US3657432A - Anti-inflammatory salicylic acid derivatives - Google Patents

Anti-inflammatory salicylic acid derivatives Download PDF

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US3657432A
US3657432A US30323A US3657432DA US3657432A US 3657432 A US3657432 A US 3657432A US 30323 A US30323 A US 30323A US 3657432D A US3657432D A US 3657432DA US 3657432 A US3657432 A US 3657432A
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mixture
methyl
salicylic acid
thienyl
added
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Tsung-Ying Shen
Gordon L Walford
Bruce E Witzel
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Merck and Co Inc
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Merck and Co Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/64—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/28—Halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/42—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms with nitro or nitroso radicals directly attached to ring carbon atoms

Definitions

  • This invention relates to novel anti-inflammatory com.- pounds. More particularly, it relates to acids of the formula:
  • A is S, So, S 0,
  • I N-acety1 NH, NR Y is CH N, 1 1 i H S or 0; wherein R is lower alkyl R is H; acyl (preferably lower acyl such as formyl, acetyl, propionyl, butyryl etc); alkyl (preferably lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, etc.); alkoxycarbonyl (for example methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, hexoxycarbonyl, etc.).
  • acyl preferably lower acyl such as formyl, acetyl, propionyl, butyryl etc
  • alkyl preferably lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, etc.
  • alkoxycarbonyl for example methoxycarbonyl, ethoxycarbonyl,
  • R may be hydrogen, halogen (such as chloro, bromo, fluoro, or iodo, preferably fluoro or chloro), haloalkyl (preferably haloloweralkyl such as trifiuoromethyl, etc.), alkyl (preferably loweralkyl, such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, etc.), cycloalkyl (for example, cyclobtuyl, cyclopentyl, cyclopropyl, cyclohexyl and cycloheptyl), or alkoxy (preferably loweralkoxy such as methoxy, ethoxy, isopropoxy or butoxy etc.);
  • halogen such as chloro, bromo, fluoro, or iodo, preferably fluoro or chloro
  • haloalkyl preferably haloloweralkyl such as trifiuoromethyl, etc.
  • X may be hydrogen, alkyl, (preferably loweralkyl, such 'as methyl, ethyl, propyl, isopropyl, butyl, pentyl, etc.), hydroxy, alkoxy (preferably loweralkoxy such as methoxy, ethoxy, isopropoxy or butoxy etc.), acyloxy (such as benzoyloxy, acetoxy or propionoxy), halogen (such as chloro, bromo, fluoro or iodo, preferably fluoro or chloro), haloalkyl (preferably haloloweralkyl such as trifluoromethyl, etc.), nitro, amino, alkylamino (preferably loweralkylamino such as methylamino, propylamino, pentylamino, etc.), diloweralkylamino (dimethylamino, dibutylamino, propylpentylamino, etc.), acylamino (preferably loweracy
  • the acid derivatives of the above description possess a high degree of anti-inflammatory activity. They are of value in the treatment of arthritic and dermatological disorders or like conditions responsive to anti-inflammatory drugs. Included within this category are diseases such as rheumatoid arthritis, osteo arthritis, gout, infectious arthritis and rheumatic fever.
  • the acid derivatives also possess a useful degree of analgesic, anti-pyretic, diuretic, anti-fibrinolytic and hypo-glycemic activity and when used for these utilities the same dosage ranges and conditions described subsequently for the treatment of inflammation will apply.
  • the compounds of the invention may be administered orally, topically, parenterally or rectally in formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • the compounds of the invention are effective in the treatment of humans.
  • the non-toxic pharmaceutical carriers indicated above include either solids or liquids.
