CA2105158A1

CA2105158A1 - 7-chromanyl esters of phenols and benzoic acids having retinoid-like activity

Info

Publication number: CA2105158A1
Application number: CA002105158A
Authority: CA
Inventors: Roshantha A. S. Chandraratna
Original assignee: Individual
Current assignee: Allergan Inc
Priority date: 1991-03-26
Filing date: 1992-03-25
Publication date: 1992-09-27
Also published as: JPH06506683A; ATE153334T1; AU1762792A; IE920948A1; WO1992017426A3; US5348975A; AU649124B2; WO1992017426A2; EP0580738B1; DE69219885D1; EP0580738A1; JP3174327B2; ES2102502T3; DE69219885T2; US5324744A; US5134159A

Abstract

Retinoid like activity is exhibited by compounds of formula (I), wherein the R1-R6 groups are independently H or straight chain or branched chain lower alkyl or cycloalkyl of 1 to 6 carbons;
X symbolizes an ester or thioester linkage, Y is lower branched chain alkyl having 2 to 6 carbons, cycloalkyl having 3 to 6 carbons or is (CH2)n where n is an integer between 0 to 6 or is an alkenyl group of 2 to 6 carbons, and having 1 or 2 double bonds, or an alkynyl group of 2 to 6 carbons; and Z is H, OH, OR', OCOR', -COOH or a pharmaceutically acceptable salt, COOR8, COONR9R10, -CH2OH, CH2OR11, CH2OCOR11, CHO, CH(OR12), CHOR13O, -COR', CR'(OR12)2, or CR'OR13O; where R' is an alkyl, cycloalkyl or alkenyl group containing 1-5 carbons, R8 is an alkyl group of 1-10 carbons, or a cycloalkyl group of 5-10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1-10 carbons, or a cycloalkyl group of 5-10 carbons or phenyl or lower alkyl phenyl, R11 is lower alkyl, and R13 is a divalent alkyl radical of 2-5 carbons.

Description

WO 92/17426 PCT/VS9~/02346 2 1 ~

7--C~RO~UIYL ~58TE~8 OF P~S~OL~ D B152~ZOIC ACID~
~AVING aB~I~OID-LI~ AC~ Y
~o~cg~,Qu~d This invention relates to novel compounds having 5 retinoid-like activity. More specifically, the invention relates to compoundc having a substituted chroman portion and a substituted phenyl portion linked to the 7-position of the chroman nucleus through an ester or thioester group.
Relate~ Art Carboxylic acid derivatives u-~eful 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 15 are disclosed in European Patent Application 0133795 published January 9, 1985. European Patent Application 176034A published April 2, 1986 discloses tetrahydronaphtAalene compound~ having an ethynylbenzoic acid group. United States Patent No.
20 4,73g,098 discloses compounds of retinoid-like activity where three olefinic units from the acid-containing moiety of retinoic acid are replaced by an ethynylphe-nyl functionality.
The publication by Sporn et. al. in J. Amer. Acad.
25 ~5~ 15:756-764 (1986) discloses the compound 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthoylamino)benzoic acid as a retinoid-like agent.
Further compounds of background interest to the present invention are disclosed by ShUdo et al. in Che~ Phar.
30 Bull. 33:404-407 (1985).
A patent application of the present inventor, assigned to the same assignee as this application, describes ccmpounds having a substituted chroman , ~

WO92/17426 PCT/US92/02~6 2 ~ 2 portion and a substituted phenyl portion linked to the 6-position of the chroman nucleus through an ester or thioester group.
Bumm~y Q~ th- I~e~tlo~
S This invention covers compounds of ~ormula 1 R, R2 10 ~X~\~, Z

Yor~ul~ 1 wherein the R~ R6 groups are independently H or straight chain or branched chain lower alkyl or cycloalkyl of 1 to 6 carbons: S symbolizes an ester or thioester linkage, Y is lower branched chain alkyl having 2 to 6 carbons, cycloalkyl ~aving 3 to 6 carbons or i6 (CH2)n where n i8 an integer betwoen O to 6 or is an alkenyl group of 2 to 6 carbon~ and hav~ng 1 or 2 double bonds, or an alkynyl group of 2 to 6 carbons;
and ~ i~ H, OH, OR', OCOR', -COOH or a pharmaceutically acceptable ~alt, COOR8, COONRgRlo, -CH20H, CH2ORll, CH20CORll, CHO, CH(OR12), C~OR130, -COR', CR'(OR12)2, or CR'OR130; where R' is an alkyl, cycloalkyl or alkenyl group containing 1-5 carbons, R8 i8 an alkyl group of 1-10 carbons, or a cycloalkyl group of 5-10 carbons, or R8 is phenyl or iower alkylphenyl, Rg and Rlo independently are hydr~gen, an alkyl group of 1-10 carbons, or a cycloalkyl group of 5-lO car~ons or ... . . - . . - . , . . . . . ..

WO92~17426 PCT/US92/02346 phenyl or lower alXyl phenyl, Rll is lower alkyl, Rl3 is divalent alkyl radical of 2-5 carbons.
In a second aspect, this invention relates to the use of the compounds of Formula 1 for treating 5 dermatoses, such as acne, Darier's disease, psoriasis, icthyosis, eczema, atopic dermatitis and epithelial cancers. These compounds are also useful in the treatment of arthritic diseases and other immunological disorders (e.g. lupus erythematosus), in promoting 10 wound healing, in treating dry eye syndrome and in reversing and preventing the effects of sun damage to skin.
This invention also relates to a pharmaceutical formulation comprising a compound of ~or~ula 1 in admixture with a pharmaceutically accept~ble excipient.
In another aspect, this invention relate~ to the process for making a compound of Yormula 1 which process compri~es reacting compounds of ror~ula 2 with compounds of Formula 3, 25 R R~

~ or~ula 2 For~ula 3 where ~ 6~ Y and 8 are defined as above in connection with Fo~ula 1, and wherein one of A' and B' 3 is an 0~ or SH group, and the other i8 a carboxylic acid (COOH) or an appropriate derivative (such as an WO92/17426 PCT/~'S92/02~6 2 i~ 31 ~ ~ 4 acid chloride) suitable for forming an ester with a hydroxyl or thiol group, and where the reaction is conducted under conditions suitable for forming an ester or thioester bond between the chroman ring of the compound of For~ula 2 and the phenyl ring of the compound of Formula 3.
In the process of reacting compounds of For~ula 2 with the compounds of For~ula 3 to form the ester or thioester linkage S of Foroula l, when 2 is an alcohol or acid function it is preferred that such alcohol or acid function be protected. When, in the esterification reaction ~ is an aldehyde or ketone, it may not need to be protected depending on the precise nature of the compounds and the conditions of the esterification reaction.
In still another aspect, the present invention also relates to preparation of compounds of ~oraula 1 by conversion of compounds having the structure of Forcula 4.

