US3867434A - Phenyl butyric acids and derivatives thereof - Google Patents

Phenyl butyric acids and derivatives thereof Download PDF

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US3867434A
US3867434A US195825A US19582571A US3867434A US 3867434 A US3867434 A US 3867434A US 195825 A US195825 A US 195825A US 19582571 A US19582571 A US 19582571A US 3867434 A US3867434 A US 3867434A
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butyric acid
biphenylyl
chloro
acid
acetylthio
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Julius Diamond
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William H Rorer Inc
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William H Rorer Inc
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Priority to DE19712162038 priority patent/DE2162038A1/en
Priority to FR7144544A priority patent/FR2128277B2/fr
Priority to GB5751071A priority patent/GB1382267A/en
Priority to CA129,890A priority patent/CA1027133A/en
Priority to NL7117006A priority patent/NL7117006A/en
Priority to IL38916A priority patent/IL38916A0/en
Priority to US05/424,628 priority patent/US3966801A/en
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Priority to FR7508269A priority patent/FR2279386A2/en
Priority to FR7508271A priority patent/FR2279387A2/en
Priority to FR7508270A priority patent/FR2282867A2/en
Priority to AR239472D priority patent/AR206491A1/en
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    • 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
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    • 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
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    • 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
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    • C07C2601/14—The ring being saturated

Definitions

  • ABSTRACT Novel substituted phenyl butyric acids and their derivatives are described. Therapeutic compositions and method of treatment of inflammation is also disclosed.
  • compositions which contain an a, B or y-halo or thiophenylbutyric acid or derivative thereof as active ingredient.
  • This invention comprises a class of novel chemical compounds which have a phenylbutyric acid group or derivative to which is attached a halo, mercapto, or thio derivative at the a-, ,B- or y-position. Also the phenyl ring may further be substituted.
  • This invention also describes a new method for treating inflammation as well as pain and fever and also novel therapeutic compositions.
  • R is alkyl, cycloalkyl, cycloalkenyl, aryloxy, arylthio, aryl or substituted aryl where the substituent is Y;
  • Y is hydrogen, alkyl, halo, nitro, amino, acylamino, mono and diloweralkylamino, mercapto, acylthio,
  • loweralkylthio loweralkylsulfinyl, loweralkylsulfohaloloweral- (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 at least one asymmetric carbon atom in the butyric 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 understood that said d and I isomers as well as the dl mixtures thereof are embraces within the scope of this invention.
  • Alk is alkyl having 3-7 carbon atoms where .r is 0-2 pi -t'c'rnm N I It I Those compounds whose properties are even more preferred are described by formulae V-Vll where Y is hydrogen or halo, .r l and R R and R are hydrogen.
  • a special embodiment of this invention describes a method for 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.
  • This method affords relief by the administration of a compound of Formula I where X is loweralkoxy, loweracyloxy, aroyloxy, carbloweralkoityoxy, carbamyloxy, loweralkylcarbamyloxy. diloweralkylcarbamyloxy. loweralkanesulfonyloxy. benzcnesulfonyloxy. tolucnesulfonyloxy, carboxyacyloxy, carboxyaroyloxy. halo. mercapto. loweralkylthio.
  • acylthio aroylthio, sulfo. sulfino, loweralkylsulfinyl. loweralkylsulfonyl, thioacylthio, thiosulfo. thiocyanato. amidinothio, carbamylthio, loweralkylcarbamylthio. diloweralkylcarbamylthio, loweralkoxythiocarhonylthio, loweralkoxycarbonylthio, diloweralkylthi ocarbamylthio, arloweralkoxycarbonylthio, carboxyaroylthio, carboxyacylthio, cyano. amino or substituted amino.
  • alkyl refers to a loweralkyl hydrocarbon group containing from 1 to about 7 carbon atoms which may be straight chained or branched.
  • alkenyl refers to an unsaturated or partially unsaturated hydrocarbon group containing from 2 to about 7 carbon atoms which may be straight chained or branched.
  • cycloalkyl refers to a hydrocarbon ring having up to about seven carbon atoms.
  • cycloalkenyl refers to a partially unsaturated hydrocarbon ring having up to about seven carbon atoms.
  • aryl refers to any benzenoid or non-benzenoid aromatic group but preferably phenyl.
  • acyl refers to any organic radical derived from an organic acid by the removal of its hydroxyl group such as formyl, acetyl, propionyl, 3-carboxy-2-propcnoyl, camphoryl, benzoyl, toluoyl or heteroyl such as pyridinoyl, piperidinoyl, thenoyl, etc.
  • the preferred aroyl is benzoyl, loweralkylbenzoyl such as toluoyl or halobenzoyl such as p-chlorobenzoyl. etc.
  • alkoxy refers to a loweralkoxy 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 morehetero atoms in the chain selected from O, N or S. such a 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 salt ofthc structure given in the formula.
  • the ammonium salts are formed with a (l) loweralkylamincs such as methylamine, diethylamine, triethylaminc; (2) hydroxyloweralkylamines such as B-hydroxyethylaminc; (3) heteroeyclic amines such as Z-aminopyridinc.
  • a-chloro-y-(o-tolyl)butyric acid a-chlor0-y-(m-t0lyl)butyric acid a-chl0r0-y-(p-t0lyl)butyric acid a-chl0ro-y-(p-cthylphenyl)butyric acid a-chloro y-(p-propylphenyl)butyric acid oz-chl0ro-'y(p-i-propylphenyl)butyric acid oz-chloro-y-(p-butylphenyl)butyric acid a-chloro-y-(p-i-butylphenyUbutyric acid a-chloro-y-(p-sec-butylphenyl)butyric acid oz-chl0ro-y-(p-t-butylphenyUbutyric acid a-chloro-y-(p-penty
  • the oz-position (laisen condensation of a substituted benzaldehyde benzyl ester) in the presence of a metal alkoxide results in a B-acrylic acid ester.
  • the aldehyde may also be sub jected to a Perkin reaction with acetic anhydride and an acetic acid salt or through a Knoevenagel condensato obtain a substituted fi-acrylie acid. Hydrogenation of the double bond in the presence of a heterogeneous catalyst results in the propionic acid or ester.
  • a-alkyl-a-hydroxy-y-substituted phenyl butyric acid may he prepared by reacting a L l-substituted phenyl propionic acid ester with an alkyl (irignard reagent to obtain a l-suhstituted phenyl-3-butanonc which on reaction with sodium cyanide in the presence of sodium bisulfite yields the Lsubstituted phenyl-3-butanone cyanohydrin. Hydrolysis gives the desired acid, ester or amide.
  • the y-ulkyl-0z-hydroxy-y-substituted phenyl butyric acids may be prepared as previously described for the a-hydroxy-y-substitutcd phenyl butyric acid compounds.
  • the reaction sequence starting material is a substituted phenyl alkyl kctone upon which a Reformatsky reaction is performed with an a-halo acetate in the presence of zinc.
  • the resultant B-hydroxy-B-alkyl- B-substituted phenyl propionate is then dehydrated v a o R II R n CHZCHZCOOR R MgI CHZCHZC-RG mso
  • the B-alkyl-a-hydroxy-y-substituted phenyl butyric acids may be prepared as previously described for the oz-hydroxy-y-substituted phenyl butyric acid compounds by starting with an a-alkylmalonic acid in the Knoevenagel condensation to obtain an a-alkyl-B- substituted acrylic acid.
  • the corresponding B-alkyl compound is h prepared when the starting material is 2-methyl-2,3 7 T c y'posmon cpoxypropyl chloride and the y-alkyl compound results Friedel-Crafts reaction of a substituted benzene with when the starting material is 2,3-epoxybutyl chloride.
  • alkyl succinyl chloride or succinic anhydride results in i cu cu-p-lci 21 22 formation of a y-suhstituted phenyl-y-keto butyric acid
  • Reduction of the wketo group may acid or ,B-alkyl-y-substituted phenyl-y-hydroxybutyric then be carried out in the presence ofa metal catalyst acid may be prepared by analogous procedures using or di b h d id t bt i the y-substitutcd hethe appropriately substituted alkyl succinyl chloride or nyl-y-hydroxy butyric acid ester with is then hydro- 5 succinic anhydride. lyzed t0 the corresponding acid.
  • the acid halide is-first formed as above and this is then catalytically reduced in the preswith a nitrog lIH) L Y R-H CH Y i iZ-(CH) -CHO R Y B Reaction of a substituted phenylbutyric acid ester en base such as ammonia, loweralkylamine, diloweralkylamine, cycloloweralkylamine, a nitrogen containing hetero compound such as pipcridine,
  • the butyric acid esters may be hydrolyzed to the corresponding ac ids. Reaction of the hydroxybutyrate or 25 anhydride XOX in the presence of a tertiary amine such as pyridine, picoline, or quinoline results in the formation of an hydroxy derivative of the butyrate.
