CA1314891C

CA1314891C - Acetylenes disubstituted with a phenyl group and a heterobicyclic group having retinoid like activity

Info

Publication number: CA1314891C
Application number: CA000560190A
Authority: CA
Inventors: Roshantha A. S. Chandraratna
Original assignee: Allergan Inc
Current assignee: Allergan Inc
Priority date: 1987-03-26
Filing date: 1988-03-01
Publication date: 1993-03-23
Anticipated expiration: 2010-03-23
Also published as: GR3003556T3; FI881446A0; AU1373288A; CN1032204C; PH27108A; PT86976B; FI92485B; FI92485C; US4810804A; HUT50153A; IL85795A; NO171636B; PT86976A; MY103250A; EP0290130B1; ES2038752T3; IE62775B1; NO881326L; JPS63264578A; NO171636C

Abstract

ABSTRACT
Retinoid-like activity is exhibited by compounds of the formula where X is S, O or NR1 where R1 is hydrogen or lower alkyl; n is 0-5; R is H or lower alkyl and A is H, -COOH
or a pharmaceutically acceptable salt, ester or amide thereof, -CH2OH or an ether or ester derivative thereof, or -CHO or an acetal derivative thereof, or -COR2 or a ketal derivative thereof where R2 is -(CH2)mCH3 where m is 0-4; or a pharmaceutically acceptable salt.

Description

1 3 ~

~e~yl~n~ ~isu~ituted with 3 ~enxl Group and a ~eterob~yçli~.GrQup ~avin~_Retinoid-Lake Act~yit~

13~.çkgEQ~I~
This invention relates to novel compound having retinoid-like activity. ~ore specifically, the invention relates ~o compounds having a substituted e~hynylphenyl ~unction and a second portion which is a tetrahydroquino-linyl, thiochromanyl, or chromanyl group. It is anticipated that the oYidation products o~ these compounds, particularly the oxides of the thiochromanyl compounds, will have activity similar to that of their parent ccmpound.
8~
Carbo~ylic acid derivatives use~ul for inhibiting the degeneration of cartilaqe of the general formula 4-~2-(9,4-dimethyl-6-X)~2-methylvinyl)benzoic acid where X
is tetrahydroquinolinyl, chromanyl or thiochromanyl are disclosed in European Patent Application 0133795 published January g, 1985. An article in J. Med. Chem., 27, 1516 (1984) by N. I. Dawson, et~ al. discloses compounds similar to the ones claimed herein, the inventor using an acetylenic group in place o~ the methyl-substituted trans double bond shown in Dawson. See also European Patent Application 176034A publishe~ April 2, 1986 where tetrahydronaphthalene compounds having an ethynylbenzoic acid group are disclosed.
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-b5645G 16562 ~3~B~g~ L

Summary of the InventiQn This invention covers compounds of formula I

(cH2)n-A
~ I

where X is S, O or NRl where Rl is hydrogen or lower alkyl; n is 0-5; R is H or lower alkyl and ~ is H, -COOH
or a pharmaceutically acceptable ~alt, ester or ~mide thereof, -CH20H or an ether or ester derivative thereof, or -CHO or an acetal derivative thereof, or -COR2 or a ketal derivative thereof where R2 is -(CH2)mCH3 where m is 0-4; or a pharmaceutically acceptable salt.
In a second aspect, this invention relates to the use of the compounds of formula I for treating dermatoses, such as acne, Darier's disease, psoriasis, icthyosis, eczema, atopic dermatitis and epithelial ca~cers. These compounds are also useful in the treatment of arthritic diseases and other immunoloqical disorders (e.g., lupus erythematosus), in promoting wound healing for treating the dry eye syndrome and in reversing the effects of sun damage on skin.
This invention also relates to a pharmaceutical formulation comprising a compoun~ of formula I in admi~ture 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 ~ompound of formula II with a compound of ~ormula III in the presence of Pd(PQ3)4 (Q
i~ phe~ e a similar comple~
-~

b5645G 16562 .. ,~

~ ,13 (CH2)n-A
II III

where X~ is a halogen, preferably I; R is hydrogen or lower alkyl, n i~ the same as defined above; and A i~ H, or a protected acid, alcohol, aldehyde or ketone giving a compound of ormula I; or deprotecting a protected acid, alcohol, aldehyde or ketone, or homologating a compound of the formula ~ ~CH2)n C~OH

where n is 0-4 to give an acid compound of formula I; or converting an acid o~ ~ormula I to an acid salt; or converting an acid of ~ormula I to an ester; or converting an acid o~ formula I to an a~ide; or reducing an acid of formula I to an alcohol or aldehyde; or converting an alcohol of formula I to an ether or ester; or o~idizing an alcohol of ~ormula I to an al~ehyde or ketone; or converting an aldehyde of ~ormula I to an acetal; or converting a ketone o~ formula I to a ~etal.

~ ,eneEal Em~odimen~
Definitions The term ~ester" as used here refers to and covers any b5645G 16562 3 ~ ~ L

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 -CH20H, this term covers compounas o~ the formula -CH200CR where R is any substituted or un~ubstituted aliphatic, aromatic or aliphatic-aromatic group.
Preferred esters are derived ~rom the ~aturated aliphatic alcohols or acids of ten or ~ewer carbon atoms or the cyclic or ~aturated aliphatic cyclic alcohol~ and acids of 5 to 10 carbon atoms. Particularly preferred aliphatic ester~ are those derived from lower alkyl acids and alcohols. Here, and wherever else used, lower alkyl means having 1-6 carbon atoms. Also preferred are the phenyl or lower alkylphenyl esters.
Amides has the meaning classically accorded that term in organic chemistry. In this instance it încludes the unsubstituted amides and all aliphatic and aromatic mono-and di-substituted amides. Preferred amides are the mono-and di-substituted amides derived from lower alkyl substituted amines or the lower alkyl aliphatic cyclic or aromatic (phenyl for e~ample) substituted amines.
Particularly preferred amides are those derived from mono-or di-lower alkyl ~ubstuted amines. ~lso preferred are mono- and di-substituted amides derived from the phenyl or lower alkylphenyl amines. Unsubstituted amides are also preferred.
Acetals and ketals include the radicals of -CK where R
is (-OR)z. Here, R i~ lower alkyl. Also, K may be -OR10- wher0 Rl is alkylene of 2-5 carbon atoms, straight chain or branched.
A pharmaceutically acceptable salt may be prepared for any compound in this disclosure having a $unctionality capable of forming such salt, for example an acid or an b5645G 16562 8 ~ ~.

amine functionality. ~ pharmaceutically acceptable ~alt 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 conte~t in which it is administered.
A pharmaceutically acceptable ~alt of an acid may be derived from an organic or inorganic base. Such salt may be a mono- or polyvalent ion. O~ particular interest are the inorganic ions, ~odium, potassium, calcium, and magnesium. Organic ~alts may be made with amines, particularly ammonium salts such as mono-O di- and trialkyl amines or ethanol amines. Salts may al~o be formed with cafeine, tromethamine and similar molecules.
Where acid addition salts are formed from amines, any inorganic or organic acid may be used. Preferred salts are hydrogen chloride salts, sulfate salts, phosphate æalts and ~alts of simple organic acids of 2 to 6 carbons, either the mono- or diacids. Quarternary ammonium compounds can be prepared ~rom alkylatin~ agents such as methyl iodide and the like.
The preferred compounds of this invention are those where the radical designated ~CH2)n-~ is para to the ethynyl group on the phenyl ring; n is 0, 1 or 2; and A is -COOH or an alkali metal salt or organic amine salt thereof or a lower alkyl ester, or -CH20H and the lower alkyl esters and ethers thereof. The more pseferred compounds are:
4-[4,4-dimethylthiochroman-S-ylethynyl]-benzoic acid;
ethyl ~ ~4,4-dimethylthiochroman-6-ylethynyl]-benzoate;
ethyl 4-~4,4-dimethylchroman-6-ylethynyl]-benzoate; and 4-~4,4-dimethylchroman-6-ylethynyl)]benzoic acid.
The compound~ of this invention may be administered b5695G 15562 8 ~ ~

