[go: up one dir, main page]

US3821268A - Alpha-acylthio biphenylylacetic acids - Google Patents

Alpha-acylthio biphenylylacetic acids Download PDF

Info

Publication number
US3821268A
US3821268A US00152366A US15236671A US3821268A US 3821268 A US3821268 A US 3821268A US 00152366 A US00152366 A US 00152366A US 15236671 A US15236671 A US 15236671A US 3821268 A US3821268 A US 3821268A
Authority
US
United States
Prior art keywords
acid
biphenylylacetic
chloro
acetylthio
biphenylylacetic acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US00152366A
Inventor
J Diamond
N Santora
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
William H Rorer Inc
Original Assignee
William H Rorer Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US034870A external-priority patent/US3864384A/en
Priority to US00152366A priority Critical patent/US3821268A/en
Application filed by William H Rorer Inc filed Critical William H Rorer Inc
Priority to BE776316A priority patent/BE776316R/en
Priority to GB5751071A priority patent/GB1382267A/en
Priority to NL7117006A priority patent/NL7117006A/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 IL38916A priority patent/IL38916A0/en
Publication of US3821268A publication Critical patent/US3821268A/en
Application granted granted Critical
Priority to SE7501716A priority patent/SE7501716L/en
Priority to SE7501717A priority patent/SE7501717L/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
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • 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
    • C07C57/62—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen containing six-membered aromatic rings and other rings
    • 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
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
    • C07C205/56—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups bound to carbon atoms of six-membered aromatic rings and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C313/00—Sulfinic acids; Sulfenic acids; Halides, esters or anhydrides thereof; Amides of sulfinic or sulfenic acids, i.e. compounds having singly-bound oxygen atoms of sulfinic or sulfenic groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C—CHEMISTRY; METALLURGY
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D277/54—Nitrogen and either oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • This invention describes certain cz-rnercapto-pbiphenylylacetic acids and their derivatives and their use in therapeutic compositions. in addition, this invention relates to the preparation of these oz-mercapto-pbiphenylylacetic 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.
  • the compounds of this invention are useful in effectively providing a method for theinhibition of inflammation and the treatment of as; sociated pain and fever.
  • This invention comprises a class of novel chemical compounds which contain a phenyl or substituted phenyl radical which is attached to a substituted phenyl or phenyl-a-mercaptoacetic acid in the para-position. This invention further comprises derivatives of said acetic 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 gen- I eral formula I t. R R
  • P is hydrogen or loweralkyl
  • R and R are hydrogen or not more than one of R or R at the same time is halo
  • Z is -OH, loweralkoxy
  • 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 racemic mixtures of their dextro and levorotatory isomers. It is to be un derstood that said d and l isomers as well as the d! mixtures thereof are embraced within the scope of this invention.
  • R, R, Ra, X & Z are as described above.
  • Ra is hydrogen or loweralkyl
  • R is halo
  • Z is OH, loweralkoxy
  • R is chloro
  • X is hydrogen
  • racemic mixtures as well as the dextro and levorotatory isomers thereof.
  • loweralkyl refers to a loweralkyl hydrocarbon group containing from one to about six 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-propenol, 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 preferred aroyl is benzoyl, loweralkylbenzoyl such as toluoyl or halobenzoyl such as p-chlorobenzoyl, 2-carboxybenzoyl, etc.
  • loweralkylidenyl refers to a loweralkylidenyl hydrocarbon group containing from two to about six carbon atoms.
  • Heteroloweralkylidenyl refers to a loweralkylidenyl hydrocarbon group containing from about two to five 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 Z-aminopyridine, piperazine, piperidine; (4) aralkylamines such as a-methylbenzylamine, phenethylamine; (5) cycloalkylamines such as cyclohexylamine; (6) alkaloids such as quinine, cinchonidine, cinchonine, ephedrine.
  • the compounds of this invention may be prepard by the following general procedures. substituted biphenyl compound and in this manner the Condensation of a biphenyl compound with a lowerresultant product would be the corresponding substialkyl or aralkyl oxalyl chloride in the presence of anhytuted a-alkylbiphenylylglycolate or the biphenylylw el n rwsb id r su t m3 ziph y ylslyetyi 5 sued-ate V. v
  • a 2' nitro-4-biphenylylglycolate may be selectively OH CN O -t J-0ooR" hydrogenated to the corresponding amine.
  • a 3-aminoflbiphenylylglycolate may then be a; monoor dialkylated with loweralkyl halides or sulfatesor acylated with loweracyl chlorides or anhydrides,
  • H f form the 3-hydroxy-4-biphenylylglycolate or i heated in an alcohol to form the 3-alkoxy-4- al biphenylylglycolate.
  • the hydroxyl group may also 0H be alkylated with loweralkyl halides or sulfates to J; the alkoxyl group or acylated with loweracyl chlofi rides or anhydrides to the acyloxy compound in the oiom presence of a tertiary amine such as pyridine,
  • Reaction of an a-sulfonate with a metal halide results in the corresponding a-halo compound.
  • the acid addition salts may then be formed by the action of one equivalent of a suitable base with the substituted a-halo-4-biphenylylacetic 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 hydroxide, 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 appropriate aluminum complex such as aluminum hydroxy chloride hexahydrate, etc.
  • ammonium salts may be made by reaction with the corresponding amine such as methylamine, diethylamine, B-hydroxyethylamine, piperazine, piperidine, a-methylbenzyla- H 4 N Hal 7 R R Ru 5 -coolt l Hal Hal 1! ⁇ i4zoowr 10 R R a I R a i where:
  • Z is -NH 6 1 5 loweralkylamine
  • Reaction of a substituted a-halo-p-biphenylylacetate i lk l i ester with a nitrogen base such as ammonia, loweralkl lk l i ylamine, diloweralkylamine, cycloloweralkylamine, a nitrogen containing hetero compound such as piperidine, morpholine, piperazine results in the correspond- 20 ing amide.
  • the acetate ester with hydroxylamine gives k the corresponding hydroxamic acid, and with hydra- V zine gives the corresponding hydrazide.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Emergency Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Novel Alpha -mercapto-p-biphenylylacetic acids and their derivatives have been prepared. Compounds of this invention possess useful anti-inflammatory, analgesic and antipyretic properties.