~ X ~ \ R
R

Formula 4 In Formula ~ the symbols Rl - R6 and ~ are defined as above in connection with For~ula l, and Y' - ~' symbolizes such precursors of the groups Y - ~ which can be readily converted by reactions well known to ' . . ............. - : - .:
- :

. .

W092/t7426 PCT/~S92/02346 2 1 9 ~

oxganic chemists, into the desired groups Y - ~. Thus, the present invention also relates to the above-noted processes involvings steps such as:
converting an acid of Yoroula 4 to a salt; or forming an acid addition salt;
converting an acid of ~or~ul- 4 to an ester; or converting an acid or ester of For~u~ 4 to an amide; or reducing an acid or ester of ~or~ula 4 to an alcohol or aldehyde; or converting an alcohol of Pormula ~ to an ether or ester; or oxidizing an alcohol of For~ula 4 to an aldehyde:
or converting an aldehyde of Formula 4 to an acetal;
or converting a ketone of Rormula ~ to a ketal, extending by homologation the length of the alkyl chain of a compound of Yo~ula ~, where Y' i~ alkyl.
~ ono~l Bmb~ ont-io~
The ter~ "ester~ as used here refers to and covers any compound falling within the definition of that term as classically used in organic chemistry. The term "thlo~stQr" as used here refers to and covers any compound falling within the definition of that term as cla~sically used in organic chemistry. With respect to the ester or thioester function symbolized by ~ in Fos~ula 1 linking the chroman and phenyl moieties of the compounds of the invention, the function includes an estex or thioester derived from a phenol or thiophenol and a 7-chromanoic acid derivative ~when the car~onyl group is directly attached to the chroman WO92/17426 PCT~US92/0 2 ~9~ 6 nucleus) and also an ester or thioester derived from a benzoic acid and 7-hydroxy-chroman or 7-thiohydroxy-chroman derivative (when the carbonyl group is directly attached to the phenyl nucleus).
Where 8 (of For~ula l) i8 -COOH, the term "ester"
covers the products derived from treatment of this function with alcohols. Where the ester is derived from compounds where g is -CH2OH, this term covers compounds of the formula -CH200CR where R is any substituted or unsubstituted aliphatic, aromatic or aliphatic-aromatic group.
Preferred esters are derived from the saturated aliphatic alcohols or acids of ten or fewer carbon atoms or the cyclic or saturated aliphatic cyclic alcohols and acids of 5 to l0 carbon atoms.
Particularly preferred aliphatic esters are t~ose derived from lower alkyl acids or alcohols. Here, and where ever else used, lower alkyl means having 1-6 carbon atoms and includes straight as well as branched chain alkyl groups. 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-su~stituted amides. Preferred amido~ are the mono- and di-substituted amldes derived from the saturated aliphatic radicals of ten or fewer carbon atoms or the cyclic or saturated aliphatic-cyclic radicals sf 5 to l0 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 alXylphenyl amines. Unsubs~ituted amides are also preferred.

.

. .
.

W092/17426 PCT/US92/02~6 Acetals and ketals include the radicals of the formula -CX where K is (-OR)2. Here, R is lower alkyl.
Also, X may be -OR10- where ~1 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 example 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 i8 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 salts such as mono-, di- and trialkyl amines or ethanol amines. Salts may al80 be formed with caffeine, tromethamine and similar molQcules. Where there is a nitrogen ~ufficiently basic as to be capable of forming acid addition salts, 6uch may be formed with any inorganic or organic ac~ds or alkylating agent such as methyl iodide. Preferred salts are tho~e 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 tri-acid may also be used.
The preferred compounds of thi~ invention are those where the S functionality of ~oraula 1 is COo-.
In other words, preferred compounds of the invention WO92/17426 PCT~US92~02~6 2~ Q3~ 8 are phenyl ester derivatives of 7-carboxy chromans.
Within the above-noted preference, still more preferred are compounds where in the Y - ~
functionality of Foroula l Y is (CH2)n and n i8 zero, S and ~ is either COOH or COOR8 (R8 being lower alkyl, lower cycloalkyl, phenyl substituted lower alkyl, phenyl or lower alkyl substituted phenyl). In other words, still more preferred are esters of 7-carboxy chromans formed with hydroxy benzoic acids, or with lO hydroxy benzoic acid esters. Within this group, esters of substituted 7-carboxy chromans with 4-hydroxy benzoic acid and particularly with 4-hydroxy benzoic acid esters are still more preferred.
Even more preferred are compounds which, in addition to having the hydroxy-benzoic acid or hydroxy-benzoic acid ester residue, include substituents in the 2,2 and/or in the 4,4 and/or in the 6 position of the 7-chromanoic acid moiety. Within this group, derivatives of 2,2,4,4-tetramethyl-7-chromanoic acid are most preferred.
The mo6t preferred specific compounds of the invention are shown in ~or~ula S, and are identified as follows: -~ ~ CO~
o ~or~ula S
Ethyl 4-(2,2,4,4-tetramethyl-7-chromanoyloxy) benzoate (co~poun~ 1, R5=~ and R8--t~yl);

WO92/17426 PCT/US92/02~6 ~ `3 8 Benzyl 4-(2,2,4,4,tetramethyl-7-chromanoyloxy)benzoate (Compoun~ 2, R5 = H and R8 = benzyl);

