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US3852323A - Phenylacetic acids - Google Patents

Phenylacetic acids Download PDF

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US3852323A
US3852323A US00152387A US15238771A US3852323A US 3852323 A US3852323 A US 3852323A US 00152387 A US00152387 A US 00152387A US 15238771 A US15238771 A US 15238771A US 3852323 A US3852323 A US 3852323A
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Prior art keywords
chloro
acid
nitro
bromo
ethyl
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US00152387A
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J Diamond
N Santora
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William H Rorer Inc
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William H Rorer Inc
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Priority claimed from US034870A external-priority patent/US3864384A/en
Application filed by William H Rorer Inc filed Critical William H Rorer Inc
Priority to US00152387A priority Critical patent/US3852323A/en
Priority to BE776316A priority patent/BE776316R/en
Priority to DE19712162038 priority patent/DE2162038A1/en
Priority to CA129,890A priority patent/CA1027133A/en
Priority to FR7144544A priority patent/FR2128277B2/fr
Priority to NL7117006A priority patent/NL7117006A/en
Priority to GB5751071A priority patent/GB1382267A/en
Priority to ES397844A priority patent/ES397844A1/en
Priority to IL38916A priority patent/IL38916A0/en
Priority to US05/423,444 priority patent/US4008269A/en
Publication of US3852323A publication Critical patent/US3852323A/en
Application granted granted Critical
Priority to SE7501717A priority patent/SE7501717L/en
Priority to SE7501716A priority patent/SE7501716L/en
Priority to FR7508269A priority patent/FR2279386A2/en
Priority to FR7508270A priority patent/FR2282867A2/en
Priority to FR7508271A priority patent/FR2279387A2/en
Priority to AR239472D priority patent/AR206491A1/en
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Expired - Lifetime legal-status Critical Current