  • 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, sesame 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 may take the form of tablets, capsules, powders, troches or lozenges, prepared by standard pharmaceutical techniques.
  • a liquid carrier is used, the preparation may be in the form of a soft gelatin capsule, a syrup or a liquid suspension. Suppositories may be prepared in a conventional manner.
  • the compounds of Formula I are present in an amount sufiicient to treat inflammation.
  • the composition will contain the active ingredient, in an amount of from about 1 mg. to 100 mg. per kg. body weight per day (50 mg. to 7 g. per patient per day), preferably from about 2 mg. to 50 mg./kg. body weight per day (100 mg. to 3 g. per patient per day).
  • the preferred method of treatment comprises internal administration to a patient (animal or human), a compound of Formula I, admixed with a non-toxic pharmaceutical carrier such as exemplified above.
  • the compounds of Formula I will be administered in an amount of from 1 mg. to 100 mg./kg. body weight per day preferably from about 2 mg. to about 50 mg. per kilogram body weight per day and especially from 4 mg. to 20 mg./kg. body weight per day.
  • the most rapid and effective anti-inflammatory effect is obtained from oral administration of a daily dosage of from about 4 to 20 mg./kg. per day. It 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 the invention may be produced utilizing the following starting materials:
  • Y and R are as defined above.
  • An oxidizing agent such as potassium permanganate is added to the sulfide; S0 added; the mixture filtered;
  • Hal chloro or fiuoro
  • COOH OOOH X is hydrogen, alkyl, halogen, haloalkyl, N acylamino,
  • Y, A, R: and R are as defined above.
  • carboxylation may be effected by the use of the Grignard reagent with carbon dioxide in dry ether, followed by hydrolysis.
  • the technique known as the Wanklyn reaction may be employed in this regard.
  • cyclopentadienyl moiety may be employed in the above reaction in place of the thiophenes and furans exemplified above.
  • Representative members of this class include:
  • dienyl dienyl; and, ethoxycyclopenta(2,4)-dienyl.
  • benzyl m-iodophenyl ether is employed in place of the p-isomer when a 4-substituted salicylic acid is ultimately desired.
  • EXAMPLE 7 Preparation of 5-(5'-fluoro-2-thienylsulfonyl) salicyclic acid An intimately ground mixture of 2- fiuoro-5(p-hydroxyphenyl)thiophene (5 g.) and anhydrous potassium carbonate g.) is heated at 100 in a 1200-1400 p.s.i. carbon dioxide atmosphere for 8 hours. The mixture is cooled, added to water (300 ml.), allowed to stir, filtered, and the filtrate acidified with dilute hydrochloric acid to yield 5-(5-fluoro-2-thienylsulfonyl)salicylic acid.
  • Purification may be effected via recrystallization or 'via chromatography of the methyl ester.
  • EXlAMPLE 14 Preparation of methyl 5-(5-carbamyl-2.'- thienylsulfonyl)-salicylate A mixture of methyl 5-(5'-cyano-2'-thienylsulfonyl)- salicylate (0.02 m.) and polyphosphoric acid (50 ml.) is heated on a steam cone for 1 hour. The mixture is cooled, added to water and the aqueous mixture extracted with chloroform.
  • EXAMPLE 16 Preparation of Z-acetoxy-S-(5'-chloro-2'-thienylsulfonyl)benzoic acid To a mixture of 5-(5'-chloro-2-thienylsulfonyl)salicylic acid (0.04 m.) in anhydrous pyridine (15 ml.) is added acetic anhydride (28 ml.) and the resultant mixture heated on the steam cone for 1.5 hrs. The mixture is kept free from moisture during this time. On cooling, the mixture is added to a stirred 500 ml. portion of water.
  • aqueous system is then extracted well with chloroform, the chloroform extracts washed with 1 N hydrochloric acid, water, and then dried over anhydrous magnesium sulfate. Concentration of the filtered solution yieIdsZ-acetOxy-S- (5'-chloro-2'-thienylsulfonyl) -benzoic acid.
  • EXAMPLE 18 Preparation of 2(3-carboxy-4'-methoxy phenoxy)-5- fluorothiophene To a mixture of 2(3'-carboxy-4'-hydroxy phenoxy)-5- fiuorothiophene (0.01 m.) in 2 N sodium hydroxide solution at 70 is added dimethyl sulfate (0.10 m.) in small portions over ten hours, the mixture being kept basic throughout the addition. Water is added, the mixture filtered, the filtrate acidified and 2(3'-carbox y-4'-methoxyphenoxy)5-fluorothiophene collected.