4-(2,2,4,4-tetramethyl-7-chromanoyloxy) benzoic acid (Compound 3, R5=~ and R8=~);
The compounds of this invention may be administered systemically or topically, depending on such considerations as the condition to be treated, need for site-specific treatment, quantity of drug to be administered, and similar considerations.
In the treatment of dermatoses, it will generally be preferred to administer the drug topically, though in certain cases such as treatment of severe cy~tic acne, oral administration may also be used. Any common topical formulation such as a solution, suspension, gel, ointment, or salve and the like may be used.
Preparation of such topical formulations are well described in the art of pharmaceutical formulations as exemplified, for example, ~ç~lng~on'~ Pharmace~ical Scienc~, Edition 17, Mack Publishing Company, Easton, Pennsylvania. For topical application, these compounds could also be administered as a powder or spray, particularly in aerosol form.
If the drug is to be administered systemically, it may be confected as a powder, pill, tablet or the like, or as a syrup or elixir for oral administrat~on. For intravenous or intraperitoneal administration, the compound will be prepared as a solution or suspension capable of being administered by injection. In certain cases, it may be useful to formulate these compounds in suppository form or as an extended release formulation for deposit under the skin or intermuscular injection.
Other medicaments can be added to such topical formulation for such secondary purposes as treating W092/17426 PCTt~lS92/02~6 skin dryness, providing protection against liqht; other medications for treating dermatoses, preventing infection, reducing irritation, inflammation and the like.
Treatment of dermatoses or any other indications known or discovered to be susceptible to treatment by retinoic acid-like compounds will be effected by administration of the therapeutically effective dose of one or more compounds of the $nstant invention. A
therapeutic 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 concentration will vary from condition to condition and in certain instances may vary w~th the severity of the condition being treated and the patient' 8 6usceptibility to treatment. Accordingly, a given therapeutic concentration will be best determined at the time and place through routine experimentation.
However, it i5 anticipated that in the treatment of, for example, acne, or other such dermatoses, that a formulation containing between 0.001 and 5 percent by weight, preferably about 0.01 to 1% will usually con-titute a therapeutically effective concentration.
I~ ad~in~stered systemically, an amount between 0.01 and lOO mg per kg body weight per day, but preferably about 0.1 to 10 mg/kg, will effect a therapeutic result in most instance6.
The retionic acid like activity of these compounds was confirmed through the classic measure of retionic acid activity involving the effects of retionic acid on ornithine decarboxylase. ~he original work on the ,, . , ~ . ~ ' .

.
.

WO92/17426 PCT/US92/02~6 ~ 3 ~

correlation between retinoic acid and decrease in cell proliferation was done by Verma & Boutwell, Cancer Xesea~ch, 1977, 37, 2196-2201. That reference discloses that ornithine decaxboxylase (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.
10 Although all causes for ODC activity increase are unknown, it is known that 12-0-tetradecanoyl-phorbol-13-acetate (TPA) induces ODC
activity. Retinoic acid inhibits this induction of ODC
activity by TPA. The compounds of this invention also inhibit TPA induction of ODC as demonstrated by an assay essentially following the procedure ~et out in canç~ Res., 35: 1662-1670, 1975.
By way of example of retinoic acid-like activity it is noted that in the assay conducted essentially in accordance with the method of Verma & Boutwell, iki~, the following examples of the preferred compounds of the present invention (Compound- 1, 2 ~ 3) elicited the following percent inhibition of TPA-induced ODC
activity at the given calculations:
25Compound Dose (nmol) % inhibition 8pO~$r~ç ~Q~ t~
The compounds of this invention can be made by a number of different synthetic chemical pathways. To illustrate this invention, there is here outlined a series of steps which have been proven to provide the - - :

.
~' '. . ' `

W092/17426 PCT/~S92/02~6 compounds of For~ula 1 when such synthesis is followed in fact and in spirit. The synthetic che~ist will readily appreciate that the conditions qet out here are specific embodiments which can be generalized to any and all of the compounds represented by ~or~ula 1.
Furthermore, the synthetic chemist will readily appreciate that the herein described synthetic steps may be varied and or adjusted by those skilled in the art without departing from th¢ scope and spirit of the 10 invention.
The compounds of the invention, in accordànce with Formula 1 are esters or thioesters containing a chroman moiety and a phenyl moiety. Accordingly, and speaking -generally, the compounds of the invention can be made from the appropriate carboxylic acid or derivatized carboxylic acid precursors on the one hand and thiol or alcohol precursors on the other, by synthetic methods which ~ç~ se are known in the art.
Specifically, the co~pounds of the invention (shown in ror2ula 1) can be made by reaction of the precursors shown in For~ula 2 and For~ula 3. A~ i5 noted above, in these formulas either A' or B' is an OH
or an SH group, and the other is a carboxylic acid (COOH) or a derivatized carboxylic acid (such as an acid chloride) which is capable of forming an ester or a thioest~r with the other group.
~ ore specifically, and by way of example, preferred compounds of the invention comprise esters of substituted 7-carboxy chromans, e. esters derived from compounds of For~ula 2 where A' i8 COOH) with hydroxybenzoic acid esters (compounds of Yor~ul~ 3 where Y is (CH2)n and n is zero, and 8 is COOR8, R8 being an esterifying alkyl, lower alkylphenyl or phenyl ' ' ~ ', . . : . .
.

WO 92tl7426 PCT/US92/02~6 2 i ~
group). These compounds can be prepared in accordance with React$on 8ch-~e 1. In this reaction the free acid, a 7-carboxychroman derivative (compound of For~ula 2) is reacted with the hydroxybenzoic acid ester (compound of Formula 3) in a suitable solvent such as methylene chloride ~CH2C12) in the prQsence of dicyclohexyl carbodiimide (DCC) and dimethylaminopyridine (DMAP). In R-aotion 8ch-m- 1 the symbols ~ through ~6 have the ~ame d-finition ~B in 10 ror~ul~ ~. R2 R, ~ + H0 DCC
DMAP
~ CH2C12 ~-~otlo~ Boh 1 ~ aotioa ~ch-m- 2 show~ an alternative process for synthezizing the compounds which are obtainable in R aotion ~hen- 1. In accordance with this process, the substituted 7-carboxychroman derivatives are first converted to the corresponding acid chloride by treatment with a ~uitable reagent, for example, thionyl - , . .
; ~ , . . , ,, ~ , . .
. . . .: :
.

WO92/17426 PCT/US92/02~6 2 ~ O ~ 14 chloride (SOC12). The corresponding acid chloride is thereafter reacted with a hydroxybenzoic acid ester in a suitable solvent and preferably in the presence of an acid acceptor, such as triethylamine.

