US3860624A - P-cyclohexyl alpha - lower alkanoylthio hydrocinamic acid - Google Patents

P-cyclohexyl alpha - lower alkanoylthio hydrocinamic acid Download PDF

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US3860624A
US3860624A US380651A US38065173A US3860624A US 3860624 A US3860624 A US 3860624A US 380651 A US380651 A US 380651A US 38065173 A US38065173 A US 38065173A US 3860624 A US3860624 A US 3860624A
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lactic acid
cyclohexylphenyl
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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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    • 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

  • This invention describes novel Ot-SLIbStItUtCd p-cycloalkylphenylpropionic acids and their derivatives and their use in therapeutic compositions.
  • this invention relates to the preparation of a-substituted p-cycloalkylphenylpropionic acids.
  • They further provide analgesic and antipyretic methods for the relief and treatment of pain and fever associated with inflammation.
  • This invention comprises a class of novel chemical compounds which contain a cycloalkyl substituted phenyl radical which is attached to an a-mercapto propionic acid in the B-position.
  • This invention further comprises derivatives of said propionic acids and the method of preparing the same.
  • This invention also describes a new method of treating inflammation and associated pain and fever as well as novel therapeutic compositions.
  • the compounds of this invention can be represented by the generic structure which is described by the general formula I.
  • n 0-2;
  • B is hydrogen or loweralkyl
  • R is halo, nitro, amino, acylamino, mono- & diloweralkylamino, mercapto, acylthio, loweralkylthio, loweralkylsulfinyl, loweralkylsulfonyl, hydroxy, I loweralkoxy, acyloxy, haloloweralkyl, cyano, acetyl or loweralkyl',
  • R is hydrogen
  • X is halo
  • R and R are hydrogen or loweralkyl; and Z is OH,
  • a N A y] i. (where A is loweralkylidenyl or heteroloweralkylidey NHOH, NHNl-l or OM (where M is an alkali, alkaline earth or aluminum metal oran ammonium salt).
  • the compounds of this invention contain asymmetric carbon atoms in the alpha-position of the 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 l isomers as well as the dl mixtures thereof are embraced within the scope of this invention.
  • two racemic mixtures may exist in the case of 2- or 3-loweralkylcyclohexyl- I phenyllactate, 2'- or 3'-loweralkylcyclopentylpheny]- lactate, 2- or 4'-loweralkylcycloheptylphenyllactate,
  • the preferred compounds of this embodiment describe the cyclohexyl class of chemical compounds which have particular usefulness as anti-inflammatory, analgesic and antipyretic agents. These compounds are described in formula II.
  • R is halo, nitro, loweralkyl
  • R is hydrogen
  • X is halo
  • R is chloro
  • R is hydrogen
  • racemic mixtures as well as the dextro and levorotatory isomers thereof.
  • R is chloro
  • R is hydrogen
  • Hal is fluoro
  • racemic mixtures as well as the dextro and levorotatory isomers thereof.
  • R is hydrogen, lower alkanoyl, aroyl, loweralkoxythiocarbonyl, loweralkoxycarbonyl, arloweralkoxycarbonyl, loweralkyl, amidino, thioacyl, cyano, carbamyl, loweralkylcarbamyl, diloweralkylcarbamyl, diloweralkylthiocarbamyl, carboxyacyl, carboxyaroyl, or sulfo;
  • R is chloro
  • R is hydrogen
  • lower alkyl carbon group containing from 1 to about 6 carbon atoms which may be straight chained or branched.
  • the acyl radical may be any organic radical derived from an organic acid by the removal of its hydroxyl group such as acetyl, propionyl, 3-carboxypropionyl, 3-carboxy-2-propenoyl, camphoryl, etc.
  • the preferred aroyl is benzoyl, loweralkylbenzoyl such as toluoyl or halobenzoyl such as p-chlorobenzoyl, 2carboxybenzyl, etc.
  • Lower alkoxy signifies an alkoxy group containing from 1 to about 6 carbon atoms which may be straight chained or branched.
  • loweralkylidenyl refers to a lowcralkylidenyl hydrocarbon group containing from 2 to about 6 carbon atoms.
  • Heteroloweralkylidenyl refers to a loweralkylidenyl hydrocarbon group containing from about 2 to 5 carbon atoms and having one or more hetero atoms in the chain selected from O, N or S, such as piperidinyl, morpholinyl, etc.
  • the preferred alkali or alkaline earth metals are sodium, potassium, calcium. and magnesium.
  • ammonium salt refers to the cation formed when ammonia or an organic amine react with the earboxyl' 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, piper-azine; piperidine,-(4) aralkylamines such as a-methylbenzylamine, phenethylamine;' (5) cycloalkylamines such as cyclohexylamine; (6) alkaloids such as quinine, cinchonidine, cinchonine, ephedrine.
  • R and R" may also be carboxy
  • X may also be refers to a lower alkyl hydrov B-(3-chl0r0-4-cyclopentylphenyl)lactic acid acid B-(3-chlor0-4-cycloheptylphenyl)lactic acid ethyl B-(3-chloro-4-cyclopentylphenyl)lactate ethyl B-(3-chloro-4-cycloheptylphenyl)lactate ,B-(3-chloro-4-cyclopentylphenyl)lactamide ,8-(3-chloro-4-cycloheptylphenyl)lactamide /3-(3-chloro-4-cyclopentylphenyl)lactic acid, diethylammonium salt B-(3-chl0ro-4-cycloheptylphenyl)lactic acid, diethylammonium salt B-[3-chl0ro-4-(2'-methylcyclopentyl)phenyll
  • acetate lB-(3-chloro-4-cyclohexylphcnyl)lactic acid acetate d B-(3-chloro-4-cyclohexylphenyl)lactic acid, diethylcarbonate l B-(3-chloro-4-cyclohexylphenyl)lactic acid dicthylcarbonate d B-(3-chloro-4-cyclohexylphenyl)lactic acid sodium salt lB-(3-chlor0-4-cyclohexylpheny
  • diethylammonium salt l B-(3,5-dichl0ro-4-cyclohexylphenyl)lactic diethylammonium salt
  • the compounds of this invention may be prepared from known starting materials.
  • p-Cycloalkylbenzaldchyde may be a) halogenated or b) nitrated to obtain a corresponding 3-hal0-4-cycloalkylbenzaldehyde or a 3-nitro-4-cycloalkylbenzaldehyde.
  • Chlorination or bromination may be carried out in the presence of a small amount of iodine dissolved in an inert solvent such as carbon tetrachloride.
  • a solution of chlorine or bromine is then added while the temperature is held near 0C.
  • Nitration is carried out with fuming nitric acid at about 0C. The following reaction equation illustrates this method.
  • a second nitration or halogenation with chlorine 0 nitr0-4-cycloalkylbenzaldehyde can be nitratcd to give bromine may be carried out on the 3-substituted4- 25 a3,5-dinitro-4-cycloalkylbenzaldehyde.
  • a 3-alkyl-comcycloalkylbenzaldehyde to obtain the corresponding pound may also be nitrated, chlorinated or brominated 3,5-disubstituted-4-cycloalkylbenzaldehyde.
  • 3-c hl0ro 3-bromo or 3-nitro-5-alkyl compounds.
  • benzaldehyde with an acetic acid ester (preferably the Thus, for example, a 3-chloro-4-cycloalkylbenzalde- 30 loweralkyl or benzyl ester) in the presence ot'a metal c1 (Br) HN03 Cl (Br) (CH )n C) CHO acid and ammonia in an amine base to obtain a 5 B-(p-cycloalkylphenyl)acrylic acid.
  • R is loweralkyl. in which halo is chloro, brornoor iodo may be A substituted p-cycloalkylbenzaldehyde may also be 25 a. reacted with cuprous cyanide in quinolinc at about condensed with bippuric acid in the presence of sodium 150C to produce a 3-cyano-4-cycloalkylphenylacetate and acetic anhydride according to the method lactate:
  • 3-cyanolactic acid orderivative may be reacted ethylxanthate followed by hydrolysis to obtain 3- withthree equivalents of m-ethylmagncsium iodide in mercapto-4-cycloalkylphenyllactic acid which can be tetrahydrofuran followed by hydrolysis to obtain the esterified to a 3-mercapto-4-cycloalkylphenyllactate.
  • 3-acetyllactic acid 3-acetyllactic acid.
  • corthio and oxidized to the loweralkylsulfinyl and responding reactions may be carried out in order to loweralkylsulfonyl groups or acylated to the acylthio convert one substituent to another.
  • a 3-chloro-5- R" SCOR" nitro-4-cyeloalkylphenyllactate can be reduced to a corresponding 3-chloro-5-amino-4-cycloalkylphenyl- 0H lactate. This may then be monoor dialkylated or acyll ated.
  • the amine may also be converted via the diazo- Z' nium salt to a variety of derivatives as described above.
  • I 5 As a further example of disubstitution, a 3-chloro-5 nitro-4-cycloalkylphenyllactatc can be reacted with cuprous cyanide in quinoline at 150C to obtain a 3 cyano-S-nitro-4-cycloalkylphenyllactate; or with tritlu- 3 equiv.
  • H20 10 150C to obtain a 3-trifluoromethyl-5-nit'ro-4-cycloalkylphenyllactate; or with cuprous methanesulfinate in B quinoline at l50C to a 3-methylsulfonyl-5-nitro-4- 0H cycloalkylphenyllactate.
  • varil ous disubstitution would be the selective reduction of i zl 0 CH2 C'COOH 15 a 3,5-dinitro-4-cycloalkylphenyllactate with hydrogen l or ammonium sulfide to obtain a 3-nitro5-amino-4- a cycloalkylphenyllactate which in turn can be diazotized B to the various derivatives.
  • Various mono-substituted products may also be nitrated, chlorinated or brominated as above and again, in turn, converted to the various desired substituents.
  • a 3-fluoro-4-cycloalkylphenyllac- 65 tate may be nitrated or brominated and the nitro and bromo groups converted to various substituents.
  • the amino group can then be diazotized as above to the Q desired substituents. This may be carried out on any of 35 HBF 2 n n the nitro compounds as outlined.
  • the diazotized prod- 4 v ucts may then be reduced to the corresponding lactate.
  • R is 2 hydrogen, CuI or KI fluoro
  • Suitable bases thus include for example the alkali metal to obtain the desired substituent.
  • B-(p-cycloalkylphenyl)pyruvates react with aqueousalcoholic alkali hydroxide or alkali carbonate to give the corresponding B-(p-cycloalkylphenyl)pyruvic acid.
  • the B-(p-cyeloalkylphenyl)pyruvate ester is converted to the corresponding B-(p-cycloalkylphenyl)lactate ester by hydrogenation in the presence of platinum oxide.
  • R and R is a substituent lactate-esters are hydrolyzed with an aqueous alcoholic l5 alkali hydroxide mixture to the corresponding B-(peycloalkylphenyl) lactic acid.
  • CH -lCCOOR CH Catalytic hydrogenation of a B-(p-eycloalkylphenyU- lactate benzyl ester over palladium results in the reduction of the keto group and hydrogenolysis of the benzyl group to give a B-(p-cycloalkylphenyl) lactic acid.
  • R or R is a hydrolyzable group such as acyloxy, acylamino, acylthio, cyano, etc.
  • This invention further describes the acid addition salts formed by the action of one equivalent of a suitable base with the B-(p-cycloalkylphenyl)lactic acid.
  • alkoxides such as sodium methoxidc, etc., and the alkali metal and alkaline earth metal hyroxides, carbonates, bicarbonates, etc. (such as sodium hydroxide, potassium hydroxide, calcium hydroxide, potassium car- RI bonate, sodium bicarbonate, magnesium bicarbonate, etc.).
  • the aluminum salts of the instant products may be obtained by treating the corresponding sodium CH2
  • the alkaloidal salts are useful for effecting optical resolutions.
  • dilowerulkylamino, cymine, diloweralkylamine, cycloloweralkylamine, a nicloloweralkylamino, trogen containing hetero compound such as piperidine, morpholine, piperazine results in the corresponding 5 amide.
  • the lactate ester with hydroxylamine gives the corresponding hydroxamic acid, and with hydrazine (where A is loweralkylidenyl or heteroloweralkylide gives the corresponding hydrazide.
  • Hal is fluoro, chloro, bromo or iodo.

