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Publication numberUS3686238 A
Publication typeGrant
Publication dateAug 22, 1972
Filing dateJan 19, 1970
Priority dateJan 19, 1970
Publication numberUS 3686238 A, US 3686238A, US-A-3686238, US3686238 A, US3686238A
InventorsAlejandro Zaffaroni
Original AssigneeSyntex Corp
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Glycerol esterified with 2-naphthyl-acetic acids and fatty acids
US 3686238 A
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Description  (OCR text may contain errors)

United Smtes Patent 01' ice 3,686,238 Patented Aug. 22, 1972 GLYCEROL ESTERIFIED WITH Z-NAPHTHYL- ACETIC ACIDS AND FATTY ACIDS Alejandro Zalr'aroni, Atherton, Calif., assignor to Syntex Corporation, Panama, Panama No Drawing. Filed Jan. 19, 1970, Ser. No. 4,060

Int. Cl. A61k 27/00; C07c 65/14, 69/76 US. Cl. 260399 Claims 10 ABSTRACT OF THE DISCLOSURE Drug lipid conjugates represented by the formulas In the formulas, R R and R each is hydrogen, fatty acyl o H a or -D wherein D and D are remainders of drug moieties, and one of said R R and R is This invention relates to drug lipid conjugates and intermediates therefor.

Most orally administered drugs pass into the blood system of the portal vein from which they are immediately passed through the liver. There, a substantial portion of the drug is usually metabolized. The drug dosage must therefore be accordingly increased to compensate for this loss. It is an object of this invention to provide novel com-- pounds which have increased absorption into the lymph system and hence reaches cellular tissue before being passed through the liver.

In summary, the compounds of this invention can be represented by the formulas:

or D*, wherein D and D each are the remainders of drug moieties, and one of said R R and R is 5 fatty acyl; R is hydrogen or fatty acyl;

R and R each hydrogen or fatty acyl, and at least one of said R and R is fatty acyl; and D and D each are remainders of drug moieties.

The term fatty acid and fatty acyl group as used herein refer to natural fatty acids and their acyl derivatives. These compounds include saturated fatty acids such as butyric, isovaleric, caproic, caprylic, capric, lauric myristric, palmitic, stearic, arachidic, behenic, lignoceric, cerotic and unsaturated fatty acids such as palmitoleic, oleic, ricinoleic, linoleic, linolenic, eleostearic, and the like. The preferred fatty acyl groups in the compounds of this invention have from 8 to 24 carbons and are saturated. The term drug moieties refers to drugs having pharmaceutical utility and having the designated chemical structure as is further exemplified hereinafter.

The compounds of Formula I wherein one of R R and R is ll a can be prepared by a procedure represented as follows:

In the above formulas,

D is as previously defined; and v R R R and R each is H, or a fatty acyl group and Ph is phenyl, and at least one of R and R and one of R and R is a fatty acyl group.

In the above procedure, the compounds of Formula IV are reacted with oxalyl chloride in a suitable solvent such as diethyl ether to yield the corresponding acyl chlorides of Formula V. The 2,3-acetonides of Formula VI are prepared by reacting the acyl chlorides of Formula V with glycerol acetonide in an inert organic solvent such as chloroform or carbon tetrachloride in the presence of an organic base such as triethylamine or pyridine. The acetonide group of the compounds of Formula VI are cleaved by reaction with triethylborate and boric acid at elevated temperatures to yield the corresponding hydroxy compounds of Formula VII. The compounds of Formula VIII are prepared by reacting the compounds of Formula VII with the corresponding fatty acyl chloride or chlorides in an inert organic solvent such as chloroform or carbon tetrachloride in the presence of an organic base such as triethylamine or pyridine. Glycerol 2-fatty acylates and glycerol 3-fatty acylates are prepared by reacting the compounds of Formula VII with one molar equivalent of the corresponding fatty acyl chloride or chlorides inan inert organic solvent in the presence of an organic base as described above to yield a mixture of monoand. diesters. The desired monoesters can be separated by chromatography on neutral alumina, eluting with hexane, hexanebenzene and cyclohexanone followed by crystallization. The corresponding 1,2-di(fatty acylates) are prepared using a molar excess of the corresponding fatty acyl chloride or chlorides.

The glycerol 1,3-benzylidene compounds of Formula IX are prepared by reacting the acyl chlorides of Formula V with glycerol 1,3-benzylidene in an inert organic solvent such as chloroform or carbon tetrachloride in the presence of an organic base such as triethylamine or pyridine, as previously described. Cleavage of the 1,3- benzylidene group is obtained by reaction of the compounds of Formula IX with tn'ethylborate and boric acid at elevated temperatures to yield the glycerol compounds of Formula X.

Glycerol 1,3-di(fatty acyl) compounds of Formula XI are prepared by reacting the compounds of Formula X with a molar excess of fatty acyl chloride or chlorides in an inert organic solvent such as chloroform or carbon tetrachloride which can also contain ethyl acetate in the presence of an organic base such as triethylamine or pyridine, as previously described. To obtain the glycerol l-fatty acylates of Formula XI, the compounds of Formula X are reacted with 1 molar equivalent of the fatty acyl chloride (as previously described) to obtain a mixture of monoand diesters from which the monoester can be separated by chromatography on neutral alumina, eluting with hexane, hexane-benzene and cyclohexanone followed by crystallization.

Included within Formulas VIII and XI are conjugates of Z-naphthylacetic acid derivatives of Formula IV. The Z-naphthylacetic acid derivatives which are included within Formula IV have been previously described together with methods for their preparation in U.S. patent applications 'Ser. No. 694,771, filed Dec. 7, 1967 and Ser. No. 810,014, filed Mar. 24, 1969, now abandoned. These compounds can be represented by the following formulas:

' Rim m Rm Rm C 0 OH C 0 0H u (IIA) Rm Rm I 115 R111 I m 0 0 OH 0 0 on M (IVA) ue m un m c 0 on 0, o OH Rm m- Rm A) (V A) COOH COOH (VIIA) (VIIIV) In the above formulas,

each of R (at position 1, 4, 7 or 8) and R (at position 1, 7 or 8) is alkyl, trifluoromethyl, fluoro, chloro,

' hydroxy, conventional hydrolyzable ester, oxyether or thioether;

R is alkyl, fluoro, chloro, hydroxy, conventional hydrolyzable ester, oxyether or thioether;

each of R (at position 1, 4, 7 or 8) and R (at position 1, 7 or 8) is alkyl, fluoro, chloro, hydroxy, conventional hydrolyzable ester, oxyether or thioether, provided that when R is hydroxy, oxyether or thioether, R or 'R is the identical group or alkyl, fluoro, chloro or conventional hydrolyzable ester; provided that when one of R or R is hydroxy, oxyether or thioether, R is the identical group or alkyl, fluoro, chloro, or conventional hydrolyzable ester;

each of R and R (at position 1 or 4) is hydroxy,

oxyether or thioether;

each of R (at position 1 or 4) and R is alkoxy or alkylthio, provided when R or R is alkoxy or alkylthio, R or R respectively is a different alkoxy or alkylthio group;

one of 'R and R each is hydrogen, methyl, ethyl, di-

fluorornethyl, fluoro or chloro; or

R and R taken together are alkylidene, halomethylene or ethylene;

R is hydrogen, alkyl, cycloalkyl, trifluoromethyl, hy-

droxymethyl, alkoxymethyl, vinyl, ethynyl, fluoro, chloro, hydroxy, conventional hydrolyzable ester, oxyether, thioether, formyl, carboxy, alkoxycarbonyl,

acetyl, cyano or aryl; and

R is hydrogen, alkyl, cycloalkyl, trifluoromethyl, fluoro,

chloro, hydroxy, conventional hydrolyzable ester, oxyether, thioether or aryl.

In the above Formulas IA-VIIIA, the term alkyl and derivations thereof refer to lower molecular weight, branched, or straight chain hydrocarbon groups of up to six carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tertbutyl, pentyl, hexyl, and the like. The term cycloalky refers to cyclic hydrocarbon groups of three to seven carbon atoms, such as cyclopropyl, cyclopentyl, cyclohexyl and the like.

The term alkoxy refers to a straight or branched chain hydrocarbon ether group of six or less carbon atoms, including methoxy, ethoxy, 2-propoxy, butoxy, 3-

pentoxy and the like.

The term alkoxymethyloxy refers to methylether groups substituted with one alkoxy group; typical alkoxymethyloxy groups include methoxymethyloxy, ethoxymethyloxy, isopropoxymethyloxy, and the like.

The term alkylthio refers to straight or branched chain hydrocarbon thioether groups of six or less carbon atoms, including methylthio, ethylthio, propylthio, 2-propylthio, Z-butylthio, pentylthio, 3-hexylthio, and the like.

The term alkylthiomethyloxy refers to methyl'ether groups substituted with an alkylthio group; typical alkylthiomethyloxy groups include methylthiornethyloxy, 2- propylthiomethyloxy, pentylthiomethyloxy, and the like.

The term alkylthiomethylthio refers to methylthio ether groups substituted with an alkylthio group, including methylthiomethylthio, ethylthiomethylthio, and the like.

The term alkoxymethylthio refers to methylthio ether I groups substituted with one alkoxy group, such as The term aryl refers to unsubstituted and p-mono substituted phenyl derivatives, such as phenyl, p-tolyl, pfiuorophenyl, p-chlorophenyl, p-hydroxyphenyl, p-methoxyphenyl, p-ethylphenyl and the like.

The term halomethylene refers to monoor dihalomethylene groups wherein halo is fluoro or chloro. The preferred halomethylenes include fluoromethylene, difluoromethylene, fluorochloromethylene, and chloromethylene.

The term conventional hydrolyzable ester as used with respect to Formulas IA-VIIIA denotes those hydrolyzable ester groups conventionally employed in the art, preferably those derived from hydrocarbon carboxylic acids or their salts. The term hydrocarbon carboxylic acid defines both substituted and unsubstituted hydrocarbon carboxylic acids. These acids can be completely saturated or possess varying degrees of unsaturation (including aromatic), can be of straight chain, branched chain, or cyclic structure and, preferably, contain from one to twelve carbon atoms. In addition, they can be substituted by functional groups, for example, hydroxy, alkoxy containing up to six carbon atoms, acyloxy containing up to twelve carbon atoms, nitro, amino, halogeno and the like, attached to the hydrocarbon backbone chain. Typical conventional hydrolyzable esters thus included within the scope of the term and the instant invention are acetate, propionate, butyrate, valerate, caproate, enanthate, caprylate, pelargonate, acrylate, undecenoate, phenoxyacetate, benzoate, phenylacetate, diphenylacetate, diethylacetate, tn'methylacetate, tbutylacetate, trimethylhexauoate, methylneopentylacetate, cyclohexylacetate, cyclopentylpropionate, adamantoate, glycolate, methoxyacetate, hemisuccinate, hemiadipate, hemi-fl,fl-dimethylglutarate, acetoxyacetate, 2- chloro-4-nitrobenzoate, aminoacetate, diethylaminoacetate, piperidinoacetate, B-chloropropionate, trichloroacetate, B-chlorobutyrate, and the like.

The term oxyether as used herein denotes those ether groups conventionally employed in the art, preferably those derived from normal chain, branched chain, aromatic hydrocarbons and x0 heterocyclic hydrocarbons. The term hydrocarbon" defines both saturated and unsaturated hydrocarbons. Those designated hydrocarbons are optionally substituted with groups such as hydroxy, alkoxy, halo, alkylthio, and the like. Preferably the hydrocarbons contain from one to twelve carbon atoms. Typical oxyethers thus include alkoxy, difiuoromethoxy, alkoxymethyloxy, alkylthiomethyloxy, tetrahydrofuran-Z'-yloxy, tetrahydropyran-2'-yloxy, and 4'-alkoxytetrahydropyran- 4-yloxy.

The term thioether as used herein denotes those ether groups conventionally employed in the art, preferably those derived from normal chain, branched chain, cyclic and aromatic hydrocarbons. The term hydrocarbon" defines both substituted and unsubstituted hydrocarbons. These hydrocarbons are optionally substituted with groups such as hydroxy, alkoxy, alkylthio, halo and the like. Preferably the hydrocarbons contain from 1 to 12 carbon atoms. Typical thioethers thus include alkylthio, difluoromethylthio, alkoxymethylthio, alkylthiomethylthio, and the like.

When one of R and R is methyl, ethyl, difluoromethyl, fluoro or chloro, the present 2-naphthylacetic acid derivatives have an asymmetric carbon atom, the a-carbon atom of the acetic acid moiety. Accordingly, these compounds can exist as enantiomorphs. Each of the optical isomers of the present Z-naphthylacetic acid derivaties is included within the present invention. In some instances, one enantiomorph exhibits greater anti-inflammatory, analgesic, anti-pyretic and anti-pruritic activity, than the other enantiomorph.