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    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/57—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and carboxyl groups, other than cyano groups, bound to the carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/26—Cyanate or isocyanate esters; Thiocyanate or isothiocyanate esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
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    • C07C205/57—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C205/59—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
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    • C07C205/57—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C205/61—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton the carbon skeleton being further substituted by doubly-bound oxygen atoms
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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    • C07C313/08—Sulfenic acids; Derivatives thereof
    • C07C313/18—Sulfenamides
    • C07C313/26—Compounds containing any of the groups, X being a hetero atom, Y being any atom
    • C07C313/30—Y being a hetero atom
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    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/56—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/20—Esters of monothiocarboxylic acids
    • C07C327/32—Esters of monothiocarboxylic acids having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C381/00—Compounds containing carbon and sulfur and having functional groups not covered by groups C07C301/00 - C07C337/00
    • C07C381/02—Thiosulfates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/52—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen
    • C07C57/58—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen containing six-membered aromatic rings
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C57/52—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen
    • C07C57/62—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen containing six-membered aromatic rings and other rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings 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
    • C07D277/34—Oxygen atoms
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    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings 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
    • C07D277/54—Nitrogen and either oxygen or sulfur atoms
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    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • ABSTRACT Novel a-halo-p-cycloalkylphenylacetic acids and their derivatives have been prepared.
  • Compounds of this invention possess useful anti-inflammatory, analgestic and antipyretic antipyretic properties.
  • This invention describes certain ashalo-p-cycloalkylphenylacetic acids and their derivatives and their use in therapeutic compositions.
  • this invention relates to the preparation of these a-halo-p-cycloalkylphenylacetic acids.
  • the compounds of this invention are administered to mammals, they afford significant treatment of inflammation and associated pain and fever.
  • They further provide analgesic and antipyretic methods for the relief and treatment of pain and fever associated with inflammation.
  • This invention comprises a class of novel chemical compounds which contain a cycloalkyl radical which is attached to a substituted phenyl-oz-haloacetic acid in the para-position. This invention further comprises derivatives of said acids and the method of preparing the same.
  • This invention also describes a new method of treating inflammation and associated pain and fever as well as novel therapeutic compositions.
  • n 0-2;
  • B is hydrogen or, loweralkyl
  • R is halo, nitro, amino, acylamino, monoand diloweralkylamino, mercapto, acylthio, loweralkylthio, loweralkylsulflnyl, loweralkylsulfonyl, hydroxy, loweralkoxy, acyloxy, haloloweralkyl, cyano, acety] or loweralkyl;
  • R is hydrogen, fluoro, chloro, bromo, trifluoromethyl, cyano, nitro or loweralkylsulfonyl
  • X is halo
  • Z is OI-I, loweralkoxy, arloweralkoxy, NH
  • the compounds of this invention contain an asymmetric carbon atom in the alpha-position of the acetic acid side chain.
  • the above compounds of formula I may be obtained as raceinic mixtures of their dextro and levorotatory isomers. It is to be understood that said d and l isomers as well as the dl mixtures thereof are embraced within the scope of this in vention.
  • two racemic mixtures may exist in the case of 2'- or 3 loweralkylcyclohexylphenyl-a-haloacetate, 2- or 3'- loweralkylcyclopentylphenyl-a-haloacetate, 2- or 3- or 4-loweralkylcycloheptylphenyl-a-haloacetate or their derivatives. It is. understood that both racemic mixtures are embraced within the scope of this invention.
  • the preferred R and R' substituents are in the 3 and 5 positions.
  • the preferred compounds of this embodiment describe the cyclohexyl class of chemical compounds which have particular usefulness as antiinflammatory, analgesic and antipyretic agents. These compounds are described in formula II n' (s 4 0 cn-coz l It where:
  • R, R, X and Z are as described above. Those compounds whose properties are even more The most preferred compounds of this invention de scribe a class of chemical compounds which have particular usefulness as anti-inflammatory, analgesic and antipyretic agents. These compounds are described in formula III where:
  • R is chloro, bromo, nitro, methylsulfonyl, trifloromethyl or cyano;
  • R is chloro, bromo or nitro
  • X is fluoro, chloro or bromo
  • Z is OH, loweralkoxy, arloweralkoxy, NH
  • racemic mixtures as well as the dextro and levorotatory isomers thereof.
  • R is chloro, bromo, nitro, methylsulfonyl, trifluoromethyl or cyano
  • R is chloro, bromo or nitro.
  • racemic mixtures as well as the dextro and levorotatory isomers thereof.
  • loweralkyl refers to a loweralkyl hydro carbon group containing from 1 to about 6 carbon atoms which may be straight chained or branched.
  • the acyl radical may be any organic radical derived from an organic acid by the removal of its hydroxyl group such as formyl, acetyl, propionyl, 3-carboxypropionyl, 3-carboxy-2-propenoyl, camphoryl, benzoyl, toluoyl or heteroyl such as pyridinoyl, piperidinoyl, thenoyl, etc.
  • Loweralkoxy signifies an alkoxy group containing from 1 to about 6 carbon atoms which may be straight chained or branched.
  • loweralkylidenyl refers to a loweralkylidenyl hydrocarbon group containing from 2 to about 6 carbon atoms.
  • Heteroloweralkylidenyl refers to a loweralkylidenyl hydrocarbon group containing from about 2 to 5 carbon atoms and having one or more hetero atoms in the chain selected from O, N or S, such as piperidinyl, morpholinyl, etc.
  • the preferred alkali or alkaline earth metals are sodium, potassium, calcium and magnesium.
  • ammonium salt refers to the cation formed when ammonia or an organic amine react with the carboxyl group to form ammonium salts of the structure given in the formula.
  • the ammonium salts are formed with a (l) loweralkylamines such as methylamine, diethylamine, triethylamine; (2) hydroxyloweralkylamines such as B-hydroxyethylamine; (3) heterocyclic amines such as 2-aminopyridine, piperazine, piperidine; (4) aralkylarnines such as a-methylbenzylamine, phenethylamine; (5) cycloalkylamines such as cyclohexylamine; (6) alkaloids such as quinine, cinchonidine, cinchonine, ephedrine.
  • piperazinium salt 1 (1,3 ,5 -trichloro-4-cyclohexyllphenylacetic acid
  • the compounds of this invention may be prepared by the following general procedures. Condensation of a cycloalkylbenzene with a loweralkyl or aralkyl oxalyl chloride in the presence of anhydrous aluminum chloride results in a p-cycloalkylphenylglyoxylate.
  • the resulting loweralkyl or aralkyl esters of the p-cycloalkylphenylglyoxylic acid may then be a) halogenated, b) nitrated or c) alkylated to obtain the corresponding loweralkyl esters of a 3-halo-4-cyclloalkylphenylglyoxylic acid, a 3-nitro-4-cycloa1kylphenylglyoxylic acid or a 3-alkyl-4-cycloalkylphenyl-glyoxylic acid.
  • Chlorination or bromination may be carried out in the presence of a small amount of iodine dissolved in an inert solvent such as carbon tetrachloride.
  • R" is loweralkyl or arloweralkyl and Hal is chloro or bromo.
  • a 3-amino-4-cycloalkylphenylglyoxylate may then 07 diazotized and heated in an aqueous medium to be form the 3-hydroxy-4-cycloalkylphenylglyoxylate a. monoor dialkylated with loweralkyl halides or 20 or heated in an alcohol to form the 3-alkoxy-4- sulfates or acylated with loweracyl chlorides or ancycloalkylphenylglyoxylate.
  • the hydroxyl group hydrides may also be alkylated with loweralkyl halides or B 0 B 0 ;F l m- (first l COOR NH: NIIR" l ⁇ 1' @O?i8" l B 0 B O f ll-3) C-COOR Hm CCOOR NI-ICOR Nut”):
  • diazotized to the diazonium fluoroborate which is sulfates to the alkoxyl group or acylated with lowthen thermally decomposed to the 3-fluoro-4- eracyl chlorides or anhydrides to the acyloxy comcycloalkylphenylglyoxylate, pound in the presence of a tertiary amine such as 40 pyridine,
  • a 3-chloro-4-cycloalkylphenylmercapto-4-cycloalkylphenylglyoxylic acid which glyoxylate may be nitrated as above to obtain a 3- can be esterified to a 3-mercapto-4-cycloalkyl- 15 chloro-S-nitro-4-cycloalkylphenylglyoxylate or chloriphenylglyoxylate.
  • This in turn can be lower alkylnated to obtain a 3,5-dichloro 4-cycloalkylphenylated to the lower alkylthio and oxidized to the glyoxylate.
  • a 3-nitro-4-cycloalkylphenylglyoxylate can loweralkylsulfinyl and loweralkylsulfonyl groups or benitrated to give a 3,5-dinitro-4-cycloalkylphenylacylated to the acylthio compounds. glyoxylate.
  • a 3-alkyl compound may also be nitrated,
  • a second nitration or halogenation with chlorine or 35 chlorinated or brominated to the 3-chloro, 3-bromo or bromine may be carried out on the 3-substituted-4- 3-nitro-5-alkyl compounds.
  • a 3-chl0r0-5-nitr0-4-cycloalkylphenylglyoxy- 15 trifluorornethyl iodide and copper powder in quinoline late can be reduced to a corresponding 3-chloro-5- at 150C to obtain a 3-trifluoromethyl-5-nitro-4- amino-4-cycloalkylphenylglyoxylate.
  • This may then be cycloalkylphenylglyoxylate; or with cuprous memonoor di-alkylated or acylated.
  • the amine may also thanesulfinate in quinoline at 150C to a 3- be converted via the diazonium salt to a variety of demethylsulfonyl-S-nitro-4-cycloalk'ylphenylglyoxylate. rivatives as described above.
  • Still another example of various disubstitution would be the selective reduction of a 3,5-dinitro-4-cycloalkyl-
  • a 3-chloro-5- phenylglyoxylate with hydrogen or ammonium sulfide nitro-4-cycloalkylphenylglyoxylate can be reacted with to obtain a 3-nitro-5-amino-4-cycloalkylphenylglyoxycuprous cyanide in quinoline at l50C to obtain a 3- late which in turn can be diazotized to the various decyano-S-nitro-4-cycl0alkylphenylglyoxylate; or with 25 riVati eS- B N02 B N02 lINOz lllilh IINOz CuBr lINOz Cul IINOz CuCN where R is lower alkyl HNOz KS CSO CzHi Cl(NO2) Cl(N 02) KNOz) -l-COOR B an 0 1) 11,
  • the p-cycloalkylphenylglyoxylate ester is converted to the corresponding p-cycloalkylphenylglycolate ester by hydrogenation in the presence of latinum oxide.
  • Various mono-substituted products may also be ni- 40 the special case when R or R are su stituents sensitive trated, chlorinated or brominated as above and again, in turn, converted to the various desired substituents.
  • a 3-fluoro-4-cycloalkylphenylglyoxylate may be nitrated or brominated and the nitro to catalytic hydrogenation, e.g., when R or R is N0 SH, SR, SOR, 1, etc., a selective reduction of the keto function is effected with sodium borohydride to give the p-cycloalkylphenylglycolate ester.
  • Reaction of a substituted p-cy-cloalkylphenylglycop y 'g lf f can be reduced f
  • a nitrogen base such as ammonia, lowehydride conditions as above to the 3-n1tr0-4-cycloalkylralkylamine, diloweralkylaminey 1 k Phenylglycolate or 3"chloro's'mtro4'cycloalkylphe' mine, a nitrogen containing hetero compound such as nyl-glycolate.
  • glycolate esters may be hydrolyzed to the corresponding p-cycloalkylphenylglycolic acid. Reaction of the glycolate ester or glycolic acid with an acid chloride YCl or acid anhydride YOY in the presence of a tertiary amine such as pyridine, picoline, or quinoline results in the formation of an hydroxy derivative of the glycolate.
  • YCl and YOY include acetyl HZNOII alck 0 II/ B R a I 0 11).. -@o1r-oo OH YCl/r YOY YCl or YOY OCONU:
  • OSOZR OSOzAI Ar is phenyl or substituted phenyl O C OCHzCHzC O OH B i C0 0 CHCOOH (05*) e030;
  • the corresponding a-haloacetic acid may be prepared by heating the ester with acetic acid containing the corresponding hydrogen halide.
  • the substituted oz-fluoro-4-cycloalkylphenylacetic acid derivatives may also be obtained from the corresponding a-iodo, oz-bromo or a-chloro-4-cycloalkyl- 5O phenylacetic acid derivatives by reaction with potassium fluoride at about l30200C.
  • This invention further relates to the acid addition salts formed by the action of one equivalent of a suitable base with the substituted a-halo-4-cycloalkylphenylacetic acid.
  • suitable bases thus include for example the alkali metal alkoxides such as sodium methoxide, etc., and the alkali metal and alkaline earth metal hydroxides, carbonates, bicarbonates. etc. (such as sodium hydroxide, potassium hydroxide. calcium hy droxide, potassium carbonate, sodium bicarbonate. magnesium bicarbonate, etc.).
  • the aluminum salts of the instant products may be obtained by treating the corresponding sodium salt with an appro riate aluminum complex such as aluminum hydroxy chloride hexahydrate, etc.
  • the ammonium salts may be made by reaction with the corresponding amine such as methylaminc, diethylamine, B-hydroxyethylamine, piperazine, piperidine, a-methylbenzylamine, cyclohexylamine, triethylamine, phenethylamine, etc.
  • the acid addition salts thus obtained are the functional equivalent of the corresponding substituted a-halo-P-cycloalkylphenylacetic acid products and one skilled in the art will appreciate that to the extent that the instant acids are useful in therapy, the variety of acid addition salts embraced by this invention are limited only by the criterion that the bases employed in forming the therapeutically useful salts be both non-toxic and physiologically acceptable.
  • the alkaloidal salts are useful for effecting optical resolutions.
  • the products of this invention may be obtained as racemic mixtures of their dextro and levorotatory isomers. These may be separated by any of the various methods of resolution.
  • One method that may be employed is combining the racemic compound with an optically active compound by salt formtion, ester formation, or amide formation to form two diastereomeric products. If the instant acids are added to an optically active base, then two diastereomeric salts are produced which possess different properties and different solubilities and can be separated by fractional crystallization. When the salts have been completely separated by repeated crystallization, the base is split off by acid hydrolysis and the pure d and I acids are obtained.
  • a cycloalkylphenylglycolic acid is reacted in alcoholic or acetone solution with an equivalent amount of the optically active primary, secondary or tertiary amine such as cinchonidine, cinchonine, quinine, ephedrine, a-methylbenzyfamine, sec-butylamine, secamylamine, etc.
  • the diastereomeric amine salts produced thereby are separated by fractional crystallization and each optically active salt is hydrolyzed with dilute mineral acid to produce the dextro or levo form of the p-cycloalkylphenylglycolic acid.
  • a p-cycloalkylphenylglycolate ester may be reacted with an optically active primary or secondary amine such as ephedrine, a-methylbenzylamine, sec-butylamine, etc., to produce a mixture of diastereomeric p-cycloalkylphenylglycolamides which may be separated by fractional crystallization.
  • an optically active primary or secondary amine such as ephedrine, a-methylbenzylamine, sec-butylamine, etc.
  • Each optically active amide may be hydrolyzed with mineral acid to its respective opti-- cally active acid.
  • a p-cycloalkylphenylglycolate may be reacted with an optically active alcohol such as l menthol or d-borneol, or l-a-methylbenzylalcohol, to produce a mixture of diastereomeric p-cycloalkylphenylglycolate esters which may be separated by fractional crystallization.
  • an optically active alcohol such as l menthol or d-borneol, or l-a-methylbenzylalcohol
  • Each optically active ester may be hydrolyzed with mineral acid or alkali to its respective optically active acid.
  • the optically active acids can also be recovered from the a-methylbenzyl esters by hydrogenolysis in the presence of palladium.
  • optically active glycolate may then be reacted with a phosphorus trihalide, phosphorus pentahalide, phosphorus oxyhalide, sulfurylhalide, thionylhalide or sulfur halide to give an optically active a-halo p-cycloalkylphenylacetic acid, ester or amide thereof.
  • racemic chloroacetic acids, esters and amides may also be resolved into their optical isomers by the processes described for the glycolic acids, esters and amides.
  • the compounds of this invention exercise a useful degree of anti-inflammatory activity in mammals and are effective in the treatment of associated pain and fever and in like conditions which are responsive to treatment with anti-inflammatory agents.
  • the compounds of this invention are indicated for a wide variety of mammalian conditions where the symptoms of inflammation and associated fever and pain are manifested.
  • rheumatic diseases such as rheumatoid arthritis, osteoarthritis and other degenerative joint diseases
  • softtissue rheumatism such as tendinitis muscluar rheumatism such as sciatica
  • pain and inflammation associated with dental surgery and similar human and veterinary disease conditions exhibiting the foregoing symptoms requiring the use of anti-inflammatory, analgesic and- /or antipyretic agent.
  • the compounds of this invention are normally administered orally, topically, parenterally or rectally. Orally, these may be administered in tablets, capsules, suspensions or syrups; the optimum dosage, of course, depending on the particular compound being used and the type and severity of the condition being treated. In any specific case the appropriate dosage selected will further depend on factors of the patient which may influence response to the drug; for example, general health, age, weight, etc. Although the optimum quantities of the compounds of this invention to be used in such manner will depend on the compound employed and the particular type of disease condition treated,oral dose levels of preferred compounds when administered to a mammal in dosages of 0.5 to milligrams per kilogram of body weight per day are particularly useful. The preferred range is 0.5 to 15 mg/Kg. Comparative dosages may be used in topical, parenteral or rectal administration.
  • Dosage forms may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents; for example, sweetening agents, flavoring agents, coloring agents, preserving agents, etc. Further, the active a-halo-p-cycloalkyphenylacetic acids or their derivatives may be administered alone or in admixture with antacids such as sodium bicarbonate, magnesium carbonate, magnesium hydroxide, aluminum hydroxide, magnesium silicate, etc., and non-toxic pharmaceutically acceptable excipients.
  • antacids such as sodium bicarbonate, magnesium carbonate, magnesium hydroxide, aluminum hydroxide, magnesium silicate, etc.
  • excipients may be, for example, inert diluents such as calcium carbonate, lactose, etc., granulating and disintegrating agents; for example maize starch, alginic acid, etc., lubricating agents; for example, magnesium stearate, talc, etc., binding agents; for example, starch gelatin, etc., suspending agents; for example, methylcellulose, vegetable oil, etc., dispersing agents; for example, lecithin, etc., thickening agents; for example, beeswax, hard paraffin, etc., emulsifying agents; for example, naturally-occurring gums, etc., and nonirritating excipients; for example, cocoa butter and polyethylene glycols.
  • inert diluents such as calcium carbonate, lactose, etc., granulating and disintegrating agents
  • Various tests in animals can be carried out to show the ability of the a-halo-p-cycloalkylphenylacetic acids and derivatives of this invention to exhibit reactions that can be correlated with anti-inflammatory activity in humans.
  • One such test is the Carrageenan paw edema test, which shows the ability of the instant compounds to inhibit edema induced by injection of an inflammatory agent such as carrageenan into the tissues of the paw of a rat against non-inflammed controls.
  • This carrageenan testing method is known to correlate well with anti-inflammatory activity in humans and is a standard test used to determine anti-inflammatory activity.
  • Antipyretic assay is carried out by yeast-induced fever tests of subcutaneously injected rats. The measurement of rectal temperatures is carried out to determine the response by the test compounds.
  • the a-halo-pcyclo-alkylphenylacetic acids and derivatives of this invention are considered to have valuable analgesic and antipyretic properties.
  • EXAMPLE 1 Ethyl p-cyclohexylphenylglyoxylate Cyclohexylbenzene 53 g. (0.33 mole) and 50.5 g. (0.37 mole) of ethyl oxalyl chloride are dissolved in 200 ml. of dry l,l,2,2-tetrachloro-ethane. Anhydrous aluminum chloride 52 g. (0.39 mole) is added in small portions to the reaction mixture with stirring over 2 hours. During the addition, the temperature of the mixture is maintained between l5-l8C. The mixture is stirred for an additional hour and allowed to stand overnight. The solution is then slowly poured into 1500 ml. of iced saline solution with stirring.
  • the aqueous layer is extracted with 500 ml. of ether and the ether extract is combined with the organic layer which is dissolved in 1500 ml. of ether and separated.
  • the ether solution is washed with X 100 ml. portions of a l:l mixture of saturated sodium chloride solution and 10 percent HCll solution, and 5 X 100 ml. portions of water.
  • the ether solution is then dried over anhydrous magnesium sulfate for 1 hour and filtered. The solvents are removed by distillation under reduced pressure and the residue distilled to obtain ethyl p-cyclohexylphenylglyoxylate. (b.p. l657C/l .1 mm.)
  • EXAMPLE 2 Ethyl 3-chloro-4-cyclohexylphenylglyoxylate Ethyl p-cyclohexylphenylglyoxylate 98.9 g. (0.38 mole) and 6.l g. of iodine (0.048 mole) and dissolved in I00 ml. of carbon tetrachloride. To this solution is added a solution of 40.4 g.
  • EXAMPLE 7 Ethyl 3-trifluoromethyl-4-cyclohexylphenylglyoxylate To a solution of 0.01 moles of ethyl 3-bromo-4 cyclohexylphenylglyoxylate in 50 ml. of dimethylformamide is added 0.15 moles of trifluoromethyl iodide and 0.02 g. of copper power. The reaction is shaken in a sealed tube for 5 hours at 140C, cooled, and then filtered and evaporated in vacuo. 200 ml. of water is added to the residue and extracted with ether. The
  • EXAMPLE 8 Ethyl 3-amino-4-cyclohexylphenylglyoxylate A mixture of 15.3 g. (0.05 moles) of ethyl 3-nitro-4- cyclohexylphenylglyoxylate in 100 m1. methanol containing 0.05 mole citric acid and 1.5 g. of 5 percent palladium-omcarbon is shaken with hydrogen at 3 atm. pressure and 27C until 3 moles of hydrogen are absorbed. The mixture is filtered, washed with methanol and the filtrate concentrated in vacuo to obtain ethyl 3-amino-4-cyclohexylphenylglyoxylate, isolated as the citrate salt.
  • EXAMPLE '9 Ethyl 3-methylamino-4-cyclohexylphenylglyoxylate To a solution of 0.01 moles of ethyl 3-amino-4- cyclohexylphenylglyoxylate in 100 ml. of pyridine is added 0.1 moles of methyl iodide. The reaction mixture is stirred overnight at room temperature, filtered and concentrated. The residue is distilled to obtain ethyl 3- methylamino-4-cyclohexylphenylglyoxylate.
  • EXAMPLE 10 Ethyl 3-dimethylamino-4-cyclohexylphenylglyoxylate A solution of 0.005 moles of ethyl 3-nitro-4- cyclohexylphenylglyoxylate and 1.6 ml. of 37 percent formaldehyde in 50 ml. of methanol is shaken with hydrogen over 0.5 g. of 5 percent palladium-on-charcoal at 42 lbs. and 27C until five moles of hydrogen are absorbed. The catalyst is filtered off and the filtrate is evaporated in vacuo. The residue is then distilled to obtain ethyl 3-dimethylamino-4-cyclohexylphenylglyoxylate.
  • EXAMPLE 1 1 Ethyl 3-cyano-4-cyclohexylphenylglyoxylate To 29.4 g. (01 moles) of ethyl 3-amino-4-cyc1ohexylphenylglyoxylate in 35 ml. of 28 percent hydrochloric acid and 100 ml. of cracked ice to maintain the temperature at 0C is added a solution of 7.1 g. (0.102 moles) of sodium nitride in 20 ml. of water. The reaction mixture is then neutralized with sodium carbonate. This diazonium mixture is added to a cuprous cyanide solution (prepared from 31.5 g. of copper sulfate and 16.2 g.
  • a cuprous cyanide solution prepared from 31.5 g. of copper sulfate and 16.2 g.