~CO,H

1' --~ R~

~-~ct~o~ 8c~-~- 2 R-action 8ch-u- 3 shows a process for making esters of substituted 7-carboxychroman with hydroxy benzoic acid derivatives, where the desired products, (compounds of the invention) have a free carboxylic ~cid group. This process is similar to the condensation, in the presence of DCC and DMAP, shown in R-~¢t~on 8ch-u- , except that a benzyl ester of the hydroxybenzoic acid is employed, and that in the last step of the process the benzyl ester function is selectively cleaved by hydrogenation over palladium (or other suitable catalyst), to provide the target co~pound having a free carboxylic acid group attached to the phenyl moiety.

.: :
.

, ' . ' ' , ' . :. .
.

WO 92/~426 PCI`/I,IS92/02346 15 ~ 3 8 R\~ ~

R~ C02CHzPlI

lC
¦ H2/Pd R~ ~O~l~CO,H

R~act~on ~ch-~- 3 ~ eactlon 8ch-c- ~ shows an examplary proces~ for the preparation of compounds of the invention derived from substituted 7-hydroxy chromans and terephtalic acid half esters, that is, compounds where, with re~erence to For~ul~ is COO with the carbonyl group attached to the phenyl moiety, Y is (CH2)n and n is zero. The condensation shown in this reaction is - ~

-' ' ~: ', ~ ,, . . . , ~ .

WO92/17426 PCT/~S92/02~6 J ~

performed in the presence of D~C and DMAP. It should be understood however, that several variations of this process are possible, for example the terephtalic acid half ester can be converted into an acid chloride (or some other activated derivative of the carboxylic acid) and the acid chloride (or other active derivative) can be reacted with the 7-hydroxy-chroman derivative in a suitable solvent and in the presence of an acid acceptor, in analogy to the reaction sequence shown in R-action 8ch~e 2. Utilizing the benzyl half ester of terephtalic acid (or of a substituted terephtalic acid) in analogy with ~-action ~ch-~- 3, permits selective cleavage of the benzyl ester function by hydrogenation, and synthesis of the corre~ponding 7-hydroxy-chroman derivative esterified with terephatalic acid and bearing, attached to the phenyl, group a free carboxylic acid function.

2Q R3 ~ ~ ¦

R~ ~ R2 Rs ~ CO~R~
DMAP /~o ~¦~

R~ction 8ch~-. .
. .
' :'. ' ' ' , ~ ' WOs2/17426 PCT/~S92/02~6 17 21 ~a^ ~38 The synthetic procedures outlined in an examplary manner in connection with R~action 8Ch~J l - ~, can also be adapted for the preparation of the thioester compounds of the present invention.
As is noted above in connection with ~or~ula 4, compounds of the invention (~or~ula l) may also be prepared by performing certain synthetic steps on compounds which are either already embraced by For~ula ~, or are such precursors shown in ~ormul~ ~, which readily lend themselves to synthetic steps leading to compounds of the invention. In this regard free carboxylic acids of Formula ~, that is compounds possessing the "chroman to phenyl" ester linkage but having a free or appropriately protected carboxylic group on the phenyl moiety, can be converted to salts, esterified, converted to an amide, reduced to an aldehyde or an alcohol. The corre~ponding alcohols and aldehydes can be esterified or converted to acetals, as applicable. Alternatively the carbon chain of Y - ~ of Pormul~ ~ may be subjected to chain elongation by homologation. As it will be recognized by those skilled in synthetic organic chemistry, the foregoing conversions can be performed by adapting generally known synthetic procedures to the compounds of the invention. In performing some of the above-noted synthetic steps on compounds of ~or~ula 1 or of ~or~ula 4, care may need to be exercised not to saponify or otherwise de~troy the ester linkage between the chroman and phenyl moieties.
The compounds of For~ula 3 which comprise starting materials or intermediates to the compounds of the present invention, are either available commercially, or are readily synthesized by known synthetic methods -, , . ~ - - : , .
: . , WO92~1~426 PCT/US92/02~6 f.'~ 'l. ~ `' ~ ' t "

within the skill of ordinary artisan in the field. For example, 4-hydroxy benzoic acid is commerically available, and can be esterified to provide, for example, ethyl 4-hydroxy benzoate which is an important intermediate for the synthesis of certain specific examples of the compounds of the present invention.
The mono ethyl ester of terephtalic acid, another intermediate in accordance with ~or~ula 3, i8 also available commercially or is readily synthe6ized by known methods.
Intermediates of Formula 2 where A' is COOH, can be synthesized by the reaction seguences described below.
Specifically, compounds of For~ula 2 where R3 ~nd R4 are hydrogen, and A' is COOH are synthesized according to R-act~on ~¢he~e 5.

. . . .
.

.

W092/]7426 PCT/US92tO2~6 ~C10)2POCI I ~ ~
R2~CH OH ~002)-P-O ~r 4 ~ li~,~R, l~o~r Rl'CH2 CH~

l C R,'C11~ CH~R~

z ~ ~

R-a¢tlon ~ch-~- S
In R-actio~ ~ch-m- 5 Q is phenyl and R~', R2" and R5 ar- hydrogen or lower alkyl having 1 to 5 carbons.
Th- r-action sesUenCe i~ hereinafter further described g-nerally but with emphasis to the preferred case where R'l and R2~ both are hydrogen, i.e. for the synthesis ~--of a 4,4-dimethyl-7-carboxy chrom~n (Compound lo). The phosphate (Co~pou~ 6) is prepared from the corre~ponding diphenyl chlorophosphate (Compound ~) and 3-methyl-3-butene-1-ol (Co~poun~ 5, R~' and R2' are both H) which is available from Aldrich, Chemical Company, or is prepared by means known in the art. It .
, .. . .. . .
:. . . . . . - . . . . .
, . . . . . .

.~ .. . . . .