systemically or topically, depending on such considerations as the condition to be treated, need for site-specific treatment, ~uantity of drug to be administered, and numerous other considerations.
In the treatment of dermatoses, it will generally be preferred to administer the ~rug topically, though in certain cases ~uch as treatment of severe cystic acne, oral administration m~y also be used. Any common topical formulation such as a solution, ~uspension, 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 e~ample, ~ , Edition 17, Mack Publishing Company, Easton, Pennsylvania. For topical application, these compounds rould also be administered as a powder or spray, particularly in aerosol form.
If the drug is to be administered systemically, it may be confected a~ a powder, pill, tablet or the like, or as a syrup or elisir 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 ormulate these compounds in ~uppository 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 ~econdary purposes as treatin~ skin dryness, providing protection again t liyht; other medications for treating dermatoses, preventing infection, redu~ing irritation, inflammation and the like.
Treatment of dermatoses or any other indications known or discovered to be susceptible to treatmen~ by retinoic aci~-like compounds will be efected by admini~tration of the therapeutically effective dose of one or more compounds of the instant invention. A therapeutic b5645G 16562 .. . .. .. .
-.,. ., ~

~ ~ 3~ J ~

concentration will be that concentration which effects reduction of the particular condition, or retards its expansion. In certain instances, the drug potentially could be used in a prophylactic manner to prevent onset of a particular condition. A given therapeutic co~centration 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, a given therapeutic concentration will be best determined at t~e time and place through routine ~perimentation. However, it is anticipated that in the treatment of, for e~ample, acne, or other ~uch dermatoses, that a formulation containing between 0.001 and 5 percent by weight, preferably about 0.01 to 1%, will usually constitute a therapeutically effective concentration. If a~miniætered ~ystemically, an amount between 0.01 and 100 mg per kg body weight per day, but preferably about 0.1 to 10 mq/kg, will ef~ect a therapeutic result in most instances.
The retinoic acid like activity of these compounds was confirmed through the classic measure of retinoic acid activity involving the effect~ of that compound on ornithine decarboxylase. The original work on the correlation between retinoic acid and decrease in cell proliferation was done by Verma & Boutwell, Ca~çer Research, 1~ 1, 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 in~rease are unknown, it is known that 12-0-tetradecanoylphorbol-13-acetate (TP~ induces ODC activity. Retinoic acid inhibits this induction of bS645G 16562 ODC activity by TPA. The compounds of this invention also inhibit TPA induction o~ ODC as demonstra~ed by an assay essentially followinq the procedure set out in can~Q~
Res.: 1662-1670, 1975.

~ E~ m~
The compounds o~ this invention can be made by a number of different ~ynthetic chemical pathways. To illustrate this invention, there i~ here outlined a series of steps used to make the compounds of formula I when such synthesis is followed in tone and in æpirit. The synthetic chemist wiil 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 X is sulfur are prepared '' ~e- ti~ ~

b5645G 16562 ` 13~8~

Rsaction Scheme I

HS ~ R 2 ~S ~ R

~ R

ZnCI X-Q-(~H2)n-A
~s~ ~ Fonnula I
7 ~

Homologues& Donva~ves Here, n is 0-5, R is hydrogen or lower alkyl, A is H, or a protected acid, alcohol, aldehyde or ketone and Q is phenyl. X' may be Br, Cl or I, but Br and I are prefersd when n is O and is I when n is 1-5.
Generalized reaction conditions applicable to the synthesis described in Reaction Scheme I ~re described below. The thiophenol of formula 1 is first treated with an appro~imately e~uimolar amount of a strong base such as an alkali metal hydro~ide, preferably sodium hydro~ide, in a polar solvent such as acetone at reflu~ for between 1 and 4 hours, preferably 2.5 hours, after which ~he solution is treated with an equimolar ~mount of formula 2, l-hromo-3-methyl-~-butene (Aldrich), and dissolved in the b5645G 16562 3~

~olvent. Then, reflu~inq is continued for about 2 days after which the ~olution is stirred for another 24 hours at about room temperature effecting ~ormation of formula 3. Product is isolated by conventional means.
Ring closure is e~ected tcompouna 4) by treating the sulide~ whose formation is described above, wi~h phosphorous pentoxide in the presence of phosphoric acid under an inert atmosphere. The sulfide is first dissolved in an inert solvent such as benzene, toluene, or the like, and then treated with a small e2cess of phosphor~us pentoside alonQ with concentrated phosphoric acid. The ~olution is heated at reflu~ with stirring under an inert gas such as argon or nitrogen for up to 24 hours. The product is then recuvered and purified by conventional means.
~ he ketone of formula 5 is obtained by treating the thiochroman compound with acetyl chloride in the presence of aluminum chloride. ~ suspension of the aluminum chloride in a polar inert ~olvent is prepared under an inert atmosphere and at reduced temperature, i.e., -10 to 10C. The inert atmosphere may be argon or nitrogen, preferably argon. The reaction is conveniently carried out in a solvent such as methylene chlorida. To the aluminum chloride cuspension is added the thiochroman and acetyl chloride via a dropping funnel or similar device.
About a 5~ molar e~cess of acetyl chloride and 10% molar excess of aluminum chloride, relative to the thiochroman material, is used. The reaction iB effected with agitation (stirring) over 0.5-4 hours at a temperature between 10-50C. Preferably the reaction is e~ected in about 2 hours at room temperature. Then the reaction is quenched with water and~or ice, the product e~tracted and further puri~ied by distillation or some other appropriate means.

b5 64 5G 1 b 5 6 2 3 ~

The acetylenic function on formula S is introdu~ed by means of lithium diisopropylamide, 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 e~ample, tetrahydrofuran, pyran or the like.
~ ore specifically, lithium diisopropylamide is generated in i~u by mi~ing diisopropylamine in a dry solvent such as tetrahydrofuran, which is then cooled, to bstween -70 and -50C under an inert atmosphere. An equimolar amount of an al~ylithium compound such as n-butyl lithium in an appropriate solvent is then added at the reduced temperature and mixed for an appropriate time to permit formation o~ lithium diisopropylamide tLDA).
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 mi~ture, and added to that solution.
After brief mixing, the solution is then treated with a dialkyl chlorophosphate, preferably diethyl chlorophosphate in about a 20% molar excess. The reaction solution is then gradually brought to room temperature.
This solution is then added to a second lithium diisopropylamide solution which is prepared i~ si~ using dry solvant and under an inert atmosphere, preferrably argon, at reduced temperature ~eg. -78C). Then the reaction mi~ture is again warmed to room temperature where it is stirred ~or an e~tended period of ~ime, preferably between 10 and 20 hours, most preferably about 15 hours.
The solution is then acidified and the product recovered by conventional means.
Formula 7 compounds, the zinc ~hloride salts, are prepared under conditions which e~clude water and osygen.
A dry, ether-type ~olvent æuch as dialkyl ether or a cyclic ether such as a furan or p~ran, particularly a tetrahydrofuran, may be used as the solvent. A solution b5645G 16562 5~

