Claims
- 1. A 1,3-diacyl-2-oxindole compound of the formula: ##STR10## and the pharmaceutically-acceptable base salts thereof; wherein X is selected from the group consisting of hydrogen, fluoro, chloro, bromo, alkyl having 1 to 4 carbons, cycloalkyl having 3 to 7 carbons, alkoxy having 1 to 4 carbons, alkylthio having 1 to 4 carbons, trifluoromethyl, alkylsulfinyl having 1 to 4 carbons, alkylsulfonyl having 1 to 4 carbons, nitro, phenyl, alkanoyl having 2 to 4 carbons, benzoyl, thenoyl, alkanamido having 2 to 4 carbons, benzamido and N,N-dialkylsulfamoyl having 1 to 3 carbons in each of said alkyls; and Y is selected from the group consisting of hydrogen, fluoro, chloro, bromo, alkyl having 1 to 4 carbons, cycloalkyl having 3 to 7 carbons, alkoxy having 1 to 4 carbons, alkylthio having 1 to 4 carbons and trifluoromethyl;
- R.sup.1 is selected from the group consisting of alkyl having 1 to 6 carbons, cycloalkyl having 3 to 7 carbons, cycloalkenyl having 4 to 7 carbons, phenyl, substituted phenyl, phenylalkyl having 1 to 3 carbons in said alkyl, (substituted phenyl)alkyl having 1 to 3 carbons in said alkyl, phenoxyalkyl having 1 to 3 carbons in said alkyl, (substituted phenoxy)alkyl having 1 to 3 carbons in said alkyl, (thiophenoxy)alkyl having 1 to 3 carbons in said alkyl and naphthyl;
- wherein the substituent on said substituted phenyl, said (substituted phenyl)alkyl and said (substituted phenoxy)alkyl is selected from the group consisting of fluoro, bromo, chloro, alkyl having 1 to 4 carbons, alkoxy having 1 to 4 carbons and trifluoromethyl;
- and R.sup.2 is alkyl having from 1 to 5 carbons.
- 2. A compound according to claim 1, wherein
- X is at the 5-position or the 6-position and it is selected from the group consisting of hydrogen, fluoro, chloro, bromo and trifluoromethyl; and Y is hydrogen;
- and R.sup.1 is selected from the group consisting of alkyl having from 1 to 6 carbons, cycloalkyl having from 3 to 7 carbons, phenyl and phenylalkyl having 1 to 3 carbons in said alkyl.
- 3. A method of eliciting an analgesic response in a mammalian subject, which comprises administering to said mammalian subject an analgesic response eliciting amount of a 1,3-diacyl-2-oxindole compound of the formula ##STR11## or a pharmaceutically-acceptable base salt thereof; wherein X is selected from the group consisting of hydrogen, fluoro, chloro, bromo, alkyl having 1 to 4 carbons, cycloalkyl having 3 to 7 carbons, alkoxy having 1 to 4 carbons, alkylthio having 1 to 4 carbons, trifluoromethyl, alkylsulfinyl having 1 to 4 carbons, alkylsulfonyl having 1 to 4 carbons, nitro, phenyl, alkanoyl having 2 to 4 carbons, benzoyl, thenoyl, alkanamido having 2 to 4 carbons, benzamido and N,N-dialkylsulfamoyl having 1 to 3 carbons in each of said alkyls; and Y is selected from the group consisting of hydrogen, fluoro, chloro, bromo, alkyl having 1 to 4 carbons, cycloalkyl having 3 to 7 carbons, alkoxy having 1 to 4 carbons, alkylthio having 1 to 4 carbons and trifluoromethyl;
- R.sup.1 is selected from the group consisting of alkyl having 1 to 6 carbons, cycloalkyl having 3 to 7 carbons, cycloalkenyl having 4 to 7 carbons, phenyl, substituted phenyl, phenylalkyl having 1 to 3 carbons in said alkyl, (substituted phenyl)alkyl having 1 to 3 carbons in said alkyl, phenoxyalkyl having 1 to 3 carbons in said alkyl, (substituted phenoxy)alkyl having 1 to 3 carbons in said alkyl, (thiophenoxy)alkyl having 1 to 3 carbons in said alkyl and naphthyl;
- wherein the substituent on said substituted phenyl, said (substituted phenyl)alkyl and said (substituted phenoxy)alkyl is selected from the group consisting of fluoro, chloro, bromo, alkyl having 1 to 4 carbons, alkoxy having 1 to 4 carbons and trifluoromethyl;
- and R.sup.2 is alkyl having from 1 to 5 carbons.
