10 ml portions of ether. The ether solution is * then separated, dried (MgSO4) and the ether removed in vacuo. The 10 residue is then purified by chromatography followed by 11 recrystallization to give the title compound. » Using the same procedure any of the other aldehydes of this ° invention can be converted to a secondary alcohol. 14 Such secondary alcohols may be converted to their corresponding 19 ketone using the procedure recited in Example 15. >« " Exqmple 32 " 2-f2-(4.4-Dimcthvlchroman-6-vnethvnvn-5- » dimethoxvmethvlpvridine 9 A round-bottomed flask is fitted with a Dean-Stark apparatus 22 under a reflux condenser protected by a drying tube. A mixture of 72 3.35 g ( 12 mmol) of 2-(4,4-dimethylchroman-6-yl)ethynyl)-pyridine- 22 5-carboxaldehyde, 4.80 mg ( 15 mmol) of anhydrous methanol, 2 mg of 24 P-toluenesulfonic acid monohydrate and 10 ml of anhydrous benzene 29 is placed in the flask and the mixture heated at reflux under nitrogen 24 until close to the theoretical amount of water is collected in the 37 Dean-Stark trap. The reaction mixture is cooled to room temperature 22 and extracted successively with 5 ml of 10% sodium hydroxide solution 2 and two 5 ml portions of water and then dried (MgS04). The solution 9 is then filtered and the solvent removed in vacuo. The residue is 1 purified by chromatography and then recrystallization to give the title i compound. 2 In a similar manner, any aldehyde or ketone of this invention 2 may be converted to an acetal or a ketal. 4 2 Example 33 4 Preferably, these compounds may be administered topically 7 using various formulations. Such formulation may be as follows: t 2 In gredien t Wei ght/Percent 10 ii Solution « Retinoid 0.1 u BHT 0.1 » Alcohol USP 58.0 u Polyethylene Glycol 400 NF 41.8 » Gel > « Retinoid 0.1 ■ » BHT 0.1 29 Alcohol USP 97.8 21 Hydroxypropyl Cellulose 2.0

Claims: WHAT IS CLAIMED IS: 1. A process of treating a mammal afflicted with a condition or disease which is susceptible to treatment by a therapeutic agent having retinoid-like activity, the process comprising administering to said mammal an effective dose of a pharmaceutical composition including a pharmaceutically acceptable excipient and a compound having the formula where X is S, 0, or NR where R is hydrogen or lower alkyl; R is hydrogen or lower alkyl; A is pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl or pyrazinyl; n is 0 - 4; and B is H, -COOH or a pharmaceutically acceptable salt thereof, or an ester thereof with a saturated aliphatic alcohol of ten or fewer carbon atoms, or with a cyclic or saturated aliphatic cyclic alcohol of 5 to 10 carbon atoms, or with phenol or with a lower alkylphenol, or an amide or a mono or di-substituted amide thereof, the subtituents on the amide being selected from a group consisting of saturated aliphatic radicals of ten or fewer carbon atoms, cyclic or saturated aliphatic cyclic radicals of 5 to 10 carbon atoms, and phenyl or lower alkylphenyl radicals, or B is CH 2 0H or an ester derivative thereof derived from a saturated aliphatic acid of ten or fewer carbon atoms, or from a cyclic or saturated aliphatic cyclic acid of 5 to 10 carbon atoms, or from benzoic acid, or an ether derivative thereof derived from a saturated aliphatic radical of ten or fewer carbon atoms, or from a cyclic or saturated aliphatic cyclic radical of 5 to 10 carbon atoms, or from phenyl or lower alkylphenyl radical, or B is -CHO or a lower alkyl acetal derivative thereof, or an acetal derivative thereof formed with a lower alkyl diol, or B is -COR.- ^ or a lower alkyl ketal derivative thereof, or a ketal derivative thereof formed with a lower alkyl diol, where R^ is -(CH 2 ) m CH 3 where m is 0-4, or a pharmaceutically acceptable salt of the compound defined in said formula. 2. The process of Claim 1 where in the formula of the compound X is S, R is hydrogen, A is pyridyl, thienyl or furyl, and n is 0 or l. 3. The process of Claim 2 where in the formula of the compound A is pyridyl and B is COOH or a pharmaceutically acceptable salt, lower alkyl ester or mono or di-lower alkyl amide thereof. 4. The process of Claim 3 where the compound is ethyl 6-[2-4,4-dimethylthiochroman-6- yl)ethynyl]nicotinate, 6-[2-4,4-dimethylthiochroman-6- yl)ethynyl]nicotinic acid or a pharmaceutically acceptable salt of said compounds. 5. The process of Claim 2 where in the formula of the compound A is thienyl. 6. The process of Claim 5 where the compound is ethyl 5-[2-(4,4-dimethyl thiochroman-6- yl)ethynyl]thienyl-2-carboxylate or a pharmaceutically acceptable salt thereof. 7. The process of Claim 1 where in the formula of the compound X is S, R is lower alkyl, A is pyridyl, thienyl or furyl, and n is 0 or 1. 8. The process of Claim 7 where the compound is ethyl 6-[2-(4,4,7-trimethylthiochroman-6- y1)ethynyl]nicotinate, 6-[2-(4,4,7-trimethylthiochroman-6-yl)ethynyl]nicotinic acid or a pharmaceutically acceptable salt thereof. 