MXPA97006361A - Salts of stable carboxyamides, of prolonged action, compositions that contain them and the use of myself - Google Patents

Abstract

The calcium, magnesium, lidocaine and benzathine salts of 2-oxyindole-1-carboxyamide are useful for the treatment of joint disease by intraarticular administration.

Description

SOLES OF STABLE CARBOXYAMIDES, OF PROLONGED FICTION, COMPOSITIONS THAT CONTAIN AND THE USE OF THE SAME FIELD OF THE INVENTION This invention provides long-acting, stable, antimicrobial carboxylic acid salts, especially salts of () - 5-chloro-2,3-dLh dro-3-- (hi-roxy-2-t-enenetilen) -? -oxo-l-H ~? ndol ~ l-carbox Lick (+ in? da?), which are useful as analgesic agents or antiinf lamatopos in the treatment of joint disease.

BACKGROUND OF THE INVENTION Kadm, U.S. Patent. No. 4,556,672 described ? ~ oxdol-l-carbox? am? das of formula and pharmaceutical salts thereof including t-emdap and its salts. Alien and O'Neill, patent of E.U.fl. No. 5,036,099, described an anhydrous crystalline form of the tenLdap sodium salt which is non-hygroscopic and stable in dosage forms. Temdap and other 2-ox-dol-1-carboxy arnides are acute-phase protein-modifying antiinflammatory drugs that are useful for the treatment of reurnatode arthritis. Similar to steroids, these compounds have been shown to cause a rapid reduction in acute phase proteins in arthritic patients. Intra-icular administration of these compounds relieves pain and swelling of the joint while minimizing overall exposure to the drug. For intimal use, prolonged acdone formulations employing sparingly soluble salts are required.

