Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
  • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
  • C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
  • C07C205/45—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
  • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
  • C07C49/687—Unsaturated compounds containing a keto groups being part of a ring containing halogen
  • C07C49/697—Unsaturated compounds containing a keto groups being part of a ring containing halogen containing six-membered aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
  • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
  • C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
  • C07C49/747—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups containing six-membered aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
  • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
  • C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
  • C07C49/755—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups a keto group being part of a condensed ring system with two or three rings, at least one ring being a six-membered aromatic ring

Definitions

• ABSTRACT Cyclised benzylidene indenyl acetic acids and pharmaceutically acceptable salts, amides and esters thereof.
• the cyclised benzylidene indenyi acetic acids have anti-inflammatory, anti-pyretic and analgesic activity.
• the invention also includes methods for the preparation of these compounds, pharmaceutical compositions and methods of treating inflammation by administering these particular compounds to patients.
• This invention relates to a class of chemical compounds which contain four fused rings and are derived from benzylideneindene compounds.
• the compounds are more specifically described by the following structural formula:
• c-con l 6 2 finyl, alkylsulfonyl, dialkylsulfamyl, carboxyl, carbalkoxy, carbamido, haloalkyl, cycloalkyl, phenyl, benzyl, benzylthio, phenoxy or cycloalkoxy;
• R is hydrogen, alkylthio, alkylsulfinyl or alkylsulfonyl
• R is hydrogen, halo, hydroxy, alkoxy, haloalkyl, al-
• M is hydroxy, loweralkoxy, loweralkenyloxy, benzyloxy, substituted loweralkoxy, amino, alkylamino, dialkylamino, Nmorpholino, hydroxyalkylamino, polyhyclroxyalkylamino, dialkylaminoalkylamino, aminoalkylamino and the group OMe, in which Me is a cation; and their anhydrides.
• R and R are each hydrogen
• R is hydrogen, C alkyl, halo, halo C alkyl, phenyl, C alkylthiogphenylthio, C alkenyl, C alkoxyphenyl, trifluoromethyl or benzyl;
• R is hydrogen, trifluoromethyl, halo.
• C alkyl, phenyl, benzyl;
• R is hydrogen, hydroxy, halo, C alkylthio, benzyloxy, C alkylsulfinyl, C dialkylsulfonyl, C,.,-, dialkylamino-C alkyl, C alkylbenzyloxy.
• R is hydrogen, C alkenyl, halo, C alkoxy, C alkyl, benzyloxy or C alkylthio, at least one of R R or R is hydrogen at any one time;
• R is hydrogen, C alkylthio, C alkylsulfinyl or C alkylsulfonyl;
• R is hydrogen, halo, hydroxy, C alkoxy, halo C alkyl, phenyl, C alkanoylamino or C alkanoyl;
• M is hydroxy, C,. alkoxy or pivallyloxy. Still more particularly, the groups may be defined as follows:
• R and R are each hydrogen
• R is C alkyl
• R is hydrogen
• R is hydrogen, C,. dialkylamino, halo (chloro, fluoro, bromo), C alkanoyloxy, C alkenyl or C alkenyloxy',
• R is hydrogen or halo (chloro, bromo, fluoro);
• R is hydrogen
• M is hydroxy
• the compounds of the instant invention can be used to treat inflammation by reducing inflammation and relieving pain in such diseases as rheumatoid arthritis, osteoarthritis, gout, infectious arthritis and rheumatic fever.
• the compounds of the invention can also be used as an anti-pyrectic and would be administered and used in the same manner and in the same dosage ranges as if they were being used to treat inflammation as discussed further on.
• the treatment of inflammation in accordance with the method of the present invention is accomplished by topically, orally, rectally or parenterally administering to patients a composition of a compound of the inven tion, particularly the especially preferred compounds,
• the non-toxic pharmaceutical carrier may be, for example, either a solid or a liquid.
• solid carriers are lactose, corn starch, gelatin, talc, sterotix, stearic acid, magnesium stearate, terra alba, sucrose, agar, pectin, cab-o-sil and acacia.
• liquid carriers are peanut oil, olive oil, seasame oil and water.
• the carrier or diluent may include a time delay material such as glyceryl monostearate'or glyceryl distearate alone or with a wax.
• compositions will contain the active ingredient; namely, the compounds of the invention in'an amount of from about 0.1 mg. to 50 mg. per kg. body weight per day (5 mg. to 3.5g. per patient per day), preferably from about 1 mg. to 15 mg./kg. body weight per day (50 mg. to 1 g. per patient per day).
• the method of treatment of this invention comprises administering to a patient (animal or human), a compound of the invention particularly an especially preferred compound admixed with a non-toxic pharmaceutical carrier such as exemplified above.
• the compounds and particularly the especially preferred compounds will be administered in an amount of from 0.1 mg. to 50 mg./kg. body weight per day, preferably from about 1 mg. to about mg. per kilogram body weight per day.
• the most rapid and effective antiinflammatory effect is obtained from oral administration of a daily dosage of from about 1 to 15 mg./kg./day.' lt should be understood, however, that although preferred dosage ranges are given, the dose level for any particular patient depends upon the activity of the specific compound employed.
• the compounds of this invention may be prepared by cyclising a 7-iodo-l-(2'-iodobenzylidene)-3-indenyl-3- aliphatic acid compound of the formula:
• the cyclization may be carried out by any well known means for ring formation such as by reaction with metals and metal compounds, i.e., cuprous oxide, copper powder, copper bronze or zinc powder.
• metals and metal compounds i.e., cuprous oxide, copper powder, copper bronze or zinc powder.
• the reaction is earried out at temperatures of from 150 to 300 in the presence of an alkali such as potassium carbonate or sodium carbonate using an inert solvent such as nitrobenzene, dimethyl formamide, N- methylpyrrolidinone or amyl alcohol.
• the compound of Formula II in turn may be prepared by condensation of a 7-iodo-indenyl-B-aliphatic acid compound with a 2-iodobenzaldehyde compound under condensation conditions well known to the art such as reaction of these compounds in the presence of trimethylammonium hydroxide, sodium methoxide or sodium hydride in the presence of solvents such as methanol, ethanol or benzene at temperatures of from 0 to 100.
• the 7-iodo-indenyl-3-aliphatic acid compound may be prepared by nitrosation of known indanone compounds, for example, by reaction with sodium nitrite or potassium nitrite in dilute acids in the presence of potassium iodide or cuprous iodide at temperatures of 0 to 50.
• the nitroindanone compound is then converted to the corresponding aminoindanone compound by methods well known to the art for converting a nitro group to an amino group such as by reaction with tin and hydrochloric acid or zinc and acetic acid or catalytically with Raney nickel in ethyl acetate and acetic acid at temperatures of from 20 to 50.
• the iodoindanone compound prepared for the aminoindanone compound in turn is converted to the 7-iodoindenyl-3- aliphatic acid compound by reaction with a haloaliphatic acid or ester in the presence of zinc in an inert solvent such as benzene or toluene at reflux temperatures.
• the 2-iodobenzaldehyde compound may be readily prepared from anthranilic acid compounds by converting the anthranilic acid compound to its corresponding iodobenzoic acid compound in a manner described previously for converting the aminoindanone compound to the iodoindanone compound.
• the iodobenzoic acid compound is then converted to the corresponding iodobenzaldehyde by well known methods for converting a carboxylic acid group to the aldehydro group.
• the iodobenzoic acid compound may be treated with an appropriate halide such as thionyl halide, sulfinyl halide or phosphorous pentahalide in the presence of a solvent such as benzene, toluene, hexane or tetrahydrofuran at a temperature of from 25 to 100 to form the corresponding acid halide.
• an appropriate halide such as thionyl halide, sulfinyl halide or phosphorous pentahalide
• a solvent such as benzene, toluene, hexane or tetrahydrofuran at a temperature of from 25 to 100 to form the corresponding acid halide.
• This latter compound is then converted to the corresponding nitrile by reaction with ammonia, then with phosphorous pentoxide or concentrated sulfuric'acid in the presence of benzene or polyphosphoric acid as solvent at a temperature of from 50 to 150.
• the above nitrile is then refluxed, for example, with Raney nickel or nickel amalgam in formic or acetic acids'at temperatures of to 150 to form the desired iodobenzaldehyde.
• EXAMPLE 1 4-Methylthio-2-indobenzaldehyde A. 4-Methylthio-2nitrobenzoic acid 4-Chloro-2-nitrobenzoic acid (prepared as described in Helv; Chim. Acta. 45 371 (1957) and J. Org. Chem. 22 639 (1957) (0.3. mole) is added in methanol (100 ml.) to a solution of methylmercaptan bubbled into sodium methoxide (fresh, 0.4 mole) in methanol (300 ml.) that was saturated. The addition was slow and when all had been added the solution is refluxed for 2 hours under nitrogen. It is then evaporated to near dryness and the acid precipitated with dilute hydrochloric acid.
• a solution of sodium nitrite (0.6 ml.) in water (200 ml.) at 0 is slowly added with stirring so that the temperature does not rise above 5.
• This solution is added at 0-10 to a solution of potassium iodide (0.6 mole) in water ml.) with stirring.
• the powdered product is heated and stirred in benzene (300 ml.) and phosphorous pentoxide (1 mole) for 3 hours.
• the reaction mixture is cooled, filtered and the filtrate washed well with cold N. sodium hydroxide solution (3 X 100 ml.), water (2 X 50 ml.) and then dried (MgSO The filtrate solution is evaporated to dryness to give 4-methylthio-Z-iodobenzonitrile.
• 6-Fluoro-4-nitro-2-methylindanone A solution of potassium nitrate (0.2 mole) in concentrated sulfuric acid (300 ml.) is added slowly to a solution of 6-fluoro-2-methylindan0ne (0.18 mole) in concentrated sulfuric acid (40 ml.) at 10 with stirring in an ice-alcohol cooling bath. At the end of the addition the solution is brought to room temperature, stirred for 2 hours and poured carefully into ice (2 l.) with stirring. The organic layer is extracted into ether (2 X l 1.), dried (MgSO filtered and the filtrate evaporated to dryness. The residual oil is fractionally distilled at 0.001 mm.
• the catalyst is filtered off, the solvent evaporated to near dryness, the residue taken up in ethyl acetate (200 ml.) and washed well with saturated sodium bircarbonate solution (2 X 40 ml.). The organic layer is dried (MgSO and filtered. The filtrate is evaporated to dryness and the amine used as is. c; 6-Fluoro-4-iodo-2-methylindanone The above amine (0.7 mole) is dissolved in 4 N. hydrochloric acid (300 ml.) and cooled well to 0. A solution of sodium nitrite (0.9 mole) in water ml.) at
• bromoester are added and the mixture is then refluxed for 8 hours.
• the mixture is poured into 700 ml. of 1:1 aqueous acetic acid.
• the organic layer is separated, and the aqueous layer is extracted twice with ether.
• the combined organic layers are washed thoroughly with water, ammonium hydroxide and water. Drying over sodium sulfate, evaporation of solvent in vacuo gives crude methyl (l-hydroxy-2-methyl-4- iodo-6-fluoro-indenyl) acetate.
• methylindanone 2-methyl-6-methylsulfonylindanone, 2-methyl-6-dimethylsulfonylindanone, 2-methyl-6-dimethylaminoethylindanone, 2-methyl-6-(p-ethylbenzyloxy)indanone, 2-methyl-6-fluoroindanone, 2-methyl-6-benzylthioindanone, 2-methyl-6-diethylaminoindanone, 2-methyl-6-(p-chlorobenzyloxy)indanone 2-methyl-5,6-methylenedioxyindanone, 2-methyl-5,6-difluoroindanone, Z-methyl-5-fluoro-6-methoxyindanone, Z-isopropyl-o-methoxyindanone, 2-phenyl-6methylindanone, Z-methylthio-6-methylindanone, Z-phenylthioindanone, Z-allyl-o-methoxyindanone, 2-fluoroindanone, 2-chloromethyl---
• bromoester are added and the mixture is then refluxed for 8 hours.
• the mixture is poured into 700 ml. of 1:1 aqueous acetic acid.
• the organic layer is separated, and the aqueous layer is extracted twice with ether.
• the combined organic layers are washed thoroughly with water, ammonium hydroxide and water. Drying over sodium sulfate, evaporation of solvent in vacuo gives crude methyl (l-hydroxy-2- methyl-4-iodo-o-fluoro-indenyl)-a-propionate.
• reaction is allowed to stir at room temperature overnight.
• the reaction mixture is poured into a mixture of ice and water, acidified with 2.5N HC1 and extracted with ether.
• the ether solution is then washed with 2.5N HCl until the washing acidifies, then with water until neutral.
• the ether layer is then extracted with 5% Na CO solution.
• the Na CO solution is washed with ether, acidified and extracted with ether.
• the ether solution is washed with water, dried over Na SO and concentrated in vacuo to yield crude product.
• the tetraglyme solution is filtered and warmed with aqueous sodium hydroxide (2.5N. 200 ml.) and alcohol (200 ml.)
• aqueous sodium hydroxide 2.5N. 200 ml.
• alcohol 200 ml.
• the alcohol is evaporated off and the aqueous solution extracted with ether (3 X 200 ml.).
• the aqueous solution is acidified and extracted into ethyl acetate (2 X ml.).
• the ethyl acetate is dried (MgSO filtered and the filtrate evaporated to dryness.
• the residue is dissolved in methanol (100 ml.) and refluxed with 0.5 ml. concentrated sulfuric acid for 2 hours.
• the solution is evaporated to 5 ml.
• a pure fraction of methyl 2-fluoro-5-methyl-9-(pmethylthiobenzylidene)-cyclopenta[j, k]- phenanthrene-4-acetate is obtained. This is refluxed in aqueous alcohol 2.5N. sodium hydroxide solution (1:1 100 ml.) for 1 hour under nitrogen. The alcohol is evaporated off and the residual aqueous layer extracted with ether (2 X 100 ml.), separated and residual ether pumped away and acidified with 2.5 N. hydrochloric acid. The solid acid is precipitated and collected, washed well with water and dried in the oven at 40 over phosphorus pentoxide and under vacuum.
• EXAMPLE 7 The following further specific special products (Column L) are obtained'by' employing the starting material under Column A below in Example 1 A to F to obtain the aldehyde compound as indicated in Column F below and reacting said aldehyde with theproduct obtained by reacting a compound under Column G below in Example 2 A to D to obtain the indene of Column J. The products of Column J is then reacted in accordance to Examples 4 and 5 to obtain the product of A. STARTING F. PRODUCT G. STARTING .1. PRODUCT L. PRODUCT MATERIAL MATERIAL l.
• Methyl (tri-O-acetyl-a-D-glucopyranosylbromide)- uronate is made according to a procedure described in J. Amer. Chem. Soc. 77 3310 (1955) or J. Amer. Chem. Soc. 82 2827 (1960).
• the crude product in dimethoxyethane (125 ml.) and 2.5N hydrochloric acid (62.5 ml.) is heated to 90 for 3 hours.
• the solution is evaporated-at 70 to onehalf volume and extracted with methylene chloride (2 X 30 ml.).
• the solution is thensaturated with sodium chloride and extracted with methylene chloride again (30 ml.), then ethyl acetate (2 X 50 ml.) and this last extraction washed with water ml.), dried (anhydrous magnesium sulfate),'filtered and evaporated to dryness. In this way the glucoronide is isolated from the starting material.
• the resi- 0 due is slurried in aqueous sodium bicarbonate and then with water until neutral.
• the resulting ethyl ester may be recrystallized from organic solvents such as ethyl acetate, benzene and the like.
• phenanthrene-4-acetate B-hydroxyethyl 2-fluoro-5- methyl-9-( p-methylsulfinylbenzylidenyl cyclopenta[j,k ]-phenanthrene-4-acetate and ,B-acetamidoethyl 2-fluoro-5-methy
• pivalloyloxymethylchloride (1.9 g.) is added in dimethylformamide (10 ml.). The stirred solution is kept at 90 for 18 hours, poured into water (300 ml.)-and extracted with ether (2 X 300 ml.). The ether extract is washed with sodium hydroxide solution (2.5N, 50 ml.), water (50 ml.), separated and dried (anhydrous magnesium sulfate). The crude product, isolated by evaporation, is purified by column chromatography on silica gel (Baker 80-100 mesh) in a 2 ft. X l in. column, eluting with methylene chloride. The product isolated in thisway is recrystallized from benzene-n-hexane.
• EXAMPLE 14 Sodium 2-fluoro 5-methyl-9-(pmethylsulfinylbenzylidene)-cyclopenta[j,k]- phenanthrene-4-acetate A mixture of 0.030 moles of 2fluoro-5-methyl-9-(pmethylsulfinylbenzylidene)-cyclopenta[j,k]-phenanthrene-4-acetic acid and 0.033 moles of sodium methoxide (25% solution in water) 7.4 ml. in 200 ml. of tetrahydrofuran is stirred for 2 hours at C. The reaction mixture is filtered and the product dried to yield the subject compound.
• the granules are dried at a temperature below 60C.
• the dry granules are passed through a 16 mesh screen and mixed with 3.8 parts of magnesium stearate. They are then compressed into tablets suitable for oral administrationv Similarly, tablets are prepared by employing an equivalent amount of the substituted phenanthrene-4- acetic acid obtained from Examples 5 to 7 or the corresponding esters, anhydrides or amides obtained from Examples 8 to 13.
• R and R are each hydrogen or lower alkyl
• R is hydrogen, C alkyl. halo. halo C alkyl. phenyl, C alkylthio. phenylthio. (2. alkcnyl. alkoxyphenyl. trifluoromethyl or benzyl;
• R is hydrogen, trifluoromethyl, halo.
• C alkyl, phenyl, benzyl;
• R is hydrogen, hydroxy. halo C alkylthio, benzyloxy, C alkylsulfinyl, C, dialkylsulfonyl, C dialkylamino-C alkyl, C,.,-, alkylbenzyloxy, benzylthio, C dialkylamino, halobenzyloxy, C alkoxy, C alkyl, C alkylsulfamyl. alkanoyloxy. phenoxy, C alkenyl, C alkenyloxy or benzyl;
• R is hydrogen, C alkenyl, halo, alkoxy. C,. al-
• R R 'or R is hydrogen at any one time
• R is hydrogen, C alkylthio, (1 alkylsulfinyl or C alkylsulfonyl;
• R is hydrogen, halo, hydroxy, C alkoxy, halo C, alkyl, phenyl, C alkanoylamino or C, alkanoyl:
• M is hydroxy, C alkoxy or pivallyloxy.
• R and R are each hydrogen
• R3 is (2 R is hydrogen;
• R is hydrogen, C dialkylamino, halo, C alkanoyloxy, (3 alkenyl or C alkenyloxy;
• R is hydrogen or halo
• R is halo, C alkylthio or C alkylsulfinyl
• R is hydrogen
• M is hydr'oxy.
• R and R are each hydrogen
• R is methyl
• R is hydrogen
• R is dimethylamino, allyloxy, chloro, acetyl, fluoro or vinyl;
• R is hydrogen
• R is methylthio
• R is hydrogen
• R and R is hydrogen
• R is methyl
• R is hydrogen
• R is hydrogen
• R is hydrogen
• M is hydroxy
• R and R is hydrogen
• R is methyl
• R is hydrogen
• R is hydrogen
• R is methylsulfinyl; R is hydrogen; and M is hydroxy.

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• 1973
  • 1973-05-04 US US357314A patent/US3867433A/en not_active Expired - Lifetime
• 1974
  • 1974-04-16 NL NL7405118A patent/NL7405118A/xx not_active Application Discontinuation
  • 1974-04-26 CH CH576874A patent/CH592597A5/xx not_active IP Right Cessation
  • 1974-04-29 GB GB1857874A patent/GB1453885A/en not_active Expired
  • 1974-05-02 FR FR7415225A patent/FR2236488B1/fr not_active Expired
  • 1974-05-02 JP JP49048871A patent/JPS5013371A/ja active Pending
  • 1974-05-03 DE DE2421541A patent/DE2421541A1/de not_active Withdrawn

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