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Abstract

Novel Alpha -halo-p-cycloalkylphenylacetic acids and their derivatives have been prepared. Compounds of this invention possess useful anti-inflammatory, analgestic and antipyretic antipyretic properties.

Description

United States Patent [1 1 Diamond et al.
PHENYLACETIC AClDS William H. Rorer, Inc., Fort Washington, Pa.
Filed: June 11, 1971 Appl. No.1 152,387
Related U.S. Application Data Continuationin-part of Scr. No. 34,870. May 5, 1970.
Assignee:
U.S. Cl 260/465 D, 260/141, 260/239 BC, 260/482 C, 260/247.2, 260/247.7 R, 260/247.7 C, 260/247.7 H, 260/247.7 K, 260/268 R, 260/485 F, 260/485 H,
260/268 C, 260/485 J, 260/488 CD,
260/284, 260/500.5 H, 260/501.16, 260/293.72, 260/515 A, 260/515 M, 260/293.8, 260/516, 260/518 a, 260/295 R, 260/519, 260/558 R, 260/293.8l, 260/558 S, 260/558 A, 260/306.7, 260/559 R, 260/559 T, 260/332.2 R, 260/559 A, 260/999,
[ Dec. 3, 1974 260/332.2 A, 260/448 R. 260/455 R.
260/456 A. 260/456 P, 260/463, 260/468 R. 260/469, 260/470. 260/471 R, 260/472,
260/473 R, 260/473 A, 260/473 S, 260/475 SC. 260/496 R, 260/479 R, 260/485 F,
260/485 H, 260/485 .1, 260/488 CD,
260/558 R, 260/558 S, 260/558 A, 260/559 R, 260/559 T, 260/559 A, 260/999 [51] Int. Cl. C07c 63/54, C070 65/14, C07c 121/64 [58] Field of Search 2601515 A. 470, 471 R, 260/472, 465 D, 501.16, 448 R, 469
Primary Examiner-James A. Patten Attorney, Agent, or FirmErich M. H. Radde 57] ABSTRACT Novel a-halo-p-cycloalkylphenylacetic acids and their derivatives have been prepared. Compounds of this invention possess useful anti-inflammatory, analgestic and antipyretic antipyretic properties.
42 Claims, N0 Drawings 1 PI-IENYLACETIC ACIDS CROSS REFERENCES TO RELATED APPLICATIONS This a COlItlIIUfitIOH-ll'l-Pfift appllcatlon of Ser. No.
34,870 filed May 5, 1970.
SUMMARY OF THE INVENTION This invention describes certain ashalo-p-cycloalkylphenylacetic acids and their derivatives and their use in therapeutic compositions. In addition, this invention relates to the preparation of these a-halo-p-cycloalkylphenylacetic acids. When the compounds of this invention are administered to mammals, they afford significant treatment of inflammation and associated pain and fever.
They further provide analgesic and antipyretic methods for the relief and treatment of pain and fever associated with inflammation.
BACKGROUND OF THE INVENTION There has been continued efforts in research to develop drugs which would significantly inhibit the development of inflammation and relieve the pain and fever associated with it. Much of these efforts have been carried on in the field of steroids. While many of these compounds have been effective, they have had the drawback of causing many side effects.
We have unexpectedly found that a-halop-cycloalkylphenylacetic acid compounds and their derivatives have valuable pharmacologic properties.
We have found that a-halo-p-cycloalkylphenylacetic acid compounds and their derivatives possess useful anti-inflammatory, analgesic and antipyretic properties.
We have also found a series of anti-inflammatory compounds which are non-steroidal.
We have further found that these a-halo-p-cycloalkylphenylacetic acid compounds and their derivatives are novel.
We have also found that the compounds of this invention are useful in effectively providing a method for the inhibition of inflammation and the treatment of associated pain and fever.
We have still further found an entirely new class of antiinflammatory, analgesic and antipyretic pharmaceutical compositions containing the a-halo-p-cycloalkylphenylacetic acids and derivatives of this invention as active ingredient.
We have again found a convenient method for synthesizing these compounds.
DESCRIPTION AND PREFERRED EMBODIMENT This invention comprises a class of novel chemical compounds which contain a cycloalkyl radical which is attached to a substituted phenyl-oz-haloacetic acid in the para-position. This invention further comprises derivatives of said acids and the method of preparing the same.
This invention also describes a new method of treating inflammation and associated pain and fever as well as novel therapeutic compositions.
The compounds of this invention can be represented by the generic structure which is described by the general formula I where:
n is 0-2;
B is hydrogen or, loweralkyl;
R is halo, nitro, amino, acylamino, monoand diloweralkylamino, mercapto, acylthio, loweralkylthio, loweralkylsulflnyl, loweralkylsulfonyl, hydroxy, loweralkoxy, acyloxy, haloloweralkyl, cyano, acety] or loweralkyl;
R is hydrogen, fluoro, chloro, bromo, trifluoromethyl, cyano, nitro or loweralkylsulfonyl;
X is halo;
Z is OI-I, loweralkoxy, arloweralkoxy, NH
loweralkylamino, diloweralkylamino, cy cloloweralkylamino,
(where A is loweralkylidenyl or heteroloweralkylidenyl), -NHOH, -NHNH or OM (where M is an alkali, alkaline earth or aluminum metal or an ammonium salt).
The compounds of this invention contain an asymmetric carbon atom in the alpha-position of the acetic acid side chain. As a result, the above compounds of formula I may be obtained as raceinic mixtures of their dextro and levorotatory isomers. It is to be understood that said d and l isomers as well as the dl mixtures thereof are embraced within the scope of this in vention.
When B is loweralkyl, two racemic mixtures may exist in the case of 2'- or 3 loweralkylcyclohexylphenyl-a-haloacetate, 2- or 3'- loweralkylcyclopentylphenyl-a-haloacetate, 2- or 3- or 4-loweralkylcycloheptylphenyl-a-haloacetate or their derivatives. It is. understood that both racemic mixtures are embraced within the scope of this invention.
The preferred R and R' substituents are in the 3 and 5 positions.
The preferred compounds of this embodiment describe the cyclohexyl class of chemical compounds which have particular usefulness as antiinflammatory, analgesic and antipyretic agents. These compounds are described in formula II n' (s 4 0 cn-coz l It where:
R, R, X and Z are as described above. Those compounds whose properties are even more The most preferred compounds of this invention de scribe a class of chemical compounds which have particular usefulness as anti-inflammatory, analgesic and antipyretic agents. These compounds are described in formula III where:
R is chloro, bromo, nitro, methylsulfonyl, trifloromethyl or cyano;
R is chloro, bromo or nitro;
X is fluoro, chloro or bromo; and
Z is OH, loweralkoxy, arloweralkoxy, NH
loweralkylamino or -OM.
Included within the scope of this further special embodiment are the racemic mixtures as well as the dextro and levorotatory isomers thereof.
The more preferred compounds of this special embodiment are those novel compounds which are effective in inhibiting inflammation and the treatment of pain and fever associated with inflammation as well as having analgesic and antipyretic effectiveness for the relief and treatment of pain and fever or symptomatically related to an inflammation indication are described by formula V where:
R is chloro, bromo, nitro, methylsulfonyl, trifluoromethyl or cyano;
R is chloro, bromo or nitro.
Included within the scope of this further special embodiment are the racemic mixtures as well as the dextro and levorotatory isomers thereof.
In the descriptive portions of this invention, the following deflnitions apply:
The term loweralkyl refers to a loweralkyl hydro carbon group containing from 1 to about 6 carbon atoms which may be straight chained or branched.
The acyl" radical may be any organic radical derived from an organic acid by the removal of its hydroxyl group such as formyl, acetyl, propionyl, 3-carboxypropionyl, 3-carboxy-2-propenoyl, camphoryl, benzoyl, toluoyl or heteroyl such as pyridinoyl, piperidinoyl, thenoyl, etc.
Loweralkoxy signifies an alkoxy group containing from 1 to about 6 carbon atoms which may be straight chained or branched.
The term loweralkylidenyl" refers to a loweralkylidenyl hydrocarbon group containing from 2 to about 6 carbon atoms.
Heteroloweralkylidenyl" refers to a loweralkylidenyl hydrocarbon group containing from about 2 to 5 carbon atoms and having one or more hetero atoms in the chain selected from O, N or S, such as piperidinyl, morpholinyl, etc.
The preferred alkali or alkaline earth metals are sodium, potassium, calcium and magnesium.
The term ammonium salt refers to the cation formed when ammonia or an organic amine react with the carboxyl group to form ammonium salts of the structure given in the formula. The ammonium salts are formed with a (l) loweralkylamines such as methylamine, diethylamine, triethylamine; (2) hydroxyloweralkylamines such as B-hydroxyethylamine; (3) heterocyclic amines such as 2-aminopyridine, piperazine, piperidine; (4) aralkylarnines such as a-methylbenzylamine, phenethylamine; (5) cycloalkylamines such as cyclohexylamine; (6) alkaloids such as quinine, cinchonidine, cinchonine, ephedrine.
Representative compounds of this invention which are particularly useful are as follows:
a-chloro-3-fluoro-4-cyclohexylphenylacetic acid 04,3-dichloro-4-cyclohexylphenylacetic acid a-chloro-3-bromo-4-cyclohexylphenylacetic acid a-chloro-3-iodo-4-cyclohexylphenylacetic acid a-chloro-3-nitro-4-cyclohexylphenylacetic acid a-chloro-3-trifluoromethyl-4-cyclohexylphenylacetic acid a-chloro-3-mercapto-4-cyclohexylphenylacetic acid oz-chloro-3-acetylthio-4-cyclohexylphenylacetic acid a-chloro-3-methylmercapto-4-cyclohexylphenylacetic acid a-chloro-3-methylsulfinyl-4-cyclohexylphenylacetic acid a-chloro-3-methylsulfonyl-4-cyclohexylphenylacetic acid a-chloro-3-cyano-4-cyclohexylphenylacetic acid a-chloro-3-carboXy-4-cyclohexylphenylacetic acid a-chloro-3-carbethoxy-4-cyclohexylphenylacetic acid a-chloro-3-amino-4-cyclohexylphenylacetic acid a-chloro-3-acetylamino-4-cyclohexylphenylacetic acid achloro-3-methylamino-4-cyclohexylphenylacetic acid a-chloro-3-dimethylamino-4-cyclohexylphenylacetic acid a-chloro3-hydroxy-4-cyclohexylphenylacetic acid a-chloro-3-acetyloxy-4-cyclohexylphenylacetic acid 9 d a, 3-dichloro -trifluoromethyl-4-cyclohexylphenylacetic acid l. a,3-dichloro-5-trifluoromethyl-4-cyclohexyld 01,3-dichloro-5-methylsulfonyl-4-cyclohexylphenylacetic acid l 01,3-dichloro-5-methylsulfonyl-4-cyclohexylphenylacetic acid (1 a-bromo-3-chloro-4-cyclohexylphenylacetic acid 1 a-bromo-3-chloro-4-cyclohexylphenylacetic acid d a-bromo-3-nitro-4-cyclohexylphenylacetic acid 1 a-bromo-3-nitro-4-cyclohexylphenylacetic acid d a-bromo-3,5-dichloro-4-cyclohexylphenylacetic acid 1 a-bromo-3,5-dich-oro-4-cyclohexylphenylacetic acid oz-br0mo-3-chloro-5-nitro-4-cyclohexylphenylacetic acid 1 a-bromo-3-chloro-5-nitro-4-cyclohexylphenylacetic acid d a-fluoro-3-chloro-4-cyclohexylphenylacetic acid 1 a-fluoro-3-chloro-4-cyclohexylphenylacetic acid d a-fluoro3-nitro-4-cyclohexylphenylacetic acid I a-fluoro-3-nitro-4-cyclohexylphenylacetic acid d a-fluoro-3,5-dichloro-4-cyclohexylphenylacetic acid I a-fluoro-3,5-dichloro-4-cyclohexylphenylacetic acid a-fluoro-3-chloro-5-nitro-4-cyclohexylphenylacetic acid 1 a-fluor0-3-chIoro-5-nitro-4-cyclohexylphenylacetic acid d methyl 01,3,5-trichloro-4-cyclohexylphenylacetic l l thyl 04,3,5-trichloro-4-cyclohexylphenylacetic d blsnzyl a,3,5-trichloro-4-cyclohexylphenylacetic l l g izyl a,3,5-trichloro-4-cyclohexylphenylacetic d N-methyl a,3,5-trichlor0-4-cyclohexylphenylacetic acid 1 N-methyl (1,3,5-trichloro-4-cyclohexylphenylacetic acid d N,N-diethyl 01,3,5-trichloro-4-cyclohexylphenylacetic acid I N,N diethyl a,3,5-trichloro-4-cyclohexylphenylacetic acid d N,N-pentamethylene 01,3,5-trichloro-4-cyclohexylphenylacetic acid I N,N-pentamethylene (1,3,5trich1oro-4-cyclohexylphenylacetic acid d N,N-oxydiethylene a,3,5-trichloro-4-cyclohexylphenylacetic acid 1 N,N-oxydiethylene a,3,5-trichloro-4-cyclohexylphenylacetic acid (1 a,3,5-trichloro-4-cyclohexylphenylacetic acid, so-
