WO1988003800A1

WO1988003800A1 - Lipoxygenase inhibitors

Info

Publication number: WO1988003800A1
Application number: PCT/US1986/002548
Authority: WO
Inventors: Russell T. Jordan; Larry M. Allen
Original assignee: Chemex Pharmaceuticals Inc
Current assignee: Abeona Therapeutics Inc
Priority date: 1986-11-19
Filing date: 1986-11-19
Publication date: 1988-06-02
Anticipated expiration: 1989-05-19
Also published as: EP0289506A1; AU6811690A; EP0289506A4; KR890700023A; JPH01501790A

Abstract

Methods of using a number of compounds for the inhibition of lipoxygenase in warm blooded animals. Pathological conditions which may be treated by the compounds described herein include psoriasis and other skin disorders involving scaling and epidermal cellular proliferation, inflammatory disorder, skin allergies, insect bites, allergic rhinitis, conjunctivitis, hay fever, bronchial asthma, allergic gastroenteritis, uterine contractions, hyperactivity of the colon and bronchospasms.

Description

LIPOXYGENASE INHIBITORS

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to the use of certain organic compounds as inhibitors of the lipoxygenase pathway of the arachidonic acid.

2. The Prior Art

A number of lipoxygenase inhibitors are known. F. Fiebrich, et al., in "Silymarin, an Inhibitor of

Lipoxygenase," Experientia 35 (1979) at 1548 report the silymarin constituents silybin, silydianin, and silychristin as lipoxygenase inhibitors.

J. Baumanor, et al., "Flavonoids and Related Compounds as Inhibitors of Arachidonic Acid Peroxidation,"

Prostaglandins, Vol. 20, No. 4, p. 627-37, October, 1980, list a number of lipoxygenase and cyclo-oxygenase pathway inhibitors and compare their abilities to inhibit each pathway. The most effective lipoxygenase inhibitors listed are 2-aminoethyl-4-t-6-iodephenol (MK447), diphenylthio-carbazone, phenidone, BW 755C, 1,5-dihydroxynaphthalene, 2,3-dihydroxynaphthalene, 1,3-dihydroxynaphthalene, and mefenamic acid, of which the first two appear to have a high degree of specificity for lipoxygenase inhibition. This article also reports that silybin, rutin, tetra- hydroxyethlyquercetin, trihydroxyethylquercetin, trihydroxyethylrutin predominantly inhibit lipoxygenase, while luteolin, dihydroxyflavone, morin and galangin inhibit both pathways. K.V. Honn, et al., in "Nafazatrom (Bay g 6575) inhibition of Tumor Cell Liposygenase Activity and Celluar Proliferation," FEBS Letters, Vol. 139, No. 1, p. 65-68, March, 1982, describe nafazatrom as a selective lipoxygenase inhibitor. R.V. Panganamala, et al., in "Differential Inhibitory Effects of Vitamin E and other Antioxidants in Prostaglandin Synthetase, Platelet Aggregation and Lipoxidase/"Prostaqlandins, Vol. 14, No. 2, p. 261-64, August, 1977, describe d1-2-tocopherol, BHT and Trolox C as specific inhibitors of lipoxygenase and describe the following compounds as non-specific inhibitors of lipoxygenase: alpha-naphthol, propyl gallate and NDGA. K» Yasumoto, et al., in "Effect of Phenolic Antioxidants on Lipoxygenase Reaction," Agr. Biol. Chem, Vol. 34, No. 8, p. 1162-68, 1970, list and rank (in order given) the following compounds as lipoxygenase inhibitors: NDGA, quercetin, propyl gallate, alpha-tocopherol, alpha- naphthol, homocathchol, pyrochtechol, BHA, BHT, hydroquinone, ploroglucinol, purogallol, resorcinol. Y. Kosihara, et al., in "Selective Inhibition of 5- Lipoxygenase by Natural Compounds Isolated from Chinese Plants, Artemisia rubripes Nakai," FEBS, Vol. 158, No. 1, p. 41, July 1983, describe caffeic acid, eupatilin and 4'-demethyleupatilin as selective inhibitors of the 5-lipoxygenase pathway.

A number of compounds structurally similar to arachidonic acid and its derivatives have been disclosed a lipoxygenase inhibitors. M.O. Fink, Jr., et al., in "A New Class of Lipoxygenase Inhibitor. Polyunsaturated Fatty Acids Containing Sulfur," Bioch. and Bioph. Res. Comm. , Vol. 114, No. 3, p. 937-43, 1983, describe 13- thia-9(Z), 11(E)-octadecadienoic acid as soybean lipoxygenase- inhibitors. CD. Perchonock, et al., in "Dimethyleicosatrienoic Acids: Inhibitors of the 5- lipoxygenase Enzyme," Tetrahedron Letters, Vol. 24, No. 24, p. 2457-60, 1983, describe 7,7'- and 10,10'- dimethyleicosa-5 (Z), 8(Z), 11(Z)-trienoic acids as 5- lipoxygenase inhibitors. J.R. Pfister et al., in "Synthesis of Three Potential Inhibitors of Leukotriene Biosynthesis," J. Medicinal Chemistry, Vol. 26, No. 8, p. 1100-03, 1983, describe 5, 6-benzoarachidonic acid as a 5-lipoxygenase inhibitor. PCT Patent Application, K.C. Nicolau, "Leukotriene Analogues," filed in the U.S. November 27, 1981, published in the PCT Gazette as No. WO 83/01897 on June 9, 1983, describes a number of leukotriene A4 derivative analogues having a cyclopropane instead of an epoxide ring, particularly 5,6-methanoleukotriene A4 derivative analogues having a cyclopropane instead of an epoxide ring, particularly 5,6-methanoleukotriene A4 analogues, as effective 5- lipoxygenase inhibitors. J.J. Voorhees, et al., "Leukotrienes and other Lipoxygenase Products in the Pathogenesis and Therapy of Psoriasis and Other Derma toses," Arch. Dermato., Vol. 119, 541,47, July, 1983 list the following compunds as inhibiting the 5- and/or 12- lipoxygenase pathways: falvonids, e.g. rutin or quercetin, ETYA (5,8,11,14 eicosatraynoic acid) and other acetylenic analogues of arachadonic acid, U-60, 257, a prostaglandin-type compound, NDGA, BW 755C, a pyrazoline derivative, timegadine, 5,6- methanoleukotriene A. and AA 861, a benzoquinone derivative.

Lipoxygenase has been shown to be an iron-containing enzyme, and H.W. Chan in "Soya-bean Lipoxygenase: and Iron-containing Dioxygenase," Biochimica et Biophysica Acta, 327, p. 32-35, 1973, describes the chelators diphenylthiocarbazonem 1,10-phenanthroline, 2,2'- dipyridyl, 3-hydroxyquinoline, KCN and EDTA as inhibitors of soybean lipoxygenase. J.E. Greenwald, et al., in "Role of Ferric Iron in Platelet Lipoxygenase Activity," Bioch. and Bioph. Res. Communications., Vol. 96, No. 2, p. 817-822, September 30, 1980, describe the ability of EDTA, EGTA, ferron and orthophenanthrolene to inhibit human platelet lipoxygenase as being direct correlation with the avidity of these compounds for ferric ion.

M. Hamberg, et al., in "On the Specificity of the Oxygenation of ϋnsaturated Fatty Acids Catalyzed by Soybean Lipoxidase," J. Biol. Chem., Vol. 242, No. 22, pp. 5329-5335, November, 1967, describe the stereospecificity of enzymatic attack on eicosatrienoic acids.

Arachidonic acid derivatives through the lipoxygenase pathway and their physiologocal effects have been discussed in a number of recent publications. Several key articles discussing the subject are: N. Nelson, et al., "Prostaglandins and the Arachidonic Acid Cascade," Chem. & Enq. News, Vol. 60, p. 30, August 16, 1982; B. Samuelson, et al., "Introduction of a Nomenclature: Leukotrienes," Prostaglandins, Vol. 17, No. 6, p. 785- 87, June, 1979; B. Samuelson, "Leukotrienes: Mediators of Immediate Hypersensitivity Reactions and Inflammation," Science, Vol. 220, p. 568-75, May 6, 1983; and R.H. Green, et al. "Leokutrienes," Tetrahedron, Vol. 39, No. 10, p. 1687-1721, 1983.

These chemicals have been reported as important in the promotion of skin tumors by TPA, in the promotion of chemotaxis of polymprphonuclear leukocytes in inflammation, in the promotion of the release of slow reacting substances of anaphylaxis, promotion of release of neutrophil lyosomal enxyme, promotion of release of glucose-induced insulin secretion, promotion of histamine release, stimulation of colonic secretions, stimulation of degranulation of neutrophils, and stimulation of thromboxane, prostaglandins and other cyclooxygenase pathway derivatives of arachodinic acid.

None of the foregoing prior art describes the ability of the compounds of this invention to inhibit lipoxygenase.

Summary of the Invention

This invention provides methods of using a number of compounds for the inhibition of lipoxygenase in humans. Pathological conditions which may be treated by the compounds described herein include psoriasis and other skin disorders involving scaling and epidermal cell proliferation, inflammatory disorders skin allergies, insect bites, allergic rhinitis, conjunctivitis, hay fever, bronchial asthma, allergic gastroenteritis, uterine contractions, hyperactivity of the colon and bronchospasms.

DETAILED DESCRIPTION

(a) Compounds

The catecholic butanes useful in the compositions of the instant invention are of the formula

wherein, D,E,F,X,Y,Z, may be H;OH; O-Alkyl or O-Acyl optionally substituted with hydroxy, alkoxy, substituted amino, carboxyl, or carbalkoxyl;

R₁-R₆ may be H; lower alkyl or lower alkoxyl optionally substituted with hydroxy, alkoxy, substituted amino, carboxyl, or carbalkoxyl; hydroxy; carbonyl; alkoxy; aryl; aralkyl;

n may be 0 to 5;

any of the aromatic rings in the molecule may contain up to 3 substituents from the following list: hydroxy; alkenoxy; alkyl, alkoxy or alkanoyl optionally substituted by hydroxy, alkoxy, substituted amino, carboxy, or carbalkoxy; CF₃; Halo; carboxy; carbalkoxy; cyano; hydroxymethyl; sulfonic acid; sulfonamido; aminosulfonyl (i.e. - NHSO₂R); nitro; alkoxy carbonyloxy; aminocarbonyloxy; aroyloxy; aralkanoyloxy; heteroaroyloxy; glycosidyloxy; and

any two phenolic groups may be joined together by the following groups:

either of the rings A or B may be replaced by cyclohexyl, napthyl, tetrahydronapthyl, pyridyl, piperidinyl, quinolinyl, indanyl, indenyl;

any of the groups R₁ to R₆ may be joined together to form together with the other carbons to which they are attached, a 5, 6, or 7 membered ring optionally interrupted by an oxygen atom, or containing an oxygen atom and a carbonyl substituent, or containing a carbonyl substituent; any of the groups R₃ to R₆ may be joined to ring A to form with it a 5, 6, or 7 membered ring;

any of the carbons in the chain between rings A and B, may be attached by a bond to theα position on ring A to form a 5, 6, or 7 membered ring.

The preferred catecholic butanes useful in the compositions of the instant invention are of the Formula

wherein R₁ and R₂ are independently H, lower alkyl or lower acyl;

R₃, R₄, R₅ and R₆ are independently H or lower alkyl; R₇, R₈ and R₉ are independently H, hydroxy, lower alkoxy or lower acyloxy; R₁₀, H₁₁ , R₁₂, and R₁₃ are independently H or lower alkyl.

Lower alkyl is intended to generally mean C₁-C₆ alkyl, and preferably R₃ and R₄ are C₁- C₃ alkyl. Lower acyl is intended to generally mean [C₁-C₆] acyl, with [C₂- C₆] being preferred. It will be appreciated by those skilled in this art that Formula II is directed to both the phenolic compounds and the conventional esters and ethers thereof.

Illustrative classes of compounds within the scope of Formula (II) are those wherein:

a) one or more of R₁, R₂, R₃, R₄, R₅, R₆ R₇, R₈, R₉,

R₁₀, R₁₂, and R₁₃, are H, e.g., those wherein R₅ is H, R₅ and R₆ are H or R₅, R₆ and R₇ are H and R₈ and R₉ are OH or OR₁;

b) R₃ and R₄ each are CH₃ or C₂H₅ including those of a), especially those wherein R₅, R₆, and R₇ are H and/or R₈ and R₉ are OH and OR₁;

c) R₁ and R₂ are lower acyl, e.g., hydrocarbonacyl, preferably, alkanoyl, e.g., acetyl, propionyl, etc., including those of a) and b);

d) R₁ and R₂ are alike and R₈ and R₉ are OR₁ including those of a), b) and c); and

e) The compound is in the form of a single optical isomer or a mixture of such isomers, e.g., a racemic mixture or diastereoisomers including each of a), b), c) and d).

As used herein, lower alkyl represents, inter alia, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, and the like.

Lower acyl represents groups having the general formula RCO-, e.g., acetyl (CH₃CO-), propionyl (CH₃CH₂CO-), butyryl (CH₃CH₂CH₂CO-), and the like. When the catecholic butane compound is named as a substituted phenyl, the corresponding groups are acetoxy (CH₃CO₂-), propionyloxy (CH₃CH₂CO₂-), and butyroyloxy (CH₃CH₂CH₂CO₂-).

Another group of compounds used in the methods of the present invention comprise catecholic butanes, butenes, and tetralins following the general formula for the butanes given below:

where R1 and R2 are independently H, CH3, 1-5 alkyl, 2-5 alkenyl acetoxy, propionxy, and R1 and R2 taken together are methylene; and R4 and R5 are, independently, H and CH3; and R6 and R7 are, independently, H and OH and O and R3 is

where R8, R9 and R10 are independently H, OH, O, R and OR where R is CH3, 1-5 alkyl, 2-5 alkenyl, acetoxy, proprionoxy; and R8 and R9 and R9 and R10 taken together methylendioxy and are in ortho relationship to each other;

and pharmaceutically acceptable salts thereof.

Another group of such compounds are compounds of formula III where R₁ is H and R₂ is not H; where R₂ is H and R₁ is not H; and where R₁ and R₂ are independently CH₃, 1-5 alkyl, 2-5 alkenyl, acetoxy, propionoxy, and R₁ and R₂ taken together are methylene; and R₃-R₁₀ are as described above.

Pharmaceutically acceptable cation for such salts include alkali, preferably sodium, alkaline earth metal cations and other metal cations (except ferric iron) including, but not limited to, zinc, cobalt, platinum, copper, gallium, vanadium and manganese.

An example of a contemplated class of the compounds depicted in formulae III and IV is:

(1) symmetrical molecules of Formula III in which R₄ and R₅ are H, R₆ and R₇ are H, R₈ R₁-oxy and R₉ = R₂-oxy and R₈ is at the 3-position and R₉ is at the 4-position of the phenyl ring, as shown below:

Illustrative of such compounds are:

1,4-bis-(3,4-divinyloxyphenyl)butane

1,4-bis-(3,4-di-1-propenyloxyphenyl)butane 1,4-bis-(3,4-diallyloxyphenyl)butane 1,4-bis-(3,4-diisopropenyloxyphenyl)butane 1,4-bis-(3,4-di-1-butenyloxyphenyl)butane 1,4-bis-(3,4-di-2-butenyloxyphenyl)butane 1,4-@is-(3,4-di-3-butenyloxyphenyl)butane 1,4-bis-(3,4-diisobutenyloxyphenyl)butane 1,4-bis-(3,4-dipentenyloxyphenyl)butane 1,4-bis-(3,4-diisopentenyloxyphenyl)butane 1,4-bis-(3,4-diacetoxyphenyl)butane

1,4-bis-(3,4-dipropionoxyphenyl)butane 1,4-bis-(3,4-methylenedioxyphenyl)butane1,4-bis-(3-hydroxy,4-methoxyphenyl)butane1,4-bis-(3-hydroxy,4-ethoxyphenyl)butane 1,4-bis-(3-hydroxy,4-propoxyphenyl)butane 1,4-bis-{3-hydroxy,4-isopropoxyphenyl)butane 1,4-bis-(3-hydroxy,4-butoxyphenyl)butane 1,4-bis-(3-hydroxy,4-tertbutoxyphenyl)butane 1 4-bis-(3-hydroxy,4-secbutoxyphenyl)butane 1,4-bis-(3-hydroxy,4-pentyloxyphenyl)butane 1,4-bis-(3-hydroxy,4-isopentyloxyphenyl)butane 1,4-bis-(3-hydroxy,4-vinyloxyphenyl)butane 1,4-bis-(3-hydroxy,4-1-propenyloxyphenyl)butane 1,4-bis-(3-hydroxy,4-allyloxyphenyl)butane

1,4-bis-(3-hydroxy,4-isopropenyloxyphenyl)butane 1,4-bis-(3-hydroxy,4-1-butenyloxyphenyl)butane 1,4-bis-(3-hydroxy,4-2-butenyloxyphenyl)butane 1,4-bis-(3-hydroxy,4-3-butenyloxyphenyl)butane 1,4-bis-(3-hydroxy,4-isobutenyloxyphenyl)butane 1,4-bis—(3-hydroxy,4-pentenyloxyphenyl)butane 1,4-bis-(3-hydroxy,4-isopentenyloxyphenyl)butane 1,4-bis-(3-hydroxy,4-acetoxyphenyl)butane 1,4-bis-(3-hydroxy,4-propionoxyphenyl)butane 1,4-bis-(3-methoxy,4-hydroxyphenyl)butane 1,4-bis-(3-ethoxy,4-hydroxyphenyl)butane 1,4-bis-(3-propoxy,4-hydroxyphenyl)butane 1,4-bis-(3-isopropoxy,4-hydroxyphenyl)butane 1,4-bis-(3-butoxy,4-hydroxyphenyl)butane 1,4-bis-(3-tertbutoxy,4-hydroxyphenyl)butane 1,4-bis-(3-secbutoxy,4-hydroxyphenyl)butane 1,4-bis-(3-pentyloxy,4-hydroxyphenyl)butane 1,4-bis-(3-isopentyloxy,4-hydroxyphenyl)butane 1,4-bis-(3-vinyloxy,4-hydroxyphenyl)butane 1,4-bis-(3-1-propenyloxy,4-hydroxyphenyl)butane 1,4-bis-(3-allyloxy,4-hydroxyphenyl)butane 1,4-bis-(3-isopropenyloxy,4-hydroxyphenyl)butane 1,4-bis-(3-1-butenyloxy,4-hydroxyphenyl)butane 1,4-bis-(3-2-butenyloxy,4-hydroxyphenyl)butane 1,4-bis-(3-3-butenyloxy,4-hydroxyphenyl)butane 1,4-bis-(3-isobutenyloxy,4-hydroxyphenyl)butane 1,4-4is-(3-pentenyloxy,4-hydroxyphenyl)butane 1,4-bis-(3-isopentenyloxy,4-hydroxyphenyl)butane 1,4-bis-(3-acetoxy,4-hydroxyphenyl)butane 1,4-bis-{3-ρroρionoxy4-hydroxyphenyl)butane

Another group of such compounds comprises 2-amino- ethyl-4-t-6-iodophenol, dipenylthiocarbazone, silybin, rutin, tetrahydroxyethylquercetin, trihydroxyethylquercetin, monohydroxyethylrutin, nafazatrom, octocopherol, BHT, Trolox C and 7,7'-and 10,10'-dimethyleiciosa-5(Z), 8(Z), 11(Z)-trienoic acids, caffeic acid, eupatilin and 4'-demethyleupatilin, and pharmaceutically acceptable salts thereof.

The compounds of this invention can also be selected from the group consisting of compounds of the following formulae:

where R1 is -OC_n (CH2)m-COOR where n is 0 or 1, m is 1- 4, and R is H, CH₃ or C₂Η₅; sugar acid moieties, amino acid moieties, fatty acid moieties, and saccharide moieties;

where R2-R4 are, independently, H or R1 and

where R5 and R6 are independently H and CH₃.

R1 is preferably ethylcarboxymethyl; 0- ethylhemisucclnyl; alpha-D-glucopyranosyl; beta-D- glucopytanosyl, glycinyl; N-methylglycinyl; ethoxycarbonylmethoxyl hemisuccinyl aminoacetyl; N- methylacetyl; methyl carbamate, N-methyl/ N-carbonyl; histidnyl; methylhistidinyl; spermidinylcarbinyl; and arachidonyl; and

R5 and R6 are preferably CH₃.

where R1-R4 are independently H and CH₂, or R1 and R2 and/or R3 and R4 taken together are CH₂; R5 and R6 are independently H or methyl; and R7 and R8 are, independently H, HSO₃, and NaSO₃.

Preferably, R1-R4. are H, R5 and R6 are CH₃ and both R7 and R8 are HSO₃, or R7 is H and R8 is NaSO₃.

where there are independently, double or single bonds at the 1 and 3 positions; and where R1-R4 are independently H, CH₃, or R1 and R2 and/or R3 and R4 taken together are CH₂; and where R5 and R6 are, independently, a 2-12 dienoic fatty acid moiety, a 1-12 mono- or dialkene, CHO, COOH, or taken together are succinic anhydride.

Preferably R1-R4 are all H or all methyl; and R5 and R6 taken together are succunic anhydride; or are both CHO, COOH, or nona-9-carboxy-1(E), 4 (E)-dienyl; or R5 is nona-9-carboxy-1(E), 4 (E) dienyl and R6 is deca-1(E), 4(E)- dienyl.

where there are, independently, double or single bonds at the 1 and 1' positions; and where R1-R4 are, independently, H, CH₃ or R1 and R2 and/or R3 and R4 taken together are CH₂. Preferably R1-R4 are H or CH₃.

where R1 and R2 are, independently, H and CH₃, or taken together, are CH₂; where R3 is a dienoic 4-12 fatty acid moiety; and where R4 is a dienoic 4-12 fatty acid moiety or a 4-12 mono or dialkene moiety.

Preferably R1 and R2 are H; and R3 is deca-1(E), 4(E)- dienyl or octa-2(Z)-enyl and R4 is nona-9-carboxy, 1(E)-4(E)-dienyl or deca-10-carboxy,2(Z) dienyl.

where R1 is CH₂, 0, NH, CF₂ or CHF; and where R2, R3, R4 and R5 are, independently, F and H.

Preferably R1 is CH₂ and R2 and R3 are F and R4 and R5 are H; or R1 is CH₂ and R2 and R3 are H and R4 and R5 are F; or R1 is CF₂ and R2, R3, R4 and R5 are H; or R1 is 0 and R2, R3, R4 and R5 are H; or R1 is NH and R2, R3, R4 and R5 are H. Where only one fluorine is present, it is preferred that this fluorine be such as to form an L--fluoro-compound.

Where R is COOH, CH₃, or CHO.

Where R is COOH, CH₃ or CHO.

Where R is COOH, CH₃ or CHO

Where R is COOH, CH₃ or CHO Compounds illustrative of Formula VI are:

1-(3,4-di-ethoxycarbonylmethoxypenyl), 4(3-hydroxy, 4- ethoxycarbonylmethoxyphenyl),2,3-dimethylbutane; 1,4- bis(3-hydrox, 4-ethoxycarbonylmethoxyphenyl),2,3- dimethylbutane; nordihydroguaiaretic acid tetra-0- ethylhemisuccinate; nordihydroguaiaretic acid-alpha-D- glucopyranoside; nordihydrogairetic acid beta-D- glucopyranoside; nordihydroguaiaretic and acid-tetra-0- methylcarbamate; nordihydroguaiaretic acid- tetraglycinate; 1,4-bis (3-archidonyl,4-hydroxyphenyl)- 2,3-dimenthylbutane; nordihydroguaiaretic acid tetra N- methylglucinatei nordihydroguiaretic acid-tetra- spermidinylcarbonate; and nordihydroguaiaretic acid tetra-0-methylhistidinyl; Compounds illustrative of Formula VII are:

1,4,-bis (3,4-dihydroxy,6-sulfonylphenyl) 2,3- dimethylbutane; and 1-(3,4-dihydroxyphenyl),4-(3,4- dihydroxy,6-sodiumsulfonylphenyl), 2,3-dimethylbutane.

Compounds illustrative of Formula VIII are:

alpha, beta bis(3,4-dihydroxybenzyl) succinic dialdehyde; alpha, beta bis(3,4-dihydroxybenzyl) succinic acid; alpha, beta bis(3,4-dihydroxybenzyl) succinic anhydride; 10,11-bis-(3,4-dihydroxybenzyl) - 5(E), 8E, 12(E), 15 (E)-eicosatetraenoic acid; 10,11- bis(3,4-dihydroxybenzyl)- 5(E),8(E),12(E),15(E) eicosatetraen-1,20-dioic acid;

Compounds illustrative of Formula IX are:

1,4-bis-(3,4-dimethoxyphenethyl) benzene; and beta, beta-bis-(3,4-dihydroxyphenyl),1,4-divinylbenzene;

Compounds illustrative of Formula X are:

4-(deca-1(E),4(E)-dienyl-5-(nona-9-carboxy-

1(E),4(E)dienyl) catachol; and 4-(octa-2(Z)-enyl)-5-

(deca-10-carboxy-2(2),5(2)-dienyl)catechol.

Compounds illustrative of Formula XI are 7,7-difluouro- 5(E),8(E), 11(E). 14(E) eicosatetraenoic acid; 7(L)- fluoro-5(E), 8(E), 11(E), 14(E) eicosatetraenoic acid; 10,10-di-fluoro-5(E), 8(E),11(E), 14(E) eicosatetraenoic acid; 10(L)-fluoro-5(E), 8(E), 11(E), 14(E) eicosatetraenoic acid; 13,13-difluoro-5(E), 8(E), 11(E), 14(E) eicosatetraenoic acid; 10-oxanorarachidonic acid; 10-azanorarchidonic acid.

A compound illustrative of Formula XII is 5- hydroxyborono-6(Z), 8(E), 11(E), 14(E)-eicosatetraenoic acid.

A compound illustrative of Formula XIII is 12- hydroxyboroncr-5(E), 8(E), 10 (Z), 14(E) eicosatetraenoic acid.

A compound illustrative of Formula XIV is 11-hydroxy- borono-5(E), 8(E), 12(Z), 14 (E)-eicosatetraenoic acid.

A compound illustrative of Formula XV is 15-hydroxy- borono-5(E), 8(E), 11(E), 13( Z)-eicosatetraenoic acid.

Contemplated classes of compounds illustrating the above formulae are the compounds of Formulae VI to XV; the compounds of Formula X; the compounds of Formulae XI to XV; the compounds of Formulae Xllto XV; the compounds of Formula VII in which R4 is a dienoic 4-12 fatty acid moeity and the compounds of Formulae XI to XV; compounds having acid and glucosyl moieties as aids to solubility; compounds having chelating moieties, including catechols and acids, as aids to interaction of the compounds with multivalent metal salts to facilitate tissue penetration; and compounds including galactosides, furancsides, and those having ester and amino moeities, intended to act as prodrugs.

Pharmaceutically acceptable salts which may be used with the above include those having alkali, preferably sodium and other alkali metal cations, alkaline earth metal cations, and other metal cations including zinc, aluminum, trivalent chromium, yttrium, .maganese, divalent cobalt, divalent nickel, magnesium, aluminum, copper, divalent iron, trivalent cobalt, divalent cadmium, mercury, platinum, gallium, rubidium, molybdenum and vanadium. Preferred salts which may be used with the organic compounds are sodium and zinc salts .

(b) Pharmaceutical Preparations and Dosages

The compounds of this invention can be administered by any means that effects inhibition of the lipoxygenase pathway in warm-blooded animals. For example, administration can be oral and/or parenteral, e.g. subcutaneous, intravenous, intraperitoneal, or most preferably topical. The dosage administration will be dependent upon the age, health, and weight of the recipient and the kind of concurrent treatment, if any, and frequency of treatment.

Daily dosage of active ingredient compounds can be determined by one skilled in the art, and generally will be from about 0.1 mg. to about 10 mg. per kg. of body weight when non-locally applied. When locally applied, at least about 100 mg. per square centimeter of dieased skin should be employed. The compounds can be employed in dosage forms such as tablets, capsules, powder packets or liquid solutions, or elixirs for oral administration; or for parenteral administration, sterile liquid solutions or suspensions. For topical use, the compounds may be prepared in aerosol sprays or preferably, creams and ointments such as vanishing creams and ointments having a polyethylene glycol base; and in other such carriers known to the art. It is preferred that ointments include agents to provide the necessary tackiness for adherence to the skin. In preparations for oral and parenteral use, the concentration of the compounds will be between about 0.1 and about 10 weight percent. For topical preparations, the concentration of the compounds will be between about 0.1 and about 30 weight percent, preferably between about 0.1 and about 5 weight percent. The active organic component may be present at high concentrations. but the dosage received by the patient will be limited to the amount which can be absorbed through the skin.

When the preparations described above are to be used topically, the curative effects thereof are enhanced by the addition of zinc chloride. Generally the molar ratio of zinc chloride to active compound should be between about 1 and about 3, and the 2inc chloride should be present in the preparation at a weight concentration between about 0.5% and about 10%, and preferably between about 1% and about 5%.

The compounds described above have not been previously known to inhibit the lipoxygenase pathway of the arachidonic cascade; and as such they have a general utility in the treatment of a number of disease conditions. Such disease conditions include skin allergies, inflammatory disorder, psoriasis and other skin disorders involving scaling and epidermal cellular proliferation, inflammatory disorders, acne, insect bites, allergic rhinitis, conjunctivities, hay fever, bronchial asthma, allergic gastroenteritis, uterine contractions, hyperactivity of the colon and bronchospasms.

The following illustrations are provided as an aid to the skilled worker in practicing this invention:

Illustration 1.

Psoriatic plaques on the skin of a patient are softened by washing with a non-allergenic, neutral soap to remove all psoriatic flaking. While the lesions are still moist, they are treated initially with a single application of an ointment containing 10% active compound selected from the compounds listed below. The reaction is observed after 2 hours and again after 24 hours, and the strength of the reaction noted. If the reaction has stopped after 24 hours, or is weak, second and subsequent treatments are done with an ointment also containing 10% active compound; and also containing 1% or 5% zinc chloride depending on the strength of the reaction. The/weaker the reaction, the higher the indicated concentration of zinc chloride. If the initial reaction appears strong after 24 hours, treatment with the initial ointment containing no zinc chloride is continued. Applications of ointment to the plaques are made approximately three times a week for two or such lesser time as the lesions are healed. Active compounds are selected from the following list:

NGDA-tetra-spermidinyϊcarbonate; NGDA-tetra-0-methyl- histidine; 1,4-bis-(3-arachidonyl,4-hydroxyphenyl),

2,3-dimethylbutane; 1,4-bis-(3,4-dihydroxy,6-sulfonylphenyl), 2,3-dimethylbutane; 1-(3,4-dihydroxyphenyl),4- (3,4-dihydroxy,5-sulfonylphenyl), 2,3-dimethylbutane; 1-(3,4-dihydroxyphenyl),4-(3,4-dihydroxy,6- soduimsulfony-lyphenyl), 2,3-dimehtylbutane; 10,11- bis(3,4-dihydroxy-benzyl)-5(E),8(E), 12(E), 15(E)- eicosatetraenoic acid; 10,11-bis(3,4-dihydroxybenzyl)5 (E),8(E),12(E),15(E)-eicosatetraen-1,20-dioic acid; 4- (deca-1(E), 4 (E)-dienyl),5-(nona-9-carboxy-1(E), 4(E)- dienyl) catechol; 4-(octa-2(Z)-enyl-5-(deca-10-carboxy- 2 (Z) dienyl) catechol; 7,7-difluouo-5(E), 8(E), 11(E), 14(E) eicosatetraenoic acid; 10,19-difluoro-5(E), 8(E), 11(E), 14(E)-eicosatetraenoic acid; 7(L)-fluoro-5(E), 8(E), 11(E), 14(E)-eicosatetraenoic acid; 10(L)-fluoro- 5(E), 8(E), 11(E), 14 (E)-eicosatetraenoic acid; 13,13- difluoro-5(E), 8(E), 11(E), 14(E)-eicosatetracnoic acid; 13(L)-fluoro-5(E), 8(E), 11(E), 14 (E)-eicosatetraenoic acid; 10-oxanorarachidonic acid; 10-azanorarachidonic acid; 5-hydroxybcrono-6(Z), 8(E), 11(E), 14(E)- eicosatetraenoic acid; 11-hydroxyborono-5(E), 8-(E), 12(2), 14(E)-eicosatetraenoic acid; 15-hydroxyborono- 5(E), 8(E), 11(E), 13(Z)-eicosatetraenoic acid; alpha, beta-bis-(3,4-dihydroxybenzyl) succinic acid; alpha, beta-bis-{3,4-dihydroxybenzyl) succinic anhydride; alpha, beta-bis (3,4-dihydroxybenzyl) succindialdehyde; NDGA tetracarbobenzyloxgylcinatel NDGA tereaglycinatel NDGA -tetra-N-methyglycinatel 1-(3,4- diethoxycarbinylmethoxyphenyl), 4-(3-hydroxy,4- ethoxycarbonylmethoxypheny 2,3-dimethylbutane; 1,4-bis- (3-hydroxy,4-ethoxycarbonylmethoxyphenyl), 2,3- dimethylbutane; NDGA tetra-O-ethylhemisuccinate; nordihydroguairetic acid alpha-D-glucopytanoside; nordihydroguairetic acid beta-D-glucopyranoside; NDGA tetra-O-methylcarbamate; beta, beta-bis(3,4- dihydroxyphenyl)l,4-divinyl benzene; 1,4-bis(3,4- dimethoxyphenethyl) benzene.

Illustration 2.

Psoriatic plaques under the hair of a patient are softened by washing with standard commercial coal tar shampoo to remove flaking. While the lesions are still moist, they are treated initially by two shampooings with a shampoo (e.g. Johnson & Johnson Baby Shampoo) containing 10% active compound selected from the compounds of Illustration 1. The reaction is observed after 2 hours and again after 24 hours, and the strength of the reaction noted. If the reaction has stopped after 24 hours, or is weak, second and subsequent treatments are done with a shampoo containing 10% active compound and also containing 1% or 5% zinc chloride, depending on the strength of the reaction. The weaker the reaction, the higher the indicated concentration of zinc chloride. If the initial reaction appears strong after 24 hours, treatment with the initial shampoo containing no zinc chloride is continued. Application of shampoo to the plaques by two shampooing per application are made approximately three times a week for two weeks or such lesser time as the lesions are healed.

Illustration 3.

The ability of the compounds of Illustration 1 to inhibit lipoxygenase activity is verified by the method set forth in the following example. A molar concentration of each compound is used to equal to that of the ID50 for NDGA tested on a daily basis.

Example 1.

The following example provides the method of assay of lipoxygenase inhibition:

Spectrophotometer temperature was set at 25°C, chart speed at 24 nm/min., and wavelength at' 234 nm. Into two silica cuvettes labeled "reference" and "sample" the following was pipetted:

Reagents Reference Sample

1. Borate buffer 2.325 ml 2.322 ml

2. Substrate 150 microliter 150 microliter

3. DMSO/buffer (40% V/V) 2.5 microliter 25 microliter or or or

4. Inhibitor 25 microliter 25 microliter

5. Enzyme -- 3 microliter

All reagents were prepared fresh daily.

Buffer used was 0.1 M borate, pH9. Substrate was soybean lipoxidase type V, 1.47 x 10⁶ units/ml. The stock solution was diluted (10% V/V) with borate buffer, then three microliters of the diluted enzyme was used in the assay. The substrate was stored on ice. The concentration of tested inhibitors used was an equimolar amount to that of the ID50 for NDGA tested that day using a stock solution of 5 mg. NDGA dissolved in 0.2 ml. DMSO and brought to volume with 0.3 ml. borate buffer.

After adding reagents 1, 2 and 3 (for unhibited control) or 4 (inhibitor) to each cuvette, both cuvettes were mixed vigorously for exactly 10 seconds. Both cuvettes were placed in the spectrophotometer and preincubated for one minute. Both cuvettes were removed and three microliters of the enzyme were added to the sample cuvette only, which was mixed by inverting ten times in 30 seconds. Both cuvettes were placed back in the spectrophotometer and the chart recorder was immediately started. The delta A₂₃₄/min. was calculated from the linear portion of the graph which typically began after four minutes of reaction.

For each inhibitor, three replicates were run plus an uninhibited control. A simultaneously run uninhibited control was necessary due to the decrease in enzyme activity with time.

The effects of known inhibitors, NDGA and alphanaphthol were tested as positive controls. Results are set forth in the tables below.

Effect of Alpha-Sapthol on the Inhibition of Soybean

Lipoxidase

Concentration of alpha-Naphthol A₂₃₄ nm/min. % Inhibition

2.5 x 10^-5M .230 12% 6.2 x 10^-5M .141 46% 7.5 x 10^-5M .074 72% 8.8 x 10^-5M .069 74% 12.5 x 10^-5M .021 92% No inhibitor .261±0.021

(N = 5)

Effect of NDGA on the Inhibition of Soybean Lipoxidase

Concentration of NDGA A_{23 4}mn/min. % Inhibition

1.3 x 10-4M 0.217 1%

2.6 x 10-4H 0.186 14%

3.2 x 10-4M 0.100 54%

3.9 x 10-4M 0.035 84%

No Inhibitor 0.218±0 .002 (N = 4)

Example 2.

The assay method of Example 1 was used to test the effectiveness of the compounds listed in the table below to inhibit lipoxygenase, with the results shown in the following table.

d

Example 3 .

NDGA and representative analogs were tested for their effect on epidermal DNA synthesis in hairless mice by the methods of Lowe et al. "Archives Dermatology, 117, 394 (1981) and Yoshino and Maibach, J. Dermatology, In Press, (1986). This is accomplished by measuring the amount of labelled thymidine that is incorporated into the DNA; the less the incorporation, the less the cell proliferation. Of existing animal models, this screen has shown the best correlation with clinical anti- psoriatic activity. In effect, these tests are a measure of the effect of compounds on the proliferative activity of epidermal cells. Certain anti-psoriatic compounds such as methotrexate decrease and proliferation in this screen. Other anti-psoriatic agents, such as anthraline, increase cell proliferation, Similarly, certain of the compounds of this invention increase cell proliferation, others inhibit it.

Example 4.

A series of compounds were screened for their ability to inhibit soybean lipoxygenase activity in. vitro. Concentrations of compounds for 50% inhibition (IC₅₀) were as follows:

Compound IC50

4 propyl catechol 4.00x10^-4 Dihydroguaiaretic acid 2.50x10^-4 Desraethyl Nordihydroguaiaretic Acid 2.75x10^-4 d, 1 NDGA 2.65x10^-4 meso Nordihydroguaiaretic Acid 2.50x10^-4

4'demethyl Zpipodophyllotoxin B, D glucoside 2.30x10^-4 1,6-(3,4 dihydroxyphenyl) butane 2.25x10^-4 1-(3,4,dihydroxyphenyl)-4-(3,4,5,-tri2.20x10^-4 hydxoxyphenyl) butane Etoposide (4'dimethyl epipodophyllotoxin ethylidene B,D glucopyranoside) 2.10x10^-4 Tetramethyl NDGA 1.50x10^-4 1-(3,4-dihycroxyphenyl)-4-(3,5 diaminophenyl) butane 1.85x10^-4 4'Demethyl Epipodophyllotoxin 1.80x10^-4 1-(3,4-Dihydroxyphenyl)-4-(2,3,4-trihydroxyphenyl) butane 1.80x10^-4 B,B-bis(3,4-dihydroxyphenyl)-1,4-divivinyl benzene 1.40x10^-4 1,2,4' (ethyl oxyacetate) Nordihydroguaiaretic Acid 1.30x10^-4 Norisoguaiacin 1.60x10^-4 NDGA tetraproprionate 1.20x10^-4

1-3,5-di(trifluoromethyl) phenyl-4-(3,4 dihydroxy phenyl) butane 1.10x10^-4 Podophyllotoxin 1.10x10^-4 1-(3,4-ddhydroxy phenyl)-4-(phenyl) butadiene 1.20x10^-4 Teniposide-(4'demethyl epidophyllotoxin thenylidene B-D, glucopyranoside) 9.00x10^-5 1-(3,4-dihydroxyphenyl)-4-(phenyl) butane 9.80x10^-5 NDGA monoglucoside 7.50x10^-5 1-(3,4-dihydroxyphenyl)-4-(2,5-dihydroxyphenyl) butane 7.20x10^-5 bis-1,4-(3,4-dihydroxyphenethyl) benzene 7.00x10^-5 Di-(NO(2))-NDGA 1.90x10^-4 NDGA Zinc Complex 1 3.80x10^-4 NDGA Zinc Comiplex 2 3.80-x10^-4

This assay involved the disappearance of substrate in the presence and absence of -inhibitor using a double beam spectrophotometer set to detect the presence of arachidonate. Enzyme was added to the sample vial, inverted for 30 seconds and incubated in the spectrometer for one minute. The IC₅₀ for each drug and a ratio reported to the compound's activity was determined. The procedure followed was a modification of that disclosed in Panganamala, et al., Protaglandins, Vol. 14, No. 2, p. 261 (1977).

It is to be understood that the invention is not limited to the illustrations described and shown herein, which are deemed to be merly illustrative of the best modes of carrying out the invention. The invention also encompasses all such modifications which are within the scope of the following claims.

Claims

What Is Claimed Is;

1. Method of inhibiting the enzymatic action of the lipoxygenase arachidonic acid metabolism comprising administering to a warm-blooded animal a pharmaceutically effective amount of a compound selected from compounds of the formula:

wherein D, E, F, X, Y, and Z may be H, OH, O-Alkyl or O-Acyl optionally substituted with hydroxy, alfeoxy, substituted amino carbaloxy or carboxy;

wherein R₁-R₆ may be H, lower alkyl or lower alkoxy optionally substituted with hydroxy, alkoxy, substituted amino, carboxyl or carbalkoxyl, hydroxy, carbonyl, alkoxy, aryl and aralkyl;

n may be 0 to 5; wherein the aromatic rings A and B may contain up to 3 substituents selected from the group comprising hydroxy; alkenoxy; alkyl; alkoxy or alkanoyl optionally substituted by hydroxy, alkoxy, substituted amino, carboxy, or carbalkoxy; CF₃, Halo; carboxy, carbalkoxy; cyano; hydroxymethyl; sulfonic acid; sulfonamido; aminosulfonyl (i.e. - NHSO₂R); nitro; alkoxy carbonyloxy; aminocarbonyloxy; aroyloxy; aralkanoyloxy; heteroaroyloxy; glycosidyloxy;

wherein any of the two phenolic groups may be joined together by the following groups:

2. The catecholic butanes of claim 1 in which either of the rings A or B are replaced by cyclohexyl, napthyl, tetrahydronapthyl, pyridyl, piperidinyl. quinolinyl, indanyl, indenyl.

3. The catecholic butanes of claim 1 wherein any of the groups R1 to R6 may be joined together so as to form a 5, 6 or 7 membered ring optionally interrupted by an oxygen atom, or containing an oxygen atom and a carbonyl substituent in combination or containing a carbonyl substituent alone.

