CHROMANS AND THIOCHROMANS WITH RETINOID-LIKE ACTIVITY

CHROMANES ET THIOCHROMANES A ACTIVITE RETINOIDE

English Abstract

2092178 9206084 PCTABS00011
Retinoid-like activity is exhibited by compounds of formula (I),
where X is S, O; R1, R2 and R3 are hydrogen or lower alkyl;
R4 and R5 are hydrogen or lower alkyl with the proviso that
R4 and R5 cannot both be hydrogen, R6 is hydrogen, lower
alkyl, lower alkenyl, lower cycloalkyl or halogen; n is 0 - 5, and
B is H, -COOH or a pharmaceutically acceptable salt, ester or
amide thereof, -CH2OH or an ether or ester derivative, or -CHO or
an acetal derivative, or -COR1 or a ketal derivative where R1
is -(CH2)mCH3 where m is 0-4, or a pharmaceutically
acceptable salt thereof.

Claims

WO 92/06084 PCT/US91/06901
WHAT IS CLAIMED IS:
1. A compound of the formula
<IMG>
where X is S or O;
R1, R2 and R3 independently are hydrogen or
lower alkyl;
R4 and R5 are hydrogen or lower alkyl with the
proviso
(i) that R4 and R5 both are not hydrogen
(ii) that R4 and R5 are not identical with
one another
n is an integer from 0 - 5;
R6 is hydrogen, lower alkyl, lower alkenyl or
lower cycloalkyl having 1 to 6 carbons, or halogen;
B is hydrogen, COOH or a pharmaceutically ac-
ceptable salt, ester or amide thereof, - CH2OH or an ether
or ester derivative thereof, or CHO or an acetal deriva-
tive thereof or -COR" or a ketal derivative thereof where
R" is an alkyl, cycloalkyl or alkenyl group containing 1
to 5 carbons.
2. A compound of Claim 1 where x is 5.
3. A compound of Claim 2 where n is 0, 1, or 2.
4. A compound of Claim 3 where n is 0.
5. A compound of Claim 3 where B is COOH or a
pharmaceutically acceptable salt, ester or amide thereof.

WO 92/06084 PCT/US91/06901
51
6. A compound of Claim 3 where R3 is hydrogen or
methyl.
7. A compound of Claim 2 where R4 is H.
8. A compound of Claim 1 where X is 0.
9. A compound of Claim 8 where the phenyl ring is
disubstituted in the 1, 4 positions and n is 0, 1, or 2.
10. A compound of Claim 9 where n is 0.
11. A compound of Claim 9 where B is COOH or a
pharmaceutically acceptable salt, ester or amide thereof.
12. A compound of Claim 9 where R3 is hydrogen or
methyl.
13. A compound of Claim 9 where R4 is H.
14. One or more compounds set forth in Claim 1,
comprised in and admixed with a pharmaceutical composition
including a pharmaceutically acceptable excipient.
15. One or more compounds set forth in claim 1,
comprised in and admixed with a pharmaceutical composition
as set forth in Claim 14, said composition being useful
for treating skin disorders in a mammal.
16. A compound of Claim 2 where R4 is lower alkyl
and R5 is lower alkyl, and R4 and R5 are different.
17. A compound of Claim 8 where R4 is lower alkyl
and R5 is lower alkyl, and R4 and R5 are different.
18. A compound of the formula
<IMG>

WO 92/06084 PCT/US91/06901
52
where R1, R2, and R3 independently are hydrogen or lower
alkyl;
R4 and R5 are hydrogen or lower alkyl with the
provisos
(i) that R4 and R5 both are not hydrogen
(ii) that R4 and R5 are not identical with
one another.
n is an integer between 0 to 5, and B is COOH or
a pharmaceutically acceptable salt, ester or amide there-
of, -CH2OH or an ether or ester derivative thereof, or CHO
or an acetal derivative thereof, or COR' or a ketal der-
rivative thereof, where R" is an alkyl, cycloalkyl or
alkenyl grop having 1-5 carbons.
19. A compound of Claim 18 wherein n is 0.
20. A compound of Claim 19 where B is COOH or a
pharmaceutically acceptable salt or an ester derrivative
thereof.
21. A compound of Claim 19 where R1, R2, are methyl,
R4 is hydrogen and R5 is methyl.
22. A compound of Claim 21 where R3 is H or CH3.
23. A compound of Claim 21 where B is COOH or a
pharmaceutically acceptable salt thereof.
24. The compound of Claim 23 where R3 is H or a
pharmaceutically acceptable salt thereof.
25. The compounds of Claim 21 where B is COOC2H5.
26. The compound of Claim 25 where R3 is H.
27. A process for synthesizing a compound of the
formula (i)
<IMG> (I)

WO 92/06084 PCT/US91/06901
53
where X is S or O;
R1, R2 and R3 are independently hydrogen or lower
alkyl;
R4 is lower alkyl;
R6 is hydrogen, lower alkyl, lower alkenyl or lower
cycloalkyl having 1 to 6 carbons or halogen;
n is an integer from 0 to 5;
B is hydrogen, COOH or a pharmaceutically acceptable
salt, ester or amide thereof, -CH2OH or an ether or ester
derivative thereof, or CHO or an acetal derivative there-
of, or -COR" or a ketal derivative thereof where R" is an
alkyl, cycloalkyl or alkenyl group containing 1 to 5
carbons, the process comprising the steps of:
reacting a compound of formula (ii)
<IMG> (II)
where R1, 22 and R3 are defined as above, and Y is halogen
when X is S and Y is hydrogen when X is O, with a Grignard
reagent having the formula R4-Mg-X' where X' is halogen,
to obtain a compound of formula (iii)

WO 92/06084 PCT/US91/06901
54
<IMG> (III)
where R1, R2, R3, R4, X and Y are defined as above;
converting the compound of formula (iii) to a com-
pound of formula (iv)
(IV)
<IMG>
where R1, R2, R3, R4, X and Y are defined as above;
saturating the compound of formula (iv) to provide a
compound of formula (v)
<IMG> (V)
where R1, R2, R3, R4, X and Y are defined as above;
converting the compound of formula (v) into the
compound of formula (i), said steps of converting (v) into
(i) including a step of reacting a compound of formula
(vi)

WO 92/06084 PCT/US91/06901
<IMG> (VI)
where R1, R2, R3, R4 and X are defined as above, with a
compound of formula (vii)
<IMG> (VII)
where X' is halogen, and R6, B and n are defined as above.
28. The process of Claim 27 where X is S.
29. The process of Claim 28 where R4 is CH3.
30. The process of Claim 29 where R1 and R2 are
methyl.
31. The process of Claim 30 where R3 is H.
32. The process of Claim 27 where X is 0.
33. A process for synthesizing a compound of the
formula (i)
<IMG>
(I)

WO 92/06084 PCT/US91/06901
56
where X is S or O;
R1, R2 and R3 are independently hydrogen or lower
alkyl;
R4 and R5 are lower alkyl, with the proviso that R4
and R5 are not the same;
R6 is hydrogen, lower alkyl, lower alkenyl or lower
cycloalkyl having 1 to 6 carbons or halogen;
n is an integer from 0 to 5;
B is hydrogen, COOH or a pharmaceutically acceptable
salt, ester or amide thereof, -CH2OH or an ether or ester
derivative thereof, or CHO or an acetal derivative there-
of, or -COR" or a ketal derivative thereof where R" is an
alkyl, cycloalkyl or alkenyl group containing 1 to 5
carbons, the process comprising the steps of:
reacting a compound of formula (ii)
<IMG> (II)
where R1, R2 and R3 are defined as above, and Y is halogen
when X is S and Y is hydrogen when X is O, with a Grignard
reagent having the formula R4-Mg-X' where X' is halogen,
to obtain a compound of formula (iii)
<IMG> (III)

WO 92/06084 PCT/US91/06901
57
where R1, R2, R3, R4, X and Y are defined as above;
reacting the compound of formula (iii) with a Grig-
nard reagent having the formula R5-Mg-X' where R5 and X'
are defined as above, to obtain a compound of formula (iv)
<IMG> (IV)
where R1, R2, R3, R4, R5, X and Y are defined as above;
converting the compound of formula (iv) to a compound
of formula (v)
<IMG>
(V)
where R1, R2, R3, R4, R5, X and Y are defined as above;
converting the compound of formula (v) into the
compound of formula (i), said steps of converting (v) into
(i) including a step of reacting a compound of formula
(vi)
<IMG> (VI)

WO 92/06084 PCT/US91/06901
58
where R1, R2, R3, R4, R5 and X are defined as above, with
a compound of formula (vii)
<IMG> (VII)
where X' is halogen, and R6 and n are defined as above.
34. The process o, Claim 33 where X is S.
35. The process of Claim 33 where X is O.

Description

W092/06084 PcT/ussl/06sol
2 ~ 8
. .
Chromans and Thiochro~nans w~th Retinoid-Like Activity
, .
. Backqround,
- 5 Cross-reference to Related APplication
',. 1. This application is a continuation-in-part of
... ~ pending application serial number 408,488, filed on Sep-
tember 19, 1989, and assigned to the same assignee as this
, application.
.~ lO Field of the Invention
2. This invention relates to novel compounds having
retinoid-like activity. More specifically, the invention
relates to compounds having an ethynylbenzoic acid portion
' and a second portion which is a 2-substituted tetrahydro-
~,, 15 quinolinyl, thiochromanyl, or chromanyl group. The acid
function may also be converted to an alcohol, aldehyde or
' ketone or derivatives thereof, or may be reduced to -CH3.
~ Related Art
.-~ Carboxylic acid derivatives useful for inhibiting the ',:
,~ 20 degeneration of cartilage of the general formula
4-(2-(4,4-dimethyl-6-X)-2-methylvinyl)benzoic acid where X
~' is tetrahydroquinolinyl, chromanyl or thiochromanyl are
J disclosed in European Patent Application 0133795 published
anuary 9, 1985. See also European Patent Application
'-l 25 176034A published April 2, 1986 where tetrahydronaph~tha-
~, lene comp~und~ having an ethynylbenzoic acid group are
~ disclosed, and United States Patent No. 4,739,098 where ~
,. three olefinic units from the acid-containing moiety of -~'
: retinoic acid are replaced by an ethynylphenyl functional~
t, 30 ity. : ,
~, Summary of the Invention
This invention covers compounds of Formula 1 :~

W092/n6084 PCT/US91/0690
. ','`
; 2~9i~178 2
. ,~ ., .
. '"' .
R4~ ~(C~2)n'B
~ s R~ ~3
.,j f .
"
i ~o~mula I
wherein x is S, o; Rl-R3 are hydrogen or lower alkyl, R~
and R5 are hydrog~n or lower alXy~ with the prov~so that
; lO R4 and R5 cannot both be hydrogen; ~6 is lower alkyl,
lower alkenyl, lower cycloalkyl having l to 6 carbons, or
halogen: n is 0-5; and B is H, -COOH or a pharmaceutically
acceptable salt, ester or amide thereof, -cH2OH or an
! ether or ester derivative, or -CHO or an acetal deriva- -
15 tive, or -CORl or a ketal derivative where Rl is an alkyl,
cycloalkyl or alkenyl group containing l to 5 carbons.
In a second aspect, this invention relates to the use
of the compounds of Formula 1 for treating dermatoses,
such as acne, Darier's disease, psoriasis, icthyosis,
20 ecæema, atopic dermatitis and epithelial cancers. These
compounds are also useful in the treatment o~ arthritic
diseases and other immunological disorders (e.g. lupus
erythematosus), in promoting wound healing, in treating
`, dry eye syndrome and in reversing the effects of sun
25 damage to skin.
This invention also relates to a pharmaceutical
formulation comprising a compound of Formiul~ 1 in admix-
!~`! ture with a pharmaceutically acceptable excipient. In another aspect, this invention relates to the
30 process for making a compound of Formula 1 which process
. .