- 4. The method according to claim 3, wherein
- X is at the 5-position or the 6-position and it is selected from the group consisting of hydrogen, fluoro, chloro, bromo and trifluoromethyl; and Y is hydrogen;
- and R.sup.1 is selected from the group consisting of alkyl having from 1 to 6 carbons, cycloalkyl having from 3 to 7 carbons, phenyl and phenylalkyl having 1 to 3 carbons in said alkyl.
- 5. A method of treating an inflammatory disease in a mammalian subject, which comprises administering to said mammalian subject an inflammatory disease treating amount of a 1,3-diacyl-2-oxindole compound of the formula ##STR12## or a pharmaceutically-acceptable base salt thereof, wherein X is selected from the group consisting of hydrogen, fluoro, chloro, bromo, alkyl having 1 to 4 carbons, cycloalkyl having 3 to 7 carbons, alkoxy having 1 to 4 carbons, alkylthio having 1 to 4 carbons, trifluoromethyl, alkylsulfinyl having 1 to 4 carbons, alkylsulfonyl having 1 to 4 carbons, nitro, phenyl, alkanoyl having 2 to 4 carbons, benzoyl, thenoyl, alkanamido having 2 to 4 carbons, benzamido and N,N-dialkylsulfamoyl having 1 to 3 carbons in each of said alkyls; and Y is selected from the group consisting of hydrogen, fluoro, chloro, bromo, alkyl having 1 to 4 carbons, cycloalkyl having 3 to 7 carbons, alkoxy having 1 to 4 carbons, alkylthio having 1 to 4 carbons and trifluoromethyl;
- R.sup.1 is selected from the group consisting of alkyl having 1 to 6 carbons, cycloalkyl having 3 to 7 carbons, cycloalkenyl having 4 to 7 carbons, phenyl, substituted phenyl, phenylalkyl having 1 to 3 carbons in said alkyl, (substituted phenyl)alkyl having 1 to 3 carbons in said alkyl, phenoxyalkyl having 1 to 3 carbons in said alkyl, (substituted phenoxy)alkyl having 1 to 3 carbons in said alkyl, (thiophenoxy)alkyl having 1 to 3 carbons in said alkyl and naphthyl;
- wherein the substituent on said substituted phenyl, said (substituted phenyl)alkyl and said (substituted phenoxy)alkyl is selected from the group consisting of fluoro, chloro, bromo, alkyl having 1 to 4 carbons, alkoxy having 1 to 4 carbons and trifluoromethyl;
- and R.sup.2 is alkyl having from 1 to 5 carbons.
- 6. The method according to claim 5 wherein
- X is at the 5-position or the 6-position and it is selected from the group consisting of hydrogen, fluoro, chloro, bromo and trifluoromethyl; and Y is hydrogen;
- and R.sup.1 is selected from the group consisting of alkyl having from 1 to 6 carbons, cycloalkyl having from 3 to 7 carbons, phenyl and phenylalkyl having 1 to 3 carbons in said alkyl;
- 7. An analgesic or antiinflammatory pharmaceutical composition, which comprises a pharmaceutically-acceptable carrier and an effective analgesic or antiinflammatory amount of a 1,3-diacyl-2- oxindole compound according to claim 1, and wherein the weight ratio of the pharmaceutically-acceptable carrier to the 1,3-diacyl-2-oxindole compound is in the range from 1:4 to 4:1.