Description

United States Patent 11 1 Diamond et a1.
[ 1 June 28, 1974 1 1 a-ACYLTl-IIO BIPHENYLYLACETIC ACIDS [75] Inventors: Julius Diamond, Lafayette Hill;
Norman Julian Santora, Roslyn,
both of Pa.
5 [73] Assignee: William H. Roi-er, Inc., Fort Washington, Pa. 22 Filed: June 11, 1971 [21] Appl. No.: 152,366
Related US. Application Data [63] Continuation-impart of Ser. No. 34,870, May 5,
i [51] Int. Cl. C07c 153/07 [58] Field Of Search 260/455 R, 576; 424/317 [56] References Cited 7 UNITED STATES PATENTS 3,098,078 7/1963 Druey et a1. 260/516 3,513,190 5/1970 Cragoe, Jr. et a1. 260/455 R 7 3,624,142 11/1971 Shen et a1. 260/516 3,674,832 7/1972 Sherlock 260/576 FOREIGN PATENTS OR APPLICATIONS 20 1/1971 Japan 260/576 OTHER PUBLICATIONS Boots, Prep. of Subs. Biphenyl Ders., (1965), CA 64, PP. 5005-5008, (1966).
Iskander et al., CarbonSu1phur Fission in Thioethers etc., (1961), J. Chem. Soc., 1961, pp. 23932397, (1961).
Reeve et a1.,The Syn. of a-Methoxyarylacetic Acids etc," (1959), J.A.C.S. 82, pp. 4062-4066, (1960).
Primary Examiner-Glennon H. Hollrah 57 ABSTRACT Novel a-mercapto-p-biphenylylacetic acids and their derivatives have been prepared. Compounds of this invention possess useful anti-inflammatory, analgesic and antipyretic properties.
12 Claims, No Drawings 7 1 a-ACYLTHIO BIPHENYLYLACETMI NEEDS CROSS REFERENCES TO RELATED APPLICATKONS This is a continuation-impart application of Ser. No. 34,870, filed May 5, 1970.
SUMMARY OF THE INVENTIION This invention describes certain cz-rnercapto-pbiphenylylacetic acids and their derivatives and their use in therapeutic compositions. in addition, this invention relates to the preparation of these oz-mercapto-pbiphenylylacetic 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 llNVENTlON 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-mercapto-pbiphenylylacetic acid compounds and their derivatives have valuable pharmacologic properties.
We have found that a-mercapto-p-biphenylylacetic 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 oz-mercapto-pbiphenylylacetic 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 theinhibition of inflammation and the treatment of as; sociated pain and fever.
We have still further found an entirely new class of antiinflammatory, analgesic and antipyretic pharmaceutical compositions containing the a-mercapto-pbiphenylylacetic acids and derivatives of this invention 7 as active ingredient.
We have again found a convenient method for synthesizing these compounds.
DESCRIPTION AND PREFERRED I EMBODI This invention comprises a class of novel chemical compounds which contain a phenyl or substituted phenyl radical which is attached to a substituted phenyl or phenyl-a-mercaptoacetic acid in the para-position. This invention further comprises derivatives of said acetic 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 gen- I eral formula I t. R R
where: y I
P is hydrogen or loweralkyl;
R and R are hydrogen or not more than one of R or R at the same time is halo,
nitro,
amino,
acylamino,
mono- & diloweralkylamino,
mercapto,
acylthio,
loweralkylthio,
loweralkylsulfinyl,
loweralkylsulfonyl,
hydroxy,
loweralkoxy,
acyloxy,
haloloweralkyl,
cyano,
acetyl or loweralkyl;
X is mercapto,
acylthio,
carboxyacylthio,
aroylthio,
carboxyaroylthio,
loweralkoxythiocarbonylthio,
loweralkoxycarbonylthio,
arloweralkoxycarbonylthio,
amidinothio,
thiocyanato,
thiosulfo,
thioacylthio,
diloweralkylthiocarbamylthio,
carbamylthio,
loweralkylcarbamylthio,
diloweralkylcarbamylthio,
loweralkylthio,
loweralkylsulfinyl,
loweralkylsulfonyl,
sulfino or sulfo; and
Z is -OH, loweralkoxy,
arloweralkoxy,
MHZ,
loweralkylamino,
diloweralkylamino,
cyclolowerallcylamino,
(where A is loweralkylidenyl or heteroloweralkylidenyl), -NHOl-I, -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 racemic mixtures of their dextro and levorotatory isomers. It is to be un derstood that said d and l isomers as well as the d! mixtures thereof are embraced within the scope of this invention.