dium salt I 01,3,5-trichloro-4-cyclohexylphenylacetic acid, so-
dium salt d 11,3,5-trichloro-4-cyclohexylphenylacetic acid, diethylammonium salt l a,3,5-trichloro-4-cyclohexylphenylacetic acid, diethylammonium salt (1 (1,3,5 -trichloro-4-cyclohexylphenylacetic acid,
piperazinium salt 1 (1,3 ,5 -trichloro-4-cyclohexyllphenylacetic acid,
piperazinium salt (1 a,3-dichloro-4-cyclopentylphenylacetic acid 1 a,3-dichloro-4-cyclopentylphenylacetic acid (1 a,3,5-trichloro-4-cyclopentylphenylacetic acid I 01,3,5-trichloro-4-cyclopentylphenylacetic acid d oz-bromo-3-ch1oro-4-cyclopentylphenylacetic acid 1 a-bromo-3-chloro-4-cyclopentylphenylacetic acid d a bromo-3,5-dichloro-4-cyclopentylphenylacetic acid 1 a-bromo-S,5-dichloro-4-cyclopentylphenylacetic acid d a-fluoro-3-chloro-4-cyclopentylphenylacetic acid 1 a-fluoro-3-chloro-4-cyclopentylphenylacetic acid d a-fluoro-3,5-dichloro-4-cyc.lopentylphenylacetic acid 1 a-fluoro'3,5-dichloro-4-cyc1opentylphenylacetic acid (1 (1,3,5-trichloro-4-cyclopentylphenylacetic acid, so-
dium salt l a,3,5-trichloro-4-cyclopentylphenylacetic acid, so-
dium salt d a,3-dichloro-4-cycloheptylphenylacetic acid 1 a,3-dichloro-4-cycloheptylphenylacetic acid d a,3,5-trichloro-4-cycloheptylphenylacetic acid 1 oz,3,5-trichloro-4-cycloheptylphenylacetic acid d a-bromo-3-chloro-4-cycloheptylphenylacetic acid I a-bromo-3-chloro-4-cycloheptylphenylacetic acid (1 a-bromo-3,S-dichloro-4-cycloheptylphenylacetic acid 1 a-bromo-3,5-dichloro-4-cycloheptylphenylacetic acid d a-fluor0-3-chloro-4-cycloheptylphenylacetic acid I a-fluoro-3-ch]oro-4-cycloheptylphenylacetic acid d a-fluoro-3,5-dichloro-4-cycloheptylphenylacetic acid 1 a-fluoro-3,5-dichloro-4-cyclohepty1phenylacetic acid d (1,3,5-trichloro-4-cycloheptylphenylacetic acid, so-
dium salt 1 0:,3,5-trichloro-4-cycloheptylphenylacetic acid, so-
dium salt The compounds of this invention may be prepared by the following general procedures. Condensation of a cycloalkylbenzene with a loweralkyl or aralkyl oxalyl chloride in the presence of anhydrous aluminum chloride results in a p-cycloalkylphenylglyoxylate. The resulting loweralkyl or aralkyl esters of the p-cycloalkylphenylglyoxylic acid may then be a) halogenated, b) nitrated or c) alkylated to obtain the corresponding loweralkyl esters of a 3-halo-4-cyclloalkylphenylglyoxylic acid, a 3-nitro-4-cycloa1kylphenylglyoxylic acid or a 3-alkyl-4-cycloalkylphenyl-glyoxylic acid. Chlorination or bromination may be carried out in the presence of a small amount of iodine dissolved in an inert solvent such as carbon tetrachloride. A solution of chlorine or bromine is then added while the temperature is held near 0C. Nitration is carried out with fuming nitric acid at about 0C. Alkylation is carried out under F riedel Crafts conditions with an alkyl halide and aluminum chloride The following reaction equations illustrate these methods.
glyoxylate: [as described in Tetrahedron Letters:
where R" is loweralkyl or arloweralkyl and Hal is chloro or bromo.
When a loweralkyl group is desired in the cycloalkyl ring, then the condensation will take place with the appropriate loweralkyl benzene cycloalkyl followed by 5 nitration, chlorination, bromination or alkylation as desired.
1 i012 or Br;
c. reacted with cuprous methanesulfinate in quinoline at about 150C to obtain a 3-methylsulfonyl-4- cycloalkylphenylglyoxylate:
Hal
o (Grim, oooa" b. reacted with trifluoromethyliodide and copper powder at about C in dimethylformamide to obtain a 3-trifluoromethyl-4-cycloalkylphenyl- A 3-nitro-4-cycloalkylphenylglyoxylate may be selectively hydrogenated to the corresponding amine.
A 3-amino-4-cycloalkylphenylglyoxylate may then 07 diazotized and heated in an aqueous medium to be form the 3-hydroxy-4-cycloalkylphenylglyoxylate a. monoor dialkylated with loweralkyl halides or 20 or heated in an alcohol to form the 3-alkoxy-4- sulfates or acylated with loweracyl chlorides or ancycloalkylphenylglyoxylate. The hydroxyl group hydrides, may also be alkylated with loweralkyl halides or B 0 B 0 ;F l m- (first l COOR NH: NIIR" l{1' @O?i8" l B 0 B O f ll-3) C-COOR Hm CCOOR NI-ICOR Nut"):
b. diazotized to the diazonium fluoroborate which is sulfates to the alkoxyl group or acylated with lowthen thermally decomposed to the 3-fluoro-4- eracyl chlorides or anhydrides to the acyloxy comcycloalkylphenylglyoxylate, pound in the presence of a tertiary amine such as 40 pyridine,
B B o (6142),, -coon" c112 @-l: co 01v a I 1120 I N112 on QNOQ IR' C or R"COC1 H2O pyridine B 0 0142 h o o o R (ER con IINOz l Cu Cl CuI \IIINO2 15 16 e. diazotized and heated with an aqueous solution of cycloalkylphenylglyoxylate to obtain the correspondpotassium iodide to prepare the 3-iodo-4-cycloalking 3,5-disubstituted-4-cycloalkylphenylglyoxylate. ylphenylglyoxylate, This may be carried out at any appropriate stage of the f. diazotized followed by reaction with potassium synthesis in order to obtain the desired substituents.
ethylxanthate followed by hydrolysis to obtain 3- Thus, for example, a 3-chloro-4-cycloalkylphenylmercapto-4-cycloalkylphenylglyoxylic acid which glyoxylate may be nitrated as above to obtain a 3- can be esterified to a 3-mercapto-4-cycloalkyl- 15 chloro-S-nitro-4-cycloalkylphenylglyoxylate or chloriphenylglyoxylate. This in turn can be lower alkylnated to obtain a 3,5-dichloro 4-cycloalkylphenylated to the lower alkylthio and oxidized to the glyoxylate. A 3-nitro-4-cycloalkylphenylglyoxylate can loweralkylsulfinyl and loweralkylsulfonyl groups or benitrated to give a 3,5-dinitro-4-cycloalkylphenylacylated to the acylthio compounds. glyoxylate. A 3-alkyl compound may also be nitrated,
A second nitration or halogenation with chlorine or 35 chlorinated or brominated to the 3-chloro, 3-bromo or bromine may be carried out on the 3-substituted-4- 3-nitro-5-alkyl compounds.
B B Cl(Br) I o (C T COOR C12 i CH I E c '2 n n H I Cl(B1) 431(Br) li ITIO: 13
cum
In turn, a 3-chl0r0-5-nitr0-4-cycloalkylphenylglyoxy- 15 trifluorornethyl iodide and copper powder in quinoline late can be reduced to a corresponding 3-chloro-5- at 150C to obtain a 3-trifluoromethyl-5-nitro-4- amino-4-cycloalkylphenylglyoxylate. This may then be cycloalkylphenylglyoxylate; or with cuprous memonoor di-alkylated or acylated. The amine may also thanesulfinate in quinoline at 150C to a 3- be converted via the diazonium salt to a variety of demethylsulfonyl-S-nitro-4-cycloalk'ylphenylglyoxylate. rivatives as described above. Still another example of various disubstitution would be the selective reduction of a 3,5-dinitro-4-cycloalkyl- As a further example of disubstitution, a 3-chloro-5- phenylglyoxylate with hydrogen or ammonium sulfide nitro-4-cycloalkylphenylglyoxylate can be reacted with to obtain a 3-nitro-5-amino-4-cycloalkylphenylglyoxycuprous cyanide in quinoline at l50C to obtain a 3- late which in turn can be diazotized to the various decyano-S-nitro-4-cycl0alkylphenylglyoxylate; or with 25 riVati eS- B N02 B N02 lINOz lllilh IINOz CuBr lINOz Cul IINOz CuCN where R is lower alkyl HNOz KS CSO CzHi Cl(NO2) Cl(N 02) KNOz) -l-COOR B an 0 1) 11,) b-ooorv 2 NaOH and brorho groups converted to various substituents.
The p-cycloalkylphenylglyoxylate ester is converted to the corresponding p-cycloalkylphenylglycolate ester by hydrogenation in the presence of latinum oxide. In
Various mono-substituted products may also be ni- 40 the special case when R or R are su stituents sensitive trated, chlorinated or brominated as above and again, in turn, converted to the various desired substituents. Thus, for example, a 3-fluoro-4-cycloalkylphenylglyoxylate may be nitrated or brominated and the nitro to catalytic hydrogenation, e.g., when R or R is N0 SH, SR, SOR, 1, etc., a selective reduction of the keto function is effected with sodium borohydride to give the p-cycloalkylphenylglycolate ester.
It is often more convenient to convert one substituent sired substituents. This may be carried out on any of to another after the reduction of the glyoxylate to the the nitro compounds as outlined. The diazotized prodglycolate. Thus, for example, a 3-nitro-4-cycloalkylucts may then be hydrolyzed to the glycolic acid.
phenylglyoxylate or a 3-chloro-5-nitro-4-cycloalkyl- 60 Reaction of a substituted p-cy-cloalkylphenylglycop y 'g lf f can be reduced f Sodium bOrO- late ester with a nitrogen base such as ammonia, lowehydride conditions as above to the 3-n1tr0-4-cycloalkylralkylamine, diloweralkylaminey 1 k Phenylglycolate or 3"chloro's'mtro4'cycloalkylphe' mine, a nitrogen containing hetero compound such as nyl-glycolate. This in turn may then be catalytically reduced to the 3 amino 4 cycloalkylphenylglycolate or 65 piperldlne,morphollne,ptperaz1ne,hydroxylamme and 3-chloro-5-amino 4-cycloalkylphenylglycolate. The hydrazine gives the Corresponding amide, hydroxamlc amino group can then be diazotized as above to the deacid, or hydrazide.
where R" is lower alkyl The glycolate esters may be hydrolyzed to the corresponding p-cycloalkylphenylglycolic acid. Reaction of the glycolate ester or glycolic acid with an acid chloride YCl or acid anhydride YOY in the presence of a tertiary amine such as pyridine, picoline, or quinoline results in the formation of an hydroxy derivative of the glycolate. Examples of YCl and YOY include acetyl HZNOII alck 0 II/ B R a I 0 11).. -@o1r-oo OH YCl/r YOY YCl or YOY OCONU:
OSOZR OSOzAI Ar is phenyl or substituted phenyl O C OCHzCHzC O OH B i C0 0 CHCOOH (05*) e030;
0 7n n H /C R where R is lower alkyl The 3'cyanoglycolate may also be reacted with two B equivalents of methylmagnesium iodide in tetrahydro- 6+ furan followed by hydrolysis to obtain the 3- 60 (\Hzln acetylglycolic acid.
COGH: 3 K H When a substituted 4-cycloalkylphenylglycolate 15 K 65 reacted with a phosphorus trihalide. phosphorus pen- B tahalide. phosphorus oxyhalide, sulfurylhzllide. thionyl 1) Mm halide or sulfur halide the corresponding substituted H2O whalo-4-cycloalkylphenylacetute is prepared.
l Hal ((5112).. -JJH4J00R where R" is lower alkyl; where Hal is fluoro, chloro, bromo or iodo.
Reaction of an a-sulfonate with a metal halide (prefl5 erably an alkali halide) results in the corresponding a-halo compound.
3 R, OSO R(Ar) i- I 1 2 MHal Hzh Hal I H2)n CHOOZ where Z is as described on page 4.
The corresponding a-haloacetic acid may be prepared by heating the ester with acetic acid containing the corresponding hydrogen halide.
| vllal u OAe cm). oucoon I lIHal Hal (011 oHCooH where R" is lower alkyl.