- 8. A compound of the formula ##STR13## wherein X is selected from the group consisting of hydrogen, 5-fluoro, 5-chloro and 5-trifluoromethyl; Y is selected from the group consisting of hydrogen 6-fluoro, 6-chloro and 6-trifluoromethyl;
- and R.sup.2 is alkyl having 1 to 5 carbons;
- provided that X and Y are not both hydrogen.
- 9. A compound according to claim 8, wherein R.sup.2 is methyl.
- 10. The compound according to claim 9, wherein X is 5-chloro and Y is hydrogen.
- 11. A compound according to claim 9, wherein X is 5-fluoro or 5-chloro and Y is 6-fluoro or 6-chloro.
- 12. The compound according to claim 11, wherein X is 5-fluoro and Y is 6-chloro.
- 13. The compound according to claim 1, wherein X is 5-chloro, Y is hydrogen, R.sup.1 is phenyl and R.sup.2 is methyl.
- 14. The compound according to claim 1, wherein X is 5-chloro, Y is hydrogen, R.sup.1 is benzyl and R.sup.2 is methyl.
- 15. The method according to claim 3, wherein X is 5-chloro, Y is hydrogen, R.sup.1 is phenyl and R.sup.2 is methyl.
- 16. The method according to claim 3, wherein X is 5-chloro, Y is hydrogen, R.sup.1 is benzyl and R.sup.2 is methyl.
- 17. The method according to claim 5, wherein X is 5-chloro, Y is hydrogen, R.sup.1 is phenyl and R.sup.2 is methyl.
- 18. The method according to claim 5, wherein X is 5-chloro, Y is hydrogen, R.sup.1 is benzyl and R.sup.2 is methyl.
CROSS-REFERENCE TO RELATED APPLICATION
This application is a continuation-in-part of application Ser. No. 652,372, filed Sept. 19, 1984, and now abandoned.
This invention relates to new chemical compounds. More particularly, these new chemical compounds are derivatives of 2-oxindole and they are further substituted at the 1- and the 3-position by an acyl group. These new chemical compounds are inhibitors of both the cyclooxygenase (CO) and lipoxygenase (LO) enzymes.
The compounds of this invention possess analgesic activity in mammals, particularly man, and they are useful therefore for acute administration for ameliorating or eliminating pain, such as the pain experienced by patients recovering from surgery or trauma.
In addition to their usefulness for acute administration to combat pain, the compounds of this invention are useful for chronic administration to mammals, particularly man, to alleviate the symptoms of chronic diseases, such as the inflammation and pain associated with rheumatoid arthritis and osteoarthritis.
This invention provides novel 1,3-diacyl-2-oxindole compounds of the formula ##STR1## and the pharmaceutically-acceptable base salts thereof, wherein
X is selected from the group consisting of hydrogen, fluoro, chloro, bromo, alkyl having 1 to 4 carbons, cycloalkyl having 3 to 7 carbons, alkoxy having 1 to 4 carbons, alkylthio having 1 to 4 carbons, trifluoromethyl, alkylsulfinyl having 1 to 4 carbons, alkylsulfonyl having 1 to 4 carbons, nitro, phenyl, alkanoyl having 2 to 4 carbons, benzoyl, thenoyl, alkanamido having 2 to 4 carbons, benzamido and N,N-dialkylsulfamoyl having 1 to 3 carbons in each of said alkyls; and Y is selected from the group consisting of hydrogen, fluoro, chloro, bromo, alkyl having 1 to 4 carbons, cycloalkyl having 3 to 7 carbons, alkoxy having 1 to 4 carbons, alkylthio having 1 to 4 carbons and trifluoromethyl;
R.sup.1 is selected from the group consisting of alkyl having 1 to 6 carbons, cycloalkyl having 3 to 7 carbons, cycloalkenyl having 4 to 7 carbons, phenyl, substituted phenyl, phenylalkyl having 1 to 3 carbons in said alkyl, (substituted phenyl)alkyl having 1 to 3 carbons in said alkyl, phenoxyalkyl having 1 to 3 carbons in said alkyl, (substituted phenoxy)alkyl having 1 to 3 carbons in said alkyl, (thiophenoxy)alkyl having 1 to 3 carbons in said alkyl, naphthyl and --(CH.sub.2).sub.n --Q--R.degree.;
wherein the substituent on said substituted phenyl, said (substituted phenyl)alkyl and said (substituted phenoxy)alkyl is selected from the group consisting of fluoro, chloro, bromo, alkyl having 1 to 4 carbons, alkoxy having 1 to 4 carbons and trifluoromethyl; n is zero, 1 or 2; Q is a divalent radical derived from a compound selected from the group consisting of furan, thiophene, pyrrole, pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazole, 1,2,3-thiadiazole, 1,3,4-thiadiazole, 1,2,5-thiadiazole, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, tetrahydrothiopyran, pyridine, pyrimidine and pyrazine; and R.degree. is hydrogen or alkyl having 1 to 3 carbons;
and R.sup.2 is alkyl having from 1 to 5 carbons.
