Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
  • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

• This invention relates to new and useful oxindole carboxamides, and to their various novel methods of preparation. More particularly, it is concerned with a novel series of 2-oxo-2,3-dihydroindole-3-carboxamides, which are of especial value in view of their chemotherapeutic properties.
• novel oxindole carboxamide compounds i.e., non-steroids
• novel compounds of this invention are 2-oxo-2,3-dihydroindole- 3-carboxamides of the formula:
• H O-NHRg and the base salts thereof with pharmacologically acceptable cations wherein X and Y are each a member selected from the group consisting of hydrogen, fluorine, chlorine, bromine, alkyl and al'koxy each having from one to five carbon atoms, trifiuoromethyl and trifluoromethoxy; R is a member selected from the group consisting of hydrogen, 2,2,2-trifluoroethyl, alkyl having from one to six carbon atoms, alkenyl having up to four carbon atoms and phenylalkyl having up to three carbon atoms in the alkyl moiety; and R is a member selected from the group consisting of naphthyl, phenyl, and monoand di-substituted phenyl wherein each substituent is chosen from the group consisting of fluorine, chlorine and bromine, alkyl having up to four carbon atoms, alkoxy and thioalkoxy each having up to three carbon atoms, tri
• R NCO isocyanates
• the product Upon completion of the reaction, the product is easily recovered from the spent reaction mixture by pouring same into an excess of ice-water containing a slight excess of acid, such as hydrochloric acid, whereby the carboxamide compound readily precipitates from solution and is subsequently collected by such means as suction filtration and the like.
• acid such as hydrochloric acid
• the 2-oxo-2,3-dihydroindole 3 carboxamide compounds of this invention may also be prepared by treating the corresponding 3- or 4-carboxylic acid esters with at least an equimolar amount of an amine of the formula R NH wherein R is as previously defined. More specifically, this particular process of the invention involves reacting a carbalkoxy ester of the aforesaid type with an appropriate amine base in a reaction-inert organic solvent medium, whereby the desired aminolysis reaction takes place. The reaction is generally conducted by mixing the two components together in said solvent system at or near room temperature, and then refluxing the resultant system for a period of about one-half to four hours.
• reaction-inert organic solvents for use in the aminolysis reaction include such lower N,N-dialkyl alkanolamides as dimethylformamide, dimethylacetamide and the like, as well as such aromatic hydrocarbon solvents as benzene, toluene, xylene and so forth.
• the desired carboxamide final product is generally most conveniently isolated from the mixture by distilling off the alcohol by-product, as aforesaid, until the temperature of the volatile alcohol solvent vapors in the distilling head approximates in terms of degrees centigrade the temperature of the reaction mixture in the flask (i.e., the distilland). At this point, the resulting distilland is cooled to room temperature and the product subsequently precipitates from solution.
• the 2-oxo-2,3-dihydroindole-3-carboxylate esters, used as described above as intermediates to form the corresponding 3-carboxamides of this invention, are themselves prepared by a facile one-step synthesis starting from readily available materials.
• 2-oxo-2,3-dihydroindole-3-carboxylate and related compounds such products are normally prepared by simply condensing a known 2-oxo-2,3,-dihydroindole starting material, like 1-methyl-2-oxo-2,3-dihydroindole (R. Stoll in German Pat. No.
• a still further method for preparing the instant compounds of this invention involves reacting a 2-oxo-2,3- dihydroindole in the form of an alkali metal or alkalineearth metal salt with an appropriate 1,1,3-trisubstituted urea of the formula (R) NCONHR wherein R" is an aryl group such as phenyl, p-chlorophenyl, p-bromophenyl, p-nitrophenyl, p-acetylaminophenyl, p-tolyl, panisyl, a-naphthyl, B-naphthyl, and the like.
• This reaction is preferably carried out in the presence of a reaction-inert polar organic solvent medium.
• Typical organic solvents for use in this connection include the N,N-dialkyl lower alkanoamides like dimethylformarnide, dimethylacetamide, diethylformamide and diethylacetamide, as well as lower dialkyl sulfoxides such as dimethyl sulfoxide, diethyl sulfoxide and di-n-propyl sulfoxide, etc., in addition to hexamethyl-phosphoramide. It is desirable that the aforesaid solvent for this reaction be present in sufficient amount to dissolve each of the previously mentioned starting materials. In general, the reaction is conducted at a temperature that is in the range of from about 20 C.
• Recovery of the desired product from the reaction mixture is then most conveniently accomplished by first diluting the reaction solution with water and then adjusting the resulting aqueous solution to at least about pH 8.0, followed by subsequent extraction of the basic aqueous solution with any water-immiscible organic solvent in order to remove minor amounts of unreacted or excess starting material that might possibly be present at this stage.
• Isolation of the desired 2-oxo 2,3-dihydroindole-3-carboxamide from the basic aqueous layer is then effected by the addition thereto of a dilute aqueous acid solution, wherein the acid is present in sufficient amount to cause precipitation of said indolec arboxamide to occur from the aqueous solution.
• the relative amounts of reagents employed are such that the molar ratio of the 2-oxo-2,3-dihydroindole to the 1,1- diaryl-3-(monosubstituted)urea is desirably in the preferred range of from about 1:1 to 1:3, although substantially equimolar ratios will still cause equally satisfactory results to be achieved. Nevertheless, an excess of the trisubstituted urea is normally employed in this reaction since this not only serves to cause a shift in the reaction equilibrium to the product side of the equation, but it is also additionally advantageous in that the excess reagent is easily removed after completion of the reaction by means of the solvent extraction step previously referred to. Moreover, it is to be noted that the formation of the carboxamide final products of this invention is greatly enhanced by the overall basic character of the reaction mixture.
• the two major type starting materials required for this reaction viz, the 2-oxo-2,3-dihydroindoles and the 1,1- diaryl-3-(monosubstituted)ureas, are both readily available to those skilled in the art.
• the 2-oxo 2,3-dihydroindoles which are also used as starting materials in the previously described isocyanate method, as well as in the preparation of the corresponding 3-carboxylic acid ester intermediates, are either available commercially or else they are well-known in the chemical prior art and/or can easily be synthesized in accordance with standard organic procedures that are commonly described therein [e.g., see P. L. Julian et al., in Heterocyclic Compounds, vol.
• the 1,1-diaryl-3-(monosubstituted)ureas are all readily prepared from common organic reagents by employing standard procedures well known in the art, e.g., the desired 1,1,3-trisubstituted urea may be prepared from the corresponding disubstituted carbamyl chloride [vR" NCOCl] and the appropriate amine (R NH in accordance with the general procedure of Reudel, as described in Recueil des Travaux Chimiques des Pays-Bas, vol. 33, p. 64 (1914).
• the chemical bases which are used as reagents in this invention to prepare the pharmaceutically acceptable salts of same are those which form non-toxic salts with the many herein described acidic 2-oxo-2,3-dihydroindole-3- carboxamides, such as 2,4' difluoro 1 ethyl 2 oxo-- bromo-2,3-dihydroindole-3-carboxanilide, for example.
• These particular non-toxic base salts are of such a nature that their cations are said to be essentially non-toxic in character over the wide range of dosage administered. Examples of such cations include those of sodium, potassium calcium and magnesium, etc.
• salts can easily be prepared by simply treating the aforementioned 2-oxo- 2,3-dihydroindole-3-carboxamides with an aqueous solution of the desired pharmacologically acceptable base, i.e., those oxides, hydroxides or carbonates which contain pharmacologically acceptable cations, and then evaporating the resulting solution to dryness while preferably being placed under reduced pressure.
• the desired pharmacologically acceptable base i.e., those oxides, hydroxides or carbonates which contain pharmacologically acceptable cations
• they may also be prepared by mixing lower alkanolic solutions of the said acidic compounds and the desired alkali metal alkoxide together, and then evaporating said resulting solution in the same manner as before. In either case, stoichiometric amounts of reagents must be employed in order to ensure completeness of reaction, with consequent maximum production of yields of the desired pure prodnot.
• the 2-oxo-2,3-dihydroindole-3- carboxamide compounds of the present invention are all readily adapted to therapeutic use as anti-inflammatory agents, particularly in view of their ability to reduce the swelling and relieve the pain caused by arthritic and other inflammatory disorders that are normally associated with such basic ailments as rheumatoid arthritis and the like.
• none of these compounds causes substantial side effects to occur in the subject to whom they are so administered, i.e., no problems of toxicity or of a harmful pharmacological nature, either gross or microscopic, are encountered when said compounds are administered for the aforestated purposes in the manner described as indicated above.
• the herein described 2-oxo-2,3-dihydroindole-3- carboxamide anti-inflammatory agents can be administered to an afflicted subject via either the oral or parenteral routes of administration.
• these compounds are most desirably administered in doses ranging from about mg. up to about 1000 mg. per day, although variations will still necessarily occur depending upon the weight of the subject being treated.
• a dosage level that is in the range of from about 0.16 mg. to about 16 mg. per kg. of body weight per day is most desirably employed in order to achieve effective results.
• dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful or deleterious side effects to occur provided that such higher dose levels are first divided into several smaller doses that are to be administered throughout the day.
• novel compounds of the invention can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically-acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like.
• Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc.
• Such oral pharmaceutical compositions can be suitably sweetened and/or flavored by means of various agents of the type commonly employed for just such a purpose.
• the therapeutically-effective compounds of this invention are present in such dosage forms at concentration levels ranging from about 0.5% to about by weight of the total composition, i.e., in amounts which are sufiicient to provide the desired unit dosage.
• tablets containing various excipients such as sodium citrate, calcium carbonate and dicalcium phosphate may be employed along with various disintegrants such as starch and preferably potato or tapioca starch, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes.
• Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules; preferred materials in the connection would also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
• the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dye, and, if so desired, emulsifying and/ or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
• solutions of these particular 2-oxo2,3-dihydroindole-3-carboxamides in either sesame or peanut oil orv in aqueous propylene glycol may be employed, as well as sterile aqueous solu tions of the corresponding Water-soluble alkali metal or alkaline-earth metal salts previously enumerated.
• aqueous solutions should be sutiably buffered if necessary and the liquid diluent first rendered isotonic with suificient saline or glucose.
• indolecarboxamide compounds topically when treating inflammatory conditions of the skin and this may preferably be done by way of creams, salves, jellies, pastes, ointments and the like, in accordance with standard pharmaceutical practice.
• a general procedure employed for detecting and comparing the anti-inflammatory activity of the compounds of the present invention is, as previously indicated, the standard carrageenin-induced rat foot edema test using the aforementioned technique of C. A. Winter et al.
• anti-inflammatory activity is determined as the inhibition of edema formation in the hind paw of male albino rats (weighing, -190 g.) in response to a subplantar injection of carrageenin.
• the carrageenin is injected as a 1% aqueous suspension (0.05 ml.) one hour after oral administration of the drug in the form of an aqueous solution.
• Edema formation is then assessed three hours after the carrageenin injection by measuring the volume of the injected paw initially as well as at the three-hour mark. The increase in volume three hours after carrageenin injection constitutes the individual response.
• Compounds are considered active if the response between the drugtreated animals (six rats/group) and the control group (i.e., animals* receiving the vehicle alone) is deemed to be significant on comparison with standard compounds like acetylsalicylic acid at 100 mg./kg. or phenylbutazone at 33 mg./kg., both by the oral route of administration.
• EXAMPLE II The procedure described in Example I was repeated using 1.15 g. (0.005 mole) of 1-ethyl-2-oxo-5,6-dichloroindole, 0.264 g. (0.0055 mole) of sodium hydride (a 50% dispersion in mineral oil), 0.655 g. (0.0055 mole) of phenyl isocyanate and 15 ml. of dry N,N-dimethylformamide.
• the corresponding product obtained was 1 ethyl 2 oxo-5,6-dichloro-2,3-dihydroindole-3-carboxanilide (1.6 g.), M.P. 194-195" C. after recrystallization from isopropanol.
• This particular compound was tested for anti-inflammatory activity in rats, using the carregeenin-induced rat foot edema test, and found to be active orally at levels of 33 mg./kg., mg./kg., 3.0 mg./kg. and 1.0 mg./kg., respectively.
• EXAMPLE VII The procedure described in Example V is repeated once again, only this time to prepare the same 2-oxo- 2,3-dihydroindole-3-carboxarnides previously reported in Example IV. In each instance, the corresponding ethyl 2-ox0-2,3-dihydro-3-carboxylate and the appropriate organic amine reagent of choice are the proper starting materials employed for the present purposes at hand.
• EXAMPLE VIII A slurry of 0.24 g. (0.005 mole) of sodium hydride (a 50% dispersion in mineral oil) in 20 ml. of hexamethylphosphoramide was prepared and subsequently treated with 1.05 g. (0.005 mole) of l-(n-propyl)-2-oxo-5-chloro- 2,3-dihydroindo1e. To the resulting suspension, there were then added with stirring 1.78 g. (0.0055 mole) of N,N- diphenyl-N'-(2,4-difluorophenyl)urea in a dropwise manner during the course of a -minute period.
• EXAMPLE IX The procedure described in Example VIII was repeated using 2.4 g. (0.01 mole) of 1-ethyl-2-oxo-5- bromo-2,3- dihydroindole, 3.56 g. (0.011 mole) of N,N-dihpenyl-N'- (2,4-difluorophenyl)urea, 0.53 g. (0.011 mole) of sodium hydride (a 50% dispersion in mineral oil) and 20 ml.
• EXAMPLE XII The sodium salt of 2',4' difiuoro 1 ethyl-Z-oxo 5- bromo-Z,3-dihydroindole-3-car-boxanilide is prepared by dissolving said compound in anhydrous methanol and then adding said solution to another methanolic solution which contains an equivalent amount in moles of sodium methoxide. Upon subsequent evaporation of the solvent therefrom via freezing-drying, there is obtained the desired alkali metal salt in the form of an amorphous solid powder which is freely soluble in water.
• potassium and lithium salts are also prepared as are the alkali metal salts of all the other acidic 2-oxo-2,3-dihydroindole-3-carboxamides of this invention, which Were reported previously in the preceding Examples.
• EXAMPLE XIII The calcium salt of 1-ethyl-2-oxo-5,6-dichloro-2,3-dihydroindole-3-carboxanilide is prepared by dissolving said compound in water containing an equivalent amount in moles of calcium hydroxide and then freeze-drying the mixture.
• the corresponding magnesium salt is also prepared in like manner, as are all the other alkaline-earth metal salts not only of this compound, but also of those acidic 2-oxo-2,3-dihydroindole-3-carboxamides described in the examples immediately preceding Example XII.
• a dry solid pharmaceutical composition is prepared by blending the following materials together in the proportions by weight specified below:
• dihydroindole-3-carboxanilide 50 Sodium citrate i 25 Alginic acid l Polyvinylpyrrolidone 1*0 Magnesium stearate After the dried composition is thoroughly blended, tablets are punched from the resulting mixture, each tablet being of such size that it contains 100 mg. of the active ingredient. Other tablets are also prepared in a similar man ner containing 5, 10, 25 and 50 mg. of the active ingredient, respectively, by merely using the appropriate amount of the 2-oxo-2,3-dihydroindole compound in each case.
• EXAMPLE XV A dry solid pharmaceutical composition is prepared by combining the following materials together in the proportions by weight indicated below:
• X and Y are each a member selected from the group consisting of hydrogen, fluorine, chlorine, bromine, alkyl and alkoxy each having from one to five carbon atoms, trifiuoromethyl and trifluoromethoxy;
• R is a member selected from the group consisting of hydrogen, 2,2,2 trifiuoroethyl, alkyl having from one to six carbon atoms, alkenyl having up to four carbon atoms and phenylalkyl 'having up to three carbon atoms in the alkyl moiety; and
• R is a member selected from the group consisting of naphthyl, phenyl, and monoand di-substituted phenyl wherein each substituent is chosen from the group consisting of fluorine, chlorine and bromine, alkyl having up to four carbon atoms, alkoxy and thioalkoxy and each having up to three carbon atoms

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Indole Compounds (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Applications Claiming Priority (1)

Publications (1)

Family

ID=25348298

Family Applications (1)

Country Status (11)

Cited By (21)

Families Citing this family (1)

• 0
  • BE BE756447D patent/BE756447A/xx unknown
• 1969
  • 1969-10-15 US US866738A patent/US3634453A/en not_active Expired - Lifetime
  • 1969-12-17 BR BR215247/69A patent/BR6915247D0/pt unknown
  • 1969-12-19 GB GB62142/69A patent/GB1247113A/en not_active Expired
• 1970
  • 1970-09-22 ES ES383868A patent/ES383868A1/es not_active Expired
  • 1970-09-22 DE DE19702046595 patent/DE2046595A1/de active Pending
  • 1970-09-22 JP JP45082604A patent/JPS4835263B1/ja active Pending
  • 1970-09-23 SE SE12949/70A patent/SE368007B/xx unknown
  • 1970-09-23 FR FR7034441A patent/FR2070130B1/fr not_active Expired
  • 1970-10-15 NL NL7015130A patent/NL7015130A/xx not_active Application Discontinuation
  • 1970-10-15 CH CH1528370A patent/CH517094A/fr not_active IP Right Cessation

Also Published As

Similar Documents