W0~2/06084 PCT/US~1/069~1
3 2 ~ 8
.~,
-; comprises reacting a compound of Formula 2 with a compound
.~ of Formula 3 in the presence of cuprous iodide and
~ Pd(PQ3)2C12 (Q is phenyl) or a similar complex
,,. ~
~'
R, X'~--(CH2)
:. .
,-~ .
:~ :
Formula 2 Formula 3
where Rl-R6 are the same as described above, Xi is a
, halogen, preferably I: and n is the same as defined above; ~.
.~ and B is H, or a protected acid, alcohol, aldehyde or
ketone, giving the corresponding compound of Formula 1; or
20 to the process of making a co~pound of Formula 1 whicn
consists of reacting a zinc salt of Formula ~ with a
: compound of ~ormula 3 in the presence of Pd(PQ3)4 (Q is ..
I phenyl) or a similar complex.
.~ R1 R2 . :,
l 25 R4 ~ZnCI
~\ "
: R X R3
.. :
Formula ~ : ~
,
.''
...... ; . , . ... . .~ ..

WO 9~/06084 PCI/~JS91/06901
. ..
~'~92178 4
where Rl-R6, and x, are the same as defined above, giving
- the corresponding compound of Formula l; or homologatlng a
~ compound of the Formula 5
~,
,:i :
y ~ (CH3)n-E3
. 10 R j5 R 3 `
, .:
,
Formiula 5
' 15 where n is o-4 to give an acid of Formula ~; or
converting an acid of Formula 1 to a salt; or :
forming an acid addition salt;
converting an acid of Formula 1 to an ester; or
? converting an acid of Formiul~ 1 to an amiide; or
reducing an acid of ~ormula 1 to an alcohol or alde-
hyde: or
~ converting an alcohol of Fo~mula 1 to an ether or
!'~ ester; oroxidizing an alcohol of Formula 1 to an aldehyde; or
converting an aldehyde of For~lula 1 to an acetal; or
converting a ketone of Formula 1 to a ketal.
General Embodiments
Definitions
The term "ester" as used here refers to and covers
30 any compound falling within the definition of that term as
classically used in organic chemistry. Where B (of ~ormiu-
.~., . , ., . , . ~ ... . .. .....

:` ~ WO92/060~4 PCI`/US~1/06901
:
2~92~7~
., .
: la 1) is -COOH, this term c~vers the products derived from
treatment of this function with alcohols, preferably with
aliphatic alcohols having 1-6 carbons. Where the ester is
derived from compounds where B is -CH2OH, this term covers
compounds of the formula -CH2OOCR where R is any substi-
; tuted or unsubstituted aliphatic, aromatic or aliphatic-
aromatic group, preferably with 1-6 carbons in the ali-
phatic portions.
Preferred esters are derived from the saturated
10 alipha~ic alcohols or acids of ten or fewer carbon atoms
or the cyclic or saturated aliphatic cyclic alcohols and
acids of 5 to 10 carbon atoms. Particularly preferred
aliphatic esters are those derived from lower alkyl acids
;j or alcohols. Here, and where ever else used, lower alkyl
15 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
; 20 unsubstituted amides and all aliphatic and aromatic mono-
and di-substituted amides. Preferred amides are the mono-
;~ and di-substituted amides derived from the saturated
aliphatic radicals of ten or fewer carbon atoms or the
cyclic or saturated aliphatic-cyclic radicals of 5 to 10
25 carbon atoms. Particularly preferred amides are those
derived from lower alkyl amines. Also preferred are mono-
and di-substituted amides derived from the phenyl or lower
alkylphenyl amines. Unsubstituted amides are also pre-
ferred.
Acetals and ketals include the radicals of the formu-
~ la -CK where K is (-OR)2. Here, R is lower alkyl. Also, K
`I may be -ORlO- where R1 is lower alkyl of 2-5 carbon atoms,
straight chain or branched.
'.
. ''.
~,: . ~ ' . .. .. . ..

~ W092/0~084 PCT/US91/~6901
` .
~ 6
1 7 8
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
5 may be any salt which retains the activity of the parent
compound and does not impart any deleterious or untoward
; effect on the subject to which it is administered and in
- the context in which it is administered.
Such a salt may be derived from any organic or inor-
10 ganic acid or base. The salt may be a mono or polyvalent
ion. of pa~ticular 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 ~ono-,
l; di- and trialkyl amines or ethanol amines. Salts may also
be formed with caffeine, tromethamine and similar mole-
cules. Where there is a nitrogen sufficiently basic as to
be capable of forming acid addition salts, such may be
formed with any inorganic or organic acids or alkylating
20 agent such as methyl iodide. Preferred salts are those
formed with inorganic acids such as hydrochloric acid,
sulfuric acid or phosphoric acid. Any of a number of
simple organic acids such as ~ono-, di- or tri-acid may
also be used.
The preferred compounds of this invention are those
where the ethynyl group and the B ~Jroup are attached to
the 1 and 4 positions respectively of a benzene ring (l.e.
where the phenyl moiety of the compound is ~ara substitut-
ed) n is O; and B is -COOH, an alkali metal salt or organ-
30 ic amine salt, or a lower alkyl ester thereof, or -CH2OH
and the lower alkyl esters and ethers thereof, or -CHO and
acetal derivatives thereof. The more preferred compounds
shown in Formula 6 are:

W092/06084 PCT/~S91/06901
7 $
ethyl 4-[(2,2,4,4-tetramethylthiochroman-6-yl)-ethynyl] .
benzoate (Compou~d 1 X = S, R3 = H, R4 = CH3, R5 = CH3, R"
. = C2H5);
,.:` 4-[(2~2~4~4-tetramethylthiochroman-6-yl)-ethynyl] benzoic ..
~! 5 acid (Compou~d 2, X = S, R3 = H, R4 = CH3, R5 = CH3, R" =
`~ H); ..
' ethyl 4-[(2,2,4,4-tetramethylchroman- 6 - yl) - ethynyl] :
; benzoate (Compou~d 3, X = 0, R3 = H, R4 = CH3, R5 = CH3, `-
i R" = c2H5);
, 10 4-[(2,2,4,4-tetramethylchroman-6-yl)-ethynyl] benzoic acid
(Compound ~, X = O, R3 = H, R4 = CH3, Rs = CH3, R" = H);
ethyl 4-[(2,2,4,4,7-pentamethylthiochroman-6-yl)-ethynyl]
benzoate (Compound 5, X = S, R3 = CH3, R4 = CH3, R5 = CH3,
R C2H5); `:
,~ 15 4-~(2,2,4,4,7-pentamethylthiochroman-6-yl)-ethynyl] benzo-
,' ic acid ~compoun~ 6, X = S, R3 = CH3, R4 = CH3, R5 = CH3, :~
R" - H)
ethyl 4-[(2,2,4,4,7-pentamethylchroman-6-yl)-ethynyl]
benzoate (Co~pound 7, X = 0, R3 = CH3, R4 = CH3, R5 = CH3,
20 R~ = C2H5):
~! 4-[(2,2,4,4,7-pentamethylchroman-6-yl)-ethynyl] benzoic
acid (Compound 8, X = 0, R3 = CH3, R4 = CH3, R5 = CH3, R"
~ H)
athyl-4[(2,4,4,trimethyl-6-thiochromanyl)- .
25 ethynyl]benzoate (Compoun~ 56, X = S, R3 = H, R4 = H, R5 =
CH3, R~ = C2~5)
4-(2,4,4,trimethyl-6-thio-chromanyl)-ethynyl benzoic
. acid (Compoun~ 57, X = S, R3 = H, R4 = H, R5 = CH3, R" =
"'' ' '`'~'
J ' ~' ~

~ W092/~6084 PCT/VS91/06901
.. i,.
;,
2~9'i~17~ 8
. ~
.~` ~ .-.,.
~ ~ r
R"
'~ R
; 5
.. ... .
!~
, .`. .
"~ 10 Formula 6
The compounds of this invention may be administered
I systemically or topically, depending on such considera-
~ tions as the condition to ~e treated, need for site-spe-
`' cific treatment, quantity of drug to be administered, and
15 similar considerations.
` In the treatment of dermatoses, it will generally be
~;` preferred to administer the drug topically, though in
certain cases such as treatment o~ severe cystic acne,
'1 oral administration may also be used. Any common topical
20 ~rmulation 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 exe~plified, for example,
~ Reminqton's Pharmace~ ca~ science, Edition 17, Mack
.
25 Publishing Company, Easton, Pennsy:vania. 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
, 30 as a syrup or elixir for oral administration. For in-
travenous or intraperitoneal administration, the compound
~ ,
. ~ . .
., ~

-` W092/06~84 PCT/US91/~6901
.
., 9 `. 2~:9~1 78 ~. .
.. . .
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 formu-
lation for such secondary purposes as treating skin dry-
ness, providing protection against light; other medica-
; tions for treating dermatoses, preventing infection,
10 reducing irritation, inflammation and the like.
i Treatment of dermatoses or any other indications
known or discovered to be susceptible to treatment by
retinoic acid-liXe compounds will be effected by adminis-
tration of the therapeutically effective dose of one or
s 15 more compounds of the instant invention. A therapeutic
concentration will be that concentration which effects
reduction of the particular condition, or retards its
expansion. In certain instances, the drug potentially
could be used in a prophylactic manner to prevent onset of
20 a particular condition. A given therapeutic concentration
will vary from condition to condition and in certain
, instances may vary with the severlty of the condition
being treated and the patient's susceptibility to treat-
ment. Accordingly, a given therapeutic concentration will
2, be best determined at the time and place through routine
experimentation. However, it is anticipated that in the
I 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-
30 stitute a therapeutically effective concentration. If
administered systemically, an amount between 0.01 and 100
mg per kg body weight per day, but preferably about 0.1 to
10 mg/kg, will effect a therapeutic result in most in-
., . ,, ', !,.. ,, ., , , ' ,. . ... '. . . . .. .. : ' ' ' ' ' ' - ' '

- W092/06084 PCT/~S91/06901
, . .
~,
~ ~09217~ lO
stances. -
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 orni-
-ii 5 thine decarboxylase. The original work on the correlation
~; between retinoic acid and decrease in cell proliferation
' !
was done by Verma & Boutwell, Cancer Research, 1977, 37,
1 2196-2201. That reference discloses that ornithine decar-
:'! boxylase (ODC) activity increased pr~cedent to polyamine
10 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, cPll hyperproliferation could
; be modulated. Although all causes for ODC activity in-
15 crease are unknown, it is known that 12-0-tetradecanoyl-
phorbol-13-acetate (TPA) induces ODC activity. Retinoic :
acid inhi~its this induction of ODC activity by TPA. The
compounds o~ this invention also inhibit TPA induction of
ODC as demonstrated by an assay essentially following the
20 procedure set out in Cancer Res., 35: 1662-1670, 1975.
By way of example of retinoic acid-like activity it
is noted that in the assay conducted essentially in ac-
1 cordance with the method of Verma ~ 80utwell, ~ , the
! ~ollowing examples o~ the pre~erred compounds oE the
25 present invention ~Compound3 1, 3 a~d 7~ attained an 80%inhibition o~ ~PA induced ODC acti.vity at the ~ollowing
concentrations (IC80):
'! Compound IC80 conc (nmols)
~ 1 1.2
i 30 3
7 1.0
56 2.2
57 .24
- - - . ; .. , .. ,.. , ,, ,,,,, " ,. . . . . .