Said compounds of formula I are active as analgesic agents, and as agents for treating inflammatory diseases, such as the arthritides. Accordingly, this invention also provides a method of eliciting an analgesic response in a mammalian subject, especially man; a method of treating an inflammatory disease in a mammalian subject, especially man; and pharmaceutical compositions comprising a compound of formula I and a pharmaceutically-acceptable carrier.
A preferred group of compounds of this invention consists of the compounds of formula I, wherein X and Y are each hydrogen and R.sup.1 is selected from the group consisting of 2-furyl, 2-thienyl, 3-pyridyl and (2-thienyl)methyl.
A further preferred group of compounds of this invention consists of the compounds of formula I, wherein X is 5-chloro, Y is hydrogen and R.sup.1 is selected from the group consisting of 2-furyl, 2-thienyl, 3- pyridyl and (2-thienyl)methyl.
Especially preferred individual compounds of the invention are:
1-acetyl-3-(2-thenoyl)-2-oxindole,
1-acetyl-3-([2-thienyl]acetyl)-2-oxindole, and
5-chloro-1-acetyl-3-(2-thenoyl)-2-oxindole.
Useful as intermediates to the analgesic and antiinflammatory compounds of the formula I are the 1-acyl-2-oxindole compounds of the formula ##STR2## wherein X, Y and R.sup.2 are as defined previously. A preferred sub-group of compounds of the formula II consists of those compounds in which X is hydrogen, 5-fluoro, 5-chloro or 5-trifluoromethyl; Y is hydrogen, 6-fluoro, 6-chloro or 6-trifluoromethyl; and R.sup.2 is alkyl having 1 to 5 carbons; provided that X and Y are not both hydrogen. The compounds of formula II in said latter preferred sub-group are novel, and as such they form part of this invention.
This invention relates to the compounds of formula I, and these compounds are named as derivatives of 2-oxindole, the compound of the structure: ##STR3##
Additionally, as will be appreciated by one skilled in the art, the analgesic and anti-inflammatory compounds of this invention of formula I, wherein X, Y, R.sup.1 and R.sup.2 are defined previously, are capable of enolization, and therefore they can exist in one or more tautomeric (enolic) forms. All such tautomeric (enolic) forms of the compounds of formula I are considered to be within the scope of this invention.