  • a tertiary amine such as pyridine, picoline, or quinoline
  • R" is lower alkyl I R I I -e (QU -T-(EHM-COOMR") a phosphorus trihalide, phosphorus pentahalide, phos- Where Hall is ChlOrO, brOmO 0r iodo.
  • the substituted fluoro compounds may also be obdrate, etc.
  • ammonium salts may be made by reactaincd from the corresponding iodo, bromo or chloro tion with the corresponding amine such as methylcompounds by reaction with potassium fluoride at amine,diethylamine,B-hydroxycthylamine,piperazinc, about l3()20(lC. piperidine, a-methylbcnzylamine, cyelohexylamine,
  • Suitable bases thus include for examloweralkylamine,
  • alkali metal alkoxides such as sodium methoxdiloweralkylamino
  • halo butyramides, butyrhydroxamic acids or butyrhydrazides can be prepared from the corresponding hydroxy butyramides with thionyl halides according to the method of l. A. Smith, Chem. Bcrichtc 718:634
  • Thc substituted halo butyric acids and acid dcrivacamitc.alkalithiosulfatc,alkali lowcralkylmcrcaptidc, tivcs such as such as their salts, amides or esters may be reacted with various nucleophilic reagents which will replace the halogen group.
  • an acid dcrivacamiosulfatc,alkali lowcralkylmcrcaptidc, tivcs such as such as their salts, amides or esters
  • alkali sulfitc or an alkali sulfinatc may be reacted with the chloro. bromo or iodo butyric acid to for the corresponding derivative of the mcrcapto butyric acid. This 45 may also be carried out on the sulfonatc compounds.
  • alkali hydrosulfide alkali thioalkanoate, alkali thiobcnzoate, alkali loweralkylxanthate, thiourea, alkali thi0 m M m 4 4 m R M nn MK m nu H 8.
  • w B m B n n n ⁇ J ⁇ I wlnw liR miR where:
  • R is alkyl or ary'l.
  • the mcrcaptobutyric acid the presence of hydrogen chloride, a loweralkylcarbamay also be reacted with succinic anhydride, maleic myl chloride, a diloweralkylcarbamyl chloride or conanhydride or phthalic anhydride to form the correverted to the metal salt which will react with a carba- 65 sponding derivative.

Abstract

Novel substituted phenyl butyric acids and their derivatives are described. Therapeutic compositions and method of treatment of inflammation is also disclosed.

Description

United States Patent [1 1 [111 3,867,434 Diamond Feb. 18, 1975 [54] PHENYL BUTYRIC ACIDS AND 424/317, 424/319, 260/332.2 A, 424/324. DERIVATIVES THEREOF 260/332.2, 260/332.5, 260/345.7, 260/346.1 I M, 260/347.3, 260/448 R, 260/454, 260/455 [75] Inventor. Julius Diamond, Lafayette Hills, Pa. R, 260,455 B, 260,456 P, 260/465 D [73] Assignee: William H. Rorer, Inc., Fort 260/465 F, 260/469 Washington, Pa. [51] Int. Cl. C07c 63/00, C07c 69/64 [58] Field of Search 260/515 A, 469, 448 R, [22] Filed. Nov. 4, 1971 26060115 [21] Appl. No.: 195,825
[56] References Cited [52] U.S. Cl. 260/515 A, 260/470, 260/471 R, UNITED STATES PATENTS 260/239 BC, 260/471 A, 260/473 R, 3,090,808 5/1963 Kharasch m al. 260/539 260/247, 260/475 R, 260/475 F, 260/247.2
260/482 C, 260/485 L, 260/248 CS, 260/488 1,430,359 1/1966 France 260/515 CD, 260/50l.15, 260/250 RA, 260/502.6, 260/507 R, 260/251 Q, 260/515 R, 260/516, 260/268 R, 260/517, 260/518 R, 260/293.8, 260/518 A, 260/520, 260/293.88, 260/544 M, 260/558 D, 260/295, 260/559 D, 260/559 T, 260/302 R, 260/559 A, 260/562 R, 260/306.7, 260/592, 260/599, 260/307 H, 260/618 D, 424/248, 260/309, 424/274, 424/275, 260/309.6, 424/283, 424/285,
Primary Examiner,lames A. Patten Attorney, Agent, or FirmErich M. H. Radde [57] ABSTRACT Novel substituted phenyl butyric acids and their derivatives are described. Therapeutic compositions and method of treatment of inflammation is also disclosed.
11 Claims, N0 Drawings PHENYL BUTYRIC ACIDS AND DERIVATIVES THEREOF SUMMARY OF THE INVENTION BACKGROUND OF THE INVENTION Continued studies have been carried out in research to develop drugs which would significantly inhibit the development of inflammation and relieve the pain and fever associated with it. While much of this effort has been carried out in the steroid field these have been compounds developed which are non-steroidal and have included such as the alkanoic acids derived from biphenyl, stilbene, indole, naphthylene and various heteryl rings. While many of these compounds have been found to be effective, they have had the drawback of causing various side effects or being effective only on a specific disorder.
I have unexpectedly found that when a halo or thio group or derivative thereof is present in the at, ,8 or postion of the side chain of a substitutedphenylbutyric acid molecule, pharmacological properties exist in the molecule which are useful for the relief and inhibition of inflammation conditions.
I have also found that the compounds of this invention are effective in the treatment of inflammation and the control of arthritic conditions associated with inflammation.
l have further found that a, B or y halo and thio phenylbutyric acids and their derivatives are novel.
I have also found that the compounds of this invention possess useful analgesic and antipyretic properties and are useful in the treatment of pain and fever.
I have still further found an entirely new class of antiinflammatory, analgesic and antipyretic pharmaceutical compositions which contain an a, B or y-halo or thiophenylbutyric acid or derivative thereof as active ingredient.
I have also found a convenient method for synthesizing these compounds.
DESCRIPTION AND PREFERRED EMBODIMENTS This invention comprises a class of novel chemical compounds which have a phenylbutyric acid group or derivative to which is attached a halo, mercapto, or thio derivative at the a-, ,B- or y-position. Also the phenyl ring may further be substituted.
This invention also describes a new method for treating inflammation as well as pain and fever and also novel therapeutic compositions.
The following numbering system is used in this inventron:
except with respect to the biphenylyl compounds which The compounds of this invention can be represented by the generic structure which is described by the general formula I;
(CH) (fH) -COZ 1 where:
R is alkyl, cycloalkyl, cycloalkenyl, aryloxy, arylthio, aryl or substituted aryl where the substituent is Y; Y is hydrogen, alkyl, halo, nitro, amino, acylamino, mono and diloweralkylamino, mercapto, acylthio,
loweralkylthio, loweralkylsulfinyl, loweralkylsulfohaloloweral- (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 at least one asymmetric carbon atom in the butyric 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 understood that said d and I isomers as well as the dl mixtures thereof are embraces 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 described by formulae II-IV:
Those compounds whose properties are preferred are described by formulae V-Vll:
where Alk is alkyl having 3-7 carbon atoms where .r is 0-2 pi -t'c'rnm N I It I Those compounds whose properties are even more preferred are described by formulae V-Vll where Y is hydrogen or halo, .r l and R R and R are hydrogen.
Compounds which are most preferred are those where X is in the 02- or B-position. r
A special embodiment of this invention describes a method for 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. This method affords relief by the administration of a compound of Formula I where X is loweralkoxy, loweracyloxy, aroyloxy, carbloweralkoityoxy, carbamyloxy, loweralkylcarbamyloxy. diloweralkylcarbamyloxy. loweralkanesulfonyloxy. benzcnesulfonyloxy. tolucnesulfonyloxy, carboxyacyloxy, carboxyaroyloxy. halo. mercapto. loweralkylthio. acylthio aroylthio, sulfo. sulfino, loweralkylsulfinyl. loweralkylsulfonyl, thioacylthio, thiosulfo. thiocyanato. amidinothio, carbamylthio, loweralkylcarbamylthio. diloweralkylcarbamylthio, loweralkoxythiocarhonylthio, loweralkoxycarbonylthio, diloweralkylthi ocarbamylthio, arloweralkoxycarbonylthio, carboxyaroylthio, carboxyacylthio, cyano. amino or substituted amino.