The present Z-naphthylacetic acid derivatives that exist as enantiomorphs can be used as mixtures of enantiomorphs or as resolved enantiomorphs.

The optical isomers can be resolved by conventional means, such as selective biological degradation; or by the preparation of diastereo-isomer salts of the 2-naphthylacetic acid derivatives with an alkaloid, such as cinchonidine, and the separation of the diastereo-isomers by fractional crystallization. The separated diastereo-isomer salts are acid cleaved to yield the respective optical isomers of the 2-naphthylacetic acid derivatives.

The conjugates of these naphthylacetic acid derivatives have high therapeutic value in the treatment of various inflammatory conditions, such as of the skin, eyes, respiratory tract, bones, and internal organs, contact dermatitis, allergic reactions, and rheumatoid arthritis. In those cases in which the above conditions include pain, pyrexia, and pruritus, coupled with the inflammation, the instant compounds are useful for relief of these associative conditions as well as the principal condition. The instant compounds are in addition, however, useful for treating pain, pyrexia, pruritus, and other syndromes thereof per se, such as those arising from bone fracture, toothache, bacterial and virus infection, contact with poisonous material, neuralgia, neuritis, lacerations, contusions, abrasions, and the like.

The compounds of Formulas IA-VIIIA can be readily prepared from known starting compounds.

One such method by which they can be prepared involves the reaction of an unsubstituted or substituted naphthalene with acetyl chloride in nitrobenzene in the presence of about three molar equivalents of aluminum chloride to afford the corresponding Z-acetylnaphthalene derivative. The resulting derivative is heated with morpholine in the presence of sulfur at 150 C.; the resulting product is refluxed with concentrated hydrochloric acid to furnish the corresponding 2-naphthylacetic acid derivative.

The naphthalenes that are used in the above process can be illustrated by the following formulas:

Rm R108 wherein R R and R are as defined above.

The naphthalenes of Formulas A and B are known to the art. Moreover, they can be prepared by conventional means. For example 1,2 dimethoxybenzene is treated with succinic anhydride and aluminum chloride in a hydrocarbon solvent to afford 4 (3',4-dimethoxyphenyl)-4- oxobutanoic acid. This is reduced by treatment with sodium borohydride, hydrogenolyzed by treating with palladium charcoal catalyst and hydrogen to furnish 4-(3',4- dimethoxyphenyl) butanoic acid. The corresponding acid chloride is prepared such as by treatment with thionyl chloride, and the acid chloride is treated with aluminum chloride to afford 6,7-dimethoxy-l-tetralone. The tetralone is reduced and hydrogenolyzed by the means described above to furnish 6,7 dimethoxytetralin which is dehydrogenated by treating with palladium charcoal catalyst to afford 2,3-dimethoxynaphthalene. By utilizing 1- methyl 3 fiuorobenzene in the above process, 6-methyl- 8 fluoro 4 tetralone and 6 fluoro 8 methyl-4-tetralone (as intermediates) and l-methyl-3-fluoro naphthalene and l fluoro 3 methyl naphthalene are prepared. The mixture of naphthalenes are separated by conventional means, such as vacuum distillation.

2-alkyl, 2-cycloalkyl, or 2-aryl substituted naphthalenes, the naphthalenes of Formula A wherein R is alkyl or aryl, can be prepared from 2-tetralone by treating the latter with an equivalent of an alkyl, cycloalkyl or aryl 7 magnesium bromide in an ether to obtain the corresponding 2 alkyl-, 2 cycloalkyl-, or 2-aryl-3,4-dihydronaphthalene which is dehydrogenated by heating with palladium charcoal catalyst to aflord the corresponding 2-alkyl, 2-cycloalkyl, or 2-aryl naphthalene.

2-vinyl naphthalenes are prepared by refluxing Z-ethyl naphthalencs with a. molar equivalent of N-bromosuccinimide in a halohydrocarbon solvent, such as chloroform, methylene chloride, dichloroethane, carbontetrachloride, 1,4-dichlorobutane, chlorobenzene, chloroethane, chlorocyclohexane, dichlorobenzene, and the like, in light and in the presence of a trace amount of peroxide, such as benzoyl peroxide, t-butylperoxide, peroxyacetic acid, and the like, to afford the corresponding 2-(a-bromoethyl)-naphthalene. The latter is dehydrobrominated by treating with lithium carbonate in dimethylformamide to afford 2-vinylnaphthalene.

Z-ethynylnaphthalene is prepared from 2-vinylnaphthalene by brominating the latter in a halo hydrocarbon solvent and then debrominating the resulting 2-( a,]3-diblOII1O- ethyl) naphthalene by conventional means, such as by treatment with sodium amide in liquid ammonia, to furnish the 2-ethynylnaphthalene.

2 cyclopropylnaphthalene is prepared from 2-vinylnaphthalene by refluxing with diiodomethane in the presence of zinczcopper couple.

2-cyclobutylnapthalene is prepared from 2-napthylmagnesium bromide by treating the latter with cyclobutanone to furnish 2-(1'-hydroxycyclobutyl)-napththalene, which is hydrogenolyzed with hydrogen in the presence of Raney nickel to furnish 2-cyclobutylnaphthalene.

2-cyclopentylnaphthalene can be prepared by heating naphthalene with cyclopentyl benzene sulfonate. 2-cyclohexylnaphthalene can be similarly prepared by employing cyclohexyl benzene sulfonate.

2-acetylnaphthalene is prepared by treating 2-(u-bromoethyl)-naphthalene, prepared as described above, with sodium acetate in acetic acid to atford Z-(a-ethanoyloxyethyl)-naphthalene which upon base hydrolysis furnishes the 2-(a-hydroxyethyl)-naphthalene. The latter is oxidized with an equivalent of chromium trioxide in glacial acetic acid or 8 N sulfuric acid to furnish 2-acetylnaphthalene.

2-carboxynaphthalene is prepared from 2-acetylnaphthalene by treating the latter with aqueous sodium hypochlorite. The Z-carboxy group is esterified by conventional means, described herein, to furnish 2-alkoxycarbonylnaphthalenes. By treating the latter with one equivalent of an alkali metal hydroxide, treating the resulting product with diborane in an ether, such as diglyme, (dimethoxydiethyleneglycol), Z-hydroxymethylnaphthalene is prepared.

The 2-hydroxymethyl group is esterified and etherified by conventional means employed to esterify and etherify primary hydroxy groups.

2-formylnaphthalene is prepared from 2-hydroxymethylnaphthalene by treating the latter with manganese dioxide in a halo hydrocarbon solvent.

2 cyanonaphthalenes are prepared by refluxing 2- formylnaphthalene with hydroxylamine hydrochloride and sodium acetate in ethanol to furnish the corresponding oxime which is refluxed with acetic anhydride in the presence of an acid catalyst to furnish Z-cyanonaphthalene.

Alternatively, the above substitutents can be introduced on a naphthylacetic acid ester derivative by using an ethyl or vinyl substituted naphthylacetic acid ester derivative as a starting material.

In the preferred embodiment, the starting materials are not substituted with trifluoromethyl, difluoromethoxy, difluoromethylthio, methylmethylenedioxy, alkoxymethylthio, alkylthiomethyloxy, alkylthiomethylthio, tetrahydropyran-2'-yloxy, tetrahydrofuran-2'-yloxy, or 4'alkoxytetrahydropyran-4'-yloxy groups, but rather, such groups are introduced on the 2-napht-halene acetic acid derivative via one of the final steps.

Another method of preparing these compounds employs unsubstituted and substituted I-tetralones and can be illustrated by the following reaction sequence:

-o o OAlkyl Run 1ts 0 0 1| l1 COOAlkyl 000E COOAlkyl Run. us-

0 0 on o 0 011 un Run COOH wherein alkyl and R are defined as above.

The l-tetralones, the compounds of Formula C, are heated with two or more equivalents of a dialkyl carbonate, such as diethyl carbonate, in the presence of one or more equivalents of an alkali metal hydride, such as sodium hydride, potassium hydride, and the like, in a hydrocarbon solvent, such as hexane, cyclohexane, heptane, isooctane, benzene, toluene, xylene, and the like, to aiford the corresponding alkoxy carbonyl compounds of Formula D. The latter are treated with an alkali metal hydride in a hydrocarbon solvent; then the resulting products are treated with an a-haloacetic acid ester, such as ethyl a-bromoacetate, methyl a-iodoacetate, and the like, to furnish the corresponding 2-alkoxycarbonyl-2- (alkoxycarbonylmethyl)-1-tetralones, the compounds of Formula E. The latter is hydrolyzed with an acid, such as hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, and the like, to obtain the 2-(carboxymethyl) compounds of Formula F. The latter is reduced with a reducing agent, such as sodium borohydride, lithium borohydride; or with one equivalent of hydrogen in the presence of Adams catalyst, and the like, to afford the hydroxy compounds of Formula G which are hydrogenolyzed by treatment with an equivalent amount of hydrogen in the presence of a hydrogenation catalyst, such as platinum, palladium, and the like, to furnish the corresponding 1,2,3,4-tetrahydro-2-naphthylacetic acid derivatives, the compounds of Formula H. The compounds of Formula H are esterified by conventional means, such as the means described above, to afford the compounds of Formula I; which are dehydrogenated by heating with palladium charcoal catalyst at temperatures of 180 C. and higher to furnish the corresponding Z-naphthylacetic acid ester derivatives, the compounds of Formula I. The latter compounds are hydrolyzed to the corresponding Z-naphthylacetic acid derivatives, the compounds of Formula K, by conventional hydrolysis, such as by treatment with an aqueous methanolic percent sodium hydroxide solution.

Disubstituted tetralones of Formula L are also employed in the above process to prepare the corresponding disubstituted Z-naphthylacetic acid derivatives of Formula M:

O ioo u R109 (several steps) 0 O OH wherein R is as defined above and R represents the same substituents as R but only at position 4, 7 or 8.

By treating the compounds of Formula D with an alkali metal hydride and then with an a-halocarboxylic acid ester, such as methyl a-bromopropionate and the like, the corresponding 2-alkoxycarbonyl-2-(a-alkoxycarbonylalkyl)-l-tetralones are obtained. These compounds can be hydrolyzed, reduced, hydrogenolyzed, esterified, dehydrogenated and hydrolyzed by the means used to similarly treat compounds of Formula E, to obtain the corresponding 2-naphthyl-u-alkyl acetic acid derivatives.

The l-tetralones of Formulas C and L are prepared by conventional techniques, for example, such as the process used to make 6,7-dimethoxy-l-tetralone described above.

Alternatively, the l-tetralones of Formulas C and L can be prepared directly from naphthalenes by conventional means known to the art. For example, the substituted l-tetralones can be prepared from substituted naphthalenes. The substituted naphthalenes are reduced with two molar e'quilavents of hydrogen in the presence of a platinum, palladium, nickel catalyst, or the like, to afford the corresponding substituted tetralin (hydrogenation of the unsubstituted ring is favored; when both rings are substituted, two products are obtained with different ring saturation). The substituted tetralin is then oxidized, such as with chromium trioxide in glacial acetic acid or 8 N sulfuric acid, to obtain the substituted l-tetralone.

The l-tetralones substituted at positions 6 and 8 of Formulas C and L can also be prepared from the corresponding 4-tetralones (which are intermediates in the above described preparation of naphthalenes substituted at positions 6 and 8) by reducing and hydrogenolyzing the latter with sodium borohydride and hydrogen in the presence of palladium respectively to afford the corresponding tetralins. The tetralins are then oxidized with chromium trioxide in acetic acid to afford the corresponding 1- and 4-tetralones substituted at positions 6 and 8. The tetralones are separated by conventional means, such as fractional crystallization or distillation.

l-substituted and 1,6-disubstituted Z-naphthylacetic acid derivatives also can be prepared from l-oxo-3,4-dihydro- 2[2H]-naphthylaceti-c acid derivatives or l-hydroxy-l,2,3, 4-tetrahydro-2-naphthylacetic acid derivatives, the compounds of Formula F or G respectively.

For example, the l-chloro-2-naphthylacetic acid derivatives are prepared by first esterifying compounds of Formula F by conventional means, such as described above, and then chlorinating the resulting l-oxo esters by a conventional technique, such as by treatment with phosphorous pentachloride, to furnish the corresponding 1- 10 chloro-3,4-dihydro compounds. The resulting l-chloro products are then dehydrogenated by conventional means, preferably by refluxing in a hydrocarbon solvent with 2,3-dichloro-5,6-dicyano 1,4 benzoquinone (DDQ) to furnish the corresponding 1-chloro-2-naphthylacetic acid derivatives.