BRIEF DESCRIPTION OF THE INVENTION This invention provides the magnesium, calcium, lidocaine and benzathine salt of 2-oxo-indole-1-carboxy? arn? das de formula wherein X is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, alkyl having 1 to 4 carbons, c-cloalkyl having 3 to 7 carbons, alkoxy having 1 to 4 carbons, alkylthio having 1 to 4 carbons, tp luoromet lo, alkylsulfmi Jo having the 4 carbons, alkylsulfonyl having 1 to 4 carbons, nitro, femlo, aJcanoilo having 2 to 4 carbons, benzollo, tenoilo, alcanam or having 2 to 4 carbons, benzamines and N, N-dialkylsulfarnoyl having from 1 to 3 carbons in each of said alkyls; and Y is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, alkyl having from 1 to 4 carbons, cycloalkyl having from 3 to 7 carbons, alkoxy having from 1 to 4 carbons, alkylthio having from 4 to carbonos yt ri f1uorome1 1o; or X and Y when taken together are a group 4,5-, ,6- or 6,7-met? lendioxy or a 4,5-, 5,6- or 6,7-ethylenedioxy group; or X and Y when taken together and when they are attached to adjacent carbon atoms, they form a divalent Z radical, wherein 7 is selected from the group consisting of Z5 wherein U is oxygen or sulfur 7 R is selected from the group consisting of alkyl having from 1 to 6 carbons, cycloalkyl having from 3 to 7 carbons, cycloalkyl having from 7 carbons, ferul, substituted phenyl, phenylaliphat which has 1 to 3 carbons in said alkyl, alkyl (phenyl substituted) having from 1 to 3 carbons in said alkyl, phenoxyalkyl having from 1 to 3 carbons in said alkyl, substituted alkylofoxi) which has of 3 carbons in said alkyl, thiophenoxyl or i having from 1 to 3 carbons in said alkyl, naphthyl, b? c? cloL "2.2.pheptan-2-? lo, biciclot? .2. l] hept -5-en-2-yl and - (CH) -QR °; wherein the substituent on said substituted phenyl, said alkyl (substituted phenyl) and said alkyl (substituted phenoxy) is selected from group consisting of fluorine, chlorine, bromine, alkyl having 4 carbons, alkoxy having 1 to 4 carbons and tpfl? oi ornotile, n is zero, 1 or 2; 0 is a divalent radical derived from a computer this selected from the group consisting of furan, thiophene, pyrrole, pyrazole, ylidazole, tlazole, isotLazole, oxazole, isoxazole, 1,2,3-tαad ?azole, 1, 3,4-tαad ?azole, 1 , 2,5-t? Ad? Azole, tetrahydrofuran, tetrahydrothiophene, tet rahydropyran, tetrahydrothiopyran, pipdine, pipmine, pyrazine, ben -. 'OCb] furan and benzoCb] thiophene; and R ° is hydrogen or alkyl having 1 to 3 carbons. These salts are sparingly soluble in water and are suitable for m < Articular raart to relieve pain and swelling associated with joint disease. The preferred and preferred compounds are the calcium and benzathine salts of 5-chloro-2,3-d? -hydro-3- (hydroxyl-2-thienyl-1-methyl-2) -2- oxo-l-H- 1 dol- ica box and 5-f 1? oro-6-c par- 2, 3-d? h? dro-3- (hydroxy-2-t? ? imet? len) -2 -oxo-1-H-? ndol-1 -c rbo iami a. In another aspect, this invention provides a method for treating joint disease comprising the intraarticular injection of a calcium, magnesium, lidocam or benzathm salt of a compound of formula I. In another aspect, this invention provides a composition pharmaceutical suitable for raarticular injection of the calcium salt, magnesium lidocaine or benzatma of a compound of formula T and a pharmaceutically acceptable carrier. In another aspect, this invention comprises a salt selected from the group consisting of magnesium, calcium, benzatma and lidocaine of a compound of formula wherein X is H, F, Cl, Br, C-C alkyl, C-C cycloalkyl, NO, CF, CN, SH, S (0) R, OR, COR or CONRR; Y is H, F, Cl, Br, C-C alkyl, C-C cloalkyl, NO, CF, CN, SH, (0) R, OR, or CONRR; R is H; R is COR, CONRR, phenyl or mono- or disubstituted phenyl wherein the substituent or substituents are each Cl, F, Br, C-C alkyl, C-C alkoxy, or CF; fl / 0 and «0 or Q-fl; B fl is H, F, Cl, Br, I, CF, OR, S (0) R, COOR, CONRR, CN, NO, COR, CHOR, OCOR, NRR, N (R) C0R, SONRR, B is H, F, Cl, Br, I, CF, OR, S (0) R, COOR, CONR, CN, NO, COR, CHOR, OCOR, NRR, N (R) COR or SONRR, provided that fl and B can not both be H, or fl and B are together, attached to the same ring carbon of 0 and equal to oxo, or when fl is not H, B is as previously defined or CC alkyl; fl is F, Cl, Br, I, CF, OR, S (0) R, COOR, CONR, CN, NO, COR, CHOR, OCOR, NRR, N (R) C0R or SONRR; n, n, p, q and t are each zero, one or two; Ul and Z are each 0, S or NR; Ul and Ul are each 0, S or NR, provided that when one of U) and U is 0, S or the other is 0 or S; R, R, R, R and R are each C-C alkyl or phenyl; R, R, R, R and R are each H, C-C alkyl or phenyl; R, R, R, and R are each H or C C C; and R is H, F, Cl, Br, CF or C-C alkyl.