of formula 6 is first prepared under an inert atmosphere such as argon or nitrogen, and then a strong base such as n-butyl lithium is added ~in about a 10% molar excess).
This reaction is begun at a reduced temperature of between -10 and +10C, preferably about 0C. The reaction mixture is stirred for a hort period, between 30 minutes and 2 hours~ and then treat~d with about a 10% molar escess of fused zinc chloride dissolved in the reaction solvent. Thi~ mi~ture is stirrea for an additional 1-3 hours at about the tarting ~emperature, then the temperature is increased to about ambient temperature for 10-40 minutes.
Compounds of Formula I are prepared by coupling the ZnCl salts of formula 7 with the halogen substituted phenyl-based fragment o~ formula 8 where A is hydrogen or a protected acid, alcohol, aldehyde or ketone or hydrogen. These latter compounds, the protected acid, etc., are all available from chemical manu~acturers or can be prepared by published methods. If the starting material is an acid, it is esterified by refluxing the acid in a solution of the appropriate alcohol in the presence of thionyl chloride. Reflu~ing ~or 2-5 hours provides the desired ester. The ester is recovered and puri~ied by conventional means. Alcohols, aldehydes and ketones all may be protected by forming respectively, ethers ~nd esters, acetals or ketal by known methods such as those described in McOmie, Plenum Publishing Press, 1973 and Protec~in~ Gro~, Ed. Greene, John Wiley ~ ~ons, 19~1 .
To increase the value of n, where such compounds are not available rom a commercial ~ource, the haloge~
substituted benzoic acid or phenylalkyl acid homlogues are subjected to homologation by successive treatment under Arndt-Eistert conditions. These acids are then esterified by the general procedure ~utlined in the preceeding b5645G 16562 paragraphO AIso, from such acids can be prepared the corresponding alcohol or aldehyde, which, after esterification or the formation of an acetal, or similar protecting reaction, is used in the coupling reaction following.
To make formula I, (via a coupling reaction) formula 8 is first dissolved in a dry reaction solvent. ~he formula 8 compound is used in an amount appro~imating the molar concentration of formula 7. 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 temperature of between about -10~ and l10C. This mi~ture is stirred briefly, for about 15 minutes. To this just prepared mi~ture is then 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 temperature. The reaction is then quenched with acid and the product separated and purified by conventional means to give the compounds of formula I.
An alternative means for making compounds where n is 1 - 5 is to 6ubject the com~ounds of formula I where n=0 and ~ is an acid function to homologation using the Arndt-Eistert method referred to above.
Compounds of formula I where X is o~ygen are prepared as per Reaction Scheme II.

b5645G 16562 \

14 ~ 3 ~

Reaction Scheme II

tQO)2POC~ ~ J~ OH (Q)2-~- ~~

OH

R

~R

~ZnCI X~-Q-(cH2)n-A
~ g _,, Formula I
~
Homologues & Derivalives Here, a8 in Reaction Scheme I, n i~ 0--~, % i~ hydrogen or lower alkyl, A i~ H, or a protected acid, alcohol, aldehyde or ketone and X' may be Bx~ Cl or ~. But ~r and I are pre~rred when n i~ 0 and I is proferred when n is 1- 5 , b5645G 16562 ~ 3 ~

These compounds are prepared as follows. The phosphate of formula 11 i prepared from the corresponding diphenyl chlorophosphate and 3-methyl-3-butene-1-ol available from Aldrich or prepared by means known in the art. It is preferred to prepare fo mula 11 by dissolving the alcohol of ormu~a 10 in about a 10% e~cess of pyridine or the like under an inert atmosphere cooled to appro~imately -10 to 10C. This solution is then added drop-wise, under an iner~ atmosphere, ~o a ~olution of diphenyl chlorophosphate in about an egual amount of t~e reaction solvent. About a 2-5~ molar e~cess of diphenyl chlorophosphate relative to the alcohol is employed. The atmosphere may be argon, nitrogen, or another inert gas.
The mi~ture is heated at reflu~ for between 1 and S hours, preferably about 3, to efEect the reaction. The product is then xecovered by conventional means.
The diphenyl phosphate ester from the prece~ding paragraph (formula 11) is then reacted with a phenol to effect ~or~ation of compound 12. For esample, phenol is added to a flask already containing stannic chloride under argon which has been cooled to between -10 to 10C. After thorough mi~ing of this combination for about 15 minutes to an hour at the reduced temperature, the phosphate is added at the reduced temperature. Both of these steps are carried out under an inert atmosphere such as argon or nitrogen. When the addition of the phosphate is completed, the mixture is stirred at about ambient temperature for up to 24 hours. Then the reaction is quenched with a dilute solution of aqueous alkali metal base or the like. The product is recovered by e~traction and other conventional means, Thereafter, compounds of ormula 12 are treated se~uentially in the ~ame manner as de~cribed ~or making the ketone, acetylenic compound and its ZnCl salts, the coupling reaction and then formation of ~ormula I

b5645G 16562 compounds by the ~ubsequent steps in ~eaction Scheme I.
Where ~ is nitrogen, such compounds may be prepared by he ~ollowing reaction scheme:
Reaction Scheme III

Cl ~ ~ - ~

CO(~13 21 H 20 ZnCl ~ -Q-(cH2)n-A
Hom~l~gues& Derivatives~- Fonnula I

Here, as above, n is 0-5, A is H, or a prote~ted acid, alcohol, aldehyde or ketone. R2 may be hydrogen or a protecting group such as -COCH3. X' may be Br, Cl or I. ~u~ Br and I are prefered when n is O and I ;s preferred when n is 1-50 b5645G 16562 ~31~

The tetrahydroquinoline moiety, that is where X is nitrogen, is made in part by the method described in European Patent Application 0130795 published September 1, 1985. First, 3-methylcrotonoyl chloride is reacted with aniline to obtain the amide (formula 18)o ~his amide is then cyclized using aluminum chloride in the absence of solvent to give formula 19. Lithium aluminum hydride or another acceptable reducing agent of ~imilar typ~ is then used to reduce the 2-oxo-1,2,3,~-tetrahydroquinoline, preferably in an inert solvent such a diethyl ether. This amine is then acetylated using acetyl chloride in a polar solvent such as pyridine followed by acetylation in the presence of aluminum chloride to give the compound of formula 21. The compound of formula 21 is then subjected to base hydrolysis to give the secondary amine of formula 22. The compound of ~ormula 22 is treated as described in Reaction Scheme I for the preparation of compounds 6 and 7 to make compounds of formula 23 and 24, respectively.
Compound of formula 25 is coupled as described before to give compounds of formula I.
~ he acids and salts derived from formula I are readily obtainable from the corresponding esters. Basic saponi~ication with an alkali metal base will provide the acid. For example, an ester of ~ormula I may be dissolved in a polar solvent such as an alkanol, preferably under an inert atmosphere at room temperature, with about a three molar e~cess o~ base, Eor example, potassium hydroxide.
The solution is stirred for an extended period of time, between 15 and 20 hours, cooled, acidified and the hydrolysate recovered by conventional means.
The amide may be formed by any appropriate amidation means known in the art. One way to prepare such compounds is to convert an acid to an acid ~hlor;de and then treat that compound with ammonium hydro~ide or an appropriate amine. For example, the acid is treated with an alcoholic b5645G 16552 18 ~3~

base solution such as ethanolic XOH ~in appro~imately a 10% molar excess) at room temperature for about 30 minutes. The solvent is removed and the residue taken up in an organie solvent such as diethyl ether, treated with a dialkyl formamide and then a 10-fold excess of o~alyl chloride. This is all effected at a moderately reduced temperature between about -10 and +10-C. The last mentioned solution is then stirred at the reduced temperature for 1-4 hour6, preferably 2 hours. Solvent removal provides a residue which is taken up in an inert inorganic solvent such as benzene, cooled to about 0C and treated with concentrated ammonium hydro~ide. The resulting mi~ture is stirred at a reduced temperature for 1-4 hours. The product is recovered by conventional means.
Alcohols are made ~y eonverting the corresponding acids to the acid chloride with thionyl chloride (J.
March, ~Advanced Organic Chemistry", 2nd Edition, McGraw-Hill Book Company), and then reducing the acid chloride with sodium borohydride (March, Ibid, pg. 1124) which gives the corresponding alcohols; or by reducing the corresponding ester with lithium aluminium hydride at low temperatures. Alkylating these alcohols with appropriate alkyl halides under Williamson reaction conditions ~March, Ibid, pg. 357) ~ives the corresponding ethers. Esters of these alcohols can be prepared by reacting the alcohols with carbo~ylic acids in the presence of acid catalysts or dicyclohe~ylcarbodiimide and dimethylaminopyridine.
Aldehydes can be prepared from the corresponding primary alcohols using mild oxidizing agents such as pyridinium dichromate in methylene chloride (Corey, E.J., Schmidt, G., ~et. Lett., 399, 1~) or dimethyl sulfoside and osalyl chloride in methylene chloride (Omura, K. Swen, D. Tetrahedron, L~7~, 34, 1651~o Acetals and ketals can be prepared from the corresponding aldehyde or ketone by the method described b5645G 16562 in March, Ibid, p 810.
The following e~amples are set out to illustrate this invention, not to limit it.

