Novel anti-inflammatory agents, pharmaceutical compositions and methods for reducing inflammation

Compounds and diastereomeric mixtures of specific 2-naphthyl-containing ester compounds, especially naproxen ester and naproxol ester compounds, having two or more chiral centers. These compounds are effective as anti-inflammatory agents, analgesic agents, and/or antipyretic agents. They are readily absorbed as the diastereomeric mixture, especially through the skin following topical application.

BACKGROUND OF THE INVENTION 
The present invention relates to compounds and diastereomeric mixtures of 
naproxen esters or naproxol esters. Diastereomeric mixtures of these 
esters are more readily absorbed by humans or lower animals, especially 
through the skin when applied topically, than naproxen or ester 
derivatives which are not diastereomeric mixtures. The present invention 
also relates to pharmaceutical compositions, especially pharmaceutical 
compositions in a form suitable for topical delivery, containing a 
diastereomeric mixture of a naproxen ester or naproxol ester. The present 
invention finally relates to methods for treating or preventing 
inflammation in humans or lower animals by administering, especially 
topically to skin, a diastereomeric ester mixture or a pharmaceutical 
composition of the present invention. 
The search for new non-steroidal anti-inflammatory ("NSAI") drugs over the 
past ten to twenty years has led to the testing by various researchers and 
companies of thousands of compounds for efficacy as anti-inflammatory 
agents. One compound which has been identified as being a good NSAI drug 
is (S)-2-(6-methoxy-2-naphthyl)propionic acid, commonly referred to as 
"naproxen". Naproxen and various derivatives of naproxen (e.g., the 
alcohol (i.e., "naproxol") and aldehyde derivatives, and certain esters of 
naproxen) have been shown to have anti-inflammatory activity when 
administered orally. Such disclosures are contained, for example, in 
Harrison et al., "Nonsteroidal Anti-inflammatory Agents. I. 6-Substituted 
2-Naphthylacetic Acids", J. Med. Chem., 13, pages 203-205 (1970); U.S. 
Pat. No. 3,641,161, to Fried et al., issued Feb. 8, 1972; U.S. Pat. No. 
3,792,167, to Fried et al., issued Feb. 12, 1974; U.S. Pat. No. 3,562,336, 
to Nelson, issued Feb. 9, 1971; Great Britain Patent Specification No. 
1,297,306, to Syntex Corporation, published Nov. 22, 1972; U.S. Pat. No. 
3,958,012, to Fried et al., issued May 18, 1976; U.S. Pat. No. 3,637,767, 
to Alvarez, issued Jan. 25, 1972; and U.S. Pat. No. 3,896,157, to Fried et 
al., issued July 22, 1975; the disclosures of all of these publications 
being incorporated herein by reference in their entirety. Straight chain 
fatty acid esters of the alcohol derivative of naproxen ("naproxol 
esters") have been disclosed in Great Britain Patent Specification No. 
2,050,363, published Jan. 7, 1981 by Del Bono, the disclosures of which 
are incorporated by reference herein in their entirety. Phenyl 
ring-containing esters of naproxen and naproxol have also been disclosed, 
for example, in U.S. Pat. No. 3,787,580, to Fried et al., issued Jan. 22, 
1974, the disclosures of which are incorporated by reference herein in 
their entirety. 
Furthermore, glycerol esters of naproxen are known, having been disclosed 
in Belgian Patent Specification No. 903,569, published Feb. 17, 1986, by 
Rainoldi, and U.S. Pat. No. 3,686,238, to Zaffaroni, issued Aug. 22, 1972, 
the disclosure of both these publications being incorporated herein by 
reference in their entirety. Esters of naproxen having two chiral centers 
in the alcohol portion of the ester are known for use for optical 
resolution of naproxen and are said to have pharmacological activity, as 
described in European Patent Application Publication No. 158,255, 
published Oct. 16, 1985, by Giordano et al. There is no disclosure of 
topical application of these compounds. 
Finally, European Patent Application Publication No. 112,130, published 
June 27, 1984, by Ladkani et al., discloses ethoxy-carbonyloxy ethyl 
esters of NSAI substances having a carboxylic acid function. These 
compounds are said to be prodrugs of the corresponding NSAI substances, 
and are generally said to be readily absorbed from the digestive tract and 
through skin following topical application. This publication discloses the 
ethoxy-carbonyloxy ethyl ester of naproxen. There is no disclosure of this 
ester of naproxen being formulated into a form suitable for topical 
application; being more or less readily absorbed through skin when applied 
as a diastereomeric mixture; or being applied topically to skin. 
Notwithstanding the great effort already put forth to identify NSAI drugs, 
particularly with regard to naproxen derivatives, there remains a 
continuing need to identify new compounds and compositions which are 
effective for treating inflammation and inflammatory diseases such as 
rheumatoid arthritis and osteoarthritis. It is accordingly an object of 
the present invention to provide compounds and diastereomeric mixtures of 
compounds which are effective anti-inflammatory agents, as well as 
pharmaceutical compositions (especially compositions suitable for topical 
application) containing these compounds and diastereomeric mixtures. 
Another object of the present invention is to provide compounds and 
diastereomeric mixtures which are easy to synthesize, formulate, and 
administer. It is a further object of the present invention to provide 
methods for treating diseases characterized by inflammation. It is also an 
object of the present invention to provide compounds which are useful as 
anti-inflammatory agents, analgesic agents, and/or antipyretic agents. An 
additional object is to provide compounds and compositions which are 
readily absorbed, especially through the skin following topical 
application. 
These and other objects will become readily apparent from the detailed 
description which follows. 
All percentages and ratios used herein are by weight unless otherwise 
specified. 
SUMMARY OF THE INVENTION 
The present invention relates to specific 2-naphthyl-containing ester 
compounds, especially naproxen ester and naproxol ester compounds, having 
two or more chiral centers. These compounds are effective as 
anti-inflammatory agents, analgesic agents, and/or antipyretic agents, and 
are readily absorbed as the diastereomeric mixture, especially through the 
skin following topical application. These compounds comprise the general 
structures: 
##STR1## 
wherein R.sup.1 is a 2-naphthyl residue of a naproxen-like compound having 
anti-inflammatory or analgesic activity; R is a C.sub.4 -C.sub.7 
unsubstituted alkyl group having at least one chiral center or a C.sub.1 
-C.sub.7 substituted alkyl group having at least one chiral center wherein 
the substituents are independently selected from halogen, --OR.sup.2, 
--SR.sup.2, --NHR.sup.2, --N(R.sup.2).sub.2, or combinations thereof; and 
each R.sup.2 is independently selected from unsubstituted alkyl groups 
having from about 1 to about 5 carbon atoms. 