The compounds of the formula I are prepared from the appropriate 2-oxindole compound of the formula III: ##STR4## wherein X and Y are as defined previously, by attaching the substituent 'C(.dbd.O)--R.sup.2 to the 1--position and the --C(.dbd.O)--R.sup.1 substituent to the 3--position. These substituents can be attached in either order, and this leads to two variations in the method for making the compounds of formula I. These are shown in Scheme A. However, the preferred method of preparing the compounds of formula I involves the sequence: compound III to compound IV to I. ##STR5##
The --C(.dbd.O)--R.sup.2 substituent can be attached to a compound of the formula IV by reaction with one molar equivalent, or a small excess, of an activated derivative of a carboxylic acid of the formula R.sup.2 --C(.dbd.O)OH, in the presence of from one to four equivalents of a basic agent in an inert solvent. An inert solvent is one which will dissolve at least one of the reactants, and will not adversely interact with either of the reactants or the product. However, in practice a polar, aprotic solvent, such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone or dimethyl sulfoxide, is commonly used. Conventional methods for activating the acid of formula R.sup.2 --C(.dbd.O)OH are used. For example, acid halides, e.g., acid chlorides; symmetrical acid anhydrides, R.sup.2 --C(.dbd.O)--O--C(.dbd.O)--R.sup.2 ; mixed acid anhydrides with a hindered low-molecular weight carboxylic acid, R.sup.2 --C(.dbd.O)--O--C(.dbd.O)--R.sup.3, where R.sup.3 is a bulky lower-alkyl group such as t-butyl; and mixed carboxylic-carbonic anhydrides, R.sup.2 --C(.dbd.O)--O--C(.dbd.O)--OR.sup.4, wherein R.sup.4 is a lower alkyl group, can all be used. In addition, N-hydroxyimide esters (such as N-hydroxysuccinimide and N-hydroxyphthalimide esters), 4-nitrophenyl esters, thiol esters (such as thiol phenyl esters) and 2,4,5-trichlorophenyl esters, and the like, can be used.
A wide variety of basic agents can be used in the reaction between a compound of formula IV and the activated derivative of the acid of the formula R.sup.2 --C(.dbd.O)OH. However, preferred basic agents are tertiary amines, such as trimethylamine, triethylamine, tributylamine, N-methylmorpholine, N-methylpiperidine and 4-(N,N-dimethylamino)pyridine.
The reaction between a compound of the formula IV and the activated derivative of the acid of formula R.sup.2 --C(.dbd.O)--OH is usually carried out in the temperature range from -20.degree. to 25.degree. C. In general, temperatures at the lower end of this range are used when highly activated derivatives of an acid of formula R.sup.2 --C(.dbd.O)--OH are used, while higher temperatures are used when only mildly activated derivatives of the acid R.sup.2 --C(.dbd.O)--OH are used. In most instances, the reaction proceeds quite quickly, and reaction times of from 30 minutes to a few hours are common. At the end of the reaction, the reaction medium is usually diluted with water and acidified, and then the product of formula I can be recovered by filtration. It can be purified by standard methods, such as recrystallization.
The --C(.dbd.O)--R.sup.1 side-chain can be attached to a compound of the formula II by reaction with one molar equivalent, or a small excess, of an activated derivative of a carboxylic acid of the formula R.sup.1 --C(.dbd.O)--OH. This acylation reaction is carried out in the same manner as that described for reaction of a compound of the formula IV with an activated derivative of a carboxylic acid of the formula R.sup.2 --C(.dbd.O)--OH.
The --C(.dbd.O)--R.sup.1 side-chain can be attached to a compound of the formula III by reaction with a derivative of the appropriate acid of the formula R.sup.1 --C(.dbd.O)--OH, in a lower-alkanol solvent (e.g. ethanol), in the presence of an alkali metal salt of the lower-alkanol solvent (e.g. sodium ethoxide), according to standard procedures. Typical derivatives of the acid of the formula R.sup.1 --C(.dbd.O)OH which can be used include acid chlorides, acid anhydrides of the formula R.sup.1 --C(.dbd.O)--O--C(.dbd.O)--R.sup.1, R.sup.1 --C(.dbd.O)--O--C(.dbd.O)--R.sup.3 and R.sup.1 --C(.dbd.O)--O--C(.dbd.O)--OR.sup.4, and simple alkyl esters of the formula R.sup.1 --C(.dbd.O)--OR.sup.4 ; wherein R.sup.3 and R.sup.4 are as defined previously. Usually, a small excess of the derivative of the acid of formula R.sup.1 --C(.dbd.O)--OH is used, and the alkoxide salt is usually present in an amount from one to two molar equivalents, based on said derivative of the acid of formula R.sup.1 --C(.dbd.O)OH. The reaction between the derivative of the acid of the formula R.sup.1 --C(.dbd.O)OH and the compound of formula III is usually started at 0.degree. to 25.degree. C., but it is then usual to heat the reaction mixture at a temperature in the range from 50.degree. to 130.degree. C., and preferably at about 80.degree. C., to complete the reaction. Under these circumstances, reaction times of a few hours, e.g. two hours, up to a few days, e.g., two days, are commonly used. The reaction mixture is then cooled, diluted with an excess of water, and acidified. The product of formula IV can then be recovered by filtration or by the standard procedure of solvent extraction.