E~
Ph.e~Yl-3-met~hy~u~-~-~nylsu~ e A misture of 14.91~ ~135.324 mmol) o~ thiophenol and 5.5~ ~137.5 mmol~ o NaOH in 100 ml acetone was heated at reflu~ for 2.5 hours and then treated dr~pwise ~ith a ~olution ~f 20~ (134~19 mmol3 of 1-bromo-3-methyl-2-butene in 20ml acetone. This ~olution ~as refluxed for 40 hours and then stirred at room temperature for 24 hours.
Solvent w~s then removed n va~W and the residue was taken up in water and e~tracted with 3~50ml ether. Ether e~tracts were c~mbined and washed with 3~30ml of 5% NaOH
solution, then water, saturated NaCl solution and dried (MgS04). Solvent was then removed in vacuQ and the residue further purified by Kugelrohr distillation (80C, 0.75mm) to give the title compound as a pale yellow oil.
PMR (CDC13) :~ 1.57 (3H, s), 1.69 (3H, 8), 3.52 (2H, d, J~7.7~z), 5.29 (lH, t, J-7.7Hz), 7.14 (lH, t, J~7.0 Hz), 7~29 ~2H, t, J~7.0 Hz), 7.32 (2H, d, J~7.0Hz).
Proceeding in a similar manner, but sub tituting for thiophenol the appropriate 3-alkylthiophenol, the following compounds can be prepared:
3-methylphenyl-3-methylbut-2-enylsulfide;
3-ethylphenyl-3-methylbut-2-enylsulfide;
3-propylphenyl-3-methylbut-2-enYlSUlfide t 3-butylphenyl-3-methylbut-2-enylsulfide;
3-pentylphenyl-3-methylbut-2-enylsulfide; and 3-hesylphenyl-3-methylbut-2-enylslllfide.
\
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b5645G 1 ~

~ 3 ~

EXA~pLE 2 4,4-PimethylthiQ~hrom~n To a solution of 15.48g (B6.824 mmol) of phenyl-3-methylbut-2-enyl~ulfide (from Example 1) in 160ml benzene were added successively 12.6g (88.767mmol) of phosphorus pento~ide and 11 ml of 85~ phosphoric acid.
This solution was reflu~ed with vigorous ~tirring under argon for 20 hour~, then ~ooled to room temperature. The supernatant organic layer wa~ decanted and the syrupy residue e~tracted with 3~50ml ether. Organic fractions were combined and washed with water, saturated NaHCO3 and saturated NaCl solutions and then ~ried t~gSO4).
Solvent was removed in VaÇ~Q and the residue purif ied by kugelrohr distillation (80C, O.Smm) to give the title compound as a pale yellow oil. PMR (CDC13) :~ 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 (lH, m), 7.30-7.33 ~lH, m).
This method can be used to make 6-position alkyl analogues as e~emplified by the following compounds:
4,4,7-trimethylthiochroman;
4,4-dimethyl-7-ethylthiochroman;
4,4-dimethyl-7-propylthiochroman;
4,4-dimethyl-7-butylthiochroman; and 4,4-dimethyl-7-he~ylthiochroman.

4.~-DimethyL-6-acetylthiochroman A solution of 14.3g (80.21 mmol) of 4,4-dimethyl-thiochroman (from E~ample 2) and 6.76~ (86.12 mmol) of acetyl chloride in 65ml benzene was cooled in an ice bath and treate~ dropwise with 26.712g (102.54 mmol) of stannic chloride. The mixture was stirred at room temperature for 12 hours, then treated with 65ml water and 33ml conc.
hydrogen chloride and heated at reflu~ ~or 0.5 hours.
After being cooled to room temperature, the organic layer b5645G 16562 21 ~3~

was separated and the aqueous layer e~tracted with 5~50ml benzene. The recovered organic fractions were combined and washed with 5% sodium carbonate, water, saturated NaCl and then dried (MgSO4). The solvent was removed n va~Q and the residue purified by flash chromatography (silica; 5~ ethyl acetate in he~anes) followed by kugelrohr distillation (150C, 0.7mm) to give the title compound as a pale yellow oil PMR (CDC13): ~ 1.35 (6H, s), 1.92-1.98 (2~, m) 2.54 (3H~ s), 3.02-3.08 ~2H, m~, 7.13 (lH, d, J-8.6 ~z), 7.58 (lH, dd, J~8.6 Hz, 2Hz), 7.99 (lH, d, J~2Hz).
ThiS procedure serves to acetylate all the compounds which can be made by the process in Example 2.

~AMPLE 4 4 4-Dimethyl-6-ethynylthiQchrQ~an To a solution of 1.441g (14.2405 mmol) of diisopropylamine in 30ml ~ry tetrahydrofuran under argon at -78C was added dropwise 9ml of 1.6M (14.4 mmol) n-butyl lithium in hexane. After stirring this solution at -78C ~or 1 hour, it was treated dropwise with a solution of 2.95y (13.389 mmol) of 4,4-dimethyl-6-acetyl-thiochroman (from Example 3) in 5ml of dry tetrahydrofuran. After another hour of stirring at -78C, the solution was treated with 2.507g (14.53mmol~ of diethyl chlorophosphate and brought to room temperature, where it was stirred for 3.75 hours. This solution was then transferred using a double ended needle to a solution of lithium diisopropylamide [prepared using 2.882g (28.481mmol~ of diisopropylamine and 18ml of 1.6M (28.8 mmol) n-butyllithium in hexane] in 60ml dry tetrahydrofuran at -78C. The cooling bath was removed and the solution stirred at room temperature for 15 hours, then quenched with water and acidified to pH 1 with 3N
hydrogen chloride. The mi~ture was e~tracted with 5 50ml b5645G 16562 ` 22 ~3~$~i pentane and the combined organic fractions washed with 3N
hydrogen chloride, water, saturated NaHCO3 and saturated NaCl, then dried (MgSQ4). Solvent was then removed in vacuo and the residue purified by kugelrohr distillation (lOO~C, 0.7mm) to give the title compound as a pale yellow solid. PMR SCDC13): ~ 1.34 (6H,S), 1.94-1.99 (2H, m), 3.04-3.08 (3H, m), 7.06 ~lH, d, J-8.4 Hz), 7.17 ~lH, dd, J-8.4 Hz, 2.1 Hz), 7.51 ~lH, d, J-2.1Hz).
Similarly, the acetyl group of all compounds prepared as per E~ample 3 can be converted to an ethynyl function.

EX~MPLE 5 Ethyl 4-iodo~nzoat~
To a suspension of lOg ~40.32 mmol) of 4-iodobenzoic acid in 100 ml absolute ethanol was added 2ml thionyl chloride and the mi~ture was then heated at reflux for 3 hours. Solvent was removed in vac~ and the residue was dissolved in lOOml ether. The ether solution ~as washed with saturated NaHCO3 and saturated NaCl solutions and dried (MgS04). Solvent was then removed an v~ç~Q and the residue kugelrohr distilled (100C; 0.55 mm) to give the title compound as a colorless oil. PMR (CDC13):
1.42 (3H, t, ~7Hz), 4.4 (2H, q, J~7Hz), 7.8 (4H).
In the same manner, but substituting for 4-iodobenzoic acid tbe appropriate acid, the ollowin~ compounds can be prepared:
ethyl 4-iodophenylacetate;
ethyl 3-(4-iodophenyl)propionate;
ethyl 4-(4-iodophenyl)butanoate; and ethyl 5-(4-iodophenyl)pentanoate.