The present invention further relates to diastereomeric mixtures of the 
ester compounds having the general formula described hereinbefore. 
The present invention also relates to pharmaceutical compositions, 
especially compositions suitable for topical application. These 
pharmaceutical compositions comprise a diastereomeric mixture of the ester 
compounds of the present invention and a pharmaceutically-acceptable 
carrier, especially a carrier suitable for topical application. 
Finally, the present invention relates to methods for treating diseases 
characterized by inflammation, such as rheumatoid arthritis and 
osteoarthritis, in humans or lower animals. Such methods comprise 
administering (especially topically to skin) to a human or lower animal in 
need of such treatment a safe and effective amount of a diastereomeric 
mixture or pharmaceutical composition of the present invention.

DETAILED DESCRIPTION OF THE INVENTION 
Anti-Inflammatory Agents 
The compounds useful in the present invention are specific 
2-naphthyl-containing ester compounds, especially naproxen ester or 
naproxol ester compounds, having two or more chiral centers. The compounds 
are useful as anti-inflammatory agents, analgesic agents, and/or 
antipyretic agents. They are readily absorbed, especially through the skin 
following topical application, as their diastereomeric mixture. 
The compounds of the present invention comprise the general structures: 
##STR2## 
wherein R.sup.1 is a 2-naphthyl residue of a naproxen-like compound having 
anti-inflammatory or analgesic activity; R is a C.sub.4 -C.sub.7 
unsubstituted alkyl group having at least one chiral center or a C.sub.1 
-C.sub.7 substituted alkyl group having at least one chiral center wherein 
the substituents are independently selected from halogen, --OR.sup.2, 
--SR.sup.2, --NHR.sup.2, --N(R.sup.2).sub.2, or combinations thereof; and 
each R.sup.2 is independently selected from unsubstituted alkyl groups 
having from about 1 to about 5 carbon atoms. The term "2-naphthyl residue 
of a naproxen-like compound", as used herein, means the naphthyl ring 
structure portion of a substituted or unsubstituted 2-naphthyl propionic 
acid compound, (e.g., naproxen) which demonstrates anti-inflammatory 
and/or analgesic activity. Such 2-naphthyl propionic acid compounds are 
known, having been disclosed for example in U.S. Pat. No. 3,686,238, to 
Zaffaroni, issued Aug. 22, 1972; U.S. Pat. No. 3,637,767 to Alvarez, 
issued Jan. 25, 1972; U.S. Pat. No. 3,896,157, to Fried et al., issued 
July 22, 1975; and Harrison et al., "Non-steroidal Anti-inflammatory 
Agents I. 6-Substituted 2-Naphthyl-acetic Acids," J. Med. Chem., 13, pages 
203-205 (1970); the disclosures of these publications being incorporated 
herein by reference in their entirety. Preferred R.sup.1 is a 
6-methoxy-2-naphthyl moiety. 
The R moiety is a C.sub.4 -C.sub.7 unsubstituted alkyl group having at 
least one chiral center or a C.sub.1 -C.sub.7 substituted alkyl group 
having at least one chiral center. Preferred R groups contain only one 
chiral center. The term "alkyl", as used herein, means carbon-containing 
chains which may be straight, branched, or cyclic; and which may be 
saturated, monounsaturated (i.e., one double or triple bond in the chain), 
or polyunsaturated (e.g., two double bonds in the chain; two triple bonds 
in the chain; one double and one triple bond in the chain). 
The R alkyl groups may be substituted or, preferably, unsubstituted. 
Substituents are selected from the group consisting of halogen, 
--OR.sup.2, --SR.sup.2, --NHR.sup.2, and --N(R.sup.2).sub.2, wherein 
R.sup.2 is an unsubstituted alkyl group having from about 1 to about 5 
carbon atoms (especially methyl and ethyl). It is preferred that 
substituted alkyl groups be C.sub.2 -C.sub.7 mono-substituted alkyl group. 
More preferred R groups are unsubstituted, saturated alkyl groups having 
from about 4 to about 7 carbon atoms. Examples of R groups include 
2-butyl, 2-pentyl, 2-methyl-1-butyl, 2-hexyl, 3-hexyl, 2-methyl-1-pentyl, 
3-methyl-1-pentyl, 2-heptyl, 3-heptyl, 2-methyl-1-cyclopropyl, 
2-methyl-1-cyclopentyl, 2-but-3-enyl, 1-methoxy-1-ethyl, 
1-methoxy-2-propyl, 1,3-dimethoxy-2-butyl, 1-(N,N-dimethylamino)-2-propyl, 
1-(N-methylamino)-3-butyl, 1-thiomethyl-1-ethyl, and 
1-(thiomethyl)-3-butyl. Preferred R groups are 2-butyl, and 2-pentyl. The 
most preferred R group is 2-butyl. 
Preferred compounds of the present invention have the structures: 
##STR3## 
wherein R is as described hereinbefore. 
Compounds of the present invention include, for example: 
(S)-naproxen-(S)-2-butyl ester; (S)-naproxen-(R)-2-butyl ester; 
(R)-naproxen-(S)-2-butyl ester; (R)-naproxen-(R)-2-butyl ester; 
(S)-naproxen-(S)-2-pentyl ester; (S)-naproxen-(R)-2-pentyl ester; 
(S)-naproxen-(S)-2-hexyl ester; (S)-naproxen-(R)-2-hexyl ester; 
(S)-naproxen-(S)-1-methoxy-2-propyl ester; 
(S)-naproxen-(R)-1-methoxy-2-propyl ester; 
(S)-5-bromo-naproxen-(S)-1-(N,N-dimethylamino)-2-propyl ester; 
(S)-5-bromo-naproxen-(R)-1-(N,N-dimethylamino)-2-propyl ester; 
(S)-naproxol-(R)-2-methyl butyrate; (S)-naproxol-(S)-2-methyl butyrate; 
(R)-naproxol-(R)-2-methyl butyrate; (R)-naproxol-(S)-2-methyl butyrate; 
(S)-naproxol-(R)-2-methyl pentanoate; (S)-naproxol-(S)-2-methyl 
pentanoate; (S)-naproxol-(R)-2-methyl-3-methoxy propanoate; 
(S)-naproxol-(S)-2-methyl-3-methoxy propanoate; 
(S)-naproxol-(R)-2-methyl-3-chloro propanoate; 
(S)-naproxol-(S)-2-methyl-3-chloro propanoate; 
(S)-naproxol-(R)-2-methyl-3-methoxy propanoate; 
(S)-naproxol-(S)-2-methyl-3-methoxy propanoate; 
(S)-5-bromo-naproxol-(R)-2-methyl butyrate; and 
(S)-5-bromo-naproxol-(S)-2-methyl butyrate. 