~ W092/0608~ PCT/US9l/0690l
.
, 11 ~as2l7s
'
Specific Embodiments
- The compounds of this invention can be made by a
number of different synthetic chemical pathways. To
-i illustrate this invention, there is here outlined a series
of steps which have been proven to provide the compounds
of Formula 1 when such synthesis is followed in fact and
in spirit. The synthetic chemist will readily appreciate
that the conditions set out here are specific embodiments
which can be generalized to any and all of the compounds
10 represented by ~ormula 1. Furthermore, the synthetic
chemist will r~adily appreciate that the herein described
synthetic steps may be varied and or adjusted by those
skilled in the art without departing from the scope and
spirit of the invention.
Compounds of Formula 1 where X is -S- and R4 and R5
are hydrogen or lower alkyl, with the proviso that R4 and
R5 both are not hydrogen, are prepared as per Reaction
8cheme I
Reaction 8cheme I
.,.~ .
.i .
2s ~¢~Br O R~ R,~ ~R~ Br
H S R3 Cl o~S~R3
9 1 0
.~. .
,. .
., .
`I ` ~
.
.

s
`WO 92/06084 P~/lJS91/06901
'"' I
-~` '2~9~17~ 12
~ ,
i~ R,,
~, ' 1>~ '
O S R 3 H R ~
.~, ...
12 1 3
' .: .
,1 :,
~ ar
.j 5
!, lS 1 5 1 4
!
.j
.
Rl R2 ~;
R 1 ~
j R /~S R,
~ ~:

W092/06084 PCT/US91/069~1 .
,j 13~92178
;.. `. :
. ".
.....
^~, .
. R~
~ X~ (C~2)n^8 R1 R2 1 6
: X ~ ~ ` '
1 6 ,. R4~S R~ " (CH2)n B
~ I X~ (CH2)n'~
,'~ 10 / :
,.,,
R4~ZnCI
,,i R S R HOMOLOGS AND :~.
s 3 DERIVATIVES
;' 15 17 19
,1, ''"~:`'`
;.~
, ~1 - :
.. , 20 In Reaction 8cheme I, Rl-R3 are hydrogen or a lower
alkyl group, R6 is defined as above in connection with -
Formul~ l, n is 0-5 and B is H, or a protected acid,
alcohol, aldehyde or ketone. S~ is Cl, Br or I when n is
O but preferably be Br or I when n is 1-5.
Compounds of Formula l where 2 is oxygen and R4 and ~
R5 are hydrogen or lower alkyl, with the proviso that R~ :
and R5 both are not hydrogen, are prepared as per Reaction ,~
8cheme 2. ; ;
'...
. .,':.'

~ ~/0 ~2/06084 PCI/US91/06901
. . .
2~2~ ~8 14
Reaction ~icheme ~
Ho~R3 Cl~ o~o~R,
s -- 2 1
~ .
. . .
21 ~ _ R~
O O R3 H R3
22 ~
. `
. l
R,~ R2 ll R1~R2
R,~ R
1 25 :~
,. .
R,~
R5 R3
~

~; WO 92/06084 P~/US91/06901
R6 15 ~9~178
X~ CH2~"-D R~ (CH~)n-B
.,. S R6 ~ ..
X ~ ( C H 2) n~ B /~
/ ': '
.'
10 R 1 ~ 2
R4~ZnCI ' ~
. /~o HOMOLOGS AND
Rs 3 DERIVATIVES
.~, 15 2~
, In Re~ctlon 8cheme 2 the definitions of Rl-R6, ~, B
and ~' are the same as in Reaction 8cheme 1.
, A general description of the synthetic steps outlined
in Reaction 8cheme~ ~ and 2 is as follows.
In ~eaction 8cheme 1 the 4-bromo-thiophenol (Compound
9) is acylated with an acylating agent, such as an acid
chloride (compou~ ~o) derived fro~ an appropriately
substituted acrylic acid. The acylation is conducted in
an inert solvent (such as tetrahydrofuran) in the presence
- 25 of strong base (for exa~ple sodium hydrdride). The re-
sulting thioester (Co~pou~d 11) which contains the olefin-
ic bond of the acrylic acid moiety is ring closed in the
presence of a Friedel Crafts type catalyst (such as alumi-
; num chloride) by stirring in a suitable solvent such as
methylene chloride. The resulting 2-oxo-6-bromo-
thiochroman (Compound 12) is usually isolated in crystal-
7 line form.
The R4 and/or R5 substituents (both of which cannot
':
,:
' ~' '

W092/06084 PCT/US91/06901
2~17~ 16
be hydrogen in accordance with the invention) are intro- î
:~ duced by treating the 2-oxo-6-bromo-thiochroman (Compoù~d
12) with a Grignard reagent, bearing the alkyl substitu-
ents R4 and R5 (such as methylmagnesium bromide when R4
- , and R5 are methyl). When the Grignard reagent (such as
methylmagnesium bromide) is in excess, the thiochroman
ring is opened and the tertiary alcohol derivative of the
4-bromo thiophenol (Compound 13) is formed.
Rins closure of the thiophenol derivative (Compound
~ lO 13 ) which has the desired Rl, R2, R3, R4 and R5 substitu-
; ents, is affected by heating in acidic conditions, prefer-
ably by heating Compound l~ in zqueous acid. The result-
- ing 6-bromothiochroman which bears the desired alkyl (or
hydrogen) substituents, Rl, ~2~ R3, ~4 and R5 is shown as
`, 15 Compound 14 in R~action 8cheme l.
To introduce the acetylene (ethyne) portion into the
molecule, the substituted 6-bromothiochroman 14 is reacted
with trimethylsilylacetylene in the presence of cuprous
4! iodide and a suitable catalyst, typically having the
20 ~ormula Pd(PQ3)2Cl2 (Q is phenyl). The reaction is typi-
cally conducted in the presence of bis(triphenylphosphine)
palladium (II) chloride catalyst, an acid acceptor, (such
as triethylamine) under an inert gas (argon) atmosphere,
by heating in a sealed tube. The resulting 6-trimethylsi-
25 lylethynylthiochroman is shown as Compou~d 15 in Reaction
Scheme 1.
As is shown on Rea~tion 8cheme l, the trimethylsilyl
moiety is removed from the 6-trimethylsilylethynyl-thio-
chroman 15 in the next synthetic step, to provide the ring
30 substituted 6-ethynyl-thiochroman derivative (Compound
; 16). The latter reaction is conducted under basic condi-
tions, preferably under an inert gas atmosphere.
In order to introduce the phenyl or substituted

W O 92/0~084 PC~r/VS91/06901
17 2~217~
phenyl substituent on the acetylene (ethyne) portion of
Compound 16, Compou~d 16 is coupled with the reagent a~-Q
(cH2)n-s (~ormula 3, Q is a di- or multi-substituted
phenyl residue) ~Aere the symbols ~, x~ and B have the
5 same meaning as defined in connection with Formula 3. In `~ -
other words, the phenyl or substituted phenyl substituent
is introduced into the 6-ethynyl-thiochroman 16 by react-
ing the latter with a halogen substituted phenyl compound
(Formula 3) in which the ben~ene nucleus either has the
10 desired substituent [(CH2)n-B] or wherein the actual
substituent (CH2)n-B can be readily converted to the
desired substituent by means of organic reactions well
known in the art.
Coupling of the 6-ethynyl-thiochroman 16 with the
lS reagent ~I-Q-(CH2)n-B is affected directly in the presence
of cuprous iodide, a suitable catalyst, typically of the
formula Pd~PQ3)2C12 and an acid acceptor, such as triethy-
lamine, by heating in a sealed tube under an inert gas
(argon) atmosphere.
The resulting disubstituted acetylene compound
~ (Compound 18) may be the target compound made in accord-
; ance with tha invention, or maybe readily converted into
the target compound by such steps as salt formation,
esterification, deesterification, homologation, amide
25 formation and the like. These steps are further discussed
below.
Compou~d 18 may also be obtained by first converting
the 6-ethynyl-thiochroman derivative 16 into the corre-
sponding metal salt, such as a zinc salt, (Compound 17)
30 and thereafter coupling the salt 17 with the reagent X'-Q-
(CH2)n~B (Formula 3 Q is phenyl or substituted phenyl
residue) in the presence of a catalyst having the formula
Pd(PQ3)4 ~Q is phenyl), or similar complex.
'

W092/06084 PCT/~S91/06901
, . ...
, 2~2178l8
Derivatization of Compound 18 is indicated in Reac-
tion 8cheme 1 as conversion to "homologs and derivatives",
Co~pound~ 19.
i More specifically with respect to either derivatiza-
tion or deblocking of pro~ected functionalities in Com-
pound 18, or with respect to the preparation of phenyl
; derivatives of the formula Xl-Q-(CH2)n-B, (which after
coupling either directly yield the compounds of the inven-
~, tion, or are readily converted into them) the following is
10 noted.
Where a protected phenyl derivatives is needed to
couple with the compounds of Formula 2 (Compoun~s 16 in
~aaction Bchem~ 1), such may be prepared from their corre-
sponding acids, alcohols, ketones or aldehydes. These
' lS starting materials, the protected acids, alcohols, alde- .
;~ hydes or ketones, are all available from chemical manufac-
turers or can be prepared by published methods. Carboxyl-
ic acids are typically esterified by refluxing the acid in
a solution of the appropriate alcohol in the presence of
20 an acid catalyst such as hydrogen chloride or thionyl
chloride. Alternatively, the carboxylic acid can be
condensed with the appropriate alcohol in the presence of
.~
;^ dicyclohexylcarbodiimide and dimethylaminopyridine. The
' ester is recovered and purified by ccnventional means.
25 Acetals and ketals are readily ~ade hy the method de-
scribed in March, "Advanced Organic ~hemistry," 2nd Edi-
tion, McGraw-Hill Book Company, p 81~). Alcohols, alde-
hydes and ketones all may be protected by forming respec-
tively, ethers and esters, acetals or ketals by known
30 methods such as those described in McOmie, Plenum Publish-
ing Press, 1973 and Protectina GrouDs, Ed. Greene, John
Wiley & Sons, 1981.
To increase the value of n before effectin~ a cou-
`" ,
~.
,.

W092/06084 PCT/~S91/06901
19 ~2~ ~
pling reaction, where such compounds are not available -
from a commercial source, the phenyl derivatives where B
is -COOH are subjected to homologation by successive
~A treatment under Arndt-Eistert conditions or other homolo-
5 gation procedures. Alternatively, phenyl derivatives
where B is different from COOH, may also be homologated by
appropriate pxocedures. The homologated acids can then be
esterified by the general procedure outlined in the pre-
ceding parzgraph.
An alternative means for making compounds where n is
1 - 5 is to subject the compounds of Formu}a 1, where B is
an acid or other functi~n, to homologation, using the
Arndt-Eistert method referred to above, or other homologa-
tion procedures.
The acids and salts derived from Formula 1 are readi-
ly obtainable from the corresponding esters. Basic sapon-
i~ication with an alkali metal base will provide the acid.
For example, an ester of Formula 1 may be dissolved in a
; polar solvent such as an alkanol, preferably under an
20 inert atmosphere at room temperature, with about a three
, molar excess of base, for example, potassium hydroxide.
~he solution is stirred for an extended period of time,
between 15 and 20 hours, cooled, acidified and the hydro- :
lysate recovered by conventional ~eans.
The amide may bQ formed by any appropriate amidation
means known in the art ~rom the corresponding esters or
carboxylic acids. One way to prepare such compounds is to
convert an acid to an acid chloride and then treat that
compound with ammonium hydroxide or an appropriate amine.
30 For example, the acid is treated with an alcoholic base
solution such as ethanolic KOH (in approximately a 10~ ;
molar excess) at room temperature for about 30 minutes.
The solvent is removed and the residue taken up in an
.

W092/0~084 PCT/US91/0690~
;
20~ 8 20
organic solvent such as diethyl ether, treated with a
dialkyl formamide and then a 10-fold excess of oxalyl
chloride. This is all effected at a moderately reduced
temperature bet~een about -10 degrees and +10 degrees C.
The last mentioned solution is then stirred at the reduced
temperature for 1-4 hours, preferably 2 hours. Solvent
removal provides a residue which is taken up in an inert
inorganic solvent such as benzene, cooled to about o
degrees c and treated with concentrated a~monium hydrox-
10 ide. The resulting mixture is stirred at a reduced tem-
perature ~or 1 - 4 hours. The product is recovered by
conventional means.
Alcohols are made by converting the corresponding
acids to the acid chloride with thionyl chloride or other
1~ means (J. March, "Advanced Organic Chemistry", 2nd Edi-
tion, McGraw-Hill Book company), then reducing the acid
chloride with sodium borohydride (March, Ibid, pg. 1124),
which gives the corresponding alcohols. Alternatively,
esters may be reduced with lithium aluminum hydride at
20 reduced temperatures. Alkylating these alcohols with
appropriate alXy halides under Williamson reaction condi-
tions (March, I~id, pg. 357) gives the corresponding
ethers. These alcohols can be converted to esters by
reacting them with appropriate acids in the presence o~
acid catalysts or dicyclohexlcarbodii~ide and dimethlami-
nopyridine.
, Aldehydes can be prepared from the corresponding
; primary alcohols using mild oxidizing agents such as
pyridinium dichromate in methylene chloride (corey~ E. J.,
30 Schmidt, G., Tet. Lett., 399, 1979), or dimethyl sulfox-
ide/oxalyl chloride in methylene chloride (Omura, K.,
Swern, D., Tetrahedron 1978. 34, 1651).
Ketones can be prepared from an appropriate aldehyde
.

