U.S. patent number 3,860,636 [Application Number 05/312,549] was granted by the patent office on 1975-01-14 for substituted indenyl phosphonic acids having anti-inflammatory activity.
This patent grant is currently assigned to Merck & Co., Inc.. Invention is credited to Howard Jones, Tsung-Ying Shen.
United States Patent |
3,860,636 |
Shen , et al. |
January 14, 1975 |
SUBSTITUTED INDENYL PHOSPHONIC ACIDS HAVING ANTI-INFLAMMATORY
ACTIVITY
Abstract
New substituted indenyl tetrazoles, sulfonic and phosphonic
acids and derivatives thereof which have anti-inflammatory,
anti-pyretic and analgesic activity. Also included are methods of
preparing said indenyl compounds, pharmaceutical compositions
having said indenyl compounds as an active ingredient and methods
of treating inflammation by administration of said indenyl
compounds.
Inventors: |
Shen; Tsung-Ying (Westfield,
NJ), Jones; Howard (Holmdel, NJ) |
Assignee: |
Merck & Co., Inc. (Rahway,
NJ)
|
Family
ID: |
23211967 |
Appl.
No.: |
05/312,549 |
Filed: |
December 6, 1972 |
Current U.S.
Class: |
562/8; 549/78;
568/424; 548/252; 549/6; 560/8; 560/48; 560/56; 562/11; 562/25;
564/387; 568/442; 548/250; 548/253; 549/68; 549/218; 549/220;
560/10; 560/51; 560/255; 562/23; 562/30; 568/41; 568/425; 568/808;
987/162; 987/166 |
Current CPC
Class: |
C07D
257/04 (20130101); C07C 309/00 (20130101); C07C
317/00 (20130101); C07C 323/00 (20130101); C07F
9/383 (20130101); C07F 9/3882 (20130101); C07C
33/50 (20130101) |
Current International
Class: |
C07C
33/00 (20060101); C07D 257/00 (20060101); C07D
257/04 (20060101); C07F 9/00 (20060101); C07F
9/38 (20060101); C07C 33/50 (20060101); C07f
009/38 (); A61k 029/00 () |
Field of
Search: |
;260/502.5,448CD,52.4R,512C |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Kresze et al., "Chem. Abstracts," Vol, 61, (1964), col. 14633.
.
Houben-Weyl, "Methoden Der Organishen Chemie," Vierte Auflage,
12/1, page 382, Q0258H7. .
Bergmann et al., "Ber. Deut.," Vol. 63 (1930), pages 1158-1173,
particularly pages 1164 and 1165, Q01D4..
|
Primary Examiner: Evans; Joseph E.
Attorney, Agent or Firm: Monaco; Mario A. Westlake, Jr.;
Harry E.
Claims
What is claimed is:
1. A compound of the formula ##SPC5##
wherein:
R.sub.2 is hydrogen, C.sub.1-5 loweralkyl or C.sub.1-5 chloro,
bromo or fluoro loweralkyl;
R.sub.4, r.sub.5, r.sub.6 and R.sub.7 are each hydrogen, halo,
C.sub.1-5 loweralkyl, halo C.sub.1-5 loweralkyl, C.sub.1-5
loweralkoxy, nitro, amino, C.sub.1-5 loweralkylamino, C.sub.1-5
diloweralkylamino, C.sub.1-5 loweralkanoyloxy, C.sub.1-5
loweralkanoylamino, hydroxy, C.sub.1-5 loweralkanoyl, C.sub.2-5
loweralkenoyl, C.sub.2-5 loweralkenyloxy or trifluoromethyl;
R.sub.8 and R.sub.9 are each hydrogen, chloro, bromo, fluoro,
C.sub.1-5 loweralkythio, C.sub.1-5 loweralkyl, trifluoromethyl,
C.sub.1-5 loweralkylsulfonyl, C.sub.1-5 loweralkylsulfinyl,
C.sub.1-5 diloweralkylsulfamyl, nitro or C.sub.1-5 loweralkoxy;
X is C.sub.1-4 alkylene, C.sub.2-4 alkenylene, C.sub.2-4 alkynylene
or --O--;
Ar is phenyl;
R' and R" are each hydrogen or C.sub.1-5 loweralkyl;
n is 0 or 1; and m is hydrogen
2. The compound of claim 1 wherein
R.sub.2 is hydrogen or C.sub.1-5 loweralkyl;
R.sub.4, r.sub.5, r.sub.6 and R.sub.7 are each hydrogen, halo,
C.sub.1-5 loweralkyl, halo C.sub.1-5 loweralkyl, C.sub.1-5
loweralkoxy, nitro, amino, C.sub.1-5 loweralkylamino, C.sub.1-5
diloweralkylamino, c.sub.1-5 loweralkanoyloxy, hydroxy, C.sub.1-5
loweralkanoyl, C.sub.2-5 loweralkenoyl, C.sub.2-5 loweralkenyloxy
or trifluoromethyl;
R.sub.8 and R.sub.9 are each hydrogen, chloro, bromo, fluoro,
C.sub.1-5 loweralkylthio, C.sub.1-5 loweralkyl, trifluoromethyl,
C.sub.1-5 loweralkylsulfonyl, C.sub.1-5 loweralkylsulfinyl,
C.sub.1-5 diloweralkylsulfamyl, nitro or C.sub.1-5 loweralkoxy;
n is 0;
Ar is phenyl; and
R' and R" are each hydrogen.
3. The compound of claim 1 wherein
R.sub.2 is methyl;
R.sub.4, r.sub.5, r.sub.7 and R.sub.8 are each hydrogen;
R.sub.9 is methylsulfinyl;
R.sub.6 is fluoro; and
n is 0.
