U.S. patent application number 10/040601 was filed with the patent office on 2002-08-08 for method for treating patients with neoplasia by administering substituted sulfonyl indenyl acetic and propionic acids and esters thereof.
Invention is credited to Brendel, Klaus, Pamukcu, Rifat.
Application Number | 20020107248 10/040601 |
Document ID | / |
Family ID | 24675397 |
Filed Date | 2002-08-08 |
United States Patent
Application |
20020107248 |
Kind Code |
A1 |
Pamukcu, Rifat ; et
al. |
August 8, 2002 |
Method for treating patients with neoplasia by administering
substituted sulfonyl indenyl acetic and propionic acids and esters
thereof
Abstract
Substituted indenyl sulfonyl acetic acids are useful in the
treatment of precancerous lesions.
Inventors: |
Pamukcu, Rifat; (Cincinnati,
OH) ; Brendel, Klaus; (Tuscon, AZ) |
Correspondence
Address: |
Cell Pathways, Inc.
702 Electronic Drive
Horsham
PA
19044
US
|
Family ID: |
24675397 |
Appl. No.: |
10/040601 |
Filed: |
December 28, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10040601 |
Dec 28, 2001 |
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09243659 |
Feb 2, 1999 |
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09243659 |
Feb 2, 1999 |
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08851943 |
May 7, 1997 |
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08851943 |
May 7, 1997 |
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08361291 |
Dec 22, 1994 |
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08361291 |
Dec 22, 1994 |
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07839203 |
Feb 20, 1992 |
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07839203 |
Feb 20, 1992 |
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07666769 |
Mar 8, 1991 |
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Current U.S.
Class: |
514/237.5 ;
514/521; 514/532; 514/534; 514/567; 514/569; 514/618; 514/619 |
Current CPC
Class: |
B07C 1/00 20130101; G07B
2017/00338 20130101; A61K 31/192 20130101; A61K 31/216 20130101;
G07B 2017/00693 20130101; A61K 31/19 20130101; A61K 31/195
20130101; G07B 2017/00677 20130101; A61K 31/198 20130101; A61K
31/215 20130101; G07B 2017/00685 20130101; G07B 17/00314 20130101;
A61K 31/16 20130101; G07B 17/00661 20130101; A61K 31/196
20130101 |
Class at
Publication: |
514/237.5 ;
514/521; 514/534; 514/532; 514/569; 514/567; 514/618; 514/619 |
International
Class: |
A61K 031/535; A61K
031/277; A61K 031/216; A61K 031/195; A61K 031/165 |
Claims
We claim:
1. A method for treating a patient with neoplasia, comprising
administering to the patient a physiologically effective amount of
a compound of the formula A: 3Wherein R.sub.1 is selected from the
group consisting of hydrogen, lower alkyl, or haloalkyl; R.sub.2 is
selected from the group consisting of hydrogen or alkyl; R.sub.3
and R.sub.4 are one or more members each independently chosen from
the group consisting of hydrogen, alkyl, acyloxy, alkoxy, nitro,
amino, acylamino, alkylamino, diakylamino, dialkylaminoalkyl,
sulfamyl, alkythio, mercapto, hydroxy, hydroxyalkyl, alkylsulfonyl,
halogen, cyano, carboxyl, carbalkoxy, carbamido, haloalkyl or
cycloalkoxy; R.sub.5 is an alkylsulfonyl; M is selected from the
group consisting of hydroxy, substituted lower alkoxy, amino,
alkylamino, dialkylamino, N-morpholino, hydroxyalkylamino,
polyhydroxyamino, dialkylaminoalkylamino, aminoalklyamino, and the
group Ome, wherein Me is a cation; and m and n each equal 1.
2. A method according to claim 1 wherein R.sub.3 and R.sub.4 are
selected from alkyl, acyloxy, alkoxy, halogen, haloalkyl or
cycloalkoxy.
3. A method according to claim 2 wherein R.sub.1 is hydrogen.
4. A method according to claim 1 wherein said compound is
administered orally.
5. A method according to claim 1 wherein said compound is
administered orally by unit dosage in a pharmaceutically acceptable
carrier.
6. A method according to claim 1 wherein M is hydroxy or
methoxy.
7. The method according to claim 1 wherein said compound is
enterically coated for colonic release.
8. The method according to claim 1 that comprises treating a
patient with colonic polyps by administering to the patient a
pharmacologically effective amount of the compound of formula
A.
9. The method according to claim 1 that comprises treating a
patient with precancerous lesions of the breast by administering to
the patient a pharmacologically effective amount of the compound of
formula A.
10. The method according to claim 1 that comprises treating a
patient with precancerous lesions of the skin by administering the
patient a pharmacologically effective amount of the compound of
formula A.
Description
[0001] This is a continuation-in-part of U.S. patent application
Ser. No. 07/666,769 filed Mar. 8, 1991.
TECHNICAL FIELD
[0002] This invention relates to methods for treatment or
prevent-on of precancerous lesions.
BACKGROUND OF THE INVENTION
[0003] Each year in the United States alone, untold numbers of
people develop precancerous lesions. These lesions exhibit the
strong tendency to develop into carcinomas. Such lesions include
lesions of the breast (that can develop into breast cancer),
lesions of the skin (that can develop into malignant melanoma) and
colonic polyps (that can develop into colon cancer).
[0004] For example, approximately 60,000 people die from colon
cancer, and over 150,000 new cases of colon cancer are diagnosed.
For the American population as a whole, individuals have a six
percent lifetime risk of developing colon cancer, making it the
second most prevalent form of cancer in the country. Colon cancer
is also prevalent in Western Europe.
[0005] To date, little progress has been made in the prevention and
treatment of colorectal cancer, as reflected by the lack of change
in the five-year survival rate over the last few decades. The only
cure for this cancer is surgery at an extremely early stage.
Unfortunately, most of these cancers are discovered too late for
surgical cure, because most victims do not experience symptoms
until the disease is advanced.
[0006] The incidence of colon cancer increases with age,
particularly after the age of 40. Since the mean ages of
populations in America and Western Europe are increasing, the
prevalence of colorectal cancer should increase in the future.
[0007] In view of these grim statistics, efforts in recent years
have concentrated on colon cancer prevention. Colon cancer usually
arises from pre-existing benign growths known as polyps. Prevention
efforts have emphasized the identification and removal of colonic
polyps. Polyps are identified by x-ray and/or colonoscopy,
and-usually removed by devices associated with the colonoscope. The
increased use of colon x-rays and colonoscopies in recent years has
detected clinically significant precancerous polyps in four to six
times the number of individuals per year that acquire colon cancer.
During the past five years alone, an estimated 3.5 to 5.5 million
people in the United States have been diagnosed with adenomatous
colonic polyps, and it is estimated that many more people have or
are susceptible to developing this condition, but are as yet
undiagnosed. In fact, there are estimates that 10-12 percent of
people over the age of 40 will form clinically significant
adenomatous polyps.
[0008] Removal of polyps has been accomplished either with surgery
or fiber-optic endoscopic polypectomy--procedures that are
uncomfortable, costly (the cost of a single polypectomy ranges
between $1,000 and $1,500 for endoscopic treatment and more for
surgery), and involve a small but significant risk of colon
perforation. Overall, about $2.5 billion is spent annually in the
United States in colon cancer treatment and prevention.
[0009] As indicated above, each polyp carries with it a chance that
it will develop into a cancer. The likelihood of cancer is
diminished if a polyp is removed. However, many of these patients
demonstrate a propensity for developing additional polyps in the
future. They must, therefore, be monitored periodically for the
rest of their lives for polyp reoccurrence.
[0010] In most cases (i.e. the cases of so-called common sporadic
polyps), polyp removal will be effective to reduce the risk of
cancer. In a small percentage of cases (i.e. the cases of the
so-called polyposis syndromes), removal of all or part of the colon
is indicated. The difference between common sporadic polyps and
polyposis syndromes is dramatic. Common sporadic polyp cases are
characterized by relatively few polyps, each of which can usually
be removed leaving the colon intact. By contrast, polyposis
syndrome cases can be characterized by many (e.g. hundreds or more)
of polyps--literally covering the colon in some cases--making safe
removal of the polyps impossible short of surgical removal of the
colon. Because each polyp carries with it the palpable risk of
cancerous development, polyposis syndrome patients invariably
develop cancer if left untreated. Many of these patients have
undergone a severe change in lifestyle as a result of the
disfiguring surgery. Patients have strict dietary restrictions, and
many must wear ostomy appliances to collect their intestinal
wastes.
[0011] Recently, several non-steroidal anti-inflammatory drugs
("NSAIDs"), originally developed to treat arthritis, have shown
effectiveness in inhibiting and eliminating polyps. Polyps
virtually disappear when the patient take the drug, particularly
when the NSAID sulindac is administered. However, the prophylactic
use of currently available NSAIDs, even in polyposis syndrome
patients, is marked by severe side reactions that include
gastrointestinal irritations and ulcerations. Once NSAID treatment
is terminated due to such complications, the polyps return,
particularly in polyposis syndrome patients.
[0012] Sulindac has been particularly well received among the
NSAIDs for polyp treatment. Sulindac is a sulfoxide compound that
itself is believed to be inactive an anti-arthritic agent. The
sulfoxide is reported to be converted by liver enzymes to the
corresponding sulfide, which is acknowledged to be the active
moiety as a prostaglandin inhibitor. The sulfide, however, is
associated with the side effects of conventional NSAIDs. The
sulfoxide is also known to be metabolized to a sulfone compound,
which is regarded to be inactive as an inhibitor of prostaglandin
synthesis.
SUMMARY OF THE INVENTION
[0013] This invention is a method of treating patients with
precancerous lesions by administering a physiologically effective
amount of a compound of formula I below to a patient in need of
such treatment. Such compositions are effective in eliminating and
inhibiting precancerous lesions, but are not characterized by the
severe side reactions of conventional NSAIDs.
[0014] The compounds used in the treatment of this invention are
believed to be effective on precancerous lesions either because
they are active themselves or because they are metabolized to
active derivatives.
[0015] It was unexpectedly discovered that while the sulfone
compounds of this invention do not greatly inhibit prostaglandin
synthesis--prostaglandin synthesis inhibition being a
characteristic of conventional NSAIDs--the compounds of this
invention nonetheless have antiproliferative effects on the cells
of a precancerous lesion or precancerous cells.