  • esters of the invention may be obtained by utilizing a diazomethane reagent.
  • esterification may be effected with an appropriate alcohol in an inert solvent in the presence of an acid catalyst such as an aryl sulfonic acid. Further exemplification of esterification procedures is indicated in the following three examples:
  • EXAMPLE 20 Preparation of methyl 5(5'-fluoro-5-thienylsulfonyl)- salicylate 5-(2-fiuoro-5-thienylsulfonyl)salicylic acid (0.01 m.) is added to a solution of anhydrous methanol (25 ml.) containing ca. 100 mg. of anhydrous sulfuric acid. The resultant mixture is heated under gentle reflux, the solvent removed in vacuo and the residue partitioned between chloroform-dilute sodium bicarbonate solution and the layers separated. The chloroform layer is dried over anhydrous sodium sulfate, filtered and evaporated to leave methyl 5 5'-fiuoro-2'-thienylsulfonyl salicylate.
  • EXAMPLE 21 Preparation of phenyl-S-(5'-fluoro-2'-furylsulfonyl)- salicylate To a mixture of polyphosphate esters (PLP.E.) chloroform is added one equivalent each of 5-(5-fluoro-2'- fury1sulfonyl)salicylic acid and phenol, and the resultant mixture is heated gently for 30 minutes. The chloroform mixture is cooled, washed with dilute bicarbonate solution. The chloroform layer is then dried, filtered and evaporated in vacuo to yield phenyl (5fiuoro-2-furylsulfon-yl salicylate.
  • PDP.E. polyphosphate esters
  • EXAMPLE 22 Preparation of 5(5'-fluoro-2-thienylsulfonyl)salicylanilide
  • a mixture of phenyl 5-(5'-fiuoro-2'-thienylsulfonyl) salicylate (0.1 m.); aniline (0.1 m.) and l-methylnaph' thalene (50 ml.) are heated slowly to 230 C., kept at this temperature until phenol has stopped distilling.
  • Charcoal (2 g.) is then added and then 20 ml. additional methylnaphthalene added.
  • the mixture is heated for min., filtered hot, and cooled.
  • the collected anilide is then recrystallized yielding pure 5(5'-fiuoro-2-thienylsulfonyl) salicylanilide.
  • EXAMPLE 23 Preparation of 5(5-chloro-2-furylsulfinyl)salicylamide
  • a mixture of methyl 5-(5'-chloro 2'-furylsulfinyl) salicylate and concentrated ammonium hydroxide (five-fold excess) is heated at 100 C. in a sealed tube for six hours. After cooling, water is added and the 5(5-chloro 2'-furylsulfinyl) salicylamide collected.
  • EXAMPLE 24 Preparation of methyl 5-(5-methoxyfurylsulfonyl)salicylate
  • a mixture of 10 g. of methyl 5(5-bromo-2-furylsulfo- 11yl)salicylate and 125 ml. of 2.5 M sodium methoxide in absolute methanol is heated for 30 min. at ca. 90 in a stoppered bottle, the excess methanol removed in vacuo, dilute hydrochloric acid added and the mixture extracted with chloroform. Concentration of the chloroform solution yields methyl 5-(5'-methoxyfurylsulfonyl)salicylate.
  • EXAMPLE 25 Preparation of sodium 3-carboxy-4-hydroxy-N-(2'-(1'- methylpyrryl acetanilide Solutions of 3-carboxy-4-hydroxy-N-(2'(1-methylpyrryl)acetanilide in methanol and sodium hydroxide (1 equiv.) in water are mixed, heated for solution, filtered, and the filtrate concentrated in vacuo to obtain sodium 3-carboxy-4-hydroxy-N-(2-(1-methylpyrryl)acetanilide.
  • EXAMPLE 26 Preparation of diethylaminoethanol salt of 5-(l'-2'4-cyclopentadienyl)-thio)-salicylic acid N,N-diethylethanolamine (0.001 m.) in ether (5 ml.) is added to a stirred solution of 5-(l'-(24'-cyclopentadien- 4 3 X ⁇ B g- A 3. wherein A is S, S0 or S0 Y is S, R2 is H, R is H,
  • X is H or halogen, and R is hydroxy
  • a pharmaceutical preparation in dosage unit form adapted for administration to obtain an antiinflammatory effect comprising a pharmaceutical diluent and, per dosage unit, an antiinflammatory effective non-toxic amount within the range from about 50 to about 7,000 milligrams of a compound of structural formula:
  • A is S, S0 or S0 Y is S
  • R2 is H
  • X is H or halogen
  • R is hydroxy