Preferred compounds of the present invention include: 
(S)-naproxen-(S)-2-butyl ester; (S)-naproxen-(R)-2-butyl ester; 
(S)-naproxen-(S)-2-pentyl ester; (S)-naproxen-(R)-2-pentyl ester; 
(S)-naproxol-(R)-2-methyl butyrate; (S)-naproxol-(S)-2-methylbutyrate; 
(S)-naproxol-(R)-2-methyl pentanoate; and (S)-naproxol-(S)-2-methyl 
pentanoate. 
Most preferred compounds of the present invention are: 
(S)-naproxen-(S)-2-butyl ester; (S)-naproxen-(R)-2-butyl ester; 
(S)-naproxol-(R)-2-methyl butyrate; and (S)-naproxol-(S)-2-methyl 
butyrate. 
For use in the compositions and methods of the present invention, the 
compounds of the present invention are utilized as diastereomeric 
mixtures. Preferred diastereomeric mixtures are those wherein the 
2-naphthyl-containing portion of the compound is only one enantiomer 
(e.g., for a naproxen-derived ester, this is the "S" absolute 
stereochemical configuration), and the R moiety portion of the compound 
utilized is a racemic mixture (i.e., both the "R" and "S" absolute 
stereochemical configurations; as described more fully in Morrison and 
Boyd, Organic Chemistry, Third Edition (Allyn and Bacon, Inc., Boston; 
1973), Chapters 4 and 7, pp. 115 and 225). It is preferred that each 
diastereomer have two chiral centers and that the diastereomers of the 
diastereomeric mixture be present in amounts within the range of from 
about 2:1 to about 1:2, and most preferably in about equal amounts to each 
other (i.e., a 1:1 mixture of diastereomers). 
Examples of such diastereomeric mixtures are: (S)-naproxen-(S)-2-butyl 
ester and (S)-naproxen-(R)-2-butyl ester; (R)-naproxen-(S)-2-butyl ester 
and (R)-naproxen-(R)-2-butyl ester; (S)-naproxen-(S)-2-pentyl ester and 
(S)-naproxen(R)-2-pentyl ester; (S)-naproxen-(S)-2-hexyl ester and 
(S)-naproxen-(R)-2-hexyl ester; (S)-naproxen-(S)-1-methoxy-2-propyl ester 
and (S)-naproxen-(R)-1-methoxy-2-propyl ester; 
(S)-5-bromo-naproxen-(S)-1-(N,N-dimethylamino)-2-propyl ester and 
(S)-5-bromo-naproxen-(R)-1-(N,N-dimethylamino)-2-propyl ester; 
(S)-naproxol-(R)-2-methyl butyrate and (S)-naproxol-(S)-2-methyl butyrate; 
(R)-naproxol-(R)-2-methyl butyrate and (R)-naproxol-(S)-2-methyl butyrate; 
(S)-naproxol-(R)-2-methyl pentanoate and (S)-naproxol-(S)-2-methyl 
pentanoate; (S)-naproxol-(R)-2-methyl-3-methoxy propanoate and 
(S)-naproxol-(S)-2-methyl-3-methoxy propanoate; and 
(S)-naproxol-(R)-2-methyl-3-chloro propanoate and 
(S)-naproxol-(S)-2-methyl-3-chloro propanoate; 
(S)-naproxol-(R)-2-methyl-3-methoxy propanoate and 
(S)-naproxol-(S)-2-methyl-3-methoxy propanoate; and 
(S)-5-bromo-naproxol-(R)-2-methyl butyrate and 
(S)-5-bromo-naproxol-(S)-2-methyl butyrate. 
Preferred diastereomeric mixtures are: (S)-naproxen-(S)-2-butyl ester and 
(S)-naproxen-(R)-2-butyl ester; (S)-naproxen-(S)-2-pentyl ester and 
(S)-naproxen-(R)-2-pentyl ester; (S)-naproxol-(R)-2-methyl butyrate and 
(S)-naproxol-(S)-2-methyl butyrate; and (S)-naproxol-(R)-2-methyl 
pentanoate and (S)-naproxol-(S)-2-methyl pentanoate. 
Most preferred diastereomeric mixtures are: (S)-naproxen-(S)-2-butyl ester 
and (S)-naproxen-(R)-2-butyl ester; and (S)-naproxol-(R)-2-methyl butyrate 
and (S)-naproxol-(S)-2-methyl butyrate. 
In order to determine and assess pharmacological activity, testing of these 
compounds in animals is carried out using various assays known to those 
skilled in the art. Thus, the anti-inflammatory activity of the compounds 
can be conveniently demonstrated using an assay designed to test the 
ability of these compounds to antagonize the local edema which is 
characteristic of the inflammatory response. Examples of such known tests 
include the carrageenan rat edema test, the oxazolone-induced inflamed 
mouse ear test, and the arachidonic acid-induced inflamed mouse ear test. 
Anti-pyretic activity may be tested using art-known rat models, and 
analgesic activity may be tested in art-known models such as the 
acetylcholine model in mice, the Randall-Selitto model in rats, and the 
hot-plate test in mice. Another useful art-known test is the adjuvant 
arthritis test which is a useful model for assessing anti-inflammatory 
activity and antiresorptive activity in a chronic, rather than acute, 
model. Certain tests for pharmacological activity are also described in 
more detail in the Examples provided hereinafter. 
The compounds of the present invention are prepared from 
commercially-available materials or readily synthesized materials by 
simple esterification techniques. The synthesis of naproxen and/or 
naproxol, and related 2-naphthyl-containing compounds, are disclosed, for 
example, in Harrison et al., "Nonsteroidal Anti-Inflammatory Agents. I. 
