US3867433A - Cyclopenta{8 j,k{9 -phenanthrene-4-acetic acids and related compounds - Google Patents

Cyclopenta{8 j,k{9 -phenanthrene-4-acetic acids and related compounds Download PDF

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US3867433A
US3867433A US357314A US35731473A US3867433A US 3867433 A US3867433 A US 3867433A US 357314 A US357314 A US 357314A US 35731473 A US35731473 A US 35731473A US 3867433 A US3867433 A US 3867433A
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methyl
fluoro
acid
phenanthrene
cyclopenta
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Tshung-Ying Shen
Howard Jones
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Merck and Co Inc
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Merck and Co Inc
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Priority to CH576874A priority patent/CH592597A5/xx
Priority to GB1857874A priority patent/GB1453885A/en
Priority to FR7415225A priority patent/FR2236488B1/fr
Priority to JP49048871A priority patent/JPS5013371A/ja
Priority to DE2421541A priority patent/DE2421541A1/en
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    • 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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Abstract

Cyclised benzylidene indenyl acetic acids and pharmaceutically acceptable salts, amides and esters thereof. The cyclised benzylidene indenyl acetic acids have anti-inflammatory, antipyretic 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.

Description

United States atent Shen et al,
CYCLOPENTALLK ]-PHENANTHRENE-4- ACETIC ACIDS AND RELATED COMPOUNDS Inventors: Tshung-Ying Shen, Westfield;
Howard Jones, Holmdel, both of Assignee: Merck & Co., Rahway; NJ.
Filed: May 4, 1973 Appl. No.: 357,314
US. Cl 260/515 A, 260/210.5, 260/247.1, 260/247.2 A, 260/247.5 B, 260/2477 C, 260/268 PC, 260/293.62, 260/326.5 E, 260/465 G, 260/469, 260/470, 260/471 R, 260/473 F, 260/479 R, 260/516, 260/518 A, 260/518 R, 260/519 Int. Cl C07c 63/44, C07c 69/76 Field of Search 260/515 R, 515 A, 515 M, 260/470, 516, 473 F, 520, 471 R, 518 A, 518 R, 519, 479 R, 546
[56] References Cited UNITED STATES PATENTS 1,951,686 3/1934 Wolfram et al 260/515 3,654,349 4/1972 Shen et al. 3,766,259 10/1973 Sletzinger et a1. 260/515 Primary Examiner-James A. Patten Att0rney,Agent, or Firm-Mario A. Monaco; Harry E. Westlake, Jr.
[57] 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.
5 Claims, No Drawings 1 Q LQP N'E IL I- ::ASETIQ ACIDS AND RELATED COMPOUNDS SUMMARY OF THE INVENTION BACKGROUND OF THE INVENTION There has been much research carried on in the past two decades for development of anti-inflammatory drugs. As a result, a great many new drugs have been synthesized. Most of these have been steroids of the l loxygenated pregnane series. These, while highly effective, have the drawback of causing many side effects. There has also been a concentrated effort in antiinflammatory research in the indole and indene series with the result of many useful drugs. One particularly useful group of indene compounds are those disclosed in US. Pat. No. 3,654,349 issued Apr. 4, 1972.
l have found that certain cyclised, benzylidene indenyl acetic acids are valuable anti-inflammatory agents. These cyclised benzylidene acetic acids are substantially different from prior art compounds in that they are cyclised benzylidene compounds containing four fused rings.
DESCRIPTION AND PREFERRED EMBODIMENTS 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-
kanoylamino or alkanoyl; and
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.
In the still more preferred aspect of this invention:
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. benzylthio, C dialkylamino, halobenzyloxy, C alkoxy, C alkyl, C alkylsulfamyl, C alkanoyloxy, phenoxy, C alkenyl, C alkenyloxy or benzyl;
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;
and 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 halo (chloro, bromo, fluoro), C .alkylthio or C alkylsulfmyl;
R is hydrogen; and
M is hydroxy.
Representative compounds of the invention are:
2-fIuoro-5-methyl-9-( p-methylthiobenzylidene)- cyclopenta [j,k]-phenanthrene-4-acetic acid,
2-fluoro-5-methyl-9-( p-methylsulfinylbenzylidene)- cyclopenta [j,k]-phenanthrene-4-acetic acid, 2-fluoro-5-methyl-9-(p-chlorobenzylidene)- cyclopenta [j,k]-phenanthrene-4-acetic acid, 2-fluoro-5-methyl-9-( p-fluorobenzylidene cyclopenta [j,k]-phenanthrene-4-acetic acid, 2-fluoro-5-methyl-9-(m-hydroxybenzylidene)- cyclopenta [j,k]-phenanthrene-4-acetic acid, 2-fluoro-5-methyl-9-( m-methoxybenzylidene cyclopenta [j,k]-phenanthrene -4-acetic acid, 2-fluoro-5-methyl-9-( m-methylsulfinylbenzylidene cyclopenta [j,k]-phenanthrene-4-acetic acid, 2-fluoro-5-methyl-9-(m-phenylbenzylidene)- cyclopenta [j,k]-phenanthrene-4-acetic acid, 2-fluoro-5-methyl-9-(o-acetamidebenzylidene)- cyclopenta [j,k]-phenanthrene-4 acetic acid, 2-fluoro-5-methyl-9-( o-acetylbenzylidene)- cyclopenta [j,k]-phenanthrene-4-acetic acid,