WO 92~1742S PCr/US~2/02346 ~' '!`~ 9~

is preferred to prepare compouna 6 by dissolving the alcohol (Compoun~ S) in about a 10% excess of pyridine (or like solvent) under an inert atmosphere cooled to approximately -10 degrees C. This solution i8 then added drop-wise, under an inert atmosphere, to a solution of diphenyl chlorophospate (Compound ~), in about an equal amount of reaction solvent. About a 2-5% molar excess of diphenyl chlorophosphate (Compound 4) relative to the alcohol tCompound 5) is employed.
The mixture is heated at reflux for 1 to S hours, preferably about 3, to affect the reaction. The product is then recovered by conventional means. The diphenyl phosphate ester (Compound 6) is then reacted with the 3-bromo phenol derivative (Compound 7) to affect formation of an isomeric mixture of chromans (Compound 8 and Compouna 9). For example, 3-bromo-phenol (Compound 7, R5zH) is added to a flask already containing stannic chloride under argon which has been cooled to -10 degrees to 10 degrees C. After thorough mixing of this combination for about 15 minutes to an hour at the reduced temperature, the phosphate (Compound 6) is added. When the addition of the phosphate (Co~pound 6) 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 isomeric mixture is then separated by conventional means to give the desired 7-bromo-chroman (Compound 8).
Alternatively, the desired 7-substituted chromans can be separated from their potential regio-isomeric impurities at the carboxylic acid stage or at the final coupling stage.
The carboxylic acid function is then introduced W092/17~26 PCT/US92/02346 into the 7-position of the 4,4-disubstituted bromochroman by metal halogen exchange. The bromochroman (Compou~d 8) is treated with tert-butyl-lithium (or other appropriate metal halogen exchange reagents) followed by carbon dioxide quench. Subsequent acidification gives the 4,4-dialkyl-7-carboxy chroman derivative which contains ths desired Rl~, R2!, R3, R4 and R5 substituents (Co~pound 10).
R-action 8ch-~- 6 illustrates an alternative method for preparing compounds of For~ula 2 where Rl -R5 are as previously described in Roaction 8ch~- 5.

.
', . ' '. ::., ' :
.

21~3~5~

R ~CH,R,' R ~C~

R ~CH CH2R2' R~'CH~ CH2R~' HO/~

J Br R,'CH2 ~CH~R~
a~'CH~ ~R~

J
5 Fll CH2 CH,R2 OH

lQ
~a-~Gt$on ~Ch~- 6 ,: . - . ., - . - .......... . .
' : , ' ''' " "

W092~17426 PCTtUS92tQ2~6 23 ~ c,~;

Thus, in accordance with React~o~ 8ch~o 6, 3-bromo phenol, or a 3-bromo phenol substituted in the 4 (para) position by an alkyl substituent (Compouna 7) is acylated with an acylating agent, such as the acid 5 chloride (Compoun~ ll) derived from ~,3-dimethylacrylic acid or from another appropriately substituted acrylic acid (Rl' and R2' is either H or lower alXyl). The acylation of the 3-bromo-phenol (Compoun~ 7) with the acid chloride (Compound l~) is preferably conducted in the presence of a strong base (e.g. sodium hydride) in an inert solvent (such as tetrahydrofuran). The resulting phenyl-acrylate (Compoun~ 12) is ring closed under Friedel-Crafts type reaction conditions (e.a.
AlCl3 catalyst, in an inert solvent such as methylene -~
chloride) to provide two positional isomers (Compoun~
13) and (Compoun~ 14) of the 2-oxo-chroman derivative, each of which bears, in the 4-po~ition, the CH2Rl' and CH2R2' substituents and where R5 is hydrogen or lower alkyl. As described previously for R-~ctlon ~ch~- 5, the mixture is then separated by conventional means to obtain the desired 7-bromo-2-oxo-chroman (Compound 13).
It should be noted that as also described previously in connection with R-act~on 8ch-~- 5 the 7-bromo-2-oxo chroman (Co~pound 13) can be ceparated from the potential regio-isomerïc impurities at the carboxylic acid stage or at the final coupling stage. The 2-oxo-7-bromo-chroman ~Compoun~ 13) is thereafter reduced with lithium aluminum hydride or an appropriate reducing agent to provide the 7-bromo-diol (Compound lS). The diol ~Compoun~ lS) is then mono-mesylated at th~ primary alcohol position followed by intramolecular nucleophilic displacement of a mesyl leaving group, to gi~e the 7-bromo-chroman (Co~poun~ 8) which bears the - . . .. . .
' - -- .' . ~',, ' .. ~ ~ ' . . :. ' . .
' -, .. . .
~ ,.. ' ~ .
.. . . , , ~ , .

~V092/17426 PCT/US92tO2~6 '3 desired CH2 Rl~, CH2R2~ and R5 substituents~ The carboxylic acid function is introd~ced into the 7-position in the same manner as described previously in R-action 8cheme 5 to give the 7-carboxy chroman ~Compoun~ 10).
The intermediate chroman derivatives of For~ula 2 where Rl - R~ are lower alkyl, R5 is H or lower alkyl, and A' is COOH may be prepared in accordance with the synthetic steps illustrated in Reaction 8¢heme 7.

W O 92/17426 Pc~ri~S92/02346 HOJ~R~ R ~CH~R~ R ~

lO R1~cH2~ CH2R2' R~'CH~ CH2R~' R X~ ~ ~

Dr 1 S R,~CH~ ~C~R~l R~ R~

Rl'CH2~ CH2R2' R~ ~ ~YX~H

1 8; o ~oact~ on 8che~o 7 - : , . < . .

.. ., , . . i ..
- .~ - .. ,. .
: ., . . ~. , : . - , . .
', . : ., ~ , ~' . , . - , . , W092/1~426 PCT/~'S92/~2~6 ~ 26 With reference to Reaction 8c~Q~e 7, the 3-bromo-phenol derivative, where R5 is hydrogen or lower alkyl, ~-(Compound 7) is acylated with an acylating agent, such as acid chloride (Compound 11) derived from 3,3-dimethyl acrylic acid or from another appropriately substituted acrylic acid. (Rl' and R2' are hydrogen or lower alkyl). As previously described cyclization of Compound 12 under Friedel-Crafts type reaction conditions results in the formation of positional isomers, (Compounds 13 and 14), where the bromo substituent of the meta (3) position of the phenol Compound 7 becomes, in the target chroman compounds the substituent either at the 5-position or the 7-position of the chroman nucleus. ~hus, with specific reference to Reaction Qchome 7, the acylation of the bromo phenol (Compound 7) with the acid chloride (Compound 11) is preferably conducted in the presence of a strong base in an inert solvent, analogus to the conditions described for React~o~ 8ch-u- 6. The phenyl-acrylate (Compund ~2) is ring closed under Friedel Craftes type reaction conditions as described for Reaction 8ch-me 6 to provide a mixture of two isomers. (Compound 13 and Compound l~) each of which bears, in the 4-position, the CH2R1 and CH2R2 substituents. The isomers are then separated as described`previously for Roaction ~c~emes 5 ~d 6. The 2-oxo-7-bromo derivative (Compound 13) is thereafter treated with a Grignard reagent to introduce the R3 and R~ substituents. In the preferred embodiments, R3 and R~ are identical, for example both are methyl or ethyl. When R3 and R~ are methyl, the Grignard reagent is preferakly methylmagnesium chloride (dissolved in tetrahydrofuran). To carry out the Grig-nard reaction a solution of Compound 13 in a suitable WO92/1~426 PCT/US92/02346 ~ ~ ~ v solvent (for example in dry diethylether) is added to this Grignard reagent. The resulting tertiary phenol that has undergone ring opening is shown as Co~pound 16 in ae~ct~on 8ch~m- 7.
Compound 16 which already has the desired Rl, R2 R3, R~ and R5 substituents, is ring closed under acidic conditions, (e.g. by heating in aqueous sulfuric acid) to provide the chroman derivative (Com~oun~ 17). The carboxylic acid moiety is introduced by metal halogen exchange followed by reaction with carbon dioxide, as described previously, to give the desired 7-carboxy c _ _ ~