Description
SUMMARY OF THE INVENTION
This invention relates to new substituted 1--AR-- alkylidene (or
heteroalkylidene) indenyl tetrazoles, sulfonic and phosphoric acids
and derivatives thereof to processes for producing the same. This
invention also relates to pharmaceutical compositions containing
said indenyl compounds as an active ingredient and to methods of
treating pain, fever or inflammation by administering these
particular compounds to patients.
DESCRIPTION AND PREFERRED EMBODIMENTS
The invention is more particularly directed to new substituted
indenyl compounds having the following general formula:
##SPC1##
Wherein:
R.sub.2 may be hydrogen, alkyl haloalkyl, alkenyl, alkynyl, or
trihalomethyl;
R.sub.4, r.sub.5, r.sub.6, r.sub.7, r.sub.8 and R.sub.9 each may be
hydrogen, alkyl, acyloxy, aryloxy, alkoxy, nitro, amino, acylamino,
alkylamino, dialkylamino, alkenyl, alkynyl, alkenyloxy,
dialkylaminoalkyl, sulfamyl, alkylthio, alkylsulfinyl,
alkylsulfonyl, hydroxy, hydroxyalkyl, acyl, halo, cyano, carboxy,
carboalkoxy, carbamido, haloalkyl, cycloalkyl, trifluoromethyl,
aroyl or cycloalkyloxy;
X may be alkylene, alkenylene, alkynylene, O, S, carbonyl or NR
wherein R is hydrogen or alkyl;
N is 0 or 1;
Ar may be aryl or heteroaryl;
R.sub.3 may be ##SPC2##
Or ##SPC3##
Wherein
M may be hydrogen, alkyl or a cation; and R' and R" each may be
hydrogen, alkyl, aryl, alkylthio, hydroxy, alkoxy, halogen or to
ether a carbonyl.
The aryl or heteroaryl substituent, Ar, may include an aryl ring
system such as benzene, naphthalene or biphenyl or a heteroaryl
ring system such as a pyrrole, furan, thiophene, pyridine,
imidazole, pyrazine, thiazole, pyrimidine, benzothiazole, pyrazole,
oxazole, pyrane, pyridazine, indole, thionaphthene, benzofuran,
benzimidazole, azaindole, benzoxyrane, quinoline, isoquinoline,
quinoxaline, naphthyridine or benzoxazole and may be substituted
with any of the aforementioned R.sub.8 and R.sub.9
substitutents.
In the preferred compounds of this invention R.sub.2 is hydrogen,
C.sub.1-5 loweralkyl or C.sub.1-5 chloro, bromo, or fluoro
loweralkyl; R.sub.4, R.sub.5, R.sub.6 and R.sub.7 may be hydrogen,
halo (chloro, bromo, fluoro), C.sub.1-5 loweralkyl, halo C.sub.1-5
loweralkyl, C.sub.1-5 loweralkoxy, cyano, nitro, amino, C.sub.1-5
loweralkylamino, C.sub.1-5 diloweralkylamino, C.sub.1-5
loweralkanoyloxy, C.sub.1-5 loweralkanoylamino, hydroxy, C.sub.1-5
loweralkanoyl, C.sub.2-5 loweralkenoyl, C.sub.2-5 loweralkenyloxy
or trifluoromethyl; R.sub.8 and R.sub.9 are each hydrogen, chloro,
bromo, fluoro, C.sub.1-5 loweralkylthio, C.sub.1-5 loweralkyl,
trifluoromethyl, C.sub.1-5 loweralkyl-sulfonyl, C.sub.1-5
loweralkylsulfinyl, C.sub.1-5 diloweralkylsulfamyl, nitro or
C.sub.1-5 loweralkoxy; X is C.sub.1-4 alkylene, C.sub.2-4
alkenylene, C.sub.2-4 alkynylene or --0--, n is 0 or 1; Ar is the
phenyl; R.sub.3 is as previously defined; R' and R" may each be
hydrogen or C.sub.1-5 loweralkyl; and M is hydrogen or C.sub.1-5
loweralkyl.
In the most preferred aspect of this invention R.sub.2 is hydrogen
or C.sub.1-5 loweralkyl; R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are
each hydrogen, chloro, bromo, fluoro, C.sub.1-5 loweralkyl,
C.sub.1-5 loweralkoxy, nitro, amino C.sub.1-5 loweralkylamino, halo
C.sub.1-5 loweralkyl, C.sub.1-5 diloweralkylamino, C.sub.2-5
loweralkanoylamino, hydroxy, C.sub.1-5 loweralkanoyloxy or
trifluoromethyl, at most only 2 of R.sub.4, R.sub.5, R.sub.6 or
R.sub.7 being other than hydrogen at any one time; R.sub.8 and
R.sub.9 are each hydrogen, C.sub.1-5 loweralkyl, C.sub.1.5
loweralkoxy, C.sub.1-5 loweralkylsulfinyl, C.sub.1-5
loweralkylsulfonyl, chloro, bromo, fluoro, C.sub.1-5
loweralkysulfamyl, C.sub.1-5 diloweralkylsulfamyl or nitro; X is
C.sub.1-4 alkylene, C.sub.2-4 alkenylene, C.sub.2-4 alkynylene or
--0--; n is 0 or 1; Ar is phenyl; R.sub.3 is as previously defined
and especially ##SPC4##
R' and R" are each hydrogen; and M is hydrogen.
This invention also relates to a method of treating pain, fever or
inflammation in patients using a compound of Formula I,
particularly and especially the preferred compounds as the active
constituent.
The compounds of the instant invention can be used to treat
inflammation by reducing inflammation and relieving pain in such
diseases as rheumatoid arthritis, osteoarthritis, gout, infectious
arthritis and rheumatic fever. The compounds of Formula I can also
be used as an anti-pyretic and would be administered and used in
the same manner and in same dosage ranges as if they were being
used to treat inflammation as discussed further on.