In the descriptive portions of this invention the following definitions apply:
alkyl refers to a loweralkyl hydrocarbon group containing from 1 to about 7 carbon atoms which may be straight chained or branched.
alkenyl refers to an unsaturated or partially unsaturated hydrocarbon group containing from 2 to about 7 carbon atoms which may be straight chained or branched.
cycloalkyl refers to a hydrocarbon ring having up to about seven carbon atoms.
cycloalkenyl" refers to a partially unsaturated hydrocarbon ring having up to about seven carbon atoms.
aryl refers to any benzenoid or non-benzenoid aromatic group but preferably phenyl.
acyl refers to any organic radical derived from an organic acid by the removal of its hydroxyl group such as formyl, acetyl, propionyl, 3-carboxy-2-propcnoyl, camphoryl, benzoyl, toluoyl or heteroyl such as pyridinoyl, piperidinoyl, thenoyl, etc.
The preferred aroyl is benzoyl, loweralkylbenzoyl such as toluoyl or halobenzoyl such as p-chlorobenzoyl. etc.
alkoxy refers to a loweralkoxy 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 morehetero atoms in the chain selected from O, N or S. such a 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 salt ofthc structure given in the formula. The ammonium salts are formed with a (l) loweralkylamincs such as methylamine, diethylamine, triethylaminc; (2) hydroxyloweralkylamines such as B-hydroxyethylaminc; (3) heteroeyclic amines such as Z-aminopyridinc. piperazine, piperidine; (4) aralkylamines such as a-mcthylbenzylamine, phenethylamine; (5) cycloalkylamincs 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-y-(o-tolyl)butyric acid a-chlor0-y-(m-t0lyl)butyric acid a-chl0r0-y-(p-t0lyl)butyric acid a-chl0ro-y-(p-cthylphenyl)butyric acid a-chloro y-(p-propylphenyl)butyric acid oz-chl0ro-'y(p-i-propylphenyl)butyric acid oz-chloro-y-(p-butylphenyl)butyric acid a-chloro-y-(p-i-butylphenyUbutyric acid a-chloro-y-(p-sec-butylphenyl)butyric acid oz-chl0ro-y-(p-t-butylphenyUbutyric acid a-chloro-y-(p-pentylphenyl)butyric acid a-chlor0'y-(p-vinylphenyl)butyric acid a-chl0r0-'y-(p-allylphenyl)butyric acid a-chloro-y-(p-cyclopentylphenyl)butyiic acid a-chloro-y-(p cyclohexylphenyl)butyric acid a-chloro-y-(p-cycloheptylphenyl)butyric acid a-chlor0-y-(p-cycl0pent-l-enylphenyl)butyric acid a-chloro-y-(p-cyclohex-l-enylphenyl)butyric acid 'oz-chloro-y-(p-cyclohept-l-enylphenyl)butyric acid a-chloro-y-(p-cycloheX-3-enylphenyl)butyric acid a-chloro-y-(p-cyclohex-l,3-dienylphenyl)butyric acid a-chloro-y-(m-phenoxyphenyl)butyric acid a-chloro-y-(p-phenylthiophenyl)butyric acid a-chloro-y-(p-biphenylyl)butyric acid a-chloro-y-[p-(Z'-chlorobiphenylyl)lbutyric acid a-chl0ro y{p-(3'-chlorobiphenylyl)]butyric acid a-chloro-y [p 14-chlor0biphenylyl)]butyric acid a-chloro-y-[p-(2-nitr0biphenylyl)lbutyric acid oz-chloro-y-(2-chlor0-4-biphcnylyl)butyric acid a-chloro-y-(3-chloro-4-biphenylyl)butyric acid a-chlor0-7(2,6-dichl0ro-4-biphenylyl)butyric acid a-chl0r0-y-(2-methyl-4-biphenylyl)butyric acid a-chloro-y*(2-br0mo-4-biphenylyl)butyric acid a-chloro-y-(2-fluor0-4biphenylyl)butyric acid a-chloro-y-(2-i0d0-4-biphenylyl)butyric acid a-chl0ro-y-(2-nitro-4-biphenylyl)butyric acid oz-chloro-y-(Z-amin0-4-biphenylyl)butyric acid a-chloro-y'(Z-acetylamin0-4-biphenylyl)butyric acid a-chloroy-(2-ethylamino-4-biphenylyl)butyric acid a-chloro-y-(Z-dimethylamin0-4'biphenylyl)butyric acid a-chloro-y-(2-mercapto-4-biphenylyl)butyric acid a-chloro-y-(Z-acetylthio-4-biphenylyl)butyric acid a-chloro-y-(2-methylthio-4-biphenylyl)butyric acid a-chloro-y(2-methylsulfinyl-4-biphenylyl)butyric acid a-chloro-y-(2-methylsulfonyl-4-biphenylyl)butyric acid a-chloro-7-(2-hydroxy-4-biphenylyl)butyric acid a-chlor0-y-( 2-methoxy-4-biphenylyl)butyric acid a-chlor0-y-(2-acetoxy-4-biphenylyl)butyric acid a-chl0ro-y-(Z-trifluoromethyl-4-biphenylyl)butyric acid a-chl0r0-y-(2-cyan0-4-biphcnylyl)butyric acid a-chloro-y-(2-acetyl-4-biphenyl)butyric acid a-chloro-y-(p-i-butylphenyl)butyric acid a-chl0ro-y-(p-cyclohexylphenyl)butyric acid a-chl0r0-y-( 3-chlor0-4-cyclohexylphenyl)butyric acid a-chl0ro-7-( 3-chlor0-4-i-butylphenyl)butyric acid achloro-a-methyl-y-(p-biphenylyl)butyric acid a-chlor0-B-methyl-y-(p-biphenylyl)butyric acid 6 a-chloro-y-methyl-y-(p-biphenylyl)butyric acid a-chloro-a,B-dimethyl-y-(p-biphenylyl)butyric acid a-chloroa,y-dimethyl-y-(p-biphenylyl)butyric acid a-chloro-fl, y-dimethyl-y-(p-biphenylyl)butyric acid oz-chloro-afi,y-trimethyl-y-(p-biphenylyl)butyric acid a-chloro-a-methyl-y-(m-phenoxyphenyl)butyric acid a-bromo-y-(p-biphenylyl)butyric acid a fluoro-y-(p-biphenylyl)butyric acid a-iodo-y-(p-biphenylyl)butyric acid a-mercapto-y-(p-biphenylyl)butyric acid a-mcthylthi0-y-(p-biphenylyUbutyric acid oz-acetylthi0=y(p-biphenylyl)butyric acid a-benzoylthio-y-(p-biphenylyl)butyric acid a-sulfo-y-(p-biphenylyl)butyric acid oz-sulfino-y-(p'biphenylyl)butyric acid a-methylsulfinyl-y-(p-biphenylyl)butyric acid a-methylsulfonyl-y-(p-biphcnylyUbutyric acid a-thioacetylthio-y (p-biphenyl)butyric acid a-thi0sulf0-y-(p-biphenylyl)butyric acid a-thiocyanat0-y-(p-biphenylyl)butyric acid a-amidinothi0y-(pbiphenylyl)butyric acid a-carbamylthio-y-(p-biphenylyl)butyric acid a-ethylcarbamylthio-y-(p-biphenylyl)butyric acid a-diethylcarbamylthi0-'y-(p-biphenylyl)butyric acid a-mcthoxythi0carb0nylthi0-y-(p-biphcnylyl)butyric acid a-dimethylthiocarbamylthi0-y-(p-biphenylyl)butyric acid a-benzyloxycarbonylthio-y-(p-biphenylyl)butyric acid a-(o-carboxybenzoylthio)-y'(p-biphenylyl)butyric acid oz-cyan0-y-(p-biphenylyl)butyric acid a-dimethylamino-y-(p-biphcnylyUbutyric acid a-(4-carboxybutyroyloxy)-'y-(p-biphenylyl)butyric acid a-(4-carb0xybut-2-enyl0xy)-y-(pbiphenylyl)butyric acid a-acetylthio-y-(p-i-butylphenyl)butyric acid a-acetylthio-7-(3-chl0ro-4i-butylphenyl)butyric acid a-acetylthio-y-(p-cyclohexylphenyl)butyiic acid a-acetylthio-y-(3-chl0ro-4-cyclohexylphenyl)butyric acid a-acetylthio-y[p-(2'-chlor0biphenylyl)]butyric acid a-acetylthio-y-(2-chloro-4-biphenylyl)butyric acid oz-acetylthio'oz-methyl-y-(p-biphenylyl)butyric acid a-acetylthio-a-methyl-y-(2-chlor0-4- bilphenylyl)butyric