3 2-methyl-5-methyl-9-(p-methylsulfinylbenzylidene)- cyclopenta [j,k]-phenanthrene-4-acetic acid, 2-hydroxy-5-methyl-9-(p-methylsulfinylbenzylidene)-cyclopenta [j,k]-phenanthrene-4-acetic acid, Z-methylthio-5-methyl-9-(p-methylsulfinylbenzylidene)-cyclopenta [j,kl-phenanthrene-4-acetic acid, 2-benzyloxy-5-methyl-9-(p-methylsulfinylbenzylidene)-cyclopenta [j,k]-phenanthrene-4-acetic acid, Z-diethylamino-S-methyl-9-(p-methylsulfinylbenzylidene)-cyclopenta [j,k]-phenanthrene-4-acetic acid, l,2-difluoro-5-methyl-9-( p-methylsulfinylbem zylidene)-cyclopenta [j,k]-phenanthrene-4-acetic acid, 2-methoxy-5-methyl-9-(p methylsulfinylbenzylidene)-cyclopenta [j,k]-phenanthrene-4-acetic acid, 2-methyl-5-methyl-9-(p-methylsulfinylbenzylidene)- cyclopenta [j,k]-phenanthrene-4-acetic acid, 2-vinyl-5-methyl-9-(p-methylsulfinylbenzylidene)- cyclopenta [j,k]-phenanthrene-4-acetic acid, l-methyl-S -methyl-9-(p-methylsulfinylbenzylidene cyclopenta [j,k]-phenanthrene-4-acetic acid, 2-vinyloxy-5-methyl-9-(p-methylsulfinylbenzylidene)-cyclopenta [j,k]-phenanthrene-4-acetic acid, 2-acetyloxy-5-methyl-9-(p-methylsulfinylbenzylideneycyclopenta [j,kl-phenanthrene-4-acetic acid, 2-fluoro-5-methyl-9-(p-methylthiobenzylidene)- cyclopenta [j,kl-phenanthrene-4-a-propionic acid, 2-fluoro-5-methyl-9-( p-methylsulfinylbenzylidene cyclopenta [j,k]-phenanthrene-4-a-propionic acid, 2-fluoro-5-methyl-9-(p-chlorobenzylidene)- cyclopenta [j,k]-phenanthrene-4-a-propionic acid, 2-fluoro-5-methyl-9-(p-fluorobenzylidene)- cyclopenta [j,k]-phenanthrene-4-0z-propionic acid, 2-fluoro-5-methyl-9-(m-hydroxybenzylidene)- cyclopenta [j,k]-phenanthrene-4-a-propionic acid, 2-fluoro-5-methyl-9-(m-methoxybenzylidene)- cyclopenta [j,k]-phenanthrene-4-a-propionic acid, 2-fluoro-5-methyl-9-(m-methylsulfinylbenzylidene)- cyclopenta [j,k]-phenanthrene-4-a-propionic acid, 2-fluoro-5-methyl-9-(m-phenylbenzylidene)- cyclopenta [j,k]-phenanthrene-4-a-propionic acid, 2-fluoro-5 -methyl-9-(o-acetamidebenzylidene)- cyclopenta [j,k]-phenanthrene-4-a-propionic acid, 2-fluoro-5-methyl-9-(o-acetylbenzylidene)- cyclopenta [j,k]-phenanthrene-4-a-propionic acid, 2-methyl-5-methyl-9-(p-methylsulfinylbenzylidene)- cyclopenta [j,k]-phenanthrene-4-a-propionic acid, 2-hydroxy-5-methyl-9-(p-methylsulfinylbenzylidene )-cyclopenta [j,kl-phenanthrene-4-apropionic acid, Z-methylthio-S-methyl-9-(p-methylsulfinylbenzylidene)-cyclopenta [j,kI-phenanthrene-4-apropionic acid, 2-benzyloxy-5-methyl-9- (p-methylsulfinylbenzylidene )-cyclopenta [j,k]-phenanthrene-4-apropionic acid, Z-diethylamino-S-methyl-9-(p-methylsulfinylbenzylidene )-cyclopenta [j,k -phen anthrene-4-apropionic acid,
4 l,2-difluoro-5-methyl-9-(p-methylsulfinylbenzylidene)-cyclopenta [j,k]-phenanthrene-4-apropionic acid, 2-methoxy-5-methyl-9-(p-methylsulfinylbenzylidene)-cyclopenta [j,k]-phenanthrene-4-apropionic acid, 2-methyl-5-methyl-9-(p-methylsulfinylbenzylidene)- cyclopenta [j,k]-phenanthrene-4-a-propionic acid, 2-vinyl-5-methyl-9-(p-methylsulfinylbenzylidene)- cyclopenta [j,k]-phenanthrene-4-a-propionic acid. l-methyl-5-methyl-9-(p-methylsulfinylbenzylidene)- cyclopenta [j,k]-phenanthrene-4-a-propionic acid. 2-vinyloxy-5-methyl-9-(p-methylsulfinylbenzylidenekcyclopenta [j,k1-phenanthrene-4-apropionic acid, 2-acetyloxy-5-methyl-9-(p-methylsulfinylbenzylidene)-cyclopenta [j,k]-phenanthrene-4-a propionic acid.
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,
7 in a non-toxic pharmaceutically acceptable carrier.
The non-toxic pharmaceutical carrier may be, for example, either a solid or a liquid. Exemplary of solid carriers are lactose, corn starch, gelatin, talc, sterotix, stearic acid, magnesium stearate, terra alba, sucrose, agar, pectin, cab-o-sil and acacia. Exemplary of liquid carriers are peanut oil, olive oil, seasame oil and water. Similarly, the carrier or diluent may include a time delay material such as glyceryl monostearate'or glyceryl distearate alone or with a wax.
Several pharmaceutical forms of the therapeutically useful compositions can be used. For example, if a solid carrier is used, the compositions may take the form of tablets, capsules, powders, troches or lozenges, prepared by standard pharmaceutical techniqueslf a liquid carrier is used, the preparation may be in the form of a soft gelatin capsule, a syrup, an aqueous solution or a liquid suspension. Suppositories may be prepared in a conventional manner by mixing the compounds of this invention with a suitable non-irritating excipient which is solid at room temperature, but liquid at the rectal temperature. Such materials are cocoa butter and polyethylene glycol. Gels and lotions for topical application may be prepared in conventional manners.
The compounds of this invention are to be administered in an amount sufficient to treat inflammation, that is, to reduce inflammation. Advantageously, the 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. Also, many other factors that modify the actions of drugs will be taken into account by those skilled in the art in the therapeutic use of medicinal agents, for example, age, body weight, sex, diet, time of administration, route of administration, rake of excretion, drug combination, reaction sensitivities and severity of the particular disease.