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
US30323A 1969-06-25 1970-04-20 Anti-inflammatory salicylic acid derivatives Expired - Lifetime US3657432A (en)

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US3032370A 1970-04-20 1970-04-20

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CH (1) CH542809A (en, 2012)
FR (1) FR2053009B1 (en, 2012)
GB (1) GB1265924A (en, 2012)
NL (1) NL7008637A (en, 2012)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3923859A (en) * 1973-08-31 1975-12-02 Merck & Co Inc Substituted fulvene acetic acids and derivatives
US5541219A (en) * 1992-03-04 1996-07-30 Rhone-Poulenc Rorer Limited 1-Alkoxy-2-(alkoxy- or cycloalkoxy-)-4-(cyclothioalkyl- or cyclothioalkenyl-) benzenes as inhibitors of cyclic AMP phosphodiesterase and tumor necrosis factor
US5783597A (en) * 1997-03-04 1998-07-21 Ortho Pharmaceutical Corporation 2,5-disubstituted thiophenes: inhibitors of 5-lipoxygenase and inducible cyclooxygenase (COX-2) enzymes, composition and use
US20050148554A1 (en) * 2003-01-13 2005-07-07 Don Zhang Anti-inflammatory and anti-thrombotic compounds and their compositions

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2197583B1 (en, 2012) * 1972-09-07 1975-10-17 Rhone Poulenc Ind
RU2540464C2 (ru) * 2012-05-28 2015-02-10 Государственное бюджетное образовательное учреждение высшего профессионального образования "Волгоградский государственный медицинский университет" Министерства здравоохранения и социального развития Российской Федерации Водорастворимое производное амида салициловой кислоты, обладающее транквилизирующей, ноотропной и анальгезирующей активностью

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2852557A (en) * 1954-04-09 1958-09-16 Schenley Ind Inc 4-sulfonyl derivatives of salicylic acid

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3923859A (en) * 1973-08-31 1975-12-02 Merck & Co Inc Substituted fulvene acetic acids and derivatives
US5541219A (en) * 1992-03-04 1996-07-30 Rhone-Poulenc Rorer Limited 1-Alkoxy-2-(alkoxy- or cycloalkoxy-)-4-(cyclothioalkyl- or cyclothioalkenyl-) benzenes as inhibitors of cyclic AMP phosphodiesterase and tumor necrosis factor
US5783597A (en) * 1997-03-04 1998-07-21 Ortho Pharmaceutical Corporation 2,5-disubstituted thiophenes: inhibitors of 5-lipoxygenase and inducible cyclooxygenase (COX-2) enzymes, composition and use
US20050148554A1 (en) * 2003-01-13 2005-07-07 Don Zhang Anti-inflammatory and anti-thrombotic compounds and their compositions

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FR2053009A1 (en, 2012) 1971-04-16
FR2053009B1 (en, 2012) 1974-05-24
GB1265924A (en, 2012) 1972-03-08
NL7008637A (en, 2012) 1970-12-29
CH542809A (de) 1973-10-15

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