More specifically, the chemical compounds of this invention which have particular usefulness as antiinflammatory, analgesic and antipyretic agents are describedby formulae lI-IV where:
R, R, Ra, X & Z are as described above.
Those compounds whose properties are even more preferred are described by formula IV Where:
Ra is hydrogen or loweralkyl;
R is halo,
nitro,
loweralkylsulfonyl,
haloloweralkyl or cyano;
X is mercapto,
acylthio,
aroylthio,
loweralkoxythiocarbonylthio,
loweralkoxycarbonylthio,
amidinothio,
thiocyanato,
thiosulfo,
carbamylthio,
loweralkylcarbamylthio,
diloweralkylcarbamylthio,
loweralkylthio,
loweralkylsulfinyl,
loweralkylsulfonyl,
sulfo; and
Z is OH, loweralkoxy,
arloweralkoxy,
loweralkylamino or A special embodiment of this invention which describes novel compounds that 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 not symptomatically related to an inflammation indication are dscribed by formula V where:
Roz is hydrogen,
methyl or ethyl;
R is chloro,
bromo,
nitro,
methylsulfonyl,
trifluoromethyl or cyano;
X is hydrogen,
acyl,
aroyl,
loweralkoxythiocarbonyl,
loweralkoxycarbonyl,
sulfo,
carbamyl,
loweralkylcarbamyl,
diloweralkylcarbamyl; and the salts thereof.
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 defmitions apply:
The term loweralkyl refers to a loweralkyl hydrocarbon group containing from one to about six 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-propenol, 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 preferred aroyl is benzoyl, loweralkylbenzoyl such as toluoyl or halobenzoyl such as p-chlorobenzoyl, 2-carboxybenzoyl, etc.
The term loweralkylidenyl refers to a loweralkylidenyl hydrocarbon group containing from two to about six carbon atoms.
Heteroloweralkylidenyl refers to a loweralkylidenyl hydrocarbon group containing from about two to five 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 Z-aminopyridine, piperazine, piperidine; (4) aralkylamines 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-mercapto-3-chloro-4-biphenylylacetic acid oz-acetylthio-3-chloro-4-biphenylylacetic acid oz-propionylthio-Ii-chloro-4-biphenylylacetic acid a-butyrylthio-3-chloro-4-biphenylylacetic acid a-butenoylthio-3-chloro-4-biphenylylacetic acid a-benzoylthio-3-chloro-4-biphenyiyiacctic acid a-(o-toiuoylthi0)-3-chloro-4-biphenyiyiacetic acid a-(cr-carboxybenzoylthio)-3-chioro-4- biphenylyiacctic acid a-methoxythiocarbonylthio-3chime-4- biphcnyiylacetic acid a-ethoxythiocarbonylthio-3-chlor0-4 biphenylylacetic acid a-methoxycarbonylthio-3-chloro-4-bipiicnylyiacetic acid a-ethoxycarbonylthio-3-chloro-4--biphcnylylacetic acid a-benzyloxycarbonylthio-3-chloro-4- biphenylylacctic acid a-thioformylthio-3-chloro-4-biphcnyiylacctic acid a-amidinothio-3-chioro-4-biphenyiyiacetic acid a-thiocyanato-3-chioro-4-biphenyiylacetic acid a-thiosulfo-3-chloro-4-biphenylylacetic acid a-carbamylthio-3-chloro-4-biphcnylylacetic acid a-ethylcarbamylthi0-3-ch]oro-4-biphenylylacetic acid a-dimethylcarbamylthio-3-chioro-4-biphenylylacetic acid a-diethylcarbamylthio-3-chlorc-4-biphenyiylacetic acid a-methyithio-3-chl0r0-4-biphenyiylacctic acid a-ethylthio-3-chloro-4-biphcnylylacetic acid a-propylthio-3-chloro-4biphenyiylacctic acid a-i-propylthio-3-chloro-4-biphenyiylacetic acid a-methylsulfinyl-3-chloro-4-biphenylyiacetic acid a-methylsulfonyi-3-chloro-4-biphenyiylacetic acid a-sulfino-3-chlorc-4-biphenyiylacetic acid a-sulfo-3-chloro-4-biphenylylacetic acid a-mercapt0-4-chl0ro-4-biphenylylacetic acid a-acetylthio-A'-chloro-4-biphenylylacctic acid a-propionylthio-4'-chlor0-4-biphenylylacetic acid a-butyrylthio-4'-ch1or0-4-biphcnyiylacetic acid a-butenoylthi0-4'-chloro-4--biphcnylylacetic acid a-benz0ylthi0-4'-chloro-4-biphenyiylacetic acid a-(o-toluoylthio)-4'-chloro-4-biphenylylacetic acid a-(o--carboxybenzoylthio)-4'-chloro-4- biphcnyiylacetic acid a-methoxythiocarbonylthio-4'-chl0ro-4- biphenylylacetic acid a-ethoxythiocarbonylthi0-4'-chloro-4- biphenylylacetic acid a-methoxycarbonylthio-4-chloi'o-4-biphenyiylacetic acid a-ethoxycarbonyIthio-4'-chloroi'biphenylylacetic acid a-benzyloxycarbonylthio-4'-chl0ro-4- biphenylylacetic acid a-thioformylthio-4'-chloro-4-biphenylylacctic acid a-amidinothio- "-chloroi-biphcnyiylacetic acid a-thiocyanato-4'-chloro-4-biphenylylacetic acid a-thiosulf0-4-chloro-4-biphenylylacctic acid a-carbamylthi04'-chioro-4-biphenylyiacetic acid a-ethylcarbamylthio-4-chloro-4-biphenylylacctic acid a-dimethylcarbamylthio-4'-chioro-4- biphenylylacetic acid a-diethylcarbamylthioi-'-chlor0-4-biphenylylacetic acid a-methylthio-4-chlor0-4-biphenyiylacetic acid a-ethylthio-4'-chloro-4-biphenylylacetic acid a-propylthi0-4'-chloro-4-biphenylylacetic acid oz-methoxycarbonyithio-Z'-chioi-o-4-biphenylylacetic acid oz-ethoxythiocarbonyithio-2'-chioro-4- biphcnyiylacctic acid oz-benzyioxycarbonyitiiio-2-chlor0-4- biphenyiylacetic acid oz-thioformyithi0-2'-chlcro-4-biphenylyiacetic acid oz-amidinothio-Z'-chloro-4-biphcnylyiacetic acid a-thiocyanato-Z'-chlor0-4-biphcnylyiacetic acid oz-thiosuif0-2'-chloro4-biphenylylacctic acid a-carbamylthio-Z'-chlorci-biphenyliyiacetic acid a-ethylcarbamylthio-2'-chl0r0-4i-biphenylylacctic acid a-dimethylcarbamylthio-2-chloi*o 4- biphenylyiacctic acid a-diethylcarbamylthio-Z'-chiom-4-biphenylylacetic acid oz-mcthylthi0-2'-chloro-4-biphenyiylacetic acid oz-ethylthi0-2-chl0ro-4-bipheny'lylacetic acid oz-propylthio-Z'-chlorc-4-biphenylylacetic acid oz-i-propylthio-Z'-chi0ro-4-biphcnyiylacetic acid cu-methyisulfinyl-Z' chloro-4-biphenylylacetic acid a-methyisuifonyl-Z'chime-4*biphenylyiacetic acid a-sulfino-Z'-chloro-4-biphenylyllacetic acid oz-sulfo-Z'-chioro-4-biphcnyiylacetic acid oz-acctylthio-Z'-flu0ro-4-biphcnylylacetic acid a-acctylthio-Z'-br0mo-4-biphenylylacetic acid oz-acetyithio-Z'-iodo-4-biphenylylacetic acid ai-acetyIthiO-Z'-nitro-4-biphcnyiylacetic acid cz-acetyithio-Z'-tiifluoromethyl-4-biphenylylacetic acid a-acctylthio-2'-mci'capto-4-biphcnylylacetic acid oz-acctylthio-T- acetylthio-4-bipheny1ylacetic acid a-acetyithio-Z'-mctiiyimercapto-4-biphenylylacetic acid cz-acctylthic-Z'-meihylsulfinyl-4-biphenylylacetic acid m-acetylthio-Z-mcthyisulfonyl-4-biphenylylacetic acid a-acctylti'ni0-2-cyano-4-biphcnylylacetic acid a-acetylthio-Z'-carboxy-4-biphcnylylacetic acid a-acctylthio-2'-carbeth0xy-4-biphenylylacetic acid a-acetylthio-2'-aminoi-biphcnylylacetic acid oz-acetylthio-2-acetylamino-4-biphenylylacetic acid a-acetylthio-Z'-mcthylamino-4-ibiphenylylacetic acid wacetyithio-Z '-dimethyiamin0-4-biphenylylacetic acid a-acetylthio-ZhydrcxyA-biphenylylacetic acid a-acetylthio-a-methyl-3-bromo-4-biphenylylacetic acid a-acetylthiowmethyl-3-nitro-4-biphenylylacetic acid a-acetylthio-a-methyl-3-trifluor0mel:hyl-4- biphenylylacetic acid a-acctylthio-a-methyl-3-cyano-4-biphenylylacctic acid a-acetylthio-a-methyl-3-methylsulf0nyl-4- biphenylylacetic acid a-acetylthiofl-methyl-W-chloro-4-biphenylylacetic acid a-propionylthio-a-methyl-4'-chloro-4- biphenylylacetic acid a-methoxythiocarbonylthio-a-methyl-4'-chloro-4- biphenylylacctic acid a-mcthoxycarbonylthio-oz-methyl-4'-chloro-4- biphenylylacetic acid a-thioformylthio-a-methyl-4-chloro-4- biphenylylacetic acid a-diethylcarbamylthio-a-mcthyl-4'-chloro-4- biphenylylacetic acid a-methylsulfonyl-a-methyl-4'-chloro-4- biphenylylacetic acid a-acetylthio-a-ethyl-4'-chloro-4-biphenylylacetic acid a-acetylthio-apropyl-4'-chl0r0-4-biphenylylacetic acid a-acetylthio-a-methyl-4'-fluoro-4-biphenylylacetic acid a-acetylthic-a-methyl-4'-bromo-4-biphenylylacetic acid a-acetylthio-a-methyl-4'-nitro-4-biphcnylylacetic acid a-acetylthio-a-methyl-4-trifluoromethyl-4- biphenylylacetic acid a-acetylthio-a-methyl-4'-cyano-4-biphenylylacetic acid a-acetylthio-a-methyl-4'-methylsulfonyl-4- biphenylylacctic acid d a-acetylthio-Z'-fluoro-4-biphenylylacetic acid 1 a-acetyltio-Z'-fluoro-4-biphenylylacetic acid (1 a-acetylthio-Z-chlro-4-biphenylylacetic acid 1 wacetylthio-Z'-chloro-4-biphenylylacetic acid d oz-acctylthio-Z'-bromo-4-biphenylylacetic acid I a-acetylthio-2'-bromo-4-biphenylylacetic acid d a-acetylthio-Z'-nitro-4-biphenylylacetic acid I a-acetylthio-Z-nitro-4-biphenylylacetic acid d a-acetylthio-Z'-trifluoromethyl-4-biphenylylacetic acid I a-acetylthi0-2'-trifluoromethyl-4-biphenylylacetic acid (1 a-acetylthio-Z'-cyano-4-biphenylylacetic acid I a-acetylthio-Z'-cyano-4-biphenylylacetic acid d a-acctylthio-3'-methylsulfonyl-4-biphenylylacetic acid 1 a-acetylthio-3'-methylsulfonyl-4-biphenylylacetic acid d a-acetylthio-3-chloro-4-biphenylylacetic acid 1 a-acetylthio-3-chloro-4-biphenylylacetic acid d a-acetylthio4'-chloro-4-biphenylylacetic acid 1 a-acetylthio-4'-chloro-4-biphenylylacetic acid (1 a-acetylthio-a-methyl-Z'-chloro-4-biphenylylacetic acid 1 a-acetylthio-amethyl-2'-chloro-4-biphenylylacetic acid 1 a-sulfino-Z chloro-4-cyclohexylphenylacetic acid d a-methylsulfinyl-Z'-chloro-4-lbiphenylylacetic acid 1 a-methylsulfinyl-Z-chloro-4-biphenylylacctic acid d a-(a-carboxybenzoylthio)-2-chloro-4- biphenylylacetic acid a-( mcarboxybenzoylthio )-2 '-chloro-4- biphenylylacetic acid d methyl a-acetylthio-Z'-chloro-4-biphenylylacetic acid 1 methyl a-acetylthio-2'-chlo ro-4-biphenylylacetic acid d benzyl a-acetylthio-Z-chlo ro-4-biphenylylacetic acid l benzyl a-acetylthio-2'-chlo ro-4-biphenylylacetic acid (1 N-methyl biphenylylacctic acid 1 N-methyl ca-acetylthioQ-chl0r0-4-biphenylylacetic acid oz-acetylthio-2'-chloro-4- d N ,N-diethyl aacetylthio-Z '-chloro-4- biphenylylacetic acid 1 N,N-diethyl a-acetylthi0-2 '-chloro-4- biphenylylacetic acid d N,N-pentamethylene biphenylylacetic acid 1 N,N'pentamethylene biphenylylacetic acid (1 N,N-oxydiethylene biphenylylacetic acid 1 N,N-oxydicthylcne biphenylylacetic acid d oz-acetylthio-Z-chloro-4-biplienylylacetic acid, so-
dium salt l a-acetylthio-2'-chloro-4-biphcnylylacetic acid, so-
dium salt d a-acetylthio-Z-chlor0-4-biphenylylacetic acid, diethylammonium salt I a-acetylthio-Z'-chloro-4-biphenylylacetic acid, diethylammonium salt d a-acetylthio-Z"chloro-4-biphenylylacetic acid, piperazinium salt l a-acetylthio-Z-chloro-4-biphenylylacetic piperazinium salt a-acctylthio-Z '-chlor0-4- acid,
The compounds of this invention may be prepard by the following general procedures. substituted biphenyl compound and in this manner the Condensation of a biphenyl compound with a lowerresultant product would be the corresponding substialkyl or aralkyl oxalyl chloride in the presence of anhytuted a-alkylbiphenylylglycolate or the biphenylylw el n rwsb id r su t m3 ziph y ylslyetyi 5 sued-ate V. v
REX"
borohydride conditions. It is convenient to start with a i late. This may then be reacted with an alkyl Grignard reagent to form the a-alkylbiphenylylglycolate or it may be reduced to the biphenylylglycolate by catalytic In the preferred aspect of this invention, it is convenient to start with a 2 or 4-nitro or halobiphenyl compound. This results in the corresponding 2' or 4-nitro hydrogenation with platinum o tide or under sodium or halobiphenylylglycolate.
ii i o ClCCOOR" (H )N 0 Q (Hal )N02 O (l-COOR" t) R MgX NaBH 0H Hal .H-COOR" v a1 )N0 Q No Q CH-LOOR C1 ICOOR a We g (Q A] C] 3 I 2 N02;
(Had) lR MgX Mp OH 0 0 ({J-CODR" A 3) CH-COOR" Compounds having substituents in the other ring may 3 5 hiphe ylxlglypqlgte qr redpeeg to the glycolate by eatabe prepared by carrying out a Friedel-Crafts, as above, I h d 1 d with an alkyl or aralkyl oxalyl chloride on biphenyl. y lonwl P a mumpXl e or un at so The resultant 4-biphenylylglyoxylate is then reacted PmPQIQ YQ iQQQfl QD$- T s yc ay t e 0 c1 ECOOR" COOR R MgX i A'lkC'l H [540W 4 .t... 0 Q ic-cooR HNO (an 0H l C-COOR" c-COOR @l O l a a W Hal 0 0 UH ll H (Pt) or L n m H-COOR" 0 Al kCl Al Cl HNO Y L 0H @@CHCOOR" LPFCOOR" N0 A k C1 or Br 2 (H CH-COOR" mum a1 Chlorination or bromination may be carried out in Appropriately desired end products having various R the presence of a small amount of iodine dissolved in 60 or R substituents can be prepared by using suitable rean inert solvent such as carbon tetrachloride. A soluactions in order to convert one group to another. Thus, tion of chlorine or bromine is then added while the for example, a 2-halo-4-biphenylylglycolate in which temperature is held near 0C. Nitration is carried out halo is chloro, bromo or iodo may be with fuming nitric acid at about 0C. Alkylation is car- 65 a. reacted with cuprous cyanide in quinoline at about ried out under Friedel-Crafts conditions with an alkyl 150C to produce a 2-cyano-4- halide. ndr lym nyms lezi a. biphenylylglycolare:
A 2' nitro-4-biphenylylglycolate may be selectively OH CN O -t J-0ooR" hydrogenated to the corresponding amine.
N b. reacted with trifluoromethyliodide and copper powder at ab out lC in dirnethylformamide to 10 OH obtain a 2'-trifluoromethyl-4-biphenylylglycolate: 0 400B [as described in Tetrahedron Letters: 47,4095 1 NHz A 3-aminoflbiphenylylglycolate may then be a; monoor dialkylated with loweralkyl halides or sulfatesor acylated with loweracyl chlorides or anhydrides,
OH OH I RIIX & Q @w Ra Rs NH: NHR- l IEQ IPCOOC): or i RIIX EH EH 1 Q -@i;ooon" O @-l i-coon" NHCOR" (R")z 0H t (l: CF31 og@ Cu 7 Ba 0H b. dlazotized to the diazonium fluoroborate which Is -+-COOR then themally decomposed to the 3-fluoro-4- F biphenylylglycolate,
OH t OH OH -(E-CO0R c. reacted with cuprous methanesulfinate m qumo- I R F line at about 150C to obtain a 2'-methylsulfonyl- 4-biphenylylglycolate:
0H diaiotiz ed and heated 'iiim aqueous medium to @J; H f form the 3-hydroxy-4-biphenylylglycolate or i heated in an alcohol to form the 3-alkoxy-4- al biphenylylglycolate. The hydroxyl group may also 0H be alkylated with loweralkyl halides or sulfates to J; the alkoxyl group or acylated with loweracyl chlofi rides or anhydrides to the acyloxy compound in the oiom presence of a tertiary amine such as pyridine,
3 ,82 1 ,268 v 29 30 Reaction of a substituted p-biphenylyl gljeblate est i' trog en containing hetero cempound sucH a S piptidin, morpholine, piperazine, hydroxylamine and hydrazine wnh a nmogen base Such as ammoma loweralkylagives the corresponding amide,hydroxamic acid, or by OH Il-coonuz") R R' R where '5 l w r le where R" is lower alkyl; where Hal is chloro, bromo or iodo.
Reaction of an a-sulfonate with a metal halide (preferably an alkali halide) results in the corresponding a-halo compound.
OSO:R(Ar) MHal 0COCH=CHCOOH C-CO0H(R") Hal (g HOAc COOR II BIIal R R Hal Ru R R where R" is lower alkyl.
The acid addition salts may then be formed by the action of one equivalent of a suitable base with the substituted a-halo-4-biphenylylacetic 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 hydroxide, 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 appropriate aluminum complex such as aluminum hydroxy chloride hexahydrate, etc. The ammonium salts may be made by reaction with the corresponding amine such as methylamine, diethylamine, B-hydroxyethylamine, piperazine, piperidine, a-methylbenzyla- H 4 N Hal 7 R R Ru 5 -coolt l Hal Hal 1!{ i4zoowr 10 R R a I R a i where:
Z is -NH 6 1 5 loweralkylamine, Reaction of a substituted a-halo-p-biphenylylacetate i lk l i ester with a nitrogen base such as ammonia, loweralkl lk l i ylamine, diloweralkylamine, cycloloweralkylamine, a nitrogen containing hetero compound such as piperidine, morpholine, piperazine results in the correspond- 20 ing amide. The acetate ester with hydroxylamine gives k the corresponding hydroxamic acid, and with hydra- V zine gives the corresponding hydrazide.
Hal (where A is loweralkyiidenyl or heteroloweralkylide- Jz-coow "3 NHOH or ,-t W 2- N v Hal 3 M I c -cowH G. R' R Ha] NH R" l L (z-comma" a R' R Ha] HN(R" l -L c-conm") R' R a 1 I A Hai r t I HN (CH I /C-C00R"--- e-cou R i R G. R R G

Claims (11)

  1. 2. The compound Alpha -benzoylthio-2''-chloro-4-biphenylylacetic acid.
  2. 3. The compound Alpha -acetylthio-2''-bromo-4-biphenylylacetic acid.
  3. 4. The compound Alpha -acetylthio-2''-nitro 4-biphenylylacetic acid.
  4. 5. The compound Alpha -acetylthio-2''-methylsulfonyl-4-biphenylylacetic acid.
  5. 6. The compound Alpha -acetylthio-2''-trifluoromethyl-4-biphenylylacetic acid.
  6. 7. The compound Alpha -acetylthio-2''-cyano-4-biphenylylacetic acid.
  7. 8. The compound Alpha -benzoylthio-2''-bromo-4-biphenylylacetic acid.
  8. 9. The compound Alpha -benzoylthio-2''-nitro-4-biphenylylacetic acid.
  9. 10. The compound Alpha -benzoylthio-2''-methylsulfonyl-4-biphenylylacetic acid.
  10. 11. The compound Alpha -benzoylthio-2''-trifluoromethyl-4-biphenylylacetic acid.
  11. 12. The compound Alpha -benzoylthio-2''-cyano-4-biphenylylacetic acid.
US00152366A 1970-05-05 1971-06-11 Alpha-acylthio biphenylylacetic acids Expired - Lifetime US3821268A (en)

Priority Applications (14)

Application Number Priority Date Filing Date Title
US00152366A US3821268A (en) 1970-05-05 1971-06-11 Alpha-acylthio biphenylylacetic acids
BE776316A BE776316R (en) 1971-03-10 1971-12-06 Phenylacetic acid derivs - as antiinflammatory agents
GB5751071A GB1382267A (en) 1970-05-05 1971-12-10 Phenylalkanoic acid derivatives
NL7117006A NL7117006A (en) 1971-03-10 1971-12-10 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
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
SE7501716A SE7501716L (en) 1971-03-10 1975-02-17 WAY TO PRODUCE NEW HYDROXY, HALO AND TIOALCANIC ACID ASSOCIATIONS.
SE7501717A SE7501717L (en) 1971-03-10 1975-02-17 WAY TO PRODUCE NEW HYDROXY, HALO AND TIOALCANIC ACID ASSOCIATIONS.
FR7508271A FR2279387A2 (en) 1970-05-05 1975-03-17 NEW DERIVATIVES OF PHENYL (SUBSTITUTE) THIOALKANOIC ACIDS
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
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
US00152366A US3821268A (en) 1970-05-05 1971-06-11 Alpha-acylthio biphenylylacetic acids

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US034870A Continuation-In-Part US3864384A (en) 1970-05-05 1970-05-05 Substituted phenylacetic acid compounds

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US05/449,548 Division US3941821A (en) 1970-05-05 1974-03-08 2-Thiosulfo biphenylylacetic acids

Publications (1)

Publication Number Publication Date
US3821268A true US3821268A (en) 1974-06-28

Family

ID=26711484

Family Applications (1)

Application Number Title Priority Date Filing Date
US00152366A Expired - Lifetime US3821268A (en) 1970-05-05 1971-06-11 Alpha-acylthio biphenylylacetic acids

Country Status (1)

Country Link
US (1) US3821268A (en)

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
US4333951A (en) * 1977-11-15 1982-06-08 A. H. Robins Company, Inc. 2-Amino-6-biphenylacetic acids
AT389508B (en) * 1984-06-05 1989-12-27 Taisho Pharmaceutical Co Ltd METHOD FOR PRODUCING NEW 2-ACETYLTHIOMETHYL-3-BENZOYLPROPIONIC ACID DERIVATIVE N
US5597825A (en) * 1991-01-24 1997-01-28 Dr. Karl Thomae Gmbh Biphenyl derivatives, pharmaceutical compositions containing these compounds and processes for preparing them
US5994539A (en) * 1995-12-28 1999-11-30 Zambon Group S.P.A. Mercapto acyl aminoacid derivatives endowed with dual ACE-NEP inhibitory activity, useful in the treatment of cardiovascular diseases

Cited By (7)

* 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
US4333951A (en) * 1977-11-15 1982-06-08 A. H. Robins Company, Inc. 2-Amino-6-biphenylacetic acids
AT389508B (en) * 1984-06-05 1989-12-27 Taisho Pharmaceutical Co Ltd METHOD FOR PRODUCING NEW 2-ACETYLTHIOMETHYL-3-BENZOYLPROPIONIC ACID DERIVATIVE N
US5597825A (en) * 1991-01-24 1997-01-28 Dr. Karl Thomae Gmbh Biphenyl derivatives, pharmaceutical compositions containing these compounds and processes for preparing them
US5736559A (en) * 1991-01-24 1998-04-07 Karl Thomae Gmbh Biphenyl derivatives, pharmaceutical compositions containing these compounds and processes for preparing them
US5922763A (en) * 1991-01-24 1999-07-13 Dr. Karl Thomae Gmbh Biphenyl derivatives, pharmaceutical compositions containing these compounds and processes for preparing them
US5994539A (en) * 1995-12-28 1999-11-30 Zambon Group S.P.A. Mercapto acyl aminoacid derivatives endowed with dual ACE-NEP inhibitory activity, useful in the treatment of cardiovascular diseases

Similar Documents

Publication Publication Date Title
TW219927B (en)
CA2282585C (en) Pyrazine compounds
EP0365183B1 (en) Biologically active compounds
US3894080A (en) Phenylacetic acids
US3933840A (en) Azole derivatives
US3705185A (en) N-aroyl sulfonamides
US3821268A (en) Alpha-acylthio biphenylylacetic acids
CZ298850B6 (en) Process for preparing diaryl pyridine derivatives
US3867434A (en) Phenyl butyric acids and derivatives thereof
PT87578B (en) METHOD FOR PREPARING NEW ALKANO-SULFONANILIDA DERIVATIVES AND A PHARMACEUTICAL COMPOSITION THAT CONTAINS THEM
GB1513320A (en) N-propargyl-2-phenylamino-2-imidazolines
US3917846A (en) Phenylacetic acids in reducing pain, fever and inflammation
JPS622571B2 (en)
US3907897A (en) Cycloalkylbenzaldehydes
US3860624A (en) P-cyclohexyl alpha - lower alkanoylthio hydrocinamic acid
CA1144556A (en) Benzothiazole derivatives, process for their preparation and their therapeutic applications
US4008269A (en) Phenylacetic acids
US3966801A (en) Phenyl butyric acids and derivatives thereof
US5280043A (en) Sulphonamido containing phenylalkanoic acids as thromboxane A2 antagonists
DE2162038A1 (en) Process for the production of synthetic alkanoic acids and their derivatives
Solodar Tetraalkylammonium Cyanides
JPH03215485A (en) Benzothienylimidazole derivatives
GB1465219A (en) Process for the preparation of a phenyl alkonoic acid and its salts
Brody et al. The Synthesis of a Pyridine Analog of Hydnocarpic Acid and of a Lower Homolog
Fisher et al. The Xylic Acids Obtained in the Oxidation of 5-Bromo and 5-Nitropseudocumene