The l-fiuoro-Z-naphthylacetic acid ester derivatives are prepared by esterifying the carboxy group of the corresponding 1 hydroxy-1,2,3,4-tetrahydro-2-naphthylacetic acid derivatives, the compounds of Formula G, and then treating the resulting ester with two or more equivalents of l-diethylamino-l,2,2-trifluoro-2-chloroethane in a halogenated hydrocarbon solvent to afford the corresponding l-fluoro derivative. The latter upon treatment with DDQ, as described above, affords the corresponding l-fluoro-Z- naphthylacetic acid ester derivative.

iBy treating the 1- oxo-3,4-dihydro-2-[ZHJnaphthylacetic acid ester derivatives with an alkyl magnesium bromide, such as methyl magnesium bromide, in a non-aqueous ether, such as diethylether, diisopropylether, dioxane, tetrahydrofuran, and the like, hydrolyzing the resulting products under acidic conditions, and then dehydrogenating the resulting l-alkyl-l,2,3,4-tetrahydro-2-naphthy1- acetic acid ester derivatives by conventional techniques, such as the techniques described above, the corresponding l-alkyl-2-n-aphthylacetic acid derivatives are obtained.

1-alkoxy-2-naphthy1acetic acid ester derivatives are prepared by treating 1-oxo-3,4-dihydro-2[2H]naphthylacetic acid ester derivatives With an alkylorthoformate, such as methylorthoformate, in the presence of an acid catalyst, such as the ones described above, in a hydrocarbon solvent and then dehydrogenating the resulting l-alkoxy-3,4-dihydro-2-naphthylacetic acid derivatives by conventional means, such as described above.

l-alkylthio-Z-naphthylacetic acid ester derivatives can be prepared by hydrolyzing a 1-a1koxy-2-naphthylacetic acid ester derivative to obtain the corresponding l-hy droxy derivatives and then treating the latter with an al kylmercaptan, such as methylmercaptan, ethylmercaptan, and the like, in an acid environment at about C. under pressure greater than atmospheric pressure for 3 hours or more.

The 1-substituted-Z-naphthylacetic acid ester derivatives are hydrolyzed by conventional methods, such as by the means described above, to the free acids.

Another method for the preparation of 4-substituted 2-naphthylacetic acid derivatives involves the treatment of benzene with an equivalent of a 3-halocarbonyl dialkyl glutarate, such as dimethyl 3-chlorocarbonyl glutarate and two or more equivalents of aluminum chloride in a hydrocarbon solvent to afford the corresponding dialkyl benzoyl glutarate, which is reduced and hydrogenolyzed as the oxo-containing compounds above to afford the corresponding dialkyl S-benzyl glutarate. The latter is hydrolyzed by conventional means and the resulting 3- benzyl glutaric acid is treated with concentrated sulfuric acid to afford the corresponding 1,2-dihydro-4-oxo-2- [3H]naphthylacetic acid derivative. The latter is reduced, halogenated, alkylated, esterified and dehydrogenated by the processes used to reduce, halogenate, alkylate, esterify and dehydrogenate the l-oxo-3,4-dihydro-2-[2H]naphthylacetic acid derivatives described above, to obtain 4- chloro-, 4-fiuoro-, 4-hydroxy-, 4-alkyl, 4-alkoxy-, and 4- alkylthio-2-naphthylacetic acid derivatives. The 4-substituted-6-substituted-2-naphthylacetic acid derivatives are obtained by employing a monosubstituted benzene, such as methoxybenzene, in the above process.

Another method of preparing the 8-substituted 2-naphthylacetic acid derivatives involves treating an ester of phenylacetic acid with two or more equivalents of succinic anhydride and aluminum chloride in a nitrobenzene or carbon disulfide to afford the corresponding alkyl p-.(3- carboxy-l-oxopropyl)phenylacetate derivative, which is reduced and hydrogenolyzed by treatment with an alkali borohydride and palladium charcoal catalyst, respectively, to aiford the ester of p-(3-carboxypropyl)-phenylacetie acid. The corresponding acid halide is prepared by treating the latter with a conventional halogenating agent, such as phosphorus trior pentabromide or -chloride or thionyl chloride. The resulting ester of p-(3-halocarbonylpropyl)phenylacetic acid is treated with three or more equivalents of aluminum chloride in -a. hydrocarbon solvent to furnish the ester of 8-oxo-5,6-dihydro-2-[7H]- naphthylacetic acid. This compound can be reduced, halogenated, alkylated, esterified and dehydrogenated by the processes described above to obtain the 8-chloro-, 8- fluoro-, 8-hydroxy-, 8-alkyl-, 8-alkoxyand 8-alkylthio- Z-naphthylacetic acid derivatives.

Another method by which the present compounds can be prepared involves the reaction of Z-tetralones with one or more equivalents of a l-alkoxycarbonylalkylidene triphenyl phosphorane, such as l-methoxycarbonylethylidene triphenyl phosphorane, to furnish the corresponding 2,2-(l-alkoxycarbonylalkylidene)tetralin. The latter upon heating with palladium charcoal catalyst affords the corresponding Z-naphthylacetic acid ester derivative.

For this purpose, the 1-alkoxycarbonylalkylidene triphenyl phosphorane reactant is conveniently provided upon reaction of triphenylphosphine with a 2-halocarboxylic acid ester in an organic reaction medium followed by reaction with a base.

Thus, for example, by reacting 6-methoXy-2-tetralone with the triphenylphosphorane derived from ethyl 2-halopropionate, 2,2 (1'-carbethoxyeth-l',1-y1idene)-6-methoxytetralin is prepared. Dehydrogenation thereof provides ethyl 6-methoxynaphthyl-u-methylacetate which upon hydrolysis affords 6-methoXynaphthy-a-methylacetic acid.

Unsubstituted and substituted Z-tetralones of the following formulas can be utilized in the above process:

wherein R R and R are as defined above.

The substituted 2-tetralones of Formulas N and O are prepared by treating the corresponding l-tetralones with butylnitrite in ether and then esterifying the resulting 2- oximino-l-tetralones with an acid anhydride, such as acetic anhydride, in an organic acid, such as acetic acid, to obtain the substituted 2-acetylimino-Z-tetralones. The acetylimino substituents are reduced to acetylamino substitutents with hydrogen in the presence of palladium and the like. The keto groups are then reduced to hydroxy groups with sodium borohydride or the like. The substituted 2-acetylamino-l-hydroxytetralins are then treated with glacial acetic acid in the presence of concentrated acid to obtain the corresponding substituted 2-tetralones of Formulas N and O.

The 3,4-dihydro-2-naphthylacetic acid derivatives of Formulas VIA, VIIA and VIIIA are prepared from the corresponding Z-naphthylacetic acid derivatives or the esters thereot by refluxing the latter in an alkanol with two or more equivalents of an alkali metal, such as lithium, potassium, sodium, and the like. Preferably the Z-naphthylacetic acid derivative starting material is not substituted with hydroxy or conventional hydrolyzable ester, but rather, these groups are introduced later by the means described herein.

The addition of an alkyl substituent at the tat-position (with respect to the acetic acid chain) to obtain the 2- naphthyl-a-alkylacetic acid derivatives is optional, but when the addition is required, it is carried out following the preparation of the Z-naphthylacetic acid derivatives or the 3,4-dehydro derivatives thereof prepared as described above. The introduction of the u-alkyl substituents can be illustrated by the following reaction sequence:

C O OH C52 o o 0 Alkyl alkyl r C 0 O Alkyl na (R) Z wherein R is alkyl, cycloalkyl, trifluoromethyl, vinyl, alkoxymethyl, fluoro, chloro, conventional hydrolyzable ester, oxyether, thioether, formyl, alkoxycarbonyl, acetyl, cyano or aryl;

Z is a carbon-carbon single bond or a carbon-carbon double bond; provided that when Z is a carbon-carbon double bond, R is alkyl, cycloalkyl, trifluoromethyl, fluoro, chloro, oxyether, thioether or aryl.

The Z-naphthylacetic acid derivatives, the compounds of Formula P, are esterified by conventional means, such as being allowed to react with an alkanol in the presence of boron trifluoride, to afford the corresponding esters, the compounds of Formula Q. The compounds of Formula Q are treated with an alkali metal hydride such as sodium hydride, potassium hydride, and the like, in an ether solvent, such as monoglyme, and then with an alkyl halide, such as methyl iodide, to afford the corresponding '2- naphthyl-a-alkylacetic acid ester derivatives, the compounds of Formula R. The latter are hydrolyzed by refluxing in a basic solution to obtain the corresponding 2- naphthyl-a-alkylacetic acid derivatives.

The ethynyl 2-naphthyl-a-alkylacetic acid derivatives are prepared from vinyl Z-naphthyl-a-alkylacetic acid derivatives by brominating and debrominating the latters vinyl group by the means described above. Oxyether or alkoxymethyl 2-naphthyl-a-alkylacetic acid derivatives are hydrolyzed to obtain the hydroxy or hydroxymethyl derivatives respectively. Alkoxycarbonyl 2-napthyl-aalkylacetic acid derivatives are hydrolyzed to obtain the carboxy derivatives.

Z-naphthylacetic acid derivatives substituted at other positions are also employed in the above process.

The a-alkyl substituents are similarly introduced into other Z-naphthylacetic acid derivatives substituted at positions 1,4,7,8 and/or 6. Prior to the above process, hydroxy groups are etherified and carboxy groups are esterified to protect them from attack by reagents used in subsequent elaborations. Such protected groups can be regenerated by hydrolysis after the process.

The introduction of other substituents on the a-carbon atoms of the acetic acid moiety is also optional, but when carried out, is preferably done after the preparation of the Z-naphthylacetic acid derivatives and the esters thereof (including the 3,4-dihydro derivatives).

The oc-dlfillOI'OIIlCthYl group can be introduced by treating the Z-naphthylacetic acid ester derivatives with an alkali metal or alkali metal hydride in a dialkyl carbonate, such as diethyl carbonate, to aiford the corresponding ot-alkoxycarbonyl derivatives. The latter is treated with chlorodifluoromethane and an alkali metal alkoxide, such as potassium t-butoxide, in an ether solvent, preferably l,2-dimethoxyethane to afford the corresponding u-alkoxycarbonyl-ot-difluoromethyl derivatives, which are hydrolyzed to furnish the corresponding 2- naphthyl-a-carboxy-a-diflouromethylacetic acid derivatives. The dcesterified product is decarboxylated by heating to between 30 C. and 150 C., until the evolution of carbon dioxide ceases to give the corresponding 2- naphthyl-a-difluoromethylacetic acid derivatives.

By treating the above 2-naphthyl-a-alkoxycarbonylacetic acid ester derivatives with an equivalent of an alkali metal hydride in a hydrocarbon solvent, then with an alkyl halide, the corresponding 2-naphthyl-a-alkoxycarbonyl-a-alkylacetic acid ester derivatives are obtained. The latter are hydrolyzed and decarboxylated to furnish the corresponding 2-naphthyl-u-alkylacetic acid derivatives. This is an alternative method of introducing the aalkyl substituent.

The a-fluoro group is introduced by treating the 2- naphthylacetic acid ester derivatives with two or more equivalents of an alkyl formate, such as ethylformate, and three or more equivalents of an alkali metal or alkali metal hydride in a hydrocarbon solvent to afford the corresponding a-hydroxymethylene derivatives which are treated with an equivalent of an alkali metal hydride and one equivalent of perchloryl fluoride to afford the corresponding ot-fllJOlO-a-fOIIDYl derivatives. The latter are oxidized by conventional means, such as with chromium trioxide in glacial acetic acid or 8 N sulfuric acid, to furnish the corresponding u-fluoro-u-carboxy derivatives which are decarboxylated by heating to temperatures of 100 C. or more to afford the corresponding 2-naphthyla-fluoroacetic acid ester derivatives. The corresponding ot-chloro derivatives are prepared by utilizing chlorine in place of perchloryl fluoride in the above process.

The a,a-difluormethy1ene group can be introduced by refluxing 2-naphthyl-ot-chloroacetic acid ester derivatives with an alkali metal hydroxide in an alkanol to afford the corresponding 2-naphthyl-u-hydroxyacetic acid derivative. The carboxy groups of the latter are re-esterified by conventional methods and the resulting esters are then oxidized by conventional means, such as described above, to obtain the corresponding cz-OXO derivatives, which upon being refluxed with one equivalent of di-fiuoromethylidene triphenylphosphorane in a hydrocarbon sol-vent, affords the corresponding 2naphthyl-a,a-difluoromethyleneacetic acid ester derivatives. The corresponding a,u-fluorochloromethylene derivatives are prepared by using chlorofluoromethylidene triphenylphosphorane in place of difiuoromethylidene triphenylphosphorane in the above process. The difluoromethylidene triphenylphosphorane is prepared by refluxing sodium chlorodifluoroacetate with triphenylphosphine in dimethylforrnamide. Similarly, triphenyl chlorotluoromethylidene phosphorane is prepared by employing sodium dichlorofluoroacetate.