WO 92/06084 Pcr/uS9l/û6901
; . . .
.,
~. . ~.
by treating the aldehyde with an alkyl Grignard reagent or
similar reagent followed by oxidation.
. Acetals or ketals can be prepared from the corre-
sponding aldehyde or ketone by the method described in
; 5 March, Ibid, p 810. :
Compounds where B is H can be prepared from the
corresponding halogenated benzene compounds, preferably
where the halogen is I.
With reference tO Reaction Scheme 2, phenol, or a
lO phenol substitut~d in the 3 (meta) position by an alkyl
substituent (R3) (Compound 20) is acylated with an acylat-
ing agent, such as an zcid chloride (Co~ound lo) derived
from an appropriately substitu,~d acrylic acid. In Reac-
tion Scheme 2, just as in Reaction Scheme 1, the Rl and R2
15 substituents of the target compounds are introduced
throùgh this acrylic acid derivative lo. The acylation -
with the acid chloride lo is preferably conducted in the
presence of a strong base ~e.g. sodium hydride) in an
inert solvent (such as tetrahydrofuran). The resulting
20 substituted phenyl-acrylate is shown in Reaction Scheme
as Compound 21.
The substituted phenyl-acrylate 21 is ring closed
under Friedel Crafts type reaction conditions (AlCl3
` catalyst, in an inert solvent, such as methylene chloride)
; 25 to provide the 2-oxo-chroman compound (Compoun~ 22) which
bears, in the 4-position, the Rl and R2 substituents and
-~ in the 6 pasition the R~ substituent (as applicable).
Just like the analogous 2-oxo-thiochroman 12 in Reaction
8ch~me 1, the 2-oxo-chroman 22 of Reaction 8cheme 2 is
j 30 treated with a Grignard reagent to introduce the R4 and R5
substituents. As it was noted out above, R4 and R5 both
cannot be hydrogen. When ~4 and R5 are methyl, the Grig-
nard reagent is preferably methylmagnesium chloride
. .

W092/06084 PCT/US91/06gOI
22
~2~7~
(dissolved in tetrahydrofuran, THF). A solution of Com-
poun~ 22 in a suitable solvent, for example in dry diethy-
lether ls added to this Grignard reagent. The resulting
phenol containing a tertiary alcohol side chain, (that is
- , a molecule ln which the chroman ring had been opened) is
shown in Reaction Schema 2 as Compound 23.
cOmpOuna 23 T~hlch already has the desired Rl, R2, R3,
R4 and R5 substituents, is ring closed under acidic condi-
tions, (e.g. by heating in aqueous sulfuric acid) to
io provide the chroman derivative (Co~pound 24). It should be
noted that up to this point in the synthetic sequence
(which is p ef~rably but not necessarily exclusively used
for making the compounds of tha invention) similar or
analogous steps are involved for making both the thiochro-
l; man (Reaction 8cheme 1) and chroman derivatives (Reaction8cheme 2), the only difference being that in Reactio~
8cheme 2 the starting phenol derivative does not have a
halogen (sUCh as a bro~o) substituent.
Because of the lac~ of the halogen substituent in the
20 preferred synthetic sequence for preparing the chroman
compounds of the invention, the preferred and herein
illustrated steps (Reactio~ 8che2e 2) for introducing the
acetylene (ethyne) ~roup into the 6-position of the chro-
man moiety are different ~rom the steps utilized ~or
2~ introducing the acetylene moiety into the analogous thio-
chroman (Raaction 8cheme 1).
Thus, in Re~cti~n 8c~eme 2 an a etyl group is intro-
duced into the 6-position of the chroman derivative 24
under
30 Friedel-Crafts type conditions. This acetylation is
preferably conducted with acetyl chloride, in nitromethane
solvent, in the presence of aluminum chloride. The re-
sulting 6-acetyl-chroman derivative is Compound 25.
.
,.,:,,

WO 92/06084 PCI/US91/06901
:` :
23
~,
The acetylenic (triple) bond is introduced into the
molecule ~y converting the 5-acetyl moiety of chroman 25
to an acetylene moiety. This is accomplished, preferably.,
by treatment with lithium diisopropylamide (at low temper-
5 ature, such as - 78 degrees C) which causes enolization of
the acetyl group. The intermediate enol c~mpound (not
; shown in Reaction ~cheme 2) is esterified by treatment
with diethylchlorophosphate (or the like) and is again
reacted at reduced temperature (e.g. - 78 degreeis C) with
10 litAium diisopropylamide, to for~ the triple bond (presum-
ably by an elimination reaction) and to yield the 6-ethy-
nyl-chroman derivative (Compou~d 2~).
It is noted at this point that the present invention
is not intended to be limited or bound by the above-men-
` 15 tioned and other theories of reaction mechanisms. Brief
description of theory of reaction mechanisms ~where ap-
plicable) are given to further enable and facilitate the
work o~ a skilled artisan in the field to modify and
adjust the synthetic conditions to fit particular specific
20 intermediates and to make the several compounds of the
invention, without departing from the scope and spirit of
the invention.
Referring back again to Rea~tlon Sche~e 2, the 6-
ethynyl-chroman derivative ~6 may be converted into the
25 tàrget compounds of the invention in synthetic steps which
are analogous to the conversion of 6-ethynyl-thiochromans
(Comp~und.16) into the corresponding target thiochroman
derivatives (See Re~ction Bchem~ 1). Briefly, Compound 26
is preferably heated with a reagent X'-Q-(CH2)n-B (~ormula
30 3 Q is phenyl or substituted phenyl residue) in the
presence of cuprous iodide, a suitable catalyst, typically
of the formula Pd(PQ3)2 C12 (Q is phenyl or the like) and
an acid acceptor, such as triethylamine. This coupling
.

W092/06084 PCT~US91/06901
i. ~
~3~ 78 24
reaction, yields the target chroman compounds, (Compound
28) or such derivatives which are readily converted into
the target compounds by protection, deprotection, esteri-
fication, homologation etc., as is discussed in connection
with Reaction ~cheme 1. The homologs are indicated, as a
group, as Compou~d 2~a in ~aaction 8chema 2.
Alternatively, the 6-ethynyl-chroman compounds 26 may
first be converted to the corresponding metal (zinc) salt
(Compound 27) and therea~^ ~r coupled with the reagent
10 X'-Q-(CH2)n-B (~ormula 3 Q is phenyl substituted phenyl
residue) under conditions which are similar to the condi-
tions described in R82ction Sch~me 1 for coupling of
Compound~ 18 with the same reagent.
R~ACTION SCHEM~ 3
o~R3 H;~R,
. 20 12 4~
;~ I
'' ~ .
Ri ~R, R?~R~
14 50
"
. ~ .
` '` '' '; '''.' ".' ' '.', ' ' "' ' ` ', "'' ''`'" ,"~'', `''.;` ' ' ',

` W O 92/06084 PC~r/US91/06901
.~ ,
2~'~2~7~
REACTION SCHEME ~
0~5<J~R3 ~R
12 ~ - :
, ' I ''`'''`''
R~ ~ R/ O~ Br
14 1~ .
Referring to Reaction 8cheme 3 substituted 6-bromo
thio chroman 14, where the R4 or R5 sub~tituent is alkyl .
and the other is hydrogen can be made by treating the 2-
oxo-6-bromo-thiochroman (Compound 12) with a Grignard
20 reagent. As in React~on 8cheme 1 the 2-oxo-thiochroman 12
is subjected to an excess of Grignard reagent, bearing the
alkyl substituents ~4 or R5 (such as methylmagnesium
bromide when R4 or RS is methyl). However, the reaction
temperature is controlled to and maintained at a relative-
1 25 ly low temperature (such as -14 degrees C) and ~he dura-
l tion of the reaction is kept relatively short (0.5 hours).
A hemiacetal derivative o~ 4-bromothiophenol (Compoun~ ~9)
is formed.in this controlled Grignard reaction, as shown
in Reactlon 8cheme ~. Cyclization of the thiophenol
'~ 30 derivative Compound 49 is affected by heating in acidic `
conditions, preferably by aqueous acid, to give the unsat-
urated thio olefin (Compound 50). The 6-bromothioolefin
:(Compound 50) is reduced by hydrogenation in the presence
of palladium sulfide-on-carbon catalyst at increased
.
. .
.:

W092/06084 PCT/US91/Ofi901
2~7~ 26
pressure (approximately 30 psi). The resulting 6-bromo-
thiochroman which bears the desired hydrogen and alkyl
substituents Rl, R2, R3, R4 and R5 with one of R4 or R5
being hydrogen, is shown as Compound l~.
Again, referring to 6-bromo-thio chroman, 14, in
Reactio~ ~chame 1 the ~ and R5 substituents, both of
which are alkyl but not identical with one another in this
example, are introduced by treating the he~iacetal deriva-
tive (Compound ~9) with a different Grignard reagent than
lO previously used, as sho~n in Sche~e 4. In this Grignard
reaction the thio chroman ring is o~ened and the tertiary
alcohol derivative of 4-bromo-t~iophenol, 13, is formed.
Ring closure of the thiophenol derivative 13 which has the
desired ~l' R2, R3, R~ and R5 substituents, is affected by
15 heating in acidic conditions, preferably by heating with
aqueous acid. The resulting 6-bromo thiochroman which
bears the desired alkyl and hydrogen substituents Rt, R2,
R3, R4 and R5 is shown as Compound 14.
REACTION SCHEME ~
~ ~ R~ j~3~R3
22
t
. : ,.
30 R, ~ R3 R ~ R ~
!'
,~ ,, ,:

': :
W092/06084 PCT/US91/~6901
.~ .
~2~8 -
~ 27
~ ~ ,-
: ,
REACTION SCHEME 6
- .
-
: R 1 R2 R 1~R2
0~(3 H~R3
~ 22 ~;1 .
:'
" 10
.,
R, R2 R, R2
R~ ~R~
' ;~ 2~
. . .
In Reaction 8cheme 5, just as in Reaction 8cheme 3,
' one o~ the R4 or R5 substituents is al~yl and the other is
20 hydrogen. Just like the analogous 2-oxo-thiochroman 12 in
I Re~ctio~ 8Oheme 3, the 2-oxochroman 22 of ~eact~on 8cheme
~; 5 is treated with Grignard reagent to introduce the R4 and
R5 substituents. With controlled reaction temperature and
time, the resulting hemiacetal derivative can be isolated
25 as Compound 51, as shown in Reaction 8ch~me 5. Under
acidic conditions, (e.g. by heating in aqueous acid) the
, hemiacetal 5t is cyclized to form the corresponding olefin
derivative (compound 52). The olefin derivative can then
, be reduced using the same conditions as described in
30 connection with Reaction Rcheme 3 for the reduction of
compoun~ ~9, or by a more general reducing procedure. The
., .
i` ~ ' .

W092/060~4 PCT/US91/06901
~ rl Y~ .
28
; resulting chroman derivative is shown as Compound 24 in
Reaction 8chemc 5. It should be noted that up to this
point in the synthetic sequence (~hich is preferably but
not necessarily exclusively used for making the compounds
5 of the invention) similar or anelogous steps are involved
for making both the thio-chroman (~eaction Scheme 3) and
; the chroman derivatives (2~action Scheme 5) the only
difference being that in Reactio~ Schema ~ the starting
lactone does not have a halogen (such as a bromo substitu-
10 entj.
Referring to Reaction 8cheme 6, in Compou~d 2~ of
that scheme the R~ and ~5 substituents are 21~yl but ar-
not identical. The ~4 and ~5 al.~yl substituen~s are
introduced by treating Compound 51 with a different Grig-
15 nard reagent than previously used to form the tertiaryalcohol (Compound 23). The tertiary alcohol 23 which
already has the desired R1, ~2~ R3, ~4 and R5 substitu-
ents, is ring closed under acidic conditions, as described
above, to provide the chroman derivative (Compou~d 24).
In order to obtain the final acetylenic praducts
where the R4 or R5 substituent is alkyl and the other is
`j hydrogen, or where the R~ and R5 substituents are alkyl
but not identical to one another, Comp~u~d~ 1~ and 24 are
! subjected to substantially the same reaction procedures as
25 outlined in Rea¢tion 8chema 1 and ~eactio~ 8cheme 2.
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
30 scope. -
S~ecific ExamPles
Ethyl-4-iodo~enzoate (Compou~d 29) ~-~
To a suspension of lO g (40.32 mmol) of 4-iodobenzoic
' :,
,.