EX~MPLE 6 Ethyl 4-~4,4-dimçthyl~hioçhroman-6-yl-e~hynyl~k~n~o~e Reaction vessels used in this procedure were flame b5645G 16562 ~ 3 ~

dried under vacuum and all operations carried out in an osygen-free, argon or nitrogen atmosphere. To a solution of 533.9 mg (2.6389 mmol) of 4,4-dimethyl-6-ethynyl-thiochroman (from Example 4) in 4ml of dry tetrahydrofuran at 0C was added dropwise 1.7ml of 1.6M (2.72 mmol) n-butyl lithium in hexane. Thi~ was stirred at 0C for 10 minutes and at room temperature for 15 minutes, cooled again to O~C and then treated with a olution of 410mg (3.005 mmol) of fused 2nC12 in ~ml dry tetrahydrofuran using a double ended needle. Thereafter, the ~olution was stirred at 0C for 45 minutes, then at room temperature for 20 minutes. A solution of 724.4mg (2.6243 mmol) of ethyl 4-iodobenzoate (from Esample 5) in 9ml dry tetrahydrofuran was transferred by double ended needle into a suspension of 520mg (O.~S mmol) of tetra~istriphenylphosphine palladium in 5ml dry tetrahydrofuran and stirred at room temperature for 20 minutes, then treated by double ended needle with the solution of the alkynyl zinc chloride prepared above.
This mixture was stirred at xoom temperature for 18 hours, then quenched with ice and 30 ml 3N hydrogen chloride.
Product was recovered by e~traction with 3~75ml ether.
Ether fractions were combined and washed successively with saturated NaHCO3 and saturate~ NaCl solutions and dried ~MgSO~). Solvent was removed in vacuo and the residue purified by ~lash chromatography (silica; 5% ethyl acetate in hexane) followed hy HPLC tWhatman Partisil M-~ 10/50;
4% ethyl acetate in he~ane) to give the title compound as a colorless oil. PMR (CDC13~ :~ 1.36 ~6H), 1.42 t3H, t, J~7Hz), 1.93-1.99 (2H, m), 3.03-3.08 (2H, m), 4.40 ~2H, q, J~7H~, 7.09 (lH, d, J~8.4Hz), 7.22 (lH, dd, J~8.4 Hz, 2.1 Hz), 7.56 (lH, d, J-2.1Hz), 7.59 (2H, d, J-7.8Hz), 8.04 ~2H, d, J~7.8Hz).
Using the same procedure, but substituting the appropriate ethynylthiochroman from Example 4 and the b5645G 16562 appropriate halo-substituted phenyl ester from E~ample 5, the following compounds may be prepared:
ethyl 4-~4,4,7-trimethylthiochroman-6-ylethynyl~-benzoate;
ethyl 3-~4,4,7-trimethylthiochroman-6-ylethynyl~-benzoate;
ethyl 2-[4,4,7-trimethylthiochroman-6-ylethynyl]-benzoate;
ethyl 3-~4,4-dimethylthiochroman-6-ylethynyl]-benzoate;
ethyl 2-[4,4-dimethylthiochroman-6-ylethynyl~-benzoate;
ethyl 4-[4,4-dimethyl-7-ethylthiochroman-6-yl-ethynyl]benzoate;
ethyl 4-[4,4-dimethyl-7-propylthiochrom3n-6-yl-ethynyl]benzoate;
ethyl 4-[4,4-dimethyl-7-he~ylthiochroman-6-yl-ethynyl~benzoate;
ethyl 2-[4-~4,4,7-trimethylthiochroman-6-ylethynyl)-phenyl]acetate;
ethyl 2-14-(4,4-dimethyl-7-ethylthiochroman-6-yl-ethynyl)phenyl]acetate;
ethyl 2-[4-~4,4-dimethyl-7-propylthiochroman-6-yl-ethynyl)phenyl~acetate;
ethyl 2-[4-(4,4-dimethyl-7-butylthiochroman-6-yl-ethynyl)phenyl]acetate;
ethyl 2-[4-(4,4-dimethyl-7-pentylthiochroman-6-yl-ethynyl)phenyl]acetate;
ethyl 2-14-(4,4-dimethyl-7-he~ylthiochroman-6-yl-ethynyl)phenyl]acetate;
ethyl 2-[3-(4,4-dimethylthiochroman-6-ylethynyl)-phenyl]acetate;
ethyl 2-[2-~4,4-dimethylthiochroman-6-ylethynyl)-phenyl]aceta~e;
ethyl 3-[4-(4,4-dimethylthiochroman-6-ylethynyl)-b5645G 16562 ~ 3 ~

phenyl~propanoate;
ethyl 3-~3-(4,~-dimethylthiochroman-6-ylethynyl)-phenyl]propanoate;
ethyl 3-~2-(4,4-dimethylthiochrom~n-6-ylethynyl)-phenyl3propano~te;
~ thyl 4-~4-(4,4-dimethylthiochroman-6-ylethynyl)-phenyl]butanoate;
ethyl 4-~3-(4,4-dimethylthiochrom~n-6-~lethynyl)-phenyljbutanoate;
ethyl 4-[2 (4,4~dimethylthiochroman-6-ylethynyl)-phenyl]butanoate;
ethyl 5-r4-(4,4-dimethylthiochroman-6-ylethynyl~-phenyl]pentanoate;
ethyl 5-[3-(4,4-dimethylthiochroman-6-ylethynyl~-phenyl]pentanoate;
ethyl 5-~2-(4,4-dimethylthiochroman-6-ylethynyl)-phenyl]pentanoate;
ethyl 2-[4-(4,4,7-trimethylthiochroman-6-ylethynyl)-phenyl~pentanoate;
ethyl 2-~4-(4,~-dimethyl-7-ethylthiochroman-6-yl-ethynyl)phenyl]pentanoate;
ethyl 2~t4~(4,4-dimethyl-7-propylthiochroman-6-yl-ethynyl)phenyl]pentanoate;
ethyl 2-~4-(4,4-dimethyl-7-butylthiochroman-6-yl-ethynyl)phenyl~pentanoate;
ethyl 2-~4-(4,4-dimethyl-~-pentylthiochroman-6-yl-ethynyl)phenyl]pentanoate; and ethyl 2-[4-(4,4-dimethyl-7-hexylthiochroman-6-yl-ethynyl)phenyl~pentanoate.

~AM~E 7 PiphQnyl-;~ t; hYl-3-k~uten-1-Yl phoFr phat~
To an ice-cooled ~olution of 12.2g (141.65 mmol) of 3-methyl-3-buten-1-ol (Aldrich3 and ll.9g (150.~4 mmol) of pyridine in lOOml of tetrahydrofuran was added dropwise b5645G 16562 26 ~3~

under argon a solution of 3~.5g (143.21 mmol) of diphenyl chlorophosphate in lOOml of tetrahydrofuran. The mi~ture was heated at reflu~ for 3 hours and then cooled and filtered. The filtrate was concentrated n vaGuo an~ the residue dissolved in ~OOml of 1:1 ether and hexane and then washed with 2~200ml water, 75ml saturated ~aCl solution and dried (MgS04). The solvent was removed vacuo to give the title compound as a pale yellow oil.
PMR (CDC13~: 61.69 ~3H, s), 2.37 (2H, t, J~7~z), 4.32 (2H, g, J~7Hz), 4.72 ~lH, s), 4.80 (lH), 7.10-7.35 (lOH, m).