The 0:,ot-flUOIOH16thYl6I16 group can be introduced by treating Z-naphthyI-a,a-hydroxymethyleneacetic acid ester derivatives with phosphorus pentachloride in a hydrocarhon solvent.

The a,ot-fluoromethylene group can be introduced to tosylating Z-naphthyl-a,ot-hydroxymethyleneacetic acid ester derivatives with p-toluenesulfonyl chloride in a hydrocarbon solvent and then treating the resulting tosylate with an alkali metal fluoride, such as sodium fluoride. By utilizing the alkali metal chloride in the above process, the corresponding a,a-chloromethylene derivatives are furnished.

The a t-methylene group is introduced by treating the 2-naphthy1 acetic acid ester derivatives with formaldehyde or paraformaldehyde and an alkali metal alkoxide, such as sodium methoxide in dimethylsulfoxide.

The aux-ethylene group is introduced by refluxing the 2-naphthy1-a,ot-methyleneacetic acid ester derivatives with 14 diiodomethane in the presence of zinc-copper couple in an ether solvent.

In the preferred embodiment of this invention the hydroxy, hydroxymethyl, conventional hydrolyzable ester, alkoxymethyloxy, allqylthiomethyloxy, tetrahydrofuran- 2-yloxy, tetrahydropyran-2-yloxy, 4-alkoxytetrahydropyran-4'-yloxy, alkoxymethylthio and alkylthiomethylthio are introduced after the introduction of substituents at the a-position of the Z-naphthyl acetic acid derivatives.

Those compounds containing a trifluoromethyl group are preferably prepared from the corresponding methyl substituted Z-naphthylacetic acid ester derivatives by treating the latter with chlorine and phosphorus trichloride in the presence of light to afford the corresponding trichloromethyl derivatives, which, when refluxed with antimony trifluoride in a hydrocarbon solvent, furnish the corresponding trifluoromethyl substituted 2-naphthy1- acetic acid ester derivatives. In the preferred embodiment of the present invention the trifluoromethyl group is introduced on the Z-naphthylacetic acid derivatives starting material prior to the preparation of the corresponding 3,4-dihydro derivatives by the above described processes.

Those compounds containing difiuoromethoxy groups are preferably prepared from the corresponding alkoxy substituted 2-naphthylacetic acid ester derivatives by re ifluxing the latter with 48 percent hydrobromic acid in acetic to furnish the free hydroxy derivatives which, upon treatment with chlorodifiuoromethane and an alkali metal hydroxide in aqueous dioxane of tetrahydrofuran, affords the corresponding difluoromethoxy substituted 2-naphthylacetic acid ester derivatives.

By utilizing alkylthio 2-naphthylacetic acid ester derivatives in the above process, the corresponding difluoromethylthio derivatives are obtained.

The hydroxy groups are etherified by conventional methods, for example, by treatment with an alkali metal hydride and then with an alkylhalide, preferably an alkylbromide or iodide; or by treatment with a diazoalkane or an alkanol in the presence of borotrifluoride in an ether solvent, and the like.

The alkoxymethyloxy groups are introduced by treating the hydroxy substituted Z-naphthylacetic acid derivatives with an alkoxychloromethane in dimethylformamide to afford the corresponding alkoxymethyloxy substituted 2-naphthylacetic acid derivatives. The alkylthiomethyloxy substituted Z-naphthylacetic acid derivatives are prepared by utilizing an alkylthiochloromethane in the above process.

The alkoxymethylthio substituted 2-naphthylacetic acid derivatives are prepared by refluxing thio substituted 2- naphthylacetic acid derivatives with an alkoxychloromethane in dimethylformamide. The alkylthiomethylthio substituted derivatives are prepared by using an alkylthiochloromethane in place of alkoxychloromethane in the above process.

The compounds containing tetrahydrofuran-2'-yloxy, tetrahydropyran-2'-yloxy, or 4'-alkoxytetrahydropyran-4- yloxy groups are preferably prepared from the corresponding hydroxy Z-naphthyl-acetic acid ester derivative by treatment with dihydrofuran, dihydropyran, or 4 alkoxy dihydropyran, such as 4'-methoxy dihydropyran, in the presence of an acid catalyst.

The 4-alkoxy-2,6-dihydropyrans are prepared by treating 4-oxotetrahydropyran with an alkanol in the presence of an acid catalyst, and then pyrolyzing the resulting 4,4- dialkoxy tetrahydropyran in the presence of acid to afford the corresponding 4-alkoxy-2,6-dihydropyran.

The compounds containing hydroxy ester groups are prepared from the hydroxy derivatives by conventional esterification means, such as by heating With an acid anhydride.

The foregoing general procedures are useful for the preparation of other naphthylacetic acid derivatives hereof.

formula (Ial) In the above formula,

R is methoxy, methylthio, difluoromethoxy, chloro,

methyl, ethyl or isopropyl; and

R is hydrogen, methyl or difluoromethyl.

The preferred method for preparing these latter compounds involves the reaction of a p-substituted naphthylene With acetyl chloride in nitrobenzene in the presence of at least 3 molar equivalents of an aluminum chloride to yield the corresponding 6-substituted-2-acetylnaphthylene derivative. The resulting derivative is heated with morpholine in the presence of sulfur at about 150 C.; the product is refluxed with concentrated hydrochloric acid to yield the corresponding 2-(6-substituted-2- naphthyl)acetic acid derivative. The addition of the alkyl substituent at the alpha position is carried out by esterifying the 2-(-6-substituted-Z-naphthyl)acetic acid derivative by conventional methods, such as by treatment with a diazoalkane, such as diazomethane, in ether or with an alkanol such as methanol in the presence of boron trifluoride to yield the corresponding alkyl ester. The ester product is then treated with sodium hydride in an ether solvent such as 1,2-dimethoxyethane, and then treated with a methyl halide such as methyl iodide to yield the corresponding 2-(6' substituted 2 naphthyl)propionic acid methyl ester. These can be hydrolyzed such as with a base in alcohol to yield the corresponding acids.

Preferably, the difluoromethoxy group at the 6-position of the naphthylene ring is introduced after the introduction of any methyl group at the a-position of the Z-naphthylacetic acid compounds. These compounds are prepared from the corresponding 2-(6alkoxy-2-naphthyl)acetic acid alkyl ester derivative by refluxing the latter compound with 48 percent hydrobromic acid in acetic acid to furnish the corresponding 6'-hydroxy derivative. The hydroxy derivative is treated with chlorodifluoromethane and an alkali metal hydroxide in aqueous dioxane or tetrahydrofuran to furnish the corresponding 2-(6-difluoromethoxy-Z-naphthyl)acetic acid derivative.

The preferred conjugates are those of the d-acids of Formula (Ial) Representative Z-naphthylacetic acid conjugates of Formulas VIII and XI can be prepared corresponding to the following Z-naphthylacetic acid derivatives of Formulas IA-VIHA.

TABLE A 16 6-acetyl-2-naphthylacetic acid, 6-cyano-2-naphthylacetic acid, 6-phenyl-Z-naphthylacetic acid, 6-p-chlorophenyl-Z-naphthylacetic acid, 6-methyl-S-fluoro-Z-naphthylacetic acid, 6-methyl-8-methoxy-Z-naphthylacetic acid, 6-chloro-8-methyl-2-naphthylacetic acid, 6,7-dichloro-2-naphthylacetic acid, 6-fiuoro-7-methoXy-2-naphthylacetic acid, 6-methoXy-7-fluoro-2-naphthylacetic acid, 6,7-dimethyl-Z-naphthylacetic acid, 6,8-dimethoxy-Z-naphthylacetic acid, G-methyl-8-fluoro-2-naphthylacetic acid, 6-chloro-8-methyl-2-naphthylacetic acid, 6-methyl-8-chloro-2-naphthylacetic acid, 6-methyl-Z-naphthyl-a-methylacetic acid, 6-methyl-2-naphthyl-a-ethylacetic acid, Z-naphthyl-a-methylacetic acid, 1-methyl-2-naphthyl-a-methylacetic acid, 1-fluoro-Z-naphthyl-a-methylacetic acid, 1-methoxy-2-naphthyl-a-methylacetic acid, 1,6-dimethylthio-2-naphthyl-a-methylacetic acid, 4ethyl-2-naphthyl-a-ethylacetic acid, Lchloro-Z-naphthyl-a-methylacetic acid, 4-methoxy-Z-naphthyl-a-methylacetic acid, 4-methyl-6-tluoro-2-naphthyl-a-methylacetic acid, 4-fluoro-6-methoXy-2-naphthyl-a-methylacetic acid, 6-ethoxy-Z-naphthyl-a-methylacetic acid, 6-ethylZ-naphthyl-ot-methylacetic acid, 6-methoxymethyl-Z-naphthyl-ot-methylacetic acid, G-trifluoro-Z-naphthyl-u-methylacetic acid, 6-isopropyl-2-naphthyl-a-methylacetic acid, 6-vinyl-2-naphthyl-a-methylacetic acid, 6-cyclopropyl-Z-naphthyl-a-methylacetic acid, 6-fluoro-2-naphthyl-a-methylacetic acid, 6-chloro-2-naphthyl u-methylacetic acid, 6-chloro-2-naphthyl-u-ethylacetic acid, 6-acetyl-2-naphthyl-a-methylacetic acid, 6-methoXy-2-naphthyl-m-methylacetic acid, 6-methoxymethylene-Z-naphthyl-wmethylacetic acid, 6-methylthio-2-naphthyla-methylacetic acid, 6-ethylthio-2-naphthyl-a-methylacetic acid, 6-fluoro-7-methyl2-naphthyl-m-methylacetic acid, 6-methyl-7-methoxy-2-naphthyl-a-methylacetic acid, 6-methylthio-7-fiuoro-2-naphthyl-a-methylacetic acid, 7-chloro-2-naphthyl-u-methylacetic acid, 7-methoxy-2-naphthyl-a-methylacetic acid, 7-methyl-2rnaphthyl-ot-methylacetic acid, 8-methyl-2-naphthyla-methylacetic acid, 8-ethoxy-Z-naphthyl-a-methylacetic acid, 8-fluoro-2-naphthyl-wmethylacetic acid, 8-isopropylthio-Z-naphthyl-wmethylacetic acid, 6,8-dimethyl-2-naphthyl-ot-methylacetic acid, 6,8-dichloro-8-methyl-2-naphthyl-a-methylacetic acid, 6-methoxy-2-naphthyl-u-difluoromethylacetic acid, 1-ethyl-2-naphthylacetic acid, 1-chloro-2-naphthylacetic acid, 1-methylthio-2-naphthylacetic acid, l,6-dimethyl-Z-naphthylacetic acid, 4-isopropyl-Z-naphthylacetic acid, 4-fiuoro-2-naphthylacetic acid, 4-ethylthio-2-naphthylacetic acid, 4-rnethyl-6-methoxy-Z-naphthylacetic acid, 4-methoxy-6-chloro-2-naphthylacetic acid, 6methyl-2-naphthylacetic acid, 6-isopropyl-2-naphthylacetic acid, 6-cyclopropyl-Z-naphthylacetic acid, 6-trifluoromethyl-2-naphthylacetic acid, 6-meth0Xy-2-naphthylacetic acid, G-methylthio-2-naphthylacetic acid, 7-fluoro-2-naphthylacetic acid, 7-methylthio-2-naphthylacetic acid, 6,7-dimethyl-Z-naphthylacetic acid, 6,7-dichloro-2-naphthylacetic acid, 6-methoxy-7-methyl-2-naphthylacetic acid,

17 S-ethyl-Z-naphthylacetic acid, 8-chloro-2-naphthylacetic acid, S-ethylthio-2-naphthylacetic acid, 6,-8-dimethoXy-2-naphthylacetic acid, 6-methoxy-2-naphthyl-a-methylacetic acid, 1,6-dimethoxy-Z-naphthylacetic acid, 6-acetyl-2-naphthyl-a-methylacetic acid, 6-carboxy-Z-naphthyI-a-methylacetic acid, 6-methoXycarbonyl-2-naphthyl-a-methylacetic acid, 6-hydroxymethyl-Z-naphthyl-u-methylacetic acid, 6-formyl-Z-naphthyl-u-methylacetic acid, 6-cyano-Z-naphthyl-u-methylacetic acid, 6-isopropylcarbonyl-Z-naphthyl-ot-methylacetic acid, 3,4dihydro-6-methoxy-Z-naphthyl-a-methylacetic acid, 3,4-dihydro-6-methylthio-2-naphthyl-a-methylacetic acid, 3,4-dihydro-6-ch1oro-2-naphthyl-a.-methylacetic acid, 3,4dihydro-6-(fluo1'o-Z-naphthyl-a-methylacetic acid, 3.4-dihydro-6-methyI-Z-naphthyI-a-methylacetic acid, 3,4-dihydro-6-difluoromethoXy-2-naphthyl-a-methylacetic acid, 3,4-dihydro-6-methoxy-2-naphthylacetic acid, 3,4-dihydro-6-methylthio-2-naphthylacetic acid, 3,4-dihydro-6-chloro-2-naphthylacetic acid, and 3,4-dihydro-6-methyl-2-naphthylacetic acid.

Also included within the scope of Formulas VIII and XI are conjugates of the 1,2,3,4-tetrahydrophenanthrene, 1,2,3,4,9,10=hexahydrophenanthrene, and l,2,3,'4,9',10,11, 12-octahydrophenanthrene acids disclosed in U.S. Pat. 3,476,859. These acids can be represented by the formula:

In the above rormula,

R is hydrogen, hydroxy, allyloxy, diethylaminoethoxy, lower alkoxy containing one to four carbon atoms, cyclopentyloxy, tetrahydrofuran-2-yloxy, tetrahydropyran-2-yloxy, or acyloxy;

R is hydrogen, methyl, ethyl or n-propyl;

R is methyl or ethyl;

R is hydrogen, methyl or ethyl;

R is hydrogen or methyl and is alphaor beta oriented when Z is a single bond; and

Z and Z each is a carbon-carbon single bond or carboncarbon double bond, Z being a single bond when Z is a single bond.

These conjugates (corresponding to Formulas VIII and XI) can be prepared from the acids of Formula 18 (which correspond to Formula IV) by the procedure described above. These conjugates have anti-fertility and estrogenic activity and are accordingly useful in the replacement therapy for estrogen deficiencies, in the control and regulation of fertility, and in the management of menstrual disorders.

Exemplary compounds of Formula IB from which the corresponding conjugates of Formula VIII and XI can be prepared follow:

TABLE B d-cis bisdehydrodoisynolic acid and the 7-methyl ester; l-cis bisdehydrodoisynolic acid and the 7-methyl ester; d-trans bisdehydrodoisynolic acid;

racemic-cis bisdehydrodoisynolic acid; racemic-cis 1-ethyl-2-methyl-7-ethoxy-1,2,3,4-tetrahydro-2-phenanthrenecarboxylic acid;

' racemic-cis1-ethyl-2-methyl-7-methoxy-1,2,3,4-tetrahydrO-Z-phenanthrenecarboxylic acid;

racemic-cis 1-ethyl-2-methyl-7-allyloxy-l,2,3,4-tetrahydro-Z-phenanthrenecarboxylic acid;

racemic-cis l-ethyl-2-methyl-7-n-propoxy-l,2,3,4-tetrahydro-2-phenanthrenecarboxylic acid;

racemic-cis l-ethyl-2-methyl-7-n-butoxy-1,2,3,4-tetrahydro-2-phenanthrenecarboxylic acid;

racemic-cis 1,2-dimethyl-7-hydroxy-l,2,3,4-tetrahydro- 2-phenanthrenecarboxylic acid;

racemic-cis 1,2-diethyl-7-hydroxy-1,2,3,4-tetrahydro-' Z-phenanthrenecarboxylic acid;

racemic-cis 1-ethyl-2-n-propyl-7-hydroxy-1,2,3,4-tetrahydro-Z-phenanthrenecarboxylic acid;

racemic-cis 7-hydroxy-1,2,3,4-tetrahydro-2-phenanthrenecarboxylic acid;

racemic-cis 1-methyl-7-hydroxy-1,2,3,4-tetrahydro-2- phenanthrenecarboxylic acid;

racemic-cis l-methyl-7-methoxy-1,2,3,4tetrahydr0-2- phenanthrenecarboxylic acid;

racemic-cis 1,2-dimethyl-1-ethyl-7-methoxy-l,2,3,4-

tetrahydro-Z-phenanthrenecarboxylic acid;

racemic-cis 1,l-diethyl-2-methyl-7-methoxy-l,2,3,4-tetrahydro-2-phenanthrenecaboxylic acid;

l-methyl-7-methoxy-1,2,3,4,9,l0,11,12-octahydro-2- phenanthrenecarboxylic acid;

1,2-dimethyl-7-methoxy- 1,2,3 ,4,9,10,1 1,12-octahydro- 2-phenanthrenecarboxylic acid;

d-trans 1-ethyl-2-methyl-7-hydroxy-l,2,3,4,9',l0, 1 1,12-

octahydro-Z-phenanthrenecarboxylic acid;

d-cis 1-ethyl-2-methyl-7-hydroXy-1,2,3 ,4,9, 10, 1 1, 12-octahydro-2-phenanthrenecarboxylic acid;

dl-trans 1-ethyl-2-methyl-7-methoxy-l,2,3,4,9,10,1 1,12-

octahydro-2-phenanthrenecarboxylic acid;

dl-cis 1-ethyl-2-mehyl-7-hydroxy-1,2,3,4,9,10, 1 1,12-

octahydro-2-phenanthrenecarboxylic acid;

dl-cis 1-ethyl-2-methyl-7-methoxy-1,2,3,4,9,10,11,12-

octahydro-Z-phenanthrenecarboxylic acid;

dl-cis 1-ethyl-2-methyl-7-methoxy-1,2,3,4,9,10,11,12-

octahydro-2-phenanthrenecarboxylic acid; and

dl-trans 1-ethyl-2-methyl-7-methoxy-1,2,3,4,9,10,1 1,12-

octahydro-Z-phenanthrenecarboxylic acid.

Other conjugates included within Formulas VIII and XI are conjugates of the following exemplary drug acids (corresponding to Formula IV in the above preparation procedure). The utility of the conjugates are also indicated. I

agent. B-(4-hydroxy-3, 5-diiodophenyl)-5- Iodine therapy in thyroalanine. co s. N-{ p-[(2, 4-diamiuo-6-pteridylmethyi)- Antimetalliastlite, folic acid amino1-benzoyllglutamic acid. antago Diammonium citrate Diuretic. 4-ch1orophcnoxy acetate Anorexigenic.

D-(2-amino-2-phenylacetamide) -3, 3-

dimethyl-7-0xo-4-thia-1-azabicyclo- [3. 2. 0]heptane-2-carboxylic acid.

B-Hydroxymethoxy tricarballylic acid 7- Antipyretic, analgesic.

lactone disahcylic acid ester.

N-[ p-{ [1-(2 tdiamino-fi-pteridinyfl- Folic acid antagonist.

ethyl1am1no i-benzoyl }glutamic acid.

p-Methoxybenzoie acid Antirheumatic.

p-Stibonobenzoic acid methyl 1, 2, 5, 6- Anthelmlntie.

tetrahydro-l-methylnicotinate.

Antimicrobial.

l[(p-carbaxnoylphenyl)-arsy1cne]- Used in filariasis.

dithio idiacetic acid.

Baeitracin Antimicrobial.

5-acetamido-2-ethoxybenzcic acid Sedative, antineuralgic.

N-benzoyl-p-aminosalicylic acid Antituberculous agent.

TABLE (J-Continued Diacetylpyrocatechol-3-carboxylic quinolme. 5-{p-[4-6-dimethyl-(2-pyrimidinyl)- sulfamoyH-phenylazo}salieylic ac G-(p-suliamoylphenylazo)salicylic id Antimicrobial agent.

ac o-[p-(2-pyridylsulfam0yl)-phenylazo]- In ulcerative colitis.

salicylic acid. o'Hydroxybenzoic acid Analgesic agent. 5,6dimethoxyphthaldehydic acid Antituberculous agent.

isonicotinoylhydrazone. p-Carboxybenzaldehyde thiosemicar- Antituberculous agent.

bazone diethauolamine salt. Stibocaptate Antischistosomal agent. 5-amino-6-(7-amino-5,8-dihyd.ro-6-me- Antimetabolite.

thoxy-5,8-dioxo-2-quinolyl)4-(2- hydroxy-3,4-dimethoxypl1enyl)-3- methylpicolinic acid. 4'-(a-ghiazolylsulfamoyl)-succinanilic Antimicrobial agent.

aci 4-su1fanilylsucclnanilic acid Do. p-Sulfanilamidosalicylic acid Do. 2-[2-[(p-chloro-a-methyl-a-phenyl- Antihistaminic.

bcnzyl)-oxy]ethyH-I-methyl-pyrrolidine hydrogen iumarate. 6,6-dihydrobenz[c] acridine-7-carboxylic Used in certain muscular acid. paralyses. 3,6-dihydr0-3,7-dimethyl-2,fi-dioxo-l Diuretic, myocardial stimu- (ZED-purineacetic acid. lant, vasodilator 1,2 3,6-tetrahydr0-1,3-dimethyl-2,6- Diuretic, myocardial dioxopurine-7-acetic acid. stimulant. p-Ureid0benzenearsylcne-dithio-di-o- Amebicide.

benzoic acid. Transl-(aminomethyl) cyclohexanecar- Antifibrinolytic agent.

boxylic aci [4-(4-Eydroxy-3-iodophenoxy)-3,5-di- Thyroid replacement therapy.

iodophenyflacetic acid. fl-[4-(4-hydroxy-3-iodophenoxy)-3,5- Do.

diiodophenyH-alanine. 5-[4-(3-iodo-4-hydroxyphenoxy)-3,5- Cholesteropenic agent.

diiodophenyll-propionic acid. 5-benzyldihydro-fi-thioxo-ZH-l,3,5- Antimycotic.

thiadiazine-3(4H)acetic, acid a-Ethyl-l-hydx0xy-4-phenyl-cyclo Choleretic agent;

hexaneacetic acid. 3-(l,4-dihydro-3-methyl-1, 4-dioxo-2- Antihemorrhagic agent.

naphthylthio)propionic acid. p-[(a-Ethoxy-p-phenylphenacyl) Antiviral agent.

amino]benzoic acid.

The compounds of Formula I wherein one of R R and R is --D can be prepared by a procedure represented as follows:

in the above formulas D is the remainder of a ketone drug moiety and D is the remainder of the enol ether drug moiety corresponding to D ketone drug moiety or an aromatic drug moiety; and

each of R R R and R is hydrogen or a fatty acyl group, and at least one of R and R and at least one of R and R is a fatty acyl group.

In the above illustrated process, the ketones of Formula IC are reacted with methyl orthoformate in dioxane in the presence of p-toluenesulfonic acid to yield the enol ethers of Formula 110. The compounds are reacted with 1,2 di O (fatty acyl) glycerols in an inert organic solvent such as benzene in the presence of p-toluenesulfonic acid to yield a mixture of the drug enol ethers, i.e. 2',3'-di-O-(fatty acy1)-glycerols of Formula IIIC and 1',3-di-O-(fatty acyl)-glycerols of Formula IVC. The compounds of Formula IHC and IVC are isolated from the mixture by conventional chromatography and crystallization.

Included within Formulas HIC and IVC are conjugates of steroid ethers corresponding to Formula IIC. These steroid ethers which are included within Formula I10 are, for the most part, derived from ketones which have been described together with methods for their preparation in US. patent applications Ser. No. 731,300, filed May 22, 1968, Ser. No. 731,301, filed May 22, 1968 and Ser. No. 731,267, filed May 22, 1968 and US. Pats Nos. 3,365,446, 3,067,194 and 3,364,203. Estrogenic steroids conjugated at an aromatic hydroxy group (phenolic group) are prepared from the corresponding ethers described in US. patent application Ser. No. 731,301, filed May 22, 1968.

Representative anabolic steroids within Formula IC can be represented by the following formulas:

1'1214 R (ID) (IID) YY y (IIID) R m R217 10MB; Z R217 0R2 213 I I I I l O O Y R220 (IVD) (VD) In the above formulas R R R R R and R each is hydrogen or methyl (preferably one of R and R is methyl);

R is hydrogen or lower alkyl;

R is hydrogen or chloro;

R is hydroxy, or a conventional hydrolyzable ester or ether thereof;

R is methyl or ethyl;

R R and R each is hydrogen, methyl, fiuoro, or ghlOO; and R is not present when Z is a double on Z and Z each is a single bond or a double bond.

The conjugates of the compounds of Formulas ID-VD represented by Formulas IIIC and IVC are anabolic agents with a favorable anaboliczandrogenic ratio, also possess anti-estrogenic, anti-gonadotrophic, and antifibrillatory activities, and can be used in the same manner as testosterone. These compounds are preferably administered orally. However, they can also be administered by other usual routes such as parenterally. In either manner of administration they can be administered either alone or in conjunction with other medicinal agents, or 1D. pharmaceutically acceptable, non-toxic compositions formed by the incorporation of any of the normally employed excipients.

The terms (lower)alkyl and derivations thereof appearing in the above and following definitions for steroids denote alkyl groups containing from one to six carbon atoms, inclusive, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, amyl, hexyl and the like.

The term conventional hydrolyzable ester as used therein denotes those hydrolyzable ester groups conventionally employed in the steroid art, preferably those derived from hydrocarbon carboxylic acid or phosphoric acid and their salts. The term hydrocarbon carboxylic acid defines both substituted and unsubstituted hydrocarbon carboxylic acids. These acids can be completely saturated or possess varying degrees of unsaturation (including aromatic), can be of straight chain, branched chain, or cyclic structure, and preferably contain from one to 12 carbon atoms. In addition, they can be substituted by functional groups, for example, hydroxy, alkoxy containing up to six carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino, halogeno, and the like, attached to the hydrocarbon backbone chain. Typical conventional hydrolyzable esters thus included within the scope of the term and the instant invention are acetate, propionate, butyrate, valerate, caproate, enanthate, caprylate, pelargonate, acrylate, undecanoate, phenoxyacetate, benzoate, phenylacetate, diphenylacetate, diethylacetate, trimethylacetate, t-butylacetate, trimethylhexanoate, methylneopentylacetate, cyclohexylacetate, cyclopentylpropionate, adamantoate, glycolate, methoxyacetate, hemisuccinate, hemiadipate, hemi-;9,B-dimethylglutarate, acetoxyacetate, 2 chloro 4 nitrobenzoate, aminoacetate, diethylaminoacetate, piperidinoacetate, B-chloropropionate, trichloroacetate, p-chlorobutyrate, dihydrogen phosphate, dibenzyl phosphate, benzyl hydrogen phosphate, sodium benzyl phosphate, cyclohexylammonium benzyl phosphate, sodium phenyl phosphate, sodium ethyl phosphate, di-p-nitrobenzyl phosphate, sodium o-methoxyphenyl phosphate, cyclohexylammonium p-cyanobenzyl phosphate, sodium phenacyl phosphate, benzyl o-carbomethoxyphenyl phosphate, and the like. The term conventional hydrolyzable ethers include tetrahydropyran-2'-yl, tetrahydrofuran 2 yl, and 4' (lower)alkoxy 4'- tetrahydrofuran-4'-yl ethers and the like.

By the term aryl are included aryl, aralkyl, and alkaryl groups, such as phenyl, p-chlorophenyl, pmethoxyphenyl, benzyl, phenthyl, tolyl, ethylphenyl, and the like. The wavy line(s) designates and includes both the alpha and beta configurations.

Representative anabolic steroid conjugates according to this invention (corresponding to Formulas 1110 and IVC) can be prepared from the following ketones by the above procedure.

TABLE D l9-norandrost-4-en-l7fi-ol-3-one, 5a,l9-norandrost-17 3-ol-3-one, Zu-methyI-Sa, l9-norandrost-17,8-01-3-one, 2u-methyl-5a-androst-17,8-01-3-one,

v4ez-methyl-5ot, 19-norandrost-l7/8-ol-3-one,

2a.,17u-dimethyl-5u,19 norandrost-17 8-ol-3-one, 4a-methyl-l7a-ethy1-5a-androst-17fl-ol-3-one, 4a-methyl-5a-androst-17p-o1-3-one, androst-4-en-17/3-o1-3-0ne,

- 17 a-methylandrost-4-en- 17,8-01-3-one,

l7m-ethylandrost-4-en-17,6-01-3 -one,

17 a-propylandrost-4-en-17fl-ol-3-one, 7u-methylandrost-4-en-l7 8-ol-3-one, 4-chlo-roandrost-4-en-l7fl-ol-3-one, 19-norandrost-4-en-175-01-3-one, 17a-methyl-19 norandrost-4-en-l7,8-o1-3-one, 17a-ethyl-l9 norandrost-4-en-l7fi-ol-3-one, l7a-propyl-19-norandrost-4-en-17/3-ol-3-one, 7a-methyl-19 norandrost-4-en-175-01-3 -one, 7a,17a-dimethyl-19-norandrost-4-en-l7fi-ol-3-one, 4-chloro-19-norandrost-4-en-l7 8-ol-3-one, 3-methyl-5u-androst-l-en-l7fi-ol-3-one, l-methyl-Sm-androst-l-en-l7B-ol-3-one, l-methyl-l7u-methy1-5u-androst-1-en-17,8-o1-3-one,

'1-methy1-17a-ethyl-5 u-androst-1-en-l75-ol-3-one,

2-methyl-5u-androst-1-en-17,8-01-3-one, Z-methyl-l7u-methyl-5'a-androst-1-en-17 3-ol-3-one,

one, 6a, l S-trimethyl-17fi-hydroxy-l9-norandrost-4-en 3- one, 17;8-hydroxy-6a,lS-dimethyl-l7u-ethyl-l9-norandrost- 4-en-3-one, l7 fl-hydroxy-6a, l7a-dimethyl-19-norandrost-4-en-3- one, 17B-hydroxy-6a-methyl-19 norandrost-4-en-3-one, 17/3-hydroxy-l9-norandrost-4-en-3-one, l7fl-hydroxyl 8-methyl- 1 9-norandrosta-4, 6-dien-3-o'ne, 17 3-hydroxy-11a,lS-dimethyl-l9-norandrosta-4,6-dien 3-one, 17fl-hydroxy-6a,l70,1S-trimethyl-19-norandrosta-4,6-

dien-3-one, 17B-hydroxy- 60:, l 8-din1ethyl-17a-ethy1-19-norandrosta- 4,6-dien-3-one, 17B-hydroXy-6a,17a-dimethyl-l9-norandrosta-4,6-dien- 3-one, l'ZB-hydroXy-Gw-methyl-19-norandrosta-4 ,6 -dien-3-one, l7B-hydroxy-6u-fluoro-flat-methyl-19*norandrost-4-en- 3-one, and o l7 3-hydroxy-6a-fiuoro-l7a,lS-dimethyl-l9-norandrost- 4-en-3-one.

Representative corticoid steroids within Formula IC can be represented by the formula:

, CHgR I zao (IE) In the above formula,

wherein R is hydroxy, chloro, or fluoro; R is hydrogen, methyl, hydroxy, or conventional hydrolyzable esters thereof;

R is hydrogen, hydroxy, conventional hydrolyzable esters thereof, or when taken together with R R is hydrogen or alkyl of up to eight carbons;'

R is hydrogen, alkyl, or an aryl group of up to eight carbons;

R is chloro, fluoro, hydroxy, conventional hydrolyzable esters thereof or conventional hydrolyzable ethers thereof;

Z and Z each is a single bond, double bond, or

each of R and R is hydrogen, chloro, or fluoro.

The conjugates of the compounds of Formula 1E have corticoid activity and are accordingly useful as antiinflammatory agents. They are useful for the same purposes as hydrocortisone. These compounds are preferably administered orally. However, they can also be administered parenterally or topically. In any manner of administration, they can be administered either singly, in conjunction with other medicinal agents, or in pharmaceutically acceptable non-toxic compositions formed'by the incorporation of any of the normally employed excipients.

Representative corticoid steroid conjugates according to this invention (corresponding to Formula IIIC and IVC) can be prepared from the following ketones by the above procedure:

TABLE E pregn-4-en-21-ol-3,20-dione pregna-1,4-diene-1 118, 17a,21-triol-3,20-dione, 6u,9a-difluoro-16a,17a-isopropylidenedioxypregna-1,4-

diene-l 113,2 1-diol-3,20-dione, 6a-fluoro-16a,17u-isopropylidenedioxypregna-1,4-diene- 1 1,8,2 1-dio1-3,20-dione, 9a-fiuoro-16a,17u-isopropylidenedioxypregna-1,4-diene- 11B,21-diol-3,20-dione, I 6a-fluoro-9a,1 1/3-dichloro-16a,l7a-isopropylidenedioxypregna-1,4-dien-21-0l-3,20-dione, 6u-chloro-16oz,17a-isopropylidenedioxypregna-1,4-diene- 11;8,2l-di0l-3,20-dione, v I 6a,9u-difiuoro-16a,17wisopropylidenedioxypregn-4-ene- 1l 3,21-diol-3,20-dione, t s y: Ga-flUOIO-l 6oz, 17a-isopropylidenedioxypregn-4-ene-1 1B,

21-diol-3,20-dione, i V 9oc-fill0r0- 16oz, 17a-isopropylidenedioxypregn-4-ene11 1p,

21-diol-3,20-dione, 6a,9a-difiuoro-l6fi-methyl-17a-valeroxypregna-1,4-diene- 11fi,2l-diol-3,20-dione, v fiat-fluoro-16/3-methyl-17d-valeryloxypregna-1,4-diene- 11,3,21-di01-3,20-dione, 9u-fiuoro-16 3-methyl-17ix valeroxypregna-1,4-diene- 11fl,21-diol-3,20-dione, i 6u,9u-difluoro-16a-methylpregna-1,4-diene-1 1,8, 1711,21- triol-3,2 -dione, oa-fiuoro-1fia-methylpregna-1,4-diene-1 1fi,17u,21-trio1- 3,20-dione, V 601,2 1-'difluoro-9u,1 1/3-dichloro-16u,17a-isopropylidenedioxypregna-1,4-diene-3,20 dione, 6ocfluOI'0-9u,1 1,8,21-trichloro-16u,17a-isopropylidenedioxypregna-1,4-diene-3,20-dione, 6a,9a,1 15,2l-tetrachloro-16a,17a,-isopropylidenedioxypregna-1,4 diene-3,20-dione, 9a-fiuoro-16a-methylpregna-1,4-diene-1 113, 17u,21 t 1i0l- 3,20-dione, V v l 6a,7a-difluoromethylenepregn-4-ene-11p,17a,21-triol- 3,20-dione, 6a,7a-methylenepregn-4-ene-l 1/3,170:,21-t1i01-3,20-di0116, 6a-methylpregna-1,4-diene-1 113,17a,21-t1'lOl-3,20-di0118, I 6a,9a-diflu0ropregna-1,4,6-triene-1 1;8,17a,2 1-triol-3,20-

dione, v 6a,9a-difiuoro-16a,17a-isopropylidenedioxypregna-1,4,6- triene-l1fl,21-diol-3,20-dione, I 1 v 26 Gu-fiuoro-16a-methylpregna-L4-diene-1'1fi,2l-diol-3,20

dione, Y 16u-acetoxypregn-4-ene-11fi,21-dio1-3,20-dione, and 16fl-acet0Xypregn-4-ene-11fi,21-di01-3,20:dione.

(I F) In the above formulas,

R and R each is hydrogen, hydroxy or a conventional hydrolyzable ester thereof, lower alkoxy, lower cycloalkoxy, lower cycloalkenyloxy, tetrahydrofuran-2'- yloxy, tetrahydropyran-2'-yloxy, or 4'-(lower)alkoxytetrahydropyran-4-yloxy;

R is hydrogen, methyl, methoxy, hydroxyl or conventional hydrolyzable esters thereof, or conventional hydrolyzable ethers thereof;

R is hydrogen or methyl; and when Z is a single bond,

R canbe alpha or beta oriented;

R is hydrogen, hydroxy or conventional hydrolyzable esters thereof (e.g. lower acyloxy or lower cycloacyloxy groups) when Z is a single bond and is hydrogen when Z is a double bond;

R is hydrogen, a lower alkyl group, such as methyl, ethyl, propyl, and the like, a lower alkenyl group, such as vinyl and the like, or a lower alkynyl (including halo lower alkynyl with a halogen, such as fluoro, cbloro or bromo), such as ethynyl, fiuoroethynyl, chloroethynyl, bromoethynyl, propynyl, trifluoropropynyl, butynyl, hexynyl, and the like, or

R 9 is, methyl or ethyl; and Z is a single or double bond.

The conjugates of the compounds of Formulas IF and IIF corresponding to compounds of Formulas IIIC and IVC have high oral anti-fertility and estrogenic activity. They are preferably administered orally but can be administered parenterally in the same manner and dosage as estradiol and when administered orally are used in the same manner as ethynylestradiol. The conjugates of this invention can be administered in any of the number of conventional pharmaceutical forms, and particularly in ones suited for oral administration, e.g. in solid form, such as in pills, powders, capsules, tablets, or the like, or in liquid form, such as syrups, emulsions, suspensions, and the like.