DETAILED DESCRIPTION OF THE INVENTION
[0016] As discussed above, the present invention is a method of
treating a patient with precancerous lesions by administering a
physiologically effective amount of a compound of formula I below:
1
[0017] wherein R.sub.1 is selected from the group consisting of
hydrogen, lower alkyl, or haloalkyl;
[0018] R.sub.2 is selected from the group consisting of hydrogen or
alkyl;
[0019] R.sub.3 and R.sub.4 are one or more members each
independently chosen from the group consisting of hydrogen, alkyl,
acyloxy, alkoxy, nitro, amino, acylamino, alkylamino, diakylamino,
dialkylaminoalkyl, sulfamyl, alkythio, mercapto, hydroxy,
hydroxyalkyl, alkylsulfonyl, halogen, cyano, carboxyl, carbalkoxy,
carbamido, haloalkyl, or cycloalkoxy;
[0020] R.sub.5 is alkylsulfonyl;
[0021] m is 0 or 1;
[0022] n is 0 or 1; and
[0023] M is selected from the group consisting of hydroxy,
substituted lower alkoxy, amino, alkylamino, dialkylamino,
N-morpholino, hydroxyalkylamino, polyhydroxyamino,
dialkylaminoalkylamino, aminoalklyamino, and the group OMe, wherein
Me is a cation.
[0024] Preferably, the aforesaid method involves the administration
of compounds of formula I wherein m and n are zero, i.e., compounds
of formula II below wherein R.sub.1-R.sub.5, and M are as defined
above: 2
[0025] As used herein, the term "precancerous lesion" refers to
lesions that exhibit histologic changes which are associated with
an increased risk of cancer development. Examples include
adenomatous polyps of the colon, dysplastic nevi of the skin and
atypical hyperplasia of the breasts. Certain syndromes that
commonly display precancerous lesions are also referred to by the
term "precancerous" including dysplastic nevus syndrome and the
colonic polyposis syndromes. "Precancerous" refers to these lesions
or syndromes of various tissues whether or not the lesions are
clinically identifiable.
[0026] As used herein, the term "halo" or "halogen" refers to
chloro, bromo, fluoro and iodo groups, and the term "alkyl" refers
to straight, branched or cyclic alkyl groups.
[0027] The present invention is also a method of treating
individuals with precancerous lesions by administering a
pharmaceutically effective amount of an enterically coated
compounds of formulae I or II above where R.sub.1-R.sub.5 are as
defined above.
[0028] Compounds of formulae I or II may be formulated into
compositions together with pharmaceutically acceptable carriers for
oral administration in solid or liquid form, or for rectal
administration, although carriers for oral administration are most
preferred.
[0029] Pharmaceutically acceptable carriers for oral administration
include capsules, tablets, pills, powders, troches and granules. In
such solid dosage forms, the carrier can comprise at least one
inert diluent such as sucrose, lactose or starch. Such carriers can
also comprise, as is normal practice, additional substances other
than diluents, e.g., lubricating agents such as magnesium stearate.
In the case of capsules, tablets, troches and pills, the carriers
may also comprise buffering agents. Carriers such as tablets, pills
and granules can be prepared with enteric coatings on the surfaces
of the tablets, pills or granules. Alternatively, the enterically
coated compound can be pressed into a tablet, pill, or granule, and
the tablet, pill or granules for administration to the patient.
Preferred enteric coatings include those that dissolve or
disintegrate at colonic pH such as shellac or Eudraget S.
[0030] Pharmaceutically acceptable carriers include liquid dosage
forms for oral administration, e.g. pharmaceutically acceptable
emulsions, solutions, suspensions, syrups and elixirs containing
inert diluents commonly used in the art, such as water. Besides
such inert diluents, compositions can also include adjuvants such
as wetting agents, emulsifying and suspending agents, and
sweetening, flavoring and perfuming agents.
[0031] Pharmaceutically acceptable carriers for rectal
administration are preferably suppositories which may contain, in
addition to the compounds of Formulae I or II, excipients such as
cocoa butter or a suppository wax.
[0032] The pharmaceutically acceptable carrier and compound of
Formulae I or II are formulated into unit dosage forms for
administration to a patient. The dosage levels of active ingredient
(i.e. compounds of Formulae I or II) in the unit dosage may be
varied so as to obtain an amount of active ingredient effective to
achieve polyp-eliminating activity in accordance with the desired
method of administration (i.e oral or rectal). The selected dosage
level therefore depends upon the nature of the active compound
administered, the route of administration, the desired duration of
treatment, and other factors. If desired, the unit dosage may be
such that the daily requirement for active compound is in one dose,
or divided among multiple doses for administration, e.g. two to
four-times per day.
[0033] The foregoing may be better understood from the following
examples, which are presented for purposes of illustration and are
not intended to limit the scope of the invention. As used in the
following examples, the references to substituents such as R,
R.sub.1, R.sub.2 etc., refer to the corresponding compounds and
substituents in the Formulae above.
EXAMPLE 1
5-Methoxy-2-Methyl-1-(.rho.-Methylsulfonylbenzylidene)-3-Indenyl
Acetic Acid
[0034] (A) .alpha.-Methyl-.beta.-(.rho.-methylthiophenyl) propionic
acid
[0035] To a solution of 2.3 g. (0.1 mole) of sodium in 100 ml. of
absolute alcohol is added 17.4 g. (0.1 mole) of diethyl
methylmalonate and 17.3 g. (0.1 mole) of
.rho.-methylthiobenzylchloride. The mixture is heated under a
reflux in a water bath for three hours. The reaction mixture is
poured into water, and the aqueous solution is extracted six times
with ether and dried. It is then evaporated to yield diethyl
methyl-.rho.-methylthio- benzyl malonate. The crude product is then
saponified by heating with excess 4% sodium hydroxide in aqueous
ethanolic solution. The solution thus formed is concentrated,
extracted with ether to remove any neutral material, and acidified
with dilute sulfuric acid. The acidic mixture is heated on a steam
bath for one hour, cooled and then extracted with ether.
Evaporation of the ether solution gives .alpha.-methyl-.beta.-(.rh-
o.-methylthiophenyl) propionic acid.
[0036] In a similar manner, using other substituted malonic esters
in place of diethyl methylmalonate and other substituted benzyl
halides in place of .rho.-methylthiobenzyl chloride, the
corresponding substituted propionic acids are obtained, for
example:
[0037] .alpha.-methyl-.beta.-(.rho.-methoxyphenyl)propionic
acid,
[0038] .alpha.-allyl-.beta.-(.rho.-nitrophenyl)propionic acid.
[0039] (B) 6-methoxy-2-methylindanone
[0040] .alpha.-Methyl-.beta.-(.rho.-methoxyphenyl)propionic acid
(15 g.) is added to polyphosdhoric acid (170 g.) at 50.degree. C.
and the mixture is heated at 83-90.degree. for two hours. The syrup
is poured into iced water, stirred for one-half hour, and then
extracted with ether three times. The ether solution is washed with
water twice, and with 5% NaHCO.sub.3 five times until all the
acidic material has been removed. The remaining neutral solution is
washed with water and dried over sodium sulfate. Evaporation of the
solution gives the indanone as a pale yellow oil.
[0041] In a similar manner, other .beta.-aryl propionic acid
compounds are converted to the corresponding indanone by the
procedure of this example.
[0042] (C) Methyl 5-methoxy-2-methyl-3-indenylacetate
[0043] A solution of 13.4 g. of 6-methoxy-2-methylindanone and 19.3
g. of methyl bromoacetate in 45 ml. benzene is added over a period
of 5 minutes to 21 g. of zinc amalgam (prepared according to Org.
Syn. Coll., vol. 3) in 110 ml. benzene and 40 ml. dry ether. A few
crystals of iodine are added to start the reaction, and the
reaction mixture is maintained at reflux temperature (ca.
65.degree.) with external heating. At three hour intervals, two
batches of 10 g. zinc amalgam and 10 g. bromoester are added, and
the mixture is then refluxed for eight hours. After addition of 30
ml. ethanol and 150 ml. of acetic acid, the mixture is poured into
700 ml. of 1:1 aqueous acetic acid. The organic layer is separated,
and the aqueous layer is extracted twice with ether. The combined
organic layers are washed thoroughly with water, ammonium hydroxide
and water. Drying over sodium sulfate, evaporation of solvent in
vacuo followed by pumping at 80.degree. (bath temp.) (1-2 mm.)
gives crude
methyl(1-hydroxy-2-methyl-6-methoxy-indenyl)acetate.
[0044] A mixture of the above crude hydroxyester, 20 g. of
.rho.-toluenesulfonic acid monohydrate and 20 g. of anhydrous
calcium chloride in 250 ml. toluene is refluxed overnight. The
solution is filtered, and the solid residue is washed with benzene.
The combined benzene solution is washed with water, sodium
bicarbonate, water and then dried over sodium sulfate. After
evaporation, the crude methyl 5-methoxy-2-methyl-3-indenylacetate
is chromatographed on acid-washed alumina, and the product is
eluted with petroleum ether-ether (v./v. 50-100%).
Methyl 2,6-Dimethyl-3-Indenylacetate
[0045] The above reactions of Example 1C are repeated except that
the starting materials are 2,5-dimethylindanone and
methylbromoacetate. With the same reaction conditions and
techniques, methyl 2,6-dimethyl-3-indenylacetate is obtained.
[0046] The above reactions of Example 1C are repeated except that
the starting materials are 6-methylthiolindanone and
methylbromoacetate. Using the same reaction conditions and
techniques, there is obtained methyl
5-methyl-thio-2-methyl-3-indenylacetate.
[0047] When any of the other indanones described in the other
examples of the specification are used in the above procedure in
place of 6-methoxy-2-methylindanone the corresponding methyl ester
is obtained.
[0048] (D)
5-methoxy-2-methyl-1-(.rho.-methylthiobenzylidene)-3-indenyl acetic
acid
[0049] To a solution of methyl 5-methoxy-2-methyl-3-indenylacetate
8.7 g. (0.037 mole) and .rho.-methylthiobenzaldhyde, 6.3 g. (1.1
equivalent) is added 16+ ml. (2.0+ equivalents) of 25% methanolic
sodium methoxide. The mixture is stirred at reflux under nitrogen
for 2 hours. An equal volume of water is added dropwise and
refluxing continues for 30 min. The solution is cooled, diluted
with water and extracted with ether (3.times.). Residual ether is
blown off with nitrogen, and then the aqueous solution is acidified
with 50% glacial acetic acid. The precipitated product is collected
and washed thoroughly with water. The crude product is crystallized
from methanol to give pure
5-methoxy-2-methyl-1-(.rho.-methylthiobenzylidene)-3-indenyl acetic
acid (M.P. 195-196.degree.).
5-methoxy-2-methyl-1-(.rho.-ethylthiobenzylidene)-3-indenyl Acetic
Acid
[0050] The above reaction of Example 1D is repeated using
.rho.-ethylthiobenzaldehyde instead of
.rho.-methylthiobenzaldehyde. Using the same reaction conditions
and techniques, there is obtained
5-methoxy-2-methyl-1-(.rho.-ethylthiobenzylidene)-3-indenyl acetic
acid.
5-hydroxy-2-methyl-1-(.rho.-methylthiobenzylidene)-3-indenyl Acetic
Acid
[0051] The reaction of Example 1D is repeated except that the
starting materials are methyl 5-hydroxy-2-methyl-3-indenylacetate
and .rho.-methylthiobenzaldehyde. Using the same reaction
conditions and techniques, there is obtained
5-hydroxy-2-methyl-1-(.rho.-methylthiobenzy- lidene)-3-indenyl
acetic acid.