The treatment of inflammation in accordance with the method of the
present invention is accomplished by topically, orally, rectally or
parenterally administering to patients a composition of a compound
of Formula I, particularly the especially preferred compounds in a
nontoxic pharmaceutically acceptable carrier.
The non-toxic pharmaceutical carrier may be, for example, either a
solid or a liquid. Exemplary of solid carriers are lactose, corn
starch, gelatin, talc, sterotix, stearic acid, magnesium stearate,
terra alba, sucrose, agar, pectin, cab-o-sil and acacia. Exemplary
of liquid carriers are peanut oil, olive oil, seasame oil and
water. Similarly, the carrier or diluent may include a time delay
material such as glyceryl monosterate or glyceryl distearate alone
or with a wax.
Several pharmaceutical forms of the therapeutically useful
compositions can be used. For example, if a solid carrier is used,
the compositions may take the form of tablets, capsules, powders,
troches or lozenges, prepared by standard pharmaceutical
techniques. If a liquid carrier is used,, the preparation may be in
the form of a soft gelatin capsule, a syrup, an aqueous solution or
liquid suspension. Suppositories may be prepared in a conventional
manner by mixing the compounds of this invention with a suitable
non-irritating excipient which is solid at room temperature but
liquid at the rectal temperature. Such materials are cocoa butter
and polyethylene glycol. Gels and lotions for topical application
may be prepared in conventional manners.
The compounds of Formula I and of the compositions of this
invention are to be administered in an amount sufficient to treat
inflammation, that is to reduce inflammation. Advantageously, the
compositions will contain the active ingredient; namely, the
compounds of Formula I in an amount of from about 0.1 mg. to 50 mg.
per kg. body weight per day (5 mg. to 3.5 mg. per patient per day),
preferably from about 1 mg. to 15 mg./kg. body weight per day (50
mg. to 1 g. per patinet per day).
The method of treatment of this invention comprises administering
to a patient (animal or human), a compound of Formula I,
particularly an especially preferred compound admixed with a
non-toxic pharmaceutical carrier such as exemplified above. The
compounds of Formula I and particularly the especially preferred
compounds will be administered in an amount of from 0.1 mg. to 50
mg./kg. body weight per day, preferably from about 1 mg. to about
15 mg. per kilogram body weight per day. The most rapid and
effective anti-inflammatory effect is obtained from oral
administration of a daily dosage of from about 1 to 15 mg./kg./day.
It should be understood, however, that although preferred dosage
ranges are given, the dose level for any particular patient depends
upon the activity of the specific compound employed. Also many
other factors that modify the actions of drugs will be taken into
account by those skilled in the art in the therapeutic use of
medicinal agents, particularly those of Formula I, for example,
age, body weight, sex, diet, time of administration, route of
administration, rate of excretion, drug combination, reaction
sensitivities and severity of the particular disease. 3-indenyl
methyl tetrazole compounds are known from U.S. Pat. No 3,631,167
issued Dec. 28, 1971. These compounds differ structurally from the
3-indenyl ethyl tetrazole compounds of this invention in that the
3-position of the indene contains a methyl group rather than an
ethyl group, and are prepared by an overall different process.
The compounds of this invention may be prepared from their
corresponding acids or esters. For example, in the case of the
3-indenyl ethyl tetrazole compounds, a 1-unsubstituted 3-indenyl
acetic acid or ester may be first converted to its corresponding
alcohol by methods well known in the art for reduction of an acid
group or ester to an alcohol group (such as with complex hydrides,
for example, lithium aluminum hydride or calcium borohydride, in
such solvents as tetrahydrofuran ether and the like), halogenation
of the alcohol to ethyl halide formation of the corresponding
nitrile by methods well known to the art, followed by reactions
with an alkali azide to form the tetrazole nucleus, and finally
condensation and dehydration with the appropriate aldehyde in the
1-position of the idene. This latter reaction may readily be
carried out by using a strong base such as alkali hydroxide or
alkoxide and the like, as the catalyst, the reaction can be carried
out in a solvent, if desired. Alternatively, the 1-substituent may
be placed in the indene moiety at any stage of the process, for
example the 1-substituent may be placed on the 3-indenyl acetic
acid or ester followed by the subsequent reactions to result in the
final 3-indenyl ethyl tetrazole compounds of this invention.
The starting material, i.e., 1-unsubstituted-3-indenyl acetic acids
or esters are known compounds as indicated by such U.S. Patents as
U.S. Pat. No. 3,654,349, 3,312,730, and others. The 1-substituted
derivatives thereof may be readily prepared by condensation and
dehydration of the 1-unsubstituted-3-indenyl acetic acids or
esters.
The following examples are given by way of illustration.
EXAMPLE 1
5-Fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-indenyl-3-ethyl-5-tetrazo
le
A. 5-Fluoro-2-methylindenyl-.beta.-ethanol
methyl 5-fluoro-2-methyl indenyl-3-acetate (9.8 g.) is added in
ether (75 ml.) to a suspension of lithium aluminum hydride (1.0 g.)
in ether (50 ml.) over 30 min. The reaction is then refluxed and
stirred for 30 min., cooled methanol (50 ml.) slowly added and
filtered through celite. The solution is dried (MgSO.sub.4)
filtered and concentrated to give an oil. The oil is
chromatographed on silica-gel 10 in. .times. 2 in. column (Baker
analyzed 60 to 200 mesh). Elution with 200 ml. portions of benzene
gives the title compound m.p. 64.degree.-66.degree..
B. 5-Fluoro-2-methylindenyl-.beta.-ethyl chloride
The above compound (0.1 mole) is refluxed in benzene (100 ml.) with
thionyl chloride (0.11 mole) with a drop of dimethylformamide for 2
hrs. and evaporated to dryness. The oily ethyl chloride compound is
used crude in the next reaction.
