U.S. patent number 3,914,253 [Application Number 05/448,151] was granted by the patent office on 1975-10-21 for 5-oxo-6-substituted-cyclopent-[f]-indole-2-carboxylic acids.
This patent grant is currently assigned to Merck & Co., Inc.. Invention is credited to Edward J. Cragoe, Jr., Otto W. Woltersdorf, Jr..
United States Patent |
3,914,253 |
Cragoe, Jr. , et
al. |
October 21, 1975 |
5-Oxo-6-substituted-cyclopent-[f]-indole-2-carboxylic acids
Abstract
5-Oxo-6-substituted-cyclopent-[f]-indole-2-carboxylic acids, the
salt, ester and amide derivatives thereof are disclosed having
diuretic-saluretic pharmacological activity. Also disclosed are
pharmaceutical compositions comprising such compounds and methods
of treatment comprising administering such compounds and
compositions.
Inventors: |
Cragoe, Jr.; Edward J.
(Lansdale, PA), Woltersdorf, Jr.; Otto W. (Chalfont,
PA) |
Assignee: |
Merck & Co., Inc. (Rahway,
NJ)
|
Family
ID: |
23779201 |
Appl.
No.: |
05/448,151 |
Filed: |
March 4, 1974 |
Current U.S.
Class: |
548/427; 514/869;
514/962; 544/109; 544/142; 548/492; 546/200 |
Current CPC
Class: |
C07D
209/70 (20130101); Y10S 514/962 (20130101); Y10S
514/869 (20130101) |
Current International
Class: |
C07D
209/00 (20060101); C07D 209/70 (20060101); C07D
209/18 () |
Field of
Search: |
;260/326.13R |
References Cited
[Referenced By]
U.S. Patent Documents
|
|
|
3682961 |
August 1972 |
Zergenyi et al. |
|
Primary Examiner: Gotts; Lewis
Assistant Examiner: Williams; S. P.
Attorney, Agent or Firm: Sudol, Jr.; Michael C. Behan; J.
Jerome Arno; James A.
Claims
What is claimed is:
1. A compound having the structural formula: ##SPC5##
wherein R is lower alkyl or cycloalkyl; R.sup.1 is hydrogen or
lower alkyl; and X is lower alkyl or halogen; and the nontoxic
pharmaceutically acceptable salt, lower alkyl ester, carboxamide,
mono-N-lower alkyl carboxamide, di-N-lower alkyl carboxamide,
piperidide and morpholide derivatives thereof.
2. A compound having the structural formula: ##SPC6##
wherein R is methyl or ethyl; R.sup.1 is hydrogen, methyl or ethyl;
and X is methyl or chloro; and the nontoxic pharmaceutically
acceptable salt, lower alkyl ester, carboxamide, mono-N-lower alkyl
carboxamide, di-N-lower alkyl carboxamide, piperidide and
morpholide derivative thereof.
3. A compound having the structural formula: ##SPC7##
wherein R is ethyl; R.sup.1 is hydrogen; X is chloro; which is
4-chloro-5-oxo-6-ethylcyclopent[f]indole-2-carboxylic acid and the
sodium and potassium salts thereof.
4. A compound having the structural formula: ##SPC8##
wherein R is ethyl; R.sup.1 is methyl; X is methyl; which is
1,4-dimethyl-5-oxo-6-ethylcyclopent[f]indole-2-carboxylic acid and
the sodium and potassium salts thereof.
5. A compound having the structural formula: ##SPC9##
wherein R is ethyl; R.sup.1 is hydrogen; X is methyl; which is
4-methyl-5-oxo-6-ethylcyclopent[f]indole-2-carboxylic acid and the
sodium and potassium salts thereof.
Description
BACKGROUND OF THE INVENTION
This invention relates to a class of compounds generically referred
to as 5-oxo-6-substituted-cyclopent-[f]-indole-2-carboxylic acids
having the structure: ##SPC1##
And the nontoxic pharmacologically acceptable salt, ester and amide
derivatives thereof; wherein R is lower alkyl, or cycloalkyl;
R.sup.1 is hydrogen or lower alkyl; and X is lower alkyl or
halo.
Further this invention relates to pharmaceutical compositions
comprising such compounds (I) and methods of treatment comprising
administering such compounds and compositions.
Pharmacological studies have shown that the compounds of the
present invention are effective diuretic and saluretic agents which
can be used in the treatment of conditions associated with
electrolyte and fluid retention such as edema and hypertension.
Thus, when administered in therapeutic dosages in conventional
vehicles, the compounds of this invention, effectively reduce the
amount of sodium and chloride ions in the body, lower dangerous
excesses of fluid levels to acceptable levels and in general
alleviate the conditions associated with edema and
hypertension.