acid a-acetylthio-a-methyl-y-(3-chl0r0-4-cyclohexylphenyl)butyric acid a-acetylthio-B-methyl-y-(p-biphenylyl)butyric acid a-acetylthio-y-methyl-y-(p-biphenylyl)butyric acid a-acetylthio-a-methyl-y-( 3-chl0ro-4-ibutylphenyl)butyric acid methyl a-chloro-y-(p-biphenylyl)butyrate ethyl a-chl0r0-'y-(p-biphenylyl)butyratc benzyl a-chloro-y-(p-biphenylyl)butyrate N-methyl a-chloro-y-(p-biphenylyl)butyramidc N,N-dimethyl a-chloro-y-(p-biphenylyl)butyramide N-cyclopropyl oz-chloro-y-(p-biphenylyl)butyramide N,N-pentamethylene a-chloro-y-( pbiphenylyl )butyramidc N,N-oxydiethylene C!ChlOr0-'y-( biphe nylyl )butyramide 7 N,N-thiotrimethylene a-chloro-y-(pbiphenylyl)butyramide a-chloro-y-(p-biphcnylyl)butyric acid, sodium salt a-chloro-y-(p-biphcnylyl)butyric acid, potassium salt a-chloro-y-(p-biphenylyl)butyric acid, calcium salt a-chloro-7-( p-biphenylyUbutyric acid, aluminum salt a-chloro-y-(p-biphenylyl)butyric acid, diethylammonium salt achloro-'y-(p-biphenylyl)butyric ylammonium salt a-chloro-y-(p-biphenylyl)butyric acid, B-hydroxyethylammonium salt a-chloro-y-(p-biphenylyl)butyric acid, piperazinium salt a-chloro-y-(p-biphenylyl)butyric acid, methylbenzylammonium salt methyl a-acetylthio-y-(p-biphenylyl)butyrate ethyl a-acetylthio-y-(p-biphenylyl)butyrate benzyl a-acetylthio-y-(p-biphenylyl)butyrate N-methyl a-acetylthio-'y-(p-biphcnylyl)butyramide N,N-dimethyl a-acetylthio-y-(pbiphenylyl)butyramide N-cyclopropyl I biphenylyhbutyramide N,N-pentamethylene biphenyIyUbutyramide N,N-oxydiethylene biphenylyl)butyramide N,N-thiotrimethylene biphenylyhbutyramide a-acetylthio-y-(p-biphenylyl)butyric salt a-acetylthio-y-(p-biphenylyl)butyric acid, potassium salt a-acetylthio-y-(p-biphenylyl)butyric acid, calcium salt a-acetylthio-y-(p-biphenylyl)butyric acid, aluminum salt a-acetylthio-y-(p-biphenylyl)butyric thylammonium salt a-acetylthio-y-(p-biphenylyl)butyric acid, cyclohexylammonium salt a-acetylthio-y-(p-biphenylyl)butyric acid, ,B-hydroxyethylammonium salt a-acetylthio-'y-(p-biphenylyl)butyric piperazinium salt a-acetylthio-y-(p-biphenylyl)butyric acid, methylbenzylammonium salt B-chloro-7-(o-t0lyl)butyric acid B-chloro-y-(m-tolyl)butyric acid Bchlr0-'y-(p-tolyl)butyric acid B-chloro-y-(p-ethylphenyl)butyric acid B-chloro-y-(p-propylphcnyl)butyric acid B-chloro-y-(p-i-propylphenyl)butyric acid B-chloro-y-(p-butylphenyl)butyric acid B-chloro-y-(p-i-butylphenyl)butyric acid B-chloro-y-(p-sec-butylphenyl)butyric acid B-chlor0-y-(p-t-butylpheny])butyric acid B-chloro-y-(p-pcntylphenyDbutyric acid B-chloro-y-(p-vinylphenyl)butyric acid B-chloro-y-(p-allylphenyUbutyric acid B-chloro-y-(p-cycloheptylphenyl)butyric acid B-chloro-7-(p-cyclohexylphenyl)butyric acid B-chloro-y-(pcycloheptylphenyl)butyric acid B-chloro-y-(p-cyclopent-l-enylphenyl)butyric acid B-chloro-y-(p-cyclohexl-enylphenyl)butyric acid B-chloro-y-(p-cycloheptl -enylphenyl butyric acid acid, cyclohexa-acetylthio-y-( pa-acetylthio-y-( pa-acetylthio-y-( poz-acetylthio-y-(pacid, sodium acid, dieacid,
8 ,B-chloro-y-(p-cyclohex-3-enylphenyl)butyric acid B-chloro-y-(p-cyclohcx-l ,3-dienylphcnyl )butyric acid B-chloro-y-(p-phenoxyphenyl)butyric acid B-chloro-y-(p-phenylthiophcnyl)butyric acid B-chloro-y-(p-biphenylyl)butyric acid ,8-chloro-y-[p-(2-chlorobiphenylyl)lbutyric acid B-chloro'y-[p-3'-chlorobiphenylyl)lbutyric acid B-chloro-y-[p-(4-chlorobiphenylyl)]butyric acid B-chloro-y-[p-(2'-nitrobiphenylyl)]butyric acid B-chloro-y-(2-chloro-4-biphenylyl)butyric acid ,8-chloro-y-(3-chloro-4-biphenylyl)butyric acid B-chloro-y-(2,6-dichloro-4-biphcnylyl)butyric acid B-chloro-y-(2-methyl-4-biphenylyl)butyric acid ,B-chloro-y-(2-br0mo-4-biphenylyl)butyric acid B-chloro-y(2-fluoro-4-biphenylyl)butyric acid B-chloro-y-(2-iodo-4-biphenylyl)butyric acid B-chloro-y-(2-nitro-4-biphenylyl)butyric acid B-chloro-y-(2-amino-4-biphenylyl)butyric acid B-chloro-y-(2-acetylthio-4-biphenylyl)butyric acid B-chloro-y-(Z-ethylamino-4-biphenylyl)butyric acid l3-chloro-y-(2-dimethylamino-4-biphenylyl)butyric acid B-chloro-'y-(2-mercapto-4-biphenylyl)butyric acid B-chloro-7-(2-acetylthio-4-biphenylyl)butyric acid B-chloro-y-(Z-methylthio-4-biphenylyl)butyric acid B-chloro-y-(2-methylsulfinyl-4biphenylyl)butyric acid ,B-chloro-y-(Z-methylsulfonyl-4-biphcnylyl)butyric acid ,8-chloro-y-(2-hydroxy-4-biphenylyl)butyric acid B-chloro-y-(2-methoxy-4-biphenylyl)butyric acid B-chloro-y-(2'acetoxy-4-biphenylyl)butyric acid B-chloro-y-(Z-trifluoromethyll-biphenylyl)butyric acid B-chloro-'y-(2-cyano-4-biphenylyl)butyric acid B-chloro-y-(2-acetyl-4-biphenylyl)butyric acid B-chloro-y-(p-i-butylphenyl)butyric acid B-chloroy-(p-cyclohexylphenyl)butyric acid B-chloro-y-(3-chloro-4-cyclohexylphenyl)butyric acid B-chloro-y-(3-chloro-4-i-butylphenyl)butyric acid a-mcthyl-B-chloro-y-(p-biphenyly])butyric acid l3-chloro-l3-mcthyl-y-(p-biphcnylyl)butyric acid ,B-chloro-y-methyl-'y-( p-biphenylyl)butyric acid B-chloro-a,B-dimethyl-y-(p-biphenylyl)butyric acid B-chl0ro-a,B,y-trimethyl-y-(p-biphenylyl)butyric acid B-chloro-B- methyl-7-(m-phenoxyphenyl)butyric acid ,B-bromo-y-(p-biphenylyl)butyric acid B-fluoro-y-(p-biphenylyl)butyric acid B-iodo-y-(p-biphenylyl)butyric acid B-chloro-F-(p-biphenylyl)butyric acid ,B-mercapto-y-(p-biphenylyl)butyric acid ,8-methylthioy-(p-biphenylyl)butyric acid B-acetylthio=y(p-biphenylyl)butyric acid B-benzoylthio-y-(p-biphenylyl)butyric acid B-sulfo-y-(p-biphenylyl)butyric acid B-sulfino-y-(p-biphenylyl)butyric acid B-methylsulfinyl-y-(p-biphenylyl)butyric acid ,B-methylsulfonyl-y-(p-biphenylyl)butyric acid B-thioacetylthio-y-(p-biphenylyl)butyric acid B-thiosulfo-7-(p-biphenylyl)butyric acid ,B-thiocyanato-y-(p-biphenylyl)butyric acid ,B-amidinothio-y-(p-biphenylyl)butyric acid B-carbamylthio'y-(p-biphenylyl)butyric acid 9 B-ethylcarbamylthio-y-(p-biphcnylyDbutyric acid B-diethylcarbamylthio-y-(p-biphenylyl)butyric acid B-mcthoxythiocarbonlythio-y-(p-biphenylyl)butyric acid B-methoxythiocarbonylthio-y-(pbi'phenylyl)butyric acid B-dimcthylthiocarbamylthio7-(p-biphenylyl)butyric acid B-bcnzyloxycarbonylthio-y-(p-biphenylyl)butyric acid