C. 5-Fluoro-2-methylindenyl-.beta.-propionitrile
5-Fluoro-2-methylindenyl-.beta. -ethylchloride (0.1 mole) and dry
sodium cyanide (0.11 mole) are stirred together at 60.degree. in
dry redistilled dimethylformamide (100 ml.) for 1 hr. The reaction
mixture is cooled, the sodium chloride filtered off, and the
filtrate evaporated to one-third volume. The crude propionitrile is
extracted into ethyl acetate (100 ml.) and washed well with water
12 .times. 25 ml. The filtrate is evaporated and put on a 1 ft.
.times. 2 in. silica gel column (Baker analyzed 60-200 mesh)
elution with mixtures of etheralcohol gives the compound pure.
D 5-Fluoro-2-methylindenyl-3-ethyl-5-tetrazole
A mixture of the above nitrile (0.003 ml.) sodium azide (0.051 ml.)
and ammonium chloride (0.049ml.) are heated at 120.degree. with
stirring for 16 hrs. in dry dimethylformamide (80 ml.). After this
time, the reaction mixture is concentrated to dryness, 100 ml.
water added and the mixture filtered (pH of filtrate 8). The
filtrate is acidified and the precipitate filtered. The combined
precipitates are recrystallized from ethanol-water to give
5-fluoro-2-methylindenyl ethyl-5-tetrazole.
E.
5-Fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)indenyl-3-ethyl-5-tetrazo
le
5-Fluoro-2-methyl-indenyl-3-ethyl-5-tetrazole (5.0 mmole) is
dissolved in 10 ml. of dry pyridine followed by
p-methylsulfinylbenzaldehyde (5.0 mmole). The flask is placed under
nitrogen and Triton B (5.1 mmole) in methanol is added. The
reaction mixture is allowed to stand overnight and then water (3
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
precipitated material is extracted into methylene chloride and
dried (MgSO.sub.4). The solution is filtered and the solvent
removed. The product is recrystallized from benzene to yield the
desired compound.
Similarly, when benzaldehyde, p-methylthiobenzaldehyde,
p-methylsulfonylbenzaldehyde, p-chlorobenzaldehyde,
m-chlorobenzaldehyde, p-fluorobenzaldehyde,
p-ethylthiobenzaldehyde, m-nitrobenzaldehyde,
m-diethylaminobenzaldehyde, p-methylbenzaldehyde or
p-methoxybenzaldehyde is used on an equivalent amount in place of
p-methylsulfinylbenzaldehyde in 1E above, there is obtained the
corresponding appropriately 1-substituted
3-indenyl-3-ethyl-5-tetrazole compound.
Similarly when
methyl 5-hydroxy-2-methyl-3-indenyl acetate,
methyl 5-methoxy-2-methyl-3-indenyl acetate,
methyl 5-cyano-2-methyl-3-indenyl acetate,
ethyl 5-fluoro-3-indenyl acetate,
methyl 5,6-difluoro-2-methyl-3-indenyl acetate,
methyl 5-chloro-2-methyl-3-indenyl acetate,
methyl 5-trifluoromethyl-2-methyl-3-indenyl acetate,
methyl 2,5-dimethyl-3-indenyl acetate,
methyl 5,7-difluoro-2-methyl-3-indenyl acetate,
methyl 5-dimethylamino-2-methyl-3-indenyl acetate,
methyl 5-allyloxy-2-methyl-3-indenyl acetate and
methyl 5-methoxy-6-fluoro-2-methyl-3-indenyl acetate
are used in place of methyl 5-fluoro-2-methylindenyl-3-acetate in
an equivalent amount, in step 1A above, and the product therefrom
carried out through step 1B-1E, there is obtained the corresponding
substituted indenyl-3-ethyl-5tetrazoles.
EXAMPLE 2
5-Fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-indenyl-3-methanesulfonic
acid
A. 5-Fluoro-2-methylindenyl-3-methylamine
5-Fluoro-2-methylindenyl-3-acetic acid (0.12 mole) is dissolved in
acetone (dry 270 ml.) and triethylamine (0.0124 mole) is added with
stirring i-butyl chloroformate is then added (0.12 mole). The
precipitate is collected after 10 minutes and the triethylamine
hydrochloride rinsed out with acetone (50 ml.). Sodium azide (0.127
mole) in water (50 ml.) is added over 10 min. to the salt in
acetone. After 2 hr. at room temperature ether (2litre) and water
(1litre) are added and the mixture separated. The ether layer is
washed with water (2 .times. 100 ml.) separated, dried
(MgSO.sub.4), filtered and evaporated to an oil. This oil is heated
at 100.degree. with stirring for 5 min. alone and then with benzyl
alcohol (35 ml.) in benzene (500 ml.) at reflux for 3 hr. The
solvents are removed under vacuum and the crude product is
catalytically reduced in methanol (150 ml.) over Pd/c (5%) (4 g.)
and concentrated hydrochloric acid (3 ml.) at room temperature.
After removing the catalyst, the solution is extracted with
chloroform (3 .times. 40 ml.) from water (50 ml.) and more 2.5N HCl
(70 ml.). The aqueous solution is made basic with saturated sodium
bicarborate solution and extracted with ethyl acetate (4 .times.
100 ml.) separated and washed with H.sub.2 O (2 .times. 20 ml.) The
organic layer is dried (MgSO.sub.4), filtered and evaporated to
dryness to give the crystalline amine.
B. 5-Fluoro-2-methylindenyl-3-methanol
The above amine (0.1 mole) is dissolved in 2.5N hydrochloric acid
(50 ml.) and the solution cooled and stirred in an ice bath at
0.degree. while 10% aqueous sodium nitrite is added slowly (0.15
mole). The solution is then heated to 60.degree. with stirring for
1 hr. and the alcohol extracted with chloroform (2 .times. 50 ml.).