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Abstract

Novel cycloalkylphenyl propionic acids and their derivatives are described. Therapeutic compositions and method of treatment of inflammation is also disclosed.

Description

United States Patent 1191 Diamond Jan. 14, 1975 P-CYCLOHEXYL ALPHA LOWER ALKANOYLTHIO HYDROCINAMIC ACID [75] Inventor: Julius Diamond, Lafayette Hills, Pa.
[73] Assignee: William H. Rorer, Inc., Fort Washington, Pa.
22 Filed; July 12, 1973 21 Appl. No.2 380,651
Related U.S. Application Data [62] Division of Ser. No. 164,822, July 21, 1971.
[51] Int. Cl. C07c 153/07 [58] Field of Search 260/455 R [56] References Cited FOREIGN PATENTS OR APPLICATIONS 528,461 ll/l972 Switzerland Primary ExaminerLewis Gotts Assistant ExaminerD. R. Phillips Attorney, Agent, or Firm-Erich M. H. Radde [57] 4 ABSTRACT Novel cycloalkylphcnyl propionic acids and their dcrivatives are described. Therapeutic compositions and method of treatment of inflammation is also disclosed.
9 Claims, N0 Drawings P-CYCLOHEXYL ALPHA LOWER ALKANOYLTHIO HYDROCINAMIC ACID CROSS REFERENCES TO RELATED APPLICATIONS This is a division of application Ser. No. 164,822, filed July 21,1971.
SUMMARY OF THE INVENTION This invention describes novel Ot-SLIbStItUtCd p-cycloalkylphenylpropionic acids and their derivatives and their use in therapeutic compositions. In addition, this invention relates to the preparation of a-substituted p-cycloalkylphenylpropionic acids. When the compounds of this invention are administered to mammals, they afford significant treatment of inflammatio and associated pain and fever.
They further provide analgesic and antipyretic methods for the relief and treatment of pain and fever associated with inflammation.
BACKGROUND OF THE INVENTION There has been continued efforts in research to develop drugs which would significantly inhibit the development of inflammation and relieve the pain and fever associated with it. Much of these efforts have been carried on in the field os steroids. While many of these compounds have been effective, they have had the drawback of causing many side effects.
I have unexpectedly found that a-mercapto-pcycloalkylphenylpropionic acid compounds and their derivatives have valuable pharmacologic properties.
I have found that a-mercapto-p-cycloalkylphenylpropionic acid compounds and their derivatives possess useful anti-inflammatory, analgesic and anti-pyretic properties.
I have also found a series of anti-inflammatory compounds which are non-steroidal.
I have further found that these a-mercapto-pcycloalkylphenylpropionic acid compounds and'their derivatives are novel.
I have also found that the compounds of this invention are useful in effectively providing a method for the inhibition of inflammation and the treatment of associated pain and fever.
I have still further found an entirely new class of antiinflammatory, analgesic and antipyretic pharmaceutical compositions containing the a-mercapto-pcycloalkylphenylpropionic acids and derivatives of this invention as active ingredient.
I have again found a convenient method for synthesizing these compounds.
DESCRIPTION AND PREFERRED EMBODIMENT This invention comprises a class of novel chemical compounds which contain a cycloalkyl substituted phenyl radical which is attached to an a-mercapto propionic acid in the B-position. This invention further comprises derivatives of said propionic acids and the method of preparing the same.
This invention also describes a new method of treating inflammation and associated pain and fever as well as novel therapeutic compositions.
The compounds of this invention can be represented by the generic structure which is described by the general formula I.
where:
n is 0-2;
B is hydrogen or loweralkyl;
R is halo, nitro, amino, acylamino, mono- & diloweralkylamino, mercapto, acylthio, loweralkylthio, loweralkylsulfinyl, loweralkylsulfonyl, hydroxy, I loweralkoxy, acyloxy, haloloweralkyl, cyano, acetyl or loweralkyl',
R is hydrogen,
fluoro, chloro, bromo, trifluoromethyl, cyano, nitro or loweralkylsulfonyl;
X is halo,
hydroxy, loweralkoxy, loweracyloxy, aroyloxy, carbloweralkoxyoxy, carbamyloxy, loweralkylcarbamyloxy, diloweralkylcarbamyloxy, loweralkanesulfonyloxy, benzenesulfonyloxy, toluenesulfonyloxy, carboxyacyloxy, carboxyaroyloxy, mercapto, loweralkylthio, acylthio, carboxyacylthio, aroylthio', carboxyaroylthio, sulfino, sulfo, loweralkylsulfmyl, loweralkylsulfonyl, thiosulfo, amidinothio, thiocyanato, thioacylthio, loweralkoxythiocarbonylthio, loweralkoxycarbonylthio, arloweral'koxycarbonylthio, carbamylthio, loweralkylcarbamylthio, diloweralkylcarbamylthio, diloweralkylthiocarbamylthio,
cyano,
amino, mono- & diloweralkylamino or acylamino;
R and R are hydrogen or loweralkyl; and Z is OH,
loweralkoxy, arloweralkoxy, z, loweralkylamino, diloweralkylamino,
cycloloweralkylamino,
A N A y] i. (where A is loweralkylidenyl or heteroloweralkylidey NHOH, NHNl-l or OM (where M is an alkali, alkaline earth or aluminum metal oran ammonium salt).
The compounds of this invention contain asymmetric carbon atoms in the alpha-position of the 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 l isomers as well as the dl mixtures thereof are embraced within the scope of this invention.
When b is loweralkyl, two racemic mixtures may exist in the case of 2- or 3-loweralkylcyclohexyl- I phenyllactate, 2'- or 3'-loweralkylcyclopentylpheny]- lactate, 2- or 4'-loweralkylcycloheptylphenyllactate,
or their derivatives. It is understood that both racemic mixtures are embraced within the scope of this invention.
A special embodiment of this invention is described by structural formula I where R an R are in the 3 and 5 positions of the phenyl ring.
The preferred compounds of this embodiment describe the cyclohexyl class of chemical compounds which have particular usefulness as anti-inflammatory, analgesic and antipyretic agents. These compounds are described in formula II.
R III where:
R is halo, nitro, loweralkyl,
haloloweralkyl or cyano;
R is hydrogen,
chloro,
bromo or nitro;
X is halo;
hydroxy,
loweralkoxy,
loweracyloxy,
aroyloxy,
carbloweralkoxyoxy,
carbamyloxy,
loweralkylcarbamyloxy,
diloweralkylcarbamyloxy,
loweralkanesulfonyloxy,
benzenesulfonyloxy,
toluenesulfonyloxy,
carboxyacyloxy,
carboxyaroyloxy,
mercapto,
loweralkylthio,
acylthio,
carboxyacylthio,
aroylthio,
carboxyaroylthio,
loweralkylsulfinyl,
loweralkylsulfonyl,
thiosulfo,
amidinothio,
thiocyanato,
thioacylthio,
loweralkoxythiocarbonylthio,
loweralkoxycarbonylthio,
arloweralkoxycarbonylthio,
carbamylthio,
loweralkylcarbamylthio,
diloweralkylcarbamylthio,
diloweralkylthiocarbamylthio,
cyano,
amino,
mono- & diloweralkylamino or acylamino. 1
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 described by formula where:
R is chloro,
bromo,
nitro,
methylsulfonyl,
trifluoromethyl or cyano;
R is hydrogen,
chloro,
l CHZ-(IH-COOH bromo or nitro.
Included within the scope of this further special embodiment are the racemic mixtures as well as the dextro and levorotatory isomers thereof.
Another special embodiment 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 or symptomatically related to an inflamma' tion indication are described by formula V.
Hal
where:
R is chloro,
bromo,
nitro,
methylsulfonyl,
trifluoromethyl or cyano;
R is hydrogen,
chloro,
bromo or nitro; and
Hal is fluoro,
chloro or bromo.
Those compounds where Hal is chloro are even more preferred.
Included within the scope of this further special embodiment are the racemic mixtures as well as the dextro and levorotatory isomers thereof.
A further special embodiment 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 or symptomatically related to an inflammation indication are described by formula VI CH CH-COOH R where:
R is hydrogen, lower alkanoyl, aroyl, loweralkoxythiocarbonyl, loweralkoxycarbonyl, arloweralkoxycarbonyl, loweralkyl, amidino, thioacyl, cyano, carbamyl, loweralkylcarbamyl, diloweralkylcarbamyl, diloweralkylthiocarbamyl, carboxyacyl, carboxyaroyl, or sulfo;
R is chloro,
bromo,
nitro,
methylsulfonyl,
trifluoromethyl or cyano; and
R is hydrogen,
chloro,
bromo or nitro.
lowing definitions apply:
The term lower alkyl carbon group containing from 1 to about 6 carbon atoms which may be straight chained or branched.
The acyl" radical may be any organic radical derived from an organic acid by the removal of its hydroxyl group such as acetyl, propionyl, 3-carboxypropionyl, 3-carboxy-2-propenoyl, camphoryl, etc.
The preferred aroyl is benzoyl, loweralkylbenzoyl such as toluoyl or halobenzoyl such as p-chlorobenzoyl, 2carboxybenzyl, etc.
Lower alkoxy" signifies an alkoxy group containing from 1 to about 6 carbon atoms which may be straight chained or branched.
The term loweralkylidenyl refers to a lowcralkylidenyl hydrocarbon group containing from 2 to about 6 carbon atoms.
'Heteroloweralkylidenyl" refers to a loweralkylidenyl hydrocarbon group containing from about 2 to 5 carbon atoms and having one or more hetero atoms in the chain selected from O, N or S, such as piperidinyl, morpholinyl, etc.
The preferred alkali or alkaline earth metals are sodium, potassium, calcium. and magnesium.
The term ammonium salt" refers to the cation formed when ammonia or an organic amine react with the earboxyl' 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, piper-azine; piperidine,-(4) aralkylamines such as a-methylbenzylamine, phenethylamine;' (5) cycloalkylamines such as cyclohexylamine; (6) alkaloids such as quinine, cinchonidine, cinchonine, ephedrine.
It will further be appreciated by one skilled in the art that the following radicals may also be employed in the practice of this invention. where:
R and R" may also be carboxy,
carbloweralkoxy,
carbamyl,
loweralkyl,
cyanato,
thiocyanato,
thiocarbamoyl,
thioformyl,
formamido,
formyl,
formyloxy,
hydroxyl oweralkyl,
mercaptoloweralkyl,
aminoloweralkyl,
hydroxyamino,
hydrazino,
sulfo,
sulfonate,
sulfamoyl,
diloweralkylsulfamoyl,
trifluoromethylsulfonyl,
trifluoroacetyl,
trifluoroacetoxy or trifluorocarbomethoxy;
X may also be refers to a lower alkyl hydrov B-(3-chl0r0-4-cyclopentylphenyl)lactic acid acid B-(3-chlor0-4-cycloheptylphenyl)lactic acid ethyl B-(3-chloro-4-cyclopentylphenyl)lactate ethyl B-(3-chloro-4-cycloheptylphenyl)lactate ,B-(3-chloro-4-cyclopentylphenyl)lactamide ,8-(3-chloro-4-cycloheptylphenyl)lactamide /3-(3-chloro-4-cyclopentylphenyl)lactic acid, diethylammonium salt B-(3-chl0ro-4-cycloheptylphenyl)lactic acid, diethylammonium salt B-[3-chl0ro-4-(2'-methylcyclopentyl)phenylllaetic acid B-[3-chloro-4-(2-methylcycloheptyl)phenyl]lactic acid B-[3-chloro-4-(2-methylcyclohexyl)phenyl]lactic acid ,8-[3-chlor0-4-(3-methylcyclohexyl)phenyl]lactic acid B-[3-chloro-4-(4-methylcyclohexyl)phenyl]lactic acid B-[3-chloro-5-amino-(2'-methylcyclohexyl)phenyl]- lactic acid B-[3-fluoro-5-amino-(2-methylcyclohexyl)phenyl]- lactic acid B-[3-bromo-5-amino-(2-methylcyclohexyl)phenyl]- i l a-mercapto-,B(3-chloro-4-cyclohexylphenyl)propionic acid d a-acetylthio-B-(3-chloro-4-cyclohexylphenyl)propionic acid I a-acetylthio-B-(3-chloro-4-cyclohexylphenyl)propionic acid a-methyl-B-( 3-chlor0-4-cyclohexylphenyl )lactic acid I a-methyl-,B(3-chl0ro-4-cyclohexylphenyl)lactic acid d a-methyl-a,3-dichloro B-(4-cyclohexylphenyl)lactic acid l a-methyl-a,3-dichloro-B-(4-cyclohexylphenyl)lactic acid a-methyl-a-mercapto-B-(3-chloro-4-cyclohexylphenyl)lactic acid I a-methyl-a-mercapto-B-(3-chloro-4-cyclohexylphenyl)lactic acid d B-(3,S-dichloro-4-cyclohexylphenyl)lactic acid lB-(3,5-dichl0ro-4-cyclohexylphenyl)lactic acid d ,B-(3-fluoro-4-cyclohexylphenyl)lactic acid d B-(3-br0m0-4-cyclohexylphenyl)lactic acid d ,B-(3-nitro-4-cyclohexylphenyl)lactic acid d B-(3-trifluoromethyl-4-cyclohexylphcnyl)laetic acid d l3-(3-methylsulfonyl-4-cyclohexylphenyl)lactic acid d B-(3-cyano-4-cyclohexylphenyl)lactic acid d ethyl B-(3-chloro-4-cyclohexylphenyl)lactate l ethyl B-(3-chloro-4-cyclohexylphenyl)lactate d B-(3-chl0ro-4-cyclohexylphenyl)laetamide lB-(3-chloro-4-cyclohexylphenyl)lactamidc d B-(3-chloro-4-cyclopentylphenyl)lactic acid 1,84 3-ehloro-4-cyclopentylphenyl)lactic acid d ,B-(3-chl0ro-4'cycloheptylphenyl)lactic acid l,B-(3-chl0ro-4-cycloheptylphenyl)lactic acid d B-(3-chloro-4-cyclohexylphenyl)lactic acid. acetate lB-(3-chloro-4-cyclohexylphcnyl)lactic acid, acetate d B-(3-chloro-4-cyclohexylphenyl)lactic acid, diethylcarbonate l B-(3-chloro-4-cyclohexylphenyl)lactic acid dicthylcarbonate d B-(3-chloro-4-cyclohexylphenyl)lactic acid sodium salt lB-(3-chlor0-4-cyclohexylpheny|)lactic acid. sodium salt 1 d B-(3-chloro-4-cyclohexylphenyl)lacticacid diethylammonium salt I l B-(3-chl0ro-4-cyclohexylphenyl)lactic acid. diethylammonium salt d B-(3,5-dichloro-4-cyclohexylphcnyl)lactic acid,
diethylammonium salt l B-(3,5-dichl0ro-4-cyclohexylphenyl)lactic diethylammonium salt The compounds of this invention may be prepared from known starting materials. p-Cycloalkylbenzaldchyde may be a) halogenated or b) nitrated to obtain a corresponding 3-hal0-4-cycloalkylbenzaldehyde or a 3-nitro-4-cycloalkylbenzaldehyde. Chlorination or bromination may be carried out in the presence of a small amount of iodine dissolved in an inert solvent such as carbon tetrachloride. A solution of chlorine or bromine is then added while the temperature is held near 0C. Nitration is carried out with fuming nitric acid at about 0C. The following reaction equation illustrates this method.
acid,
HNO
l B B CH I CHO (CH CHO When a loweralkyl group is desired in the benzene hyde may be nitrated as above to obtain a 3-chloro-5-' ring, then alkylation may be carried out using the alkylnitro-4-cycloalkylbenzaldehyde or chlorinated to obhalide and aluminum chloride as desired. tain a 3,5-dichloro-4-cycloalkylbenzaldehydc. A 3- B B l Alk-Cl a o Alk A second nitration or halogenation with chlorine 0 nitr0-4-cycloalkylbenzaldehyde can be nitratcd to give bromine may be carried out on the 3-substituted4- 25 a3,5-dinitro-4-cycloalkylbenzaldehyde. A 3-alkyl-comcycloalkylbenzaldehyde to obtain the corresponding pound may also be nitrated, chlorinated or brominated 3,5-disubstituted-4-cycloalkylbenzaldehyde. However, to the 3-c hl0ro, 3-bromo or 3-nitro-5-alkyl compounds. this may also be carried out at any appropriate stage of Claisen condensation of a p-cycloalkyl substituted the synthesis in order to obtain the desired substituents. benzaldehyde with an acetic acid ester (preferably the Thus, for example, a 3-chloro-4-cycloalkylbenzalde- 30 loweralkyl or benzyl ester) in the presence ot'a metal c1 (Br) HN03 Cl (Br) (CH )n C) CHO acid and ammonia in an amine base to obtain a 5 B-(p-cycloalkylphenyl)acrylic acid. Addition to the double bond with chlorine or bromine results in a pcycloalkylphenyl) pyruvic acid or ester which on hydrogenation in the presence of platinum oxide catalyst yields the desired lactic acid or ester. This hydrogenation may also be accomplished by selective reduction 'with sodium borohydride when catalytic hydrogenation is impractical because of the presence of a sensitive nitro group.
(:9 CH COOR". H G NaOR" CH CHCOOR CH2(C0OH)2 NH3 zln H=CHCOOH r Br C12 or Brz D r B .u
R' M Yl (BrHBr) l c1 c1 c1 c1 l I l z n CH-CH-COOR" alkali a] B v r R! o v 0 H or NaBH cycloalkylphenyl-a,B-dihalopropionic acid or ester. Alkali hydrolysis of the dihalide results in the B-(p- H or NaBH where R" is loweralkyl or bcnzylr acted with one equivalent of a Grignard reagent to and R substituents can be prepared by using suitable form the a-substituted lactic ester which is then hydroreactions in order to convert one group to another. lyzed to the acid. Thus, for example, a 3-halo-4-cycloalkylphenyllactate i 0 OH H I (t 2). o R:-
where R is loweralkyl. in which halo is chloro, brornoor iodo may be A substituted p-cycloalkylbenzaldehyde may also be 25 a. reacted with cuprous cyanide in quinolinc at about condensed with bippuric acid in the presence of sodium 150C to produce a 3-cyano-4-cycloalkylphenylacetate and acetic anhydride according to the method lactate:
B v B t 0H 0H I l H CuCN l H (0H H (CH CH $C0OR v R I R1 Hal CN of Cavalline and Massarani as outlined in their ltalian b. reacted 'with trifluoromethyliodide and copper Patent No. 611,973 (1960): [Chem Abstracts powder at about 150C in dimethylformamidc to 55,19868g]. This condensation results in a-2-phenyl-4- obtain a 3-trifluoromethyl-4-cycloalkylphcnyllao.
(p-cycloalkyl)-5-oxazolone which on basic hydrolysis tate: [as described in 'I'elrahedron Letters: 47,4095
results in the B-(p-cycloalkylphenyl)pyruvic acid. This (1959)] 0H 0H H CH i: COOR" CFBI I H -t':-cooR" 2 n 2". i zl 2 I Cu l a] a CF Re may then be reduced or treated with a Grignard reac. reacted with cuprous methanesulfinate in quino-- gent as above to the corresponding lactic acid. line at about 150C to obtain a 3-mcthylsulfonyl-4- Appropriately desired end products having various R yc ylphenyllactatez uoco COC 'H (CH CH0 7 in i 0=c c-c H R R 0 6 5 alkali B OH on l CUSO2CH CHZ-IIZ-COOR (CH CH lCC00R" R Ra Hal 2 3 c. diazotized and heated in an aqueous mediumto form the 3-hydr0xy-4-cycloalkylphenyllactatc or A 3-nitro-4-cycloalkylphenyllactate may be hydrogenated to the corresponding amine.
0H OH I ll g i (fi ln (CH H -CO0R' R0, I RC1. N0 NH A 3-amino-4-cycloalkylphenyllactate may then be heated in an alcohol to form the 3-alkoxy-4-cycloalkyla. monoor dialkylated with loweralkyl halides 0r sulfates or acylated with loweracyl chlorides 0r anhyphenyuactate' The hydroxyl group he amyldrides, ated with loweralkyl halides or sulfates to the alkm yl 5 OH OH Ii R||X l r CH C-COOR (5 m H -C- OOR l l R R1 NHR" R"COCl or (R"C0) 0 OH 1 OH I l (c CH -CCOOR" (CH2) 0 H -CCO0R" 1 R R1 NHCOR" 2 b. diazotized to the diazonium fluorohorate which is 7 group or acylated withloweracyl chlorides or anhythen thermally decomposed to the 3-fluoro-4-cycloalkdrides to the acyloxy compound in the presence of a ylphenyllactate, tertiary amine such as pyridine,
OH OH I HN0 l (CH CH -C-CO0R (C CH -CCOOR" 2 l HBF 2 n 2 l R RtI 2 i 3 (H H -lc-cooR" (CHM cu -c-eooii COOR" a F g coma OH I CH -(lI-C0OH RC1 COOH g. diazotized followed by reaction with potassium The 3-cyanolactic acid orderivative may be reacted ethylxanthate followed by hydrolysis to obtain 3- withthree equivalents of m-ethylmagncsium iodide in mercapto-4-cycloalkylphenyllactic acid which can be tetrahydrofuran followed by hydrolysis to obtain the esterified to a 3-mercapto-4-cycloalkylphenyllactate. 3-acetyllactic acid. This in turn can be lower alkylated to the lower alkyl- When 3,5-disubstituted compounds are desired, corthio and oxidized to the loweralkylsulfinyl and responding reactions may be carried out in order to loweralkylsulfonyl groups or acylated to the acylthio convert one substituent to another. Thus, a 3-chloro-5- R" SCOR" nitro-4-cyeloalkylphenyllactate can be reduced to a corresponding 3-chloro-5-amino-4-cycloalkylphenyl- 0H lactate. This may then be monoor dialkylated or acyll ated. The amine may also be converted via the diazo- Z' nium salt to a variety of derivatives as described above. I 5 As a further example of disubstitution, a 3-chloro-5 nitro-4-cycloalkylphenyllactatc can be reacted with cuprous cyanide in quinoline at 150C to obtain a 3 cyano-S-nitro-4-cycloalkylphenyllactate; or with tritlu- 3 equiv.
2) H20 10 150C to obtain a 3-trifluoromethyl-5-nit'ro-4-cycloalkylphenyllactate; or with cuprous methanesulfinate in B quinoline at l50C to a 3-methylsulfonyl-5-nitro-4- 0H cycloalkylphenyllactate. Still another example of varil ous disubstitution would be the selective reduction of i zl 0 CH2 C'COOH 15 a 3,5-dinitro-4-cycloalkylphenyllactate with hydrogen l or ammonium sulfide to obtain a 3-nitro5-amino-4- a cycloalkylphenyllactate which in turn can be diazotized B to the various derivatives.
NO2 0H 1 i l CuCN (CH Q CHg-tf-COOR" 2 0H NH? 0H (CH CH i COOR" H2 or I 2 2 CH CH -C-CO0R" n (NH4)25 2 n 2 C1(NO2) c (N02) a B H t I NHCOR I OH on CH i: COOR" I C) -CH ilC00R" z' n 2- p 2 n f I R c1 (N02) RH Cl (N0 oromethyl iodide and copper powder in quinoline at B NH Q OH l (CH CH C-COOR" C1 c1 (N02) Of course, other reactions may be carried out on the above products by diazotization to obtain the desired- 60 be carried out solely on the lactate but rathcr at any convenient step of the synthesis that will afford the desired product without having any changes in the resubstituents as previously described.
Various mono-substituted products may also be nitrated, chlorinated or brominated as above and again, in turn, converted to the various desired substituents. Thus, for example, a 3-fluoro-4-cycloalkylphenyllac- 65 tate may be nitrated or brominated and the nitro and bromo groups converted to various substituents.
B F 0H HN02 l "CHzC'COOR" HBF c1.( N02) Ra B OH OH HNOZ l l CH2CCO0R H2O l cmm OR OH HNOZ y (m H2- -CO0R R"OH v i B I BY- OH HNO2 9 C H C-CO0R" CuBr 2 l cflmo B 1 Y 0H HNOZ (CH l H -C-COOR" CuI or J 2 n 2 l KI Rd on OH HNO 2 V (C 2)" Q -CH2CC00R CuCN v 1 l F R at (N02) a B l )HNO Q OH scso 2H5 O I (CH2 CH -CCO0R" 2) NaOH n 2 l H maining part of the molecule.
pyruvatc to the lactate The conversion of the R and R substituents need not Thus, for example. it is often convenient to convert one substituent to another before the reduction of the A 3-nitro-4-cycloalkylphenylpyruvate or a 3-ehloro- B B NO OH 0H l HNO (CH cH -r z-cooR" --9 H CH -(|ICO0R" l iBr 2 B Br OH B 2 H CH -C-CO0R" (CH )n cH -t z-cooR (CH 2 I R F R F CuCN CF 1 B CN B CF OH l t (H 1 CH CH -CCOOR" (CH CH CCOOR" 2 n O 2 g n n 2 1 R R F F 5-nitro-4-cycloalkylphenylpyruvate may be selectively I V v I 3 catalytically hydrogenated to the corresponding amine. The amino group can then be diazotized as above to the Q desired substituents. This may be carried out on any of 35 HBF 2 n n the nitro compounds as outlined. The diazotized prod- 4 v ucts may then be reduced to the corresponding lactate.
HNO
2 m H O ll H B (fl l CH -C-COOR HNO R --9 M B NH 0 B n HNO f (CH H (C CuBr where: HNQ
R is 2 hydrogen, CuI or KI fluoro,
O ll cH -c c00R 0 ll CHg-C-COOR" chloro,
bromo, trifluoromethyl,
cyano,
nitro or loweralkylsulfonyl.
HHOZ
Other reactions can be carried on in a similar manner 15 Suitable bases thus include for example the alkali metal to obtain the desired substituent.
B-(p-cycloalkylphenyl)pyruvates react with aqueousalcoholic alkali hydroxide or alkali carbonate to give the corresponding B-(p-cycloalkylphenyl)pyruvic acid.
The B-(p-cyeloalkylphenyl)pyruvate ester is converted to the corresponding B-(p-cycloalkylphenyl)lactate ester by hydrogenation in the presence of platinum oxide. In the special case when R and R is a substituent lactate-esters are hydrolyzed with an aqueous alcoholic l5 alkali hydroxide mixture to the corresponding B-(peycloalkylphenyl) lactic acid.
a1 c. KOH
CH -lCCOOR" (CH Catalytic hydrogenation of a B-(p-eycloalkylphenyU- lactate benzyl ester over palladium results in the reduction of the keto group and hydrogenolysis of the benzyl group to give a B-(p-cycloalkylphenyl) lactic acid. This 50 is particularly useful when R or R is a hydrolyzable group such as acyloxy, acylamino, acylthio, cyano, etc.
This invention further describes the acid addition salts formed by the action of one equivalent of a suitable base with the B-(p-cycloalkylphenyl)lactic acid.
alkoxides such as sodium methoxidc, etc., and the alkali metal and alkaline earth metal hyroxides, carbonates, bicarbonates, etc. (such as sodium hydroxide, potassium hydroxide, calcium hydroxide, potassium car- RI bonate, sodium bicarbonate, magnesium bicarbonate, etc.). Also, the aluminum salts of the instant products may be obtained by treating the corresponding sodium CH2|C-COOH R a ing ,B-(p-cycloalkylphenyl )lactic acid products and one skilled in the art will appreciate that to the extent that the instant acids are useful in therapy, the variety of acid addition salts embraced by this invention are limited only by the criterion that the bases employed in forming the therapeutically useful salts be both non toxic and physiologically acceptable. The alkaloidal salts are useful for effecting optical resolutions.
B. OH l Reaction of a B-(p-cycloalkylphenyl)lactate ester where: with a nitrogen base such as ammonia, loweralkyla- Z is NH- loweralkylamine. dilowerulkylamino, cymine, diloweralkylamine, cycloloweralkylamine, a nicloloweralkylamino, trogen containing hetero compound such as piperidine, morpholine, piperazine results in the corresponding 5 amide. The lactate ester with hydroxylamine gives the corresponding hydroxamic acid, and with hydrazine (where A is loweralkylidenyl or heteroloweralkylide gives the corresponding hydrazide. nyl), -NHOH or -NHNH B B R OH 0H CH 2 n cH -pH-cooR" (CH 4302 3 0H he -CH iJH CONH B 0H NH R" i 2 n CH |CHCONHR" R 1 OH HN(R) v v M H :H- .N(R") R RIG B 2 n R 0H (r31 H N 2 CH -CH-COOH H -CH-CONH l I n) (C 2 RH R11 OH HN A I V H (|IHC0H A OH H NOH --9 -CH CHC0NHOH l R Ra R (1H 1 @-CH $HCONHNH2 Reaction of the B-(p-cycloalkylphenyl)lactate or the lactic acid with an acid chloride or acid anhydride in the presence of a tertiary amine such as pyridine, picoline or quinoline results in the formation of an hydroxy derivative of the lactate or lactic acid. Examples of the acid chloride or acid anhydride include acetyl chloride,
cu -f-cooma") \f B Q B R 0H ll oco- I ClCNR"R" 2)n H -(lI-C00H( m -CH -(I3-C00H(R R R R B I RI n where: c] 502R" 0S0 R R" is loweralkyl and CH H C COOH R Arisphenylor r n O 2 I tolyl. R
' v 050 A)" ClSO AY The corresponding acid salts, esters and amides of halide, or sulfuric halide the corresponding a-halo-B- the foregoing alcohol derivatives may be prepared ac- (p-cycloalkylphenyl)propionate is prepared RI B I R4 OH I Hal I V l a O -CH -(IICOQR" (cH G CH -(|IC00R-" cording to the previously described procedures, or the where alcohol derivatives may be prepared directly on the R islowe'r alkyl;
acid salts, esters and amides. 40 Hal is fluoro, chloro, bromo or iodo.
B 4 (')H v x ({JY cH -iz-coz 5s H @cn -lc-coz R I R R C1 (1 ElY (CH CH -EI-COOH When a substituted a-(p-cycloalkylphenyl)lactate is reacted with a phosphorus trihalide, phosphorus penpared by heating the ester with acetic acid containing tahalide, phosphorus oxyhalide, sulfurylhalide', thionyl the corresponding hydrogen halide.
R v i B RI H5] Hal R R. U.
I M u The corresponding.a-halopropionic acid may be pre-