DESCRIPTION OF THE INVENTION Tenidap, an oxnindole, is an acute phase protein anti-inflammatory modulator drug intended for use in the treatment of arthritis reurnat oi .. Similar to steroids, oxytolenes have been shown to cause a rapid reduction in acute phase proteins in Arthritic patients and in vitro studies have shown that they inhibit the production of IL-6 and TL-1. These properties suggested the use of tenidap and other oxygens for the intraarticular treatment of arthritis. B.H. Littman et al., Flrthptis and Rhernu tisrn 35/9 Suppl., 341, 1992. A dosage form was developed for the suspension of the tetrahydrate suspension of ten-dap free acid as a product in two bottles. One vial contained the femdap-free acid. sterile that was aseptically synthesized and ground in a jet mill aseptically. The second bottle consisted of a constitution vehicle, sterile, aqueous, regulated in its pH that contained a surfactant. fll constitute the pharmaceutical substance with the vehicle, the product needed to be mixed in tow to provide dispersability a form of the drug as well as to ensure the release of the required dose. After an open clinical study, a double-blind, placebo-controlled clinical study was conducted in patients with reu atoid arthritis or osteoarthritis. The drug or placebo was administered by injection mtraarticulai *. All the patients, who received 120 mg of tempera free or placebo-free acid, had effusions in the knee, the first hours after the dose was observed improvement in the swelling and improvement in the maximum degree of relief (by global determination) about the placebo. However, at two weeks after the dose, the improvement was less evident. Also, the determination of plasma levels of tenidap indicated a rapid exit of the drug from the joint between 1 to 2 hours after the dose. These observations are similar to those reported with short-acting corticosteroids. Based on these clinical observations, it was concluded that a longer-acting dosage form of tenidap and other oxnolds would be necessary for effective treatment in reunatoid arthritis, B.H. Litttnan and others, Orthitns and Rheurnatism 35/9 Suppl., S341, 1992. Slightly soluble oxn ndol-1-carboxylated salts were synthesized and evaluated for the development of an intraarticular dosage form. Calcium, magnesium, lidocaine and benthyl a salts showed adequate solubility characteristics (see Table 3) and benzathine was identified as the most effective salt form based on its aqueous solubility, low dissolution rate and superior stability in solid state on the other salt forms investigated. 2-Oxadol-1-carboxyarides were prepared by the procedures described in US Pat. No. 4,556.67 ?, the description of which is incorporated herein by reference. Compounds of formula TI were prepared by the procedure described in U.S. Pat. Do not. ,047,554, the description of which is incorporated herein by reference. The salts of calcium, magnesium, or ega-diet larn? No-2, 6 -dinetylacetanilide (Jidocaine) and N, N-d? Benc? letilendiainine (benzathine) of 2-oxnindole-1-carboxyamides are easily prepared by dissolving or suspending 2-oxo-indole-1-carboxyarnide in a suitable liquid such as glyce-phane, ethanol, isopropanol or diketiacetam and adding equivalent amounts of calcium oxide, calcium hydroxide, magnesium oxide, magnesium hydroxide, lidocaine or benzatma either pure or in the same liquid or different at room temperature or heated at about 50 ° C to 100 ° C. The salt can be precipitated by cooling or the addition of a second liquid such as water or aqueous alcohol can be precipitated inert. The salts obtained in this manner can be removed by recirculation of a suitable solvent. In the frame 3 below shows the rates of in vitro release of 2-oxo-indole-1-carboxamide from the salts. Preferred salts are calcium tempdand benzath tonidap. In a study of irritation in albino rabbits, a single intraarticular dose of 0.5 ml of a suspension of free acid of tenidap containing 30 or 60 rng of tempera activity (acid liter) / ml was shown to be non-irritating. In a separate group of rabbits dosed in a manner similar to the more concentrated suspension of the test, the results of the test indicated that the individual dose of 30 g was clarified in excess of 50% of the knee joint at 2 hours after of the dose, and practically all the compound was clarified from the joint at 24 hours after the dose. The salt is calcium and benzatma at the time they were selected to develop a long-acting dosage form. In the first studies, these salts were found to have substantially lower dissolution rates in comparison to the tempered free acid. Formulations were prepared by suspending the appropriate amount of the calcium salt or benzathine salt form of the compound in the clinical vehicle (Tenidap Suspension Vehicle; see Table 1) to obtain a concentration of 120 rng of the active entity (free acid of ten? dap) / ml. The suspensions of the tempera salts were wet milled for 12 hours to reduce * the particle size to about 10 microns. The test suspensions were maintained at room temperature until they were used for the dosage. The calcium tenidap suspension was strong yellow, opaque and slightly viscous, while the benzatma tenidap suspension was light yellow and opaque. Prior to dosing each animal, the vial containing the appropriate test suspension was shaken vigorously to ensure homogeneity. 17 adult white rabbits were used in the study New Zealand (randomly procreated), which weighed 3.34 to 4.40 kilograms. One day before dosing, the area around the knee joint was shaved on both hind legs of each animal using an electric shaver. On the day of dosing, eight of the animals were given a single intra-articular injection of 0.5 nmol of calcium tenidap suspension (intended dose equivalent to 60 ng of free tenidap acid) in the left knee, a second group of Eight rabbits were given a single intraparticular injection of 0.5 ml of the suspension of benzathine tempera- ture (intended dose equivalent to 60 mg of tepid free acid) in the left knee. He did not inject the left knee of each animal. The remaining rabbit was returned as a non-dosed control for baseline purposes. The animals were manually stopped in an upright position during the brief dosing procedure and were not anesthetized. Each injection was made through the patellar ligament into the intra-articular space using a sterile 1 ml plastic syringe, disposable, equipped with a sterile, hypodermic needle of 1.6 crn, disposable, caliber 25. All animals were returned to their respective cages after dosing. Rabbits were observed intermittently throughout the day of dosing and then daily to check for clinical signs of discomfort and / or general toxicity and for major changes at the site of injection. Every day the feed consumption of the animals was evaluated and individual body weights were recorded. Plasma and both joints of the knees of the non-dosed animal and of two rabbits per treatment group were obtained, each at 2, 24, 48 and 120 hours after the two treatments. After adequate dosing, approximately 5 ml of blood was taken from each animal by cardiac puncture, and the animals were sacrificed by injection of an overdose of sodium pentobarbite into a marginal vein of the ear. The blood was treated with hepap na, and the plasma was collected. Both knee articulations of each rabbit were excised (the joint space was not opened). The plasma and the knees were stored frozen until they were analyzed. The concentration of tep dap in plasma and in the joints of the knees was determined by high performance liquid chromatography with ultraviolet light detection. In this test, the detection limit for tenidap was 0.5u /? Nl. The procedures used for the determination of tempera in the knee joint were as indicated below. After removal of the entire knee joint, the knee was placed in a plastic bag and frozen until used. For the extraction of the drug, the rodLlla was partially thawed (approximately 15 minutes). The tissue was excised from the joint using a scalpel and scissors, and placed in three Nalgene thick walled centrifuge tubes (100 ml). FJ remaining bone material was separated into three portions, cut into small pieces with a bone cutter, and combined with the portions of tissue in the tubes (that is, each knee was cut into three segments for extraction). Thirty milliliters of rnetanoJ / 1% tetillanna (TEA) [solvent] was added to each tube, and the tissue was homogenized to a pulp using a PoJytron (speed setting 11 for 2 minutes). The tubes were centrifuged (International Centpfuge, adjusted to 50 for 10 minutes), and the supernatant was decanted into a 500-milliliter round bottom flask. The peel was washed three times with solvent, and the washings were combined in the round bottom flask. The solvent was removed under vacuum (Rotavapor Buchi RE 121 at 40 ° -50 ° C at 80 kPa). The residue is reconstituted with a portion of 10 rnl of the solvent by swirling vigorously to disperse the film. A 5-milliliter portion of the above solution was pipetted into a 10-milliliter volumetric flask and brought to volume with 0.1 M Tris pH buffer (24.2 g Tris, 4.6 rnl HPO, 2 1 HO). Temdap was added to the sample as an internal standard at approximately 2 urn / ml in the sample). Then, the intact tenidap levels were quantified using a high resolution liquid chromatography method. The chromatographic conditions were as follows: column Uaters Novapak C-18 (39 m x 150 mrn: particle size of 5 u); 55% methanol, mobile phase of pH regulator Tris 0.025M (pH 6.3 with HPO), 45%; flow rate 1 rnl / rnin; detection at 276 nm. The levels of tenidap both in plasma and in the knee joint after the intra-articular administration of the calcium and benzathine salts are presented in Table 2. For comparative purposes, the results of a previous study with an acid suspension were also included. free of tempera. An earlier study indicated that a 30 mg dose of free acid was essentially cleared from the knee joint within 24 hours after injection. However, in the present invention, after the intraarticular administration of a dose of 60 mg, either of the salt or the benzatma of the tempera salt, the 12 to 14% of the two s in the joint were still present. of the knee 24 hours after the dose. In addition, there were detectable levels of tenidap in the knee joint at 24 hours and possibly at 5 days after the dose. However, the tempera was still detectable in the plasma 5 days after dosing with any form of salt.