B-(o-carboxybenzoylthio)-'y-(p-biphenylyl)butyric acid B-cyano-y-(p-biphenylyl)butyric acid B-dimethylamino-y-(p-biphenylyl)butyric acid ,8-(4-carboxybutyroyloxy)-y-(p-biphcnylyl)butyric acid B(4-carboxybut-2-cnyloxy)-y-(p-biphcnylyl)butyric acid B-acetylthio-y-(p-i-butylphenyUbutyric acid ,8-acetylthio-y-(3-chloro-4-i-butylphenyl)butyric acid ,8-acetylthio-y-(p-cyclohexylphenyl)butyric acid B-acetylthio-'y-(3-chloro-4-cyclohexylphenyl)butyric acid B-acctylthio-y-[p-(2'-chl0robiphenylyl)]butyric acid B-acetylthioy-(2-chlor0-4-biphenylyl)butyric acid B-acetylthio-a-methyl-y-(p-biphenylyl)butyric acid B-acetylthio-a-methyl-y-(2-chloro-4- biphenylyl)butyric acid B-acctylthi-a-mcthyl-y-(3-chloro-4-cyclohexylphenyUbutyric acid B'acetylthio-y-methyl-y-(p-biphenylyUbutyric acid B-acctylthio-a-mcthyl-y-(3-chloro-4-ibutylphenyhbutyric acid methyl ,B-chloro-y-(p-biphenylyl)butyratc ethyl B-chloro-'y-(p-biphenylyl)butyrate benzyl B-chloro-y-(p-biphenylyl)butyrate N-methyl [3-chloro-y-(p-biphenylyUbutyramide N,N-dimethyl B-chloro-y-(p-biphenylyl)butyramide N-cylopropyl B-chlor0-y(p-biphenylyl)butyramide N,N-pcntamcthylenc B-chloro-y-(pbiphenylyUbutyramidc N,N-oxydiethylene biphenylyl)butyramide N,N-thiotrimethylene biphenylyhbutyramide B-chloro-7-(pbiphenylyl)butyric acid, sodium salt ,8-chl0ro-y-(p-biphenylyl)butyric acid, potassium salt /3chloro-'y-(pbiphenylyl)butyric acid, calcium salt ,B-chloro-y-(p-biphenylyl)butyric acid, aluminum salt ,8-chloro-y-(p-biphenylyl)butyric acid, diethylammonium salt ,B-chloro-y-(p-biphenylyl)butyric ylammonium salt B-chloro-y-(p-biphenylyl)butyric thylammonium salt B-chloro-y-(p-biphcnylyDbutyric salt B-chloro--y-(p-biphenylyl)butyric acid, methylbenzylammonium salt methyl ,8-acetylthio-y-(p-biphenylyl)butyrate ethyl B-acetylthio-y-(p-biphenylyl)butyrate benzyl B-acetylthio-'y-(p-biphenylyl)butyrate N-methyl B-acetylthio-y-(p-biphenylyl)butyramide N,N-dimethyl B-acetylthio-y-(pbiphenylyhbutyramide N-cyclopropyl biphenylyl)butyramide B-chloro-y-( pacid, cyclohexacid, ,B-hydroxyeacid pipcrazinium 10 N,N-pentamethylene ,B-acetylthio-y-(pbiphenylyl)butyramide N,N-oxydiethylenc biphenylyl)butyramide N,N-thiotrimethylene biphenylyl)butyramide ,B-acetylthio-y-(p-biphenylyl)butyric acid, sodium salt B-acctylthio-7-(p-biphenylyl)butyric acid, potassium salt ,B-acetylthioy-(p-biphenylyUbutyric acid, calcium salt B-acetylthio-y-(p-biphcnylyl)butyric acid, aluminum salt B-acctylthio-'y(p-biphenylyl)butyric thylammonium salt B-acctylthio-y-(p-biphcnylyl)butyric acid, cyclohcxylammonium salt B-acetylthio-y-(p-biphenylyl)butyric acid. ,B-hydroxyethylammonium salt B-acetylthio-y-(p-biphcnylyl)butyric piperazinium salt B-acetylthio-y-(p-biphenylyl)butyric acid, methylbcnzylammonium salt y-chloro-y-(o-tolyl)butyric acid y-chl0ro--y-(m-tolyl)butyric acid 'y-chloro'y-(p-tolyl)butyric acid 7-chloro-y-(p-ethylphenyl )butyric acid y-chl0ro-y-(p-propylphcnyl)butyric acid y-chloro-y-(p-i-propylphcnyl)butyric acid 'y-chloro-ylp-butylphenyl)butyric acid y-chloro-y-(p-i-butylphcnyl)butyric acid 7-chloro-y-(p-sec-butylphcnyl)butyric acid y-chl0r0-y-(t-butylphenyl)butyric acid y-chloro-y-(pentylphenyl)butyric acid 7-chloro-y-(p-vinylphcnyl)butyric acid y-chloro-y-(p-allylphenyl)butyric acid y-chloro-y-(cyclohexylphenyl)butyric acid 'y-chlor0-y-(cyclopcntylphenyl)butyric acid y-chloro-y-(p-cycloheptylphenyl)butyric acid 'y-chloro-y-(pcyclopent-l-enylphenyl)butyric acid 'y-chloro-'y-(p-cyclohex-l-enylphenyUbutyric acid y-chloro-y-(p-cyclohept1-cnylphenyl)butyric acid y-chloro-7-(p-cyclohex-3-enylphenyl)butyric acid y-chloro-y-(p-cyclohex-l ,3'dienylphenyl)butyric acid y-chloro-y-(p-phenoxyphcnyl)butyric acid y-chl0ro'y-(p-phenylthiophenyl)butyric acid 'y-chloro-y-(p-biphenylyl)butyric acid y-chlor0-y-[P-(2-chlorobiphcnylyl)]butyric acid 'y-chloro-y-[P-(3-chlorobiphenylyl)]butyric acid 'y-chlor0-7-[p-(4'-chl0robiphcnylyl)]butyric acid 'y-chloro-y[p-(2'-nitrobiphenylyl)lbutyric acid y-chloro-y-(2-chloro-4-biphcnylyl)butyric acid 'y-chloro-y-(3-chloro-4-biphcnylyl)butyric acid y-chlor0-y-(2,6dichloro-4-biphenylyl)butyric acid y-chloro-7-(2-mcthyl-4-biphenylyl)butyric acid 'y-chloro-y-(2-bromo-4-biphenylyl)butyric acid 'y-chloro-y-(2-fluoro-4-biphenylyl)butyric acid y-chlor0-y-(2-iodo-4-biphenylyl)butyric acid 'y-chloro-y-(2 nitro-4-biphenylyl)butyric acid 'y-chl0ro-y-(2-amin0-4-biphenylyl )butyric acid y-chloro-y-(2-acetylamino-4-biphenylyl)butyric acid 'y-chloro-7-(2-cthylamino-4-biphenylyl)butyric acid 'y-chloro-y-(2-dimethylamino-4-biphenylyl)butyric acid -y-chloro-y-(2-mercapto-4-biphenylyl)butyric acid B-acetylthio-y-(pacid, dicacid,
1 1 y-chloro-y-(2-acetylthio-4-biphenylyl)butyric acid y-chloro-7-(Z-methylthio-4-biphenylyl )butyric acid 'y-chloro-y-(2-methylsulfinyl-4-biphenylyl)butyric acid 7-chloro-y-(Z-methylsulfonyl-4-biphenylyl)butyric acid 'y-chloroy-(2-hydroxy-4-biphenylyl )butyric acid y-chloro-y-(2-methoxy-4-biphenylyl)butyric acid y-chloro-y-(2-acetoxy-4'biphenylyl)butyric acid 'ychloro-y-(2-trifluoromethyl-4-biphcnylyl)butyric acid y-chloro-y-(2-cyano-4-biphenylyl)butyric acid 'y-chloro-y-(2-acetyl-4-biphenylyl)butyric acid 'y-chloro-y-(p-i-butylphenyl)butyric acid y-chloro-y-(p-cyclohexylphenyl)butyric acid 'y-chloro-y-(3-chloro-4-cyclohexylphenyl)butyric acid y-chloro-y-(3-chloro-4-i-butylphenyl)butyric acid y-chloroa-methyl-y-(p-biphenylyl)butyric acid y-chloro-B-methyl-y-(p-biphenylyl)butyric acid y-chloro-y-methyl-y-(p-biphenylyl)butyric acid 'y-chloro-a,B-dimethyl-y-(p-biphenylyl)butyric acid y-chloro-aq-dimethyl-y-(p-biphenylyl)butyric acid y-chloro-B,y-dimethyl-y-(p-biphenylyl)butyric acid y-chloro-a,B,'y-trimethyl-y-(p-biphenylyl)butyric acid y-chloro-a-methyl-y-(m-phenoxyphenyl)butyric acid y-bromo-y-(p-biphenylyl)butyric acid y-fluoro-y-(p-biphenylyl)butyric acid y-iodo7-(p-biphcnylyl)butyric acid y-mercapto-y-(p-biphenylyl)butyric acid y-methylthio-y-(p-biphenylyl)butyric acid y-acetylthio-y-(p-biphenylyl)butyric acid y-benzoylthio-y-(p-biphenylyl)butyric acid y-sulfo-y-(p-biphenylyl)butyric acid y-sulfino-y-(p-biphenylyl)butyric acid y-methylsulfinyl-y-(p-biphcnylyUbutyric acid 