EX~MPLEQ
~.4-Dimethylchroman To a dry, ice-cooled flask containing 34.95g (0.134 mol) of stannic chlori~e was added quickly under arqon 63.09 (0.669 mol) of phenol. The mixture was stirred at 0C for 0.5 hour and then treated with 43.0g (0.135 mol) of diphenyl-3-methyl-3-buten-1-yl phosphate (from E~ample 7), followed by a 5ml carbon disulfide rinse. The mixture was stirred at room temperature ~or 21 hours and then quenched by pouring onto 700g ice and 1 lître of 1.5N
NaOH. The mixture was extracted with lx600ml and 2~300 ml ether. The combined ether fractions were washed with 2N
NaOH, saturated NaCl and dried (MgS04). Solvent was removed ~a Y~~Q and the residue purified by flash chromatography (silica; 2% ether in he~ane) to give the title compound as a colorless oil. PMR ~CDC13)~: 1.34 R6HçA 180-185 ~2HA mçA 415-420 R2HA mçA 680 ÆlHA ddA
J~8.1Hz, 1.5Hz), 6.87 (lH, td, J~8.1Hz, 1.5 ~z), 7.07 ~lH, td, J~8.1Hz, l.5Hz), 7.26 (lH, dd, J-8.1Hz, l.5HZ)-In a similar manner, but substituting thecorrespondin~ 3 alkylphenol for phe~ol, there may be prepared the following compounds:

b5645G 16562 ~3~$~ 1 4,4,7-trimethylchroman;
4,4-dimethyl-7-ethylchroman;
4,4-dimethyl~7~propylchroman; and 4,9-dimethyl-7-pentylchroman.

4,4-~methyl-6-a~ylchrom~n To a stirred solution of 7.94g (48.9425 mmol) of 4,~-dimethylchroman (rom E~ample 8) in 70 ml of nitromethane was added under argon 4.0g (50.96 mmol) of acetyl chloride followed by 6.89 (51 mmol) of aluminum chloride. This was stirred at room temperature for 5.5 hours and then cooled in an ice bath and treated slowly with 70ml of 6N hydrogen chloride. The resultant mi~ture was stirred at room temperature for 10 minutes a~d then treated with lOOml ether and the organic layer separated.
The organic layer was washed with water, saturate~
NaHC03 and saturated NaCl solutions and dried (MgS04). Solvent was removed ~n Q~Q and the residue purified by flash chromatography ~silica; 10~ ethyl acetate in he~anes). This was followed by kugelrohr distillation ~95-100C; 0.15 mm) to give the title compoun~ as a colorless oil. PMR (CDC13): ~ 1.40 ~6H), 1.95-2.00 (2H, m), 2.58 (3H), 4.25-4.30 (2H, m), 6.83 (lH, d, J~8.0Hz), 7.62 (lH, dd, J-8.0Hz, 1.5Hz), 8.00 (lH, d, J~1.5Hz).
Proceeding in the same manner, the other chroman compounds mads as per E~ample 8 are converted to their respectiv~ acetyl analogs.

EXAMP~E 10 4,4-Dime~hyl-6-ethynylckroman To a ~olution of 2.47g (24.41mmol) ~f diisopropylamine in 40ml dry tetr~hydrofuran under argon at -78C was added dropwise 15.2ml of 1.6M (Z4.3~ mmol) n-butyl lithium in b5645G 16562 28 ~3~g~3i he~ane. This mi~ture was stirred at -78C for 1 hour and then treated dropwise with a solution of 4.98g ~24.38 mmol) of 4,4-dimethyl-6-~cetylchroman (from E~ample 9) in 9ml dry of tetrahydrofuran. After stirring at -78C for 1 hour, the solution was treated with 4.2g (24.36 mmol) of diethyl chlorophosphate. The cooling bath was then removed and the reaction mi~ture ~tirred at room tempera~ure for 2.75 hours. This ~olution was th~n transferred u~ing a double ended needle to a solution of lithium diisopropyl amide tprepared using 4.959 (98~92 mmol) of diisopropylamine and 30.5 ml of 1.6M (4~.8 mmol3 n-butyllithium in he~ane~ in 80ml dry tetxahydro~uran at -78C. The cooling bath was removed and mi~ture stirred at room temperature for 18 hours and then quenched with 50ml water and 25ml of 3N hydrogen chloride. The misture was extracted with 2xlOOml and 3x50ml of pentane and the combine~ organic fractions washed with 3N hydrogen chloride, water, saturated NaHC03 and saturated NaCl solutions and then dried (MgSO~). Solvent was then removed ia vaçUQ and the residue purified by f lash chromatography (silica; 10% ethyl acetate in hexane) $ollowe~ by kugelrohr distillation t70C: 0.35mm) to give ~he title compound as a colorless crystalline solid. PMR
(CDC13): ~ 1.33 (6H), 1.81-1.86 (2H, m), 3.00 (lH, s), 4.19-4.24 (2H, m), 6.75 (lH, d, J~8.5~z~, 7.22 (lH, dd, J~8.5 Hz, 2.3Hz), 7.44 ~lH, d, J~2.3Hz).
Using this method, the acetyl derivatives made in Esample 9 are converted to the ethynyl form.

EXAMP~E 11 Ethyl 4-r4.4-qimethylchroman-~-ylethynyl~ben~o~te Reaction ~essels used in this procedure were flame dried under vacuum and a~l operations were carried out in an o~ygen-free, argon or nitrogen atmosph~re. To a solution of 509.4 mg (2.74 mmol) of 4,~-dimethyl-6-ethynyl b5645G 16562 ~L 3 ~ L

chroman ~from E~ample 10) in 4 ml of dry tetrahydrofuran at 0C was added dropwise 1.72 ml of 1.6M (2,75 mmol) of n-butyl lithium in he~ane. Stirring was commenced at O9C
for 30 minutes and at room temperature for 15 minutes, after which the solution was cooled again to 0C and then treated with a solution of 380 mg (2.79 mmol) of fused zinc chloride in 5 ml of dry tetrahydrofuran using a double ended needle. ~he resulting solution was ~tirred at 0C for 1 hour and then at room temperature for 15 minutes. A solution of 628.6 mg (2.74 mmol) of ethyl 4-bromobenzoate in 4 ml o dry tetrahydrofuran was transfPrred by double ended needle into a suspension of 380 mg (0.33 mmol~ of tetrakistriphenylphosphine palladium in 5 ml dry tetrahydro~uran and stirred at room temperature for 15 minutes, then treated by double ended needle with the solution of alkynyl æinc chloride prepared above. The mixture was stirred at room temperature for 20 hours and then quenched with ice and 30 ml of 3N hydrogen chloride. The mi~ture was then extracted with 3x75 ml ether and ether extracts were combined and washed successively with saturated NaHCO3 and saturated NaCl solutions and then dried (MgS09). Solvent was removed ia vacuo and the residue further puri~ied by f lash chromatography (silica; 10% ethyl acetate in hexane~ to obtain the captioned compound as a white solid. PMR
~C~C13): ~1.36 ~6H), 1.42 ~3H, t, J~7.3Hz), 1.82-1.86 (2H, m), 4.21-4.25 (2H, m), 4.40 (2H, q, J~7.3Hz), 6.79 (lH, d, J~8.1Hz), 7.28 (lH, dd, J~8.1Hz, 2.2 Hz), 7.50 (lH, d, J~2.2 Hz), 7.58 (2H, d, J~8.7~z), 8.03 (2H, d, J~8.7Hz).
Using the same procedure, but substituting an appropriate ethynylchroman from E~ample 10 and the appropriate halo-~ubstituted phenyl ester ~rom ~ample 5, the following exemplary compounds can be prepared.

b5645G 16562 3 o ~ 3 ~ ~ 8 c) i ethyl 4-[4,4,7-trimethylchroman-6-ylethynyl]-benzoate;
ethyl 4-~4,4-dimethyl-7-ethylchroman-6~yl-ethynylJbenzoate;
ethyl 4-[g,4-dimethyl-7-propyl~hr~man-6-yl-ethynyl]ben~oate;
ethyl 4-[4,4-dimethyl 7-he~ylchr~man-6-yl-ethynyl]benzoate;
ethyl 3-[4,4,7-trimethylchroman-6 ylethynyl]-benzoate;
ethyl 2-t4,4,7-trimethylchroman-6-ylethynyl~-benzoate;
ethyl 3-[4,4-dimethylchroman-6-ylethynyl]-benzoate;
ethyl 2-~9,4-dimethylchroman-6-ylethynyl]-benzoate;
ethyl 2-[4-(4,4,7-trimethylchroman-6-ylethynyl)-phenyl~acetate;
ethyl 2-C4-(4,4-dimethyl-7-ethylchroman-6-yl]-ethynyl)phenyl]acetate;
ethyl 2-~4-~4,~-dimethyl-7-propylchroman-6-yl~-ethynyl)phenyl~acetate;
ethyl 2-t4-(4,4-dimethyl-7-butylchroman-6-yl]-ethynyl)phenyl~acetate;
ethyl 2-~4-(4,4-dimethyl-7-pentylchroman-6-yl]-sthynyl)phenyl]acetate;
ethyl 2-~4-(4,4-dimethyl-7-he~ylchroman-6-yl]-ethynyl)phenyl]acetate;
ethyl 2-~3-(4,4-dimethylchroman-6-ylethynyl~-phenylJacetate;
ethyl 2-(2-(9,4-dimethylchroman-~-ylethynyl]-phenyl]acetate;
ethyl 3-~4-(4,4-dimethylchroman-~-ylethynyl]-phenyl]propanoate;
ethyl 3-~3-(4,4-dimethylchroman-6-ylethynyl]-b5645G 16562 31 ~ 3~$~.1.