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. Preferably, 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. For example, 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. 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.
The following examples are given by way of illustration:
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. The solid is filtered and used as is. B. 4-Methylthioanthranilic acid The above nitro compound (0.2 mole) is catalytically reduced with 10% Pd/C in ethyl acetate (1 1.) at 40 p.s.i. and room temperature until the theoretical amount of hydrogen was taken up. The catalyst was filtered off and the solution evaporated to dryness to give the 4-methylthioanthranilic acid. C. 4-Methylthio-2-iodobenzoic acid The above anthranilic acid (0.5 mole) is refluxed in 4N hydrochloric acid (2 l.) for 1 hour and is then filtered and cooled to 0. 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 reaction is slowly brought to reflux and kept there for 1 hour. The reaction is cooled and made acid. 4-methylthio-2-iodobenzoic acid is extracted into ether (4 X 200 ml.) and the ether layer washed with water (2 X 100 ml.) and dried (MgSO The ether solution is filtered and evaporated to dryness to give solid 4-methylthio-2-iodobenzoic acid which can be recrystallized from benzene.
D. 4-Methylthio-2-iodobenzoyl chloride The above benzoic acid (0.2 mole) is refluxed in thionyl chloride (200 ml.) with three drops of dimethylformamide for 1 hour and then evaporated to dryness and pumped out under very high vacuum. The crude product is used as is.
E. 4-Methylthio-Z-iodobenzonitrile The above acid chloride (0.3 mole) in water (200 ml.) at is added over minutes to a stirred solution of concentrated ammonium hydroxide (200 ml.). After 2 hours the solution is evaporated to dryness.
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.
F. 4-Methylthio-2-iodobenzaldehyde The above nitrile (0.3 mole) is stirred and refluxed in 80% formic acid (200 ml.) while nickel-aluminum amalgam (l:l Maleinckdrot 2 mole) is added over 2 hours. The solution is then filtered, the filtrate evaporated to dryness, taken up in benzene (200 ml.) and washed with water (2 X 50 ml.). The organic layer is dried (MgSO and filtered. The filtrate is evaporated to dryness and carefully distilled under 0.001 mn. of H pressure to give a pure fraction of 4-methylthio-2- iodobenzaldehyde.
Similarly, when 4-methylanthranilic acid,
4-bromoanthranilic acid,
4-chloroanthranilic acid,
4-fluoroanthranilic acid,
4-hydroxyanthranilic acid,
4-methylsulfinylanthranilic acid,
S-bromoanthranilic acid,
S-chloroanthranilic acid,
S-fluoroanthranilic acid,
S-hydroxyanthranilic acid,
S-methoxyanthranilic acid,
5-methylsulfinylanthranilic acid,
S-methylanthranilic acid,
S-phenylanthranilic acid,
3-hydroxyanthranilic acid,
3-methylanthranilic acid,
6-methylanthranilic acid,
6-acetamidoanthranilic acid,
6-acetylanthranilic acid, or
anthranilic acid is used in place of 4-methylthioanthranilic acid in Example l C above and the corresponding substituted 2- iodobenzoic acid compound carried'through Steps 1 a-f, there is obtained the correspondingly substituted 2-iodobenzaldehyde EXAMPLE 2 Methyl-5-fluoro-7-iodo-2-methylindenyl-3-acetate A. 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. Hg pressure and the final pure factor of 6- fluoro-4-nitro-2-methylindanone isolated and characterized by analysis and nuclear magnetic resonance spectrocopy. B. 4-Amino-6-fluoro-2-methylindanone The above nitro compound (0.15 mole) is catalytically hydrogenated over Raney nickel (0.5 teaspoonful) in ethyl acetate (200 ml.) and glacial acetic acid (20 ml.) at 40 psi. and room temperature until the theoretical amount of hydrogen (0.45 mole) had been taken up. 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
0 is added slowly with stirring so that the temperature does not rise above 0-l0. To this solution is added a solution of potassium iodide (0.9 mole) in water (200 ml.) at 0l0. The reaction mixture is then stirred well for 2 hours and gradually brought up to 60 and kept there until the nitrogen emmision ceases.
The organics are then extracted with ethyl acetate (2 X 400 ml.), the organic layer washed with water (2 X l00'ml.), separated and dried (MgSOQ. The solution is filtered and evaporated to dryness. The oil is fractionally distilled at 0.001 mm. pressure to get pure 6- fluoro-4-iodo-2-methylindanone.
Similarly when the following indanones are used in place of 6-fluoro-2-methylindanone in Example 2 A above and the product therefrom carried through Example 2 B-C',-there is obtained the corresponding substituted 4-iodoindanones:
2-methylindanone, 6-fluoroindanone, 2,6-dimethylindanone, I 2-methyL6-hydroxyindanone, 2-methyl-6-methylthioindanone, Z-methyl 6-benzyloxyindanone, 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 -m ethyl-6-(p-chlorobenzyloxy)indanone, 2-methyl-5,6-methylenedioxyindanone, 2-methyl-5,6-difluoroindanone, 2-methyl-5-fluoro-6-methoxyindanone, 2-isopropyl-6-methoxyindanone, 2-phenyl-6-methylindanone, 2-methylthio--methylindanone,
Z-phenylthioindanone,
2-allyl-6-methoxyindanone,
Z-fluoroindanone,
Z-chloromethyl-6-dimethylsulfamylindanone,
2-(p-methoxyphenyl)-6-t-butylindanone,
2-trifluoromethyl--ethoxyindanone, 2-(t-butyl)-6-methoxy-7-trifluoromethylindanone, 2-(p-methoxphenyl)-5-chloro-6-methoxyindanone, 6-vinylindanone,
S-methoxyindanone,
6-methoxyindanone,
6-methyl-2-benzylindanone,
S-methylindanone,
-methyl-6-methoxyindanone,
2-methyl-6-vinyloxyindanone, 2-methylb-acetyloxyindanone, 5-methyl-7-chloroindanone,
7-phenylindanone,
2-phenylindanone,
6,7-benzoindanone,
5,6,7-trichloroindanone,
S-benzyloxyindanone,
Z-n-butylindanone, and
S-methylthioindanone D. Methyl 5-fluoro-7-iodo-2-methylindenyl-3-acetate A solution of 0.075 mole of 6-fluoro-4-iodo2- methylindanone and 0.075 mole of methyl bromoacelate in 45 ml. benzene is added over a period of 5 minutes to 21 g. of zinc amalgam (prepared according to Org. Syn. Coll., vol. 3) in 110 ml. benzene and 40 ml. dry ether. A few crystals of iodine are added to start the reaction, and the reaction mixture is maintained at reflux temperature (ca. 65) with external heating. At 3 hour intervals two batches of g. zinc amalgam and 10 g. bromoester are added and the mixture is then refluxed for 8 hours. After addition of 30 ml. of ethanol and 150 ml. of acetic acid, 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.
A mixture of the above crude hydroxyester, g. of p-toluenesulfonic acid monohydrate and 20 g. of anhydrous calcium chloride in 250 ml. toluene is refluxed overnight. The solution is filtered and the solid residue is washed with benzene. The combined benzene solution is washed with water, sodium bicarbonate, water and then dried over sodium sulfate. After evaporation the crude methyl 5-fluoro-4-iodo-2-methyl-3- indenylacetate is chromatographed on acid-washed alumina, and the product is eluted with petroleum ether-ether (v.v. 50l00%).
Similarly when the substituted 4-iodoindanones obtained from Example 2 C above are used in place of 6- fluoro-4-iodo-Z-methylindanone in the above example, there is obtained the corresponding substituted 7- iodoindenyl-B-acetate compounds.
Similarly when 2-methylindanone,
o-fluoroindanone,
2,6-dimethylindanone,
2-methyl-6-hydroxyindanone,
2-methyl-6-methylthioindanone, 2-methyl-6-benzyloxyindanone,
. 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--dimethylsulfamylindanone, Z-(p-methoxyphenyl)-6-t-butylindanone, 2-trifluoromethyl-6-ethoxyindanone, Z-(t-butyl)-6-methoxy-7-trifluoromethylindanone, Z-(p-methoxyphenyl)-5-chloro-6-methoxyindanone, o-vinylindanone, S-methoxyindanone, 6-methoxyindanone, 6-methyl-2-benzylindanone, 5-methylindanone, 5-methyl-o methoxyindanone, S-methyl-7-chloroindanone, 7-phenylindanone, Z-phenylindanone, 6,7-benzoindanone, 5,6,7-trichloroindanone, S-benzyloxyindanone, 2-n-butylindanone, and S-methylthioindanone are used in place of 6,-fluoro-Z-methylindanone in Example 2 A and the product carried out through Steps B-D, there is obtained the corresponding substituted 7-iodo-indenyl 3-acetate compounds.
EXAMPLE 3 5-Fluoro-7-iodo-2-methylindenyl-Iv-oz-propionate A solution of 0.075 mole of 6-fluoro-4-iodo-2- and 0.075 mole of methyl-abromopropionate in 45 ml. benzene is added over a period of 5 minutes, to 21 g. of zinc amalgam (prepared according to Org. Syn. Coll., vol. 3) in ml. benzene" and 40 ml. dry ether. A few crystals of iodine are added to start the reaction, and the reaction mixture is maintained at reflux temperature (ca. 65) with external heating. At 3 hour intervals two batches of 10 g. zinc amalgam and 10 g. bromoester are added and the mixture is then refluxed for 8 hours. After addition of 30 ml. of ethanol and ml. of acetic acid, 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.
A mixture of the above crude hydroxyester, 20 g. of p-toluenesulfonic acid monohydrate and 20 g. of anhydrous calcium chloride in 250 ml. toluene is refluxed overnight. The solution is filtered and the solid residue is washed with benzene. The combined benzene solution is washed with water, sodium biicarbonate, water and then dried over sodium sulfate. After evaporation the crude methyl -fluoro-4 iodo-2-methyl-3-indenyla-propionate is chromatographed on acid-washed alumina, and the product is eluted with petroleum etherether (v.v. 50-10070).
Similarly when the substituted 4-iodoindanones obtained from Example 2 C above are used in place of 6- fluoro-4-iodo-2-methylindanone in Example 2 C above, there is obtained the corresponding substituted 7-iodoindenyl-3-acetate compounds.
Similarly when 2-methylindanone,
6-fluoroindanone,
2,6-dimethylindanone,
2-methyl-6-hydroxyindanone,
2-methyl-6-methylthioindanone, 2-methyl-o-benzyloxyindanone, 2-methyl-6-methylsulfonylindanone, 2-methyl-6-dimethylsulfonylindanone, 2-methyl-6-dimethylaminoethylindanone, 2-methyl-6-(p-ethylbenzyloxy)indanone, 2-methyl-6-fiuoroindanone, 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-S-fluoro-6-methoxyindanone,
2-isopropyl'6methoxyindanone,
2-phenyl-6-methylindanone, 2-methylthio-6-methylindanone,
Z-phenylthioindanone,
2-allyl-6-methoxyindanone,
2-fluoroindanone,
2-chloromethyl-6-dimethylsulfamylindanone,
2-(p-methoxyphenyl)-6-t-butylindanone, 2-trifluoromethyl-o-ethoxyindanone,
Z-(t-butyl)-6-methoxy-7-trifluoromethylindanone,
2-(p-methoxyphenyl)-5-chloro-6-methoxyindanone,
o-vinylindanone,
S-methoxyindanone,
unethoxyindanone,
6-methyl-2-benzylindanone,
S-methylindanone,
5 methyl-6-methoxyindanone,
5-methyl-7-chloroindanone,
7-phenylindanone,
Z-phenylindanone,
6,7-benzoindanone,
5,6,7,-trichloroindanone,
S-benzyloxyindanone,
2-n-butylindanone, and
5-methylthioindanone are used in place of 6-fluoro-2-methylindanone in Example 2 A and the product carried out through Steps B-D, there is obtained the corresponding substituted 7-iodo-indenyl-3-acetate compounds.