WO 92/06084 PCI/US91/06901
.: .
~ 29 ~921~8
acid in lOO ml absolute ethanol was added 2 ml thionyl
chloride and the mixture was then heated at reflux for 3
hours. Solvent was removed in vacuo and the residue was
dissolved in 100 ml ether. The ether solution was washed
5 with saturated NaHCO3 and saturated NaCl solutions and
dried (MgSO4). Solvent was then removed in vacuo and the
residue kugelrohr distilled (lOO degrees c; 0.55 mm) to
give the title compound as a colorless oil, PM~ (CDC13):
1.42 (3H, t, J~7 Hz), 4,4 (2H, q, J 7 Hz), 7.8 (~H).
In the same manner, but substituting for 4-iodobenzo- `
ic acid the appropriate acid, the following examples of
compounds can be prepared:
ethyl 4-iodophenylacetate:
ethyl 3-(4-iodophenyl)propionate;
ethyl 4-(4-iodophenyl)butanoate; and
' ethyl 5-(4-iodohenyl)pentanoa~e.
;; S-~4-bromoPenyl) 3,3-dimethYlthioacrylate (Compou~d 30)
To an ice bath cooled solution of 1.92 g (80 mmol) of
;,j NaH (obtained from a 60~ suspension in mineral oil by 3 x
' 20 15 ml hexane wash) in 30 ml o~ dry THF was added slowly
under argon a solution of 15.1 g ~80 mmol) of 4-b~omothio-
phenol in 60 ml o~ dry THF over 1 h. The mixture was
stirred at 0 degrees C for a ~urther 30 min and then
treated with a solution of 10.1 g (85 ~mol) o~ dimethyla-
25 cryloyl chloride in 30 ml of dry THF. The cooling bath
was then removed and the mixture then stirred at room
temperature for 40 h. The reaction ~ixture was poured
into 200 ml of water containing 2 ml of glacial acetic
, acid and the organic layer was separated. The organic
! 30 layer was washed with 2 x 75 ml of water and then dried
(MgSO4). The solvent was removed in vacuo to give the
' title compound as a yellow oil. PMR (CDC13): & 1.91 (3H,
s), 2.14 (3H, s), 6.03-6.06 (lH, m), 7.28 (2H, d, J-8.6:'

WO 92/06084 PCI'/US91/06901
Hz), 7.53 (2H, d, J-8.6 Hz) .
4,4-Dimethyl-6-bromo-2-oxo-thiochroman (Compound ~1)
To a stirred, ice-cooled suspension of 15.9 g (llg
mmol) of aluminum chloride in 140 ml of methylene chloride
was added under nitrogen a solution of 21.64 g (79.9 mmol)
of S-(4-bromophenyl) 3,3-dimethyl-thioacryiate tCompound
30) in 100 ml of methylene chloride. The mixture was then
, stirred at room temperature for 72 h and then poured into
j 250 g of an ice and brine mixture. The mixture was ex-
10 tracted with methylene chloride and the con~ined organic
extracts were washed with saturated NaCl solution and then
dried (MgS04). The solvent was removed in vacuo and the
residue recrystallized from he~anes to giv- .he tltle
compound as white crystals. PMR (CDC13): & 1.40 (6H, s),
15 2.67 (2H, s), 7.31-7.40 (3H, m). MS exact mass, m~e
269.9714 (calcd. for cllHll SOBr, 269.9714).
4-Bromo-2-(1.1,3-trimethvl-3-hydroxybutyl2 thiophenol
(Compound 32) - `'
To 3.49 g (32.8 mmol) of lithium perchlorate was
20 added under argon 35 ml of 3.OM (105 mmol) methyl magnesi-
um bromide in ether. ,The above mixture was treated drop-
wise with stirring with a solution o~ 2.961 g (lC.926
~ol) of 4,4-dimethyl-6-bromo-2-oxo-thiochroman (Compound
31) and the reaction mixture was then heated at reflux for
25 70 h. The reaction mixture was then allowed to cool and
poured onto a mixture oP 100 g of iCI~ and 8 ml of conc.
, H2S04. The organic layer was separa~ed and the aqueous ,
; layer was extracted with 2 x 25 ml of ether. The organic
; layers were combined and washed successively with 2 x 25 ''
30 ml of saturated NaHC03 solution, 25 ml of water and 25 ml
of saturated NaCl solution and then dried (MgS04). The '
solvent was removed in-vacuo and the residue purified by
flash chromatography to give the ti.le compound as a pale
. . . . . .. .. . .. .. . . . . .. . . . . . . . .

~ W092/06084 PCT~US91/06901 ~
.
31 2 ~ 7 '~
; .
yellow oil. PMR (CDC13): h 1.05 (6H, s), 1.52 (6H, s),
2.30 (2H, s), 3.71 (lH, s), 7.22 (lH, dd, J^8.5 Hz, 2.1
Hz), 7.28 (lH, d, J-8.5 Hz), 7.35 (lH, d, J-2.1 Hz)
. Using ethyl magnesium ~romide, instead of methyl
5 magnesium bromide, provides the corresponding 4-bromo-2-
~1,1 dimethyl 3-ethyl-3-hydroxypentyl)-thiophenol.
2 2.4.4-Tetramethvl-6-bromothiochroman (Compound 33)
A mixture of 500 mg (1.49 mmol) of 4-bromo-2-(1,1,3-
trimethyl-3-hydroxybutyl) thiophenol (Compound 32) and 8
lO ml of 20 percent aqueous H2S04 was heated at reflux for 24
h. The mixture was extracted with hexanes, the organic
; extracts were combined and washed successively with water,
saturated NaHC03, water again, saturated NaCl and then
dried (MgSO4). The solvent was removed in vacuo and the
15 residue purified by flash chromatography (silica; hexanes)
to give the title compound as a colorless oil. PMR
(CDC13): & 1.35 (6H, s), 1.40 (6H, s), 1.93 (2H, s), 7.17
(lH, dd, J-8.4 Hz, 2.1 Hz), 7.23 (lH, d, J-8.4 Hz), 7.26
~ (lH, d, J-2.1 Hz). MS exact mass, m/e 284.0221 (calcd.
; 20 for C13H17 S Br, 284.0234).
2.2 4 4-TetramethYl-6-trimethYlsilYlethynYl-thiochroman
(Compou~d 34)
A solution of 600 mg (2.11 mmol) of 2,2,4,4-tetra-
methyl-6-bromothiochroman (Compou~d 33) in 1.5 ml of
' 25 triethylamine was placed in a heavy-walled tube and de-
~ gassed and then treated under argon with 1.4 g t14.3 mmol)
J of trimethylsilylacetylene and a powdered mixture of 75 mg
(0.39 mmol) of cuprous iodide and 150 mg (0.21 mmol) of
bis(triphenylphosphine) palladium (II) chloride. The
30 reaction mixture was degassed again, then placed under
argon and the tube was sealed. The mixture was heated at
lO0 degrees C for 24 h, allowed to cool to room tempera-
ture and then treated with a furthe- 1.4 g (14.3 mmol) of
.
,; .,. ,, . ~ . . . , . . .. . ... ~ . . ,

W092/06084 PCT/US91/06901
. ..
` ~ 9 2 1~ g 32
':
trimethylsilylacetylene and a powdered mixture of 75 mg
(0.39 mmol) of cuprous iodide and 150 mg (0.21 mmol) of
bis(triphenylphosphine) palladium (II) chloride. The
mixture was then degassed, placed under argon and then
heated in the sealed tube at lOO degrees C for 96 h. The
mixture was cooled to room temperature and extracted with
3 x lO ml of ether. The organic extracts were combined,
:, washed successively with 25 ml of water and 25 r~l of
saturated sodium chloride solution and then dried (MgSO4).
10 The solvent was removed in vacuo and the residuP ~urified
by flash chromatography (silica; hexanes lollowed by 3%
ethyl acetate in hexanes) to give the title compound as a
yellow, crystalline solid. PMR (CDC13): & 0.23 (9H, s),
1.36 (6H, s), 1.39 (6H, s), 1.94 (2H, s), 7.17 (lH, dd,
15 J-8.2 HZ, 1.8 Hz), 7.25 (lH, d, J-1.8 Hz), 7.30 (lH, d,
J-8.2 Hz). MS exact mass, m/l 302.1519 (calcd. for Cl8H26
S Si, 382.1524).
2.2,g,4-~etramethyl-6-ethynylthiochroman (Compou~d 35)
To a solution of 527.6 mg (1.75 mmol) of 2,2,4,4-
;; 20 tetramethyl-6-trimethylsilylethynylthiochroman (Compound
34) in 4 ml of isopropanol was added, under argon, 4 ~1 of
lN KOH solution. The reaction mixture was stirred at room
temperature for 20 h and the isopropanol was then removed
! under vacuum. The residue was extracted with ether and
25 the combined ether extracts were washed successively with
water and saturated NaCl solution and then dried (MgS04).
` The solvent was removed in vacuo to give the title com- ~
pound as a yellow oil. PMR (CDC13): ~ 1.34 (6H, s), 1.37 - -
(6H, s), 1.91 (2H, s), 2.99 (lH, s), 7.17 (lH, dd, J-8.1
30 Hz, 1.8 Hz), 7.26 (lH, d, J-1.8 Hz), 7.30 (lH, d, J-8.1
Hz). MS exact mass, m/e 230.1122 (calcd. for C15H18S,
230.1129)
; Ethyl 4-[(2 2.4 4-tetramethyl-thiochroman-6-vl~-ethynyl~
: '
'

WO 92/060B4 PfCI/~lS91/06901
~ 2~2178
:.
benzoate (Compound 1)
A solution of 110.7 mg (o.481 mmol) of 2,2,4,4-
tetramethyl-6-ethynylthiochroman (Compou~d 35) and 142.3
- mg (0.516 mmol) of ethyl 4-iodobenzoate (Compou~d 29) in 2
5 ml of triethylamine was placed in a heavy walled glass
tube and degassfPd under argon. The mixture was then
i treated with a finely ground mixture of 42 mg (0.221 mmol)
of cuprous iodide and 63 mg (o~o9 mmol) of bis ~triphenyl-
i phosphine) palladium (II) chloride. The reaction mixture
10 was degassed under argon again and the tube was sealed.
The mixture was stirred at room temperatures for 40 hours.
The triethylamine was removed under vacuum and the residue
purified by flash chromatography (silica, 3% ethyl acetate
in hexanes) to give the title compound as a pale yellow
15 solid. PMR ~CDCl3) : & 1.37-1.42 (15H, m), 1.96 (2H, s),
4.38 (2H, q, J-7.0 Hz), 7.25 (lH, dd, J-8.2 Hz, 1.8 HZ),
7.33 (lH, d, J-1.8 HZ), 7.37 (lH, d, J-8.2 Hz), 7.65 (2H,
d, J-8~6 ~z), 8.01 (2H, d, J~8.6 ~z). MS exact mass, m/e
378.1636 (calcd. for C24H2602S, 378-165-3)-
Using the method for the preparation o~ Compound 1,
f but substituting the appropriate ethynylthiochroman
(Compou~d 16 in Reactio~ 8chema 1) and the appropriate
halo substituted phenyl ester (Formula 3, prepared for
example as specifically described for Compound ~9) the
1 25 ~ollowing compounds of the invention may be prepared:
ethyl 4-~(2/2/4/4/7-pentamethylthiochroman-6-yl)
ethynyl]b~nzoate;
ethyl 4-~(2,2,4,4-tetramethyl-7-ethylthiochroman-6-
yl)-ethynyl]benzoate;
ethyl 4-~(2,2,4,4-tetramethyl-7-propylthiochroman-6-
yl)-ethynyl]benzoate:
ethyl 4-[(2,2,4,4-tetramethyl-7-hexylthiochroman-6-
yl)-ethynyl]benzoate;
J
i ~ .. . , ., . . , ., . , , . , . . . . . . . . - - . : -
`",``.'. . : ` ': ` ' ,, ` ' ' ' .,. `' ~ '~ ` `'.' ' '