6-Substituted 2-Naphthylacetic Acids", J. Med. Chem., 13, pages 203-205 
(1970); U.S. Pat. No. 4,395,571, to Dvorak, issued July 26, 1983; European 
Patent Application Publication No. 158,255, published Oct. 16, 1985, by 
Giordano et al.; U.S. Pat. No. 3,792,167, to Fried et al., issued Feb. 12, 
1974; and U.S. Pat. No. 3,641,161, to Fried et al., issued Feb. 8, 1972; 
the disclosures of these patents and publications being incorporated 
herein by reference in their entirety. Representative procedures for 
synthesizing compounds and diastereomeric mixtures of the present 
invention are provided in the Examples hereinafter. 
As noted hereinbefore, a large number of naproxen derivatives and other 
2-naphthyl-containing compounds have been prepared and tested for 
pharmacological activity. Surprisingly, however, the compounds of the 
present invention are absorbed more readily as their diastereomeric 
mixture (especially through skin upon topical application) than naproxen 
or derivatives having the same number of carbon atoms but not a 
diastereomeric mixture. As a result of this greater bioavailability 
(especially topical bioavailability), the compounds of the present 
invention are therefore easy to formulate into forms which utilize lesser 
amounts or lesser concentrations of compound to get an effective dose. 
The diastereomeric mixtures of the present invention typically comprises 
from 0.1% to 99.9% by weight of the pharmaceutical compositions of the 
present invention, preferably from about 0.1% to about 75%, and most 
preferably from about 1% to about 50%. 
Pharmaceutically-Acceptable Carrier 
In addition to the anti-inflammatory agent as described hereinbefore, the 
pharmaceutial compositions of the present invention essentially contain a 
pharmaceutically-acceptable carrier, especially a 
pharmaceutically-acceptable carrier suitable for topical dose forms. The 
term "pharmaceutically-acceptable carrier", as used herein, means one or 
more compatible solid or liquid filler diluents or encapsulating 
substances which are suitable for administration to a human or lower 
animal. The term "compatible", as used herein, means that the components 
of the pharmaceutical composition are capable of being commingled with the 
anti-inflammatory agent, and with each other, in a manner such that there 
is no interaction which would substantially reduce the pharmaceutical 
efficacy of the pharmaceutical composition under ordinary use situations. 
Pharmaceutically-acceptable carriers must, of course, be of sufficiently 
high purity and sufficiently low toxicity to render them suitable for 
administration to the human or lower animal being treated. Some examples 
of substances which can serve as pharmaceutically-acceptable carriers are 
sugars such as lactose, glucose, and sucrose; starches such as cornstarch 
and potato starch; cellulose and its derivatives such as sodium 
carboxymethylcellulose; ethylcellulose, cellulose acetate; powdered 
tragacanth; malt; gelatin; talc; stearic acid; magnesium stearate; calcium 
sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, 
olive oil, corn oil, and oil of theobroma; polyols such as propylene 
glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; agar; 
alginic acid; pyrogen-free water; isotonic saline; and phosphate buffer 
solutions, as well as other non-toxic compatible substitutes used in 
pharmaceutical formulations. Wetting agents and lubricants such as sodium 
lauryl sulfate, as well as coloring agents, flavoring agents, excipients, 
tableting agents, stabilizers, antioxidants, and preservatives, can also 
be present. Other compatible pharmaceutical additives and actives, (e.g., 
other NSAI drugs; pain killers; muscle relaxant; counter irritants) may be 
included in the pharmaceutically-acceptable carrier for use in the 
compositions of the present invention. 
The choice of a pharmaceutically-acceptable carrier to be used in 
conjunction with the anti-inflammatory agents of the present composition 
is basically determined by the way the compound is to be administered. If 
the compound is to be administered orally, the preferred unit dosage form 
is tablets, capsules, and the like, comprising a safe and effective amount 
of the anti-inflammatory compound of the present invention. 
Pharmaceutically-acceptable carriers for the preferred topical application 
forms include those suitable for use in creams, gels, tapes, and the like. 
Pharmaceutically-acceptable carriers suitable for topical dose forms will 
depend on secondary considerations like cost, shelf stability, and 
cosmetic aesthetics, which are not critical for the purposes of the 
present invention, and can be made without difficulty by a person skilled 
in the art. 
Topical dose forms of the compositions of the present invention include 
lotions, creams, ointments, solutions, gels, solids and patches. These 
topical compositions comprise a safe and effective amount, usually from 
about 0.1% to about 75%, and preferably from about 1% to about 50%, of the 
compound of the present invention. Pharmaceutically-acceptable carriers 
suitable for topical dose forms to administer these compounds preferably 
remain in place on the skin as a continuous film and resist being washed 
off easily by perspiration or by immersion in water. Generally, the 
pharmaceutically-acceptable carrier suitable for topical dose forms is 
either organic in nature or an aqueous emulsion, and is capable of having 
the anti-inflammatory agent dispersed or dissolved therein. The carrier 
may include pharmaceutically-acceptable emollients, skin penetration 
enhancers, coloring agents, fragrances, emulsifiers, thickening agents, 
and solvents. A more detailed description of topical dose forms, and 
pharmaceutically-acceptable carriers suitable for topical dose forms, 
follows: 
1. Lotions 
The lotions can comprise an effective amount (preferably from about 0.1% to 
about 75%) of the compound of the present invention; from 1% to 25%, 
preferably from 3% to 15%, of an emollient; the balance being water, a 
C.sub.2 or C.sub.3 alcohol, or a mixture of water and the alcohol. Several 
emollients are known. Examples of such emollients are as follows: 
a. Hydrocarbon oils and waxes. Examples are mineral oil, petrolatum, 
paraffin, ceresin, ozokerite, microcrystalline wax, polyethylene, and 
perhydrosqualene. 
b. Silicone oils, such as dimethylpolysiloxanes, methylphenylpolysiloxanes, 
water-soluble and alcohol-soluble silicone-glycol copolymers. 
c. Triglyceride fats and oils such as those derived from vegetable, animal 
and marine sources. Examples include castor oil, safflower oil, cottonseed 
oil, corn oil, olive oil, cod liver oil, almond oil, avocado oil, palm 
oil, sesame oil, soybean oil, and cocoa butter. 
d. Acetoglyceride esters, such as acetylated monoglycerides. 