'y-methylsulfonyl-y-(p-biphenylyl)butyric acid 'ythioacetylthio-y-(p-biphenylyl)butyric acid y-thiosulfo-y-(p-biphenylyl)butyric acid 'y-thiocyanato-y-(p-biphenylyl)butyric acid y-arnidinothio 'y-(p'biphenylyhbutyric acid 'y-carbamylthio-y-(p-biphenylyl)butyric acid 'y-ethylcarbamylthio-y-(p-biphenylyl)butyric acid y-diethylcarbamylthio-y-(p-biphenylyl)butyric acid y-methoxythiocarbonylthio-y-(p-biphenylyl)butyric acid y-dimethylthiocarbamylthio-y-(p-biphenylyl)butyric acid 'y-benzyloxycarbonylthio-'y-(p-biphenylyl)butyric acid y-(o-carboxybenzoylthio)-y-(p-biphenylyl)butyric acid -y-cyano-'y-(p-biphenylyl)butyric acid 'y-dimethylamino-y-(p-biphenylyl)butyric acid 'y-(4-carboxybutyroyloxy)-'y-(p-biphcnylyl)butyric acid y-(4-carboxybut-2-enyloxy)-y-(p-biphenylyl)butyric acid 'y-acetylthio-y-(p-i-butylphenyl)butyric acid y-acetylthio-y-(3-chloro-4-i-butylphenyl)butyric acid y-acetylthio-y-(p-cyclohexylphenyl)butyric acid 'y-acetylthio-'y-(3-chloro-4-cycloheXylphenyl)butyric acid y-acetylthio-y-[p-(Z-chlorobiphenylyl)]butyric acid y-acetylthio-y-(2-chloro-4-biphenylyl)butyric acid 12 'y-acetylthio-a-methyl-y-(p-biphenylyl)butyric acid y-acetylthio-oz-methyl-y-(2-chloro-4- biphenylyl)butyric acid y-acetylthio-a-methyl-y-(3-chloro-4-cyclohexylphenyDbutyric acid y-acetylthio-/3-methyl-y-(p-biphenylyl)butyric acid y-acetylthio-y-methyl-y-(p-biphenylyl)butyric acid y-acetylthio-a-methyl-y-( 3-chloro-4-ibutylphcnylyhbutyric acid methyl y-chloro-y-(p-biphenylyl)butyrate ethyl 'y-chloro-y-(p-biphcnylyl)butyrate benzyl y-chloro-y-(p-biphenylyl)butyrate N-methyl 'y-chloro-y-(p-biphenylyl)butyramide N,N-dimethyl 'y-chloro-y-(p-biphenylyl)butyramidc N-cyclopropyl y-chloro-y-(p-biphcnylyl)butyramidc N,N-pentamethylene 'y-chloro-y-( pbiphenylyl )butyram ide N,N-oxydiethylene 'y-chl0r .y
y-chloro-y-(py-chloro-y-(p-biphcnylyl)butyric acid, diethylammonium salt ychloro-y(p-biphenylyl)butyric acid, cyclohcxylammonium salt y-chloro-y-(p-biphenylyl)butyric acid, B-hydroxycthylammonium salt y-chloro-y-(p-biphe ylyl)butyric acid, piperazinium salt 'y-chloro-y-(p-biphenylyl)butyric acid, methylbcnzylammonium salt I methyl y-acetylthio-'y-(p-biphenylyl)butyrate ethyl 'y-acetylthio-y-(p-biphenylyl)butyrate benzyl 'y-acetylthio-y-(p-biphenylyl)butyratc N-methyl 'y-acetylthio-'y-(p-biphcnylyl)butyramide N,N-dimethyl 'y-acetylthio-y-(pbiphenyIyDbutyramide N-cyclopropyl biphenylyl)butyramide N,N-pentamethylene biphenylyl)butyramide N,N-oxydiethylene biphenylyhbutyramide N,N-thiot rimethylene biphenylyllbutyramide 'y-acetylthio-y-(p-biphenylyl)butyric salt y-acetylthio-y-(p-biphenylyl)butyric acid, potassium salt 'y-acetylthio-y-(p-biphenylyl)butyric acid, calcium salt y-acetylthio-'y-(p-biphenylyl)butyric acid, aluminum salt 'y-acetylthio-y-(p-biphenylyl)butyric acid, diethylammonium salt 'y-acetylthio-y-(p-biphenylyl)butyric acid, cyclohexylammonium salt 'y-acetylthio-y-(p-biphenylyl)butyric acid, ,B-hydroxyethylammonium salt 'y-acetylthio-y-(p-biphenylyl)butyric piperazinium salt y-acetylthio-y-(p-biphenylyl)butyric acid, methylbenzylammonium salt acid, sodium acid,
The oz-position (laisen condensation of a substituted benzaldehyde benzyl ester) in the presence ofa metal alkoxide results in a B-acrylic acid ester. The aldehyde may also be sub jected to a Perkin reaction with acetic anhydride and an acetic acid salt or through a Knoevenagel condensato obtain a substituted fi-acrylie acid. Hydrogenation of the double bond in the presence of a heterogeneous catalyst results in the propionic acid or ester. Conver sion of the propionic acid to the acid halide followed by Rosenmund reduction in the presence of a supported catalyst results in the propionaldehyde This in turn is treated with cyanohydrin to afford the propionaldehyde cyanohydrin which is then hydrolyzed to the a-hydroxybutyric acid. The ester or amide may also be tion using malonic acid and ammonia in an amine base 10 prepared in the same manner.
CH COOR" w mcoo n men" Y Y z z "z cu-cucoou ZCHZCOOR" cn cu coon S0261 CHZCHZCOCI H /Pd-BaS0 CHZCHZCHO on I @m cH CHCN a CHZCHZCHEOW The a-alkyl-a-hydroxy-y-substituted phenyl butyric acid 'may he prepared by reacting a L l-substituted phenyl propionic acid ester with an alkyl (irignard reagent to obtain a l-suhstituted phenyl-3-butanonc which on reaction with sodium cyanide in the presence of sodium bisulfite yields the Lsubstituted phenyl-3-butanone cyanohydrin. Hydrolysis gives the desired acid, ester or amide.
The y-ulkyl-0z-hydroxy-y-substituted phenyl butyric acids may be prepared as previously described for the a-hydroxy-y-substitutcd phenyl butyric acid compounds. The reaction sequence starting material is a substituted phenyl alkyl kctone upon which a Reformatsky reaction is performed with an a-halo acetate in the presence of zinc. The resultant B-hydroxy-B-alkyl- B-substituted phenyl propionate is then dehydrated v a o R II R n CHZCHZCOOR R MgI CHZCHZC-RG mso The B-alkyl-a-hydroxy-y-substituted phenyl butyric acids may be prepared as previously described for the oz-hydroxy-y-substituted phenyl butyric acid compounds by starting with an a-alkylmalonic acid in the Knoevenagel condensation to obtain an a-alkyl-B- substituted acrylic acid.
l" R .ctt(cooH) R with acid at raised temperatures to the B-alkyl-B-- substituted phenylacrylic acid. This may also be ac eomplished by carrying out a Doebner modification of 30 the Perkin reaction on a substituted phenyl alkyl ketone with malonic acid in the presence of pyridine to obtain the B-alkyl-B-substituted phenyl acrylic acid.
CHZKCOOH culucu HZO/HCT CH tF-IIICOOH This, in turn, is then reacted as previously described to obtain the desired y-alkyl-a-hydroxy-y-substituted phenyl butyric acid.
C==0 rm cn cooa" a y Zn Y uncounpyridine 2 )2 (irignard conditions results in the substituted phcnyl magnesium bromide. When this is condensed .with 2,3- epoxypropyl chloride the resultant product is l-chloroacid H /Pd-BaS0 R CHCHZCOCI ucu cno l" R cu cncoou n OIHCl R CHCH CHCN z E 2 p I 2 Y Y r A combination of the previously described reactions affords diand tri-substitution in the side chain.