The chloroform layer is separated, dried (MgSO.sub.4), filtered and
evaporated to give the crystalline alcohol.
C. 5-Fluoro-2-methylindenyl-3-methylchloride
The above alcohol (0.1 mole) in benzene (50 ml.) and thionyl
chloride (0.11 mole) is refluxed for 1 hr. and the solution then
evaporated to give an oil.
D. 5-Fluoro-2-methylindenyl-3-methyl-5-thiouronium chloride
The above chloro compound (0.1 mole) in isopropanol (100 ml.) is
stirred and refluxed with thiourea (0.11 mole) for 3 hrs. The
5-thiouronium chloride is precipitated as it is formed and is used
as is.
E. 5-Fluoro-2-methylindenyl-3-methylmercaptan
The above thiouronium salt (0.1 mole) is stirred and refluxed under
nitrogen in aqueous alcoholic potassium hydroxide (1:1 10% 100 ml.)
for 4 hrs. The alcohol is evaporated off under reduced pressure and
the gummy material extracted into ether (2 .times. 50 ml.).
Evaporation of the ether gave the crystalline mercaptan.
F. 5-Fluoro-2-methylindenyl-3-methylsulfonic acid
The above mercaptan (0.1 mole) in isopropanol (300 ml.) is oxidized
with 30% hydrogen peroxide (100 ml.) at room temperature for 24
hrs. The isopropanol is evaporated off and the aqueous layer
neutralized with sodium bicarbonate. The aqueous layer is extracted
with ethyl acetate (3 .times. 100 ml.), acidified with
concentrataed hydrochloric acid and again extracted with ethyl
acetate (2 .times. 100 ml.). The ethyl acetate solution is dried
(MgSO.sub.4), filtered and evaporated to dryness to give the
crystalline sulfonic acid.
G. 5-Fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)
indenyl-3-methylsulfonic acid
The product from Example 2F is reacted with
p-methylsulfinylbenzaldehyde by the procedure given in Example 1E,
to yield the desired product.
Similarly, when benzaldehyde, p-methylthiobenzaldehyde,
p-methylsulfonylbenzaldehyde, p-chlorobenzaldehyde,
m-chlorobenzaldehyde, p-fluorobenzaldehyde,
p-ethylthiobenzaldehyde, m-nitrobenzaldehyde,
m-diethylaminobenzaldehyde, p-methylsulfamylbenzaldehyde,
p-methylbenzaldehyde or p-methoxybenzaldehyde is used in an
equivalent amount in place of p-methylsulfinylbenzaldehyde 2G
above, there is obtained the corresponding appropriately
1-substitutedindenyl-3-methyl sulfonic acid.
Similarly when an equivalent amount of
5-hydroxy-2-methyl-3-indenyl acetic acid,
5-methoxy-d2-methyl-3-indenyl acetic acid,
5-cyano-2-methyl-3-indenyl acetic acid,
5-fluoro-3-indenyl acetic acid,
5,6-dichloro-2-methyl-3-indenyl acetic acid,
5-chloro-2-methyl-3-indenyl acetic acid,
5-trifluoromethyl-2-methyl-3-indenyl acetic acid,
5-methyl-2-methyl-3-indenyl acetic acid,
5,7-difluoro-2-methyl-3-indenyl acetic acid,
5-dimethylamino-2-methyl-3-indenyl acetic acid,
5-allyloxy-2-methyl-3-indenyl acetic acid and
5-methoxy-6-fluoro-2-methyl-3-indenyl acetic acid are used in place
of 5-fluoro-2-methylindenyl-3-acetic acid in Example 2A, and the
product further reacted in accordance with Example 2 B-G, there is
obtained the corresponding substituted indenyl-3-methane sulfonic
acid.
EXAMPLE 3
5-Fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-indenyl-3-methylphosphori
c acid
A. 5-Fluoro-2-methyl-indenyl-3-methyl phosphonic acid
5-Fluoro-2-methylindenyl-3-methyl chloride (see Example 2C) (0.5
mole) is heated in isopropylphosphite (300 ml.) at 180.degree. for
2 days while removing isopropanol. At the end of this time all the
excess isopropylphosphite is removed by distillation at 40.degree.
and 2 mm. and the crude ester is chromatographed on Baker analyzed
silica gel (2 ft. .times. 3 in.) using mixtures of benzene
petroleum benzene as eluants. In this way, pure
isopropylphosphonate ester is obtained by evaporation of pure
fractions.
The ester is heated to reflux in 5N hydrochloric acid (200 ml.)
with strong stirring for 8 hrs. At the end of this time the
solution is evaporated to dryness and the crude phosphonic acid
recrystallized from ethyl alcohol.
B.
5-Fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-indenyl-3-methylphosphon
ic acid
The product of Example 3A is reacted with
p-methylsulfinylbenzaldehyde in accordance with the procedure of
Example 1E to obtain the desired product.
Similarly when benzyladehyde, p-methylthiobenzaldehyde,
p-methylsulfonylbenzaldehyde, p-chlorobenzaldhyde,
m-chlorobenzaldehyde, p-fluorobenzaldehyde,
p-ethylthiobenzaldehyde, m-nitrobenzaldehyde,
m-diethylaminobenzaldehyde, p-methylsulfamylbenzaldehyde,
p-methylbenzaldehyde or methoxybenzaldehyde is used in an
equivalent amount in place of p-methylsulfinylbenzaldehyde in 3B
above, there is obtained the corresponding appropriately
1-substituted-indenyl-3-methyl phosphonic acid.
