US3914253A

US3914253A - 5-Oxo-6-substituted-cyclopent-{8 f{9 -indole-2-carboxylic acids

Info

Publication number: US3914253A
Application number: US448151A
Authority: US
Inventors: Jr Edward J Cragoe; Jr Otto W Woltersdorf
Original assignee: Merck and Co Inc
Current assignee: Merck and Co Inc
Priority date: 1974-03-04
Filing date: 1974-03-04
Publication date: 1975-10-21
Anticipated expiration: 1992-10-21
Also published as: ZA75249B

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.

Description

United States Patent Cragoe, Jr. et al.

[4 Oct. 21, 1975 l 5-OXO-6-SUBSTITUTED-CYCLOPENT-[F]- lNDOLE-Z-CARBOXYLIC ACIDS [75] Inventors: Edward J. Cragoe, Jr., Lansdale;

Otto W. Woltersdorf, Jr., Chalfont,

both of Pa.

[73] Assignee: Merck & Co., Inc., Rahway, NJ.

[22] Filed: Mar. 4, 1974 21 Appl. No.: 448,151

UNITED STATES PATENTS 3,682,961 8/1972 Zergenyi et 260826.13 R

Primary Examiner-Lewis Gotts Assistant ExaminerS. P. Williams Attorney, Agent, or Firm-Michael C. Sudol, Jr.; J. Jerome Behan; James A. Arno [57] ABSTRACT 5-Oxo-6-substituted-cyclopent-[f]-indole-2-carb0xylic 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.

5 Claims, N0 Drawings 5-OXO-6-SUBSTITUTED-CYCLOPENT-[F]- ,INDOLE-Z-CARBOXYLIC ACIDS 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;

and the nontoxic pharmacologicall'y acceptable salt,

ester and amide derivatives thereof; wherein R is lower pounds 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 fir coon Lewis l-ce Acid -a fully enabling disclosure relative to all species em-' braced by structure II for purposes of practicing this invention. For this reason U.S. Pat. No. -3,682,96l is in-' corporated herein by reference.

In general the substituted indoles (II, above) are prepared according to the procedure of US. 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:

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 S-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 alkyla= mine 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.

COOH

EXAMPLE 1 4-Chloro-5-oxo-6-ethylcyclopent[f] indole-2- carboxylic acid EXAMPLE 2 l,4-Dimethyl-5-oxo-6-ethylcyclopent[f]indole-2- carboxylic acid A solution of l,4-dimethyl-5-(2-methylenebutyryl)- indle-2-carboxylic acid g.) in concentrated sulfuric acid (25 ml.) is stirred at 5560C. for 6 hours then poured into ice water (200' ml.) affording l,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 wherein R is methyl, cyclopentyl, and isopropyl; X is fluoro, bromo, ethyl and isopropyl; and R is methyl, and ethyl, there is obtained an equivalent amount of the corresponding indole of the present invention having the structure:

. COOM R I wherein M is hydrogen, sodium and potassium; R is methyl, cyclopentyl, and isopropyl; R 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-ethylcyclopent[flindole-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. v

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 tabletscontaining 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 stea-fl rate and placing the 200 mg. mixture into a No. l gela sary 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 tocombine 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 nu- 'tritive 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-Z-carboxylic acid 50 mg. Lactose 149 mg. Magnesium stearate 1 mg. Capsule (Size No. l 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.

What is claimed is:

1. A compound having the structural formula:

COOH

wherein R is methyl or ethyl; R 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, diN-lower alkyl carboxamide, piperidide and morpholide derivative thereof.

3. A compound having the structural formula:

wherein R is ethyl; R is hydrogen; X is chloro; which is 4-chloro-5-oxo-6-ethylcyclopent[f]indole-Z- carboxylic acid and the sodium and potassium salts thereof.

4. A compound having the structural formula:

wherein R is ethyl; R is methyl; X is methyl; which is l,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:

wherein R is ethyl; R 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.

Claims

1. A COMPOUND HAVING THE STRUCTURAL FORMULA:

2. A compound having the structural formula:

3. A compound having the structural formula:

4. A compound having the structural formula:

5. A compound having the structural formula: