Anti-Inflammatory 1-Heteroaryl-Oxindole-3-Carboxamides

1. Field of the Invention

This invention relates to new and useful nonsteroidal anti-inflammatory agents. More particularly, it relates to certain N-(substituted)-1-heteroaryloxindole-3-carboxamides which are potent inhibitors of cyclooxygenase (CO) and lipoxygenase (LO) and which are of value as anti-inflammatory agents in mammals.

2. Description of Related Art

U.S. Pat. No. 3,634,453, issued Jan. 11, 1972, describes a series of anti-inflammatory N-(substituted)oxindole-3-carboxamides, the 1-position of which may be substituted by, inter alia, C.sub.1-6 alkyl or phenylalkyl; and the carboxamide moiety of which carries a phenyl, substituted phenyl or naphthyl group.

Oxindole-3-(N-2-thiazolyl)carboxamides, the 1-position of which is unsubstituted or bears an alkyl, aryl or aralkyl group, and their use as antipyretic, analgesic and anti-inflammatory agents are disclosed in U.S. Pat. No. 3,749,731, issued July 31, 1973. Each of U.S. Pat. No. 4,644,005 and 4,686,224 describes N-(substituted)-1-phenyl oxindole-3-carboxamides wherein a monoor bicyclic ring system is fused to the 5,6-positions of the oxindole and wherein the N-substituent can be pyridyl or 2-thiazolyl. The compounds are anti-inflammatory agents.

Tricyclic oxindole 3-carboxamides, the 1-position of which is substituted with a phenyl group, and the carboxamide moiety of which bears a phenyl, substituted phenyl or heterocyclyl moiety, and their use as anti-inflammatory agents are disclosed in U.S. Pat. No. 4,695,571.

U.S. Pat. No. 4,730,004 discloses anti-inflammatory 1-acyloxindole-3-carboxamides, the carboxamide moiety of which is substituted by a heterocyclic (thienyl, furyl, thiazolyl, etc.), furylmethyl, thenyl or substituted phenyl group.

A variety of anti-inflammatory oxindoles, the 1,3-positions of which are substituted by carboxamide or substituted carboxamide groups; or the 1-position of which bears a carboxamide group and the 3-position an acyl group, or vice versa, are known. However, said oxindoles are structurally different from the oxindoles of this invention and are merely mentioned to indicate the rather extensive and intensive efforts to develop non-steroidal anti-inflammatory agents.

It has been found that certain N-(substituted)-1-heteroaryl-2-oxindole-3-carboxamides of formula (I) ##STR1## or a pharmaceutically acceptable base salt thereof wherein

R.sup.1 is thienyl, furyl or 2-thiazolyl;

R.sup.2 is thienyl, furyl or ##STR2## wherein

X is hydrogen, fluoro, chloro, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, nitro or trifluoromethyl;

Y is hydrogen, fluoro or chloro;

and each of R.sup.3 and R.sup.4, which may be alike or different, is hydrogen, fluoro, chloro, bromo, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, nitro or trifluoromethyl are potent inhibitors of CO and LO enzymes, and are of value as anti-inflammatory agents for treating an inflammatory disease in a mammal. They are especially useful for treatment of rheumatoid arthritis in mammals.

A favored group of compounds are those wherein R.sup.2 is phenyl or substituted phenyl. Within this group of compounds those wherein each of R.sup.3 and R.sup.4 is hydrogen; and one or both of X and Y are hydrogen, fluoro or chloro are preferred compounds. Especially preferred in this latter group are those compounds wherein each of X and Y is hydrogen, chloro or fluoro; and R.sup.1 is 2- or 3-thienyl.

Included within this invention are pharmaceutical compositions, useful as anti-inflammatory agents in a mammal, comprising a pharmaceutically acceptable carrier and an anti-inflammatory disease treating amount of a compound of formula (I).

Additionally, the present invention includes a method of treating an anti-inflammatory disease in a mammal which comprises administering to said mammal an anti-inflammatory disease treating amount of a compound of formula (I).

The compounds of this invention are readily prepared from appropriate reactants by the following process: ##STR3##

The first step of the overall process is carried out by reacting indole (or an appropriately substituted indole) with the desired R.sup.1 Br in a suitable solvent in the presence of a base and a catalytic amount of cuprous bromide. As solvent, N-methyl-2-pyrrolidinone serves especially well. Other aprotic solvents such as dimethylsulfoxide, dimethylformamide or diethylformamide can be used. The reaction is conducted at an elevated temperature, e.g. from about 50.degree. C. to 200.degree. C., desirably under a nitrogen atmosphere. The choice of base is not critical, but can be any of a variety of inorganic and organic bases. Representative of such bases are alkali metal hydrides, carbonates or hydroxides; triethylamine, pyridine, N-methylmorpholine, 4-(N,N-dimethylamino)pyridine and N-methylpiperidine.

The above-named ingredients are all generally placed in a reaction vessel, stirred and heated to the desired temperature until reaction is complete. Although the indole, R.sup.1 Br, and base reactants can be used in stoichiometric proportions, it is preferred to use about 5-10% excess of each of R.sup.1 Br and base in order to expedite the reaction. A greater excess of R.sup.1 Br can be used but is generally avoided for economic reasons. The cuprous bromide is employed at a level of from about 0.01 to 0.03 moles per mole of R.sup.1 Br reactant. The product is recovered by known methods. The required indole reactants are known compounds or are conveniently prepared according to known procedures.

The second step, conversion of the 1-substituted indole (b) to the corresponding oxindole (c) is accomplished by reacting indole (b) with N-chlorosuccinimide (NCS) in a reaction-inert solvent at ambient temperature. A 5-10% excess of NCS is generally used. Reaction periods of from 1 to 5 hours, depending upon the indole (b) reactant normally lead to complete reaction. The reaction-inert solvent (i.e., one which does not react with reactants or products) can be any of a variety of solvents, such as diethyl ether, dioxane, tetrahydrofuran, aromatic hydrocarbons, (benzene, toluene, xylene), chloroform, acetonitrile and mixtures thereof.

Upon completion of the NCS reaction, the reaction is concentrated under reduced pressure and the 3-chloro indole derivative taken up in glacial acetic acid and heated to from about 50.degree.-80.degree. C. Phosphoric acid (85%) is then added to the reaction which is refluxed for 1-24 hours, cooled and poured into ice-water. The aqueous mixture is adjusted to pH 11-12 and then extracted with ethyl acetate to recover the oxindole. Work-up of the extract and purification of the oxindole product is by standard methods.

Introduction of the carboxamide moiety at the 3-position of oxindole (c) is conveniently accomplished by reacting (c) with a requisite isocyanate (R.sup.2 NCO). The reaction is carried out in a reaction-inert solvent. Preferred solvents are polar, aprotic solvents such as dimethylformamide, diethylformamide, N-methyl-2-pyrrolidone or dimethylsulfoxide. Further, it is preferred that the reaction be carried out in the presence of a base. Such bases include alkali and alkaline earth metal hydrides or a tertiary organic amine. The preferred base is sodium hydride.

In practice, the isocyanate is added to the oxindole derivative and base in the appropriate solvent. It is desirable to employ at least about a molar equivalent of the isocyanate and base, with best results achieved by using an excess of as much as 50% of each. It is preferred that the reagents be combined in the cold, generally from -10.degree. to 0.degree. C., and that the reaction mixture be allowed to warm to room temperature. At from room temperature to 45.degree. C. the reaction proceeds to completion in about a few minutes to overnight depending on the reactivity of the isocyanate.

Upon completion of the reaction, the product is isolated by adding the mixture to ice-water and treating with sufficient acid to provide a pH of between 2 and 5. The product can be filtered or extracted with a water immiscible solvent.

The product is purified by chromatography or by recrystallization from an appropriate solvent. The requisite isocyanates are either commercially available or can be prepared by standard procedures known in the art, for instance, Zook and Wagner, Synthetic Organic Chemistry, John Wiley and Sons, Inc., New York, 1956, page 640.

As those skilled in the art will recognize, other reaction sequences can be used to prepare formula (I) compounds. The particular route chosen is dependent upon the availability of appropriate reactants. For instance, an oxindole of the formula shown below can be used as starting material ##STR4## and reacted by known procedures with the proper R.sup.1 Br reactant to afford a compound of formula (c) above. Alternatively, it can be reacted with the requisite isocyanate (R.sup.2 NCO) to give the corresponding N-(substituted)-3-carboxamide derivative which is then reacted with R.sup.1 Br to afford formula (I) compounds. The required oxindole starting materials are prepared by known procedures or by procedures analogous to known procedures. Consult: "Rodd's Chemistry of Carbon Compounds," Second Edition, S. Coffey editor, Volume IV Part A, Elsevier Scientific Publishing Company, 1973, pp. 448-450; Gassman et al., Journal of Organic Chemistry, 42, 1340 (1977); Wright et al., Journal of the American Chemical Society, 78, 221 (1956); Beckett et al., Tetrahedron, 24, 6093 (1968); U.S. Pat. Nos. 3,882,236, 4,006,161 and 4,160,032; Walker, Journal of the American Chemical Society, 77, 3844 (1955); Protiva et al., Collection of Czechoslovakian Chemical Communications, 44, 2108 (1979); McEvoy et al., Journal of Organic Chemistry, 38, 3350 (1973); Simet, Journal of Organic Chemistry, 28, 3580 (1963); Wieland et al., Chemische Berichte, 96, 253 (1963); and references cited therein; and U.S. Pat. No. 4,658,037, issued Apr.14, 1987.

A common characteristic of the oxindole carboxamides of this invention is their acidic nature. Therefore, included in this invention are the pharmaceutically acceptable salts of the compounds of formula (I). The preferred cations of said salts include the ammonium, sodium and potassium ions. The pharmaceutically acceptable salts of the compounds described herein are prepared by conventional procedures, as for example, by adding the acid to an aqueous solution containing an equivalent amount of the pharmaceutically acceptable base, i.e., a base containing one of the above preferred cations, followed by concentration of the resultant mixture to obtain the desired product. The bases can be selected from hydroxides, oxides or carbonates.

Also considered part of the present invention are prodrugs of the herein described compounds of formula (I). These prodrugs, which have fewer gastrointestinal side effects, break down in situ to the parent compound. Representative prodrugs of formula (I) compounds are enol esters and ethers thereof of formula (II) ##STR5## wherein each of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is as defined above; and R.sup.5 is alkanoyl, cycloalkylcarbonyl, phenylalkanoyl, chlorobenzoyl, methoxybenzyl, phenyl, thenoyl, omegaalkoxycarbonylalkanoyl, alkoxycarbonyl, phenoxycarbonyl, 1-alkoxyalkyl, 1-alkoxycarbonyloxyalkyl, alkyl, alkylsulfonyl, methylphenylsulfonyl or dialkylphosphonate.

In formula (II), the wavy lines on the carbon atom of the exocyclic double bond at the 3-position are intended to represent the syn-, the anti- and mixtures of the syn- and anti- forms of formula (II) compounds.

Formula (II) compounds are prepared by treating the appropriate oxindole-3-carboxamide of formula (I) and an equimolar amount of triethylamine in a reactioninert solvent (e.g., chloroform) with a slight excess of the requisite acid chloride, chloroformate, oxonium salt or alkylating agent at 0.degree. C. The reaction is allowed to warm to room temperature and, after 2-3 hours, the product is recovered by known procedures.

A second procedure for preparation of formula (II) compounds consists of contacting, in an anhydrous reaction-inert solvent such as acetone, the appropriate oxindole-3-carboxamide of formula (I), a three-fold molar excess of the requisite alpha-chloroalkylcarbonate, a five-fold molar excess of sodium iodide and a two-fold molar excess of anhydrous potassium carbonate and heating said reaction mixture at reflux for 16 hours.

The reaction mixture is diluted with water and the product extracted with a water-immiscible solvent, such as diethyl ether or chloroform. Concentration of the solvent containing the product provides the crude material, which can be purified by recrystallization and/or chromatography.

As previously indicated, the oxindole carboxamides of the present invention and their pharmaceutically acceptable salts are useful anti-inflammatory agents in mammals. These compounds are of value in alleviating swelling and inflammation which are symptomatic of rheumatoid arthritis and related disorders which are responsive to treatment with anti-inflammatory agents. Either as individual therapeutic agents or as mixtures of therapeutic agents, they may be administered alone, but are generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets or capsules containing such excipients as starch, milk sugar or certain types of clay, etc. They may be administered orally in the form of elixirs or oral suspensions with the active ingredients combined with emulsifying and/or suspending agents. They may be injected parenterally, and for this use they, or appropriate derivatives, may be prepared in the form of sterile aqueous solutions. Such aqueous solutions should be suitably buffered, if necessary, and should contain other solutes such as saline or glucose to render them isotonic. The weight-ratio of the pharmaceutically-acceptable carrier to compound can be from 1:4 to 20:1.

The dosage required to reduce inflammation or swelling in arthritic subjects would be determined by the nature and extent of the symptoms. Generally, small doses will be required initially, with a gradual increase in the dose until the optimum level is determined. It will generally be found that when the composition is administered orally, larger amounts of the active ingredient will be required to produce the same level as produced by a smaller quantity administered parenterally. In general, from about 10 to about 300 mg of active ingredient per kilogram of body weight, administered orally in single or multiple dose units, will effectively reduce inflammation and swelling. Parenteral administration requires doses of from about 5 to about 200 mg of active ingredient to achieve the same end point.

A standard procedure for detecting and comparing anti-inflammatory activity of compounds is the carrageenin rat foot edema test, which is described by C. A. Winter et al., Proc. Soc. Exp. Biol. vol III, page 544 (1962).

In addition to being useful as anti-inflammatory agents, the compounds of the present invention can be used in the treatment of asthma, bronchitis and psoriasis; they can also be used as analgesic agents.

The following examples are provided solely for the purpose of further illustration. Nuclear magnetic resonance spectra (NMR) were measured at 60 MHz for solutions in deuterochloroform (CDCl.sub.3) and peak positions are expressed in parts per million (ppm) downfield from tetramethylsilane or sodium 2,2-dimethyl-2-silapentane5-sulfonate. The following abbreviations for peak shapes are used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; b, broad.

To a stirred suspension of NaH (0.17 g) in 10 ml of dry dimethylformamide (DMF) under a nitrogen atmosphere was added a solution of 1-(3-thienyl)oxindole (0.5 g, 2.3 mM) in 10 ml of dry DMF. The reaction mixture was stirred at room temperature for 10 minutes after which a solution of 4-fluorophenyl isocyanate in 5.0 ml of dry DMF was added dropwise. The reaction mixture was heated to 85.degree. C. for 7 hours, then cooled to room temperature and poured into 300 ml of ice water and acidified to pH 1 with 6N HCl. The resulting solid was filtered, air dried and recrystallized from isopropyl alcohol to give 0.38 g (47%) of red-brown solid; m.p. 189.degree.-190.degree. C. TLC indicated it to be the desired product with a small amount of less polar impurity. Additional recrystallization from isopropyl alcohol gave an analytically pure sample. MS: M.sup.+ =352. IR(KBr) 5.8 .mu.(s), 6.0 .mu.(s, CONH).

Analysis calculated for C.sub.19 H.sub.13 N.sub.2 O.sub.2 SF:

C, 64.76; H, 3.72; N, 7.95%.

Found: C, 64.53; H, 3.91; N, 7.87%.

The following compounds are prepared in like manner from appropriate 1-(heteroaryl)oxindoles and isocyanates R.sup.2 NCO:

Using the appropriate isocyanates (R.sup.2 NCO) and the proper oxindole of Preparation D, the following N-(substituted)-1-heteroaryloxindole-3-carboxamides are prepared according to the procedure of Example 1: ##STR7## wherein each of R.sup.1, R.sup.3 and R.sup.4 is as defined in Preparation C and R.sup.2 is:

A mixture of indole (16 g, 0.136 M), 3-bromothiophene (24.75 g, 0.146 M), potassium carbonate (20.1 g, 0.146 M) and copper bromide (0.84 g, 0.003 M) in 160 ml of N-methyl-2-pyrrolidinone was stirred and heated to 180.degree. C. (under nitrogen atmosphere) for 42 hours. After this time, the reaction mixture was poured onto 800 ml of water and extracted with ethyl acetate (2.times.350 ml). The combined ethyl acetate extracts were washed with water, brine, dried over magnesium sulfate, filtered and concentrated in vacuo leaving a dark brownblack oil. The crude reaction product was chromatographed on a silica gel column with hexane/CH.sub.2 Cl.sub.2 3:1 as eluant. Yield=9.14 g of yellow liquid which was homogeneous by thin layer chromatography. MS: M.sup.+ =199.

Analysis calculated for C.sub.12 H.sub.9 NS:

C, 72.32; H, 4.55; N, 7.23%.

Found: C, 72.06; H, 4.71; N, 7.47%.

In like manner the following 1-(heteroaryl)indoles are prepared from the appropriate bromoheteroaryl reactant:

To a solution of 1-(3-thienyl)indole (9.14 g, 0.0459 M) in 350 ml of dry methylene chloride under a nitrogen atmosphere was added 6.44 g (0.0482 M) of N-chlorosuccinimide (NCS) at room temperature. The reaction was stirred at room temperature for 2 hours, then concentrated in vacuo. The resulting foamy residue was immediately dissolved in 190 ml of glacial acetic acid. The resulting mixture was heated to 70.degree. C. followed by the addition of 49.5 ml of 85% H.sub.3 PO.sub.4 and heating of the reaction mixture to reflux for one hour. The mixture was then cooled to room temperature, poured onto ice water, basified to pH .about.11-12 with Na.sub.2 CO.sub.3 and extracted with ethyl acetate (3.times.500 ml). The combined ethyl acetate extracts were washed with water, brine, dried (MgSO.sub.4), filtered and concentrated in vacuo leaving dark brown-black oil. Purification of the crude product on a silica gel column (elution with CH.sub.2 Cl.sub.2, followed by elution with 90% CH.sub.2 Cl.sub.2 -10% CH.sub.3 OH) gave a total of 7.2 grams (72.8%) of brown crystalline solid; m.p. 62.degree.-67.degree. C. MS: M.sup.+ =215. IR(KBr) 5.9.mu.(s) c=O. NMR(CDCl.sub.3)delta: 3.6 (s, 2H), 6.7-7.4 (m, 7H).

The following 1-(heteroaryl)indoles are prepared according to the above procedure from the products of Preparation A.

Starting with the appropriate substituted indole and R.sup.1 Br reactants, the following compounds are prepared according to the procedure of Preparation A.

The compounds of Preparation C are converted to the corresponding oxindoles having the formula shown below by means of the procedure of Preparation B: