CA1267849A - Naphthalene anti-psoriatic agents - Google Patents

Abstract

ABSTRACT
The present invention is directed to a composition in a form suitable for topical administration for treating the condition of psoriasis. The composition comprises 2,3-dimethoxy-1,4-diacetyloxynaphthalene and pharmaceutically acceptable non-toxic carriers.

Description

l~t7~9 NAPHTHALENE ANTI-~SORIATIC AGENTS
.~

BACKGROUND OF THE INVENTION
Field of the Invention . .
The invention relates to naphthalene deriva~ives 5 whic~ are useful in inhibiting certain dermatolosic~l conditions. This invention also relates to pharmaceutical compositions usefui in relieving the effects of certain chronic recurr~nt papulosquamous dermatoses, e.g., psoriasis. This invention also relates to a process for preparing compounds of this invention.
~ELATED DISCLOSURES
. ~ _ Psoriasis is a skin disease characterized in part by excessive proliferation of cells of the epide:rmis which remain strongly adherent and build up into a scaley plaque typical of the d~sease. Currently~available therapies, which are not curative, depend on the control of epidermal eell proliferation through the use o : hormonal agen~s, such as corticosteroids or through the use of compounds related to cancer c~.emotherapy such as hydroxyurea, methotreXate, and the nitrogen mustards.
While tne above agents are effective ~o a-certain extent, they cause numerous severe undesirable side effects including renal ir~itation, hepatio toxicity, and erythema.

7410J ~ 23420-FF

.

t

-2- ~Z~78~

The compound/ 2,3-dimethoxy~1,4-diacetyloxy-naphthalene is known and is disclosed to be useful as a syntnetic intermediate, but no useful biological activity has been ascribed to it. See J. Chem. ~es., Synop.
1980(4), 156-7 and An. Quim. 1976, 72(3):247-53. Certain naphthoquinones are known to be useful in treating psoriasis. See, for example; U.S~ Patent No. 4,229,478 and British Patent No. 1,243,401-. But, these compounds have one or more drawbacks such as causing skin irritation, staining the skin and sensitizing the patient. Surprisingly, it has been discovered that the compounds of the instant invention are less irritating, do not stain the skin and do not sensitize when used in the treatment of psoriasis. ~urther, the compounds of 1S the present invention are more stable in the topical formulations normally used.

SUMMARY
The present invention relates to a pharmaceutical composition in a form suitable ~or topical administration to mammals comprising a compound of the following formula OC(O)W

R ~ (I) ~C(O)I~

wherein:
Rl and R~ are lower alkoxy of sne to six carbon atoms or lower alkyl~hio of one to six carbon atoms;
R3 is hydrogen, lower alkyl of one to six carbon atoms, lower alkoxy of one to six carbon atoms, optionally substituted phenyl, optionally substitute~
phenyl lower alkyl, optionally substituted phenyl lower 7410J ~34~0~FF

_3_ ~2~'7~

alkoxy, amino, lower alkylamino, lower dialkylamino, halo, cyano, or S(O)nR wherein R is lower alkyl of one ~o six carbon atoms; optionally substituted phenyl;
optionally substituted phenyl lower alkyl; or heterocyclic aryl of three to nine ring atoms containing one or two heteroatoms selec~ed from the group consistin~
of nitrogen, oxygen and sulf~r wherein the heterocyclic aryl is optionally substituted by one or more substituents selected from the group consisting of lower i alkyl, lower alkoxy, halo and cyano and the pharmaceutically acceptable acid addition salts tnereof;
and n is 0, l or 2; and W is alkyl of one to seven carbon atoms.
Another aspect of the invention is a method for relievin~ the condition o~ psoriasis in a mammal which comprises topically administering to said ~ammal a psoriasis-relieving amount of a compound of formula ~I).
Another aspect of the invention is the nvvel compounds of formula (I) wherein Rl, R2, R3, W and n are as defined above with the proviso that R3 is not hydrogen when Rl and RZ are methoxy and W is methyl.
Yet another aspect of the invention is preparing compounds of formula (I) by reacting compounds of formula (XI)(infra) with an acid anhydride~
~5 DETAILED DESCRIPTION AND PREFER~ED EMBODIMENT
In its broadest aspect, the present invention relates to a pharmaceutical composition in a form suitable for topical administration to mammals comprising :
a compound of t~e following formula ~:
OC (O) W

~R3 ~ (I)

3~ lc(o)l~l 7410J 23~20-FF

_ ,.. ., ,. ~, . .. , , .. , _.. . ..

-4- ~z~7~
wherein:
Rl and R2 are lower alkoxy of one to six carbon atoms or lower alkylthio of one to six carbon atoms;
R3 is hydrogen, lower alkyl of one to six carbon atoms r lower alkoxy of one to six carbon a~oms, optionally substituted phenyl, optionally substituted phenyl lower alkyl, optionall-y substituted phenyl lower alkoxy, amino, lower alkylamino,.lower dialkylamino, halo, cyano, or S(~)nR wherein R is lower alkyl of one to six carbon atoms; optionally subs~itu~ed phenyl;
optionally subs-ti~uted phenyl lower alkyl; or heterocyclic aryl of three to nine ring atoms containing one or two heteroatoms ~elected ~rom ~he gsoup consisting of:nitrogen, oxygen and sulfur wherein the heterocyclic aryl is optionally substituted by one os more substituents selected from the group consisting of lower alkyl, lower alkoxy, halo and cyano and the pharmaceutically acceptable acid addition salts t~ereof;
and n is 0, 1 or 2; and W is alkyl of one to seven carbon atoms.
The present invention also relates to compounds o~
the formula fC(O)Wl R3 -I ~ ~ 2 (I) OC (O) W

30 wherein: :
Rl~and R2 are lower alkoxy of one to six ~arbon atoms :~
- or }ower alkylthio of one~ to six carbon:atoms;
~:~ : R3~is hydrogen, lower: alkyl of one kO six carbon atoms, lower alkoxy of one to six carbon atoms, 3~ optionally substituted phenyl, optiona11y substituted 7410J ~ 23420-~F

:

_ 5_ ~Z~7~

phenyl lower alkyl, optionally substituted phenyl lower ~lkoxy, amino~ ~ower alkylamino, lower dialkylamino, halD, cyano, or S(O)nR wherein R is lower alkyl of one to six carbon atoms; optionally substituted phenyl;
optionally substituted phenyl lower alkyl; or heterocyclic aryl of three to nine ring atoms c~ntaining one or two ~e~eroatoms sele~ted.from ~he group consisting of nitrogen, oxygen and sulfur wherein the heterocyclic aryl is optionally substituted by one or more substituents selected from tne group consisting of lower alkyl, lower alkoxy, halo and cyano and the pharmaceuti~ally acceptable acid addi~ion ~alts thereof;
and n is 0, 1 or 2; and W is alkyl of one to seven carbon atoms; with the proviso that R3 i~ not hydrogen when Rl and R2 are methoxy and W is methyl.
Moxe specifically, the present invention relates ~o compositions containing compounds of formula (I) wherei~
R3 is in the 6-position and is hydrogen, bromo, chloro, ~ fluoro or cyano.
An even more specific embodiment of the instant invention are compounds of formula (I) wherein R3 is at the 6-position and is bromo, chloro, fluoro, cyano, methoxy, et~oxy, n-propoxy, i-propoxy, n butoxy, and i-butoxy.
Within this specific embodim~nt of the instan~
invention, a preferred group of compounds of formula ~I) are those wherein Rl and: R2 are lower alkoxy of one to three carbon atoms and W is lower alkyl of one ~o five 3a carbon atoms.
In the present specification and claims the term "alkyl" is intended to mean alkyl groups containing one to seven carbon atoms including straight chain groups, or branched chain groups. Illustrative of such groups are for example, methyl, ethyl, n-propyl, i-propyl, ~-hexyl,:
.

. ' . ' . i ' ;;: - ,, - !

:J~Z~7t~

2-methylpentyl, and n-heptyl. The term "lower alkyl"
refers to alkyl groups of one to six carbon atoms as defined above. Examples of "lower alkyl" groups are methyl, ethyl, n-propY1, i-propyl, n-butyl, i-butyl, s-butyl, 2~2-dimethylpropyl and t-hexyl~ The term "p~enyl lower alkyl" re~ers to an optionally substituted pnenyl ring attached to an a~kylene chain of one to six carb~n atoms. ~
The term "lower alkoxyn refers to a straight or branched chain aliphatic group of one to six carbon atoms having bonded thereto an oxygen moiety~ Examples of "lower alkoxy" are met~oxy, e~hoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy and n~pentyloxy.
"Phenyl lower alkoxy~ refers to a phenyl ring attached to an alkylene chain of one to six carbon atoms ha~ing bonded thereto an oxygen atom~ Examples of "phenyl lower alkoxy" are benzyloxy, 4-chlorophenylethoxy and phenyl-n-propox~.
The term nlower alkylthio" refers to a straight or 2~ branched chain aliphatic group of one to six carbon atoms havng bonded thereto a sulfur moiety. Examples of "lower alkylthio" are methylthio~ ethylthio, n-propylthio, i-butylthio an n-hexylthio.
Optionally substituted phenyl refers to a phenyl ring optionally substituted by one or more substituents selected ~rom tne group consisting o~ lower alkyl, lower alkoxy, halo, lower acyl, lower acyloxy, cyano, nitro, amino and lower acylamino.
The term "halon refers to fluoro, chloro, 30 and bromo. The term "cyano" refers to the group -CN. The term "aminol' refer~ to tne group -NH2.
The term "lower alkylaminol' refers to an amino group substituted by lower alkyl as i~ defined above. Examples of "lower alkylamino" are methylamino, ethylamino and n~butylamino.

7410J 23420-F~

-7~ 7~9 The term "lower dialkylamino~ refers to an amino group substituted by ~wo lower alkyl groups. Examples of "lower dialkylamino n are dimethylamino, dipropylamino and methylethylamino.
The term "lower acyl" refers to the group R4C~o)-wherein R4 is a lower alkyl group of one to six carbon atoms or an optionally substi~uted phenyl group.
Examples of ~lower acyl~ are ac~tyl, propanoyl, butanoyl and ben~oylO The term "lower alkoxycarbonylalkyl" refers to an ester ~roup of the formula RSOC(O)- su~stituted on an alkyl ~roup wherein R5 is lower alkyl as is de~ined abovQ. Examples of "lower alkoxycarbonylalkyl" are methoxycarbonylmethyl, ethoxycarbonylmethyl, ethoxy-carbonylethyl, propoxycarbonylethyl and the like.
The term "heterocy~lic aryl" is defined as those cyclic aromatic compounds having 3 to 9 ring carbon atoms and having one or two heteroato~s in the ring selected from the ~roup consisting of nitrogen, oxygen and sulfur. Examples of such include the groups thiapyranyl, benzothiapyranyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, indolyl, ~uinolinyl, indazolyl and the like. These heterocyclic aryls may be optionally substituted with halo, lower alkyl, cyano and lower alkoxy.
By the term "pharmaceutically acceptable acid addition salts" as used in the case of the various R3 containing heterocycli~ aryl substituents herein iS intended to mean those non-toxic pharmaceutically acceptable acid addition salts w~ich do not adversely affect tne pharmaceutical properties:of the parent compounds. With respect ~o these addition salts, suitable inorganic anions include, for example, chloride, bromide, iodide, suIfate, phosphate, nitrate, and the like:. S~itable organic anions include, for example, aeetate, benzoa~e, lactate, 35 picrate, propionate, butyrate, valerate, tartrate, 2 ~'7 maleate, fumarate, citrate, succin~te, tosylate, ascorbate, nicotinate, adipate, gluconate and the like.
FORM~LATION AND ADMINISTR~TION
The compositions of the present invention may be S formulated for administration in any convenient way by analogy with other topical compositions adapted for use in mammalsO Thase compositi~ons may be presented for use in any conventional manner wit~-the aid of any of a wide variety of pharmaceutical carriers or vehiclesO
The naphthalenes of formula tI) may be formulated witn suitable pharmaceutical vehicles known in the art to form particularly effective topical compositions. An effective ~mount of the naph halene compound is about 0.001%w to abo~t lO~w of the total ~ormula~ed composition. The rest of t~e formulated composition will be about 90%w to about 99.999%w of a sui~able excipient wnich may include a pharmaceu~ically acceptable solvent and other pharmaoeutically acceptable additives to form a topically ef~ective pharmaceuticaI formulation.
A pharmaceutically accepta~le solvent is one which is substantially non-toxic and non-irritating under the conditions used and may be readily formulated into any of the classical drug formulations such as powders, creams, ointments, lotions~ gels, foams, aerosols, solutions and tne likeO Particularly suitable solvents include wa~er, ethanol, acetone, glycerine, propylene caxbonate, dimethylsulfoxide (DM50), and glycols such as 1,~
propylene diol, i.e., pr~pylene glycol, 1,3-propylene diol, polyethylene glycol having a molecular weight of from 100 to~10,000, dipropylene glycol, eto. and mixtures of the aforementioned solvents with each other.
A ~opical cre~m may be prepared as a semi-solid emulsion of oil in water or water in oil. A cream base formulation::by definition is an emulsion, whicn is a 3~ two-phase system with one li~uid (for example fats or 7410J ~ 234Z0-FF

-9~ 3~9 oils) being dispersed as small globules in another substance (e.g., a glycol-water solvent pi~,ase) which may ' be employed as the primary solvent for the naphthalenes therein. The cream formulation may c~ntain fatty alcohols, surfacrants, mineral oil or petrolatum and other typical pharmaceutical adjuvants such as anti-oxidants, antiseptics, or compatible adjuvants. A
typical cream base formulation -is as follows:
Water/glycol mixture50 - 99 parts by weight 10 tl5% or more glycol) Fatty Alcohol 1 - 20 Non-ionic Surfactant 0 .- 10 Mineral Oil 0 - 10 15 Typical Pharmaceutical 0 - 5 - Adjuvants Active Ingredients 0.001 - 10 The fatty alcohol, non-ionic surfactant, and other . 20 adjuvants are discussed in U.S. 3,934,013 to Poulsen.

The naphthalenes of formula (I) may also be formulated as topical ointments. A "classical" ointment is a semisolid anhydrous composition which may contain mineral oil, white petrolatum, a suitable solvent such as a glycol and may include-propylene carbonate and other pharmaceutically suitable additives such as surfactants, for example Span*and Tween* or wool fat (lanolin), along with stabilizers such as antioxidants and other adjuvants as mentioned before. Following is an example of a typical "classical" ointment base:
White Petrolatum40 ~ 94 parts by weight Mineral~Oil 5 - 20 Glycol Solvent 1 - lS
Surfactant 0 - 10 Stabilizer 0 - 10 Active Ingredients0.001 - 10.0 -7410J , 23420-FF
*trade mark ; ~ ,' ... i , .. . .; , . ~ . . . . . . - . . .

- 1 o - 1Z~i'7~ 3 Otner s~itable ointment base formulations which employ propylene carbonate are described in U.S. patent , 4,017,615 issued April 12, 1977 by S~astri et al entitled "Propylene Carbonate Ointment Vehicle" and U.S. 3,924,004

- 5 issued December 2, 1975 by Chang et al entitled "Fatty Alcohol-Propylene Carbonate-Glycol Solvent Cream Vehicle". Following is a typical ointment base formulation containing propylene carbonate:

Active Ingredients 0.001 - 10.0 parts by weight Propylene Carbonate 1 - 10 Solvent 1 - 10 Surfactant 0 - 10 White Petrolatum 70 - 97 Suitable solvents, surfactants, stabilizers, etc.
are discussed in U.S. 3,934,013.

A suitable topical "non-classical" anhydrous, water washable "ointment type" base is described in U.S. Patent No. 3,592,930 to Katz and Meiman. A representative com-position of this invention utilizing such base is as follows:

Glycol Solvent40 - 35 parts by weignt Fatty Alcohol 15 - 45 Compatible Plasticizer 0 - 15 Compatible Coupling 0 - 15 Agent Penetrant 0 - 20 - ~ .
Active Ingredients 0~001 - 10.0 Another aspect of the invention is a method for relieving the condition o psoriasis in a mammal by topically adminis~ering a composition containing a compound of formula (I) wherein R3, n, Rl, and R2 are as defined above. Generally, the anti-psoriatic manifestation in mammals, particularly humans, is combatted by contacting the inflamed areas with a therapeutically ef fective amount of the naphthalene~containing compositions of this invention, that is, an amount which results-in a lessening of the epidermal cell proliferation (an anti-psoriatic effe~').
10 Preferably the naphthalenes are first formulated to prepare a suitablP pharmaceutical formulation, as discussed hereinabove, which is then placed in contact wi~h the afflicted area(s). An effective amount of the naphthalene compound will depend upon the particular conditi~n and the mammal receiving the treatment and will vary between ~.001~ to 10% by weight of the pharmaceutical composition and preferably will be between 0.01~ and 1~ by weight of the formulation~ Using these levels in the formulation, a therapeutically effective and non-side effect producing amount, i.e. enoug~ to affect an anti-psoriatic response, but not enough to adversely effect the recipient, is applied to the afflicted area(s).

PREpA~A~IoN
The compounds of formula (I) may be prepared from compounds of formula ~V) or ~VI).
The intermediates of formula ~V) or (VI) wherein R3 is a substituent other than hydrogen may be prepared by the reactlon sequence below.

7410J ~3420-FF

-120 ~2~7~

~ ~~~7 ~2 ~ C

(II3 tIII) 2~

(IV) (V) 25 , 0 ~ 1 (VI) ~ :

wherein Rl, ~ , and R are as defined above.
Compounds of formula~(III) are~prepared hy starting : with a 2,3-di~alonaphth~quinone,~preferably 2,3-dichloro-1,4-naphthoguInone (compound of formula (II)), WhiCh is availab:le from, - a., ~ldrich Chemical Co., and directly nitrating. The rea~tion ~ :

7410J : : 23420-FF

.

~.Z~;'7~

proceeds in the manner known for polycyclic aromatic compounds to yield a mixture of the 5- and 6-nitro-2, 3-dichloro-1, 4-naphthoquinones, compounds of formula (III). The reaction is conducted typically with concentrated nitric acid in a low p~ solvent medium, preferably concentrated sulfuric acid, typically at 20C
to 1~0C for a time sufficient to complete the reaction.
Depending on the reaction temperature and times of reaction, ratios of t~e 5-nitro isomer:6-nitro isomer mixture may range from 10:1 to 1:10, typically 8:1~
Compounds of formula ~IV) are synthesized from 5-and 6-nitro-2,3-dichlor~-1,4-naphthoguinone, compound of formula (III), by condensing them with an alkali metal alkoxide, wherein the alkoxy moiety is Rl ~ R2. The reaction is pre~era~ly conducted in an inert organic solvent such as tetrahydrofuran, dimethylsulfoxide, dimethylformamide and the like at ~emperatures from about ~0C to about 100C for a time su~ficient ~o assure completeness of reaction, i.e., for about 2 hours to about 48 hours.
Compounds of formula (IV) wherein Rl-R2 and is lower alkylthio are prepared from compounds of formula tIII) in the same manner as for the alkoxy compounds except that an alkali metal salt of an alkyl mercaptan is substituted for an alkali metal alkoxide.
The compounds of formula (V) are prepared from compounds of formula tIV) by catalytic or non-catalytic reduction processes k~own in the pzior artO Metal-acid reducing agent compositions, such as granulated iron and hydrochloric;acid, tin and hydrochloric acid, and the like or neutral reducing agent compositions such as zinc dust and aqueous alcohol or al~inum amalgam and aqueous alcohol as well as organo-metallic reducins agents such as lithium aluminum hydride, sodium borohydride and the like may be use~ in this reduction. Preferably, the 74103 ~ 23420-FF

-14- ~LZ:S'~

reduction is accomplished by treating the compounds of formula (IV) with excess hydrazine in the presence of a catalytically sufficient amount of palladium, typically on carbon. The reaction readily occur~ at room temperature~ the time of reaction being governed by the rate of addition of the hydrazine to the reaction mixture such typically being about i to about 10 hours~
Compounds of formula ~VI) wherein R3 is hydrogen may be prepared by reacting compound of formula (II) wi~h an 10 alkali metal alkoxide or alkali metal salt of a mercaptan as described hereinabove.
Compounds of formula (VI) wherein R3 is lower alkylamino or lower dialkylamino are prepared by reacting compounds of formula (V) with an alkyl halide such as met~yl iodide by methods well known in the art for alkylating amino groups. T~e following compounds, for example, may be prepared:

6-methylamino-2,3-dimet~oxy-1,4-naphthoquinone;
6-diethylamino-2,3-dimetho~y-1,4-naphthoguinone;
6-ethylmethylamino-2,3-dimethoxy-1,4-naphthoquinone;
and 6-methylamino-2,3-dimethylthio-1,4-naphtho~uinone.
Compounds of formula (V) are converted into çompounds o formula (VI) where R3 is halo by adding to the compound of formula ~V) in an acidified aqueous solution, a solution of an alkali metal nitrite, This initial reaction forms the diazonium salt at the S- or 6-position of the naphthoquinone ring. The salt is decomposed with a solution of cuprous halide dispersed or dissolved in the corresponding halogen acid (the Sandmeyer reaction). Thi~ classical reaction is trea ed ex~ensively in~Bigelow, Ors. Svnthesis, Coll. Vol. I, 126-133 (1941~. ~
A modification of the above Sandmeyer reaction is useful in tne preparation of the compounds of formula -15- ~2~'7~

(VI) where R3 is cyano in that the diazonium salt, rather than being decomposed in the presence of cuprous halide/halogen acid is decomposed in the presence of an alkali metal cyanide and a cuprous halide. See Clarke and Read, Org. Synthesis, Coll. vol~ I, 514 (1941) for a further explanation of the considerations involved i~
this modified Sandmeyer reac~ion.
The compounds of formula (VI) where R3 is an optionally substituted heterocyclic aryl hio group, optionally substituted phenylthio or al~ylthio may also be prepared from ~he diazonium salt (above), ~or example, the diazonium saIt of the compound o formula (V~ is reacted with an alkali solution of thiophenol to yield the compounds o formula (VI) where ~3 is phenylthio. Typicall~, the displacement reaction of t~e diazonium salt is carried out at 30-75C by adding an alkali solution of t~iophenol in an inert organi~
solvent. Solvents of preference are the inert solvents such as e~rlyl acetate, tetrahydrofuran and the like~
Reaction times may vary from 10 minutes to about 24 hours.
The heterocyclic arylthio compounds are preferably :prepared by adding the 2,3-dialkoxy-5 ~r 6-nitro-1,4-napht~oquinone of formula (IV) to a solution of tkJe tniol-substitute:d heterocyclic aryl compound admixed with ; 25 an alkali metal hydride i~ an inert organic solvent such as dimethylformamide. The reaction is typically conducted at -75~ to -25C over aiperiod of about 10 to about 60 minutes~
T~e preferred procedure for the preparation of the compounds of formula (VI) where R3 is a linear or bra~he~d alkyltrlio or an optionally subs~itut d p~enylalkylthio i5 by f`irst converting a comp~und of formula ~V) to the :
di(2,3-Rl,~2~ 4-naphthoquinone~-5 or 6-disulfide of the ~ollowing formula:

7410J 2~420-FP

-16- ~Z ~

(~11 RR12 ` 5 q O

1~ " ~

(VII) wnerein Rl and R2 are as defined above. A mixture of an alkaline ear~h or alkali metal thiol carboxylate such as tne aoetate, propanoate, butanoate and the like ~compounds of t~e formula ~OC~CH~)yS~)X w~ere y is ~he integer 0 to 18, M is an alkali or alkaline earth metal and x is the valence of ~aid metal) in an inert organic solvent i5 added to a solution or dispersion of compound of ~ormula (V) at a temperature of -10 to ~10C over a period of about l to about 120 minutes, preferably ~ to 30 minutes. Reaction media include a variety of polar inert solvents ~uch as dimethylformamide t ~imethylsulfoxide and the like. After fur~her reaction, typically for a~out l to a~out lO hours at 20 to 50C, tne dis~lfide is isolat~d. ~nis compound can then be u~ed to prepare ~he alkyl or phenylalkyl sulfides of formu}a (VI) by ~irst treatin~ the disul~ide wit~ a mixture of sodium borohydride i~ an inert organic solvent and adding to such mixture at a temperature o~.about -10C to a~out 75C for l to lO:hours an appropriate alkyla~ing agent such as a dialkyl sulfate, an alkyl halide, an pnenylaIkyl halide and the like. IIlustra~ive of suc~ alkylating agents are the compounds meth 7410J ~3~20-~

~17~ ~ Z ~

bromide, methyl iodide, dimethyl ~ulfate and benæyl bromide, Preferably alkyl iodide is used as the alkylating agent herein.
W~ere appropriate, salts of the compounds bearing ~eterocyclic aryl substituents are prepared. For example, the methylsulfate salt of the 2,3-dialkoxy-5-(pyridin-4-ylthio)-1,4-naphthoquinone is readily prepared by ~dmixture with dime~hylsulfate in an inert organic solvent such as tetrahydrofuran. S~lt formations of t~is type arR well known in the prior art.
A particularly preferred method of preparing compounds of formula (VI) wherein~R3 is 6-halo is shown in the following reaction sequence.

~EACTION SEQUENCE II

3/~ R3 ~VIII) (IX) O O

R3~ ~/~R~

30 (X) (VI) wherein Rl and RZ are as defined above.
Compounds of formula (VIII) are prepared a cording to the method disclosed in J. Am. Chem. Soc.~ 70, 316~ ~1948) 7410J 23420-F~

-18- ~2~4~

and Ibid., 71, 3615 (1949). Halo substituted butadiene is reacted wit~ 1,4-benzoquinone in a solvent sucn as acetic acid at a temperature of -lO~C to 30C, preferab}y at 25C
for 24 to 72 hours, preferably from ~0 to 48 hours. The 5,7-dihydro compound of formula (VIII) is recovered and treated wit~ an oxidizin~ agent such as sodium dichromate, sodium nitrite and the like as described in the abov~
articles to form compounds of formula (VIII). Compounds of formula (IX) are prepared by bubbling chlorine gas into a solution of compound of formula ~VIII) dissolved in a solvent such as glacial acetic acid, nitrobenzene, carbon tetrachloride and the like, preferably glacial acetic acid at room temperature. T~is compound, which may ~e isolated by known means~ dissolved in a solvent suc~ as a~etic acid is treated with chlorine gas and a suitable catalyst sucn as sodium acetate, iodine, iron(III)chloride, dimethylformamide or alcohols with heating under reflux for 1/2 to 4 hours, preferably for 1 to 2 1/2 hours to yield ~ompounds of formula (X). Compounds of formula (V~) wherein R3 is halo are prepared by reacting compound of formula (X) with an alkali metal alkoxide such as sodium alkoxide, e.g., sodium methoxide in an anhydrous solvent such as methanol, dimethylformamide and the like, the solvent being chosen according to the length of the alkyl chain on tne alkoxy group. T~,e reaction mixture is heated under reflux for 1/2 to 3 hours, preferably for 1/2 to 1 1/2 hours. Compounds of formula ~I) are recovered by conventional means su~h as ~y crystallization.
Tne compounds of formula (VI) wherein Rl and R2 are lower alkylthio may be prepared by the method described for the alkoxy compound except that the alkali metal alkoxide is replaced by t~e alkali metal salt of the alkyl mercaptan with the solvent ~eing dimethyl-formamide and the like.

~26~

The interm~diate, 2-chloro-l~3-butadiene (chloroprene) is available from, i.a., Pfaltz and Bauer Chemical Co. 2-Bromo-1,3-butadiene and 2-fluoro-1,3-butadiene may be prepared by meth~ds well known in the art, for example, by the methods dis~ussed in J. ~m. Cnem. Soc., 55 786 (1~33) and U. S. patent No~
2,401,850, respectively.
T~e intermediates of formulà ~VI) wherein R3 is lower alkyl, lower alkoxy, optionally substituted p~enyl, 10 optionally substituted phenyl lower alkyl or optionally substituted phenyl lower alkoxy may be prepared by methods well known in the art such as by reacting the diazonium salt of ~iompound of formula (V) with an appropriate compound such as an alcohol e.g. methanol, ethanol, benzyl alcohol and the like. These intermediates may also be prepared by the method set out in ~eaction Se~uence tII) wherein the 2-halo-1,3-butadiene is replaced by the appropriate 1,3-butadiene such as 2-methyl-1,3-butadiene(isoprene), 20 2-etnyl-1,3-buta~iene and the like.
Compounds of formula (I) are prepared from~compounds of formula (V~) by first reducing to form compounds of formula (XI) OH
R3 ~ I RRZ

OH

(XI) ~

by, ~or example, hydrogenation a~ atmospheric pressure in the presence of a catalyst such as palladium on 35 charcoal. Alternatively, ~his reduction may be achieved 7410J 2342~-F~

-20~

using Zn/acetic acid (preferably for R3=H compounds), NaB~4 in a solvent such as THF or DME, NA2S208 in aqueous systems, catalytic transfer hydrogenation with cyclohex (adi)ene, and the like~
The compounds of formula (XI) are then acylated with tne required alkanoic acid, or reactive derivative thereof. Suitably this acylation may be carried out using an alkanoyl anhydride and pyridine suc~ as acetic annydride and the like in a solvent su~ as 10 tetrahydrofuran, diethyl ether and the like. (Of course, this acylation can, if convenient and with an appropriate choice of reaction conditions, be carried DUt as part of a one step conversion of a compound of formula (VI) into a compound of formula (I)). Compounds of formula (I) are 15 recovered by recrystallization.
The sulfinylnaphthalenes of formula ~I) are prepared by oxidation of the corresponding ~hio compounds Wit~J a stoichiometric amount of a suitable peracid in an inert organic solvent.
The compounds of formula (I) bearing a sulfonyl substituent are prepared by further oxidizing the compounds of formula (I) wnerein R3 is a sulfinyl group with a suitable peracid typically at -lO to 75C for l ~o lO hours. Preferably, m-chloroperbenzoic acid in an 25 inert organic solvent at room temperature is used to prepare the desired sulfonyl compounds.
The ~ollowing specific description is given to enable those skilled in the art to more clearly understand and practice the presen~ invention. It should 3~not be considered as a limita~ion upon the scope of ~he invention but merely as illustrative and represe~tative thereof.

74lOJ 23420-FF

-21~ 7~4~

Pre~
2,3-Dichloro-5- and 6-nitro-1,4-naPhthoquinone ~Preparation of Compounds of Formula (III)).
Finely powdered 2,3 dichloro-1,4-naphthoquinone 5 50 g. 0.22 mol) was added to a stirred mixture of concentrated sulfuric acid (170 ml) and 90% nitric acid (102 ml) at a rate so that the exothermic reaction raised the temperature to 60C. The resultiny mixture was stirred at 6UC for a further 2 hours. The yellow crystalline soli~ was filtered off, washed thoroughly with water and recrystallized from chloroform giving 22~9 g of the 5-nitro isomer, mp 156-157C. The above strongly acidic filtrate was poured onto ice water~ The resultant solid was filtered off, washed thoroughly with water and dried giving 20.8 9 of a mixture of the 5- and 6-isomer. Fractional crystallization of tnis mixture from acetic acid and chloroform:isopropanol afforded ~.8 g of the 6-ni~ro isomer, mp lB4-187C.
Further quantities of botn ~- and 6-isomer were 20 obtained from the recrystallization mother li~uors by ChrOmatosraphy on a silica gel column eluting with chloroform:cyclohexane mixtures.
.
Preparati_n 2 2~3-D~ t~h~3~L-cL-L2=~r4-naphthoquinone.
(Preparation of Compounds of ~ormula (IV)).
A. A solution of 2~3-dichloro-5-nitro-1,4-naphtho-quinone (~.72 9, 10 mmol~ in anhydrous tetrabydrofuran (15 ml) was added to a solution of 1 ~ sodium methoxi~e 30 (25 ml, 25 mmol) and the resulting solution stored at : ~
22 ~or 16 hours. ~cetic acid ~1 ml) was then added, the solution concentrated in vacuo and the residue partitioned between water (50 ml) and chloroform (100 ml:). The aqueous phase w~s further ex~racted wi h 35 chloroform (2 x 50 ml). The com~ined chloroform extracts

7~10J 23420-~

."~ ", ", . ,.., . ,.; , . " ,. ~, ., ,. ; --22- ~ ~ ~ 7~
were dried with MgSO4 and conce~trated an vacuo. The residue was recrystallized from methanol giving 1.99 g of 2,3-dimethoxy-5-nitro-1,~-naphthoquinone, mp 156-157~.
~. Similarly, using the above procedure in Part A, substituting 2,3-dicnloro~ 6-nitro-1, 4-naphthoquinone, where appropriate, for 2,3-dichloro-5-nitro-1,4-naphthoquinone and the appropriate sodium alkoxide for sodium methoxide, the following compounds are prepared:
2,3-dimethoxy-6-nitro-1,4-r~aphthoquinone mp 113-114C;
2,3-dietnoxy-5-nitro-1,4-naphthoquinone;
2,3-diethoxy-6-nitro-1,4-naphthoquinon~;
2,3-di-n-propoxy-5-nitro-1,4-naphthoquinone;
2,3-di-n-propoxy-6-nitro-1,4-naphtho~uinone;
2,3-di-i-propoxy-5-nitro-1,4-naphthoquinone;
2,3-di-i-propoxy-6-nitro-1,4-naphthoquinone;
2,3-di-n-butoxy-~-nitro-1,4-naphthoquinone;
2,3-di-n~butoxy-6-nitro-1,4-naphthoquinone;
2,3-di-s-butoxy-5-nitro-1,4-naphthoquirlone;
2,3-di-s-butoxy-6-nitro-1,4-naphthoquinone;
2,3-di-n-pentyloxy-5-nitro-1,4-napht~,o~uinone;
2,3-di-n-pentyloxy-6-nitro-1,4-naphtho~uinone;
2,3-di-s-pentyloxy 5-nitro-1,4-naphtho~uinone;
2,3-di-s-pentyloxy-6-nitro-1,4-naphthoquinone;
2,3-di-n-hexyloxy-5-nitro-1/4-naphtho~uinone;
2,3-di-n-hexyloxy-6-ni~ro-1,4-naphthoquinone;
2,3-di-i-hexyloxy-5-nitro-1,4-naphthoquinone, 2,3-di-i-hexyloxy-~ nitro-1,4~naphthoquinone;
2,3-di~2,2-dimethylpropoxy)-5-nitro-1,4-naphthoquinone; and --2,3-di(2,2-dimethylpropoxy)-6-nitro-l, naphthoquinone.
C. Similarly, using the above procedure in part A, 35 substituting 2,3-dichloro-~-nitro~1,4-napbtho~uinone, 7410J 23420-F~

where appropriate, for 2,3-dichlor~ nitro-1,4-naphth~-quinone and t~e appropriate sodium salt of alkylmeracaptan for sodium methoxide, the following compounds, for example, are prepared:
2,3~dimethylthio-6-nitro-1,4-naphtho~uinone;
2,3-di-i-propylthio-6-nltro-1,4-naphthoquinone; and 2,3-di-n-hexylthio-6-nitro-1,4-naphthoquinone.

PreParation 3 2,3-Dimetho~y-5-aminc-1,4- aphtho~uinone.
(Preparation of Compound~ of Formula (V)).
Hydrazine (4.0 ml, 125 mmol of 97%) was added dropwise, over a 2 hour period, to a stixred mix~ure of t~e captioned compound of Preparation 2 (I9.9 g, 7~.6 mmol), 5% palladium on carbon (10 q) and ethanol (750 ml) in a nitrogen atmosp~ere. The catalyst wa~
filtered off ~hrough a celite pad that was washed with hot ethanol (2 x 3Q0 ml)~ The combined filtrate and washings were 20 concentrated to dryness in vacuo and the residue recrystallized from water:ethanol (1.5:1) gi~ing 14.6 ~
of 2,3-dime~hoxy~5-amino-1,4-naph hoquinone, mp 116-117.
Similarly, substi~uting the compounds ~rom Preparation 2 for 2,3-dimethoxy-5-nitro-1,4-25 naphthoquinone the fo}lowing compounds are prepared:2,3-dlmethoxy-6-amino~1,4-naphtho~uinone, mp 196-lg7C;
2,3-diethoxy-S-amino-1,4-naphtho~uinone;
2,3-diethoxy-6-amino-1,4-naphthoquinone;
2,3-di-n-propoxy-5-amino-1,4-naphthoquinone;
2,3-di-n~propoxy-6-amin~-1,4-naphthoquinone;
2,3-di-i-propoxy-~-amino~Ir4-naph:thoqu:inone 2,3-di-i-propoxy-6-amino-I,4~napnthoquinon2;
2,3-di-n-butoxy-5-amino-1,4-naphtho~ulnone;
2,3-d1-n-butoxy-6-amino-1,4-naphtho~ulnune;

:

7~
-2~-2,3-di-s-butoxy-S-amin~-1,4-naphthoquinone;
2,3-di-s-butoxy-6-amino-1,4-naphthoquinone;
2,3-di-n~pentyloxy-5-amino-1,4-naphtho~uinone;
2,3-di-n-pentyloxy-6-amino-1,4 naphthoquinone;
2,3-di-s-pentyloxy-5-ami~-1,4-naphtho~uinone;
2,3-di-s-pentyloxy-6-amino lr4-napht~oquinone;
2,3-di-n-hexyloxy-5-amino-i!4-naphthoquinone;
2,3 di-n-hexyloxy-6-amino-1,4-naphthoquinone;
2,3-di-i hexyloxy-5-amino-1,4-naphtho~uinone;
2,3-di-i-hexyloxy-6-amino-1,4-naphtho~uinone;
2,3-di(2,2-dimethylpropoxy)-S-amino-1,4 naphthoquinone;
2,3-di~2,2~dimethylpropoxy)-6-amino-1~,4-naphthoquinone;
2,3-dimethylthio-6-amino-1,4-naphthoquinone;
2,3-di-i-propylthio-6-amino-1,4-naph~hoquinone and 2,3-di-n-hexylthio-6-amino-1,4-nap~thoquinone.
.
: Pxeparation 4 S-Chloro-2,3-d~methoxy-1,4-naphtho~inone.
(Preparation o~ ~ompounds of Formula (VI) w~ere R3 is S-chloro).
A solution of sodium nitrite (0.69 g, 10 mmol) in wa~er (S ml) was added at 0-5C to a solution of 5-amino-2,3-dimethoxy-1,4-naphthoquinone (1.17 g, 5 mmol) in 5:1 acetic acid:water (25 ml) containin~ concentra~ed hydrochloric acid (1.7 ml). A further 4uan~ity of i~odium nitrite (0.69 9) was~then added to ~he reaction mixture after ooling to -5C, followed by a solution of cuprous 30 chloride (0.6 ~) in concent~a~ed hydrochloric acid (S :
ml). The mixture was allowed to warm ~o 2~C~ and solid cuprous chloxide was added portionwise unti} the mixture assumed a green color. Water was then added to the r~action mixture and the precipitate~ yellow solid 35 filtered:off, washed with water and recrystallized from -25~ 7~ ~

methanol:water ~2:1) giving 1.01 9 of 5-chloro-2,3-dimethoxy-1,4-naphthoquinone, mp 120-121~C.
Similarly, proceedin~ as above substituting the appropriate compounds for 2,3-dimethoxy-5~amino-1,4-naphtho~uinone the following compound are prepared:
6-chloro-2,3-dimethoxy 1,4-naphthoguinone;
5-chloro-2,3-diethoxy-1,4-naphtho~uinone;
6-chloro-2,3-diethoxy-1,4-~aphthoquinone;
5-chloro-2,3-di-n-propoxy-1,4-naphthoquinone;
6-chloro-2~3-di-n-propoxy-1,4-naphthoquinone;
5-chloro-2,3-di-i-propoxy-1,4-naphthoquinone;
6-chloro-2,3-di-i-propoxy-1,4-naphthoquinone;
5-chloro-2,3-di-n-butoxy-1,4-naphthoquinone;
i~ 6-chloro-2,3-di-n-butoxy-1,4-naphthoquinone;
5-chloro-2,3-di-s-butoxy-1,4-naphthoquinone;
6-chloro-2,3-di-s-butoxy-1,4-naphtho~uinone;
5-chloro-2~3-di-n-pentyloxy-1,4-naphthoquînone;
6-chloro-2,3-di-n-pen~yloxy-1,4-naphthoquinone;
5-chloro-2,3-di-s-pentyloxy-1,4-naphthoquinone;
6-chloro-2,3-di~s-pentyloxy-1,4-naphtho~uinone;
5-cnlorc-2,3di-n-hexyloxy-1,4-naphthoquinone;
6-chloro-2,3-di-n-hexyloxy-1,4-naphthoquinone;
5-chloro-2,3-di-i-hexyloxy-1,4-naphthoquinone;
6-chloro-2,3-di-i-hexyloxy-1,4-naphthoguinone;
5-chloro~2~3-di(2~2-di~ethylpropoxy)-l~4 - naphthoquinone;
6-chloro-2,3-di(2,2-dimethylpropoxy)-1,4-napnthoquinone;
6-methoxy-2,3-dimethoxy-1,4-naphthoquinone;
6-ethoxy-2,3-diethoxy-1,4-naphthoquinone;
6~i-butoxy-2,3-dimethoxy-1,4-naphthoquinonë;
6-phenylethoxy-2,3-dim~thoxy-1,4-naphehoquinone;
6-chloro-2,3-dimethylthio~1,4-naphthoquinone;
6-cnloro-2,3-di-i-propylthio-1,4-naphthyloqinone, and 6-cnloro-2,3-di-n-hexylthio-1,4-naphthyloginone;
: :
7410J 23420-~

~,"''" " ''' ','''"-' .,- ',''' ',.', '''.',';'.''"'.. ''-' ~ ' ''' 26 ~ 7~

Preparation 5 5-Cyano-2,3-dimethoxy~1,4-n~phthoquinone.
(Preparation of Compounds of Formul~ ~VI) where R3 is cyano).
A solution of sodium nitrite (2.21 g, 32 mmol) in water (~ ml) was added at 0-5C to a stirred suspension of 5-amino-2j3-dimethoxy-1,4-naphthoquinone (3.73 g, 16 mmol) in 3:1 water:tetrahydrofuran ~20 ml) containing concentrated hydrochloric acid (6.7 ml) and the resulting lO mixture was stirred at 0-5C for a further 1-1/4 hour.
T~e almost clear solution is then neutralized wi~h sodium carbonate, filtered and added at ~C ~o a vigorously stirred solution of cuprous c~loride (~.75 g) and sodium cyanide (5.88 g) in water (80 ml). Ethyl acetate (100 ml) was added and the mixture is heated Bt 45C for 0.5 hours, filtered througn a celite bed`and separated into the two phases. The agueous phase was extracted with ethyl a~etate (2x 100 ml~. The combined orsanic phases were extracted with brine (1~0 ml), dried over 20 ~gSO4 and concentrated to dryness in vacuo. The ~residue was recrystallized from isopropanol giving 2.96 g of 5-cyano-2,3-d:imethoxy-1,4-naphtho~inone, mp 171-172C.
Similarly, proceeding a~ above the following compou~d is prepared: :
6-cyano-2,3-dimethoxy-1,4-naphthoquinone.

Preparation_6 Di-(;2,3-dimethoxy-1,4-naphtho~uinone-S)-disulfide.
(Preparation of Compounds of Formula (VII)).
A slurry of potassium thiolacetate (l.S y, l~ol :
~: mmol) in dimethylformamide (25 ml~ was added over 10 minutes to a solution a~ 0-5C of 5-amino-2r3-dimethoxy-1,4-naph~hoquinone (2.63 9, 10 mmol) in dimethylformamide ~25 ml). The mixture was allow~d to warm to 22C and, 35 after 2 hours, an additional ~uantity of potassium ~:

~','...,'''. ''..:.'.'..' ', ., ~,, -27- ~ Z ~ 3 tniolacetate (1.2~ g) was added. After a further 45 minute reaction, the mixture was added ~o ice water (500 ml) that was adjusted to p~ 6 with acetic acid. The precipitated solid was filtered off, washed with water and recrystallized from chloroform:methanol (1~ iving 1.32 g. of di(2,3-dimethoxy-1,4-naphtho~uinone-5)-disul~ide, mp 220-221C.

Preparation 7 2-r3-DimethDxy-5-phenylth-io-l~4-naphtho~uinone~
(Preparation of Compounds of ~ormula (VI) wbexe R3 is phenylthio).
Method A. Sodium ni~rite (0.18 9) was added a~
0-5C to a stirred suspension of 5^amino-2,3-dimethoxy-1,4~naphthoquinone (233 mg, 1 mmol) in 0.6 N hydrochloricacid (10 ml) and tetrahydr~furan tl ml). The mixture was stirred at 5C for 10 minutes until a clear solution was obtained and was then neutralized by the addition of sodium carbonate. The ice cold solution was then slowly ad~ed to a ~igorously stirred two-phase mixture in a nitrogen atmosphere at 50C composed of potassium hydroxide (0.16 9), water (10 ml), thiophenol (0.32 ml) and ethyl acetate (35 ml)~ Af~er a total reaction time of 20 min, the mixture was partitioned between ethyl acetate (40 ml) and brine (100 ml). The ethyl acetate phase was dried over MsS04 and concentrate~ .in vacuo.
The residue was purified by chromatography on a thick layer silica gel plate using acetone:toluene:chlorororm (1:20:2D) giving a solid th~t, after recrystallizing ~rom 30 isopropanol, afforded 70 mg of 2,3-dimethoxy-5-phenylthio-1,4-naphthoquinone, ~p 76-77C.
Similarly, using imida201yl-2-~hiol in place of thiophenol t 2,3~dimethoxy-~-(imida201-2-yl)thio-1,4-naphthoquinone, mp 97-10~C, was prepared.

-28- ~ 9 Method B. Thiophenol (6.0 ml, 59 mmol) was added at -30C to a stirred mixture of 100% sodium hydride ~1.4 ~, 59 mmol) and dimethylformamide (200 ml) and the resulting mixture was stirred at 22C for 16 hours. This mixture was then cooled to -50C and a solution of di(2,3-dimethoxy-1,4-naphthoquinone-5)-disulfide (13.0 g, 49 mmol) in dimethylformamide (100 ml3 was added over 30 min. The resul~ing mixture was illowed to warm to 22C
over 1 hour before being cooled to ~50~C and neutralized 10 with acetic acid. (5.4 ml, 90 mmol). The reaction mixture was then poured into a mixture of watPr (1.8 1) and metbanol (700 ml). T~e precipitated makerial was filtered o~f and recrystallized from methanol giving 10.3 g of ~,3-dimethoxy-5-phenylthio-1, 4-naphthoquinone, 15 mp 76-79C. A further amoun~ (2.2 9) mp 76-77C was obtained in a second crop ~rom the recrystalli~ation.
Similarly, substituting of the appropriate thiol for thiophenol and the appropriate compound from Preparation 3, the following compounds are prepared:
2l3-dimethoxy-6-(2-chlorophenylthio)-1,4-naphtho-quinone;
2,3-dimet~oxy-5-(3-chlorophenylthio)-1,4~naph~ho-quinone, mp 125-126C;
2,3-dimethoxy-6-(4-chlorophenylthio)-1,4-naphtho-25 quinone;
2,3-dimethoxy-5-(2,6-dichlorophenylthio)-1,4~naphtho-quinone, mp 158-159C:
2,3-dimethoxy-5-(4~fluorophenylthio)-1,4-naphtho-quinone, mp 124-125C;
2,3-dimethoxy-5-(2-bromophe~yl~hio)-1, 4-naphtho-quinone, mp 152-153~C;
2,3-dimethoxy-6-(4-bromophenylthio)-1,4-naphtho~
quinone;
2l3-die~hoxy-~-(4-methoxyphenylthio)-1,4-naphtho-35 quinone;

.~, ;:;;,. . .. - . ., . .. --.: -. . .

-29~ 7~ a3 2,3-di-n-propoxy-6-(4-nitrophenylthio)-1~4-naphtho quinone;
2,3-di-n~butoxy-6-(2-ethylpbenylthio)-1,4-naphtho-~uinone;
~,3-di-n-pentyloxy-6-pyridin-2-yl~hio-1,4-naphtho-guinone;
2,3-di-n-~exyloxy-6-pyrldin-4-ylthio-1,4-naphtho-quinone; and 2,3dimethoxy-~-(4-acetylaminophenylthio)-10 1,4-naphthoquin.one, mp 118-127CC.

Pre~aration B
2,3-Dimethoxy-5-methv thio-1,4-na~hthoquinone.
(Preparation of Compounds of Formula (VI) where R3 is 15 methylthio).
Sodium boro~ydride (100 mg) was added portionwise to a stirred suspension of di(2,3-dimethoxy-1,4-naphtho-~uinone-5)-disulfide ~0.5 9, 1 mmol) in 7:1 tetrahydrofuran:isopropanol (40 ml) in a nitrogen 20 atmosphere until TLC analysis indicated that no starting material remains. Methyl iodide (0~2 ml) was then added and, after 5 minutes, the reaction mixture was poured into i~e water (300 ml). 10% ~erric chloride (10 ml) was sub~e~uently ad~ed. The precipitated solid w2S filtered 25 of~, washed wi~h water and recrystallized from isopropanol givin~ O . 36 g of 2, 3-dimethoxy-5-methylthio 1,4-naphthoguinone, mp 112-113C.
By substitutin~ other alkyl iod~des for methyl iodide the following are prepared;
2,3-dimethoxy-6-methylthio-1,4-naphthoquinone;
2,3-dimethoxy-5-benzylthio-1,4-naphthoguinone, : :: m.p~ 142W143~C;
2,3-dimethoxy-6-ethylthi~-1,4-naphtbo~uinone; and 2,3-dimethoxy-5-methoxycarbonylmethylthio-1,4 3~ naphtho~uinone, m.p. 119-120C.

7410J ~ 23420~F~

o ~30- ~ 2 Preparation 9 2,3-Dimethoxy-5-(4-methylpyridiniumthio~-1,4-naphtho-~uinone methYl sul ate.
A mixture of dimethylsulfate (0.19 ml, 2 mmol) and 2,3-dimethoxy-5-(4-metbylpyridinylthio)-1,4-naphthoquinone (327 mg, 1 mmol) in tetrahydrofuran (10 ml) was heated under re~lux for 3 hours and-then cooled to 20C. The orange s~lid was filtered off, w~shed with tetrahydrofuran and recrystallized from 10 e~hanol:isopropanol giving 279 mg of 2,3 dimethoxy-5-(4-methylpyridiniumthio)-1,4-naphtho-~uinone methyl sulfate mp 160-162C and a second crop of 110 mg.
Similarly prepared is 2,3-dimethoxy-5-(2-methyl-pyridiniumthio)-1,4-naphthoquinone methyl sulfate.
Similarly, the following compounds are prepared by the above method:
2,3-dimethoxy-5-(~-methylpyridiniumsulfinyl)-1,4-naphthoguinone met~yl sulfate, m.p. 175 - 176~C; and 202,3-diemthoxy-~-(4-methylpyridiniumsulfinyl)-1,4-naph~hoquinoile methyl sulfate, m p. 175 - 176C.

Preparation 10 (Preparation of compounds of formula IX) wherein 25 R3 is 6-Chloro) A. Into a solution of 6-chloro-1,4-naphthoquinone (193 g) in g}acial acetic acid ~1600 mL) was bubbled chlorine gas un~il TLC of an aliquot showed complete disappearance of 6-chloro-1,4-naphthoquinone. The 30 resulting precipitate was collected by filtration, an~
washed with acetic acid ~200 mL) and hexane (2.X 300 mL) and air dried to yield t~e 2,3,~-trichloro-2,3-dinydro-1,4-naphtho~uinone (157 g)O The solid was transferred into a flask eguipped with a mechanical stirrer and 35 reflux condenser. Sodium acetate (98.4 9) and ace~ic 7410J - 2342Q-F~

-31~ t~

acid (1.5 L~ were ~dded, and into the suspension was bubbled chlorine gas. T~e mixture was brought to reflux and maintained there for 2 hours. The cooled mixture was poured over water (3.5 L), and the resulting precipitate 5 was collected by filtration, and was washed with water (2 x 500 mL), air dried and then vacuum dried over phosphorus pentoxide, to yield 2,3,6-trichloro-1,4-naphthoquinone (139 9), mp 14~5-148.5~C.
Similarly, using the above procedure are prepared:
6-bromo-2,3-dichloro-1,4 naphthoquinone;
6-fluoro-2, 3-dichloro-1 ,4-naphthoquinone;
6-methyl-2,3-dichloro-1,4-naphthoquinone;
6-i-propyl~2,3-dichloro-1,4-naphthoquinone;
6-phenyl-2,3-dichloro-1,4-naphtho~uinone; and 6-benzyl-2, 3-dichloro-1, 4-napntho~uinone. .
B. Into a suspension of 6-chloro-lr4-naphthoquinone ~100 9, 520 mmol) in aceti~ acid (800 mL) heated to 70C
with mechanical stirring was bubbled chlorine gas.
Heating was increased to bring the mixture to reflux, at 2ownich time solid iodine (13.2 g, }04 mmol, 0.2 eq.) was added. Chlorine addition at reflux was continued until ThC showed complete conversion to product, 7-10 hours total. The reaction was cooled to give a thick precipitate of product, collected by filtration. A
25~econd crop was obtained by concentration and/or dilution with water. Tot~l yield of dried product 2,3,6-trichloro-1,~-naph~hoquinone is 121.2 g (464 mmol, 89%), mp 147.5-148.5C. ~nal. Calcd. fo~
CloH3C13O~: C, 45.93; Ht 1.17; Cl, 40.67. Found:
30CO 46.05; H, 1.17; Cl, 40.56.
:
Preparation 11 ~Preparation of compounds of fQrmula (VI) wherein R3 is 6-chloro) 7410J ~34~0-F~

32 ~fi7f~ 9 To a mechanically stirred solution of sodium methoxide (55.5 g) in anhydrous methanol (}.5 ~) under a blanket of nitrogen was added 2,3,6~trichloro-1,4-naphtho-~uinone ~rom Preparation 10 (130 9) as rapidly as possibleu The temperature rose to 50C during the addition, and the reaction was then heated to reflux for 1 hour. The mixture was cooled and acidified with 6M
hydrochlvric acid to give a brilliant yellow color.
After the addition of water (3~0 mL), the reaction 10 mixture was filtered, and the precipitate was washed with aqueous methanol (4:1 water-methanol) until the filtrate was yellow orange.. The precipitate was air dried to yield 6-chloro-2,3-dimethoxy-1,4--naphthoquinone (102 9), mp 125-126 C.
: 15 Similarly, using the above procedure, the following compounds are prepared: .
6-bromo-2,3-dimethoxy-1,4-naphthoquinone;
6-fluoro-2,3-dimethoxy-1,4-naphthoquinone;
6~chloro-2,3-diethoxy-1,4-naphthoquinone;
6-methyl-2,3-dimethoxy-1,4-naphtho~uinone;
6-i-propyl-2,3-dimetnoxy-1~4-naphthoquinone;
6-phenyl-2,3-dimethoxy-1 r ~ -naphthoquinone; and 6-benzyl-2~3-dimethoxy-1,4-naphthoquinone.

Preparation 12 A. To a solution of sodium-n-butoxide.(25.8 ~) in dry dimethylformamide (125 ml) was added 2,3g6-trichloro-1,4^naphthoquinone (28 g) in one amoun~. ~he mixture was refluxed ~or 2 ~ours, then cooled, acidified with 6M
30 hydrochloric acid and eYaporated. The residue was chromatogxaphed over silica gel using dichloromethane as eluant to yield 2,3-di-n-~utyloxy-6-chloro-1,4-nap~thoquinQne (12.3 g) as a red oily solid.
B. Similarly, proceeding as above in Part ~, 35 su~stituting the appropriate compound for 7410J 234~0-FF

! -33- ~ 2 ~ 78~t9 2,3,6-trichloro-1,4-naphthoquinone and ~he appr~priate sodium alkoxide for sodium-n-butoxide, the following compounds are prepared:
6-chloro-2,3-di-i-butoxy-},4-naphtho~uinone;
6-chloro-2,3-(2,2 dimethylpropoxy)-1,4-naphthoquinone;
2,3-di-~-butoxy-1,4-naphtho~uinone;
2,3-di(2,2-dimethylpropoxy)~--1,4-naph~h~quinone; and 2,3-di-n-hexyloxy-1,4-naphtho~uinone.
10 C. Similarly, proceeding as above in Part A, substituting the appropriate sodium salt of alkyl mercaptan for sodium-n-b~toxide, the following compounds, l~ for example, are prepared:
6-chloro-2,3-dimethylthio-1,4-naphthoquinone;
1~ 6-chloro-2,3-di-i-propylthio-I/4-naphthoquinone;
6-chloro-2,3-di-n-hexylthio-1,4-napht~oquinone; and 2,3-dimethylthio 1,4-naphthoquinone.

Preparation 13 (Compound of formula (VI) wherein ~3 is hydrogen) To a mechanically stirred solution of sodium methoxide (11.1 g) in anhydrous methanol (200 mL) un~er a blanket of nitrogen was added 2,3-dichloro-1,4-naphthoquinone (22.7 ~) as rapidly as possible. The temperature rose to 50C during tbe addition, and ~he reaction was then heated to reflux for 1 hour. The mixture was cooled and acidified with 6M hydrochloric acid'to give a brilliant yellow color. A~ter the addition of water (800 mL), the reaction mixture was 30 filtered~ and tne precipi~ate was washed~with aqueous methanol (4:1 water-methanol) until the filtrate was yellow-srange. The precipitate ~as air dried to yield 21.2 g of 2,3-dimethoxy-1,4-naphtho~uinone, mOp. 116-117C.

.

7~

Similarly, substituting the appropriate ~odium alkoxide for ~odium methoxide the following compound~ are prepared.
2,3-diethoxy~1,4-naphthoquinone;
2,3-di-n-propoxy-1,4-naphthoquinone;

A. A solution of 6-chloro-2,3-~imethoxy-1,4-naphtho-quinone ~50.5 9, 200 mmol) in tetrahydrofuran (500 mL) was hydrogenated at atmospheric prssure over palladium-on-c~barcoal ~10%~ 5.0 g) until the solution was colorless, approximately 4 hours.
B. While still under a ~lanket of hydrogen, a solution o~ acetic anhydride ~47 mL) pyridine (40 mL) and DMAP
1~ (1.22 g) in tetrahydrofuran (50 mL) was added to the mixture. After stirring for 1 hour, the mixture was evaporated. The residue was dissolved in ether (500 mL) and was wasned with lM ~Cl (3 x 250 mL) and with brine (2 x 250 mL). The organic layer wa.~ dried over sodium ~ sulfate, ~iltered, and evaporated to give an oil which crystallized at high vacuum. Recrystalliz~tin from ether-petroleum ether af~orded 6-chloro-1,4-diacetyloxy- :
2,3-dimethoxynaphthalene, m.p. g3-94C.
Simil~rly, using he above procedure substituting the appropriate compound of formula (VI) or 6ochlvrQ-2,3-dimethoxy-1,4-nap~tho~uinone, where ap~ropriate, and the appropriate acid anhydride for ace~ic annydride, - where appr~opriate, ~he following compounds are prepare~:
6-chlor~-2,3dime-thoxy-1,4-di-n-propanoyloxy-naphthalene; ~ ~
: 6-chloro-2,3-dimethoxy-1,4~di-i-butanoyloxy naphthalene; ~ `
6-chloro-2,3-dimethoxy-1,4-di~2,2-dimethylpropanoyl-oxy)naphthalene;
35 . : : :

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6-chloro-2,3-dimethoxy-1,4-di-n octanoyloxy-naphthalene;
6-chloro-2,3-di-n-butoxy-1,4-dii~cetyloxynaphthalene;
6-chloro-2,3-~i-s-butoxy-1,4-diacetyloxynaphthalene;
6-chloro-2,3-di(2,2 dimethylpropoxy)-1,4-diacetyloxy-naphthalene;
2,3-di-n-butoxy-1,4-di-n-pe~toyloxynapbthalene;
6-chloro-2,3-di-n propoxy-1,4-dipropanoyloxy-naphthalene;
6-chl~ror-2;3-di-i~propoxy-l~4-dioctan naphthalene;
6-bromo-2,3-dimethoxy-1,4-diacetyloxynaphthalene;
6-fluoro-2,3-dimethoxy-1,4-diacetyloxynaphthalene;
5-chloro-2,3-dimethoxy-1,4 diacetyloxynaphthalene;
5 cyano-2,3-dimethoxy-1,4-diacetyloxynaphthalene;
6-cyano-2,3-dimethoxy-1,4-diacetyloxynaphthalene;
6-methylamino-2,3-dimethoxy-1,4-dia~etyloxy-naphthalene;
6-diethylamin~-2,3-dimethoxy-1,4-dipropanoyl-20 oxynaphthalene;
6-ethylmethylamino-2,3 dimethoxy-1,4-di-n-butanoyl-oxynaphthalene;
6-methoxy-2,3-dimethoxy-1,4~di-n-pentanoyl-oxynaphthalene~;
6-ethoxy-2,3-diethoxy-1,4-di-n-hexanoyl-oxynaphthalene;
6-i bu~oxy-2,3~dimet~,oxy-1,4~di~2,2 dimethyl-propanoyloxy~naphtnalene;
6-pr.enylethoxy-2,3-dimethoxy-1,4-diacetyloxy-naphthalene;
6-methyl-~,3-dimethoxy-1,4-diacetyloxyn~phthalene;
6-i-propyl-2,3 dimethoxy-1,4-di n-octanoyl-oxynaphthalene;
6-pnenyl-2,3-dimethoxy-I,4-diacetyloxynapht~alene;
6~benzyl-2,3-dime~hoxy-1,4-dipropanoyloxynaphthalene;

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5-chloro-2,3-di-n-pentyloxy-1,4-di-n-butanoyloxy-naphthalene;
5-chloro-2,3-di-s-pentyloxy-1,4-diacetyl-oxynaphthalene;
5-chloro-2,3-di-n-hexyloxy-1,4-di n-octanoyl oxynaphthalene; ~-5-chloro-2,3-di-i-hexyloxy-1,4-diacetyloxy-naphthalene;
6-chloro-2,3-dimethyl~hio-1,4-diacetyloxynaphthalene;
6-chloro-2;3-di-i-propylthio-1,4-diacetyloxy-naphthalene, 6-chloro-2,3-di-n-hexylthio-1,4-diacetyloxy-naphthalene;
2,3-dimethoxy-6-~2-chlorophenylt~io)-1,4-diacetyloxy-naphthalene;
2,3-dimethoxy-5-(3-chlorophenylthio)-1,4-diacetyloxy-naphtnalene;
2,3~dimethoxy-6-~4-chlorophenylthio)-1,4-diacetyloxy-napnthalene;
2,3-dimethoxy-5-(2,6-dichlorophenylthio)-1,4-diacetyl-oxynaphthalene;
2,3-dimethoxy-5-(4-fluorophenylthio)-1,4 diacetyloxy-naphthalene;
2,3-dimethoxy-5-(2-bromophenylthio)-1,4-diacetyloxy-25 napntnalene, 2,3-dimethoxy-6-(4-bromophenylthio)-1,~-diacetyloxy-naphthalene;
2,3-diethoxy-6-(4-methoxyphenylthio)-l,~diacetyloxy-naphthalene; :
: 30 2,3-dipropoxy-6-(4-nitroph~nyl~hio)-1,4-diacetyloxy-: :
naphthalene;
: 2,3-di-n-butoxy-6-(2-ethylp~enylthio)-l,4-diacetyloxy naphthalene; ~
: ~ 2,3-di-n-pentyloxy-6-pyridin-2-ylthio-1,4-dlacetyloxy-35 napht~alene; ~

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12~ 9 - 3 ~ -2,3-di-n-hexyloxy-6-pyridin-4-ylthio-1,4-diacetyl-oxynaphthalene; and 2,3-dimethoxy-5-(4-acetylaminophenylthio)--1,4-di-acetyloxynaphthalene.

A solu~ion of 2,3-dimethoxy-1,4-naphtho~inone (20.0 g) in tetrahydrofuran (150 m~) was hydrogenated at atmospneric pressure over Pd-C (10~, 0.5 g) until t~e 10 solution was colorless, approximately 4 hours. While still under a blanket of hydrogen, a solution of acetic anhydride (20 mL~ and pyridine (18 mL) in tetrahydrofuran (S0 mL) was added to the mixture. After stirring for 1 hour, the mixture was evaporated. The residue was dissolved in ether (100 mL) and was washed with lM
hydrochloric acid (3 x 5Q mL) and with brine (2 x 50 mL). The organic layer was dried over sodium sulfate, filtered, and evaporated. Recrystallization from eth3r afforded 2,3-dimethoxy-1,4-diacetyloxynaphthalene (22.5:g), m.p. 138-139C.
Similarly proceeding as above, substi~uting the appropriate compound for 2, 3-dimethoxy-1~4naph~hoguinone and the appropriate acid ~nhydride, where appropriate, for acetic anhydride, t~e following compounds, for 25 example, are prepared:
2,3-di-n~propoxy-1,4-di-n-propanoylox~naphthalene;
2,3-di-s-butoxy-1~4 di-i-butanoyloxynaphtnalene;
2,3-di(2,2~dimethylpropoxy)-1,4-di-n-pentanoyl-oxynaphthalene;
2t3-di-n-hpxyloxy-lt4-di(2~2-dimethylpropanoyloxy) naphthalene;
2,3-dimetnoxy-1,4-di-n-propanoyloxynaphthalene;
2,3-dietnsxy-1,4-diacetyloxynaphthalene; and 2,3-dimethylthio-1,4-diacetyloxynaphthalene.

' EXA~IPLE 3 ~Preparation of Compounds of Formula (I) where R3 is , phenylsulfinyl).
Forty percent (w/v) peracetic acid in acetic acid ~1 ml) is added over 30 minutes to a solution of 2,3-dimethoxy-5-phenylthio-1,4-diacetyloxynaphthalene (0.98 g, ~ mmol) in methylene chloride (15 ml). Excess p~racetic acid is destroyed by the addition of a few milligrams of 5% palladium on carbon and the mixture filtered through a celite*bed. The filtrate is concentrated in vacuo and the xesidue recrystallized from methanol giving 0.59 9 of 2,3-dimethoxy-5-phenylsulfinyl-1,4-diacetyloxynaphthalene.
Similarly, using either peracetic acid or 15 m-chloroperbenzoic acid, the following compounds are prepared from the respective thio compounds:
2,3-dimethoxy-5-(imidazol-2-ylsulfinyl)-1,4-diacetyl-oxynaphthalene;
2,3-dimetnoxy-6-(2-chlorophenylsulfinyl)-1,4-diacetyl-20 Oxynaphtnalene;
2,3-dimetnoxy-5-(3-chlorophenylsulfinyl)-1~4-diacetyl-oxynaphthalene;
2~3-dimethoxy-6-(4-chlorophenylsulfinyl)-1,4-diacetyl oxynaphthalene;
2,3-dimethoxy-5-(2,6-~ichlorophenylsulfinyl)-1,4-di-acetyloxynap~Jthalene~; ' 2,3-dimethoxy-5-(4-fluorophenylsulfinyl)-1,4-diacetyl-oxynaphthalene;
2,3-dimethoxy-5-(2-bromophenylsulfinyl)-1,4 diacetyl-oxynaphthalene;
2,3-dimethoxy-5-(4-bromopnenylsulfinyl)-1,4-diacetyl oxynaphthalene;
2,3-diethoxy-6-(4-methoxyphenylsulfinyl)-1,4-diacetyl~
oxynaphthalene;
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2,3-dipropoxy 6-~4-nitrophenylsulfinyl~-1,4-diacetyl-oxynaphthalene;
2,3-di-n-butoxy-6-~2-ethylphenylsulfinyl)~ di-acetyloxynaphthalene;
2,3-dimethoxy-6-(pyrimidin-2-ylsulfinyl)-1~4-di-acetyloxynaphthalene; ~
2,3-dimethoxy-5-(pyrimidin-4-ylsulfinyl)-1,4-diacetyl-oxynaphthalene;
2,3-dimethoxy-6-methylsulfinyl-1l4-diacetyloxy~
10 naphthalene;
2,3-dimethoxy-5-benzylsulfinyl-1,4-diacetyloxy-naphthalene; and 2,3-dimethoxy-5-methsxycarbonylmethylsulfinyl-1,4-di-ace~yloxynapnthalene.

2,3-Dimethoxy-S-phenylsulfonyl-1,4-diacety~loxy-naPhthalene .
(Preparation of Compound of Formula tI) where R3 is 20 phenylsulfonyl).
A mixture of m-chloroperbenzoic acid (300 mg) and 2,3-dimethoxy-5-phenylthio~ naphthoguinone (200 mgr 0.61 mmol) in methylene chloride ~5 ml) is stirred at 22C for 16 hours and the re~ulting solution then passed 25 tnrough an alumina column (10 g of Activity 1) eluting with chloroform. The eluates are concentrated to dryness and the residue is crystallized from isopropanol giving 95 mg of 2,3-dimethoxy-5-pnenylsulfonyl-1,4-diacetyloxynaphthalene.
EXAMPLY
The compounds of the invention prepared accQrding to the previous Examples, and their characterizing data, are conveniently summarized in the ~able below:

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OCO~

R3~R2 C~W
. --R3 ~ ~2 mp _ _ _ . _ H CH3 c~3138-~39 ~t c~3111-112 n-Pr CH3 53-54 i-Pr CH3 95-96 t-Bu C~3178-180 5-Cl c~3 CH3133-1349 t-Bu ~H31~3-130 6-F CH3 c~3102-103 15 6-Br c~3 C~3102-103 6-Cl C~ C~393-94 Et C~384-~5 n-Pr CH3 oil i-Pr C~364-65 t-Bu C~3132-133 c~3 Et 91-92 Et Et 81-82 i-Pr Et77-78 9 6-Cl t-Bu Et104-105 i-Pr n-Pr51-52 t-Bu n-Pr59-60 C~3 n-Bu74-75 : 25 5-C~30 CH3 CH369-70 Et c~372-73~
t-Bu : C~3153-1~4 6-C~30 Et CH386-87 t-BU C~3amorphous :~
30 5 CN CH3 ~ c~3 152-1539 6-CN CH3 ~13 12~-125 5-NHAc C~3 C~3 l~f7-178 : 35 -41~ 7~9 6-Cl C~3 n-Pr 53-54 Et n-Pr 39-40 n-Pr n-Pr 28-29 C~3 i-Pr132-133 Et i-Pr SB-59 n-Pr i-Pr oil i-Pr i-Pr oil t-Bu i-Pr oil 6-OCH3 CH3 CH~ 77-~8 5-CH3 CH3 c~3114-115 Et CH3 i-Pr CH3 ~ t-Bu C~3 E.t CH3 57-58 -Pr CH3 oil ` t-Bu C~3110-1~11 15 5-SPh CH3 c~3138-140 EXAMPLE _6 Toxicity The LD~o f 6-chloro-1,4-diacetyloxy-2,3-dimethoxynaphthalene (the compound~ was examined as follows:
Acute Subcutaneous Dosin~
Nice were given single subcutaneous doses of up to 25640 mg/kg of the compound, and observed for thxee weeks.
No deaths occurrea during this study. The subcutaneous LD50 f the compound in mice was estimated to be grea~er than 640 mg/kg.
~C9~La9~
~ice were given single oral doses of up to 1280 mg/kg of the compound~ and observed ~or three we~ks.
Dose relateà~deaths occurred in 1/12 mlce dosed with 640 mg/kg, and in 4/12 mice dosed wit~ 12B0 mg/kg. T~le oraI
LD50 f the compound in mice was estimated to be 35greater than 1280 ms/kg~
::

, -42- ~2~7 EX,AMPLE ?
Biological Data As indicative of anti-psoriatic activity/ the following test was carried out.

Test for Topical Anti-inflammatory ~ctivity by Inhibition of Arachidonic Acid~Induced Mouse Ear Edema MATERIA~S AND METHODS
Male or female Swiss Webster mice weiyhing lB-27 g were randomly assiyned to treatment groups of 8 ~r l0 animals, caged together, and given food and water ad libitum.

The test materials were prepared as solutions or 15 suspensions in reagent grade acetone at a dose level of l00 mg/ml and arachidonic acid was prepared as a solution in acetone also at l00 mg/ml. The te~t materials were applied to tne right ears of mice by means o~ an -automatic microliter pipet so that l0 ~l of solution 20 was applied to each of the inner and outer surfaces.
Each ear therefore received a total of 20 ~l of solution containing 2 mg of test materialr One hour after application of the test mater~al, the arachidonic acid solution was applied in ~ne same manner. One hour 25 after the arachidonic acid application the animals were sacrific~d by cervical dislocation and the rigrJt ears were removed. An 8 mm disc was punched from each ear with a biopsy punch, and the discs were weighed t~ t~e nearest 0~.l m~. For the purpose OI- de~ermining the 30 anti-inflammatory effect of test ma erials a negative control ~roup receiving two appl~cations of acetone only, and a positive control group receiving aceton~ alone followed by arachidonic acid were run in each experiment. The perc~nt inhibi ion resultlng from 35 treatment with tne test material was calculated as follows:

~2~7~ ~9 -43~
. _ Plug wt. (Pos. Control~ - Plug wt~ (Treated) l00 % Inhlb- Plug wt~ (Pos. Control) - Plug wt. (Neg. control) X
RESULTS
Table Inhibition of Arachidonic ACid Induced ~ouse Ear Inflammation OR
1D~ R2 R R2 X Y % Edema In~ibition 15 COCB3 ~ CH3 Cl H. Sl : COCH2CH3 CH3 Cl ~ 49 COCH(CH3)2 CH3 Cl ~ 23 COCH3 CH2C~3 Cl ~ 38 ~: COCH2CH3 ~ CH2CH3 ~ Cl H 50 20 COC(C~3)3 CH2CH3 ~~ Cl ~ ~ l9 COCH~CH3~2 CH2CH2CH3Cl H 28 COCH3 ~H2C~2CH2CH3 23 COC~3 c~3 ; H H ~9 ~:
COC~X3 CH3 ; H H 33 25 CCH2CH2C~2CH3 C~3 H H 59 COC~(CH3)23 ~ ~ ~ 53 COCH3: CH3 F H 40 : COC~3~ C~3 ~~r ~ ~ 42 COCH2CH3~ CH3 O~3 ~ : 49 : 30 COCR3 ~ :~ CH3 ~ H~ ~OCH3 4~
COCH2CH3 ~ ~ C~3 ~ ~ OCH3 ~57 . ~COCH3 ;~ CH3 ~ ~ ~; CN 2~

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Claims (2)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A composition in a form suitable for topical administration for treating the condition of psoriasis which comprises a psoriasis treating amount of 2,3-dimethoxy-1,4-diacetyloxynaphthalene and a pharmaceutically acceptable non-toxic carrier.

2. The use of a composition comprising a psoriasis treating amount of 2,3-dimethoxy-1,4-diacetyloxynaphthalene and a pharmaceutically acceptable non-toxic carrier for treating the condition of psoriasis.