' , " ' ' " ' , ., ',: ' ~ , ':: ', , ' , ' , '' ,' ,' ' . '. '. " ., . ' ' ~ ' ', :' ' '' ' ' . "

" ' ' ' ' ' ' ~' . . ' ' ' . ' ' , i2~

R,'CH2 ~C~2Ri R1 CH2X~ R~ ~

R,~ NE~, 5 R~ 19 ,~ O ., S-BuLl, TMEDA
~ Rs-X

R,'CH2 CH2R2' R~ ~ NEI, , I ~

R~'Ctl2 ~CH2R2 ` ~ ~

2~.

2 5 Roaction 802lel~le 8 :.

29 2~

An alternative route for synthesizing compounds of Formula 2 where R3 and R~ are hydrogen or lower alkyl, R5 is lower alkyl and A~ is COOH, is shown in Reaction 8chemo 8. This scheme serves as an illustrative example for the synthesis of compounds of the invention having substituents in the 4,4 and 6 positions or in the 2,2,4,4 and 6 positions of the chroman nucleus. In this scheme, the 7-carboxy-chromans (Compoun~ 18~ where R3 and R~ are hydrogen or lower alkyl serve as starting materials. Compound 18 is obtained in accordance with Re~ction 8cheme 5, 6 when R3 and R~ = H and in accordance with Reaction 8ch~o 7 (when R3 and R~ =
CH3). Compoun~ 18 is converted to the corresponding acid chloride, and thereafter to the corresponding diethylamide (Compound 19) through treatment with thionyl chloride and subseguently by treatment with diethylamine. The lower alkyl substituent at the 6 position of the chroman nucleus is introduced by alkylation of Compoun~ 19 with an alkyl halide (R5 -X), after treating Compound 19 with secondary butyl lithium in tetramethylethylenediamine (TMEDA). The resulting 6-substituted diethylamide (Compou~d 20) is thereafter converted into the corresponding 4,4,6 substituted or 2,2,4,4,6 substituted 7-carboxy chroman (Compoun~ 21) by hydrolysis, for example under appropriate acidic or basic conditions.

- - ' :
.

WO 92/17426 PCI'/USg2~02346 ~ ~ V ~ s O, ~

o~ ?~a s ~ 2 R j X ~OH
2~ 0 R-action 8ch-m- 9 The synthetic sequence which provides 7-car~oxychroman intermediates unsubstituted in the 4 position, and substituted or unsubstituted in the 6-position, is shown in R-actlon ~ch-m- 9. The 7-bromo-2-oxo-chroman, also known as dihydrocoumarin (Compound 22) can be obtained, for example, by the steps outlined in R-actio~ 8¢hem- 7 using acrylic acid chloride (Rl, ~2 = H in Compound 11) and 3-bromo phenol derivative (Rs = H or lower alkyl in Compound 7).
Dihydro coumarin (Compound 22) is subjected to the reaction sequence outlined in R-action 8ch-m- 9 to yield, through the intermediate compounds 23 and 2~, the 2,2 disubstituted 7-carboxychroman (Compound 25). ..
Compoune 25 then can be reacted with an appropriate compound of Formula 3 to provide the esters of the invention, in accordance with For~ula 1. Alterna-. . .
.
. .
" '' ' W092/17426 PCT/US92/02~6 tively, the 2,2 disubstituted l-carboxy chroman (Compound 25) where ~5 is hydrogen may be alkylated in the 6- position of the chroman nucleus in accordance with the synthetic sequence described above in Re~ction 8ch~me 8 in connection with the analogous alkylation of 4,4 disubstituted and 2,2,4,4 tetrasubstituted 7-carboxy chromans (Compoun~ ~8). Thus, with specific reference now to Reaction 8¢~eme 10, Compound 26 is first converted to the corresponding diethylamide (Compound 27). The diethylamide (Compound 27) is alkylated with an alkyl halide (R5X) in the presence of secondary butyl lithium in tetramethylethylene diamine.
The resulting 6-substituted diethylamide (Compound 28) is thereafter converted into the corresponding 2,2,6-subRtituted 7-carboxy chroman (Compoun~ 29) for example by hydrolysis with base or acid.

R,~ ¦ NEI~

R~ ;OH ~ ~NEI, R~ctio~ 8c~ o . .
.
.: :

.