Representative estrogenic steroid conjugates according to this invention (of Formulas IIIC and IVC) can be prepared from the following exemplary ketones and aromatic ethers by the above procedure.

TABLE CF 3-methoxyestra-.1,3,5 (10)-trien-l7-one,

3-methoxyestra- 1,3,5 10) -trien-17 ,3-01,

B-methoxy-17u-ethyny1estra-1,3,5 10 )-trien- 17[3-ol,

3-methoxy-7a-methy1-17-ethynylestra-1,3,5 10) -trien- 17fi-ol,

3-methoxy-17j3-oyclopentoxyestrasl,3,5 (10)-triene,

B-hydroXyestra-I3,5610),7-tetraen-17-one Representative progestational steroids within Formula IC can be' represented (IIIG) In the-above formulas,

by the following formulas:

(IIG) 0mm C =O Rm R24 rvo) i1 is hydrogen or methyl; R is hydroxyor conventional hydrolyzable esters or ethers thereof;

R is methyl or ethyl;

wherein R219 and R each is hydrogen, chloro, or fiuoro; R R and R each is hydrogen, methyl, :fluoro, or

chloro;

in Formula IG when Z is a double bond, R is absent;

in Formula IVG when Z is a single bond, R can have either an a or B orientation; R and R each is hydrogen or, taken together, a

methylenergroup having the formula wherein R and R3 each is hydrogen, chloro, or-fluoro;

wherein R is hydrogen, chloro, or hydroxyl; and when R is hydrogen, R and R is hydrogen;

wherein R and R each is hydrogen or methyl, or

taken together with R is wherein R and R each is hydrogen, alkyl, or aryl, the latter two groups having up to eight carbons;

R is hydrogen, hydroxyl, or conventional hydrolyzable esters thereof; R is hydrogen or zfluoro;

Z and Z each is a single bond or double bond; and bond in Z is a single bond, double bond, or a single combination with a methylene group having mula wherein R and R each is hydrogen, chloro, or fluoro.

The conjugates of the compounds of Formulas IG- IVG, inclusive, corresponding to compounds of Formulas IHC and IVC are progestational agents useful in the treatment of menstrual disorders and fertility control and can be used in the same manner as 17a-acetoXy-6-chloropregna 4,-6 diene-3,20-dione (chloromadinone acetate). The l6-methylene species are particularly useful in estrus synchronization in domestic animals. These compounds are preferably administered orally but they can also be administered parenterally. In any mode of administration the conjugates can be used either alone or in conjunction with other medicinal agents, or in pharmaceutically acceptable, nontoxic compositions formed by the incorporation of any of the normally employed excipients.

Representative progestational steroid conjugates according to this invention (of Formulas IIIC and IVC) can be prepared from the following ketones by the above procedure.

TABLE G 6-chloro-17a-acetoXypregna-4,'6-dien-3p-o1-20 one, 6-chloro-17a-acetoxy-19-norpregna-4,6-dien-3fl-ol-20-one,

1a,2a-methylene-6-chloro-17a-acetoxypregna- 4,6-dien-3fl-ol-20-one,

G-methyl-17a-acetoxypregna-4,6-dien-3 3-ol-20-one, 6-methy1-17a-acetoxy-19 norpregna-4,-6-dien-3B-ol-20-one, 6-ch1oro-16-methylene-17u-acetoxypregna-4,6-dien- 3 B-ol-20-one,

6-methyl-1tS-methylene-17at-acetoxypregna-4,6-dien- 16m,17u-isopropylidenedioxypregn-4-en-3fi-ol-20-one,

'31 Other conjugates included within Formulas IIIC and IVC can be prepared from the following exemplary drug ketones and aromatic ethers by the above procedure.

TABLE H Z-Bornanone Anesthetic, expectorant. 3-diethylcarbamoyl-l-methylpyridini- Analeptic, respiratory and umcamphor sulionate. circulatory stimulant.

Carbomycin Antimicrobial.

Cedrin Antimalarial. Chlortetracycline- Antimicrobial. Toylmycin Antimicrobial, antimctabohte.

7-chloro-4-(dimethylamino)-1,4,4a,5,5a, Antimicrobial.

6,11,12a-ctahydro-3,6,l0,12,12apenta- Y hydroxy-N-(hydroxymethyD-G- methyl-1,1l-dioxo-2-naphthaceneearboxamide. Coumingine Cardiac tonic and stimulant. 7-Chloroodemethyltctracyclinm Antimicrobial. Dihydrocodenione Antitussive, analgesic. 4 (diruethylamino)-1,4,4a,6,5a,6,11,12a- Antimicrobial.

octahydr0-3,5,10,12,12a-pentahydroxy-6-methyl-1,ll-dioxo-Z-naphthaeenecarboxamide. Erythromycin A Antimicrobial. Erythrornycin estolate D0. Frequentin Do. 4-meth0xy-B-methyl-o-phthalaldehyde- Antifungal antibiotic.

B-carboxylic acid. 3B-hydroxy-11-oxo0lean-12-en-30-oic acid. Used in treatment of Addison's disease.

Griseolulvin Antihmgal antibiotic. Isogriseofulvin D 0. Dihydromorphinone- Analgesic. Hydroxycodeine Do. 14-hydroxycodeneinone Do. 2-(Z-hydroxy-l-naphthyl)-cyc1ohexa- Antitussive.

none. 1,3,4,6 8,13-Hexahydr0xy-10,11-di- Antidepressant.

methylphenanthro-[l,10,9,8-0pqra] perylene-7,14-dione. 64sopropyl-3-methyl-2-cyelohexene-1- CNS stimulant.

one. -hydroxy-1,4-naphthoquir1one Antihernorrheic activity. 4,9-dimethoxy-7-methyl-5H-Iuro [3,2-g] Coronary vasodilator, broncho [1]ben zopyran-Mme. dilator. 2-hydroxy-3-(3-methyl-2-butenyl) -1,4- Antimalarial.

naphthoquinone.

2-hydroxy-3-(9-hydroxy-9- Do.

pentyltetradecyl)-1,4-naphthoquinone. Lucensomycin Antifungal agent. N -lysinomethyltetracycline Antimicrobial. 2 methyl-lA-naphthoquinone Prophylaxis. Menadinone carboxymethoxime Do.

ammonium salt. -(dimethylamino)-l,4,4a,5,5a,6,11,12- Antimicrobial.

octahydro'3,6,10,12,12a-pentahydroxy- N-{ [4-(2-hydroxyethyl) -1-pip erazinylJ- methyll-(i-methyl-Lll-dioxo-2 naphthacyeineearboxamido. -dimethylamino-l,4,4a,5,5a,6,11,12a- Do.

octahydro-3,5,i0,12,12a-pentahydroxy- 6-methylene-1,ll-dioxo-Z-naphthacenecarboxamide. Methyldihydromorphenone Analgesic. Methy'mycin Antimicrobial. 3,3-diethyl-5-methyl-2,4 sedative.

piperidinedione. Mikamycin Antimicrobial. 1-N-allyl-7,8-dihydro-l4- Narcotic antagonisthydroxynorphenone. Dihydrohydroxycodetnone Analgesic. Dihydrohydroxymorphenone o. 2-hydroxy-3-pinanone For respiratory insufficiency. 4-(dimethylamino) -1,4,4a,5,5a,6,11,12a- Antimicrobial.

octahydro-3,5,6,10,12,12a-hexahydroxy6-methyl-1,11-dioxo-2- naphthaceneearboxamide. 2-(l-cyclopentene-1-yl)-2-(2- Antitusslve.

morpholinoethyl)cyciopentanone. Perivine-'. Antimetabolite. Pirnaricin Antimicrobial. Z-(piperidinomethyl)eyclohexanone. Respiratory stimulant. 3,3-diethyl-2,4-dioxopiperidine sedative, antitussive. Protstaglandins (E1, E2, E3, F, PGF Smooth muscle stimulant.

e c. 3,3,4,5,7-pentahydroxyfiavone Decreases capillary fragility. N,N-diethylrifomycin B amide Antimicrobial. Riiomycin (B, S, 0, SB, X, AG, etc.).- Do. 4r(d.imethylamino)-1,4,4a,5,5a,6,11,12a- Do.

oetahydro-3,6,10,12,12a-pentahydroxy- 6-methyl-1,11-dioxo-N-(1- pyrrolidinylmethyD-Z- naphthacenecarboxamide. 4-(di1nethylamino)-1,4,4a,5,5a,6,11,12a- Do.

octahydrrr3,10,12,12a-tetrahydroxy- 1,11-dioxo-2-naphthacenecarboxamide. Decahydro-4a,7,9-trihydroxy-2-methyl D0.

6,8-bis(methylamino) 4H-pyranol2,3-b] [1,41-benxodiozin-4-one. Spimmycin (I, II, III, the correspond- Do.

ing acetates, ete.). Staphylomycin (M1, S, etc.) Do. Tetracycline Do. Thiocolchicine Muscle relaxant. a-methylcahromone. Antispasmodic, coronary vasodilator. Viridin- Antifungal agent.

2-methy1-3 hyty 4-naphthoquinono Prophylaxis.

32 The compounds of Formula II can be prepared 'bya procedure which can be represented as follows:

In the above formulas, D and R are as previously defined.

In the above procedure, the ketones of Formula I] are reacted with glycerol and dry methyl orthoformate in a suitable inert organic solvent in the presence of perchloric acid to yield the glycerol ketals of Formula II]. The latter compounds are then esterified by reaction with a fatty acid in. a -pyridine solution containing p-toluenesulfon ic acid to yield the compounds of Formula 111].

Included within Formula 1111 are conjugated ketals of anabolic steroids of Formulas ID, IID, IIID, IVD and VD and exemplary compounds, listedin Table D; of corticoid steroids of Formula IE and exemplary compounds listed in Table F supra; and of progestational steroids of Formula I6, I16, IIIG and IVG and exemplary compounds listed in Table G supra. Also included within Formula III] are conjugated ketals of other drug ketones exemplified by the ketones listed in Table H, supra.

The preferred conjugated ketals of steroids of Formula III] are derived from steroid ketones (corresponding to Formula II) represented by the formulas by the above In the above formulas,

R and R each is hydrogen or methyl; 1 R is hydrogen, lower alkyl, cyclopropyl, lower alkenyl,

lower alkynyl or propadienyl; OR is hydroxy or a conventional hydrolyzable ester thereof; R is hydrogen, chloro, fluoro or methyl; R is dihydrogen, dihalomethylene, preferably dichloromethylene or difluoromethylene, but is not present if Z is a double bond; I R is hydrogen, methyl or methylene; OR is hydroxy or a conventional hydrolyzable ester thereof; and Z is a single bond or a double bond but is a single'bond if R is present.

The ketal conjugates of the compounds of Formula IVJ wherein R is hydrogen, lower alkyl or cyclopropyl are anabolic agents with a-favorable antiboliczandrogenic ratio, also possess anti-estrogenic, antigonadotropic, and anti-fibrillitory activities, and can be orally administered for the same purposes as testosterone. The ketal conjugates of the compounds of Formula IVJ wherein R is lower alkenyl, lower alkynyl, or propadienyland the compounds of Formula VJ ,are progestational agents useful in the treatment of menstrual disorders and fertility control and can be orally administeredfor the same purposes as 17a aeetoxy 6 chloropregna 4,6 dien 3,20 dione (chloromadanone acetate). These compounds are preferably administered orally, but they can also be administered by other routes. These compounds are administered either alone or in conjunction with other medicinal agents or in pharmaceutically acceptable, non-toxic compositions formed by the incorporation of any of the normally employed excipients. v

The preferred process for preparing ketal conjugates of ketones of Formula IV] and certain ketones of Formula VJ can be represented as follows:

HzC-O Ego 4) (VIK) Hg C O R In the above formulas,

R R R and R are as previously defined, and R is a fatty acyl group.

The 3,3-(3-hydroxymethyl-1,2-propylenedioxy) compounds of Formulas UK and VK are preferably prepared by reacting the respective 3-keto compounds of Formulas IK and IVK with glycerol and dry methyl orthoformate under nitrogen at room temperature in a suitable inert organic solvent such as diglyme in the presence of perchloric acid. The glycerol ketals of Formulas IIK and VK can be reacted with a fatty acid in a pyridine solution containing p-toluenesulfonic acid to yield the 3,3-[3-(fatty acyloxy)-1,2-propylenedioxy] compounds of Formulas IIIK and VIK.