TABLE 1 COMPOSITION OF THE VEHICLE OF THE TENIDAP SUSPENSION Ingredient rng / rnl Polyethylene glycol 3350 NF / FCC 30.0 Polysorbate 80 NF 3.00 Sodium chloride USP / FCC 9.00 Benzyl alcohol NF 10.00 Citric acid USP 9.60 Sodium hydride NF / FCC 2.70 Injectable water USP 935.70 Approximate amount used as an 8% solution (p / p) to adjust the pH CUODRO 2 INDIVIDUAL CONCENTRATIONS OF TENIDOP IN THE PLOSMO AND KNEE JOINT OF ALBINO RABBITS AFTER ONE INJECTION ONLY INTRO-ORTICULOR Total Poreiento of rng of teni ap terudap in i yecado Ho as Cons. Fabrics of remnant Rabbit < lespues in articulation in the # of the articular plasma Treatment (05-9) dose (μg / ml) knee of the knee Control no 31323 NA < 0.5 - --do L fic do 31324 NA < 0.5 - - 31297 NA < 0.5 - - 31367 NA < 0.7 - - Suspension of 31314 2 13.2 9.9 33 free acid of 31315 2 20.3 11.7 39 teru ap (equi - 31316 2 19.7 9.6 32 va lens at a dose of 3 (1 ing of tempered free acid) 31317 24 1.3 0.10 0.3 31318 24 0.6 0.02 0.08 31319 24 ..07 < 0.01 0.02 31320 48 < 0.5 < 0.0l &31321 48 < 0.5 < 0.01-31322 48 < 0.5 < 0.01 -Suspension of 31333 2 18.0 16 30.2 tenidap of cal31368 2 18.0 13 24.5 cio (equivalent to a dose of 60 rn of acid or 11 e of teni dap) 31369? 9 9.2.22 7.6 14.3 3J370 2 244 2 299..00 7.7 14.5 31371 4 488 7 7..77 r> 9.8 31372 4 488 7 7..44 4.2 7.9 31335 112200 11..66 6.9 13.0 31334 112200 00..77 < 0.01 Total percent of rng of temperature in injected hours of fabric of remnant Rabbit (jesipues on articulation in the # of the plasma of ai ~ t iculaci n T atamie or (05-9) do1 is (μg / ml) knee surgery Suspension of 31379 2 7.0 16 1.4 tempered of 31380 2 7.5 15 29.4 benzat na (equivalent to a dose of 60 mg of acid 31381 2Í 18.0 7.6 14.9 free of tension 31382 24 15.0 6.3 12.4 31383 48 3.4 0.70 1.4 31384 48 9.0 1.1 2.2 31338 120 0.7 <0.5 _ 31386 120 1.9 3.2 6.3 The animals were given a single intraarticular injection of 0.5 ml of the appropriate tempera suspension in the left knee. The free acid was administered as a suspension of 60 mg / ml, while the calcium and benzathine temperature suspensions contained 120 mg / ml. The values for suspensions of temperate calcium and benzatine temperature are based on doses of 53 and 51 rng of tempera respectively, according to the test results of the test suspensions. The limit of detection test was 0.5 μg / ml. An unexplained peak with the same retention time as the tempera as determined by means of the HPLC test. What appeared to be test suspension was evident in the muscles below the knee joint.

TABLE 3 VELOCITIES OF IN VITRO RELEASE OF TENIDOP OF THE SUSPENSIONS Formulation Percent of drug released after 24 hours Suspension of free acid (5 μ particles) 60 Free acid suspension (10 μ particle) 52 Suspension of calcium tenidap 17 Suspension of magnesium tenidap 30 Suspension of tenidop of lidocaine 34 Suspension of benzathine tenidap (low viscosity) 5 Benzathine tenidap suspension (high viscosity) 2 Benetanin tenidap suspension 19 EXAMPLE 1 TENIDAP BENZATINE SALT A portion of 16.05 grams (50 millimoles) of tenidap in 300 milliliters of isopropyl alcohol was stirred. The resulting suspension of yellow color was heated to 50 ° C. At 50 ° C, a solution of 6.6 grams (27.5 millirnol.es) of benzathine in 60 milliliters of isopropyl alcohol in a single addition was added. The yellow suspension quickly turned light orange. After about 1 minute, the orange suspension began to turn light * yellow and slightly thick. The heat was removed and the reaction was stirred under ambient conditions for 2 hours. The product was collected by filtration and washed with a 50 milliliter portion of isopropyl alcohol. The solids, light yellow, were dried at 45 ° C under vacuum. The yield was 99% as the bis-crystalline salt. The purity of the product had activity of 72%, which is correct for the bis salt. The product could be recrystallized by dissolving in hot N, N-dinethylacetamide and roprecipitation by the addition of 4 volumes or more of isopropyl alcohol.