WO92/17426 PCT/~'S92~02~6 ~ 32 It should be noted that in accordance with For~ula 2 the R5 substituent may be attached to the 6-position, which has been described and is preferred, but also to the 5 position or 8-position of the chroman nucleus.
In addition, although the bromo substituted phenols are described and preferred, the iodo, chloro and other appropriately halogenated phenols can also be used in the above described synthetic steps leading to the compounds of the present invention.
The following examples of specific compounds of the invention, and specific examples of the synthetic steps in which the compounds and certain intermediates are made, are set out to illustrate the invention, not to limit its scope.
~ecl~
5-Bro~pnhçnyi 3.3-di~thyl ac~y~ (Compound 30) To an ice-cooled 6uspension of 4g (100 mmol) of sodium hydride (60% in mineral oil) in 50 ml of dry THF
was added dropwise a solution of 15.7 g( 90.7 mmol) of 3-bromo phenol in 25 ml of dry THF. The mixture was stirred at 0 degrees C for 0.5 hours and then treated with a solution of 10.65 g (90.0 mmol) of dimethyl acryloyl chloride in 30 ml of dry THF. The mixture was allowed to warm to room temperature and stirred for 24 hours. The rQaction miXture was poured onto 200 ml of ice water containing 3 ml of glacial acetic acid. The mixture was extracted with 2 x 250 ml ether and the combined ether extracts were washed with 200 ml of water and 100 ml saturated NaCl solution and dried (MgS04). The solvent was removed ~n vacuo and the residue purified by kugelrohr distillation to give the title compound as a clear oil.
PMR (CDC13): & 2.02 (3H, s), 2.28 (3H, s), 5.94 W092/17426 ~ PCT/US92/0~6 (lH, broad s), 7.06 - 7.12 (lH, m ), 7.28 (lH, t, J -a.o Hz), 7.34 (lH, t, J - 2.0 Hz), 7.37 - 7.42 (lH, m).
3-Bromo-2-(1.1 t 3-trimethvl-3-hydroxybutyl)pbçnol (Compound 32) s To a stirred, ice-cooled suspension of 21 g (158 mmol) of aluminum chloride in 200 ml of methylene chloride was added 810wly a solution of 23.74 g (93.1 mmol) of 5-bromophenyl-3,3-dimethyl acrylate (Compound 30) in 100 ml of methylene chloride. The mixture was warmed to room temperature and stirred for 52 hours.
The mixture was poured into a mixture of ice and brine and the organic layer was separated. The aqueous layer was extracted with 2 X 100 ml ether. The organic extracts were combined and washed with 2 X 250 ml of water and 50 ml of saturated NaCl solution and dried (MgS04). The solvent was removed i~ ~acuo and the residue was partially purified by flash colu~n chromatography, (silica; 5% ethyl acetate/hexane) to give impure 4,4-dimethyl-7-bromo-2-oxochroman (Compoun~
31) as a yellow oil which was used in the next step without further purification. To an ice-cooled solution of 10 g of this impure 4,4,dimethyl-7-bromo-2-oxo-chroman (Compound 31) in 200 ml of dry THF was added und~r argon 39.2 ml of 3.0 M Methyl Magnesium Chloride (117.6 ~mol) in THF. The reaction mixture was allowed to warm to room temperature and stirred for 5 hours. The reaction mixture was then poured into ice water containing 2 ml of sulfuric acid and the organic layer was separated. The aqueous layer was extracted with 200 ml of ether. The organic extracts were combined and washed with 200 ml of water and 200 ml of brin~ and dried (MgS04). The solvent was removed n vacuo and the residue purified by flash column W092/l7426 PCT/US92/02~6 ~ 34 chromatography (silica; 10% ethylacetate/hexanes) to give the title compound as a pale yellow oil.
PMR (CDC13): & 0.98 (6H, s), 1.36 ~6H, s), 2.15 (2H, s), 6.82 (lH, d, J - 1.9 Hz), 6.86 (lH, dd, J -5 8.3 Hz, 1.9 Hz), 7.04 (lH, d, J - 8.3 Hz).
2.2~4.4-tetramethyl-7-bromQçhroman (Compound 33) A mixture of 5.42 ~18.9 mmol) of 3-bromo-2(1,1,3 trimethyl-3-hydroxy-butyl) phenol ~Compound 32) and 50 ml of 20 percent aqueous sulfuric acid was heated at reflux for 24 hours. The reaction mixture was cooled to room temperature and treated with loO ml of ether.
The organic layer was separated and the aqueous layer was extracted with 50 ml of ether. The ether extracts were combined and washed with 100 ml of water and 100 ml saturated NaCl solution and dried (MgS04). The solvent was removed in y~ç~Q and the residue was purified by Kugelrohr distillation to g$ve the impure title compound as a pale yellow oil.
PMR (C~C13): ~ 1.22 (6H, s), 1.24 (6H, s), 1.72 (2H, s), 6.87 (lH, d, J - 2.0 Hz), 6.92 (lH, dd, J -8.3 Hz, 2.0 Hz), 7.02 (lH, d, J - 8.3 Hz).
2.2.4.4-Tetramethyl-7-carboxych~QE3n (Compound 3~) A solution of 1.78g (6.6 mmol) of 2,2,4,4-Tetramethyl-7-bromochroman (Compound 33) in 10 ml of ether was cooled to -78 dQgrees C under Argon and treated dropwise with 7.76 ml (13.19 mmol) of 1.7M t-Butyl Lithium solution. The mixture was stirred at -78 degrees C for 5 hours. A rapid stream of carbon dioxide gas was then bubbled throu~h the mixture for 1 hour while warming to room temperature. The mixture was then taken up with water and ether and the layers were separated. The ether layer was extracted with water and the combined aqueous extracts were washed ~, .

w092/17426 PCT~US92/02~6 with ether and then acidified with lN HCl until a white precipitate formed. The acidified mixture was cooled overnight and then extracted with ether. The organic }ayer was then washed with water and with saturated sodium chloride solution and dried (MgSO4). The solvent was removed in vacuo to give the title compound as a white solid.
PMR (CDC13): & 1.36 (6H, s), 1.38 (6H, s), 1.87 (2H, s), 7.38 (lH, d, J - 1.8 Hz), 7.56 (lH, d J - 1.8 Hz) 7.65 (lH, dd, J - 8.1 Hz, 1.8 Hz).
Ethyl-4-(2.2.4.4-Tetramethyl-7-chromanoyl-oxy)benzoate (compoun~ 1) A solution of 450 mg (1.923 mmol) of 2,2,4,4-Tetramethyl-7-carboxychroman (Compound 3~) and 320 mg (1.926 mmol) of Ethyl-4-hydroxy benzoate in 15 ml of methylene chloride was treated sequentially with 397 mg (1.924 mmol) of Dicyclohexylcarbodiimide and 58 mg (.475 mmol) of 4-Dimethyl-aminopyridine. The mixture was stirred for 18 hours and then filtered. The filtrate was concentrated in-vacuo and the resulting residue was purified by flash chromatography (silica:
10% ethyl acetate in hexanes) to give the title compound as a white solid.
PMR (CDC13): & 1.34 - 1.45 (15 H, m), 4.39 (2H, q, J - 7.0 Hz), 7.28 (2H, à, J - 8.7 Hz), 7.42 (lH, d, J -8.2 Hz), 7.65 (lH, d, J - 1.8 Hz), 7.73 (lH, dd, J -8.2 Hz, 1.8 Hz), 8.12 (2H, d, J - 8.7 Hz).
Benzy~-4(2.2.4.4-tetramethyl-7-chromanoyloxy~benzoate (Compound 2) A solution of 450 mg ~1.923 mmol) of 2,2,4,4 Tetramethyl-7-carboxychroman (Compound 34) and 440 mg (1.930) of Benzyl-4-hydroxy benzoate in 15 ml of methylene chloride was treated sequentially with 400 mg - , '~ , . .
. ~ .
. .-... . .