phenyl]propanoate;
ethyl 3-~2-(4,4-dimethylchroman-6-ylethynyl]-phenyl]propanoate;
ethyl ~-C4-~4,4-dimethylchroman-6-ylethynyl]~
phenyl]butanoate;
ethyl 4-[3-(4,4-dimethylchroman-6-yl~thynyl~-phenyl]butanoate;
ethyl 4-t2-(4,4-dimethylchroman-6-ylethynyl~-phenyl]butanoate;
ethyl 5-t4-(4,4-dimethylchroman-6-ylethynyl~-phenyl]pentanoate;
ethyl 5-~3-(4,4-dimethylchroman-6-ylethynyl3-phenyl]pentanoate;
ethyl 5-~2-(4,4-dimethylchroman-6-ylethynyl~-phenyl]pentanoate;
ethyl 2 ~4~(4,4,7-trimethylchroman-6-ylethynyl]-phenyl~pentanoate;
ethyl 2-[4-(4,4-dimethyl-7-ethylchroman-6-yl)-ethynyl]phenylJpentanoate;
ethyl 2-~4-(4,4-dimethyl-7-propylchroman-6-yl)-ethynyl)phenyl~pentanoate;
ethyl 2-[4-(4,q-dimethyl-7-butylchroman-6-yl)-ethynyl)phenyl]pentanoate;
ethyl 2-C4-~4,4-dimethy1-7-pentylchroman-6-yl)-ethynyl)phenyl]pentanoate; and ethyl 2-~4-(4,4-dimethyl-7-hexylchroman-6-yl)-ethynyl)phenyl~pentanoate.

~XAMPLE 12 4-r4.4-dimethylchroman-6-ylethynyl~benzoic ~cid and 4-~4,4-dime~hyl~hiochroman-6-ylethynyllbenzoic acid The absolute ethanol used in this experiment was degassed by applying a vacuum while simul~aneously bubbling nitrogen through it. A solution of lOl.lmg (0.30 mmo1) of ethyl 4-[(4,4-dimethylchroman-6-yl)-b5645G 16562 32 13~

ethynyl3benzoate (from Esample 11) in 2 ml ethano' wastreated under argon with 0.7 ml of a 1.81M ~1.27 mmol) solution of potassium hydro~ide in ethanol and water.
This mi~ture was stirred at room temperature for 60 hours and then solvent was removed La vac~Q. The residue was dissolved in 25 ml of water and e~tracted with 25ml of ether and the ether e~tract discarded. The ~queous layer was acidified with glacial acetic acia and estra~ted with 4x50ml of ether. Ether e~tracts were combined and washed with water, then sa~urated NaCl solution and dried (MgSO4). Solvent was then removed i~ Y~CuO to give the title compound as a white solid. PMR ~(CD3)2CO): ~
1.39 (6~, 1.86-1.90 (2H, m), 4.23-4.27 (2H, m), 6.79 (lH, d, J~8.4Hz), 7.28 (lH, dd, J~8.4Hz, l.9Hz), 7.S0 (1~, d, J~1.9Hz), 7.61 (2H, d, J~8.3Hz), 8.08 (2H, d, J~8.3Hz).
Employing the general procedure described above but using instead ethyl 4-~4,4~dimethylthiochroman-6-yl-ethynyl~benzoate ~from E~ample 6), 4-[4,4-dimethyl-thiochroman-6-ylethynyl~benzoic acid was synthesized as a white solid. PMR (~CD3)2CO): ~ 1.34~6H), 1.93-1.98 (2H, m), 3 06-3.10 (2H, m), 7.09 (lH, d, J~8.5 Hz), 7.23 (lH, dd, J~8.5 Hz, 1.7 Hz), 7.62 (lH, d, J~1.7 Hz), 7.63 (2H, d, J~ 9.0 Hz), 8.03 (2H, d, J~9.0 Hz~.
Proceeding in a similar manner, esters of this invention may be converted to their corresponding acids.

Example 1~
4-[~,4-~im3thylchroman-6~ylethynyl]~enzyl alcohQl A 250 ml 3-necked flask is fitted with a stirrer, a dripping funnel, a nitrogen inlet and a thermometer. In the ~lask is placed a solution of 379.5 mg (10 mmol) of lithium aluminum hydride in 30 ml of dry diethyl ether.
The solution is cooled to -65C under nitrogen and a b5645~ 16562 33 ~31~

solution of 3.3441 g ~10 mmol~ of ethyl-4-~(4,4-dimethyl-chroman-6-ylethynyl)ben~oate in 15 ml of dry ether is added dropwise at a rate such that the temperature does not exceed -60C. The mi~ture i~ stirred at -30C for 1 hour and the excess hydride is then destroyed by the aadition of 300 mg ~3.4 mmol) of ethyl acetate. ~he reaction mi3ture is tben hydrolyzea by adding 3 ml of saturated ammonium chloride soluti~n and allowing the temperature to rise ko room temperature. The mi~ture is ~hen fil~ered and the residue washed with ether. The ether layer is then washed with saturated sodium chlorid~
solution, dried ~MgSO4) and then concentrated ~ ~~.
The residue is purified by chromatography followed by recrystallization to give the title compound.
8y the same process, the esters or acids of this invention may be converted to their corresponding primary alcohol analog.

E~ample ~4 ,,4-dim~hylch~oman-6-ylethynyl~ ace ~ nethy,l-benz~
A solution of 2.92 g (10 INmol) of 4-~(4,4-dimethyl-chroman-6~ylethynyl~benzyl alcohol, 600 mg ~10 mmol) of glacial acetic acid, 2.06 9 (10 mmol) of dicyclohe~ylcarbodiimide and 460 mg (3.765 mmol) of 4-dimethylaminopyridine in 150 ml methylene chloride is stirred at room temperature for 48 hours. The reaction mi~ture is then filtered and the residue washed with 50 ml of meth~lene chloride. The filtrate is then concentrated in vac~o and the residue is purified by chromatography followed by recrystallization to give the title compound.
This ~rocedure may be used to esterify any of the primary alcohols of thi invention.

b5645G 16562 , :

~amplQ 15 4-~4 t ~-dimethyl~hromzn-~-yleth~nyl]-kçnzald~hYd~
~ solution of 1.396 g (11 mmol) of freshly distilled o~alyl chloride in 25 ml of methylene chloride is placed in a 4-necked flask equipped with a stirrer, a thermometer and two pressure-equalizing addition funnels fitted with drying tubes. The solution is cooled to -60DC and then treated dropwiæe with a solution of 1.875 g (24 mmol) of dimethyl sulfo~ide (distilled from calcium hydride) in 5 ml of methylene chloride over a five minute period. The reaction mi~ture is then stirred at -60C for an additional 10 minutes. A solution of 2.92 g ~10 mmol) of 4,4-dimethylchroman-6-ylethynyl]benzyl alcohol in 10 ml of methylene chloride is then added to the reaction mixture over a pexiod of 5 minutes. The mixture is stirred for a further 15 minutes and is then treated with 5.06 g (50 mmol) of triethylamine. The cooling bath is then removed and the misture is allowed to warm to room temperature. Thirty ml of water is then added to the mixtuxe and stirring is continued for a further 10 mintues. The organic layer is then separated and the aqueous layer is extracted with 20 ml of methylene chloride. Ths organic layers are then combined and washed successively with dilute HCl, water and dilute Na2CO3 solution and then dried ~MgSO4). The solution is then filtered and concentrated in vacuo and the residue is purified by chromatography followed by recrystallization to ~ive the title compound.
The alcohols of this invention may be oxidized to the~r re~ aldehyde or ketone by this method.