The substituted oz-fluoro-4-cycloalkylphenylacetic acid derivatives may also be obtained from the corresponding a-iodo, oz-bromo or a-chloro-4-cycloalkyl- 5O phenylacetic acid derivatives by reaction with potassium fluoride at about l30200C.
This invention further relates to the acid addition salts formed by the action of one equivalent of a suitable base with the substituted a-halo-4-cycloalkylphenylacetic acid. Suitable bases thus include for example the alkali metal alkoxides such as sodium methoxide, etc., and the alkali metal and alkaline earth metal hydroxides, carbonates, bicarbonates. etc. (such as sodium hydroxide, potassium hydroxide. calcium hy droxide, potassium carbonate, sodium bicarbonate. magnesium bicarbonate, etc.). Also, the aluminum salts of the instant products may be obtained by treating the corresponding sodium salt with an appro riate aluminum complex such as aluminum hydroxy chloride hexahydrate, etc. The ammonium salts may be made by reaction with the corresponding amine such as methylaminc, diethylamine, B-hydroxyethylamine, piperazine, piperidine, a-methylbenzylamine, cyclohexylamine, triethylamine, phenethylamine, etc. The acid addition salts thus obtained are the functional equivalent of the corresponding substituted a-halo-P-cycloalkylphenylacetic acid products and one skilled in the art will appreciate that to the extent that the instant acids are useful in therapy, the variety of acid addition salts embraced by this invention are limited only by the criterion that the bases employed in forming the therapeutically useful salts be both non-toxic and physiologically acceptable. The alkaloidal salts are useful for effecting optical resolutions.
l on n UOOM where R" is lower alkyl.
l. A. Smith, Chem. Berichte 71B: 634 (1938).
I OH
The products of this invention may be obtained as racemic mixtures of their dextro and levorotatory isomers. These may be separated by any of the various methods of resolution. One method that may be employed is combining the racemic compound with an optically active compound by salt formtion, ester formation, or amide formation to form two diastereomeric products. If the instant acids are added to an optically active base, then two diastereomeric salts are produced which possess different properties and different solubilities and can be separated by fractional crystallization. When the salts have been completely separated by repeated crystallization, the base is split off by acid hydrolysis and the pure d and I acids are obtained. Preferably, a cycloalkylphenylglycolic acid is reacted in alcoholic or acetone solution with an equivalent amount of the optically active primary, secondary or tertiary amine such as cinchonidine, cinchonine, quinine, ephedrine, a-methylbenzyfamine, sec-butylamine, secamylamine, etc. The diastereomeric amine salts produced thereby are separated by fractional crystallization and each optically active salt is hydrolyzed with dilute mineral acid to produce the dextro or levo form of the p-cycloalkylphenylglycolic acid. Alternatively, a p-cycloalkylphenylglycolate ester may be reacted with an optically active primary or secondary amine such as ephedrine, a-methylbenzylamine, sec-butylamine, etc., to produce a mixture of diastereomeric p-cycloalkylphenylglycolamides which may be separated by fractional crystallization. Each optically active amide may be hydrolyzed with mineral acid to its respective opti-- cally active acid.
Still alternatively, a p-cycloalkylphenylglycolate may be reacted with an optically active alcohol such as l menthol or d-borneol, or l-a-methylbenzylalcohol, to produce a mixture of diastereomeric p-cycloalkylphenylglycolate esters which may be separated by fractional crystallization. Each optically active ester may be hydrolyzed with mineral acid or alkali to its respective optically active acid. The optically active acids can also be recovered from the a-methylbenzyl esters by hydrogenolysis in the presence of palladium.
The optically active glycolate may then be reacted with a phosphorus trihalide, phosphorus pentahalide, phosphorus oxyhalide, sulfurylhalide, thionylhalide or sulfur halide to give an optically active a-halo p-cycloalkylphenylacetic acid, ester or amide thereof.
The racemic chloroacetic acids, esters and amides may also be resolved into their optical isomers by the processes described for the glycolic acids, esters and amides.
We have found that the compounds of this invention exercise a useful degree of anti-inflammatory activity in mammals and are effective in the treatment of associated pain and fever and in like conditions which are responsive to treatment with anti-inflammatory agents. In general, the compounds of this invention are indicated for a wide variety of mammalian conditions where the symptoms of inflammation and associated fever and pain are manifested. Exemplary of such conditions are: rheumatic diseases such as rheumatoid arthritis, osteoarthritis and other degenerative joint diseases; softtissue rheumatism such as tendinitis muscluar rheumatism such as sciatica; pain and inflammation associated with dental surgery and similar human and veterinary disease conditions exhibiting the foregoing symptoms requiring the use of anti-inflammatory, analgesic and- /or antipyretic agent.
For these purposes, the compounds of this invention are normally administered orally, topically, parenterally or rectally. Orally, these may be administered in tablets, capsules, suspensions or syrups; the optimum dosage, of course, depending on the particular compound being used and the type and severity of the condition being treated. In any specific case the appropriate dosage selected will further depend on factors of the patient which may influence response to the drug; for example, general health, age, weight, etc. Although the optimum quantities of the compounds of this invention to be used in such manner will depend on the compound employed and the particular type of disease condition treated,oral dose levels of preferred compounds when administered to a mammal in dosages of 0.5 to milligrams per kilogram of body weight per day are particularly useful. The preferred range is 0.5 to 15 mg/Kg. Comparative dosages may be used in topical, parenteral or rectal administration.
Dosage forms may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents; for example, sweetening agents, flavoring agents, coloring agents, preserving agents, etc. Further, the active a-halo-p-cycloalkyphenylacetic acids or their derivatives may be administered alone or in admixture with antacids such as sodium bicarbonate, magnesium carbonate, magnesium hydroxide, aluminum hydroxide, magnesium silicate, etc., and non-toxic pharmaceutically acceptable excipients. Such excipients may be, for example, inert diluents such as calcium carbonate, lactose, etc., granulating and disintegrating agents; for example maize starch, alginic acid, etc., lubricating agents; for example, magnesium stearate, talc, etc., binding agents; for example, starch gelatin, etc., suspending agents; for example, methylcellulose, vegetable oil, etc., dispersing agents; for example, lecithin, etc., thickening agents; for example, beeswax, hard paraffin, etc., emulsifying agents; for example, naturally-occurring gums, etc., and nonirritating excipients; for example, cocoa butter and polyethylene glycols.
Various tests in animals can be carried out to show the ability of the a-halo-p-cycloalkylphenylacetic acids and derivatives of this invention to exhibit reactions that can be correlated with anti-inflammatory activity in humans. One such test is the Carrageenan paw edema test, which shows the ability of the instant compounds to inhibit edema induced by injection of an inflammatory agent such as carrageenan into the tissues of the paw of a rat against non-inflammed controls. This carrageenan testing method is known to correlate well with anti-inflammatory activity in humans and is a standard test used to determine anti-inflammatory activity. This correlation can be shown by the activities of compounds known to be clinically active including such as aspirin, phenylbutazone, cortisone, hydrocortisone and prednisolone. In view of the results of this test, the a-halo-p-cycloalkylphenylacetic acids and derivatives can be considered to be active antiinflammatory agents.
One method for measuring the pain threshold of the a-halo-p-cycloalkylphenylacetic acids and derivatives is the Randall-Selitto test. Analgesic activity is shown by antinocieceptive testing of the inflammed foot of rats and a measurement of their pain response.
Antipyretic assay is carried out by yeast-induced fever tests of subcutaneously injected rats. The measurement of rectal temperatures is carried out to determine the response by the test compounds.
In view of the results of the above tests, the a-halo-pcyclo-alkylphenylacetic acids and derivatives of this invention are considered to have valuable analgesic and antipyretic properties.
Other tests which can be correlated to show signifi' cant activities are the phenylquinone writhing test for analgesia, polyarthritis in rats and ultraviolet erythema in guinea pigs.
The following are detailed examples which show the preparation of the compounds of this invention. They are to be construed as illustrations of said compounds and are not intended to be limitations thereof.
EXAMPLE 1 Ethyl p-cyclohexylphenylglyoxylate Cyclohexylbenzene 53 g. (0.33 mole) and 50.5 g. (0.37 mole) of ethyl oxalyl chloride are dissolved in 200 ml. of dry l,l,2,2-tetrachloro-ethane. Anhydrous aluminum chloride 52 g. (0.39 mole) is added in small portions to the reaction mixture with stirring over 2 hours. During the addition, the temperature of the mixture is maintained between l5-l8C. The mixture is stirred for an additional hour and allowed to stand overnight. The solution is then slowly poured into 1500 ml. of iced saline solution with stirring. After standing, two layers form. The aqueous layer is extracted with 500 ml. of ether and the ether extract is combined with the organic layer which is dissolved in 1500 ml. of ether and separated. The ether solution is washed with X 100 ml. portions of a l:l mixture of saturated sodium chloride solution and 10 percent HCll solution, and 5 X 100 ml. portions of water. The ether solution is then dried over anhydrous magnesium sulfate for 1 hour and filtered. The solvents are removed by distillation under reduced pressure and the residue distilled to obtain ethyl p-cyclohexylphenylglyoxylate. (b.p. l657C/l .1 mm.)
When cyclohexylbenzene in the above example is replaced with cyclopentylbenzene, cycloheptylbenzene, 2'-methylcyclohexybenzene, 3'-methylcyclohexylbenzene, 4-methylcyclohexylbenzene, 2-methylcyclopentylbenzene or 2-methylcycloheptylbenzene then the product obtained is ethyl p-cyclopentylphenylglyoxylate, ethyl p-cycloheptylphenylglyoxylate, ethyl 4-(2-methylcyclohexyl)phenylglyoxylate, ethyl 4-(3'-methycyclohexyl)phenyl-glyoxylate, ethyl 4-4-methylcyclohexyl)phenylglyoxylate, ethyl 4(2- methylcyclopentyl)phenylglyoxylate or ethyl 4-(2- methylcycloheptyl)phenyl-glyoxylate.