Thus it is an object of the present invention to provide the indole
derivatives of the above general description and to provide
processes for preparation of such compounds. Further, it is an
object of this invention to provide pharmaceutical compositions
comprising such indole derivatives and to provide methods of
treatment comprising administering such compounds and
compositions.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of this invention (I, above) are preparaed by the
cyclialkylation of an appropriately substituted
4-substituted-5-(2-methylene-2-substituted-acetyl)indole-2-carboxylic
acid (II) by treatment with a Lewis Acid such as sulfuric acid,
polyphosphoric acid, boron trifluoride, trifluoroacetic acid,
aluminum trichloride, and the like at a temperature of from about
0.degree. to about 60.degree.C. ##SPC2##
wherein R is lower alkyl, or cycloalkyl having from 1 to about 6
carbon atoms; R.sup.1 is hydrogen, or lower alkyl having from 1 to
about 6 carbon atoms; and X is halo, such as chloro, fluoro or
bromo, or lower alkyl having from 1 to about 6 carbon atoms.
The substituted indoles II (above) are known compounds. See for
example U.S. Pat. No. 3,682,961 (August 8, 1972) which expressly
discloses representative species of structure II and by general
teaching provides a fully enabling disclosure relative to all
species embraced by structure II for purposes of practicing this
invention. For this reason U.S. Pat. No. 3,682,961 is incorporated
herein by reference.
In general the substituted indoles (II, above) are prepared
according to the procedure of U.S. Pat. No. 3,682,961 by reacting
under Friedel-Crafts conditions an appropriately substituted
indole-2-carboxylic acid with a carboxylic acid halide or anhydride
thereof: ##EQU1## wherein R has previously been defined and Q is
halogen. When the first-mentioned acid halide (or anhydride
thereof) is employed, the corresponding indole (II) is obtained
from the resulting 5-alkanoyl Friedel-Crafts product via the
Mannich intermediate obtained on treating the 5-alkanoyl species
with paraformaldehyde and a secondary organic amine.
Also included within the scope of this invention are the ester,
salt and amide derivatives of the compounds of this invention which
are prepared by conventional methods well known to those skilled in
the art. Thus for example, the ester derivative may be prepared by
reaction of the compounds of this invention with an alcohol, for
example, a lower alkanol. The amide derivatives may be prepared by
converting the 2-carboxylic acids of the present invention to their
corresponding acid chloride by treatment with thionyl chloride
followed by treating said acid chloride with ammonia, an
appropriate mono-lower alkylamine, di-lower alkylamine or a hetero
amine such as piperidine, morpholine and the like, to produce the
corresponding amide compound. These and other equivalent methods
for the preparation of the ester and amide (and salt) derivatives
of the instant invention will be apparent to one having ordinary
skill in the art and to the extent that said derivatives are both
nontoxic and pharmaceutically accpetable, they are functionally
equivalent as diuretics and saluretics when compared to the
carboxylic acid form.
The following examples specifically illustrate, but do not limit,
the present invention.
EXAMPLE 1
4-Chloro-5-oxo-6-ethylcyclopent[f]indole-2-carboxylic acid
A solution of 4-chloro-5-(2-methylenebutyryl)-indole-2-carboxylic
acid (5 g.) in concentrated sulfuric acid (25 ml.) is stirred at
55.degree.-60.degree.C. for 6 hours then poured into ice water (200
ml.) affording
4-chloro-5-oxo-6-ethylcyclopent[f]indole-2-carboxylic acid after
filtering and drying.
The respective sodium and potassium salts of
4-chloro-5-oxo-6-ethylcyclopent[f]indole-2-carboxylic acid are
obtained from saturated alcoholic (ethanol) solution of
4-chloro-5-oxo-6-ethylcyclopent[f]indole-2-carboxylic acid on
dropwise addition of saturated alcoholic (ethanol) solution of
sodium hydroxide and potassium hydroxide, respectively. The
resulting salt crystals are separated by filtration and dried.
EXAMPLE 2
1,4-Dimethyl-5-oxo-6-ethylcyclopent[f]indole-2-carboxylic acid
A solution of
1,4-dimethyl-5-(2-methylenebutyryl)-indole-2-carboxylic acid (5 g.)
in concentrated sulfuric acid (25 ml.) is stirred at
55.degree.-60.degree.C. for 6 hours then poured into ice water (200
ml.) affording
1,4-dimethyl-5-oxo-6-ethylcyclopent[f]indole-2-carboxylic acid
after filtering and drying.