The B-position Reaction of a substituted bromobenzene under 3-substituted phenylpropan-Z-ol. Reaction of the latter chlorohydrin with an aqueous solution of potassium cyanide affords the l-cyano3-substituted phenylpropan- 2-ol which on hydrolysis and esterification results in the 7-substituted phenyl-B-hydroxybutyrate. Acid hydrolysis of this ester gives the 'y-substituted phenyl-B- hydroxybutyric acid.
-J.d HgBr 19 20 6 m l" R L K R CH HCH CN H20 CHCH C'I R"0H-H 0 HCl 1'' Y l R HIM cu cacu coon" H 0 cu cucu coon Y Y When the oz-alkyl-B-hydroxy-y-substituted phenyl Again, using the desired epoxyalkylchloride the corre butyric acid is desired l-methyl-2,3-epoxypropyl chlosponding di or tri alkyl substituted compound results. ride is used. The corresponding B-alkyl compound is h prepared when the starting material is 2-methyl-2,3 7 T c y'posmon cpoxypropyl chloride and the y-alkyl compound results Friedel-Crafts reaction of a substituted benzene with when the starting material is 2,3-epoxybutyl chloride. alkyl succinyl chloride or succinic anhydride results in i cu cu-p-lci 21 22 formation of a y-suhstituted phenyl-y-keto butyric acid The a-alkyl-y-substituted phenyl-'yhydroxybutyric ester or the acid. Reduction of the wketo group may acid or ,B-alkyl-y-substituted phenyl-y-hydroxybutyric then be carried out in the presence ofa metal catalyst acid may be prepared by analogous procedures using or di b h d id t bt i the y-substitutcd hethe appropriately substituted alkyl succinyl chloride or nyl-y-hydroxy butyric acid ester with is then hydro- 5 succinic anhydride. lyzed t0 the corresponding acid.
0 0 R ll R ll (21 -C-CH -CH -C00R" C-CH CH COOR" A161 Y 3 Y H2(Pt) or NaBH GI GI R I R -CH CH C0OH F alcKOH -CH CH C00R 0 J J: 0 0 a ll C-CH CH COOH A161 H (Pt) r NaBH on a n-cu cu coou l i Y il CICCHZCHCOOR" c1 CCHCHZCOOR" A1613 mc o R ll R ll CH2IIIHCOOR" C(ILHCHZCOOR" Y Y RB a (Pt) (a) 0? mm or man;
CH CHCOOR CHCH COOR" The 'y-alkyl-y-substituted-y-hydroxybutyric acid is prepared from the y-keto butyric acid and an alkyl an aldehyde through a Rosenmund reduction in the CHZHCH COOH where R" is lower alkyl conventional manner. The acid halide is-first formed as above and this is then catalytically reduced in the preswith a nitrog lIH) L Y R-H CH Y i iZ-(CH) -CHO R Y B Reaction of a substituted phenylbutyric acid ester en base such as ammonia, loweralkylamine, diloweralkylamine, cycloloweralkylamine, a nitrogen containing hetero compound such as pipcridine,
morpholine, piperazine, hydroxylamine and hydrazine gives the corresponding amide, hydroxamic acid, or by drazide.
( HM-Y-( im -coon"- Re R Help, R i
(EM-i4 to -sou EM -CONHR" im -comm 0 im -couuon Y R l lg The butyric acid esters may be hydrolyzed to the corresponding ac ids. Reaction of the hydroxybutyrate or 25 anhydride XOX in the presence of a tertiary amine such as pyridine, picoline, or quinoline results in the formation of an hydroxy derivative of the butyrate. Ex umples of X'Cl and X'OX' include acetyl Chloride,
acetic unhydride, propionyl chloride, hutyryl chloride. 5
0x or R l R l w wim -coou @-lcn) -f-(fu) -cooa" 0 ll OCOAr mm R (0H) CO0H(R") (who :2 m
Y "Y a RI! CICOR" R l2 comm") m r R 0 Y RY 8 ll NH crcouu \R l 2 m -i-(yn -cooflm R 8R0" on i Y Y I (en -urn -cowm 0 Y B u l" Y RY mko/ -(c m -coon" were Rf is lower-alkyl and v CISOZR" R 02R" Ar is phenyl or Fl -E-(I-O -CDQM substituted pheny'l Y P\ B a I C'ISO Ar R i H fl -c-( w -coonm" L Y B a 010R" R Icon" W IH) -(cH) -c00H(R") ll Y lg R u R I CHZCHZCOOH 9 tl -f-( l -cwllm") o:
\ Y a m (fw i-(t tm coomw) Y RY Ra Ra cu cucoou "'J on -c-(un -coomn") v' RY 9 where '0C0C5H4C00H 0 c\ a a l /L Y When a substituted hydroxybutyrate is reacted with where R" is lower alkyl;
R" is lower alkyl I R I I -e (QU -T-(EHM-COOMR") a phosphorus trihalide, phosphorus pentahalide, phos- Where Hall is ChlOrO, brOmO 0r iodo.
phorus oxyhalide, sulfurylhalide, thionyl halide, or sul- Reaction of a sulfonate derivative with a metal halide fur halide, the corresponding substituted halo butyrate 0 (preferably an alakli halide) results in the correspondis prepared. ing halo compound.
GI Hal R 2: R I
I n'L (l )m'cw 'Z Y 'U -COOR" v s Y Y a u R(Ar) HIT R ml'l R E) -l-(r1) -COZ CH) -(CH) -COZ Y B Y B a where Z is as described on page '4. ide, potassium carbonate, sodium bicarbonate. magne- The corresponding halo butyric acid may be prcl sium bicarbonate, etc.). Also, the aluminum salts of the pared by heating the ester with acetic acid containing instant products may be obtained by treating the correthe corresponding hydrogen halide. sponding sodium salt with an appropriate aluminum R Hal I] I HON: R ca) -c-( -CO0R"---) til-l) -(CH) 0 n I! n m l-Hal l 0 B a a Y B a where R" is lower alkyl. complex such as aluminum hydroxy chloride hexahy- The substituted fluoro compounds may also be obdrate, etc. The ammonium salts may be made by reactaincd from the corresponding iodo, bromo or chloro tion with the corresponding amine such as methylcompounds by reaction with potassium fluoride at amine,diethylamine,B-hydroxycthylamine,piperazinc, about l3()20(lC. piperidine, a-methylbcnzylamine, cyelohexylamine,
' Ha! Hal R l R l (IH) -I-(H) -CO0H ((IIH) -(I-((IH) -COOM R R R R Y RY B a Y U- R Br triethylamine, phenethylamine. etc.
c") i cm n 40 Reaction of a substituted halo butyrate ester with a n nitro en base such as ammonia, lowcralkylamine,
g R diloweralkylamine. cycloloweralkylamine. a nitrogen Y containing hetero compound such as pipcridine. morpholine, piperazine results in the corresponding amide. KF The butyrate ester with hydroxylaminc gives the corrc- 4 F sponding hydroxamic acid, and with hydrazine gives R the corresponding hydrazide.
CH) C-(Cl'l) -COOR" l I Y T R a Hal R F' l -f-(FU -COOR" coo -l -(cu) -coz "W B u Y 6 3 The acid addition salts may be formed by the action Where:
of one equivalent ofa suitable base with the substituted Z is -NH halo butyric acid. Suitable bases thus include for examloweralkylamine,
ple the alkali metal alkoxides such as sodium methoxdiloweralkylamino,
ide. etc.. and the alkali metal and alkaline earth metal cycloloweralkylamino. hydroxides, carbonates. bicarbonates, etc. (such as sodium hydroxide. potassium hydroxide. calcium hydrox- U 31 (where B is loweralkylidenyl or heteroloweralkylidenyl),
NHOH or NHNH where R" is lower a'lky] The halo butyramides, butyrhydroxamic acids or butyrhydrazides can be prepared from the corresponding hydroxy butyramides with thionyl halides according to the method of l. A. Smith, Chem. Bcrichtc 718:634
---------5 cu) -C-(CH) -com+ I n I m Hm R i p cHi -c-( m Y K, e u
Hal
I S0 Ha1 H) -(CH) -C(HHR" 5 i "l a (m PW R8 0 2 w H N H H m N 0 c C m m G H 5 H C R C R 1 a B a B.
a M R mmw R m rv R m l-w h m R wi m I.