When ethyl oxalyl chloride in the above example is replaced with methyl oxalyl chloride, propyl oxalyl chloride, i-propyl oxalyl chloride, t-butyl oxalyl chloride, or benzyl oxalyl chloride then the product obtained is methyl p-cyclohexylphenylglyoxylate, propyl p-cyclohexylphenylglyoxylate, i-propyl p-cyclohexylphenylglyoxylate, t-butyl p-cyclohexylphenylglyoxylate, or benzyl p-cyclohexylphenylglyoxylate.
EXAMPLE 2 Ethyl 3-chloro-4-cyclohexylphenylglyoxylate Ethyl p-cyclohexylphenylglyoxylate 98.9 g. (0.38 mole) and 6.l g. of iodine (0.048 mole) and dissolved in I00 ml. of carbon tetrachloride. To this solution is added a solution of 40.4 g. (0.57 mole) of chlorine dis ethyl 3-chloro-4-cyclopentylphenylglyoxylate ethyl 3-chloro-4-( 2'-methylcyclopentyl )phenylglyoxylate ethyl 3-chloro-4-cycloheptylphenylglyoxylate ethyl 3-chloro-4-( 2-methylcycloheptyl )phenylglyoxylate ethyl 3-chloro-4-( 2 '-methylcyclohexyl )phenylglyoxylate ethyl 3-chloro-4-( 3 '-methylcyclohexyl )phenylglyoxylate ethyl 3-chloro-4-(4-methylcyclohexyl )phenylglyoxylate methyl 3-chloro-4-cyclohexylphenylglyoxylate propyl 3-chloro-4 cyclohexylphenylglyoxylate i-propyl 3-chloro-4-cyclohexylphenylglyoxylate t-butyl 3*chloro-4-cyclohexylphenylglyoxylate benzyl 3-chloro-4-cyclohexylphenylglyoxylate EXAMPLE 3 Ethyl 3,5-dichloro-4-cyclohexylphenylglyoxylate Ethyl p-cyclohexylphenylglyoxylate, 49.5 g (0.l9 mole) and 6.1 g. of iodine are dissolved in ml. of carbon tetrachloride. to this solution is added a solution of 56.7 g (0.8 mole) of chlorine dissolved in 500 ml. of carbon tetrachloride over a period of 3 hours. During the addition, the temperature of the reaction mixture is maintained at 0C. The mixture is stirred for 3 hours and allowed to stand with gradual warming to room temperature over 30 hours. The solvent is removed in vacuo. The residue is fractionally distilled to obtain ethyl 3,5-dichlorofou1r-cyclohexylphenylglyoxylate.
When ethyl p-cyclohexylphenylglyoxylate in the above example is replaced by the esters of Example 1, then the corresponding product of Table 1 below is prepared.
TABLE I ethyl 3,5-dichloro-4-cyclopentylphenylglyoxylate ethyl 3,5-dichloro-4-(2-methylcyclopentyl)phenylglyoxylate ethyl 3,5-d ichloro-4-cycloheptylphenylglyoxylate ethyl 3,5-dichloro-4-(2-methylcycloheptyl)phenylglyoxylate ethyl 3,5-dichloro-4-(2-methylcyclohexyl)phenylglyoxylate ethyl 3,5-dichloro-4-(3'methylcyclohexyl)phenyl glyoxylate ethyl 3,5-dichloro-4-(4-methylcyclohexyl)phenylglyoxylate methyl 3,5-dichloro-4-cyclohexylphenylglyoxylate propyl 3,5dichloro-4-cyclohexylphenylglyoxylate i-propyl 3,S-dichloro-4-cyclohexylphenylglyoxylate 35 t-butyl 3,5-dichloro-4-cyclohexylphenylglyoxylate benzyl 3,5-dichloro-4-cyclohexylphenylyoxylate When the esters of Table l, Example 2 are used then the same products are obtained.
EXAMPLE 4 When bromine is used in place of chlorine in Examplcs 2 and 3, the products obtained are shown in Tables I and II below.
TABLE I ethyl 3-bromo-4-cyclopentylphenylglyoxylate ethyl 3-bromo-4-( 2 '-methylcyclopentyl )phenylglyoxylate ethyl 3-bromo-4-cycloheptylphenylglyoxylate ethyl 3-bromo-4-( 2 '-methylcycloheptyl )phenylglyoxylate ethyl 3-bromo4-cyclohexylphenylglyoxylate ethyl 3-bromo-4-(2'-cyclohexyl)phenylglyoxylate ethyl 3-bromo-4-(3-cyclohexyl)phenylglyoxylate ethyl 3-bromo-4-(4'-cyclohexyl)phenylglyoxylate methyl 3-bromo-4-cyclohexylphenylglyoxylate propyl 3-bromo-4-cyclohexylphenylglyoxylate i-propyl 3-bromo-4-cyclohexylphenylglyoxylate t-butyl 3-bromo-4-cyclohexylphenylglyoxylate benzyl 3-bromo-4-cyclohexylphenylglyoxylate TABLE II EXAMPLE 5 Ethyl 3-nitro-4-cyclohexylphenylglyoxylate Ethyl p-cyclohexylphenylglyoxylate 17.2 g. (0.066 mole) is added to ice-cold concentrated sulfuric acid (18 ml) and stirred with cooling for 5 minutes. Concentrated nitric acid (Sp. 0. 1,51) 2.5 ml.) is added dropwise, maintaining the temperature between 30 and 40 by water cooling if necessary. After addition of the nitric acid is complete, the mixture is stirred for /zhour, then poured into water. The mixture is made alkaline with sodium hydroxide, then extracted with ether. The ether extract is washed, dried over sodium sulfate, evaporated and the residue is fractionally distilled to obtain ethyl 3-nitro-4-cyclohexylphenyl-glyoxylate.
When ethyl p-cyclohexylphenylglyoxylate in the above example is replaced by the esters of Example I, then the corresponding product of Table l below is prepared.
Table l ethyl 3-nitro-4-cyclopcntylphenylglyoxylate 36 ethyl 3-nitro-4-(2'methylcyclopentyl)phenylglyoxylate ethyl 3-nitro-4-cycloheptylphenylglyoxylate ethyl 3-nitro-4-(2'-methylcycloheptyl)phenylglyoxylate ethyl 3-nitro-4-(2-methylcyclohexyl)phenylglyoxylate ethyl 3-nitro-4-( 3 '-methylcyclohexyl )phenylglyoxylate ethyl 3-nitro-4-(4'-methylcyclohexyl)phenylglyoxylate methyl 3-nitro-4-cyclohexylphenylglyoxylate propyl 3-nitro- 4-cyclohexylphenylglyoxylate i-propyl 3-nitro-4-cyclohexylphenylglyoxylate t-butyl 3-nitro-4-cyclohexylphenylglyoxylate benzyl 3-nitro-4-cyclohexylphenylglyoxylate When ethyl p-cyclohexylphenylglyoxylate in the above example is replaced by the esters of Example 2 and Table l of Example 4, then the corresponding product of Table ll below is prepared.
TABLE II ethyl 3-chloro-5-nitro-4-cyclopentylphenylglyoxylate ethyl 3-chloro-5-nitro-4 (2'methylcyclopentyl)- phenylglyoxylate ethyl 3chloro-5-nitro-4-cycloheptylphenylglyoxylate ethyl 3-chloro-5-nitro-4-(2-methylcycloheptyl)- phenylglyoxylate ethyl 3-chloro-5-nitro-4-(2'-methylcyclohexyl)- phenylglyoxylate ethyl phsz yks yqxylaw ethyl 3-chloro-5-nitro-4-(4'-methylcyclohexyl)- phenylglyoxylate methyl 3-chloro-5-nitro-4-cyclohexylphenylglyoxylate ethyl 3-chloro-5nitro-4cyclohexylphenylglyoxylate propyl 3-chloro-5-nitro-4-cyclohexy[phenylglyoxylate i-propyl 3-chloro-5-nitro-4-cyclohexylphenylglyoxylate t-butyl 3-chloro-5-nitro-4-cyclohexylphenylglyoxylate benzyl 3-chloro-5-nitro-4-cyclohexylphenylglyoxylate ethyl 3-bromo-5-nitro-4-cyclopentylphenylglyoxy late ethyl 3-bromo-5nitro-4-( 2-methylcyclopentyl phenylglyoxylate ethyl 3-bromo-5-nitro-4-cycloheptylphenylglyoxylate ethyl 3-bromo-5-nitro-4-( 2 -methylcycloheptyl propyl 3-bromo-5-nitro-4-cyclohexylphenylglyoxylate i-propyl 3-bromo-5-nitro-4-cyclohexylphenylglyoxylate t-butyl 3-bromo-5-nitro-4-cyclohexylphcuylglyoxylate 3-chloro-5-nitro-4-(3-methylcycl0hexyl)- benzyl 3 bromo--nitro 4-cyclohexylphenylglyoxy- Ethyl 3,5-dinitro-4-cyclohexylphenylglyoxylate Ethyl p-cyclohexylphenylglyoxylate 17.2 g. (0.066 mole) is added to ice-cold concentrated sulfuric acid (54 ml.) and stirred with cooling for 5 minutes. Concentrated nitric acid (Sp. G. 1.51) (7.5 ml.) is added dropwise, maintaining the temperature between 30 and 40 by water cooling if necessary. After addition of the nitric acid is complete, the mixture is stirred for 3 hours, then poured into water. The mixture is made alkaline with sodium hydroxide, then extracted with ether. The ether extract is washed, dried over sodium sulfite, evaporated and the residue is fractionally distilled to obtain ethyl 3,5-dinitro-4-cyclohexylphenylglyoxylate.
When ethyl p-cyclohexylphenylglyoxylate in the above example is replaced by the esters of Example 1, then the corresponding product of Table I below is prepared.
TABLE I EXAMPLE 7 Ethyl 3-trifluoromethyl-4-cyclohexylphenylglyoxylate To a solution of 0.01 moles of ethyl 3-bromo-4 cyclohexylphenylglyoxylate in 50 ml. of dimethylformamide is added 0.15 moles of trifluoromethyl iodide and 0.02 g. of copper power. The reaction is shaken in a sealed tube for 5 hours at 140C, cooled, and then filtered and evaporated in vacuo. 200 ml. of water is added to the residue and extracted with ether. The
ether extract is dried, evaporated to dryness and distilled to obtain ethyl 3-trifluoromethyl-4-cyclohexylphenylglyoxylate.
When ethyl 3bromo-4-cyclohexylphenylglyoxylate in the above example is replaced by equimolar amounts of the compounds of Tables 1 and 11 of Example 4 and Table 11, Example 5, then the corresponding product is obtained.
EXAMPLE 8 Ethyl 3-amino-4-cyclohexylphenylglyoxylate A mixture of 15.3 g. (0.05 moles) of ethyl 3-nitro-4- cyclohexylphenylglyoxylate in 100 m1. methanol containing 0.05 mole citric acid and 1.5 g. of 5 percent palladium-omcarbon is shaken with hydrogen at 3 atm. pressure and 27C until 3 moles of hydrogen are absorbed. The mixture is filtered, washed with methanol and the filtrate concentrated in vacuo to obtain ethyl 3-amino-4-cyclohexylphenylglyoxylate, isolated as the citrate salt.
When ethyl 3-nitro-4-cyclohexylphenylglyoxylate in the above example is replaced by equimolar amounts of the compounds of Tables I and 11, Example 5 and Table 1, Example 6, then the corresponding products are obtained.
EXAMPLE '9 Ethyl 3-methylamino-4-cyclohexylphenylglyoxylate To a solution of 0.01 moles of ethyl 3-amino-4- cyclohexylphenylglyoxylate in 100 ml. of pyridine is added 0.1 moles of methyl iodide. The reaction mixture is stirred overnight at room temperature, filtered and concentrated. The residue is distilled to obtain ethyl 3- methylamino-4-cyclohexylphenylglyoxylate.
When ethyl 3-amino4-cyclohexylphenylglyoxylate in the above example is replaced by equimolar amounts of the compounds of Example 8, then the corresponding products are obtained.
When 0.01 moles of acetyl chloride is used in place of methyl iodide in the above example, then the product prepared is ethyl-3-acetylamino-4-cyclohexylphenylglyoxylate.
EXAMPLE 10 Ethyl 3-dimethylamino-4-cyclohexylphenylglyoxylate A solution of 0.005 moles of ethyl 3-nitro-4- cyclohexylphenylglyoxylate and 1.6 ml. of 37 percent formaldehyde in 50 ml. of methanol is shaken with hydrogen over 0.5 g. of 5 percent palladium-on-charcoal at 42 lbs. and 27C until five moles of hydrogen are absorbed. The catalyst is filtered off and the filtrate is evaporated in vacuo. The residue is then distilled to obtain ethyl 3-dimethylamino-4-cyclohexylphenylglyoxylate.
When ethyl 3-nitro-4-cyclohexylphenylglyoxylate in the above example is replaced by equimolar amounts of the compounds of Tables 1 and 11, Example 5 and Table 1, Example 6, then the corresponding products are obtained.
EXAMPLE 1 1 Ethyl 3-cyano-4-cyclohexylphenylglyoxylate To 29.4 g. (01 moles) of ethyl 3-amino-4-cyc1ohexylphenylglyoxylate in 35 ml. of 28 percent hydrochloric acid and 100 ml. of cracked ice to maintain the temperature at 0C is added a solution of 7.1 g. (0.102 moles) of sodium nitride in 20 ml. of water. The reaction mixture is then neutralized with sodium carbonate. This diazonium mixture is added to a cuprous cyanide solution (prepared from 31.5 g. of copper sulfate and 16.2 g. of sodium cyanide in ml. of water). 250 ml. of toluene is also added and the mixture is stirred for /2 hour. The reaction is then allowed to stir an. additional 2 hours while warming gradually to 50C. This is then cooled and the toluene separate, dried over sodium sulfate and evaporated to dryness to obtain ethyl 3-cyano-4- cyclohexylphenylglyoxylate.
When ethyl 3-amino-4-cyclohexylphenylglyoxylate in the above example is replaced by equimolar amounts