W O 92/06084 PC~r/~S91/06901
h ~ 7 8 34
~' .
ethyl 2-[4-[(2,2,4,4-tetramethylthiochroman-6-
yl)ethynyl)-phenyl]acetate;
ethyl 2-t[4-(2,2,4,4, 7-pentamethylthiochroman-6-
yl)ethynyl)-phenyl]acetate;
~: 5 ethyl 2-[4(2,2, 4,4-tetramethyl--7-ethylthiochroman-6-
. yl)-ethynyl)phenyl]acetate;
- ethyl 2-t4 (2,2,4,4 -tetramethyl-7-he~cylthiochroman-6-
yl)-ethynyl)phenyl]acetate;
s ethyl 3-[4-(2,2,4,4-tetramethyl.hiochroman-2-yl)-
10 ethynyl)phenyl]propionate;
. ethyl 3-[4-(2,2,4,4,7-pentamethylthiochroman-6-yl)- .
ethynyl)phenyl]propionate;
. ethyl
3-[4-2(2t2l4l4-tetramethyl-7-ethylthiochroman-6-yl)- :
15 ethynyl)phenyl]propionate;
ethyl 3-[4-(2,2,4,4-tetramethyl-7-hexylthiochroman-6-
yl)-ethynyl)phenyl]propionate;
ethyl 5-~4-(2,2,4,4-tetramethylthiochroman-6-
yl)ethynyl)-
. 20 phenyl]pentanoate;
;' ethyl 5-~4-(2,2,4,4,7-pentamethylthiochroman-6-yl)-
ethynyl)phenyl]pentanoate; .
ethyl $-~4-(2,2,4,4-tetramethyl-7-ethylthiochroman-6-
yl)-ethynyl)phenyl]pentanoate: .
The positional isomers of the a~,ove-noted examples
~and of analogous compounds) can also be prepared in
accordance with the ~oregoing procedures or by apparent .
modifications of such procedures. :.
Phenvl 3.3-dimethylacrylate (Compound 37) .
To an ice bath cooled solution of 1.29 g (54 ~mol) of
NaH (obtained from a 60% suspension in mineral oil by 3xlO
ml hexane wash) in 20 ml of dry THF was added slowly under
oxygen a solution of 5 g (53 mmol) 5f phenol in 50 ml of
, :
~ '
,: .

WO 92/06084 PCT/US91/06901
~ 2~
~ dry THF. The mixture was then treated with a solution of
: 7 g ( 59 mmol J of dimethylacryloyl chloride in 3 0 ml of dry
THF. The cooling bath was then removed and the mixture
was stirred for a further 2 . 5 h. The reaction mixture was
5 then poured into 150 ml of water containing 1 ml of gla-
cial acetic acid. The mixture was extracted with 150 ml
ether and the ether extract washed with saturated NaCl
solution and then dried (MgSO4). The solvent was removed
in vacuo and the residue purified by flash chromatography
1~ (silica; 5% ether in hexanes) to give the title compound
as a yellow oil. PMR (CDC13)): & 1.99 (3H, s), 2.24 (3H,
s), 5.93 (lH, broad s), 7.10 (2H, d, J-7.8 Hz) 7.22 (lH,
t, J-7.8 Hz), 7.38 (2H, t, J-7.8 Hz).
4 4-Dimethvl-2-oxo-chroman (Compou~d 38)
To a stirred, ice-cooled suspension of 10.4 g (78
1 mmol) of aluminum chloride in 160 ml of methylene chloride
.J was added slowly under argon a solution of 7 g (39.8 mmol)
~, o~ phenyl 3,3-dimethylacrylate (Compound 37) in 40 ml of
methylene chloride. The coolinq bath was removed and the
- 20 mixture stirred for a further 42 h. The mixture was
poured into a mixture of ice and brine and the organic
layer separated. The aqueous layer was extracted with
methylene chloride and the organic extracts were combined
- and washed with saturated NaCl solution and then dried
2; (MgS04). ~he solvent was removed in vacuo and the residue
; puri~ied by ~lash chromatography (silica: 10~ ether in
hexane) to give the title compound as a colorless oil.
PMR ~CDC13: h 1.30 (6H, s), 2.56 (2H, s), 7.06 (lH, dd,
J-8.0 Hz, 1.4 Hz), 7.16 (lH, td, J-8.0 Hz, 1.4 Hz), 7.26
(lH, td, J-8.0 Hz, 1.7 Hz), 7.33 (lH, dd, J-8.0 Hz, 1.7
Hz). MS exact mass, m/e 176.0852 (calcd. for C11H12O2,
176.0837.
i
:',
., .

~ WO92/060B4 PCT/US91/06901
:'.
~'
~: 2~92178
2~ 3-Trimethyl-3-hydroxybutyl)phenol (Compound 39)
To 11 ml of 3 . O M (33 mmol) methyl magnesium chloride
-; in THF, cooled in an ice bath, was added, under nitrogen,
a solution of 1. 96 g (11.1 mmol) of 4,4-dimethyl-2-oxo-
5 chroman (compou~a 38) in 35 ml of dry ether. The cooling
i bath was then removed and the mixture stirred at room
temperature for 72 h. The reaction mixture was then
poured onto a mixture of loo g of ice and 3 ml of conc. `
H2SO4 and stirred until the magnesium salts ware dis-
10 solved. The organic layer was separated and the aqueous
layer extracted with 2x50 ml of ether. The organic layers
; were combined and washed successively with water, saturat-
ed NaHCO3 and saturated NaCl solutions and then dried
; ~MgSO4). The solvent was removed in vacuo and the residue
15 was purified by flash chromatography (silica; ~0% ethyl
acetate in hexanes) to give the title compound as a pale -~
yellow solid. PMR ~CDC13):
& 1.13 (6H, s), 1.48 (6H, s), 1.89 (lH, s), 2.23 (2H, s),
6.60 (lH, dd, J-7.9 Hz, 1.4 Hz), 6.83 (lH, s), 6.84 (lH,
20 td, J-7.9 Hz, 1.4 Hz), 7.07 ~lH, td, J-7.9 Hz, 1.6 Hz),
7.31 (lH, dd, J-7.9 Hz, 1.6 Hz). MS exact mass, m/e
208 14s8 ~calcd. for C13H202~ 208-14
2.2.4,4-Tetra~ethyl-chro~an ~Co~pou~d 40)
A mixture of 2.98 g (14.3 mmol) of 2-~1,1,3-trimeth-
25 yl-3-hydroxybutyl) phenol ~Compound 39) and 40 ml of 20~
aqueous H2SO4 was heated at re~lux, under nitrogen, ~or 4
h. ~he mixture was stirred at room temperature for a
further 72 h and then diluted with 50 ml of water. The
mixture was extracted with 3x20 ml of hexanes. The organ-
ic eXtracts were then combined and washed successively
with water and saturated NaCl solution and then dried
(MgSO4). The solvent was then removed in vacuo to give
the title compound as a colorless oil. PMR (CDC13):
':
':,'

~ W092/06084 PCT/US91/06901
''
` 37 ~9~78
... .
: & 1.36 (6H, s)l 1.37 (6H, s), 1.83 (2H, s), 6.71 (lH, dd,
J-8.2 Hz, 1.5 Hz) 6.92 (lH, td, J~8.2 Hz, 1.5 Hz), 7.09
:~: (lH, td, J-a~2 Hz, 1.5 Hz), 7.29 (lH, dd, J-8.2 Hz, 1.5
Hz).
5 2 2 4.4-Tetramethyl-6-aCetyl-ChrOman (Compound 41)
To an ice bath cooled solution of 2 g (10.53 mmol) of
2,2,4,4-tetramethylchroman (Compound 40) in 25 ml of
nitromethane was added, under nitrogen, 941 mg (11.99
- mmol) of acetyl chloride followed by 1.59 g (11.92) mmol)
10 of aluminum chloride. The cooling bath was then removed
and the mixture stirred at room temperature for 16 h. The
mixture was then cooled again in an ice bath and treated
with 25 ml of conc. Hcl. The mixture was then filtered
and the residue washed with methylene chloride. The
15 filtrate was concentrated in vacuo and the resultant
residue was purified by flash chromatography (silica: 10%
ethyl acetate in hexanes) to give the title compound as a
yellow oil. PMR (CDC13): ~ 1.38 (6H, s), 1.39 (6H, s),
1.87 (2H, s), 2.56 (3H, s), 6.83 (lH, d, J 8.7 HZ), 7.71
20 (lH, dd, J 8.7 HZ, 2.1 HZ), 7.98 (lH, d, J 2.1 HZ). MS
exact mass, m/e 232.1468 (calcd. for Cl3H20O2, 232.1464).
! 2 . 2 . ~, 4-Tetramethyl-6-ethynYl-ch~o~an (Compou~d 42)
,.
; ~o a cooled ~-78 degree5 C) solution Of 522 mg (5.17
mmol) of diisopropylamine in 8 ~1 of dry THF was added
slowly, under nitrogen, 3.23 ml o~ 1.6 M (5.17 ~mol) n-
I butyl lithium in hexane. ~he mixture was stirred at - 78
J, degrees C for 40 minutes and then treated with a solution
of 1.24 g (5.17 mmol) of 2,2,4,4-tetramethyl-6-acetylchro-
man (Compoun~ 41) in 2 ml of dry THF. The mixture was
30 stirred at - 78 degrees C for a further 1 h and then
treated with 895 mg (5.19 mmol) of diethylchlorophosphate.
The reaction mixture was allowed to warm to room tempera-
ture and transferred by double-ended needle into a solu-
.

WO 92/06084 PCI`/US91/06901
~13~L78 38
; tion of lithium diisopropylamide in THF at -78 degrees C
[prepared as described above from 1.04 g tlO.34 mmol of
diisopropylamine and 6.46 ml of l. 6 M (10. 34 mmol) Of n-
butyl lithium in hexane]. The cooling bath was removed
and the mixture was stirred at room temperature for 16 h.
The mixture was then treated with 10 ml of ice water and
acidified to a pH of 2 with 10~ HCl. The organic layer
was separated and the aqueous layer was extracted with
3x30 ml of pentane. The organic extracts were combined
10 and washed successively with 2x30 ml of dilute HCl, water,
3x30 ml of saturated NaHC03 solution and saturated NaCl
solution and then dried (MgS04). The solvent was removed
in vacuo and the residue was purified by flash chromatog-
raphy (silica; 2% ethyl acetate in hexane) to give the
15 title compound as a pale yellow oil. PMR (CDC13): & 1.31
(6H, s), 1.32 (6H, s), 1.50 (2H, s), 3.00 (lH, s), 6.72
( lH, d, J-8.4 Hz), 7.20 (lH, dd, J-8.4 Hz, 2.1 Hz), 7.42
(lH, d, J~2.1 Hz). MS exact mass, m/e 2.14.1251 (calcd.
for C15H18O, 214.1357)
20 EthYl 4-r(2.2,4,4-tetramethylchroman-6-Yl-ethynyllbenzoate
Compound 3)
A solution of 233 mg (1.088 ~ol) of 2,2,4,4-tetra-
methyl-6-ethynyl-chroman (Compound 42) and 308 mg (1.087
mmol~ o~ ethyl 4-iodo-benzoate (Compcu~d 29) in 1 ml of
25 triethylamine was placed in a heavy-~alled tube and de-
gassed under argon. The mixture was treated with a finely
ground mixture o~ 50 mg (0.263 m~nol) of cuprous iodide and
loO mg (0.142 mmol) of bis ~triphenylphosphine) palladium
(II) chloride and the tube was then sealed. The reaction
30 mixture was then heated at 55 degrees C for 48 hours. The
triethylamine was removed in vacuo and the residue was
purified by flash chromatography (silica, 5% ethyl acetate
in hexans) to give the title comoound as yellow oil. PMR