[0052] The other methyl esters of Example 1C are reacted with
.rho.-methylthiobenzaldehyde according to the above procedure to
produce the corresponding indenyl acetic acid.
[0053] (E)
5-methoxy-2-methyl-1-(.rho.-methylsulfonylbenzylidene)-3-indeny- l
acetic acid.
[0054] A solution of sodium periodate (0.214 g.; 0.001 mole) in 3
ml. of water is added dropwise to
5-methoxy-2-methyl-1-(.rho.-methylthiobenzylid- ene)-3-indenyl
acetic acid (0.352 g.) (0.001 mole) in 25 ml. methanol and enough
acetone to cause solution. This solution is stirred overnight at
room temperature and filtered. The filtrate is evaporated at
30.degree. to a sufficiently small volume that causes the product
to precipitate. The suspension is diluted with several volumes of
water, cooled and collected. The product is dried in vacuo over
potassium hydroxide pellets and then in a vacuum oven at 70.degree.
to give 5-methoxy-2-methyl-1-(.rh-
o.-methylsulfinylbenzylidene)-3-indenyl acetic acid (M.P.
200.5-203.5.degree.).
[0055]
5-methoxy-2-methyl-1-(.rho.-methylsulfonylbenzylidene)-3-indenyl
acetic acid is prepared by the dissolving 0.03 moles of the
sulfoxide in 25 ml. methanol, and 50 ml. acetonitrile are added.
The solution is stirred at 0 C., and 0.03 moles of sodium methoxide
are added dropwise. Stirring is continued, and 0.06 mole sodium
bicarbonate is added as well a 0.06 moles of H.sub.2O.sub.2 (30%
solution in water). The temperature is then dropped to -10 C., and
stirring continued for 30 hours. At this time the NaHCO.sub.3 is
filtered and washed on the filter with a few ml. of cold methanol.
The washings are returned to the filtrate and the NaHCO.sub.3 is
discarded. The filtrate is neutralized with 0.07 moles of HCl
(concentrated HCl), partially evaporated to 50% of the original
volume, and returned to the freezer for crystallization. Crystals
of the sulfone derivative are collected. Additional sulfone can be
collected from the mother liquor in a similar manner.
(R.sub.1=hydrogen; R.sub.2=CH.sub.3; R.sub.3=5-OCH.sub.3;
R.sub.4=hydrogen; R.sub.5=p-CH.sub.3SO.sub.2)
[0056] Similarly,
5-methoxy-2-methyl-1-(.rho.-ethylsulfonylbenzylidene)-3-- indenyl
acetic acid and 5-hydroxy-2-methyl-1-(.rho.-methylsulfonylbenzylid-
ene)-3-indenyl acetic acid be produced following the reaction of
Example 1E using the compounds from Example 1D.
EXAMPLE 2
5-Methoxy-2-Methyl-1-(.rho.-Methylsulfonylbenzylidene)-3-Indenyl
Acetic Acid
[0057] (A) 6-methoxy-2-methylindanone
[0058] In a 500 ml. 3-necked flask is placed 36.2 g. (0.55 mole) of
zinc dust, and in a 250 ml. addition funnel is charged a solution
of 80 ml. anhydrous benzene, 20 ml. of anhydrous ether, 80 g. (0.58
mole) of .rho.-anisaldehyde and 98 g. (0.55 mole) of
ethyl-2-bromopropionate. About 10 ml. of the solution is added to
the zinc dust with vigorous stirring, and the mixture is warmed
gently until an exothermic reaction commences. The remaining
reactants are added dropwise at such a rate that the reaction
mixture is refluxing smoothly on its own accord (ca. 30-35 min.)
After addition is completed, the mixture is placed in a water bath
and refluxed for 30 minutes. After cooling to 0.degree., 250 ml. of
10% sulfuric acid is added with vigorous stirring. The benzene
layer is extracted twice with 50 ml. portions of 5% sulfuric acid,
and washed twice with 50 ml. portions of 5% sulfuric acid and
washed twice with 50 ml. portions of water. The aqueous acidic
layers are combined and extracted with 2.times.50 ml. ether. The
combined ethereal and benzene extracts are dried over sodium
sulfate. Evaporation of solvent and fractionation of the residue
through a 6" Vigreux column affords the product,
ethyl-2-hydroxy-(.rho.-methoxyphenyl)-1-methylpropionate, B.P.
155-160.degree. (1.5 mm).
[0059] By the method described i-n Vanden Zanden, Rec. trav. chim.,
68, 413 (1949), the above compound is converted to
6-methoxy-2-methylindanone- .
5-ethyl-2-Methylindanone
[0060] The above reactions of Example 2A are repeated except that
the starting materials are o-ethylbenzaldehyde and
ethyl-2-bromopropionate. Using the same reaction conditions and
techniques, there is obtained 5-ethyl-2-methylindanone.
[0061] When the benzaldehydes listed in Table I below are utilized
in the procedure of Example 2A, the corresponding indanone is
obtained.
1 TABLE I Aldehyde Indanone p-o-, or m-tolualdehyde 2,6-dimethyl,
2,5-dimethyl, or 2,4-dimethylindanone p-o-, or
m-hydroxybenzaldehyde 4,5 or 6-hydroxy- 2-methylindanone p-o-, or
nitrobenzaldhyde 2-methyl-(4,5 or 6) nitroindanone p-o-, or
m-chlorobenzaldehyde (4,5, or 6) chloro-2- methylindanone p-o-, or
m-cyanobenzaldehyde (4,5, or 6) cyano-2 methylindanone Vanillin
6-hydroxy-5-methoxy 2-methylindanone p-o-, or
m-sulfamylbenzaldehyde 2-methyl-(4,5 or 6- sulfamylindanone
3-chloro-4-methylbenzaldehyde 5-chloro-2,6 dimethylindanone
4-carbamide-5-methylbenaldehyde 6-carbomide-2,5 dimethylindanone
3,4-difluorobenzaldhyde 5,6 difluoro-2- methylindanone
[0062] (B)
5-methoxy-2-methyl-1-(.rho.-methylsulfonylbenzylidene)-3-indeny- l
acetic acid
[0063] The reactions of Examples 1C, 1D and 1E are repeated, and
5-methoxy-2-methyl-1-(.rho.-methylsulfonylbenzylidene)-3-indenyl
acetic acid is obtained. (R.sub.1=hydrogen; R.sub.2=CH.sub.3;
R.sub.3=5-O--CH.sub.3; R.sub.4=hydrogen;
R.sub.5=.rho.-CH.sub.3SO.sub.2)
EXAMPLE 3
1-(.rho.-Methylsulfonylbenzylidene-2-Methyl-5-Methoxy-3-Indenyl)-Propionic
Acid
[0064] (A)
Methyl-.alpha.(5-methoxy-2-methyl-3-indenyl)propionate
[0065] The procedure of Example 1C is followed using methyl
.alpha.-bromopropionate in equivalent quantities in place of methyl
bromoacetate used therein. There is obtained methyl
.alpha.-(1-hydroxy-6-methoxy-2-methyl-1-indenyl)propionate, and it
is then dehydrated to methyl
.alpha.-(5-methoxy-2-methyl-3-indenyl)propionat- e in the same
manner.
[0066] (B)
.alpha.-[1-(.rho.-methylthiobenzylidene)-2-methyl-5-methoxy-3-i-
ndenyl]propionic acid
[0067] To a solution of 0.5 g. (0.00192 mole) of methyl
.alpha.-(5-methoxy-2-methyl-3-indenyl) propionate and 0.595 g.
(0.0039 mole) of .rho.-methylthiobenzaldehyde in 3 ml. of anhydrous
pyridine is added 1.63 g. of a 40% solution of
benzyltrimethylammonium hydroxide (Triton-B) in methanol. The
resulting red-purple solution is stirred at room temperature
overnight.
[0068] The reaction mixture is poured into a mixture of ice and
water, acidified with 2.5 N HCl, and extracted with ether. The
ether solution is then washed with 2.5 N HCl until the washing
acidifies (once), then with water until neutral. The ether layer is
then extracted with 5% Na.sub.2CO.sub.3 solution. The
Na.sub.2CO.sub.3 solution is washed with ether, acidified and
extracted with ether. The ether solution is washed with water,
dried over Na.sub.2SO.sub.4 and concentrated in vacuo to a yellow
oil that foams up to a clear yellow solid on pumping at 0.5-1 mm.
Thin layer chromatography of the product shows only one spot when
eluted with a (v./v. 4:3:5) of isopropanol: 10% NH.sub.4OH: ethyl
acetate mixture;
[0069] U.V. absorption: >max, 3525, 2910, 2540, 2450. E %, 399,
260, 510 and 498.
[0070] (C) .alpha.-[1-(.rho.-methylsulfonylbenzylidene)-2-methyl
5-methoxy-3-indenyl]-propionic acid
[0071] The procedure of Example 1E is followed using
.alpha.-[1-(.rho.-methylthiobenzylidene)-2-methyl-5-methoxy-3-indenyl]-pr-
opionic acid in place of
5-methoxy-2-methyl-1-(.rho.-methylthiobenzylidene- )-3-indenyl
acetic acid thereby producing a-[1-(.rho.-methylsulfinylbenzyl-
idene)-2-methyl-5-methoxy-3-indenyl]-propionic acid (M.P.
115-1200).
[0072]
.alpha.-[1-(.rho.-methylsulfonylbenzylidene-2-methyl-5-methoxy-3-in-
denyl]-propionic acid is produced following the procedure of
Example 1E using the corresponding sulfoxide derivative.
(R.sub.1=CH.sub.3; R.sub.2--CH.sub.3; R.sub.3=5-methoxy;
R.sub.4=hydrogen; R.sub.5=CH.sub.3SO.sub.2--)
EXAMPLE 4
1-.rho.-Methylsulfonylbenzylidene-5-Dimethylamino-3-Indenyl Acetic
Acid
[0073] (A) Methyl-3-hydroxy-2-methyl-5-nitro-3-indenylacetate
[0074] The procedure of Example 1C is followed using
2-methyl-6-nitro indanone in equivalent quantities in place of
6-methoxy-2-methyl-indanone used therein. After the mixture is
condensed, 30 ml. of ethanol and 50 ml. of acetic acid are added.
The mixture is then poured into 700 ml. of water. Extraction with
ether gives methyl 3-hydroxy-2-methyl-5-nitro-3-in-
denylacetate.
[0075] (B) Methyl 5-dimethylamino-2-methyl-3-indenylacetate
[0076] A solution of 0.05 mole of methyl
3-hydroxy-2-methyl-5-nitro-3-inde- nylacetate, 0.2 mole of 38%
aqueous formaldehyde and 2 ml. of acetic acid in 100 ml. ethanol is
reduced catalytically in the presence of a 10% Pd/C catalyst under
40 lb. p.s.i. hydrogen pressure at room temperature. The solution
is filtered, evaporated and chromatographed on 300 g. of silica gel
to give methyl 5-dimethylamino-3-hydroxy-2-methyl-3-indenylacetate.