Similarly when an equivalent amount of
5-hydroxy-2-methyl-3-indenyl acetic acid,
5-methoxy-2-methyl-3-indenyl acetic acid,
5-cyano-2-methyl-3-indenyl acetic acid,
5-fluoro-3-indenyl acetic acid
5,6-dichloro-2-methyl-3-indenyl acetic acid,
5-chloro-2-methyl-3-indenyl acetic acid,
5-trifluoromethyl-2-methyl-3-indenyl acetic acid,
2,5-dimethyl-3-indenyl acetic acid,
5,7-difluoro-2-methyl-3-indenyl acetic acid,
5-dimethylamino-2-methyl-3-indenyl acetic acid,
5-allyloxy-2-methyl-3-indenyl acetic acid and
5-methoxy-6-fluoro-2-methylindenyl-3-indenyl acetic acid are used
in place of 5-fluoro-2-methylindenyl-3-acetic acid in Example 2A,
the product further reacted in accordance with Example 2 B and C
and the 3-methylchloride compound obtained is reacted according to
Example 3A and B, there is obtained the corresponding substituted
indenyl-3-methane phosphonic acid.
EXAMPLE 4
cis- and
trans-5-Fluoro-2-methyl-1-(4'-methysulfinylcinnamylidenyl)-indeny-3-ethyl-
5-tetrazole
To a solution of 0.02 mole of
5-fluoro-2-methyl-indenyl-3-ethyl-5-tetrazole in methanol (60 ml.)
is added sodium methoxide (2.16 g., 0.04 mole) and after solution
p-methylsulfinylcinnamaldehyde (0.02 mole). The mixture is heated
at reflux for 5 hours, cooled, poured into etherwater, extracted
with ether, dried (MgSO.sub.4), and concentrated to an oil in
vacuo. The oil is taken up in methylene chloride and
chromatographed on silica gel and eluted with ethyl acetate. The
fractions of eluate are concentrated to yield cis- and
trans-5-fluoro-2-methyl-1-(4'-methylsulfinylcinnamylidenyl)-indenyl-3-ethy
l-5-tetrazole.
Similarly, when an equivalent amount of any of the other tetrazole
compounds obtained from Example 1 are used in place of
5-fluoro-2-methyl-indenyl-3-ethyl-5-tetrazole there is obtained the
corresponding
1-(4'-methylsulfinylcinnamylidenyl)-indenyl-3-ethyl-5-tetrazole
compound.
Similarly, when an equivalent amount of the aldehyde of Table I
below is used in place of 4-methylsulfinylcinnamaldehyde in the
above procedure, the corresponding
1-substituted-2-methyl-5-fluoro-indenyl-3-ethyl-5-tetrazole is
obtained.
TABLE 1
.alpha.-tolualdehyde
cinnamaldehyde
hydrocinnamaldehyde
2-methoxycinnamaldehyde
4-methoxycinnamaldehyde
4-ethoxycinnamaldehyde
3,4-dimethoxycinnamaldehyde
4-methylcinnamaldehyde
4-t-butylcinnamaldehyde
2-nitrocinnamaldehyde
3-nitrocinnamaldehyde
4-nitrocinnamaldehyde
4-dimethylaminocinnamaldehyde
4-diethylaminocinnamaldehyde
2-chlorocinnamaldehyde
4-chlorocinnamaldehyde
2,4-dichlorocinnamaldehyde
4-bromocinnamaldehyde
4-methylthiocinnamaldehyde
4-methylsulfinylcinnamaldehyde
4-methylsulfonylcinnamaldehyde
4-chloro-.alpha.-methylcinnamaldehyde
4-chloro-2-nitrocinnamaldehyde
4-chloro-3-nitrocinnamaldehyde
5-chloro-2-methylcinnamaldehyde
4-nitro-.alpha.-methylcinnamaldehyde
4-nitro-.beta.-methylcinnamaldehyde
4-nitro-.beta.-phenylcinnamaldehyde
.alpha.-methylcinnamaldehyde
.alpha.-ethylcinnamaldehyde
.beta.-methylcinnamaldehyde
.beta.-ethylcinnamaldehyde d
.alpha.-.beta.-dimethylcinnamaldehyde
.alpha.-pentylcinnamaldehyde
.alpha.-cyclopentylcinnamaldehyde
3,4-methylenedioxycinnamaldehyde
3,4,5-trimethoxycinnamaldehyde
3,4-dimethoxy-.alpha.-methylcinnamaldehyde
4-isopropyl-.alpha.-methylcinnamaldehyde
4-methoxyhydrocinnamaldehyde
2-methylhydrocinnamaldehyde
4-methylhydrocinnamaldehyde
4-sec butylhydrocinnamaldehyde
4-nitrohydrocinnamaldehyde
4-chlorohydrocinnamaldehyde d
4-methylthiohydrocinnamaldehyde
4-methylsulfinylhydrocinnamaldehyde
4-methylsulfonylhydrocinnamaldehyde
4-nitro-.alpha.-methylhydrocinnamaldehyde
4-nitro-.beta.-methylhydrocinnamaldehyde
4-chloro-.alpha.-methylhydrocinnamaldehyde
4-chloro-.beta.-methylhydrocinnamaldehyde
.alpha.-methylhydrocinnamaldehyde
.beta.-methylhydrocinnamaldehyde
.alpha.,.alpha.-dimethylhydrocinnamaldehyde
4-chloro-.alpha.-tolualdehyde
4-methoxy-.alpha.-tolualdehyde
4-methylthio-.alpha.-tolualdehyde
.alpha.-ethyl-.alpha.-tolualdehyde
4-nitro-.alpha.-methyl-.alpha.-tolualdehyde
4-chloro-.alpha.-methyl-.alpha.-tolualdehyde
4-phenylbutanal
4-phenyl-2-butanal
2'-thienylacetaldehyde
.beta.-(2'-thienyl)propenal
.beta.-(2'-thienyl)propanal
3'-pyridylacetaldehyde
4'-pyridylacetaldehyde
2'-pyridylacetaldehyde
2'-furylacetaldehyde
5'-chloro-2'-thienylacetaldehyde
.alpha.-naphthylacetaldehyde
.beta.-naphthylacetaldehyde
.beta.-(2'-furyl)propenal