~ W092/060~4 PCT/U~91/06901
' 39 ~ '7$
(CDCl3) : & 1.33 (~H~ S), 1.34 ~6H~ S)~ 1.37 (3H~ t~ J-7.2
~ ~z), 1.83 (2H, s)~ 4.35 (2H, q~ J-7.2 HZ)~ 6.75 (lH, d,
: J-~.4 Hz), 7.24 (lH, dd, J-8.4 Hz, 2.1 Hz), 7.46 (lH, d,
J-2.1 Hz), 7.54 (2H~ d, J-~.1 Hz), 7.99 (2H, d, J-8.1 Hz)
~ MS exact mass, m/e 362 .1880 (calcd. for C24H26O3,
! 362.1881).
3-Methyl-~henYl-3 .3-dimethylacrvlate (Compound 44)
A 60% suspension of sodium hydride (3.22 g: 81 mmol)
in mineral oil was washed with 3x10 ml of hexane and then
lo treated with ~o ml of dry THF. This mixture was cooled in
an ice-bath and then treated with a solution of 8.6 g
(79.5 mmol) of m-cresol in 80 ml of dry THF. The reaction
mixture was stirred for 10 min and then treated with a
solution of 10.5 g (88.5 mmol) of dimethylacryloyl chlo-
15 ride in 40 ml of dry THF. The reaction mixture wasstirred at room temperatuxe for 96 h and then poured into
a mixture of 150 ml o~ water and 1 ml of glacial acetic
acid. The mixture was stirred for 10 min and the organic
layer was separated. The aqueous layer was extracted with
20 2x50 ml of ether. The organic layers were combined and
` washed successively with water and saturated NaCl solution
and then dried (MgS04)~ ~he ~olvent was removed in vacuo
and the xesidue was purified by flash chromatography
(silica; 10% ethyl acetate in hexane) to give the title
25 compound as a pale yellow oil. P~ (CDC13): ~ 1.95 (3H,
d, J-1.3 Hz), 2.21 (3H, d, J-1.2 Hz), 2.34 (3H, s), 5.90
(lH, broad S~, 6.86 - 6.93 (2H, m), 7.01 (lH, d, J-7.2
Hz), 7.24 (lH, t, J-7.2 Hz).
; 2-(1.1.3-Trimethyl-3-hvdroxybutYl) 5-methyl-~henol (Com-
l 30 POund ~5)
3~ To an ice-bath cooled suspension of 13 g (97.5 mmol)
of aluminum chloride in 200 ml of methylene chloride was
added dropwise under argon a solution of 9.0 g (47.4 mmol)

W O 92/06084 P~r/US91/06901
,,
. :
.' 2~3~32178~ ~
of 3-methyl-phenyl-3,3-dimethylacrylate (compou~ 44) in
oo ml of methylene chloride. The reaction mixture was
stirred at o degrees c for a further 30 min and then at
" ~; .
-; room temperature for 15 h. The reaction mixture was
, poured into 200 ml of an ice water/salt mixture and the
organic layer was separated. The aqueous layer was ex-
tracted with 50 ml of ether. The organic layers were
.
combined and washed successively with water and saturated
NaCl solution and then dried (MgS04). The solvent was
10 removed in vacuo and the residue purified by flash chroma-
tography (silica; 5% ethyl acetate in hexane) to give an
approximately 2.5:1 mixture of isomeric products, 4,4,7-
trimethyl-2-oxo-chroman and 4,4,5-trimethyl-2-oxo-chroman
~ as a pale yellow oil. To a solution of 3.8 g (20 mmol) of
;' 15 this mixture of isomeric 2-oxo-chromans in 60 ml of ether
at o degrees C was added under argon 20 ml of 3.0 M (60
mmol) of methyl magnesium bromide in ether. The reaction
,' mixture was stirred at room temperature for 48 h and then
c poured onto a mixture of ice and 1 ml of conc. H2S04. The
20 organic layer was separated and the a~ueous layer extract-
ed with 2xS0 ml of ether. The organic layers were com-
bined and washed successively with water, saturated NaHC03
solution, water again and then saturated NcCl solution and
then dried (MgS04). The solvent was removed in vacuo and
25 the residue was puri~ied by flash chromatography ~silica;
~ ethyl acetate in hexanes) to give the title compound
`1 as a colorless oil. PMR (CDC13): & 1.14 (6H, s), 1.45
(6H, s), 2.19 (3H, s), 2.21 (2H, s), 6.39 (lH, d, J-1.8
Hz), 6.67 (lH, dd, J-7.9 Hz, 1.8 Hz), 7.16 (lH, d, J-7.9
30 Hz), 7.44 (lH, s).
2.2.4,4 7-Pentamethyl-chroman (Compound 46)
~1l To 2.16 g (11.7 mmol) of 2-(1,1,3-trimethyl-3-
hydroxybutyl) 5-methyl-phenol (Compound 45) was added
. ' " .
` '
. ~ .
.
, :, .

W092/06084 PCT/US91/06gOl
,~
41 2~9217
. .
under nitrogen 50 ml of 20~ aqueous sulfuric acid. The
reaction mixture was heated at reflux for 13 h and then
cooled. The organic layer was separated and the aqueous
layer was extracted with ether. The or~anic extracts were
5 combined and washed successively with water, saturated
NaHC03 solution~ water again and saturated NaCl solution
and then dried (MgS04). The solvent was removed in vacuo
to give the tltle compound as a yellow oil. PMR (CDC13):
~ 1.32 ~5H, s), 1.34 (6H, s), 1.81 (2H, s), 2.26 (3H, s),
10 6.63 (lH, s), 6.72 (lH, d, J-7.9 Hz), 7.15 (lH, d, J-7.9 -~-
Hz).
2,2.4,4,7-Pentamethvl-6-acetvl-chroman (Compound ~7) `
To an ice-bath cooled solution Of 1. 96 g (9.6 mmol)
of 2,2,4,4,7-pentamethyl-chroman (Compound 46) in 30 ml of
15 nitromethane was added under argon 1.059 g (13.5 mmol) of
, acetyl chloride followed by 1.9 g (14.3 mmol) of aluminum
chloride. The reaction mixture was stirred at room tem-
perature for 14 h and then cooled in an ice-bath and
treated with 25 ml of conc. HCl. The mixture was warmed
20 to room temperature and diluted with ether and water. The
organic layer was separated and the aqueous layer extract-
ed with ether. The orsanic ext~acts wero combined and
washed successively with water, saturated NaHCO3 solution,
water again, and saturated NaCl solution, and then dried
~ 25 (MgSO4). The solvent was re~oved in vacuo and the residue
i was purified by flash chromatography (silica; 5% ethyl
acetate in hexanes) to give the title compound as a pale
yellow oil. PMR (CDC13): & 1.36 (6H, s), 1.37 (6H, s),
1.86 (2H, s), 2.49 (3H, s), 2.56 (3H, s), 6.65 (lH, s),
' 30 7~74 (lH, s).
J 2,2.4,4, 7-Pentamethvl-6-ethvnvl-chroman Compound 48)
To a solution of 455 mg (4.5 mmol) of disopropylamine
; in 5 ml o f dry THF at -7 8 degrees c was added under argon
.. . . ~ . . ~ . . ~ ,- . . . . - ... . .

W092/06084 PCT/US91/~6901 ~
~ 2~.2~ ~8 42
3 ml of 1.5 M n-BuLi in hexane. The mixture was stirred
at -78 degrees C for a further 45 min and then traated
with a solution of 1.07 g (4.3 mmol) of 2,2,4,4,7-penta-
- methyl-6-acetyl-chroman (Compound 47) in 4 ml of dry THF.
5 The reaction mixture was stirred at -78 degrees C for 1 h
and then tre~ted with 776 mg (4.5 mmol) of diethyl chloro- '
, phosphate. The mixture was allowed to warm to room tem- '
perature and then transferred by a double-ended needle '
into a solution of lithium diisopropyl amide in 10 ml dry , '
10 THF at -78 degrees c which was prepared as described above - '
using 910 mg (9. 0 mmol) of diisopropylamine and 6 ml of
,, 1. 5 M ( 9 . O mmol ) n-BuLi in hexane. The mixture was
stirred at room temperature for 15 h and then poured into
lo ml of iced water. The mixture was acidified to pH=2 -'
15 with 10~ HCl solution. The organic layer was separated
and the aqueous layer extracted with pentane. The organic ',
extracts were combined and washed successively with water,
saturated NaHC03 and saturated NaCl solutions and then
dried (MgS04). The so,lvent was removed in vacuo and the , ,
20 residue purified by Kugelrohr distillation (82 degrees C,
0.3 mm) to give the title compound as a pale yellow oil.
PMR (CDC13): & 1.32 (6H, s), 1.34 (6H, s), 1.81 (2H, s),
2.36 (3H, s), 3.18 (lH, s), 6.64 (lH, s), 7.40 lH (s). MS
, exact mass, m/e 228.1520 (calcd. for ^16H20o~ 228.1514).
; 25 ,Ethyl~4-~(2,2.4,4,7-pentamethylch~oman-6-~,yl)-ethynyll
~ , benzoate (Compou~ 7)
', Nitrogen was bubbled for 15 min through a solution of
, 200 mg. (0.877 mmol) of 2,2,4,4,7-pentamethyl-6-ethynyl-
chroman (Compound ~8) and 245.3 mg (0.888 mmol) of ethyl
1, 30 4-iodobenzoate (Compound 29) in 2 ml of triethylamine.
The mixture was then placed under an argon atmosphere and
treated with a finely ground mixture of 50 mg (0.2625
~mol) o~ cuprous iodide and 100 mg (0.1425 mmol) of
"'.
''-;'''.

W o 92/06084 P~r/US91/06901
..
43 ~ a~ 2 1~ 8
bis (triphenylphosphine) palladium (II) chloride. The
reaction vessel was then fitted with a reflux condenser
and the mixture was heated at 55 degrees c under argon for
72 hours. The triethylamine was then removed under vacuum
5 and the residue purified by flash chromatography (silica,
5~ ethyl acetate in hexane) to give the title compound as
a yellow oil. PMR (CDC13) : & 1.32 (12H, s), 1.37 (3H, t,
J-7.0 Hz), 1.80 (2H, s) 2.40 (3H, s), 4.36 (2H, q, J-7.0
Hz), 6.66 (lH, s, 7.42 (lH, s), 7.54 (2H, d, J-8.6 Hz),
10 7-99 (2H, d, J-8.6 Hz). MS exact mass, m/e 376.2 038
~i (calcd. for C25H28O3, 376.2038).
2 4 4-Trimethvl-6-Bromo-2-HydroXV-thiochroman. (Compou~d
. 49)
` To a solution of 68g (182.5 mmol) of cerium chloride
1~ (dri2d on a high vacuum line at 135 degrees c for four
days) in 160 ml THF and 62 ml of 3M (186 mmol) methyl
magnesium bromide in ether was added to a solution of 5g
(18.45 mmol) of 4-4 dimethyl-6-bromo-2-oxo-thiochroman and
2Oml of dry THF at -14 degrees C. The mixture was stirred
' 20 for 0.5 hours and then poured onto 300 ml of ice/water
mixture containing 10 ml of concentrated sulfuric acid.
The layers were separated and th~ aqueous layer was ex-
~j tracted with 100 ml o~ ether. The organic layers were
combined and washed with 2X250 ml of water, 1 X 100 ml of
25 saturated sodium chloride solution and then dried (MgS04).
The solvent was removed in vacuo and the residue purified
by flash chromatography (silica: 10~ EtOAc/Hexanes) to
give the title compound as a yellow oil. PMR (CDC13): &
1.35(3H, s) 1.47(3H, s), 1.71(3H, s), 2.09-2.18 (AB dou-
80 blet), 2.42 (lH, s), 7.17 - 7.24 (2H, m), 7.27 (lH, d, ~ =
8.1 Hz).
2l4,4. TrimethYl-6-Bromo-(4H)-l-benzothioPvran (Compouud
50)
:
. . .
,.: .~ .. . .. , . . . . , ,.: , . .. , ~ .