The hydroxy ester is then dehydrated to methyl
5-dimethylamino-2-methyl-3- -indenylacetate.
[0077] (C)
1-.rho.-methylthiobenzylidene-5-dimethylamino-2-methyl-3-indeny- l
acetic acid
[0078] To a solution of 2.5 g. of the ester from Part B of this
example in 15 ml. of 1,2-dimethoxyethane at 0.degree. is added 1.5
g. of .rho.-methylthiobenzaldehyde followed by 1.1 g. of potassium
t-butoxide. The reaction mixture is kept in the ice-bath for 4
hours, and then allowed to stand at room temperature for 18 hours.
The mixture is diluted with 15 ml. of ether and the potassium salt
is filtered. The salt is dissolved in 30 ml. of water and
neutralized with dilute hydrochloric acid to pH 6-6.5. The crude
acid precipitated is collected by filtration and chromatographed on
a silica gel column, using ether-petroleum ether (v./v. 50-100%) as
eluent to give pure 1-.rho.-methylthiobenzylidene-5-di-
methylamino-2-methyl-3-indenyl acetic acid which may be oxidized to
1-.rho.-methylsulfinylbenzylidene-5-dimethylamino-2-methyl-3-indenyl
acetic acid and
1-.rho.-methylsulfonylbenzylidene-5-dimethylamino-2-methy-
l-3-indenyl acetic acid as described above. (R.sub.1=hydrogen;
R.sub.2=CH.sub.3; R.sub.3=5-N(CH.sub.3).sub.2; R.sub.4=hydrogen;
R.sub.5=CH.sub.3SO.sub.2--)
EXAMPLE 5
(1-.rho.-Methylsulfonylbenzylidene)-2-Methyl-5-Dimethylamino-3-Indenyl-Pro-
pionic Acid
[0079] (A)
.alpha.-[1-(.rho.-methylsulfonylbenzylidene)-2-methyl-5-dimethy-
lamino-3-indenyl]-propionic acid
[0080] The procedure of Examples 2A, B and C is followed using
6-dimethylamino-2-methylindanone in place of
6-methoxy-2-methylindanone and methyl-.alpha.-bromopropionate in
place of methyl bromoacetate used therein. There is obtained
.alpha.-[1-(.rho.-methylsulfonylbenzylidene)-2-
-methyl-5-dimethylamino-3-indenyl]-propionic acid.
(R.sub.1=CH.sub.3; R.sub.2=CH.sub.3; R.sub.3=5-dimethylamino;
R.sub.4=hydrogen; R.sub.5=p-CH.sub.3SO.sub.2)
EXAMPLE 6
5,6-Difluoro-2-Methyl-1-(.rho.-Methylsulfonylbenzylidene)-3-Indenyl
Acetic Acid
[0081] (A) 3,4-difluorobenzaldehyde
[0082] In a 250 ml. three-necked flask equipped with a magnetic
stirrer, thermometer, condenser, and dropping funnel is placed 25.6
g (0.2 mole) of 3,4 difluorotoluene. The liquid is heated to
105.degree. and illuminated as 67 g. (0.42 mole) of bromine is
added slowly. The temperature is kept between 105-110.degree. while
the first half of the bromine is added over a period of one hour.
The rest of the bromine is added over approximately a 2 hour period
and the temperature is raised to 150.degree. and kept there for 5
minutes.
[0083] The reaction mixture is cooled and transferred to a 1 liter
3-necked flask with a motor driven stirrer and condenser. 120 ml.
H.sub.2O and 90 g. of calcium carbonate are added, and the mixture
is refluxed for 20 hours with good stirring. The reaction mixture
is steam distilled until no further oil is collected. The oil is
taken up in methylene chloride and dried over MgSO.sub.4.
Evaporation of the solvent yields 3,4-difluorobenzaldehyde which is
used without further purification.
[0084] (B) 3,4-difluoro-.alpha.-methylcinnamic acid
[0085] A mixture of 2.88 g. (0.02 mole) of
3,4-difluorobenzaldehyde, 3.24 g. (0.025 mole) of propionic
anhydride and 0.92 g. (0.02 mole) of sodium propionate under
nitrogen is heated at 135.degree. with a magnetic stirrer for 20
hours. The reaction mixture is poured onto 50 ml. of water. A solid
precipitates that dissolves when 50 ml. of saturated
K.sub.2CO.sub.3 is added with stirring. The basic solution is
extracted with ether (2.times.100 ml.). The aqueous phase is then
poured into an excess of concentrated HCl and ice. The precipitated
white solid is filtered and dried to give
3,4-difluoro-.alpha.-methylcinnamic acid, M.P. 122-125.degree..
4-trifluoromethyl-.alpha.-methylcinnamic Acid
[0086] The above reaction of Example 6A is repeated except that
4-trifluoromethylbenzaldehyde is used as a starting material in
place of 3,4-difluorobenzaldehyde. Using the same reaction
conditions and techniques there is obtained
4-trifluoromethyl-.alpha.-methylcinnamic acid.
[0087] Similarly using other benzaldehydes such as
4-methylthiobenzaldehyd- e, 4-chlorobenzaldehyde, and
3-methyl-4-chlorobenzaldehyde, there is obtained
4-methylthio-.alpha.-methylcinnamic acid,
4-chloro-.alpha.-methylcinnamic acid and
3-methyl-4-chloro-.alpha.-methyl- cinnamic acid respectively.
[0088] (C) 3,4-difluoro-.alpha.-methylhydrocinnamic acid
[0089] 28 g. (0.141 mole) of 3,4-difluoro-.alpha.-methylcinnamic
acid, 1 g. of PtO.sub.2 in 250 ml. of MeOH is hydrogenated at 45
p.s.i. until the theoretical uptake is completed. The catalyst is
filtered off, and the material evaporated to one-third its volume.
A 15% potassium hydroxide solution (10 ml.) is added, and the
mixture refluxed for 30 minutes when it is poured into water and
extracted with ether (2.times.100 ml.). The aqueous layer is
acidified with concentrated HCl and ice. The oil which comes out is
extracted into ether, the ether solution dried over MgSO.sub.4 and
evaporated to leave a Mwear oil which crystallizes.
3,4-difluoro-.alpha.-methylhydrocinnamic acid, M.P. 55-56.degree.,
is isolated.
[0090] (D) 5,6-difluoro-2-methyl-1-indanone
[0091] 20 g. (0.1 mole) of 3,4-difluoro-.alpha.-methylhydrocinnamic
acid is added to 250 g. of polyphosphoric acid. The mixture is
efficiently stirred and heated on a steam bath for 2 hours. The
mixture is poured onto ice-water (400 ml.). The precipitate is
extracted with ether (3.times.100 ml.). The extract is washed with
saturated potassium carbonate, water and then dried (MgSO.sub.4).
The ether solution, when evaporated, leaves solid
5,6-difluoro-2-methyl-1-indanone (M.P. 66-68.degree.) which is used
without further purification.
[0092] (E) 5,6-difluoro-2-methylindene-3-acetic acid methyl
ester.
[0093] A mixture of 9.1 g. (0.05 mole) of
5,6-difluoro-2-methyl-1-indanone- , 4.0 g. of "activated" zinc
dust, 7.6 g. (0.05 mole) of methyl bromoacetate, and a crystal of
iodine in 250 ml. of dry benzene is refluxed for 4-5 hours. Tlc
(20% Et.sub.2O-80% pet. ether on Si gel) shows greater than 95%
conversion at this time. The reaction mixture is poured onto 250
ml. of 5% H.sub.2SO.sub.4, separated, and dried (MgSO.sub.4).
Removal of solvent leaves an oily hydroxy ester. The crude ester is
redissolved in 100 ml. of benzene and phosphorus pentoxide (20 g.)
is added. The mixture is refluxed for 30 minutes (no stirrer
necessary) and decanted. The residue is washed with benzene, the
organic layers combined, washed with water (2.times.100 ml.) and
dried (MgSO.sub.4). The benzene, when evaporated, leaves
5,6-difluoro-2-methylindene-3-acetic acid methyl ester, M.P.
86-90.degree..
5-methylthio-2-methylindene-3-acetic Acid Methyl Ester
[0094] The above reaction of Example 6E is repeated using
5-methylthio-2-methylindanone instead of
5,6-difluoro-2-methyl-1-indanone- . Using the same conditions and
techniques, there is obtained 5-methylthio-2-methylindene-3-acetic
acid methyl ester.
[0095] When an acylamino or sulfonyl indanone is employed as the
starting material in the above procedure, the corresponding methyl
ester is obtained.
[0096] (F)
5,6-difluoro-2-methyl-1-(.rho.-methylthiobenzylidene)-indene-3--
acetic acid
[0097] 1.19 g. (5.0 mole) of 5,6-Difluoro-2-methylindene-3-acetic
acid methyl ester is dissolved in 10 ml. of dry pyridine followed
by 0.76 g. (5.0 mole) of .rho.-methylthiobenzaldehyde. The flask is
placed under nitrogen, and 5.0 g (5.1 mole) of Triton B is added.
The deeply colored solution is allowed to stand overnight, and then
water (2 ml.) is added. After standing for 15 minutes, it is poured
into an excess of water. The organics are extracted with ether
(2.times.50 ml.). The aqueous phase is added to 10% HCl-ice. The
orange, gummy solid that precipitates is extracted into methylene
chloride and dried (MgSO.sub.4). The solvent is removed to leave an
orange solid. The solid is filtered to give a crude product which
is recrystallized from benzene to give
5,6-difluoro-2-methyl-1-(.rho.-methyl-thiobenzylidene)-indene-3-acetic
acid. M.P. 181-182.5.degree.. When 3-methylthio-2-furaldehyde or
2-methylthio-5-pyrazine aldehyde is utilized in the above procedure
instead of .rho.-methylthiobenzaldehyde the corresponding indene
acetic acid is obtained.
[0098] (G)
5,6-difluoro-2-methyl-1-(.rho.-methylsulfonyl-benzylidene)-inde-
ne-3-acetic acid
[0099] To a solution of 0.358 g. (1.0 mole) of
5,6-difluoro-2-methyl-1-(.r-
ho.-methylthiobenzylidene)-indene-3-acetic acid in acetone (10 ml.)
is added 10-15 ml. MeOH. With magnetic stirring, 0.32 g. (1.5 mole)
of sodium meta periodate is added in 5 ml. of water. The
proportions of acetone, methanol and water are adjusted if
necessary to preserve homogeneity. After several minutes, a
precipitation of sodium iodate appears. The suspension is stirred
at room temperature for 16 hours, and then poured into
approximately 50 ml. of water and 100 ml. methylene chloride. The
two phases are separated and the water layer is extracted twice
with methylene chloride. The organic phases are washed with water
and dried (MgSO.sub.4). The residue after evaporation is dissolved
in the minimum amount of boiling ethyl acetate and allowed to stand
for 12 hours in the freezer compartment. The deep orange crystals
are filtered. The filtrate is reduced to 1/2 volume and allowed to
stand in the cold for several hours to give a large second crop. In
this way,
5,6-difluoro-2-methyl-1-(.rho.-methylsulfinylbenzylidene)-3-indenylacetic
acid is isolated, M.P. 200-210.degree., which is converted to
5,6-difluoro-2-methyl-1-(.rho.-methylsulfonylbenzylidene)-3-indenylacetic
acid with the procedure of Example 1. (R.sub.1=hydrogen;
R.sub.2=CH.sub.3; R.sub.3=5-fluoro; R.sub.4=6-fluoro;
R.sub.5=CH.sub.3--SO.sub.2).