.beta.-(2'-pyridyl)propenal
.beta.-(.alpha.'-naphthyl)propenal
.beta.-(3'-pyridyl)propenal
.beta.-(4'-pyridyl)propenal
.beta.-(2'-furyl)propanal
.beta.-(2'-pyridyl)propanal
.beta.-.alpha.'-naphthyl)propanal
.beta.-(2'-quinolyl)propanal
.beta.-(2'-pyrrolidinyl)propanal
.beta.-(2'-benzofuranyl)propanal
.beta.-(2'-quinolyl)propenal
.beta.-(2'-pyrrolidinyl)propenal
.beta.-(2'-naphthyl)propenal
.beta..beta.-diphenylpropenal
2'-indanacetaldehyde
.beta.-(2'-benzothiazole)propenal
.beta.-(3'-nitro-2'-thienyl)propenal
.beta.-(1'-methyl-2'-pyrrolyl)propenal
.beta.-(1'-methyl-2'-pyridyl)propenal
EXAMPLE 5
A. (3-Chloro-4-methylthio)-phenylpropargaldehyde
A mixture of 3-chloro-4-methylthiocinnamaldehyde (2.0 mole) and
acetic acid (1.5 liter) is stirred vigorously while bromine (320
g., 2.0 mole) is added dropwise at 25.degree.. Powdered anhydrous
potassium carbonate is added at 25.degree.. When the evolution of
gas stops the mixture is refluxed for 30 minutes, cooled and poured
into cold water (2.5 liters). The mixture is cooled to
0.degree.-5.degree. with stirring and stirred at this temperature
overnight. The precipitate is separated by filtration without
drying and crystallized from ethanol-water.
3-Chloro-4-methylthio-.alpha.-bromocinnamaldehyde is filtered,
washed and dried in air.
The aldehyde (1.6 mole) methyl orthoformate (244 g., 2.3 mole),
absolute ethanol (320 ml.) and ammonium chloride (4.0 g.) are
refluxed for 30 minutes, low boiling components distilled at
atmospheric pressure and distilled in vacuo to yield
1,1-dimethoxy-3-(3'-chloro-4'-methylthiophenyl)-2-propene. To this
compound (1.35 mole) is added potassium hydroxide (132 g., 2.0
moles) in methanol (1400 ml.). The mixture is refluxed for 3 hours
and poured into water (11.3 liters). The mixture is extracted with
chloroform (3 .times. 1.5 liter), the combined chloroform extracts
washed with water (3 .times. 660 ml.) and dried (Na.sub.2
SO.sub.4). The chloroform is distilled and the residue fractionated
in vacuo to obtain
1,1-dimethoxy-(3'-chloro-4'-methylthiophenyl)-2-propyne. This
compound (1.0 mole) is added to water (1 liter) containing
concentrated sulfuric acid (70 ml.) and the mixture is heated on
the steam bath for 30 minutes with occasional mixing. The mixture
is extracted with ether (3 .times. 750 ml.), the ether extract
washed with water and saturated salt solution, dried (Na.sub.2
SO.sub.4) and concentrated to an oil at atmospheric pressure. The
oil is distilled in vacuo to yield
(3-chloro-4-methylthio)-phenylpropargaldehyde.
B. cis- and
trans-5-Fluoro-2-methyl-1-(3'-chloro-4'-methyl-thiophenylpropargylidene)-i
ndenyl-3-ethyl-5-tetrazole
(3-Chloro-4-methylthio)-phenylpropargaldehyde 0.2 mole and
5-fluoro-2-methyl-indenyl-.beta.-ethyl-5-tetrazole (0.2 mole) are
condensed by the method of Example 4 to yield the subject
compound.
Similarly, when the other tetrazole compounds obtained from Example
1 are used in place of
5-fluoro-2-methyl-indenyl-3-ethyl-5-tetrazole in the above Example,
there is obtained the corresponding
1-(3'-chloro-4'-methyl-thiophenylpropargylidene substituted indenyl
tetrazole compounds.
Similarly, when an equivalent amount of
5-fluoro-2-methyl-indenyl-3-methylsulfonic acid or
5-fluoro-2-methylindenyl-3-methyl phosphonic acid obtained from
Example 2 and 3 respectively are used in place of
5-fluoro-2-methyl-indenyl-3-ethyl-5-tetrazole in the above Example,
there is obtained
5-fluoro-2-methyl-1-(3'-chloro-4'-methylthiophenylpropargylidene)-indenyl-
3-methylsulfonic acid or
5-fluoro-2-methyl-1-(3'-chloro-4'-methylthiophenylpropargylidene)-indenyl-
3-methylphosphonic acid respectively.
EXAMPLE 6
A. t-Butyl 5-fluoro-2-methyl-3-indenyl acetate
Ethyl 5-fluoro-2-methyl-3-indenyl acetate (1.0 mole), t-butyl
acetate (700 g., 6.0 mole) and sodium methoxide (108 g., 2 mole)
under nitrogen are stirred and refluxed at 10:1 ratio through a
1.5' column packed with glass one-eighth inch helices. The mixture
is distilled for 18 hours and 250 ml. of distillate is collected.
The excess of t-butylacetate is distilled in vacuo and the residue
is taken up in methylene chloride, filtered through diatomaceous
earth then through acid-washed alumina. The methylene chloride is
removed and the residue crystallized from acetone-n-hexane to yield
t-butyl 5-fluoro-2-methyl-3-indenyl acetate.