e. Ethoxylated glycerides, such as ethoxylated glyceryl monostearate. 
f. Alkyl esters of fatty acids. Methyl, isopropyl and butyl esters of 
C.sub.10 -C.sub.20 fatty acids are useful herein. Examples include hexyl 
laurate, isohexyl laurate, isohexyl palmitate, isopropyl palmitate, decyl 
oleate, isodecyl oleate, hexadecyl stearate, decyl stearate, isopropyl 
isostearate, diisopropyl adipate, diisohexyl adipate, dihexyldecyl 
adipate, diisopropyl sebacate, lauryl lactate, myristyl lactate, and cetyl 
lactate. 
g. Alkenyl esters of fatty acids having 10 to 20 carbon atoms. Examples 
thereof include oleyl myristate, oleyl stearate, and oleyl oleate. 
h. Fatty acids having 9 to 22 carbon atoms. Suitable examples include 
pelargonic, lauric, myristic, palmitic, stearic, isostearic, 
hydroxystearic, oleic, linoleic, ricinoleic, arachidonic, behenic, and 
erucic acids. 
i. Fatty alcohols having 10 to 22 carbon atoms. Lauryl, myristyl, cetyl, 
hexadecyl, stearyl, isostearyl, hydroxystearyl, oleyl, ricinoleyl, 
behenyl, erucyl, and 2-octyl dodecyl alcohols are examples of satisfactory 
fatty alcohols. 
j. Fatty alcohol ethers. Ethoxylated fatty alcohols of 10 to 20 carbon 
atoms include the lauryl, cetyl, stearyl, isostearyl, and oleyl alcohols 
having attached thereto from 1 to 50 ethylene oxide groups or 1 to 50 
propylene oxide groups, or a mixture thereof. 
k. Ether-esters such as fatty acid esters of ethoxylated fatty alcohols. 
l. Lanolin and derivatives. Lanolin, lanolin oil, lanolin wax, lanolin 
alcohols, lanolin fatty acids, isopropyl lanolate, ethoxylated lanolin, 
ethoxylated lanolin alcohols, propoxylated lanolin alcohols, acetylated 
lanolin, acetylated lanolin alcohols, lanolin alcohols linoleate, lanolin 
alcohols ricinoleate, acetate of lanolin alcohols ricinoleate, acetate of 
ethoxylated alcohols-esters, hydrogenolysis of lanolin, ethoxylated 
hydrogenated lanolin, ethoxylated sorbitol lanolin, and liquid and 
semisolid lanolin absorption bases are illustrative of emollients derived 
from lanolin. 
m. Polyhydric alcohols and polyether derivatives. Propylene glycol, 
dipropylene glycol, polypropylene glycol (M.W. 2000-4000), polyoxyethylene 
polyoxypropylene glycols, polyoxypropylene polyoxyethylene glycols, 
glycerol, ethoxylated glycerol, propoxylated glycerol, sorbitol, 
ethoxylated sorbitol, hydroxypropyl sorbitol, polyethylene glycol (MW. 
200-6000), methoxy polyethylene glycols 350, 550, 750, 2000, 5000, 
poly[ethylene oxide]homopolymers (M.W. 100,000-5,000,000), polyalkylene 
glycols and derivatives, hexylene glycol (2-methyl-2,4-pentanediol), 
1,3-butylene glycol, 1,2,6-hexanetriol, ethohexadiol USP 
(2-ethyl-1,3-hexanediol) C.sub.15 -C.sub.18 vicinal glycol, and 
polyoxypropylene derivatives of trimethylolpropane are examples thereof. 
n. Polyhydric alcohol esters. Ethylene glycol mono- and di-fatty acid 
esters, diethylene glycol mono- and di-fatty esters, polyethylene glycol 
(M.W. 200-6000) mono- and di-fatty acid esters, propylene glycol mono- and 
di-fatty acid esters, polypropylene glycol 2000 monooleate, polypropylene 
glycol 2000 monostearate, ethoxylated propylene glycol monostearate, 
glyceryl mono- and di-fatty acid esters, polyglycerol poly-fatty acid 
esters, ethoxylated glyceryl monostearate, 1,3-butylene glycol 
monostearate, 1,3-butylene glycol distearate, polyoxyethylene polyol fatty 
acid ester, sorbitan fatty acid esters, and polyoxyethylene sorbitan fatty 
acid esters are satisfactory polyhydric alcohol esters. 
o. Wax esters such as beeswax, spermaceti, myristyl myristate, stearyl 
stearate. 
p. Beeswax derivatives, e.g., polyoxyethylene sorbital beeswax. These are 
reaction products of beeswax with ethoxylated sorbitol of varying ethylene 
oxide content, forming a mixture of ether-esters. 
q. Vegetable waxes including carnauba and candelilla waxes. 
r. Phospholipids such as lecithin and derivatives. 
s. Sterols. Cholesterol, cholesterol fatty acid esters, and ethoxylated 
cholesterol are examples thereof. 
t. Amides such as fatty acid amides, ethoxylated fatty acid amides, solid 
fatty acid alkanolamides. The lotions further comprise from 1% to 10%, 
preferably from 2% to 5%, of an emulsifier. The emulsifiers can be 
nonionic, anionic or cationic. Examples of satisfactory nonionic 
emulsifiers include fatty alcohols having 10 to 20 carbon atoms, fatty 
alcohols having 10 to 20 carbon atoms condensed with 2 to 20 moles of 
ethylene oxide or propylene oxide, alkyl phenols with 6 to 12 carbon atoms 
in the alkyl chain condensed with 2 to 20 moles of ethylene oxide, mono- 
and di-fatty acid esters of ethylene oxide, mono- and di-fatty acid esters 
of ethylene glycol wherein the fatty acid moiety contains from 10 to 20 
carbon atoms, diethylene glycol, polyethylene glycols of molecular weight 
200 to 6000, propylene glycols of molecular weight 200 to 3000, glycerol, 
sorbitol, sorbitan, polyoxyethylene sorbitol, polyoxyethylene sorbitan and 
hydrophilic wax esters. Suitable anionic emulsifiers include the fatty 
acid soaps, e.g. sodium, potassium and triethanolamine soaps, wherein the 
fatty acid moiety contains from 10 to 20 carbon atoms. Other suitable 
anionic emulsifiers include the alkali metal, ammonium or substituted 
ammonium alkyl sufates, alkyl arylsulfonates, and alkyl ethoxy ether 
sulfonates having 10 to 30 carbon atoms in the alkyl moiety. The alkyl 
ethoxy ether sulfonates contain from 1 to 50 ethylene oxide units. 