9. The process of Claim 1 where in the formula of the compound X is 0, R is hydrogen, A is pyridyl, thienyl or furyl, and n is 0 or 1. 10. The process of Claim 9 where in the formula of the compound A is pyridyl and B is COOH or a pharmaceutically acceptable salt, lower alkyl ester or mono or di-lower alkyl amide thereof. 11. The process of Claim 10 where the compound is ethyl 6-[2-(4,4-dimethylchroman-6- yl)ethynyl]nicotinate, 6-[2-(4,4-dimethylchroman-6- yl)ethynyl]nicotinic acid, or a pharmaceutically acceptable salt thereof. 12. The process of Claim 1 where in the formula of the compounds X is NR' , R is hydrogen, A is pyridyl, thienyl or furyl, and n is 0 or 1. 13. The process of Claim 12 where in the formula of the compound A is pyridyl and B is COOH or a pharmaceutically acceptable salt, lower alkyl ester or mono or di-lower alkyl amide thereof. 14. The process of Claim 13 where the compound is ethyl 6-[2-(4,4-dimethyl-l,2,3,4-tetrahydroquinolin-6- yl)ethynyl]nicotinate, 6-[2-(4,4-dimethyl-l,2,3,4- tetrahydroquinolin-6-yl)ethynyl]nicotinic acid, or a pharmaceutically acceptable salt thereof. 15. A process of treating a mammal afflicted with a condition or disease selected from actinic keratoses, arsenic keratoses, inflammatory acne, non-inflammatory acne, psoriasis, ichthyoses, keratinization, hyperproliferative disorders of the skin, eczema. atopic dermatitis, Darriers disease, lichen planus, glucocorticoid damage (steroid atrophy) , topical microbial infection, skin pigmentation, aging and photo damage to the skin, premalignant and malignant hyperproliferative diseases, cancers of the breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynxy, oral cavity, blood and lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias, papillo as of the mucous membranes, Kaposi's sarcoma, proliferative vitreoretinopathy (PVR) , retinal detachment, dry eye and other corneopathies, dyslipidemias, post- angioplasty restenosis, diseases associated with Human papilloma virus (HPV) , inflammatory diseases, pulmonary fibrosis, ileitis, colitis, Krohn's disease, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease and stroke, improper pituitary function, modulation of apoptosis, diseases of the immune system, modulation of organ transplant rejection and facilitation of wound healing, and as agent to increase the level of circulating tissue plasminogen activator (TPA) and for restoring hair growth, the process comprising administering to said mammal an effective dose of a pharmaceutical composition including a pharmaceutically acceptable excipient and a compound having the formula where X is S, O, or NR where R is hydrogen or lower alkyl; R is hydrogen or lower alkyl; A is pyridyl, thienyl, furyl, pyridazinyl, pyri idinyl or pyrazinyl; n is 0 - 4; and B is H, -COOH or a pharmaceutically acceptable salt thereof, or an ester thereof with a saturated aliphatic alcohol of ten or fewer carbon atoms, or with a cyclic or saturated aliphatic cyclic alcohol of 5 to 10 carbon atoms, or with phenol or with a lower alkylphenol, or an amide or a mono or di-substituted amide thereof, the subtituents on the amide being selected from a group consisting of saturated aliphatic radicals of ten or fewer carbon atoms, cyclic or saturated aliphatic cyclic radicals of 5 to 10 carbon atoms, and phenyl or lower alkylphenyl radicals, or B is CH 2 OH or an ester derivative thereof derived from a saturated aliphatic acid of ten or fewer carbon atoms, or from a cyclic or saturated aliphatic cyclic acid of 5 to 10 carbon atoms, or from benzoic acid, or an ether derivative thereof derived from a saturated aliphatic radical of ten or fewer carbon atoms, or from a cyclic or saturated aliphatic cyclic radical of 5 to 10 carbon atoms, or from phenyl or lower alkylphenyl radical, or B is -CHO or a lower alkyl acetal derivative thereof, or an acetal derivative thereof formed with a lower alkyl diol, or B is -COR j or a lower alkyl ketal derivative thereof, or a ketal derivative thereof formed with a lower alkyl diol, where R^ ^ s "( CH 2 * , m CH 3 where m is 0-4, or a pharmaceutically acceptable salt of the compound defined in said formula. 16. The process of Claim 15 where in the formula of the compound X is S. 17. The process of Claim 16 where in the formula of the compound A is pyridyl. 18. The process of Claim 15 where in the formula of the compound X is 0. 19. The process of Claim 18 where in the formula of the compound A is pyridyl. 20. The process of Claim 15 where in the formula of the compound X is NR 1 and R" is H. 21. The process of Claim 20 where in the formula of the compound A is pyridyl.

Inventors: CHANDRARATNA ROSHANTHA A, CHANDRARATNA, ROSHANTHA, A.
Applicants: ALLERGAN INC, ALLERGAN, INC.
Application year: 1995
Main classification: A61K31
IPC codes: A61K31