EXAMPLE 2 DIHYDRATED CALCIUM TENIDAP SALT A portion of 64.15 grams (200 rnrols) of tea was added with 7.94 grams (105 mmol) of 98% calcium hydroxide in 160 milliliters of dimethyacetarnide. The resulting slurry was heated at 65 ° C for 15 minutes producing a cloudy solution. The reaction was cooled to 25 ° C and filtered to bubble the solution. Precipitation was achieved by the addition of 480 milliliters of a 50/50 mixture of isopropanol and water. The slurry was granulated at room temperature for J hour. The partially crystalline product was collected by means of crystallization. This product was loaded in 1240 milliliters of a 9/1 mixture of isopropanol and water. The suspension was heated to reflux for 1 hour. During this reflux period, the suspension changed color from yellow to intense orange upon formation of the dLhLdrate. The suspension was cooled to 60 ° C and filtered at that temperature. The collected crystalline product was dried under vacuum at 45 ° C. An 83% yield was obtained using this procedure. The product is bis salt (5.6% calcium) and di hydrate (5.03% water). The microanalysis was correct for this product and the cnstality was confirmed both by microscopy and by powder X-ray diffraction.

Claims (8)

00 NOVELTY OF THE INVENTION CLAIMS

1. - A salt selected from the group consisting of magnesium, calcium, benzathine and lidocaine of a compound of formula wherein X is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, alkyl having 1 to 4 carbons, cycloalkyl having 3 to 7 carbons, alkoxy having 1 to 4 carbons, alkylthio having 1 at 4 carbons, trifluoromethyl, alkylsulfonyl having 1 to 4 carbons, to the alkylsulfonyl having 1 to 4 carbons, nitro, enyl, alkanoyl having 2 to 4 carbons, benzoyl, tenoyl, alcanarnide having 2 to 4 carbons, benzarnide and N, N-dialkylsulphane oyl having from 1 to 3 carbons in each of said alkyls; and Y is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, alkyl having from 1 to 4 carbons, cycloalkyl having from 3 to 7 carbons, alkoxy having from 1 to 4 carbons, alkyl having from 1 to 4 carbons and trifluoromethyl; or X and Y when taken together are a 4,5-, 5,6- or 6,7-methylenedioxy group or a 4,5-, 5,6- or 6,7-ethylenedioxy group; or X and Y when taken together and when bonded to adjacent carbon atoms, form a divalent Z radical, wherein Z is selected from the group consisting of wherein U is oxygen or sulfur; R is selected from the group consisting of alkyl having from 1 to 6 carbons, cycloalkyl having from 3 to 7 carbons, cycloalkenyl having from 4 to 7 carbons, phenyl, substituted phenyl, phenylalkyl having from 1 to 3 carbons in said alkyl, alkyl (substituted phenyl) having from 1 to 3 carbons in said alkyl, phenoxy phenyl having from 1 to 3 carbons in said alkyl, alkyl (substituted phenoxy) having from 1 to 3 carbons in said alkyl, thiophenoxyalkyl having of 1 to 3 carbons in said alkyl, naphthyl, bicycloC2.2.1] he-tan-2-yl, bicycloC2.

2. lJhept-5-enfyl and - (CH) -Q-R °; wherein the substituent on said substituted phenyl, said alkyl (substituted phenyl) and said substituted alkyl phenoxy) is selected from the group consisting of fluorine, chlorine, bromine, alkyl having from 1 to 4 carbons, alkoxy having from 1 to 4 carbons and tp lororornetiio, n is zero, 1 or 2; 0 is a divalent radical substituted by a compound selected from the group consisting of furan, thiophene, pyrrole, pyrazole, iamidazole, thiazole, isothiazole, oxazole, isoxazole, 1,2,3-tαadiazole, 1, 3, 4 Adiazo, 1,2,5-t? ad? azol, t et ra fu fu ra no, tera ra hidro 11 o fe no, tet ra hid ro pi ra no, tetrahydrothiopyran, pipdin, pyrimidine, pyrazine , bonzoCb] furan and benzoTb] iofen; and R ° is hydrogen or alkyl having 1 to 3 carbons. The salt according to claim 1, further characterized in that it is the calcium bis salt of 5-chloro-2,3-d? H? dro-3- (h? rox? -2- t? enilrnet? ien) -2-oxo-l-H- i dol -1-carboxamide.

3. The salt according to claim 1, further characterized in that it is the bis-benzathine salt of 5-chloro-2,3-d? H? Dro-3- (hydrox? -2-t lenylnetiien) - ? ~ oxo-l ~ H ~? ndol ~ 1-carbox lamida.

4. The salt according to claim 1, further characterized because it is the calcium bis salt of 5-fluoro-6-chloro-2,3-dihydro-3- (hydrox? -2-t in ? lrnet? len) -2-oxo-lH-mdol-1-carbox? arn? gives.

5. The salt according to claim 1, further characterized in that it is the bis-benzathine salt of 5-fluoro-6-chloro-2,3-d? H? Dro-3- (hydrox? -2- t? emJrnet? len) -2-oxo-l-H-mdo-1-carboxyamide. OKAY.

6. The use of an effective amount of a salt according to claim 1 in the preparation of compositions for the treatment of pain and inflammation of joint disease in a mammal in need of such treatment.

7. A pharmaceutical composition for intra-articular injection comprising a salt according to claim 1 and a pharmaceutically acceptable carrier.

8. A salt selected from the group consisting of magnesium, calcium, benzatma and lidocaine of a compound of fo wherein X is H, F, Cl, Br, C-C alkyl, C-C cycloalkyl, NO, CF, CN, SH, S (0) R, OR, COR or CONRR; And H, F, Cl, Br, C-C alkyl, C-C cycloalkyl, NO, CF, CN, SH, S (0) R, OR, or CONRR; R is H; R is COR, CONRR, femlo or mono- or disubstituted femlo wherein the substituent or substituents are each Cl, F, Br, C-C alkyl, C-C alkoxy, or CF; 0 is A / Q or Q-A; \ B A is H, F, Cl, Br, I, CF, OR, S (0) R, COOR, CONRR, CN, NO, COR, CHOR, OCOR, NRR, N (R) COR, SONRR, B is H, F, Cl, Br, I, CF, OR, S (0) R, COOR, CONR, CN, NO, COR, CHOR, OCOR, NRR, N (R) COR or SONRR; provided that A and B can not both be H, or A and B are taken together, attached to the same carbon of the ring of 0 and equal to oxo, or when fl is not H, B is as defined above or alkyl of DC; fl is F, Cl, Br, I, CF, OR, S (0) R, COOR, CONR, CN, NO, COR, CHOR, OCOR, NRR, N (R) COR or SONRR; What is it m, p, p, q and t are each zero, one or two; U) and Z are each 0, S or NR; U and U are each 0, S or NR, provided that when one of U and W is 0, S or the other is 0 or S; R, R, R, R and R are each C-C alkyl or phenyl; R, R, R, R and R are each H, C-C alkyl or femlo; R, R, R, and R are each H or C-C alkyl; and R is H, F, Cl, Br, CF or C-C alkyl.