Satisfactory cationic emulsifiers are the quaternary ammonium, 
morpholinium and pyridinium compounds. Certain emollients described in 
preceding paragraphs also have emulsifying properties. When a lotion is 
formulated containing such an emollient, an additional emulsifier is not 
needed, though it can be included in the composition. 
The balance of the lotion is water or a C.sub.2 or C.sub.3 alcohol, or a 
mixture of water and the alcohol. The lotions are formulated by simply 
admixing all of the components together. Preferably the compound of the 
present invention is dissolved in the mixture. Conventional optional 
components can be included. One such additive is a thickening agent at a 
level from 1% to 10% of the composition. Examples of suitable thickening 
agents include: cross-linked carboxypolymethylene polymers, ethyl 
cellulose, polyethylene glycols, gum tragacanth, gum karaya, xanthan gums 
and bentonite. 
2. Creams 
Compositions of this invention also can be formulated in a cream form. The 
creams comprise an effective amount (preferably from about 0.1% to about 
75%) of the compound of the present invention; from 5% to 50%, preferably 
from 10% to 25%, of an emollient; the balance being water. The emollients 
above described can also be used in the cream compositions. Optionally the 
cream form contains a suitable emulsifier, as previously described. When 
an emulsifier is included, it is in the composition at a level from 3% to 
50%, preferably from 5% to 20%. 
3. Solutions 
The compositions of this invention can be also formulated in a solution 
form. The solution form comprises an effective amount (preferably from 
about 0.1% to about 75%) of the compound of the present invention; the 
balance being water and/or a suitable organic solvent. Suitable organic 
materials useful as the solvent or a part of a solvent system are as 
follows: propylene glycol, polyethylene glycol (M.W. 200-600), 
polypropylene glycol (M.W. 425-2025), glycerine, sorbitol esters, 
1,2,6-hexanetriol, ethanol, isopropanol, diethyl tartrate, butanediol, and 
mixtures thereof. Such solvent systems can also contain water. 
These compositions in the solution form can be applied to the skin as is, 
or else can be formulated into an aerosol and applied to the skin as a 
spray-on. The aerosol compositions further comprise from 25% to 80%, 
preferably from 30% to 50%, of a suitable propellant. Examples of such 
propellants are the chlorinated, fluorinated and chlorofluorinated lower 
molecular weight hydrocarbons. Nitrous oxide, carbon dioxide, butane, and 
propane are also used as propellant gases. These propellants are used at a 
level sufficient to expel the contents of the container. 
4. Gels 
Compositions herein can be formulated into a gel form by simply admixing a 
suitable thickening agent to the previously described solution 
compositions. Examples of suitable thickening agents have been previously 
described with respect to the lotions. 
The gelled compositions comprise an effective amount (preferably from about 
0.1% to about 75%) of the compound of the present invention; from 5% to 
75%, preferably from 10% to 50%, of an organic solvent as previously 
described; from 0.5% to 20%, preferably from 1% to 10% of the thickening 
agent; the balance being water. 
5. Solids 
The compositions of this invention can also be formulated into a solid 
form. Such forms have use as a stick-type composition intended for 
application to the lips or other parts of the body. Such compositions 
comprise an effective amount (preferably from about 0.1% to about 75%) of 
the compound of the present invention and from 50% to 98%, preferably from 
60% to 90%, of the previously described emollients. This composition can 
further comprise from 1% to 20%, preferably from 5% to 15%, of a suitable 
thickening agent, and optionally emulsifiers and water. Thickening agents 
previously described with respect to lotions are suitable herein. 
6. Patches 
Compositions herein can be further formulated into a patch form suitable 
for transdermal delivery of the compounds of the present invention. 
Compositions in patch form are preferred for the present invention, 
especially when systemic anti-inflammatory activity is desired. 
Compositions in patch form may be readily prepared by one skilled in the 
art using known patch carrier materials as described more fully in 
"Transdermal and Related Drug Delivery Systems", Chemical Technology 
Review No. 228 (Noyes Data Corporation, Park Ridge, N.J.; 1984; Jones, 
editor), especially pages 109-296, the disclosures of which are 
incorporated herein by reference in their entirety. 
Additives commonly found in topical compositions such as preservatives, 
e.g., methyl and ethyl-paraben, dyes and perfumes can be included in any 
of the previously described topical compositions. 
The preferred dosage forms for topical administration are lotions or 
patches comprising a safe and effective amount of the anti-inflammatory 
agent of the present invention. Lotions preferably comprise an 
anti-inflammatory agent at a concentration of from about 1 mg/ml to about 
750 mg/ml, and more preferably from about 10 mg/ml to about 500 mg/ml. 
The pharmaceutically-acceptable carrier employed in conjunction with the 
anti-inflammatory agents of the present invention is used at a 
concentration sufficient to provide a practical size to dosage 
relationship. The pharmaceutically-acceptable carriers, in total, may 
comprise from about 0.1% to about 99.9% by weight of the pharmaceutical 
compositions of the present invention, preferably from about 25% to about 
99.9%, and most preferably from about 50% to about 99%. 
Methods of Treating Diseases Characterized by Inflammation 
Another aspect of the present invention is methods for treating diseases 
characterized by inflammation. Such methods comprise administering to a 
human or lower animal in need of such treatment a safe and effective 
amount of an anti-inflammatory agent described hereinbefore. 
The preferred mode for administration is topical, but other known methods 
for administration are contemplated as well, e.g., oral and parenteral 
(for example, by subcutaneous injection, intramuscular injection, 
intra-articular injection, intravenous injection, and the like). Ocular 
administration and inhalation is also included. Thus, specific modes of 
administration include, without limitation, oral, transdermal, mucosal, 
sublingual, intramuscular, intravenous, intraperitoneal, and subcutaneous 
administration, as well as the preferred topical application. 
The term "diseases characterized by inflammation", as used herein, means 
conditions which are known to involve inflammation, such as arthritis 
(e.g., rheumatoid arthritis; osteoarthritis; psoriatic arthritis; juvenile 
arthritis; Reiter's syndrome; infectous arthritis; ankylosing spondylitis; 
systemic lupus erythematosus; and gout), as well as the presence of 
inflammation whether or not it is associated with an identifiable disease. 
Diseases characterized by inflammation further include inflammation of the 
gastrointestinal tract, including the oral cavity (e.g., inflammation 
associated with gingivitis or periodontal disease) and bowels (e.g., 
inflammation associated with inflammatory Bowel Disease); inflammation 
associated with dermatological diseases (e.g., psoriosis); and 
inflammation associated with the respiratory tract (e.g., pulmonary 
inflammation). 
The phrase "safe and effective amount", as used herein, means an amount of 
a compound or composition high enough to significantly positively modify 
the condition to be treated, but low enough to avoid serious side effects 
(at a reasonable benefit/risk ratio), within the scope of sound medical 
judgment. The safe and effective amount of the anti-inflammatory agent 
will vary with the particular condition being treated, the age and 
physical condition of the patient being treated, the severity of the 
condition, the duration of the treatment, the nature of concurrent 
therapy, the specific anti-inflammatory agent employed, the particular 
pharmaceutically-acceptable carrier utilized, and like factors within the 
knowledge and expertise of the attending physician. However, single 
dosages can range from about 100 mg to about 2000 mg. Preferred single 
dosages are from about 250 mg to about 1000 mg. Up to about 4 single 
dosages per day may be administered. 
Topical administration can be used to reduce inflammation through directly 
laying on or spreading a safe and effective amount of the compound or 
composition of the present invention on epidermal or epithelial tissue, 
including outer skin and oral, gingival, and nasal tissue. The amount of 
the pharmaceutical composition to be topically administered may vary from 
about 0.1 mg/cm.sup.2 to 10 mg/cm.sup.2, and if a patch is worn over the 
affected area possibly higher concentrations, depending upon such factors 
as the sensitivity, type and location of tissue to be treated, the 
composition and carrier (if any) to be administered, and the particular 
compound to be administered as well as the particular disorder to be 
treated and the extent to which systemic (as distinguished from local) 
effects are desired. The extent of systemic anti-inflammatory activity 
also depends upon such factors as the amount of compound, the area of 
tissue to be covered, and the ability of the compound to penetrate the 
skin tissue. 
The following Examples further describe and demonstrate embodiments within 
the scope of the present invention. The Examples are given solely for the 
purpose of illustration, and are not to be construed as limitations of the 
present invention since many variations thereof are possible without 
departing from its spirit and scope. 
EXAMPLE I 
Synthesis of a Diastereomeric Mixture of the Sec-Butanol Ester of Naproxen 
Thionyl chloride (6.08 ml; 0.084 mole; Baker reagent, redistilled) is added 
dropwise over 20 minutes to a suspension of S(+)-naproxen (6.45 grams; 
0.028 mole; Sigma Chemical Co.) in 120 ml of anhydrous diethyl ether and 
15 ul N,N-dimethylformamide. After two hours of refluxing, a clear 
solution results. The solvent is removed under reduced pressure and the 
resulting solid is devolatilized for 5 hours (1 mm Hg and ambient 
temperature). This naproxen acid chloride is used for ester preparations 
without further purification. 
The S(+)-naproxen acid chloride (6.45 grams; 0.028 mole) is dissolved in 
120 ml of dichloromethane and cooled in an ice bath. 2-Butanol (racemic 
mixture; 2.57 ml; 0.028 mole; Aldrich Chemical Co.) and pyridine (2.14 ml) 
in dichloromethane (20 ml) is added to the stirred solution over 20 
minutes. After stirring 16 hours at ambient temperature, the solution is 
poured into ice water and washed successively with 1N aqueous hydrochloric 
acid, water, and 10% sodium carbonate. The solvent is then dried 
(anhydrous sodium sulfate) and the solvent removed to give a yellow oil. 
Purification by flash chromatography on silica gel (hexane/ethyl acetate, 
96:4) provides 7.43 grams (93%) of colorless oil product 
(S)-naproxen-(S,R)-2-butyl ester. 
HPLC (150.times.4.6 mm i.d. Zorbax ODS column eluted at 2.0 ml/minute with 
650:349:1 CH.sub.3 CN:H.sub.2 O:HOAc) indicates the presence of a 
diastereomeric mixture of S,R diastereomer and S,S diastereomer in a ratio 
of 49:51. [.alpha.]D (25.degree. C.)=+22.degree. (C, 3.2, CHCl.sub.3). 
.sup.1 H-NMR (CDCl.sub.3): 0.6-1.75(superimposed m), 1.09 (d, J=7) 1.21 
(d, J=7), 1.58 (d, J=8), 3.86 (q, J=7), 3.95 (s), 4.92 (q of t, J=7,7), 
7.07-7.92 ppm (m). 
EXAMPLE II 
Synthesis of a Diastereomeric Mixture of Naproxol 2-Methyl Butyrate 
A solution of 2-methyl butyryl chloride (5.46 ml, 0.0455 mole; racemic 
mixture; Eastman Kodak) in 50 ml of dry dichloromethane is added over 15 
minutes to a stirred solution of 7.19 gm (0.0333 mole) of 
S(-)-2-(6-methoxynapth-2-yl)-1-propanol ("naproxol", which is prepared as 
described in J. Med. Chem., 13, 203 (1970), [.alpha.]D (25.degree. 
C.)=-18.6.degree. (C, 1.5, CHCl.sub.3)) and 2.69 ml (0.0333 mole) of dry 
pyridine in 90 ml of dichloromethane maintained at 0.degree.-3.degree. C. 
in an ice bath and under a nitrogen atmosphere. After 16 hours at ambient 
temperature, the reaction is washed successively with water, 0.1N aqueous 
hydrochloric acid, water, 10% sodium carbonate, water, and brine. Removal 
of solvent under vacuum from the dried solution (anhydrous sodium sulfate) 
gives the product (S)-naproxol-(R,S)-2-methyl butyrate as an oil. 
Purification by flash chromatography on silica gel (hexane/ethyl acetate, 
95:5) gives 8.38 g (84%) of colorless liquid product. [.alpha.]D 
(25.degree. C.)=-16.0.degree. (C, 3.0, CHCl.sub.3). .sup.1 H-NMR 
(CDCl.sub.3): 0.6-1.90(superimposed m), 0.90 (d, J=7), 1.09 (d, J=7), 2.35 
(septet, J=7), 3.26 (sextet, J=7), 3.94 (s), 4.29 (d, J=7), and 7.03-7.87 
ppm (m). 