The other ketal conjugates of ketones of Formula VJ are preferably prepared by a process illustrated as follows:

in the above formulas,

R R R R R and Z are as previously defined.

The glycerol ketals of Formula VIIIK are prepared by reacting the 3-keto compounds of Formula VIIK with glycerol in a chloroform solution in the presence of p-toluenesulfonic acid at reflux until the reaction is eventually complete, that is, preferably about 36 hours. The glycerol ketals of Formula VZIIIK are esterified to form the corresponding fatty esters of Formula IXK by reaction at room temperature with the desired fatty acyl chloride in pyridine which can, if desired, contain additional solvent such as dioxane. Usually from 5 minutes to 1 hour are suflicient for completion of the reaction.

The compounds of Formula III can be prepared by a procedure which can be represented as follows:

In the above formulas, D R and R are as previously defined.

In the above procedure, the compounds of Formula IL (suitable protected) are reacted with potassium or sodium isopropylidene glycerate in a mixture of pyridine and a lower alkanol such as ethanol. While the mixture is maintained at a temperature of 0 C. or lower, a solution of p-toluenesulfonyl chloride in pyridine is added, and the mixture is then allowed to warm to room temperature. The compounds of Formula IIL are then separated from the reaction mixture by conventional techniques such as by diluting the reaction mixture with water to precipitate the product which can be separated by filtration or the like, extraction, crystallization, chromatography and combinations of these techniques.

The isopropylidene ether group is then cleaved by conventional acid treatment such as with a strong mineral or organic acid, e.g. trifluoroacetic acid, to yield the compounds of Formula IIIL. These are reacted with the desired fatty acyl chloride or chlorides in an inert organic solvent such as chloroform or carbon tetrachloride in the presence of an organic base such as triethylamine or pyridine followed by conventional purification procedures to yield the compounds of Formula IVL.

In the above procedure, it may be necessary to protect reactive groups to increase the yield of the desired prodnets, and such conventional procedures can be used as are routinely followed for this purpose.

l'ncluded within Formula IVL are conjugates of 2-naphthyl-ethanol derivatives corresponding to Formula IL. Suitable Z-naphthylethanol derivatives which are included within Formula IL have been previously described together with methods for their preparation in U.S. patent application Ser. No. 741,904, filed July 2, 1968. These can be represented by the following formulas:

R303 R303 R303 R302 R304 CHzOH CHzOH (1M) (IIM) ana 302 CH2OH (IIIM) wherein,

oneof R and R is hydrogen, the other is hydrogen, methyl, ethyl or difluoromethyl; or R and R taken together are methylene, halomethylene or ethylene;

R (at position C-l,4,5,7 or 8) is hydrogen, alkyl, trifluoromethyl, fluoro, chloro, hydroxy, a conventional hydrolyzalble ester, oxyether or thioether;

R is alkyl, cycloalkyl, hydroxymethyl, alkoxymethyl, trifluoromethyl, vinyl, ethynyl, fluoro, chloro, hydroxy, a conventional hydrolyzable ester, oxyether, thioether, formyl, acetyl or aryl; and

each of R and R (at position C-1,4,5,7 or 8) is alkyl, fluoro, chloro, hydroxy, a conventional hydrolyzable ester, oxyether, or thioether; provided that when one of R and R is hydroxy, oxyether or thioether, the other is the identical group or alkyl, fluoro, chloro or a conventional hydrolyzable ester.

An especially preferred group of compounds are conjugates of compounds of Formulas IM, HM and HIM including fl-[Z-naphthyH-ethanol, ,6 [2 naphthyl]-fimethylethanol, p [2 naphthyl] p difluoromethylethanol, ,3 [2 naphthyl] 18,18 methyleneethanol, t?- [Z naphthyl] 5,,8 difiuoromethyleneethanol and the C-5, 6- or 7-methyl, -fluoro, -cholo, trifluoromethyl, -methoxy and -methyl thio derivatives thereof.

When one of R and R is hydrogen and the other is methyl, ethyl or difluoromethyl, the compounds of.

Formulas IM, HM and HIM can exist as pairs of enantiomorphs. Conjugates of each of the optical isomers thereof are included within the present invention. In some instances, one conjugated enantiomorph exhibits greater antiinflammatory, analgesic, anti-py-retic and/or anti-pruritic activity than the other conjugated enantiomorph. For example, conjugates of the levorotatory form, the 1 or form, of ,8-(6-methoxy 2- naphthyl)-,3-methylethanol exhibits greater anti-inflammatory activity than conjugates of the corresponding dextrorotatory form.

Preferably, the resolved compounds of Formulas IM, HM and IIIM can be prepared from the corresponding resolved acid starting compounds used to prepare the compounds of Formulas IM, HM and 'I'IIM. The resolved compounds of Formulas IM-IIIM and their respective resolved starting compounds will not necessarily have the same optical rotation although they will have the same absolute configuration. For example, 1 /3-(6-methoxy 2 naphthyl) p methylethanol is prapared from d '6-methoxy-2-naphthyl-a-methyl' acetic acid.

The conjugates of the compounds of Formulas IM, HM and HIM exhibit anti-inflammatory, analgesic, antipyretic and anti-pruritic activity in mammals. These conjugates are useful in the treatment of inflammation of the skin, respiratory tract, muscular skeletal system, joints, internal organs and tissues. Accordingly, these compounds are useful in the treatment of conditions characterized by inflammation, such as contact dermatitis, allergic conditions, burns, rheumatism, contusion, arthritis, bone fracture, post-traumatic conditions and gout. In those cases in which the above conditions include pain, pyrexia, and pruritus, coupled with the inflammation, the instant compounds are useful for relief of these conditions as well as the inflammation. For example, the instant compounds are useful in the treatment of pain associated with post-operative conditions, post-traumatic conditions, post-partum conditions, dysmenorrhea, burns, gout, contusions, neuralgia, neuritis, headaches and rheumatic fever. As stated above, these compounds also exhibit antipyretic activity, accordingly, these compounds are useful in the treatment of pyrexia where reduction of a fever is indicated, for example, cases where high fever is associated with diseases such as rheumatic fever, bronchitis, pneumonia, typhoid fever, Hodgkins disease, and the like. The present compounds are also useful in the treatment of pruritus where the condition exists contemporaneously with inflammation, pain and/or high fever. Moreover, the compounds are useful for treating pruritus per se.

The compounds of Formulas IM, HM and IIIM are prepared from the corresponding 2-naphthyl acetic acid derivatives or esters thereof (described supra Formulas IAVIIIA) via a process which can be illustrated as follows:

C O O R C HzQH (VIM) (VIIM) In the above formulas,

R and R are as defined above and R is hydrogen or alkyl. In the above scheme, the naphthyl moiety of the compounds of Formula VIM, naphthyl acetic acid derivatives and esters thereof, and the naphthyl moiety of the compounds of Formula VIIM, -[2- naphthyl] ethanol derivatives, can be substituted with an R group at position C-1,4,5,7 or 8; or an R group at position C6 or an R group at position C6 and an R group at position C-1,4,5,7 or 8 corresponding to these groups as described with respect to Formulas IM, IIM, and IIIM, supra.

The process is conducted by treating the compound of Formula VIIM with lithium aluminum hydride. If the free carboxylic acid form of the compound of Formula VIM (wherein R is hydrogen) is used as a starting material, at least 0.75 molar equivalents of lithium aluminum hydride are used, and preferably about 1.0 to 2.5 molar equivalents are used. If the ester form of the compound of Formula VIM (wherein R is alkyl) is used as a starting material, at least 0.5 molar equivalents of lithium aluminum hydride are used, and preferably about 0.6 to 2.0 molar equivalents are used. The novel process is carried out in an inert organic ether, such as diethyl ether, dipropyl ether diisopropyl ether, di'butyl ether, tetrahydrofuran, or the like. The reaction is carried out at a temperature between 0 C. and the boiling point of the solvent employed, preferably between 15 C. to 35 C.

The compound of Formula VIIM is isolated by destroying the excess lithium aluminum hydride, if any, such as by the addition of excess ethyl acetate, or aqueous solutions of sodium hydroxide or ammonium chloride. The mixture is then diluted with water, filtered and extracted with an inert organic solvent immiscible with Water. The compound of Formula VIIM can be further purified by standard techniques, such as crystallization, chromatography, etc.

Alternatively, the compounds of Formula VIM can be reduced by treating them with diborane in tetrahydrofuran at a temperature between about 0 C. and about 65 C.

Certain groups present on the starting compound of Formula VIM are are reduced by lithium aluminum hydride or diborane. For example, an acetyl group is reduced to an a-hydroxy ethyl group and a formyl group is reduced to a hydroxy methyl group. These reduced groups are regenerated after completion of the above novel process via an oxidation process using manganese dioxide (active) in an inert organic solvent, such as acetone, petroleum ether, and the like, at about room temperature.

When a resolved enantiomorph of Formula VIM is employed as starting material in the above process, the corresponding resolved enantiomorph of Formula VIIM is obtained. As stated above, although the absolute configuration of the Z-naphthyl acetic acid starting compound and the corresponding [3-[2-naphthyl]-ethanol product Will be identical, the optical rotation of the starting compound and product will not necessarily be the same.

Representative conjugates of Z-naphthylethanol derivatives of Formula IVL can be prepared as described above from the following exemplary Z-naphthylethanol derivatives corresponding to Formulas IM, HM and IIIM.

TABLE J 1,8- (6-methoxy-2-naphthyl -B-methylethanol,

38 fi-(l-methoxy-Z-naphthyl) ethanol, f3-(4-difluoromethylthio-Z-naphthyl)-l3-methylethanol, 3-(S-methylthio-Z-naphthyl)-fl-methylethanol, ,B-(S-chloro-Z-naphthyl) ethanol,

5- 5-trifluoromethyl-Z-naphthyl) -fi,;3-difiuoromethyleneethanol,

fl-(G-methyl-Z-naphthyl) ethanol,

fl-(6-methoxy-2-naphthyl) ethanol,

,6- (6-difiuoromethoxy-Z-naphthyl) 8- difiuoromethylethanol,

3- 6-methoxy-2-naphthyl 8-ethylethanol,

3-(6-chloro-2-naphthyl)- 3-methylethanol,

B-(7-methoxy-2-naphthyl)-fi-methylethanol,

fl-(7-methylthio-2-naphthyl)-B-ethylethanol,

5- (7- chloro-2-naphthyl 13, ,B-methyleneethanol,

[3- 8-trifiuoromethyl-2-naphthyl) -B,5-methyleneethanol,

[3-(5,6-dimethyl-2-naphthyl)/3-methylethanol,

fl- S-methoxy-Z-naphthyl) -B-methylethanol,

B-(S-methyI-Z-naphthyl)-B-methylethanol,

fi-(S-methoxy-Z-naphthyl) ethanol,

1% G-methyl-Z-naphthyl) -B-methylethanol,

[3-(6-chl0r0-2-naphthy1) -B-difluoromethylethanol,

fi- 6-methylthio-2-naphthyl -fl, 3-methyleneethanol,

fl- 6-trifiuoromethyl-Z-naphthyl -,6-methylethanol,

,6- 7-rnethyl-2-naphthyl) -,B-methylethanol,

fl-(7-trifluoromethyl-Z-naphthyl)-/3-methylethanol,

3- 4-ethoxy-2-naphthyl) -[i,,8-ethyleneethanol,

B- 6,7 -dimethoxy-2-naphthyl) 3-methylethanol,

fi-(8-hydroxy-2-naphthyl)-;3-ethylethanol,

13- (4-acetoxy-2-naphthyl) -B,;8-difiuoromethyleneethanol,

5- S-methoxymethyloxy-Z-naphthyl) -B-ethylethanol,

fl-(5-isopropyl-2-naphthyl) ethanol,

,6- 6-vinyl-2-naphthyl) -,8-methylethanol,

18-(6-acetyl-2-naphthyl) ethanol,

,H- 7-acetoxy-2-naphthyl -/3-difiuoromethylethanol,

5- [8- (4'-methoxytetrahydropyran-4'-yloxy) -2-naphthyl1- B-methylethanol, and

fi-(6,7-dirnethyl-2-naphthyl)-,8-methylethanol.

Included within Formula IVL are conjugates of steroid alcohols corresponding to Formula IL. Suitable steroid alcohols are described together with methods for their preparation in US. patent applications Ser. No. 731,300,

filed May 22, 1968; Ser. No. 731,301, filed May 22, 1968, and Ser. No. 731,267, filed May 22, 1968, and US. Pat. Nos. 3,365,446; 3,067,194 and 3,364,203.

Representative anabolic steroids corresponding to Formula IL can be represented by the following formulas:

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