Thc substituted halo butyric acids and acid dcrivacyanatc.alkalithiosulfatc,alkali lowcralkylmcrcaptidc, tivcs such as such as their salts, amides or esters may be reacted with various nucleophilic reagents which will replace the halogen group. Thus, for example, an
alkali sulfitc or an alkali sulfinatc may be reacted with the chloro. bromo or iodo butyric acid to for the corresponding derivative of the mcrcapto butyric acid. This 45 may also be carried out on the sulfonatc compounds.
alkali hydrosulfide, alkali thioalkanoate, alkali thiobcnzoate, alkali loweralkylxanthate, thiourea, alkali thi0 m M m 4 4 m R M nn MK m nu H 8. w B m B n n n \J \I wlnw liR miR where:
R is alkyl or ary'l.
$50 M i550 M R I fl fH) -i-(CAH) C00H M m p i ll S "H2 nscm R l CH) -C-(CH) CO0H S s I ll II I SCOR"(AY) HSCOR"(Ar) R (|ZH) -|-(CH) CO0H The mercapto butyric acids may then be reacted with 60 myl chloride to form the corresponding mercapa loweralkyl chlorocarbonate, an alkali isocyanate in tobutyric acid derivatives. The mcrcaptobutyric acid the presence of hydrogen chloride, a loweralkylcarbamay also be reacted with succinic anhydride, maleic myl chloride, a diloweralkylcarbamyl chloride or conanhydride or phthalic anhydride to form the correverted to the metal salt which will react with a carba- 65 sponding derivative.

Claims (11)

1. A COMPOUND OF THE FORMULA
2. A compound according to claim 1 of the fomula
3. A compound according to claim 2, where n is 0 and m is 2; X is chloro; Y is chloro; R and R are hydrogen; and Z is selected from the group consisting of -OH and lower alkoxy, said compound being a compound selected from the group consiting of gamma -chloro- gamma -(2''-chloro-4-biphenylyl) butyric acid and lower alkyl ester thereof.
4. A compound according to claim 1 of the formula
5. A compound according to claim 1 of the formula
6. A compound according to claim 1 of the formula
7. A compound according to claim 2 where Y is hydrogen or halo; R , R and R are hydrogen.
8. A compound according to claim 7 where Y is 2''-chloro, X is chloro and Z is -OH.
9. A compound according to claim 8 where n 2.
10. A compound according to claim 8 where n 1 and m 1.
11. A compound according to claim 8, where m is 2, said compound being gamma -chloro- gamma -(2''-chloro-4-biphenylyl)butyric acid.
US195825A 1970-05-05 1971-11-04 Phenyl butyric acids and derivatives thereof Expired - Lifetime US3867434A (en)

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US195825A US3867434A (en) 1971-11-04 1971-11-04 Phenyl butyric acids and derivatives thereof
BE776316A BE776316R (en) 1971-03-10 1971-12-06 Phenylacetic acid derivs - as antiinflammatory agents
NL7117006A NL7117006A (en) 1971-03-10 1971-12-10 Phenylacetic acid derivs - as antiinflammatory agents
FR7144544A FR2128277B2 (en) 1970-05-05 1971-12-10
GB5751071A GB1382267A (en) 1970-05-05 1971-12-10 Phenylalkanoic acid derivatives
CA129,890A CA1027133A (en) 1971-03-10 1971-12-10 Substituted alkanoic acids and their derivatives, and process
DE19712162038 DE2162038A1 (en) 1970-05-05 1971-12-10 Process for the production of synthetic alkanoic acids and their derivatives
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
US05/424,628 US3966801A (en) 1971-11-04 1973-12-13 Phenyl butyric acids and derivatives thereof
FR7508269A FR2279386A2 (en) 1970-05-05 1975-03-17 NEW DERIVATIVES OF PHENYL (SUBSTITUTE) HYDROXYALKANOIC ACIDS
FR7508271A FR2279387A2 (en) 1970-05-05 1975-03-17 NEW DERIVATIVES OF PHENYL (SUBSTITUTE) THIOALKANOIC 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

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3997589A (en) * 1971-03-17 1976-12-14 Boehringer Ingelheim Gmbh 4-(2'-Fluoro-4-biphenylylr-4-oxo-butyric acid and esters and salts thereof
US4021479A (en) * 1971-03-17 1977-05-03 Boehringer Ingelheim Gmbh Derivatives of 4-(4-biphenylyl)-butyric acid
US4219668A (en) * 1979-07-05 1980-08-26 American Cyanamid Company 4-Hydroxy,4-biphenylbutyric acid
US4851440A (en) * 1987-07-25 1989-07-25 Hoechst Aktiengesellschaft Leukotriene antagonists, processes for the preparation thereof, the use thereof for the treatment of diseases, and precursors
US4855323A (en) * 1987-07-25 1989-08-08 Hoechst Aktiengesellschaft Leukotriene antagonists, a process for the preparation thereof, and the use thereof for the treatment of diseases
US4904822A (en) * 1988-02-19 1990-02-27 Kuraray Co., Ltd. Process for the optical resolution of (+)-2-hydroxy-4-phenylbutanoic acid
US4946999A (en) * 1988-03-04 1990-08-07 Japan Tobacco Inc. Novel intermediates for synthesis of trichostatic acid or trichostatin A, and processes for preparing trichostatic acid and trichostatin A
US5248816A (en) * 1991-10-11 1993-09-28 Imperial Chemical Industries Plc Process for making 2-hydroxymandelic acid and 2-hydroxybenzaldehydes
US5859047A (en) * 1994-11-15 1999-01-12 Bayer Corporation Substituted 4-biarylbutyric acid derivatives as matrix metalloprotease inhibitors
US6166082A (en) * 1994-11-15 2000-12-26 Bayer Corporation Substituted 5-biarylpentanoic acids and derivatives as matrix metalloprotease inhibitors
WO2012067322A1 (en) * 2010-11-17 2012-05-24 전북대학교산학협력단 Pharmaceutical composition for treatment of asthma containing 4-phenylbutyric acids or pharmaceutically acceptable salts thereof as active ingredient

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3997589A (en) * 1971-03-17 1976-12-14 Boehringer Ingelheim Gmbh 4-(2'-Fluoro-4-biphenylylr-4-oxo-butyric acid and esters and salts thereof
US4021479A (en) * 1971-03-17 1977-05-03 Boehringer Ingelheim Gmbh Derivatives of 4-(4-biphenylyl)-butyric acid
US4219668A (en) * 1979-07-05 1980-08-26 American Cyanamid Company 4-Hydroxy,4-biphenylbutyric acid
US4851440A (en) * 1987-07-25 1989-07-25 Hoechst Aktiengesellschaft Leukotriene antagonists, processes for the preparation thereof, the use thereof for the treatment of diseases, and precursors
US4855323A (en) * 1987-07-25 1989-08-08 Hoechst Aktiengesellschaft Leukotriene antagonists, a process for the preparation thereof, and the use thereof for the treatment of diseases
US4904822A (en) * 1988-02-19 1990-02-27 Kuraray Co., Ltd. Process for the optical resolution of (+)-2-hydroxy-4-phenylbutanoic acid
US4946999A (en) * 1988-03-04 1990-08-07 Japan Tobacco Inc. Novel intermediates for synthesis of trichostatic acid or trichostatin A, and processes for preparing trichostatic acid and trichostatin A
US5248816A (en) * 1991-10-11 1993-09-28 Imperial Chemical Industries Plc Process for making 2-hydroxymandelic acid and 2-hydroxybenzaldehydes
US5859047A (en) * 1994-11-15 1999-01-12 Bayer Corporation Substituted 4-biarylbutyric acid derivatives as matrix metalloprotease inhibitors
US5861427A (en) * 1994-11-15 1999-01-19 Kluender; Harold Clinton Eugene Substituted 4-biarylbutyric acid derivatives as matrix metalloprotease inhibitors
US5874473A (en) * 1994-11-15 1999-02-23 Bayer Corporation Substituted cycloalkanecarboxylic acid derivatives as matrix metalloprotease inhibitors
US5886024A (en) * 1994-11-15 1999-03-23 Bayer Corporation Thiophene-containing butonic acid derivatives as matrix metalloprotease inhibitors
US5886043A (en) * 1994-11-15 1999-03-23 Bayer Corporation Substituted 4-biarylbutyric acid derivatives as matrix metalloprotease inhibitors
US6166082A (en) * 1994-11-15 2000-12-26 Bayer Corporation Substituted 5-biarylpentanoic acids and derivatives as matrix metalloprotease inhibitors
WO2012067322A1 (en) * 2010-11-17 2012-05-24 전북대학교산학협력단 Pharmaceutical composition for treatment of asthma containing 4-phenylbutyric acids or pharmaceutically acceptable salts thereof as active ingredient
KR101374241B1 (en) 2010-11-17 2014-03-14 전북대학교병원 Pharmaceutical composition for treating asthma comprising 4-phenylbutyric acid or pharmaceutically acceptable salts thereof

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