The --C(.dbd.O)--R.sup.2 side-chain can be attached to a compound of the formula III by reaction with the appropriate acid anhydride of the formula [R.sup.2 --C(.dbd.O)].sub.2 O. Usually the compound of formula III is reacted with from one to three equivalents, and preferably 1.2 to 1.5 equivalents, of the anhydride in the absence of solvent, at a temperature in the range from 80.degree. to 130.degree. C., and preferably about 100.degree. C., for several hours (e.g., about 4 hours). If desired, however, an inert solvent such as toluene can be used. At the end of the reaction, the product of formula II can be recovered by removal of the excess anhydride and any solvent by evaporation. The crude product is usually pure enough for conversion into a compound of formula I. The 2-oxindole compounds of formula III are prepared by known methods, or methods analogous to known methods. 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.
The compounds of the formula I are acidic and they form base salts. All such base salts are within the scope of this invention and they can be prepared by conventional methods. For example, they can be prepared simply by contacting the acidic and basic entities, usually in a stoichiometric ratio, in either an aqueous, non-aqueous or partially aqueous medium, as appropriate. The salts are recovered either by filtration, by precipitation with a non-solvent followed by filtration, by evaporation of the solvent, or, in the case of aqueous solutions, by lyophilization, as appropriate. Typical salts of the compounds of formula I which can be prepared are primary, secondary and tertiary amine salt, alkali metal salts and alkaline earth metal salts. Especially valuable are the ethanolamine, diethanolamine and triethanolamine salts.
Basic agents suitably employed in salt formation belong to both the organic and inorganic types, and they include organic amines, alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydrides, alkali metal alkoxides, alkaline earth metal hydroxides, alkaline earth metal carbonates, alkaline earth metal hydrides and alkaline earth metal alkoxides. Representative examples of such bases are primary amines, such as n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine, p-toluidine, ethanolamine and glucamine; secondary amines, such as diethylamine, diethanolamine, N-methylglucamine, N-methylaniline, morpholine, pyrrolidine and piperidine; tertiary amines, such as triethylamine, triethanolamine, N,N-dimethylaniline, N-ethylpiperidine and N-methylmorpholine; hydroxides, such as sodium hydroxide; alkoxides, such as sodium ethoxide and potassium methoxide; hydrides, such as calcium hydride and sodium hydride; and carbonates, such as potassium carbonate and sodium carbonate.
The compounds of formula I possess analgesic activity. This activity has been demonstrated in mice by showing blockade of the abdominal stretching induced by administration of 2-phenyl-1,4-benzoquinone (PBQ), using a method based on that of Siegmund et al., Proc. Soc. Exp. Biol. Med., 95, 729-731, (1957), as adapted for high throughput (see further Milne and Twomey, Agents and Actions, 10, 31-37, [1980]). The mice used in these experiments were Carworth males, albino CF-1 strain, weighing 18-20 g. All mice were fasted overnight prior to drug administration and testing.