EXAMPLE 7
5,6-Difluoro-2-Methyl-1-(.rho.-Methylsulfonylbenzylidene)-indenyl-3-Acetic
Acid
[0100] (A)
5-6,difluoro-2-methyl-1-(.rho.-methylsulfonylbenzylidene)-inden-
e-3-acetic acid
[0101] To
5,6-difluoro-2-methyl-1-(.rho.-methylsulfinylbenzylidene)-indene-
-3-acetic acid (0.005 mole) in acetone (15 ml.) is added, slowly
with stirring, m-chloroperbenzoic acid (0.005 mole). The mixture is
heated and evaporated to near dryness at 40.degree.. The solid is
washed with boiling water (4.times.50 ml.) and dried yielding
5,6-difluoro-2-methyl-1-
-(.rho.-methylsulfonylbenzylidene)-indene-3-acetic acid, M.P.
228-230.degree.. (R.sub.1=hydrogen; R.sub.2=CH.sub.3;
R.sub.3=5-fluoro; R.sub.4=6-fluoro;
R.sub.5=CH.sub.3--SO.sub.2--).
EXAMPLE 8
5,6-Difluoro-2-Methyl-1-(.rho.-Methylsulfonylbenzylidene)-3-Indenyl
Acetic Acid
[0102] (A) 3,4-difluorobenzaldehyde
[0103] 57 g. (0.5 mole) of ortho-difluorobenzene in 250 ml. of
methylene chloride is added to 100 g. (0.75 mole) of anhydrous
aluminum chloride. The mixture is stirred (motor) and cooled in an
ice bath while 85.5 g. (0.75 mole) of dichloromethyl methylether is
added dropwise. Vigorous HCl evolution takes place, and the
reaction mixture turns orange-red. After the addition, the mixture
is stirred at room temperature for 15 minutes, and the liquid phase
is decanted into 500 ml. of ice and water. The unreacted residue of
aluminum chloride is washed with methylene chloride until
colorless, and the washings are added to the water. The mixture is
shaken well in a separation funnel until the methylene chloride
layer is green. The organic layer is washed with saturated
potassium carbonate solution until neutral, then dried (MgSO.sub.4)
and distilled to give 3,4-difluorobenzaldehyde, B.P.
70-74.degree./20 min. The dark residue in the distillation pot
solidifies on cooling to give tris-(3-4,difluorophenyl)methane,
M.P. 95-96.degree..
3,4-dimethylbenzaldehyde
[0104] The above reaction of Example 6A is repeated except that
o-xylene and dichloromethyl methylether are the starting materials.
Using the same reaction conditions and techniques, there is
obtained 3,4-dimethylbenzaldehyde.
4-mercaptobenzaldehyde
[0105] The above reaction of Example 6A is repeated except that the
starting materials are mercaptobenzene and dichloromethyl
methylether. Using the same reaction conditions and techniques,
there is obtained 4-mercaptobenzaldehyde.
[0106] (B)
5,6-difluoro-2-methyl-1-(.rho.-methylsulfonylbenzylidene)-3-ind-
enyl acetic acid
[0107] The reactions of Examples 6B, 6C, 6D, 6E, 6F and 6G are
repeated and
5,6-difluoro-2-methyl-1-(.rho.-methylsulfonylbenzylidene)-3-indenyl
acetic acid is obtained. (R.sub.1=hydrogen; R.sub.2=CH.sub.3;
R.sub.3=5-fluoro; R.sub.4=6-fluoro; R.sub.5=CH.sub.3SO.sub.2).
[0108] Similarly, when 3,4-dimethylbenzaldehyde is used in the
reactions in Example 8B,
5,6-dimethyl-2-methyl-1-(.rho.-methylsulfonylbenzylidene)--
3-indenyl acetic acid is obtained.
[0109] When 6-mercaptobenzaldehyde is used in the reactions in
Example 8B,
6-mercapto-2-methyl-1-(.rho.-methylsulfonylbenzylidene)-3-indenyl
acetic acid is obtained.
EXAMPLE 9
.alpha.-(1-.rho.-Methylsulfonylbenzylidene)-2-Methyl-5-Methoxy-6-Fluoro-3--
Indenyl-Acetic Acid
[0110] (A) 3-fluoro-4-methoxybenzaldehyde
[0111] To a solution of o-fluoroanisole, 101 g. (0.80 mole) in 500
ml. dry methylene chloride is added dropwise over 30 minutes a
solution of titanium tetrachloride, 182 g. (0.96 mole, 1.2 equiv.)
and .alpha.,.alpha.-dichloromethylmethyl ether, 110 g. (0.96 mole)
in an equal volume of methylene chloride. The temperature is
maintained at 10-20.degree. C. with an ice-bath. The mixture is
stirred at room temperature for 1 hour longer and then poured over
crushed ice-water with stirring. Ether (1 l.) is added, and the
mixture stirred under nitrogen until solution occurs. The organic
layer is extracted with water (3.times.), sodium bicarbonate
solution (3.times.) and dried (MgSO.sub.4). The solvent is
evaporated off at 30.degree. to give crude product as an oil. The
oil is vacuum distilled through a jacketed Vigreux column when it
gives 3-fluoro-4-methoxybenzaldehyde, B.P. 120-121.degree. C., at
10 mm. Hg; R.sub.f 0.6 on a silica-gel G plate with methylene
chloride.
[0112] (B) 3-fluoro-4-methoxy-.alpha.-methylcinnamic acid
[0113] A mixture of 3-fluoro-4-methoxybenzaldehyde, 34.2 g. (0.22
mole), propionic anhydride, 50 g. (0.38 mole) and sodium
propionate, 21 g. (0.22 mole) is stirred under nitrogen at
150.degree. C. for 15 hours. The reaction mixture is then poured
into 1.3 l. of water with stirring, and the product is
precipitated. 2.0 N potassium hydroxide solution (500 ml.) is
added, and the mixture stirred for several hours, until the acid
has dissolved.
[0114] The aqueous solution is extracted with ether (3.times.) and
then acidified with concentrated hydrochloric acid with stirring.
The precipitated product is collected, washed thoroughly with water
and dried in a vacuum oven at 50.degree. C. over potassium
hydroxide pellets to give 3-fluoro-.alpha.-methyl-4-methoxycinnamic
acid, M.P. 167-169.degree. C.; R.sub.f 0.5 on silica-gel G with
methylene chloride-methanol (1:1).
[0115] (C) 3-fluoro-4-methoxy-.alpha.-methyl dihydrocinnamic
acid
[0116] 3-Fluoro-4-methoxy-.alpha.-methylcinnamic acid, (49.5 g.;
0.236 mole) in 800 ml. methanol is hydrogenated at 43 lbs. pressure
and room temperature until the theoretical uptake of hydrogen has
occurred (24 min at 20.degree. C., using 1.5 g. platinum oxide
catalyst). The solution is filtered and then evaporated with
warming to 60.degree. to give 3-fluoro-4-methoxy-.alpha.-methyl
dihydrocinnamic acid, R.sub.f 0.5 on silica-gel G with methylene
chloride-methanol (9:1).
[0117] (D) 5-fluoro-6-methoxy-2-methylindanone
[0118] A mixture of 3-fluoro-.alpha.-methyl-4-methoxy
dihydrocinnamic acid, 49.3 g. (0.23 mole) in 500 g. of
polyphosphoric acid is heated at 95.degree. C. on a steam bath with
occasional agitation for 75 min. The dark red solution is poured
into 3.0 liters of water, and the mixture is stirred overnight. The
precipitated product is collected, washed thoroughly with water and
then taken up in ether. The ether solution is extracted with
aqueous potassium bicarbonate (4.times.), diluted with methylene
chloride, and dried (MgSO.sub.4).
[0119] The organic solution is evaporated and recrystallized from
methylene chloride-petroleum ether to give
5-fluoro-6-methoxy-2-methylind- anone, (M.P. 76-78.degree.).
[0120] (E) Methyl 6-fluoro-5-methoxy-2-methyl-3-indenylacetate
[0121] Into a 500 ml. three-necked flask fitted with mechanical
stirrer, reflux condenser, drying tube, dropping funnel and
nitrogen inlet is placed 8.0 g. zinc sheet and 100 ml. of dry
benzene. A few milliliters of a solution of 21.3 g. (0.11 mole) of
5-fluoro-6-methoxy-2-methylindanone and 18.36 g. (0.121 mole) of
methyl bromoacetate in 100 ml. of dry benzene is added at a time. A
crystal of iodine is added. The mixture is gently heated with
stirring. After the iodine color has disappeared, the remainder of
the mixture is added gradually. The reaction is heated at reflux
temperature for about 18 hours. The mixture is poured onto 600 ml.
of 5% H.sub.3SO.sub.4 and about 500 g. of ice. Some ether is added.
The organic layer is separated and washed with three portions of 5%
H.sub.2SO.sub.4 water, KHCO.sub.3 solution and finally water again.
The organic layer is dried (MgSO.sub.4) and concentrated to give
27.6 g. of reddish oil which crystallizes upon standing. Thin-layer
chromatography on silica-gel G with methylene chloride methanol
(99:1) shows product at R.sub.f (0.5).
[0122] Without further purification, the hydroxy ester is
dehydrated to the indenylacetate. In 200 ml. of dry benzene, 14.2
g. (53 mole) of crude ester and 36 g. of phosphorus pentoxide are
refluxed with stirring for 1/2 hour. After cooling, the reaction
mixture is filtered and the solid residue washed well with benzene.
The benzene filtrate is washed with two portions of salt water and
dried (MgSO.sub.4). The organic solution is concentrated and gives
a slightly colored oil which rapidly crystallizes. The crude
product is recrystallized from methylene chloride-petroleum ether
to give methyl-6-fluoro-5-methoxy-2-methyl-3-indenylacetate (M.P.
61-62.degree.).
[0123] (F)
6-fluoro-5-methoxy-2-methyl-1-(.rho.-methylthiobenzylidene)-3-i-
ndenyl acetic acid
[0124] To a solution of
methyl-6-fluoro-5-methoxy-2-methyl-3-indenyl acetate, 9.3 g. (0.037
mole) and .rho.-methylthiobenzaldehyde, 6.3 g. (1.1 equivalent) is
added 16 ml. (2.0 equivalents) of 25% methanolic sodium methoxide.
The mixture is stirred at reflux under nitrogen for 2 hours. An
equal volume of water is added dropwise and refluxing continues for
30 minutes. The solution is cooled, diluted with water and
extracted with ether (3.times.). Residual ether is blown off with
nitrogen, and then the aqueous solution is acidified with 50%
glacial acetic acid. The precipitated product is collected and
washed thoroughly with water. The crude product is recrystallized
from methanol to give
6-fluoro-5-methoxy-2-methyl-1-(.rho.-methylthiobenzylidene)-2-indenyl
acetic acid, M.P. 172-174.degree..
[0125] (G)
6-fluoro-5-methoxy-2-methyl-1-(.rho.-methylsulfonylbenzylidene)-
-3-indenyl acetic acid
[0126] A solution of sodium periodate, 4.28 g. (20 mole) in 40 ml.
of water is added dropwise to
6-fluoro-5-methoxy-2-methyl-1-(.rho.-methylthi-
obenzylidene)-3-indenyl acetic acid, 3.70 g. (10 mole) in 300 ml.
methanol and enough acetone to cause solution. This solution is
stirred over night at room temperature and filtered. The filtrate
is evaporated at 30.degree. to a small volume which causes the
product to precipitate. The suspension is diluted with several
volumes of water, cooled and collected. After rinsing with water
and cold methanol-water (1:1), the product is dried in vacuo over
potassium hydroxide pellets, and then in a vacuum oven at
70.degree. C. The crude product is recrystallized from methylene
chloride-petroleum ether to give 6-fluoro-5-methoxy-2-methyl-1--
(.rho.-methylsulfinylbenzylidene)-3-indenyl acetic acid (M.P.
190-193.degree.).
[0127]
6-Fluoro-5-methoxy-2-methyl-1-(.rho.-methylsulfonylbenzylidene)-3-i-
ndenyl acetic acid is prepared according to the procedure of
Example 7 by the addition of 1.0 mole of m-chloroperbenzoic acid
per mole of
6-fluoro-5-methoxy-2-methyl-1-(.rho.-methylsulfinylbenzylidene)-3-indenyl
acetic acid in an acetone solution.
[0128]
.alpha.-[1-(.rho.-Methylsulfonylbenzylidene)-2-methyl-5-methoxy-6-f-
luoro-3-indenyl]-propionic acid is prepared by the procedures of
Examples 3A, 3B and 3C. (R.sub.1=hydrogen; R.sub.2=CH.sub.3;
R.sub.3=5-CH.sub.3--O--; R.sub.4=hydrogen;
R.sub.5=CH.sub.3--SO.sub.2--)
EXAMPLE 10
.alpha.-(1-.rho.-Methylsulfonylbenzylidene)-2-Methyl-5-Fluoro-3-Indenyl-Ac-
etic Acid
[0129] (A) .rho.-Fluoro-.alpha.-methylcinnamic acid
.rho.-Fluorobenzaldehyde (200 g., 1.61 mole), propionic anhydride
(3.5 g., 2.42 mole) and sodium propionate (155 g., 1.61 mole) are
mixed in a 1 l. three-necked flask which had been flushed with
nitrogen. The flask is heated gradually in an oil-bath to
140.degree.. After 20 hours, the flask is cooled to 100.degree. and
poured into 8 l. of water. The precipitate is dissolved by adding
potassium hydroxide (302 g.) in 2.1 of water. The aqueous solution
is extracted with ether, and the ether extracts washed with
potassium hydroxide solution. The combined aqueous layers are
filtered, acidified with concentrated HCl, filtered and the
collected solid washed with water, thereby producing
.rho.-fluoro-.alpha.-methylcin- namic acid which is used as
obtained.
[0130] (B) .rho.-Fluoro-.alpha.-methylhydrocinnamic acid
[0131] To .rho.-fluoro-.alpha.-methylcinnamic acid (177.9 g., 0.987
mole) in 3.6 l. ethanol is added 11.0 g. of 5% Pd/C and the mixture
is reduced at room temperature under a hydrogen pressure of 40
p.s.i. Uptake is 31/32 lbs. (97% of theoretical). After filtering
the catalyst, the filtrate is concentrated in vacuo to give the
product .rho.-fluoro-.alpha.-methylhydrocinnamic acid used without
weighing in next step.
[0132] (C) 6-Fluoro-2-methylindanone
[0133] To 932 g. polyphosphoric acid at 70.degree. on the steam
bath is added .rho.-fluoro-.alpha.-methylhydrocinnamic acid (93.2
g., 0.5 mole) slowly with stirring. The temperature is gradually
raised to 95.degree. C., and the mixture kept at this temperature
for 1 hour. The mixture is allowed to cool and added to 2 l. of
water. The aqueous layer is extracted with ether, the ether
solution washed twice with saturated sodium chloride solution, 5%
Na.sub.2CO, solution, water, and then dried. The ether filtrate is
concentrated with 200 g. silica-gel, and added to a five pound
silica-gel column packed with 5% ether-petroleum ether. The column
is eluted with 5-10% ether-petroleum ether and followed by TLC to
give 6-fluoro-2-methylindanone.
[0134] (D) 5-fluoro-2-methylindanone-3-acetic acid
[0135] A mixture of 6-fluoro-2-methylindanone (18.4 g., 0.112 g.
mole), cyanoacetic acid (10.5 g., 0.123 mole), acetic acid (6.6
g.), and ammonium acetate (1.7 g.) in dry toluene (15.5 ml.) is
refluxed with stirring for 21 hours, as the liberated water is
collected in a Dean Stark trap. The toluene is concentrated, and
the residue dissolved in 60 ml. of hot ethanol and 14 ml. of 2.2 N.
aqueous potassium hydroxide solution. 22 g. of 8.5% KOH in 150 ml.
of water is added, and the mixture refluxed for 13 hours under
nitrogen. The ethanol is removed under vacuum, 500 ml. water added,
the aqueous solution washed well with ether and then boiled with
charcoal. The aqueous filtrate is acidified to pH 2 with 50%
hydrochloric acid, cooled and the precipitate collected. In this
way dried 5-fluoro-2-methylindenyl-3-acetic acid (M.P. 164-1660) is
obtained.
[0136] (E)
5-fluoro-2-methyl-1-(.rho.-methylthiobenzylidene)-3-indenyl acetic
acid
[0137] 5-fluoro-2-methyl-3-indenyl acetic acid (15 g., 0.072 mole)
.rho.-methylthiobenzaldehyde (14.0 g., 0.091 mole) and sodium
methoxide (13.0 g., 0.24 mole) are heated in methanol (200 ml.) at
60.degree. under nitrogen with stirring for 6 hours. After cooling,
the reaction mixture is poured into 750 ml. of ice-water, acidified
with 2.5 N hydrochloric acid, and the collected solid triturated
with a little ether to produce
5-fluoro-2-methyl-1-(.rho.-methylthiobenzylidene)-3-indenyl acetic
acid (M.P. 187-188.2.degree.). U.V. in methanol .lambda..sub.max.
348 m.mu. (E % 500), 258 (557), 258 (495), 353 (513), 262.5 (577),
242.5 (511).
[0138] (F)
5-fluoro-2-methyl-1-(.rho.-methylsulfinylbenzylidene)-3-indenyl
acetic acid
[0139] To a solution of
5-fluoro-2-methyl-1-(.rho.-methylthiobenzylidene)-- 3-indenyl
acetic acid (3.4 g., 0.01 mole) in a mixture of methanol (250 ml.)
and acetone (100 ml.) is added a solution of sodium periodate (3.8
g., 0.018 mole) in water (50 ml.) with stirring.
[0140] Water (450 ml.) is added after 18 hours, and the organic
solvents removed under vacuum below 30.degree.. The precipitated
product is filtered, dried and recrystallized from ethyl acetate to
give
5-fluoro-2-methyl-1-(.rho.-methylsulfinylbenzylidene)-3-indenyl
acetic acid. Upon repeated recrystallization upon ethylacetate
there is obtained
cis-5-fluoro-2-methyl-1-(.rho.-methylsulfinylbenzylidene)-3-indenyl
acetic acid, M.P. 184-186.degree.. U.V. in methanol;
.lambda..sub.max 328 (E % 377), 286 (432), 257.5 shldr. (413), 227
(548).
[0141] Further runs reveal the existence of a second polymorph of
cis-5-fluoro-2-methyl-1-(.rho.-methylsulfinylbenzylidene)-3-indenyl
acetic acid, M.P. 179-181.degree. C.
[0142]
5-chloro-2-methyl-1-(.rho.-methylsulfinylbenzylidene)-3-indenyl
acetic acid is prepared by the procedure as described previously in
this Example 10, and can be converted to the corresponding sulfonyl
compound by the procedure set forth below.
[0143]
5-fluoro-2-methyl-1-(.rho.-methylsulfonylbenzylidene)-3-indenyl
acetic acid is prepared by adding sodium methoxide (4.4 M in MeOH,
68.5 ml, 0.3 mol) dropwise to a stirred cooled mixture of
5-fluoro-2-methyl-1-(.rho.-methylsulfinylbenzylidene)-3-indenyl
acetic acid (100 g, 0.281 mol) in methanol (250 ml) and
acetonitrile (500 ml). Sodium bicarbonate (0.56 mol) and hydrogen
peroxide (30% in water, 0.56 mol) are added and allowed to react
for 18 hours at -10.degree. C. Excess sodium bicarbonate is
filtered off, and cooled filtrate (0.degree. C.) neutralized
dropwise to pH 7 with 1 M hydrochloric acid (350 ml). The resulting
product is then filtered and washed with methanol. A thin layer
chromatography system to check for purity utilizes
chloroform:methyl isobutyl ketone (8:2); the R.sub.f value is 0.21.
A tetrahydrofuran/diisopropyl ether combination can be used for
product recrystallization. Reaction yield is 89%. The product has a
m.mu. of 205-206.degree. C. (R.sub.1=hydrogen; R.sub.2=CH.sub.3;
R.sub.3=5-fluoro; R.sub.4=hydrogen; R.sub.5=CH.sub.3SO.sub.2--)
[0144]
.alpha.-[1-(.rho.-Methylsulfonylbenzylidene)-2-methyl-5-fluoro-3-in-
denyl]-propionic acid is prepared by the procedures of Examples 3A,
3B and 3C.
EXAMPLE 11
[0145]
Cis-5,7-Difluoro-2-Methyl-1-(.rho.-Methylsulfonylbenzylidene)-3-Ind-
enyl Acetic Acid
[0146] (A) 2,4-difluorobenzaldehyde
[0147] A 250 ml., three-necked flask is fitted with a stirrer, a
thermometer, a dropping funnel with a long stem to the bottom of
the flask and a reflux condenser with a tube leading to the back of
a hood. 50 g. (0.38 mole) of 2,4-difluorotoluene is heated to
reflux with stirring and irradiated with a Hanovia ultraviolet
lamp. 41.5 ml. of bromine is gradually added. The reaction is
completed in 2.5 hours during which time the reflux temperature
rises from 112.degree. to 155.degree..
[0148] A 2 l. three-necked flask is fitted with a stirrer and
reflux condenser. In the flask is placed 200 ml. of water and 140
g. calcium carbonate. The cooled above-described reaction mixture
is transferred using some ether for rinsing. The hydrolysis is
completed by refluxing with stirring for 18 hours. The aldehyde is
isolated by steam distillation from the reaction flask. The oil is
separated and the aqueous phase is extracted once with ether. The
combined oil and ether extract is dried over anhydrous MgSO.sub.4
and concentrated under reduced pressure to leave
2,4-difluorobenzaldehyde, still containing some ether which is
distilled through a short Vigreux column under reduced pressure and
separated into several fractions. These are combined to give
2,4-difluorobenzaldehyde, B.P. 56-58.degree. 12 mm.
[0149] (B) 2,4-difluoro-.alpha.-methylcinnamic acid
[0150] A 500 ml., three-necked flask is fitted with reflux
condenser, drying tube, stirrer and N.sub.2 inlet. To a mixture of
55.4 g. (0.39 mole) of 2,4-difluorobenzaldehyde and 56 ml. of
propionic anhydride is added 38 g. (0.39 mole) of sodium
propionate. The reaction mixture is heated at 135-140.degree. (oil
bath temp.) for 19 hours with stirring under nitrogen. The still
warm solution is poured into 1 l. of water with stirring. A solid
separates, which upon adding 56 g. of potassium hydroxide,
dissolves. The solution is extracted with ether, and then heated on
the steam bath to remove the ether. After cooling in an ice-bath,
concentrated hydrochloric acid is added with stirring. The product
which separates is collected and washed with cold water. After
drying at 60.degree. over KOH, 2,4-difluoro-.alpha.-methylcinnamic
acid, M.P. 126-128.degree. is obtained.
[0151] (C) 2,4-difluoro-.alpha.-methylcinnamic acid
[0152] In 800 ml. of methanol, 60 g. (0.3 mole) of
2,4-difluoro-.alpha.-me- thylcinnamic acid with 1.5 g. of platinum
oxide catalyst is shaken under an initial pressure of 42 lbs. of
hydrogen until one equivalent of hydrogen is absorbed. The reaction
time is 30 minutes. The catalyst is removed by filtration and
washed with methanol. The methanol, when evaporated off, leaves
near colorless 2,4-difluoro-.alpha.-methyldihydroc- innamic acid as
an oil which is used in the next step without further
purification.
[0153] (D) 4,6-difluoro-2-methylindanone
[0154] A solution of 2,4-difluoro-.alpha.-methyldihydrocinnamic
acid, 54.8 g. (0.274 mole) in 125 ml. thionyl chloride is stirred
for 90 minutes, and then at reflux for 90 minutes longer. The
reaction solution is evaporated under reduced pressure leaving the
acid chloride product as an oil.
[0155] To a suspension of ice-bath cooled anhydrous powdered
aluminum chloride, 60 g. (0-45 mole), in 250 ml. of dry carbon
disulfide is added dropwise over 10 minutes, a solution of the acid
chloride, 60 g., in 100 ml. carbon disulfide. After the addition,
the ice bath is removed, and the temperature raised slowly to room
temperature. The mixture is stirred at room temperature for 20
hours, and then is poured into 2 l. of 10 aqueous hydrochloric
acid-crushed ice with stirring. Ether is added, and the stirring
continued until everything dissolves. The ether layer is extracted
with 5% hydrochloric acid (2.times.), water (2.times.), and sodium
bicarbonate solution (2.times.), when it is diluted with methylene
chloride and dried (MgSO.sub.4). The filtered solution is
evaporated with warming to 70.degree. C. to give the crude
4,6-difluoro-.alpha.-methylind- anone as an oil which crystallizes
on standing. The crude product is purified by chromatography of a
column (7.0.times.35 cm.) of silica-gel, 400 g. of J. T. Baker 3405
packed in petroleum ether-methylene chloride (2:1). The column is
developed and eluted with the same solvent system, and upon
recrystallization from methylene chloride-petroleum ether gives
4,6-difluoro-2-methylindanone, M.P. 68-69.degree. C.
[0156] (E) Methyl 5,7-difluoro-2-methylindenyl-3-acetate
[0157] About 20% of a solution containing
4,6-difluoro-2-methylindanone, 15.0 g. (83 mole), and methyl
bromoacetate, 14.0 g. (1.1 equiv.) in 100 ml. dry benzene is added
to a stirred suspension of powdered zinc dust (Merck dried
120.degree./22 mm.), 6.5 g. (1.2 equiv.) in 74 ml. dry benzene
under a nitrogen atmosphere. Several crystals of iodine are added,
and the mixture slowly brought to a reflux. The remainder of the
solution is added dropwise over 10 minutes, and the mixture stirred
at reflux overnight, i.e., 17 hours. The reaction is cooled to room
temperature, the mixture poured into 2.0 l. of 20% aqueous sulfuric
acid-crushed ice with stirring, and ether added until a clear
solution is obtained. The ether layer is extracted with 5% aqueous
sulfuric acid (3.times.), water (3.times.), diluted with methylene
chloride and dried (MgSO.sub.4). The filtered ethereal solution is
evaporated to give crude hydroxy ester.
[0158] Powdered phosphorus pentoxide (60.0 g.) is added to the
hydroxy ester (20.0 g.) in 400 ml. of dry benzene. The mixture is
stirred at reflux for 30 minutes, and the clear benzene solution
decanted. The residue is rinsed with benzene and then with ether.
The combined organic solutions are diluted with ether, extracted
six times with aqueous sodium sulfate solution, twice with aqueous
potassium bicarbonate solution, diluted with methylene chloride and
dried (MgSO.sub.4). The crude indenyl acetate product is obtained
by evaporation of the filtered elution to give an oil. The product
is crystallized from petroleum ether and gives methyl
5,7-difluoro-2-methylindenyl-3-acetate, M.P. 69-70.degree. C.
[0159] (F) 5,7
difluoro-2-methyl-1-(.rho.-methylthiobenzylidene)-3-indenyl acetic
acid, a mixture of geometric isomers
[0160] Powdered sodium methoxide, 2.2 g. (40 mole) is added to a
suspension of methyl 5,7-difluoro-2-methyl-indenyl-3-acetate (4.78
g.) (20 mole) and .rho.-methylthiobenzaldehyde, 3.35 g. (22 mole),
in 40 ml. dry methanol under nitrogen. A clear solution results
which is refluxed for 60 minutes. An equal volume of water is
added, and refluxing continued under nitrogen for 30 minutes to
complete saponification. The solution is diluted with several
volumes of water and extracted with ether. Nitrogen is bubbled
through the aqueous solution to remove the residual ether solvent.
Fifty percent aqueous acetic acid (40 ml.) is used to precipitate
the product. The product is collected and washed well with water.
Then it is dried in a desiccator over potassium hydroxide pellets,
and finally in the oven at 100.degree.. The crude product is
recrystallized from methylene chloride-petroleum ether and gives a
mixture of the cis and trans isomers of the acid, M.P.
164-173.degree. in a 1:3 ratio, identifiable by integrating the
2-CH.sub.3 signal in the N.M.R. spectra at 7.82.gamma. for cis and
8.20.gamma. for trans.
[0161] (G)
Cis-methyl-5,7-difluoro-2-methyl-1-(.rho.-methylthiobenzylidene-
)-3-indenylacetate isolation by column chromatography
[0162] Four drops of concentrated sulfuric acid are added to a
solution of
5,7-difluoro-2-methyl-1-(.rho.-methylthiobenzylidene)-3-indenyl
acetic acid, 1.0 g. (2.8 mole) in 60 ml. of dry methanol, and the
solution stirred at reflux overnight. The solution is cooled and
crystals separated which are collected, rinsed with cold
methanol-water (1:1) and dried over potassium hydroxide pellets.
These crystals are found to be about 95% of the trans-isomer, and
could be further purified by recrystallizing from methanol giving
the trans-isomer, M.P. 106-106.5.degree.C. Powdered potassium
bicarbonate is added to the filtrate from the first crop of
crystals, followed by water. A second crop of mixed ester is
obtained in this way which is cis-enriched and used for
chromatography.
[0163] 1.7 g. of cis and trans-mixed esters are chromatographed on
a column (3.0.times.90 cm.) of silica-gel, 250 g. of J. T. Baker
3405, packed in methylene chloride-petroleum ether (1:9). The
column is developed and eluted with a 1:4 ratio of the same
solvents. 0.3 to 0.4 l. cuts are taken as the yellow bands are
eluted. In this way the trans-isomer and the cis-isomer (M.P.
94-94.degree.) are obtained; U.V. of trans in MeOH .sub.max 217
m.mu.., 256 and 362 m.mu.; U.V. of cis-isomer in MeOH
.lambda.max.sub.218 m.mu.., 260 and 357 m.mu..
[0164] (H)
Cis-5,7-difluoro-2-methyl-1-(.rho.-methylthiobenzylidene)-3-ind-
enyl acetic acid
[0165] 1.0 N aqueous sodium hydroxide 3.0 ml. (3.0 mole) is added
to cis-methyl
5,7-difluoro-2-methyl-1-(.rho.-methylthiobenzylidene)-3-indeny-
lacetate, 250 mg. (0.64 mole) in 20 ml. methanol under nitrogen.
The mixture is refluxed for 1 hour, cooled, diluted with water and
acidified with several ml. of 50% acetic acid. Crystals form and
after further chilling in ice bath, they are collected, worked
thoroughly with water and sucked nearly dry. The product is
recrystallized from methanol-water, dried over potassium hydroxide
pellets in a vacuum desiccator and finally in a vacuum oven at
100.degree.. In this way cis-5,7-difluoro-2-methyl-1--
(.rho.-methylthiobenzylidene)-3-indenyl acetic acid (M.P.
182-184.degree.) is obtained.
[0166] (I) Cis-5,7-difluoro-2-methyl-1-(.rho.-methyl
sulfonylbenzylidene)-3-indenyl acetic acid
[0167] Sodium periodate 214 mg. (1.0 mole) in 2 ml. water is added
to
cis-5,7-difluoro-2-methyl-1-(.rho.-methylthiobenzylidene)-3-indenyl
acetic acid, 170 mg. (0.475 mole) in 12 ml. of methanol and about
0.5 ml. acetone at room temperature. The mixture is stirred
overnight when inspection of tlc on silica-gel G using methylene
chloride-methanol elution (1:1) shows that there is no starting
material present but a trace of sulfone at R.sub.f 0.55. The
reaction mixture is filtered and concentrated to a small volume
without heating and diluted with water. The product is collected,
rinsed with water and dried over potassium hydroxide pellets in a
vacuum desiccator and finally in the oven desiccator at 80.degree..
The product is recrystallized from ethyl acetate-petroleum ether
and gives pure cis-5,7-difluoro-2-methyl-1-(.rho.-
-methylsulfinylbenzylidene)-3-indenyl acetic acid, M.P.
188-189.degree. C., which is converted to
cis-5,7-difluoro-2-methyl-1-(.rho.-methylsulfon-
ylbenylidene)-3-indenyl acetic acid in the procedure of Example 1E.
(R.sub.1=hydrogen; R.sub.2=CH.sub.3; R.sub.3=5-fluoro;
R.sub.4=7-fluoro; R.sub.5=CH.sub.3SO.sub.2)
EXAMPLE 12
.alpha.-(1-Methylsulfonylbenzylidene-2-Methyl-5,6-Difluoro-3-Indenyl)-Prop-
ionic Acid
[0168]
.alpha.-[1-.rho.-methylsulfinylbenzylidene)-2-methyl-5,6-difluoro-3-
-indenyl]-propionic acid (0.01 mol.) is prepared by the procedure
of Example 3A, B and C, and converted to the sulfonyl derivative
using the procedure of Example 1E. The procedure yields the desired
compound (R.sub.1=hydrogen; R.sub.2=CH.sub.3; R.sub.3=5-fluoro;
R.sub.4=6-fluoro; R.sub.5=CH.sub.3SO.sub.2).
EXAMPLE 13
.alpha.-(1-.rho.-Methylsulfonylbenzylidene-2-Methyl-5-Fluoro-6-Methoxy-3-I-
ndenyl)-Propionic Acid
[0169]
.alpha.-[1-(.rho.-methylsulfinylbenzylidene)-2-methyl-5-fluoro-6-me-
thoxy-3-indenyl]-propionic acid is prepared by the procedures of
Examples 3A-3C, and converted to the sulfonyl derivative using the
procedure of Example 1E (R.sub.1=methyl; R.sub.2=methyl;
R.sub.3=5-fluoro; R.sub.4=6-methoxy;
R.sub.5=CH.sub.3--SO.sub.2).
EXAMPLE 14
.alpha.-(1-.rho.-Methylsulfonylbenzylidene-2-Methyl-5-Fluoro-3-Indenyl)-Pr-
opionic Acid
[0170]
.alpha.-[1-(.rho.-methylsulfinylbenzylidene)-2-methyl-5-fluoro-3-in-
denyl propionic acid is prepared by the procedures of Examples
3A-3C, and converted to the sulfonyl derivative using the procedure
of Example 1E (R.sub.1=methyl; R.sub.2=methyl; R.sub.3=5-fluoro;
R.sub.4=hydrogen; R.sub.5=CH.sub.3--SO.sub.2)
EXAMPLE 15
N-[5-fluoro-2-methyl-1-(.rho.-methylsulfonylbenzylidene)-3-indenylacetyl]g-
lycine
[0171] (A)
Benzyl-N-[5-fluoro-2-methyl-1-(.rho.-methylsulfinylbenzylidene)-
-3-indenylacetyl]-glycinate. The procedure of Example 14 is
followed using benzylamine acetate in place of the morpholine to
produce the above-named compound.
[0172] (B)
N-[5-fluoro-2-methyl-1-(.rho.-methylsulfinylbenzylidene)-3-inde-
nylacetyl]-glycine.
Benzyle-N-[5-fluoro-2-methyl-1-(.rho.-methylsulfinylbe-
nzylidene)-3-indenylacetyl]-glycinate (0.03 mole) in a mixture of
25 ml. of anhydrous ethanol and 2.5 ml. of 1 N sodium hydroxide is
allowed to stand at room temperature for 18 hours. The solution is
diluted with water and extracted with ether. The aqueous layer is
acidified with dilute hydrochloric acid and the organic product is
extracted with ethyl acetate, washed with water and dried over
sodium sulfate. Evaporation of the solution gives
N-[5-fluoro-2-methyl-1-(.rho.-methylsulfinylbenzyliden-
e)-3-indenylacetic acid, the corresponding indenyl acyl glycine is
obtained, which can be converted to the corresponding sulfonyl
derivative using the procedure of Example 1E.
EXAMPLE 16
(A) Sodium
5-fluoro-2-methyl-1-(.rho.-methylsulfonylbenzylidene)-3-indenyl-
acetate
[0173]
5-fluoro-2-methyl-1-(.rho.-methylsulfonylbenzylidene)-3-indenylacet-
ic acid (1.79 g.) in methanol (10 ml.) is added to a solution of
sodium methoxide (0.27 g.) in methanol (5 ml.). The reaction
mixture is stirred for 20 minutes and evaporated to dryness to
yield sodium
5-fluoro-2-methyl-1-(.rho.-methylsulfonylbenzylidene)-3-indenylacetate.
[0174] (B) Calcium
5-fluoro-2-methyl-1-(.rho.-methylsulfonylbenzylidene)-3-
-indenylacetate
[0175] The above reaction is repeated using 2 moles of acid per
mole of calcium methoxide. Using the same reaction conditions and
techniques there is obtained calcium
5-fluoro-2-methyl-1-(.rho.-methylsulfonylbenzyl-
idene)-3-indenylacetate.
EXAMPLE 17
5-Methoxy-2-methyl-1-(.rho.-methyl-sulfonylbenzylidene)-3-indenyl-.gamma.--
trans-crotonic acid
[0176] According to procedures C & D in Example 1,
6-methoxy-2-methylindan- one is allowed to react with
.gamma.-bromocrotonic acid methyl ester to give the desired
methylthio product.
[0177] Similarly, if any of the other indanones listed in Table I
and synthesized according to Example 2 are used in the above
procedure with either .gamma.-bromocrotonic acid methyl ester or
with .gamma.-bromo-.gamma.-methylcrotonic acid methyl ester, the
corresponding indenylcrotonic acids are obtained. All of these are
oxidized from methylthio to methyl sulfonyl compounds with
periodate according to Example 1E.
EXAMPLE 18
5-methoxy-2-methyl-1-(p-methylsulfonyl-cinnamilydene)-3-indenyl-acetic
acid
[0178] According to procedure D in Example 1, methyl
5-methoxy-2-methyl-3-indenyl acetate is condensed with
.rho.-methylthio cimamaldehyde to give the desired methylthio
product, which can be oxidized according to procedure 1E to the
title compound.
[0179] Similarly, if other 3-indenyl acetates, propionates or
crotonates (See Example 17) are used, the corresponding sulfonyl
compounds are obtained, after oxidation of the intermediate
methylthio compounds according to Example 1E.
EXAMPLE 19
.alpha.-(1-.rho.-Methylsulfonylbenzylidene)-2-Methyl
-5-Fluoro-3-Indenyl-Acetic Acid Methyl Ester
[0180] 5-fluoro-2-methyl-1-(.rho.-methylsulfonylbenzylidene)
-3-indenyl acetic acid is prepared by the procedure of Example 10,
and converted to the methyl ester derivative by the following
procedure. Sodium methoxide (4.4 M in methanol, 1.36 ml, 0.006 mol)
is added to a stirred cooled solution (0.degree. C.) of
5-fluoro-2-methyl-1-(.rho.-methylsulfonylbenzy- lidene) -3-indenyl
acetic acid (1.04 g, 0.0028 mol) in methanol (5 ml) and
acetonitrile (10 ml). After 30 min, the reaction mixture is dropped
into concentrated hydrochloric acid (50 ml) and extracted with
methylene chloride (3.times.25 ml). The organic layer is extracted
with saturated sodium bicarbonate (3.times.25 ml), dried with
sodium sulfate, and concentrated in vacuo. The resulting oil is
crystallized from tetrahydrofuran/hexane to yield 0.2 g of the
desired compound. The melting point is 165-166.degree. C.
(R.sub.1=hydrogen; R.sub.2=CH.sub.3; R.sub.3=5-fluoro;
R.sub.4=hydrogen; R.sub.5=CH.sub.3SO.sub.2--; M=OCH.sub.3) Other
methyl esters of compounds of this invention can be prepared in a
similar fashion.
EXAMPLE 20
Biological Effects
[0181] The compounds of Examples 10 and 19 were assayed for their
effect on various cell lines to ascertain the degree of growth
inhibition following treatment with compounds of this invention.
Cytotoxicity data obtained using these cell lines is thought to be
indicative of the effect on precancerous lesions. The cell lines
employed for these experiments were well characterized, and are
used by the United States National Cancer Institute in their
screening program for new anti-cancer drugs.
[0182] Tumor cell cytotoxicity was assessed using the
Sulforhodamine B Assay. In this assay, tumor cells were plated in
96-well plates and treated with drug-containing media for seven
days (continuous exposure). At the end of the exposure period, the
cells were fixed and stained with sulforhodamine B (a pink
fluorescent dye). The dye was then solubilized, and the optical
density of the resulting pink solution determined on a 96-well
plate reader. The mean dye intensity of the treated wells was then
divided by the mean dye intensity in the control wells (6 wells of
each) to determine the effect of the drug on the cells. Dye
intensity is proportional to the number of cells or amount of
protein per well. The resultant "percent of control" value then
represents the degree of growth inhibition caused by the drug.
[0183] For each experiment, an IC.sub.50 value was determined and
used for comparative purposes. This value is equivalent to the
concentration of drug needed to inhibit tumor cell growth by 50%.
IC.sub.50 values were obtained graphically by connecting the mean
values for each drug concentration tested. Each experiment included
at least six wells per drug concentration. Concentration was
plotted on a log scale on the X-axis. The IC.sub.50 values obtained
are provided in Table I below.
2TABLE I Cell I.C..sub.50 Values (.mu.M) Line Type Example 10
Example 19 SW480 Colonic 141 -- Adenocarcinoma of epithelial origin
Ht-29 Colonic 183 >100 Adenocarcinoma - moderately well defined
DLD-1 Colonic 51 -- Adenocarcinoma A-427 Lung Carcinoma 128 --
MCF-7 Breast Carcinoma 90 63 UACC 375 Melanoma Line 90 40
[0184] The compounds of Examples 1-19 can be formulated with
pharmaceutically acceptable carriers into unit dosage forms in a
conventional manner so that the patient in need of therapy for
precancerous lesions can periodically (e.g. once or more per day)
take a compound according to the method of this invention. It has
been found that colonic bacteria will convert the sulfonyl
derivatives in part to still unidentified metabolite(s).
Specifically, when
cis-5-fluoro-2-methyl-1-[.rho.-(methylsulfonyl)benzylidene]indene-3-aceti-
c acid prepared according to the procedure of Example 10 is
introduced into an anerobic chamber containing an aqueous
suspension of human fecal material, and incubated for 1 to 24
hours, the sulfonyl compound is converted to an unknown derivative,
as verified by high pressure liquid chromatography.
[0185] The exact initial dose of the sulfonyl derivatives used in
the method of this invention can be determined with reasonable
experimentation, but is believed to be larger than that found to be
effective for sulindac.
[0186] It will be understood that various changes and modifications
can be made in the details of procedure, formulation and use
without departing from the spirit of the invention, especially as
defined in the following claims.
* * * * *