Claims (42)

1. A COMPOUND OF THE FORMULA
2. A compound of the formula
3. A compound according to claim 2 which is dextrorotatory.
4. A compound according to claim 2 which is levorotatory.
5. A compound according to claim 2 of the formula
6. A compound according to claim 5 which is dextrorotatory.
7. A compound according to claim 5 which is levorotatory.
8. A compound according to claim 5 where: R is chloro and R'' is chloro thus forming Alpha ,3,5-trichloro-4-cyclohexylphenylacetic acid.
9. A compound according to claim 5 where: R is bromo and R'' is chloro thus forming Alpha ,3-dichloro-5-bromo-4-cyclohexylphenylacetic acid.
10. A compound according to claim 5 where: R is nitro and R'' is chloro thus forming Alpha ,3-dichloro-5-nitro-4-cyclohexylphenylacetic acid.
11. A compound according to claim 5 where: R is methylsulfonyl and R'' is chloro thus forming Alpha ,3-dichloro-5-methylsulfonyl-4-cyclohexylphenylacetic acid.
12. A compound according to claim 5 where: R is trifluoromethyl and R'' is chloro thus forming Alpha ,3-dichloro-5-trifluoromethyl-4-cyclohexylphenylacetic acid.
13. A compound according to claim 5 where: R is cyano and R'' is chloro thus forming Alpha ,3-dichloro-5-cyano-4-cyclohexylphenylacetic acid.
14. A compound according to claim 5 where: R is bromo and R'' is bromo thus forming Alpha -chloro-3,5-dibromo-4-cyclohexylphenylacetic acid.
15. A compound according to claim 5 where: R is nitro and R''is bromo thus forming Alpha -chloro-3-bromo-5-nitro-4-cyclohexylphenylacetic acid.
16. A compound according to claim 5 where: R is methylsulfonyl and R'' is bromo thus forming Alpha -chloro-3-bromo-5-methylsulfonyl-4-cyclohexylphenylacetic acid.
17. A compound according to claim 5 where: R is trifluoromethyl and R'' is bromo thus forming Alpha -chloro-3-bromo-5-trifluoromethyl-4-cyclohexylphenylacetic acid.
18. A compound according to claim 5 where: R is cyano and R'' is bromo thus forming Alpha -chloro-3-bromo-5-cyano-4-cyclohexylphenylacetic acid.
19. A compound according to claim 5 where: R is nitro and R'' is nitro thus forming Alpha -chloro-3,5-dinitro-4-cyclohexylphenylacetic acid.
20. A compound according to claim 5 where: R is methylsulfonyl and R'' is nitro thus forming Alpha -chloro-3-methylsulfonyl 5-nitro-4-cyclohexylphenylacetic acid.
21. A compound according to claim 5 where: R is trifluoromethyl and R'' is nitro thus forming Alpha -chloro-3-nitro-5-trifluoromethyl-4-cyclohexylphenylacetic acid.
22. A compound according to claim 5 where: R is cyano and R'' is nitro thus forming Alpha -chloro-3-cyano-5-nitro-4-cyclohexylphenylacetic acid.
23. A compound according to claim 6 where: R is chloro and R'' is chloro thus forming d Alpha ,3,5-trichloro-4-cyclohexylphenylacetic acid.
24. A compound according to claim 7 where: R is chloro and R'' is chloro thus forming l Alpha ,3,5-trichloro-4-cyclohexylphenylacetic acid.
25. A compound according to claim 6 where: R is bromo and R'' is chloro thus forming d Alpha ,3-dichloro-5-bromo-4-cyclohexylphenylacetic acid.
26. A compound according to claim 7 where: R is bromo and R'' is chloro thus forming l Alpha ,3-dichloro-5-bromo-4-cyclohexylphenylacetic acid.
27. A compound according to claim 6 where: R is nitro and R'' is chloro thus forming d Alpha ,3-dichloro-5-nitro-4-cyclohexylphenylacetic acid.
28. A compound according to claim 7 where: R is nitro and R'' is chloro thus forming l Alpha ,3-dichloro-5-nitro-4-cyclohexylphenylacetic acid.
29. A compound according to claim 6 where: R is methylsulfonyl and R'' is chloro thus forming d Alpha ,3-dichloro-5-methylsulfonyl-4-cyclohexylphenylacetic acid.
30. A compound according to claim 7 where: R is methylsulfonyl and R'' is chloro thus forming l Alpha ,3-dichloro-5-methylsulfonyl-4-cyclohexylphenylacetic acid.
31. A compound according to claim 6 where: R is trifluoromethyl and R'' is chloro thus forming d Alpha ,3-dichloro-5-trifluoromethyl-4-cyclohexylphenylacetic acid.
32. A compound according to claim 7 where: R is trifluoromethyl and R'' is chloro thus forming l Alpha ,3-dichloro-5-trifluoromethyl-4-cyclohexylphenylacetic acid.
33. A compound according to claim 6 where: R is cyano and R'' is chloro thus forming d Alpha ,3-dichloro-5-cyano-4-cyclohexylphenylacetic acid.
34. A compound according to claim 7 where: R is cyano and R'' is chloro thus forming l Alpha ,3-dichloro-5-cyano-4-cyclohexylphenylacetic acid.
35. A compound according to claim 6 where: R is bromo and R'' is bromo thus forming d Alpha -chloro-3,5-dibromo-4-cyclohexylphenylacetic acid.
36. A compound according to claim 7 where: R is bromo and R'' is bromo thus forming l Alpha -chloro-3,5-dibromo-4-cyclohexylphenylacetic acid.
37. A compound according to claim 6 where: R is trifluoromethyl and R'' is bromo thus forming d Alpha -chloro-3-bromo-5-trifluoromethyl-4-cyclohexylphenylacetic acid.
38. A compound according to claim 7 where: R is trifluoromethyl and R'' is bromo thus forming l Alpha -chloro-3-bromo-5-trifluoromethyl-4-cyclohexylphenylacetic acid.
39. A compound according to claim 8 which is the sodium salt.
40. A compound according to claim 8 which is the diethylammonium salt.
41. A compound according to claim 23 which is the sodium salt.
42. A compound according to claim 24 which is the diethylammonium salt.
US00152387A 1970-05-05 1971-06-11 Phenylacetic acids Expired - Lifetime US3852323A (en)