EXAMPLE 3
4-Methyl-5-oxo-6-ethylcyclopent[f]indole-2-carboxylic acid
A solution of 4-methyl-5-(2-methylene-butyryl)-indole-2-carboxylic
acid (5 g.) in concentrated sulfuric acid (25 ml.) is stirred at
55.degree.-60.degree.C. for 6 hours then poured into ice water (200
ml.) affording
4-methyl-5-oxo-6-ethylcyclopent[f]indole-2-carboxylic acid after
filtering and drying.
Following the procedure exactly as described in Example 1 except
that the 4-chloro-5-(2-methylenebutyryl)-indole-2-carboxylic acid
is replaced by an equivalent amount of a substituted indole of the
structure: ##SPC3##
wherein R is methyl, cyclopentyl, and isopropyl; X is fluoro,
bromo, ethyl and isopropyl; and R.sup.1 is methyl, and ethyl, there
is obtained an equivalent amount of the corresponding indole of the
present invention having the structure: ##SPC4##
wherein M is hydrogen, sodium and potassium; R is methyl,
cyclopentyl, and isopropyl; R.sup.1 is methyl and ethyl, X is
fluoro, bromo, ethyl, and isopropyl, respectively.
EXAMPLE 4
N-Ethyl
[4-chloro-5-oxo-6-ethylcyclopent[f]indole-2-carboxamide]
A solution of
4-chloro-5-oxo-6-ethyl-cyclopent[f]indole-2-carboxylic acid (0.6
g.) and thionyl chloride (0.3 ml.) in benzene (10 ml.) is refluxed
for 1 hour. The solvent is distilled at reduced pressure and the
residue is treated with benzene (20 ml.) and ethylamine (0.5 ml.).
After 1 hour the reaction mixture is poured into water and
extracted with ether which is washed with dilute hydrochloric acid
and aqueous sodium bicarbonate. The ether solution is dried over
magnesium sulfate and evaporated at reduced pressure to afford
N-ethyl
[4-chloro-5-oxo-6-ethylcyclopent[f]indole-2-carboxamide].
EXAMPLE 5
Ethyl [4-chloro-5-oxo-6-ethylcyclopent[f]indole-2-carboxylate]
To a solution of
4-chloro-5-oxo-6-ethylcyclopent[f]indole-2-carboxylic acid (8.0 g.)
in ethanol (50 ml.) is added boron trifluoride etherate (13 ml.).
The reaction mixture is refluxed for 0.5 hours, treated with water
and cooled to afford ethyl
[4-chloro-5-oxo-6-ethylcyclopent[f]indole-2-carboxylate] after
filtration and drying.
The novel compounds of this invention are diuretic and saluretic
agents which can be administered in a wide variety of therapeutic
dosages in conventional vehicles as, for example, by oral
administration in the form of tablets or by intravenous injection.
Also, the daily dosage of the products may be varied over a wide
range as, for example, in the form of scored tablets containing 5,
10, 25, 50, 100, 150, 250 and 500 mg. of the active ingredient.
A suitable unit dosage form of the products of this invention can
be administered by mixing 50 mg. of a
5-oxo-6-substituted-cyclopent[f]indole-2-carboxylic acid (I) or a
suitable salt, ester or amide derivative thereof with a 149 mg. of
lactose and 1 mg. of magnesium stearate and placing the 200 mg.
mixture into a No. 1 gelatin capsule. Similarly, by employing more
of the active ingredient and less lactose, other dosage forms can
be put up in No. 1 gelatin capusles and should it be necessary to
mix more than 200 mg. of ingredients together larger capsules may
be employed. Compressed tablets, pills and other desired unit
dosages can be prepared to incorporate the compounds of this
invention by convention methods, and if desired, can be made up as
elixirs or as injectable solutions by methods well known to
pharmacists. An effective amount of the drug is ordinarily supplied
at a dosage level of from about 1 mg. to about 50 mg. per kilogram
of body weight. Preferably the range is from about 1 mg. to 7 mg.
per kg. of body weight. It is also within the scope of this
invention to combine 2 or more of the compounds of this invention
in a unit dosage form or to combine 1 or more of the compounds of
this invention with other known diuretics and saluretics or with
desired therapeutic and or nutritive agents in unit dosage
form.
The following example is included to illustrate the preparation of
the representative dosage form.
EXAMPLE 6
Dry-filled capsules containing 50 mg. of active ingredient per
capsule.
______________________________________ Per capsule
5-Oxo-4-chloro-6-ethyl-cyclopent- [f] indole-2-carboxylic acid 50
mg. Lactose 149 mg. Magnesium stearate 1 mg. Capsule (Size No. 1)
200 mg. ______________________________________
Similar dry-filled capsules can be prepared by replacing the active
ingredient of the above example by any of the other novel compounds
of this invention.
* * * * *