EXAMPLE 4 5-Fluoro-7-iodo-2-methyll-(2 '-iodo-4 methylthiobenzylidene)-indenyl-3-acetic acid To a solution of (0.00192 mole) of methyl-S-fluoro- 7-iodo-2-methylindenyl-3-acetate and (0.0039 mole) of 2-iodo-4- methylthiobenzaldehyde in 3 ml. of anhydrous pyridine is added 1.63 gm. of a 40% solution of benzyltrimethylammonium hydroxide in methanol. The
resultant 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.
Similarly when the substituted 7-iodoindenyl- 3-acetate compounds obtained from Example 3 are used in place of methyl-5-fluoro-7-iodo-2- methylindenyl-3-acetate in the above example, there is obtained the corresponding substituted 7-iodo-l-(2'- iodo-4'-methylthiobenzylidene)-indenyl-3-acetic acid.
Similarly when the substituted 2-iodobenzaldehyde compounds obtained from Example 1 are used in place of 2-iodo-4-methylthiobenzaldehyde in the above example, there are obtained the corresponding S-fluoro- 7-iodo-2-methyl-1-(substituted 2'- iodobenzylidene)indenyl-3-acetic acid compounds.
EXAMPLE 5 2-Fluoro-5-methyl- 9-(p-methylthiobenzylidene)- cyclopenta[j,k]-phenanthrene-4-acetic acid The above compound (0.1 mole) in ethyl acetatealcohol (1:1 200 ml.) is esterified with excess diazomethane at 10 and the excess diazomethane and solvent evaporated off at room temperature. The crude ester (0.09 mole) is then mixed with tetraglyme (50 ml.), bright copper powder (50 gm.) and heated and stirred at 200 under nitrogen for 72 hours while more copper powder is added during the reaction (5 gm.). After this time the tetraglyme solution is filtered and warmed with aqueous sodium hydroxide (2.5N. 200 ml.) and 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. dissolved in saturated sodium bicarbonate (100 ml) and extracted with ether (3 X 50 ml.). The ether layers are separated, combined and dried (MgSO The filtrate is evaporated to dryness and chromatographed on a column of silica-gel (3 ft. X 2 in.) using proportions of ether-n-hexane as eluants over ether-alcohol.
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.
Similarly when the substituted 7-iodo-(2'-iodo-4- methylthiobenzylidene)-indenyl-3-acetic acid compounds, 5-fluoro-7-iodo-2-methyl-l-(substituted 2- iodo-benzylidene)-indenyl-3-acetic' acid compounds and the substituted 7-iodo-l-(substituted 2'- iodobenzylidene)indenyl-3-acetic acid compounds obtained from Example 4 are used in place of 5-fluoro-7- iodo-2-methyl-l-(2'-iodo-4'-methylthiobenzylidene)- indenyl-3-acetic acid in the above example, there is obtained the corresponding substituted 9-(p-methylthiobenzylidene)-cyclopenta [j,k]-phenanthrene-4-acetic acid compounds, 2-fluoro-5-methyl-9 -(substituted benzylidene)-cyclopenta [j,kl-phenanthrene-4-acetic acid compounds and substituted Q-(substituted benzylidene)-cyclopenta [j,kl-phenanthrene-4-acetic acid compounds, respectively.
Similarly when 5-fluoro-7-iodo-2-methyl-l-(2-iodophenanthrene-methylthiobenzylidene)-indenyl-3-apropionic acid obtained from Example 4 above is used in place of 5-fluoro-7-iodo- 2-methyl-l-(2 iodo-4- methylthiobenzylidene)-indenyl-3-acetate, there is obtained 2-flu0ro-5-methyl-9-(p-methylthiobenzylidene cyclopenta[j,k]-phenanthrene-4-a-propionic acid.
2-Fluoro-5-methyl-9-( prene-4-acetic acid M 2-Fluoro-5-methyl-9-(pin. X2 in. 250p. silica-gel chromotoplates and observing the elution with ethyl acetate. The sulfinyl compound runs with a lower R When the reaction is observed to be complete (can be anytime from 2 hours to 3 days) the reaction mixture is evaporated to 300 ml. under high vacuum at 10. The organics are extracted into ethyl acetate (3 X 300 ml.), dried (MgSO filtered and evaporated to dryness. The residue solidifies and has the 9.8p. peak in its inframed spectrum indicating the sulfinyl residue. I
Similarly when 2-fluoro-5-methyl-9-(p-methylthiobenzylidene)-cyclopenta [j,k]-phenanthrene-4-apropionic acid obtained from Example 3 is used in place of 2-fluoro-5-methyl-9-(p-methylthiobenezylidene)-cyclopenta [j,k]-phenanthrene-4- acetic acid in the above example, there is obtained the corresponding methylsulfinyl compound.
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. 4-Fluoro-2-nitro- 4-Fluoro-2- 5-Fluoro-2methyl Methyl 6- l-Fluoro-5-methyl-9- benzoic acid iodobenzindanone fluoro-7- (p-fluorobenzylidene)- aldehyde iodo-Z-methylcyclopenta[j,k ]-phenanindenyl-3- threne-4-acetic acid acetate 2. 4-Chloro-2-nitro- 4-Methylthio- 6-Cyano-2-methyl Methyl 5- 2-Cyano-5-methyl-9- benzoic acid 2-iodobenzindanone 1 cyano-7-iodo- (p-methylthiobenzylidene)- aldehyde 2-methylcyclopenta[j,k]-phenanindenyl-3- threne-4-acetic acid acetate p 3. 4-Chloro-2-nitro' 4-Methylthio- 6-Dimethylamino- Methyl 5- Z-Dimethylamino-S-methylbenzoic acid 2-iodobenz- Z-methyl indanone dimethylamino- 9-(p-methylthiobenzylidene)- aldehyde 7-iodo-2- cyc1openta[j,k ]-phenanmethyl-indenylthrene-4-acetic acid 3-acetate 4. 4-Chlol'o-2 -nitro- 4-Methylthio- 6-Allyloxy-2- Methyl 5- 2-Allyloxy-5-methyl-9- benzoic acid 2-iodobenzmethyl indanone all loxy-7- (p-methylthiobenzylidene)- aldehyde io o-2-methylcyclopenta[j,k]-phenanv indenyl-3- threne-4-acetic acid acetate 5. 4-Chloro-2-nitro- 4-Methylthio- 6-Chloro-2-methyl Methyl 5- 2-Chloro-5-methyl-9- benzoic acid Z-iodobenzindanone chloro-7-iodo- (p-methylthiobenzylidene)- aldehyde Z-methylcyclopenta{j,k ]-phenanindenyl-3- threne-4-acetic acid acetate 6. 4 Chloro-2-nitro- 4-Methylthio- 6-Acetyl-2-methyl Meth 15- 2-Acet l-5-methyl-9- benzoic acid 2-iodobenzindanone acety -7- (p-metliylthiobenzylidenc)- aldehyde iodo-Z-methylcyclopentaIj.k]-phcnanindenyl-3- threnc-4-acctic acid acetate 7. 4-Chloro-2-nitro- 4-Methylthio- 6-Vinyl-2-methyl Methyl 5- 2-Vinyl-5-mcthyl-9- benzoic acid 2-iodobenzindanone vinyl-7- (p-mcthylthiobcnzylidenc)- aldehyde iodo-2-methylcyclopenta[h.kl-phcnnnindenyl-3- threnc-A-acetic acid acetate EXAMPLE 8 2-Fluoro-5-methyl-9-(p-methylsulfinylbenzylidene)- cyclopentafi,k]-phenanthrene-4-acetoxy-B-D- glycopyranosiduronic acid Sodium methoxide (25% solution 30 ml.) is added to a stirred solution of 2-fluoro-9-(pmethylsulfinylbenzylidene)-cyclopenta[j,k]-phenanthrene-4-acetic acid (0.13 M) in tetrahydrofuran (800 ml.). The precipitate is filtered off and dried at 60 under vacuum.
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 dry sodium salt (0.1 M) and the bromopyranoside (0.12 M) are heated in dry dimethyl sulfoxide with stirring at 60for 2 hours. The product is used as is, the free acid, is a biproduct of the next reaction. 7
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.
Similarly when an equivalent amount of 2-fluoro-5- methyl-9-(p-methylsulfinylbenzylidenyl)- -cyclopenta[j,k]-phenanthrene-4-a-propionic acid or EXAMPLE 9 2-Fluoro-5-methyl-9-(p-methylsulfinylbenzylidene)- cy'clopenta[j,k]-phenanthrene-4-acetic acid anhydride A solution of 0.05 mole of N,N-dicyclohexyl carbodimide in 60 ml. of tetrahydrofuran is added to 0.05 mole of 2-fluoro-5-methyl-9-(pmethylsulfinylbenzylidene)-cyclopenta[j,k]-phenanthrene-4acetic acid in ml. of tetrahydrofuran. The reaction mixture is shaken vigorously at about 25 for 16 hours. The dicyclohexylurea is filtered off and 2 ml. of glacial acetic acid is added to the filtrate. The solution is allowed to stand for 1 hour, filtered and 200 ml. of ether added to the filtrate. The filtrate is then extracted well with water, dried and concentrated. The desired product is purified by column chromatography on silica gel using ether-petroleum ether as an eluent.
Similarly when an equivalent amount of 2-fluoro-5- methyl-9-(p-methylsulfinylbenzylidene)- cyclopenta[j,k]-phenanthrene-4-a-propionic acid or the other substituted phenanthrene-4-acetic acids obtained from Examples 5 to 7 are used in place of 2- fluoro-S-methyl-9-(p-methylsulfinylbenzylidene)- cyclopenta[j,k]-phenanthrene-4-acetic acid, there are obtained the corresponding anhydrides.
EXAMPLE l0 Esters of 2-fluoro-5-methyl-9-(pmethylsulfinylbenzylidene)-cyclopenta[j,kl-phenanthrene-4-acetic acids (A) Simple Esters A mixture of .1 mole of 2- fluoro-5-methyl-9-(p-methylsulfinylbenzylidene)- cyc|openta[j,k]-phenanthrene-4-acetic acid, .2 g, of p-toluene sulfonic acid, 100 ml. of absolute ethanol and ml. of dry benzene is refluxed on a steam bath while slowly distilling the solvent. After 17 hours, the residual solvent is removed under reduced pressure. 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.
When methanol, propanol, t-butanol and benzyl alcohol are used instead of the ethanol in the above procedure, there is obtained the corresponding methyl, propyl, t-butyl and benzyl esters.
(B) Alkoxyalkyl Esters Chloromethyl methyl ether (0.055 mole) is added to a suspension of 2- fluoro-5-methyl-9-(p-methylsulfinylbenzylidene)- cyclopenta[j,k] phenanthrene-4-acetic acid (0.05 mole) and anhydrous potassium carbonate (0.15 mole) in 250 ml. of anhydrous acetone. The mixture is allowed to stir overnight at room temperature. Diethyl ether is added (about 200 ml.) and the mixture is filtered. The filtrate is washed once with ml. of water .and dried over anhydrous sodium sulfate. It is then filtered and the solvent is removed in vacuo. The residue is chromatographed on 200 g. of acid-washed alumina. using ether-petroleum ether (varying from 10 to 60% ether by volume) as the elu ent,-to give methoxymethyl 2-fluoro-5-methyl-9-(p-methylsulfinylbenzylidene)- cyclopenta[j,k]-phenanthrene-4-acetate.
(C) Phenyl A solution of 0.0054 mole of N,N -dicyclohexylcarbodiimide in 6 ml. ofanhydro'us tetrahydrofuran is added to a solution of 2-fluoro-5-methyl-9-(pmethylsulfinylbenzylidenyl)-cyclopenta[j,k]-phenanthrene-4-acetic acid (0.005 mole) and phenol (0.0054 mole) in 17 m1. of anhydrous tetrahydrofuran. The mixture is shaken vigorously and allowed to sit, stoppered, at room temperature overnight.
After filtering off the N.N-dicyclohexylurea, 2ml. of glacial acetic acid is added to the filtrate and the mixture allowed to stand one hour. After filtering, 200 ml; ether is added to the filtrate and the ether solution and 3 X 100 ml. water and then dried over anhydrous sodium sulfate. The mixture is filtered, concentrated in vacuo to 25 ml. and chromatographed on a g. acid washed alumina column using ether-petroleum ether (v./v. l0-60) as eluent to give phenyl 2-fluoro-5- methyl-9-(p-methylsulfinylbenzylidenyl)- cyclopenta[j,k]-phenanthrene-4-acetate.
Similarly using 2-(2-methoxyethoxy)-ethanol, glycol or N-acetyl-ethanolamine in place of phenol in the above procedure gives (2-(2"-methoxyethoxy)- ethyl)-2-fluoro-5-methyl-9-(pmethylsulfinylbenzylidenyl )-cyclopenta[j,k]-
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|-9-(pmethylsulfinylbenzylidenyl )-cyclopenta[j,k phenanthrene-4-acetate, respectively.
Similarly when 2-fluoro-5-methyl-9-( pmethylsulfinylbenzylidene)-cyclopenta[j,k]- phenanthrene-4-a-propionic acid or the other substi- 2-fluoro-5-methyl-9-(pmethylsulfinylbenzylidenyl)-cyclopenta[j,k]-4-acetate 17 tuted phenan threne acetic acids obtained from Exampics to 7 are used in place of the above-described acid in any of the above preparations, the corresponding esters are obtained.
EXAMPLE ll PivailoyloxymethyI-2-fluoro-5-methyl-9-(pmethylsulfinylbenzylidene)-cyclopenta[j,k]- phenanthrenei-acetate Trimethylamine (l.2 gm.) in dimethylformamide 10 ml.) is added over 5 minutes to a stirred solution of the 2-fluoro-5-methyl-9-(p-methylsulfinylbenzylidene)- cyclopenta[j,k]-phenanthrene-4-acetic acid (0.01 mole) in dimethylformamide (100 ml.) at room temperature. After 10 minutes 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.
Similarly when an equivalent amount of 2-fluoro-5- methyl-9-(p-methylsulfinylbenzylidene)- cyclopenta[j,k]-phenanthrene-4-a-propionic acid or the substituted phenanthrene-4-acetic acids obtained from Examples 5 to 7 is used in place of Z-fluoro-S- methyl-9-(p-methylsulfinylbenzylidene)- cyclopenta[j,k]-phenanthrene-4-acetic acid above, there is obtained'the corresponding pivalloyloxymethyl esters.
EXAMPLE l2 2-Fluoro-5-m ethyl-9-( p-m ethylsulfinylbenzylidene cyclopenta[j,k]-phenanthrene-4-acetmorpholide A mixture of 2-fluoro-5-methyl-9-(pmethylsulfinylbenzylidene)-cyclopenta[j,k]-phenanthrene-4-acetic acid (0.01 mole) and thionyl chloride (0.03 mole) in a dried flask, condenser and drying tube set-up is heated on the steam bath until evolution of gas ceases. Excess thionyl chloride is then removed in vacuo, the residue taken up in a slight excess of anhydrous ether and added slowly to a vigorously stirred, ice-cooled solution of dry morpholine (0.035 mole) in 100 ml. of ether. The mixture is stirred overnight at room temperature, filtered, the morpholine hydrochloride washed with 2 X 100 ml. water, dried over anhydrous sodium sulfate, filtered and the ether removed in vacuo. Chromatography of the crude product on a silica-gel column, using v./v. 50-l00% ether in petroleum ether as eluent gives the desired morpholide.
Similarly when morpholine is replaced by an equivalent amount of the following amines, the corresponding amides are obtained:
Dimethylamino Ethanolamine Benzylamine N,N-diethylethylenediamine Benzylglycinate Piperidine Pyrrolidine N-methylgperazine N phenylpiperazine N-hydroxyethylpiperaz ine Piperazine Diethylamine Diethanolamine Aniline p-Ethoxyaniline p-Chloroaniline p-Fluoroaniline p-Trifiuoromethylaniline Butylamine Cyclohexylamine Methylamine D-glucosamine Tetra-o-acetyl-d-flucosamine D-galactosylamine D-mannosylamine N,N-dimethyl-glycine amide N,N-dibutylglycine amide ,B-ethoxyethylamine Di(B-ethoxyethyl)amine B-Phenethylamine Dibenzylidene D-mannosamine Similarly when an equivalent amount of 2-fluoro-5- methyl-9-(p-methylsulfinylbenzylidene),- cyclopenta[j,k1-phenanthrene-4-a-propionic acid or the substituted phenanthrene-4-acetic acids obtained from Examples 5 to 7 are used in place of the 2-fluoro- 5-methyl-9-(p-methylsulfinylbenzy-lidene)- cyclopenta[j,k]-phenanthrene-4-acetic acid in the above example, there is obtained the corresponding morpholide compounds.
EXAMPLE l3 N-[2-fluoro-5-methyl-9-(pmethylsulfinylbenzylidene)-cyclopenta[j,k]- phenanthrene-4-acetoxy]-glycine I A. Benzyl-N-[2-fluoro-5-methyl-9-(pmethylsulfinylbenzylidene)-cyclopenta[j,k]- phenanthrene-4-acetoxy]-glycinate The procedure of Example 1 2 is followed using benzylamino acetate in placeof the morpholine to produce the above-named compound.
B. Benzyl-N-[2-fluoro-5-methyl-9-(pmethylsulfinylbenzylidene)-cyclopenta[j,k]- phenanthrene-4-acetoxy]-glycinate (0.003 mole) in a mixture of 25 ml. of anhydrous ethanol and 2.5 ml. of l N sodium hydroxide is allowed to stand at room temperature for 18 hours. The solution is diluted with water and extracted with ether. The aqueous layer is acidified with dilute hydrochloric acid and the organic product is extracted with ethyl acetate, washed with water and dried over sodium sulfate. Evaporation of th e so lution gives N-[2-fluoro-5-methyl-9-(pmethylsulfinylbenzylidene)-cyclopenta[j,k]- phenanthrene-4-acetoxy]-glycine.
When an equivalent amount of 2-fluoro-5-methyl-9- (p-methylsulfinylbenzylidene)-cyclopenta[j,k]- phenanthrene-4-a-propionic acid or the substituted phenanthrene-4-acetic acids obtained from Examples 5 to 7 are used in place of the 2-fluoro-5-methyl-9-(pmethylsulfinylblenzylidene )-cyclopenta[j,k l-phenanthrene-4-acetic acid in the above example, there is obtained the corresponding glycine compound.
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.
Similarly when an equivalent amount of calcium hydride or potassium methoxide is used in place of so dium methoxide in the above example, there is ob mined the corresponding calcium or potassium salt.
Similarly when 2-fluoro-5-methyl-9-(pmethylsulfinylbenzylidene)-cyclopcnta[j,k]- phenanthrene-4-oz-propi0nic acid or the other substituted phenanthrene-4-acetic acids obtained from Examples 5 to 7 are used in place of 2-fluoro-5-methyl-9- EXAMPLE A mixture of 260 parts of 2-fluoro-5-methyl-9-(pmethylsulfinylbenzylidene)-cyclopenta[j,k]-phenanthrene-4-acetic acid and 25 parts of lactose is granulated with suitable water and to this is added 100 parts of maize starch. The mass is passed through a 16 mesh screen. 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.
What is claimed is:
1. The compound of the formula:
C-COM wherein:
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-
kyl, benzyloxy or C alkylthio; at least one of 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: and
M is hydroxy, C alkoxy or pivallyloxy.
2. The compound of claim 1 wherein:
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; and
M is hydr'oxy.
3. The compound of claim 2 wherein:
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; and
M is hydroxy.-
4. The compound of claim 2 wherein:
R and R is hydrogen;
R is methyl;
R is hydrogen;
R is hydrogen;
R is hydrogen; and
M is hydroxy.
5. The compound of claim 2 wherein:
R and R is hydrogen;
. R is methyl;
R is hydrogen;
R is hydrogen;
R is methylsulfinyl; R is hydrogen; and M is hydroxy.

Claims (5)

1. THE COMPOUND OF THE FORMULA:
2. The compound of claim 1 wherein: R1 and R2 are each hydrogen; R3 is C1-5 alkyl; R4 is hydrogen; R5 is hydrogen, C1-5 dialkylamino, halo, C1-5 alkanoyloxy, C2-5 alkenyl or C2-5 alkenyloxy; R6 is hydrogen or halo; R7 is halo, C1-5 alkylthio or C1-5 alkylsulfinyl; R8 is hydrogen; and M is hydroxy.
3. The compound of claim 2 wherein: R1 and R2 are each hydrogen; R3 is methyl; R4 is hydrogen; R5 is dimethylamino, allyloxy, chloro, acetyl, fluoro or vinyl; R6 is hydrogen; R7 is methylthio; R8 is hydrogen; and M is hydroxy.
4. The compound of claim 2 wherein: R1 and R2 is hydrogen; R3 is methyl; R4 is hydrogen; R5 is hydrogen; R6 is fluoro; R7 is fluoro; R8 is hydrogen; and M is hydroxy.
5. The compound of claim 2 wherein: R1 and R2 is hydrogen; R3 is methyl; R4 is hydrogen; R5 is fluoro; R6 is hydrogen; R7 is methylsulfinyl; R8 is hydrogen; and M is hydroxy.
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US4704467A (en) * 1986-12-12 1987-11-03 Stauffer Chemical Company Method for preparation of mercaptobenzoates
EP0272742A1 (en) * 1986-12-12 1988-06-29 Stauffer Agricultural Chemicals Company, Inc. Method for preparation of mercaptobenzoates
US6180629B1 (en) 1998-08-14 2001-01-30 Cell Pathways, Inc. [4,5]-Fused-1,3-disubstituted-1,2-diazine-6-one derivatives with nitrogen containing substitutents in position one for the treatment of neoplasia

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GB9714302D0 (en) 1997-07-07 1997-09-10 Rhone Poulenc Agrochimie Process

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US3654349A (en) * 1970-05-01 1972-04-04 Merck & Co Inc Substituted indenyl acetic acids
US3766259A (en) * 1970-05-01 1973-10-16 Merck & Co Inc Preparation of 1-aryl-3-indenyl acetic acids

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US1951686A (en) * 1929-02-01 1934-03-20 Gen Aniline Works Inc New process of preparing arylacetic acids and new product obtainable thereby
US3654349A (en) * 1970-05-01 1972-04-04 Merck & Co Inc Substituted indenyl acetic acids
US3766259A (en) * 1970-05-01 1973-10-16 Merck & Co Inc Preparation of 1-aryl-3-indenyl acetic acids

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US4692545A (en) * 1986-12-12 1987-09-08 Stauffer Chemical Company Method for preparation of mercaptobenzoates
US4704467A (en) * 1986-12-12 1987-11-03 Stauffer Chemical Company Method for preparation of mercaptobenzoates
EP0272742A1 (en) * 1986-12-12 1988-06-29 Stauffer Agricultural Chemicals Company, Inc. Method for preparation of mercaptobenzoates
AU603846B2 (en) * 1986-12-12 1990-11-29 Syngenta Crop Protection, Inc. Method for preparation of mercaptobenzoates
US6180629B1 (en) 1998-08-14 2001-01-30 Cell Pathways, Inc. [4,5]-Fused-1,3-disubstituted-1,2-diazine-6-one derivatives with nitrogen containing substitutents in position one for the treatment of neoplasia

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CH592597A5 (en) 1977-10-31
NL7405118A (en) 1974-11-06
JPS5013371A (en) 1975-02-12
FR2236488B1 (en) 1978-02-03
FR2236488A1 (en) 1975-02-07
GB1453885A (en) 1976-10-27
DE2421541A1 (en) 1974-11-21

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