B. t-Butyl 5-fluoro-1-hydroxymethylene-2-methyl-3-indenyl acetate,
Sodium Salt
To a mixture of t-butyl 5-fluoro-2-methyl-3-indenyl acetate (0.2
mole) in benzene (500 ml.) and ethyl formate (74.1 g., 1.0 mole) is
added oil-free sodium hydride (7.2 g., 0.3 mole). The mixture is
stirred at room temperature 1 hour each day for 2 days. Any
remaining sodium hydride is decomposed by the addition of methanol
(20 ml.) in ether (100 ml.). The salt is filtered washed with ether
and dried in vacuo.
C. cis- and
trans-t-Butyl-5-fluoro-2-methyl-1-(p-methylthiophenoxymethylidene)-3-inden
yl acetate
The sodium salt (0.01 mole) from Example 6B in dimethoxyethane (200
ml.) is heated at reflux with stirring for 15 hours with
p-methylthiophenyl iodide (25.0 g., 0.01 mole). The mixture is
concentrated in vacuo to remove solvent, taken up in methylene
chloride-water, the layers separated and the water layer extracted
with methylene chloride (2 .times. 100 ml.). The combined methylene
chloride layers are concentrated to one-third volume and
chromatographed over silica gel and eluted by methanolic chloroform
to separate cis- and trans- isomers.
D.
5-Fluoro-2-methyl-1-(p-methylthiophenoxymethylidene)-3-indenyl-5-tetrazole
The product of Step C above is reacted in accordance with Example
A-D to yield the subject product.
Similarly, when an equivalent amount of
p-methylsulfinylphenyliodide is used in place of
p-methylthiophenyliodide in Example 6C above, and the product
reacted by the method of 6D above, there is obtained the
corresponding 1-(p-methylsulfinylphenoxymethylidene) compound.
Similarly, when an equivalent amount of any one of the methyl or
ethyl acetate compounds from Example 1 is used in place of
ethyl-5-fluoro-2-methyl-3-indenyl acetate in Example 6A above and
the resulting product used in Example 6B-D, there is obtained the
corresponding 3-indenyl-5-tetrazole compound.
Similarly, when the product of step 6C is reacted in accordance
with Example 2 A-F, or (Example 2 A-C and 3A), there is obtained
the corresponding 3-methylsulfonic acid or 3-methylphosphonic acid
respectively.
EXAMPLE 7
5-Fluoro-2-methyl-1-(4'-methylsulfinylcinnamylidenyl)-indenyl-3-methane
sulfonic acid
To a solution of 0.02 moles of
5-fluoro-2-methyl-indenyl-3-methylsulfonic acid in methanol (60
ml.) is added sodium methoxide (2.16 g., 0.04 mole) and after
solution p-methylsulfinylcinnamaldehyde (0.02 mole). The mixture is
heated at reflux for 5 hours, cooled, poured into etherwater,
extracted with ether, dried (MgSO.sub.4), and concentrated to an
oil in vacuo. The oil is taken up in methylene chloride and
chromatographed on silica gel and eluted with ethyl acetate. The
fractions of eluate are concentrated to yield
5-fluoro-2-methyl-1-(4'-methylsulfinylcinnamylidenyl)-indenyl-3-methane
sulfonic acid.
Similarly, when an equivalent amount of the aldehyde compounds from
Table 1 are used in place of 4-methylsulfinylcinnamaldehyde in the
above Example, there is obtained the corresponding 1-substituted
compounds.
Similarly, when the other substituted indenyl-3-methylsulfonic
acids obtained from Example 2 are used in the above Example, there
is obtained the corresponding
substituted-1-(4'-methylsulfinylcinnamylidenyl)-indenyl-3-methanesulfonic
acid.
EXAMPLE 8
5-Fluoro-2-methyl-1-(4'-methylsulfinylcinnamylidenyl)-indenyl-3-methylphosp
honic acid
To a solution of 0.02 mole of
5-fluoro-2-methylindenyl-3-methylphosphonic acid in methanol (60
ml.) is added sodium methoxide (2.16 g., 0.04 mole) and after
solution p-methylsulfinylcinnamaldehyde (0.02 mole). The mixture is
heated at reflux for 5 hours, cooled, poured into ether-water,
extracted with ether, dried (MgSO.sub.4), and concentrated to an
oil in vacuo. The oil is taken up in methylene chloride and
chromatographed on silica gel and eluted with ethyl acetate. The
fractions of eluate are concentrated to yield
5-fluoro-2-methyl-1-(4'-methylsulfinylcinnamylidenyl)-idenyl-3-methylphosp
honic acid.
Similarly, when an equivalent amount of the aldehyde compounds
obtained from Table I are used in place of
p-methylsulfinylcinnamaldehyde in the above Example, there is
obtained the corresponding 1-substituted
5-fluoro-2-methylindenyl-3-methylphosphonic acid compound.
Similarly, when an equivalent amount of the other
substituted-indenyl-3-methylphosphonic acid compounds obtained from
Example 3 are used in place of
5-fluoro-2-methyl-indenyl-3-methylphosphonic acid in the above
Example, there is obtained the corresponding
substituted-1-(4'-methylsulfinylcinnamylidenyl)-indenyl-3-methylphosphonic
acid.
EXAMPLE 9
A mixture of 260 parts of
5-fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-indenyl-3-ethyl-5-tetraz
ole and 25 parts of lactose is granulated with suitable water and
to this is added 100 parts of maize starch. The mass is passed
through a 16 mesh screen. The granules are dried at a temperature
belwo 60.degree.C. The dry granules are passed through a 16 mesh
screen and mixed with 3.8 parts of magnesium stearate. They are
then compressed into tablets sutiable for oral administration.
Similarly, tablets are prepared by employing an equivalent amount
of
5-fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-indenyl-3-methylsulfonic
acid or
5-fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-indenyl-3-methylphosphon
ic acid.
* * * * *