Claims (8)

  1. 2. A compound according to claim 1 where: R is chloro, R'' is hydrogen, X is acetylthio and Z is -OM where M is sodium thus forming Alpha -acetylthio- Beta -(3-chloro-4-cyclohexylphenyl)propionic acid, sodium salt.
  2. 3. A compound of the formula
  3. 4. A compound according to claim 3 where: R1 is acetyl.
  4. 5. A compound according to claim 4 which is dextrorotatory.
  5. 6. A compound according to claim 4 which is levorotatory.
  6. 7. A compound according to claim 4 where: R is chloro and R'' is hydrogen thus forming Alpha -acethylthio-Beta -(3-chloro-4-cyclohexylphenyl)propionic acid.
  7. 8. A compound according to claim 5 where: R is chloro and R'' is hydrogen thus forming d Alpha -acethylthio- Beta -(3-chloro-4-cyclohexylphenyl)propionic acid.
  8. 9. A compound according to claim 6 where: R is chloro and R'' is hydrogen thus forming 1 Alpha -acetylthio- Beta -(3-chloro-4-cyclohexylphenyl)propionic acid.
US380651A 1971-07-21 1973-07-12 P-cyclohexyl alpha - lower alkanoylthio hydrocinamic acid Expired - Lifetime US3860624A (en)

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US380651A US3860624A (en) 1971-07-21 1973-07-12 P-cyclohexyl alpha - lower alkanoylthio hydrocinamic acid

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4501727A (en) * 1981-12-08 1985-02-26 The Boots Company Plc Therapeutic agent

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH528461A (en) * 1968-10-25 1972-09-30 Ciba Geigy Ag Analgesic beta-phenylcrotonic acids - from satd derivs by heating with acids or bases

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH528461A (en) * 1968-10-25 1972-09-30 Ciba Geigy Ag Analgesic beta-phenylcrotonic acids - from satd derivs by heating with acids or bases

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4501727A (en) * 1981-12-08 1985-02-26 The Boots Company Plc Therapeutic agent

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