Priority Applications (16)

Application Number Priority Date Filing Date Title
US00152387A US3852323A (en) 1970-05-05 1971-06-11 Phenylacetic acids
BE776316A BE776316R (en) 1971-03-10 1971-12-06 Phenylacetic acid derivs - as antiinflammatory agents
DE19712162038 DE2162038A1 (en) 1970-05-05 1971-12-10 Process for the production of synthetic alkanoic acids and their derivatives
CA129,890A CA1027133A (en) 1971-03-10 1971-12-10 Substituted alkanoic acids and their derivatives, and process
FR7144544A FR2128277B2 (en) 1970-05-05 1971-12-10
NL7117006A NL7117006A (en) 1971-03-10 1971-12-10 Phenylacetic acid derivs - as antiinflammatory agents
GB5751071A GB1382267A (en) 1970-05-05 1971-12-10 Phenylalkanoic acid derivatives
ES397844A ES397844A1 (en) 1971-03-10 1971-12-10 A procedure to produce a substituted fenilhaloalconoic acid and its derivatives. (Machine-translation by Google Translate, not legally binding)
IL38916A IL38916A0 (en) 1971-03-10 1972-03-07 Substituted alkanoic acids and their derivatives,processes for their preparation and pharmaceutical compositions comprising the same
US05/423,444 US4008269A (en) 1970-05-05 1973-12-10 Phenylacetic acids
SE7501717A SE7501717L (en) 1971-03-10 1975-02-17 WAY TO PRODUCE NEW HYDROXY, HALO AND TIOALCANIC ACID ASSOCIATIONS.
SE7501716A SE7501716L (en) 1971-03-10 1975-02-17 WAY TO PRODUCE NEW HYDROXY, HALO AND TIOALCANIC ACID ASSOCIATIONS.
FR7508269A FR2279386A2 (en) 1970-05-05 1975-03-17 NEW DERIVATIVES OF PHENYL (SUBSTITUTE) HYDROXYALKANOIC ACIDS
FR7508270A FR2282867A2 (en) 1970-05-05 1975-03-17 NEW DERIVATIVES OF PHENYL (SUBSTITUTE) HALOGENOALKANOIC ACIDS
FR7508271A FR2279387A2 (en) 1970-05-05 1975-03-17 NEW DERIVATIVES OF PHENYL (SUBSTITUTE) THIOALKANOIC ACIDS
AR239472D AR206491A1 (en) 1971-03-10 1976-07-30 A PROCEDURE FOR PRODUCING A SUBSTITUTED PHENYLHALOALKANOIC ACID AND ITS DERIVATIVES

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US034870A US3864384A (en) 1970-05-05 1970-05-05 Substituted phenylacetic acid compounds
US00152387A US3852323A (en) 1970-05-05 1971-06-11 Phenylacetic acids

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US034870A Continuation-In-Part US3864384A (en) 1970-05-05 1970-05-05 Substituted phenylacetic acid compounds
US00152387A Continuation-In-Part US3852323A (en) 1970-05-05 1971-06-11 Phenylacetic acids

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US00152387A Continuation-In-Part US3852323A (en) 1970-05-05 1971-06-11 Phenylacetic acids
US05/423,444 Division US4008269A (en) 1970-05-05 1973-12-10 Phenylacetic acids

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3978124A (en) * 1971-11-04 1976-08-31 Syntex Corporation 6-Substituted 2-naphthyl α-substituted acetamides
US3985788A (en) * 1971-07-21 1976-10-12 William H. Rorer, Inc. Phenyl propionic acids and derivatives thereof
US4173577A (en) * 1970-09-09 1979-11-06 Ciba-Geigy Corporation Phenylacetohydroxamic acids
US4329487A (en) * 1979-06-05 1982-05-11 Director-General Of Agency Of Industrial Science And Technology Method for the asymmetric hydrogenation of α-ketoesters
US5227511A (en) * 1988-12-23 1993-07-13 Hodogaya Chemical Co., Ltd. Benzamide derivatives and plant growth regulants containing them

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4173577A (en) * 1970-09-09 1979-11-06 Ciba-Geigy Corporation Phenylacetohydroxamic acids
US3985788A (en) * 1971-07-21 1976-10-12 William H. Rorer, Inc. Phenyl propionic acids and derivatives thereof
US3978124A (en) * 1971-11-04 1976-08-31 Syntex Corporation 6-Substituted 2-naphthyl α-substituted acetamides
US4329487A (en) * 1979-06-05 1982-05-11 Director-General Of Agency Of Industrial Science And Technology Method for the asymmetric hydrogenation of α-ketoesters
US5227511A (en) * 1988-12-23 1993-07-13 Hodogaya Chemical Co., Ltd. Benzamide derivatives and plant growth regulants containing them

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