W092/17426 PCT/~S92/02~6 A t~j~

(1.940) of 1,3-Dicyclohexyilca~bodiimide and 58 mg (.475 mmol) of Dimethylaminopyridine. The mixture was stirred for 18 hours and filtered. The filtrate was concentrated in-vacuo and the residue was purified by flash chromatography (silica; 10% ethylacetate in hexanes) to give the title compound as a white solid.
PMR (CDC13): & 1.39 (6H, s), 1.40 (6H, s), 1.89 (2H, s), 5.38 (2H, s), 7.29 (2H, d, J - 8.3 Hz), 7.34 -7.49 (6H, m), 7.66 (lH, d, J - 1.8 Hz), 7.73 (lH, dd, J
- 8.1 Hz, 1.8 Hz), 8.16 (2H, d, J - 8.3 Hz).
8y substituting, for example, methyl or propyl 4-hydroxybenzoate for benzyl 4-hydroxybenzoate or for ethyl 4-hydroxybenzoate as in the immediately preceding two specific examples, methyl 4-(2,2,4,4,tetramethyl-7-chromanoyloxy benzoate and propyl 4-(2,2,4,4-tetramethyl-7-chromanoyloxy) benzoate can be obtained, respectively.
4-~2~2,4 4-tetramethy~-7-ch~omanoylgxy~ benzoic acid (co~poun~ 3) To a degassed solution of 400 mg (.9 mmol) of Benzyl 4~(2,2,4,4-tetramethyl-7-chromanoyloxy) benzoate (Compoun~ 2) in 15 ml of Ethylacetate, under argon was added 130 mg of 10% Palladium on carbon. The mixture was placed under a hydrogen atmosphere at 5 PSI and hydrogenated for 3 hour`s. The mixture was then fil-tered through celite and the filtrate was concentrated in-vacuo to give the title compound as a white solid.
PMR (CDC13): & 1.39 (6H, s), 1.40 (6H, s), 1.90 (2H, s), 7.34 (2H, d, J - 8.7 Hz), 7.43 (lH, d, J - 8.1 Hz~, 7.67 (lH, d, J - 1.6 Hz), 7.74 (lH, dd, J - 8.1 Hz, 1.6 Hz), 8.21 (2H, d, J - 8.7 Hz).

~, .

Claims

WHAT IS CLAIMED IS:

1. A compound of the formula wherein the R1 - R6 groups are independently H or straight chain or branched chain lower alkyl or cycloalkyl groups of 1 to 6 carbons;
X is -COO-, -COS-, -OOC- or -SOC-;
Y is cycloalkyl or branched chain alkyl group of 3 to 6 carbons, or is (CH2)n where n is an integer between 0 to 6, and Z is H , OH , OR', OCOR', -COOH or a pharmaceutically acceptable salt, COOR8, CONR9R10, -CH2OH, CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -COR', COR'(OR12)2, or CR'OR13O where R' is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1-10 carbons, or a cycloalkyl group of 5-10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1-10 carbons, or a cycloalkyl group of 5-10 carbons or phenyl or lower alkyl phenyl, R11 is lower alkyl, R13 is divalent alkyl radical of 2 to 5 carbons.

2. A compound of Claim 1 where X is -COO-.

3. A compound of Claim 2 where Y is (CH2)n and n AMENDED CLAIMS
[received by the International Bureau on 4 December 1992 (04.12.92) original claims 7, 9, 11, 14, 19 and 21 amended; remaining claims unchanged (3 pages)]

is zero.

4. A compound of Claim 3 where Z is COOR8 wherein R8 is H, lower alkyl.

5. A compound of Claim 4 where R8 is hydrogen or lower alkyl.

6. A compound of Claim 2 wherein R1 and R2 are methyl, R3, R4 and R5 are hydrogen.

7. (Amended) A compound of Claim 6 wherein R5 is attached to the 6-position of the chroman nucleus.

8. A compound of Claim 2 wherein R3 and R4 are methyl, R1 R2 and R5 are hydrogen.

9. (Amended) A compound of Claim 8 wherein R5 is attached to the 6-position of the chroman nucleus.

10. A compound of Claim 2 wherein R1, R2. R3, and R4 all are methyl.

11. (Amended) A compound of Claim 10 wherein R5 is attached to the 6-position of the chroman nucleus.

12. A pharmaceutical composition comprising one or more compounds set forth in Claim 1 and a pharmaceutically acceptable excipient.

13. The pharmaceutical composition of Claim 12 which is useful for treating skin disorders in a mammal.

14. (Amended) A compound of the formula wherein the R1 - R6 groups are independently H or straight chain or branched chain lower alkyl or cycloalkyl groups of up to 6 carbons;
n is an integer between 0 to 6;
W is COOR8 and R8 is H, or lower alkyl, or W is CONR9R10 where R9 and R10 independently are H or lower alkyl or phenyl.

15. A compound of Claim 14 wherein n is zero.

16. A compound of Claim 14 wherein R1 - R4 groups are independently H or CH3.

17. A pharmaceutical composition comprising one or more compounds set forth in Claim 14 and a pharmaceutically acceptable excipient.

18. The pharmaceutical composition of Claim 17 which is useful for treating skin disorders in a mammal.

19. (Amended) A compound of the formula wherein R1 - R4 are independently H or CH3, R5 is H or lower alkyl of 1 - 6 carbons;
W is COOR8 and R8 is H, lower alkyl, phenyl or benzyl, or W is CONR9R10 where R9 and R10 independently are H or lower alkyl or a pharmaceutically acceptable salt thereof.

20. A compound of Claim 19 wherein R1 - R4 all are methyl.

21. Amended) A compound of Claim 20 wherein R5 is or methyl, W is COOR8 and R8 is H, lower alkyl or benzyl.

22. A compound of Claim 21 wherein R5 is H.

23. The compound of Claim 22 wherein R8 is ethyl.

24. The compound of Claim 22 wherein R8 is hydrogen, and pharmaceutically acceptable salts thereof.

25. The compound of Claim 22 where R8 is benzyl.