EXAMPLE III 
Procedure for Skin Penetration Measurements (Maximum Flux Experiments) 
Human skin is obtained from cadavers by dermatoming after the hair has been 
clipped and the skin washed. The skin thickness is approximately 0.25 mm 
and the samples are stored at -80.degree. C. Prior to use, the samples are 
rapidly thawed and the glycerol used in the storage process is removed by 
washing in distilled water. 
The skin samples are mounted in 5-mm diameter glass diffusion cells (E. W. 
Merritt and E. R. Cooper, "Diffusion Apparatus for Skin Penetration", J. 
Controlled Release, 1(2), 161-162 (1984)) with closed tops and a magnetic 
stirring bar in the lower compartment. The diffusion cells (nonjacketed) 
are placed in an aluminum block regulated at 37.degree. C. with a stirring 
magnet below the block. The dermis is bathed in 4 ml of a 1:1 (v:v) 
solution of ethanol and distilled water containing 0.02% sodium azide to 
inhibit microbial growth. The ethanol is used in order to ensure the 
solubility of the compounds in the receptor phase and to minimize the 
effect of unstirred aqueous layers in the epidermis and remaining dermis. 
After an overnight equilibration, the receptor solution is exchanged with 
fresh solution and the stratum corneum is dosed with 200 ul of a saturated 
solution of the test compound in propylene glycol. The receptor solution 
is removed for the penetration assay after elapsed times of 6, 24, 48, and 
72 hours and replaced with a fresh 4 ml volume. 
Steady state flux is often not achieved until the 24-48 hour time interval. 
The reported value of maximum flux (Jm) is the flux from 48-72 hours. In 
no case are the vehicles more than 10% depleted by the end of the 
experiment. 
The diasteriomeric mixture of compounds of the present invention penetrate 
human skin substantially better than naproxen or derivatives having the 
same number of carbon atoms but not a diastereomeric mixture. 
EXAMPLE IV 
Carrageenan Rat Paw Edema Tests 
Compounds of the present invention are tested for anti-inflammatory 
activity following subcutaneous or topical administration using the 
carrageenan rat paw edema test. 
(a) Subcutaneous 
Male Sprague-Dawley rats weighing 170-210 g are divided into 4 groups of 6 
animals and fasted for 24 hours. The drug is dissolved in a solvent 
composed of 10 parts of ethanol, 10 parts of Polysorbate 80, and 80 parts 
of normal saline. One ml of the solution is injected subcutaneously into 
the dorsal neck area 1 hour prior to the carrageenan injection. 
Immediately thereafter the animals are given 5 ml of tap water by gavage. 
Paw volumes are determined with a mercury displacement device equipped 
with a transducer and digitizer. One hour after receiving the drug, 50 ul 
of 1% (w/w) carrageenan (Viscarin, Marine Colloids, Inc.) in normal saline 
are injected into the ventral left rear paw of each animal. Four hours 
later, paw volumes are again measured. 
(b) Topical 
Male Sprague-Dawley rats weighing 170-210 g are divided into 4 groups of 6 
animals and fasted during the course of the experiment. The backs of the 
animals are clipped with a small animal clippers and the 200 mg of the 
topical preparation applied to a 20 cm.sup.2 area (4.times.5 cm). The 
drugs are dissolved at a 5% concentration in a 1:1 mixture of propylene 
glycol and ethanol. Applications are made 19.5 and 2.5 hours prior to 
injection of the 1% carrageenan solution. A plastic Elizabethan collar is 
fitted around the neck to prevent ingestion of the topical drug. Two hours 
after the last application the collars are removed and the animals are 
given 5 ml of water by gavage. Following injection of carrageenan, all 
procedures are the same as for the subcutaneous dose. 
(c) Calculations and Statistical Methods 
The results are expressed as percent inhibition of the mean paw volume of 
the test group relative to the control group according to the formula: 
EQU (C-T.sub.a . . . n).times.100/C=Percent Inhibition 
where: C is the average difference in paw volume before and after 
carrageenan-induced swelling, and T.sub.a . . . n is the difference in paw 
volume swelling in treated animal (a . . . n). Statistical significance is 
determined by a one-way analysis of variance of the carrageenan-treated 
paw volume differences. Generally, the diastereomeric mixtures of the 
present invention demonstrate anti-inflammatory activity similar to 
naproxen. 
EXAMPLE V 
Oxazolone-Induced Inflammed Mouse Ear Test 
Adult male Cox ICR mice, 20-28 g, are sensitized by application of 3% 
oxazolone in olive oil to the clipped abdomen of each animal. One week 
later the animals are challenged on the inner aspects of the left ear with 
3% oxazolone in acetone. At the same time 25 ul of the drug solution is 
applied to the same ear. Six hours later a second application of the drug 
solution is made. Twenty-four hours after challenge, the animals are 
sacrificed and 5-mm punch biopsies are taken from each ear and weighed. 
Ten to twelve animals are used per group. The control group is only 
challenged on the left ear. 
The results are expressed as percent inhibition of the swelling response 
compared to the control group according to the formula: 
(C-T.sub.a . . . n).times.100/C=Percent Inhibition 
where: C is the average difference between the left and right ear weights 
of the control group, and T.sub.a . . . n is the difference between left 
and right ear weights of animal (a . . . n) in a treated group. 
Statistical tests for signficance between groups are made using a one-way 
analysis of variance of the ear weight differences. Generally, the 
diastereomeric mixtures of the present invention demonstrate 
anti-inflammatory activity similar to naproxen. 
EXAMPLE VI 
A composition for topical administration is prepared by combining the 
following ingredients: 
______________________________________ 
Component Weight % 
______________________________________ 
Naproxol 2-Methyl Butyrate.sup.1 
5.0 
Propylene Glycol 47.5 
Ethanol 47.5 
______________________________________ 
.sup.1 A 1:1 diastereomeric mixture of the S,S and S,R diastereomers, 
prepared as in Example 2. 
Topical application of 0.4 ml of this liquid to a 80 cm.sup.2 portion of 
inflammed skin of a human produces anti-inflammatory activity. Similar 
anti-inflammatory activity is obtained when the naproxol 2-methyl butyrate 
is replaced with the 2-butanol ester of naproxen.