The compounds of formula I were dissolved or suspended in a vehicle consisting of ethanol (5%), emulphor 620 (a mixture of polyoxyethylene fatty acid esters, 5%) and saline (90%). This vehicle also served as control. Doses were on a logarithmic scale (i.e., . . . 0.32, 1.0, 3.2, 10, 32 . . . mg/kg). The route of administration was oral, with concentrations varied to allow a constant dosage volume of 10 ml/kg of body weight. The aforesaid method of Milne and Twomey was used to determine efficacy and potency. Mice were treated with compounds orally, and one hour later received PBQ, 2 mg/kg, intraperitoneally. Individual mice were then immediately placed in a warmed Lucite (transparent plastic) chamber, and, starting five minutes after PBQ administration, the number of abdominal constrictions during the subsequent 5 minutes was recorded. The degree of analgesic protection (% MPE) was calculated on the basis of suppression of abdominal constriction relative to counts from response data for generation of an MPE.sub.50, the best estimate of the dose that reduces abdominal constriction to 50% of control levels.
The compounds of formula I also possess anti-inflammatory activity. This activity has been demonstrated in rats by a method based on the standard carrageenin-induced rat-foot edema test. (Winter et al., Proc. Soc. Exp. Biol. Med., 111, 544, [1963]).
Unanesthetized, adult, male, albino rats of 150 g to 190 g body weight were numbered, weighed, and an ink mark placed on the right lateral malleolus. Each paw was immersed in mercury exactly to the ink mark. The mercury was contained in a glass cylinder, connected to a Statham Pressure Transducer. The output from the transducer was fed through a control unit to a micro-voltameter. The volume of mercury displaced by the immersed paw was read. Drugs were given by gavage. One hour after drug administration, edema was induced by injection of 0.05 ml of 1% solution of carrageenin into the plantar tissue of the marked paws. Immediately thereafter, the volume of the injected foot was measured. The increase in foot volume 3 hours after the injection of carrageenin constitutes the individual inflammatory response.
The analgesic activity of the compounds of formula I makes them useful for acute administration to mammals for the control of pain, e.g., post-operative pain and the pain of trauma. Additionally the compounds of formula I are useful for chronic administration to mammals for the alleviation of the symptoms of chronic diseases, such as the inflammation of rheumatoid arthritis, and the pain associated with osteoarthritis and other musculoskeletal disorders.
When a compound of the formula I or a pharmaceutically acceptable salt thereof is to be used as either an analgesic agent or an anti-inflammatory agent, it can be administered to a mammalian subject either alone, or, preferably, in combination with pharmaceutically-acceptable carriers or diluents in a pharmaceutical composition, according to standard pharmaceutical practice. A compound can be administered orally or parenterally. Parenteral administration includes intravenous, intramuscular, intraperitoneal, subcutaneous and topical administration.
In a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically-acceptable salt thereof, the weight ratio of carrier to active ingredient will normally be in the range from 1:4 to 4:1, and preferably 1:2 to 2:1. However, in any given case, the ratio chosen will depend on such factors as the solubility of the active component, the dosage contemplated and the precise route of administration.
For oral use of a compound of formula I of this invention, the compound can be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch, and lubricating agents, such as magnesium stearate, are commonly added. For oral administration in capsule form, useful diluents are lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifiying and suspending agents. If desired, certain sweetening and/or flavoring agents can be added. For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled to render the preparation isotonic.
When a compound of formula I or salt thereof is used in a human subject, the daily dosage will normally be determined by the prescribing physician. Moreover, the dosage will vary according to the age, weight and response of the individual patient, as well as the severity of the patient's symptoms and the potency of the particular compound being administered. However, for acute administration to relieve pain, an effective analgesic response eliciting dose in most instances will be 0.1 to 1.0 g as needed (e.g., every four to six hours). For chronic administration to alleviate (treat) inflammation and pain, in most instances an effective dose will be from 0.1 to 1.5 g per day, and preferably 0.3 to 1.0 g per day, in single or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases.
The following examples and preparations are being provided solely for the purpose of further illustration.
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| Number |
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Apr 1971 |
JPX |
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Continuation in Parts (1)
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652372 |
Sep 1984 |
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Patent Grant
4690943