W092/0608~ PCT/US91/06901
S2 ~ 7 ~
44
.' `
A mixture of 2.03g (7.1 mmol) of 2,4,4-trimethyl-6-
bromo-2-hydroxy thiochroman (Compound 49) and 20 ml of 20%
- aqueous sulfuric acid was heated at reflux for 4 hours.
The mixture was extracted with ether. The combined organ-
, ic extracts were washed with 2 x 25 ml H2O and 1 X 25 ml
of saturated NaCl solution and then dried (MgS04). The
; solvent was removed in vacuo and the residue purified by
flash chromatography (silica; hexanes) to give the title
compound as a colorless oil. P~ (CDC13): & 1.34 (6H, s),
15 2.00(3H, d, J = 1.4Hz), 5.45(1H, d, J = 1.4Hz), 7.19 - 7.38
(3H, m).
2 4, 4-trimethY1-6-bromo-thiochroman (Compound 53)
A solution of 500 mg (1.9 ~ol) of 2,4,4-trim~thyl-5-
bromo-(4H)-l-benzothiopyran (Compound 50) in 5 ml of ethyl `
l; acetate was treated with 500 mg of 10% palladium sulfide
on carbon and then shaken under an atmosphere (30 psi) of
hydrogen in a Parr apparatus for 24 hours. The mixture
was filtered through celite and the solvent was removed -
in-vacuo. The residue was purified by flash chromatogra- -
20 phy (silica; hexanes) to give the ~itle compound as a
! colorless oil. PMR (CD~13): & 1.21 (3H, s), 1.33 (3H, d,
J a 6.6Hz), 1.36 (3H, s), 1.64-1.89 (2H, m), 3.37-3.50
(1~, m), 7.10 (lH, dd, J = 8.4 Hz, 2.1Hæ), 7~19 (lH, d,
i 8.4 Hz), 7.20 (lH, d, 2.1 H2)
1 2~ 2,4,4-t~i~et~yl-6-trimethylsi~y~ g3~u~Ll-thioch~oman
(Compound 5~)
A solution of 201 mg (74 mmol) of 2,4,4-trimethyl-6-
bromo-thiochroman (Compou~d 53) in 1 ml of distilled
triethylamine was placed in a heavy walled tube and de- -
30 gassed. The mixture was then treated under argon with
O.53 ml (3.72 mmol) of trimethylsilylacetylene and a
powdered mixture of 52 mg (0.074 mmol) of bis-triphenyl-
hosphine palladium (II) chloride and 28 mg (0.15 mmol) of :
. .

W092/06084 PCT/US91/06901
13 '17~
cuprous idodide. The reaction mixture was placed under
argon and the tube was sealed. The mixture was heated at
55 degrees C for 72 hours. The mixture was cooled to room
temperature and filtered through celite and the residue
5 washed with CH2C12. The filtrate was concentrated in-
vacuo and the residue was purified by flash chromatography
, (silica; hexanes) to give the title compound as a yellow
'"! oil. PMR (CDC13): & 0.24 (9H, s), 1.22 (3H, s), 1.33 (3H,
d, J = 6.6 Hz), 1.37 (3H, s), 1.71 (lH, t, J - 13.0 Hz)
10 1.86 ~lH, dd, J - 13.0 ~z, 3.0 Hz) 38 - 3.50 (lH, m~,
; 7.07 (lH, dd, J = 8.1 Hz, 1.8Hz), 7.18 (lH, d, J = 1.8
HZ), 7.26 (1~, d, J = 8.1 Hz)
2 4 4-tri~thvl-5-~thvnvl-thiochrom2n (Comt~ound 55)
To a solution of 186 mg (0.647 mmol) o~ 2,4,4-tri-
l; methyl-6-trimethylsilyl ethynyl thiochroman (Compound 54)
was added 11 ml of ethanolic KOH solution. The reaction
mixture was stirred at room temperature for 16 hours. The
~j ethanol was then removed in-vacuo and the residue was
extract2d with ether. The ether extracts were combined
~ 20 and washed with water and saturated sodium chloride solu-
i~ tion and then dried (MgS04). The solvent was removed in-
vacuo and the residue purified by Kugelrohr distillation
to give the title compound as a colorless oil. PMR
(CDC13): & 1.21 (3H, s), 1.32 (3H, d, J = 6 Hæ), 1.40 (3H,
s,) 1.70 (lH, t, J - 13.0 Hæ), 1.~8 (lH, dd, J - 13.0 Hz,
3.0 Hz), 3.0 (lH, s, ), 3.39-3.51 (lH, m), 7.13 (lH, dd, J
s - 9.1 Hz, 2.1 Hz), 7.21 (lH, d, J - 2.1 Hz) 7.28 (lH, d, J
, 9, 0 ~IZ ) -
Ethyl-4t(2.4 4-trimethyl-6-thiochromanyl)-ethynyl] benzo-
30 ate (Compound 56)
A solution of 55 mg (0.26 mmol) of 2,4,4-trimethyl-6-
ethynyl-thiochroman (Compu~d 55) and 70.5 mg (0.26 mmol)
of ethyl 4-iodo benzoate (29) in 1.5 ml of distilled
~.~
.. ~ . .. . , ., . . ., . . . , , .. . . , , , ~ ,

w092/06084 PCT/US91/06901
;~92~7~ 46
.'~ . .
triethylamine was placed in a heavy walled tu~e. Argon
was bubbled through the mixture for 20 minutes under
slightly reduced pressure. To the mixture was added 18 mg
(0.051 mmol) of bis triphenylphosphine palladium (II)
5 chloride and 9.7 mg (0.051 mmol) of cuprous iodide. The
tube was then sealed and the mixture was stirred at 55
degrees c for 72 hours. The mixture was then cooled to
room temperature. The reaction mixture was diluted wth
c~2cl2 and treated ~ith a small amount of silica. The
10 solvent was then removed in-Yacuo and the residue was
; subjected to flash chromatography (silica; 1.5%
~tOAc/Hexanes) to give the title compound as a white
crystalline solid. P~R(CdC13): 1. 25 (3H, s), 1.35 (3H, d,
J = 6.6 Hz), 1.37-1.44 (6H, m), 1.75 (lH, t, J = 13 Hz),
15 1.88 (lH, dd, J = 13 Hz, 3.5 Hz), 3.40~3.50 (lH, m), 4.38
I (2H, q, J = 7Hz), 7.17 (lH, dd, J = 8.1 Hz, 1.8 Hz), 7.26
(lH, d, J = 1.5 Hz), 7.33 (lH, J = 8.1 Hz), 7.55 (2H, d, J
= 8.4 Hz, 8.01 (2H, d, J - 8.4 Hz).
4-(2~4~4-trimethvl-6-thiochromanYl)-ethvnyl benzoic acid
' 20 (Compound 57)
A mixture o~ 37 mg (0.102 mmol) of ethyl 4(2,4,4-
trimethyl-6-thiochromanyl)-ethynyl]benzoate (Compou~d 56)
and 11 ml o~ ethanolic potassium hydroxide solution was
; stirred at room temperature ~or 16 h~urs. The solvent was
25 removed in vacuo and the residue was taken up with water
and then acidified with lN HCl~ The mixture was extracted
with three porti~ns o~ ether. The org~nic extracts were
co~bined and then washed with water and saturated NaCl
solution and dried (MgSO4). The solvent was removed in-
30 vacuo to give the title compound as an orange solid. PMR(CDC13): 1.17 (3H, s), 1.26 (3H, d, J = 6.3 Hz), 1.34 (3H,
s), 1.58 (lH, t, J = 13.1 Hz), 1.92 (lH, dd, J = 13.1 Hz,
2.4 Hz), 3.33-3.48 (lH, m), 7.20 (lH, d, J = 8.1 Hz), 7.21

: WO 92/06084 PCI/US91/06901
47 7li~2~
(lH, s), 7.45 (lH, d, J = 8.1 H~, 7.62 (2H, d, 8.4 Hz),
7.95 (2H, d, J = 8.4 Hz).
Following the procedures set forth above, with such
modificiation and/or application of standard synthetic
5 organic procedures which will be readily apparent to a
synthetic organic chemist of ordinary skill, in light of
the present disclosure, the following further examples of
compounds can be prepared:
2,2,4,4-tetramethyl-6-acetyl-7-ethylchro3an:
lo 2,2,4,4-tetramethyl-6-acetyl-7-propylchroman;
2,2,4,4-tetrametnyl-6-acetyl-7-butylchroman;
2,2,4,4-tetramethyl-6-acetyl-7-pentylchroman;
2,2, 4, 4-tetramethyl-6-acetyl-7-hexylchroman;
2,2-diethyl-4,4-dimethyl-6-acetyl-chroman;
2,2-diethyl,-4,4,7-trimethyl-6-acetyl-chroman;
. ethyl 4-[(2,2,4,4-tetramethyl-7-ethylchroman-6-yl)-
:~ ethynyl]benzoate;
ethyl 4-t(2,2,4,4-tetramethyl-7-propylchroman-6-yl)-
ethynyl]benzoate:
ethyl 4-~(2,2,4,4-tetramethyl-7-hexylchroman-6-yl)-
ethynyl]benzoate;
ethyl
[2-(4-(2,2,4,4-tetramethylchro~an-6-yl)ethynyl)-
phenyl]acetate;
ethyl [2-(4-(2,2,4,4,7-pentamethylchroman-6-yl)ethy-
nyl)-phenyl]acetate;
i ethyl
[2-(4-(2,2,4,4-tetramethyl-7-ethylchroman-6-yl)-
ethynyl)phenyl]acetate;
eth
[2-(4-(2~2~4~4-tetramethyl-7-hexylchroman-6-yl)
ethynyl)phenyl~acetate;
ethyl 3-~4-((2,2,4,4-tetramethylchroman-2-yl)-
.
.

W092/06~84 PCT/US91/G6901
2 ~ 9 ~ ~ ~ 8
48
,::' ""
ethynyl)phenyl]propionate;
: ethyl 3-[4-((2,2,4,4,7-pentamethylchroman-6-yl)-
ethynyl)-phenyl]propionate; . :
i ,...... .
. ethyl 3-[4-(2l2l4l4-tetramethyl-7-ethylchroman-6-yl)- :
: 5 ethynyl)phenyl]propionate;
. .,
! ethyl 3-[4-(2,2,4,4-tetramethyl-7-hexylchroman-6-yl)-
ethynyl)phenylpropionate; ..
ethyl
s-[4-((2,2,4,4-tetra~ethylchroman-6-yl)ethynyl)-
.. lO phenyl]pentanoate;
ethyl ~-[4-~(2,2,4,4,7-pentamethylchro~an-6-yl)-
~: ethynyl)phenyl]pentanoate;
ethyl ..
5-[4-((2,2,4,4-tetramethyl-7-ethylchroman-6-yl)- -~
: l; ethynyl)phenyl~pentanoate; .
ethyl 5-[4-((2,2,4,4-tetramethylchroman-6-yl-ethynyl) :
:; phenyl]pentanoate;
.1 ethyl 4-[2,2-diethyl-4,4-dimethylchroman-6-yl)-
ethynyl]benzoate; and
. 20 ethyl 4-[2,2-diethyl-4,4,7-trimethylchroman-6-yl)-
ethynyl]benzoate~ . :
The positional iso~ers of the above-listed examples
can also be prepared in accordance with the foregoing :
procedures or by such modifications thereof which will be
25 readily apparent to the practicing che~ist in light of the
~oregoing disclosure.
ExamPles of Formulation for Topical Administration -
Preferably the compounds of the invention may ~e ::.
~ administered topically using various formulations. Such -~
; 30 formulations may be as follows:
. Ingredient Weight/percent :
Solution
; Retinoid (active ingredient) O.l
,;~ .
.,
. .
.~

, W092/~6084 PCT/US91/06901
~2i 7~
49
BHT 0.1
~ Alcohol USP 58.0
Polyesthylene Glycol 400 NF 41.8
, ~ .
- ~ Gel
~` Retinoid (active ingredient~ O.l
BHT 0.1
Alcohol USP 97.8
Hydrox-propyl Cellulose 2.0
.
,,,

Representative Drawing