b5645G 16562 3s E~a~P~ ç~
4-[4~4-Dim~thylchroman-6-~lethynyl~-l-(l-h~drQ~yprQ~yl2benzene Four ml of a 3M (12 mmol) solution of ethyl magnesium bromide in ether is placed in a 3-necked flask fitted with a mechanical 6tirrer, a reflu~ condenser protected by a drying tube and a prçssure-equalizing dropping funnel protected by a drying tube. The ~lask is ~ooled in an ice-bath and a solution of 2.9 g (10 mmol) of the carbo~aldehyde rom E~ample 15 ;n 10 ml of dry ether is added 610wly with vigorous stirring. The cooling bath is then removed and the mi~ture heated at reflux for 3 hours. The mixture is then cooled in an ice-salt bath and 5 ml of saturated ammonium chloride solution is added.
The misture is stirred for a ~urther 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 residue is then purified by chromatography followed by recrystallization to give the title compound.
Using the same proce~ure, but substituting ano~her aldehyde, any of the other aldehydes of this invention can be converted to a secondary alcohol.

E~ample 17 LI~ ~a~h~m~r=~-Ylethynyl]
l-dimethoxymethyl~nzene A round-bottomed ~lask is fitted with a Dean-Stark apparatus under a reflus condenser protected by a drying tube~ A mi~ture o~ 3.48 g (12 mmol~ of 4-~(4,4-dimethyl-chroman-6-ylethynyl]benzaldehyde, 4.80 mg (15 mmol) of anbydrous methanol, 2 mg of p-toluenesulfonic acid monohydrate and 10 ml o anhydrous benzene is placed in the ~lask and the mi~ture heated at ref lu2 under ~itrogen until close to the theoretical amount of water is b5645G 16562 .. ,, ~ .

collected in the Dean-Stark trap. The reaction mi~ture is cooled to room temperature and e~tracted successively with 5 ml o 10~ sodium hydro~ide ~olution and two 5 ml portions of water and then dried (MgS04). The solution is then filtered and the solvent removed in vacuo. The residue is puri~ied by chromatography and then recrystalliztion to give the title compound.
In a similar manner, any al~ehyde or ketone of this invention may be converted to an acetal or a ketal.

~a~le 1~
Preferably, these compounds may be administered topically using various formulations. Such formulation may be as follows~

InqEedientWei~ht/Pe~cent ~lution Retinoid 0.1 BHT O . 1 Alcohol USP 58.0 Polyethylene Glycol 400 NF 41.8 Q~
Retinoid 0.1 BHT 0.1 Alcohol USP 97.8 Hydro~ypropyl Cellulose2.0 -\

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Claims

1. A compound of the formula where X is S, O or NR1 where R1 is hydrogen or lower alkyl; n is 0-5; R is H or lower alkyls and A is H, or A
is -COOH, a pharmaceutically acceptable salt thereof, an ester of a saturated aliphatic alcohol of ten or fewer carbon atoms or a cyclic or saturated aliphatic cyclic alcohol of 5 to 10 carbon atoms or phenol or an amide or mono- or di-substituted amide of saturated aliphatic amines of ten or fewer carbon atoms, or the cyclic or saturated aliphatic cyclic radicals of 5 to 10 carbon atoms thereof, or A is -CH2OH or a lower alkyl ether or ester of a saturated aliphatic acid of ten or fewer carbon atoms or a cyclic or saturated aliphatic cyclic acid of 5 to 10 carbon atoms or benzoic acid, or A is -CHO or a lower alkyl acetal derivative thereof, or A is -COR2 or A lower alkyl ketal derivative thereof where R2 is -(CH2)mCH3 where m is 0-4; or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 where X is S and n is 0, 1 or 2.

3. A compound of claim 2 where A is -COOH or a pharmaceutically acceptable salt, ester or amide thereof.

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4. A compound of claim 3 which is 4-[4,4-dimethylthiochroman-6-ylethynyl]benzoic acid or a pharmaceutically accpetable salt or ethyl 4-[4,4-dimethylthiochroman-6-ylethynyl]benzoate.

5. A compound of claim 2 where A is hydrogen.

6. A compound of claim 2 where A is -CH2OH or an ether or ester derivative thereof.

7. A compound of claim 2 where A is -CHO or an acetal derivative thereof.

8. A compound of claim 2 where A is -COR2 or a ketal derivative thereof where R2 is -(CH2)mCH3 where m is 0-4

9. A compound of claim 1 where X is O and n is 0, 1 or 2.

10. A compound of claim 9 where A is -COOH or a pharmaceutically acceptable salt, ester or amide thereof.

11. A compound of claim 10 which is ethyl 4-[4,4-dimethylchroman-6-ylethynyl]benzoate or 4-[4,4-dimethylchroman-6-ylethynyl]benzoic acid or a pharmaceutically acceptable salt thereof.

12. A compound of claim 9 where A is hydrogen.

13. A compound of claim 9 where A is -CH2OH or an ether or ester derivative thereof.

14. A compound of claim 9 where A is -CHO or an acetal derivative thereof.

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15. A compound of claim 9 where A is -COR2 or a ketal derivative thereof where R2 is -(CH2)mCH3 where m is 0-4

16. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of the formula where X is S, O or NR1 where R1 is hydrogen or lower alkyl; n is 0-5; R is H or lower alkyl; and A is H, or A
is -COOH, a pharmaceutically acceptable salt thereof, an ester of a saturated aliphatic alcohol of ten or fewer carbon atoms or a cyclic or saturated aliphatic cyclic alcohol of 5 to 10 carbon atoms or phenol or an amide or mono- or di-substituted amide of saturated aliphatic amines of ten or fewer carbon atoms, or the cyclic or saturated aliphatic cyclic radicals of 5 to 10 carbon atoms thereof, or A is -CH2OH or a lower alkyl ether or ester of a saturated aliphatic acid of ten or fewer carbon atoms or a cyclic or saturated aliphatic cyclic acid of 5 to 10 carbon atoms or benzoic acid, or A is -CHO or a lower alkyl acetal derivative thereof, or A is -COR2 or a lower alkyl ketal derivative thereof where R2 is -(CH2)mCH3 where m is 0-4; or a pharmaceutically acceptable salt thereof.

17, A composition according to claim 16 having anti-psoriatic activity in a mammal.

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18. The use of a therapeutically effective amount of a compound of the formula where X is S, Q or NR1 where R1 is hydrogen or lower alkyl; n is 0-5; R is H or lower alkyl; and A is H, or A
is -COOH, a pharmaceutically acceptable salt thereof, an ester of a saturated aliphatic alcohol of ten or fewer carbon atoms or a cyclic or saturated aliphatic cyclic alcohol of 5 to 10 carbon atoms or phenol or an amide or mono- or di-substituted amide of saturated aliphatic amines of ten or fewer carbon atoms, or the cyclic or saturated aliphatic cyclic radicals of 5 to 10 carbon atoms thereof, or A is -CH2OH or a lower alkyl ether or ester of a saturated aliphatic acid or ten or fewer carbon atoms or a cyclic or saturated aliphatic cyclic acid of 5 to 10 carbon atoms or benzoic acid, or A is -CHO or a lower alkyl acetal derivative thereof, or A is -COR2 or a lower alkyl ketal derivative thereof where R2 is -(CH2)mCH3 where m is 0-4; or a pharmaceutically acceptable salt thereof;
alone or in conjunction with a pharmaceutically acceptable excipient, for treating psoriasis in a mammal.

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