4. The catecholic butanes of claim 1 wherein any of the groups R3 to R6 may be joined to ring A so as to form a 5, 6 or 7 membered ring.

5. The catecholic butanes of claim 1 wherein any of the carbons in the chain between rings A and B may be bonded to the α position on ring A to form a 5, 6 or 7 membered ring.

6. Method of inhibiting the enzymatic action of the lipoxygenase arachadionic acid metabolism comprising administering to a warm-blooded animal a pharmaceutically effective amount of a compound selected from compounds of the formula:

wherein R1 and R2 are independently H, lower alkyls or lower acyls; wherein R3, R4 , R5 and R6 are independently H or lower alkyls;

wherein R7, R8 and R9 are independently H, hydroxy, lower alkoxy or lower acyloxy;

wherein R10, R11, R12 and R13 are independently H or lower alkyls.

7. Method of inhibiting the enzymatic action of the lipoxygenase arachidonic acid metabolism comprising administering to a warm-blooded animal a pharmaceutically effective amount of a compound selected from compounds of the formulu:

where R1 and R2 are independently H, CH₃, 1-5 alkyl, 2-5 alkenyl, acetoxy, propionoxy, and R1 and R2 taken together are methylene; and R4 and R5 are, independently, H and CH3; or taken together are methyloxycarbonyl; and R6 and R7 are, independently H, OH and 0; and R3 is

where R8, R9 and R10 are independently- OH, 0, R, H and OR where R is CH₃, 1-5 alkyl, 2-5 alkenyl, acetoxy, propionoxy; and R8 and R9 or R9 and R10 taken together are methylenedioxy and are in ortho relationship to each other;

corresponding butenes and tetralins; and pharmaceutically acceptable salts thereof.

8. The method of Claim 7 in which the preparation also contains zinc chloride in an amount of between about 0.5 and about 30 weight percent.

9. Method of inhibiting the lipoxygenase pathway of the arachidonic acid cascade in a warm-blooded animal comprising administering to said warm blooded animal a pharmaceutically effective amount of a preparation comprising a compound selected from compounds of the formula:

where R1 is OH and R2 is not H; where R2 is H and R1 is not H; and where R1 are independently CH3, 1-5 alkyl, 2-5 alkenyl, acetoxy, propionoxy, and R1 and R2 taken together are methylene; and R4 and R5 are, independently, H and CH₃; or taken together are methyl oxycarbonyl; and R6 and R7 are, independently E, OH and O; and R3 is

where R8, R9 and R10 are independently H, OH, O, R and OR where R is CH₃, 1-5 alkyl, 2-5 alkenyl, acetoxy, propionoxy; and R8 and R9 or R9 and R10 taken together are methylenedioxy and are in ortho relationship to each other;

10. Method of reducing the size of a psoriatic lesion in a patient comprising administering to said patient a pharmaceutically effective amount of lipoxygenase inhibiting compound selected from the group consisting of:

2-aminoethyl-4-t-6-iodophenol, diphenylthiocarbazone, silybin, rutin, tetrahydroxyethylquercetin, trihydroxyethylquercetin, monohydroxyethyllrutin, nafazatrom, cc-tocopherol, BHT, Trolox C and 7,7'- and 10,10' -dimethyleiciosa-5 (Z), 11(Z)-trienoic acids, caffeic acid, eupatilin and 4'- demethyleupatilin; and pharmaceutically acceptable salts thereof.

11. Method of treating a disease condition in a patient which is responsive to agents which inhibit the lipoxygenase pathway of the arachidonic acid cascade, such disease condition being exemplified by skin allergy, insect bites, allergic rhinitis, conjunctivitis, hay fever, bronchial asthma, allergic gastroenteritis, uterine contractions, hyperactivity of the colon and bronchospasms, comprising administering to said patient a preparation containing a pharmaceutically effective amount of compound selected from compounds of the formula:

where R1 and R2 are independently H, CH₃, 1-5 alkyl, 2-5 alkenyl, acetoxy, propionoxy, and R1 and R2 taken together are methylene; and R4 and R5 are, independently, H and CH₃ or taken together are methyloxcarbonyl; and R6 and R7 are, independently H, OH and O; and R3 is

where, R8, R9 and R10 are independently H, OH, O, R and OR where R is CH₃, 1-5 alkyl, 2-5 alkenyl, acetoxy, propionoxy; and R8 and R9 or R9 and R10 taken together are methylenedioxy and are in ortho relationship to each other;

12. The method of Claim 11 in which the treatment is administered topically to treat a skin or subcutaneous pathology and the preparation also contains zinc chloride in an amount between about 0.5 and about 30 weight percent.

13. A method of inhibiting the enzymatic action of lipoxygenase on arachidonic acid metabolism comprising contacting said lipoxygenase with an effective amount of a preparation comprising a compound selected from compounds of the formulae:

where R1 is (OC)n (CH2)m-COOR where n is 0 or 1, m is 1-4, and R is H, CH₃ or C₂H₅; sugar acid moieties, amino acid moieties, fatty acid moieties, and saccharide moities; where R2-R4 are, independently, H or R1; and. where R5 and R6 are independently H and CH₃;

where R1-R4 are independently H and CH₃, or R1 and R2 and/or R3 and R4 taken together are CH₂; R5 and R6 are independently H or methyl; and R7 and R8 are, independently H, HSO₃, and NaSO₃;

where there are independently, double or single bonds at the 1 and 3 positions; and where R1-R4 are independently H, CH3, or R1 and R2 and/or R3 and R4 taken together are CH2;. and where R5 and R6 are, independently, a 2-12 dienoic fatty acid moiety, a 1-12 mono- or dialkene, CHO, COOH, or taken together are succinic anhydride;

where there are, independently, double or single bonds at the 1 and 1' positions; and where R1-R4 are, independently, H, CH₃ or R1 and R2 and/or R3 and R4 taken together are CH₂;

where R1 and R2 are, independently, H and CH₃, or taken together, are CH2; where R3 is a dienoic 4-12 fatty acid moiety; and where R4 is a dienoic 4-12 fatty acid moiety or a 4-12 mono or dialkene moiety;

where R1 is CH₂ , O, NH, CF2 or CHF; and where R2, R3, R4 and R5 are, independently, F and H; and where R1 is CH₂, at least one of R2, R3, R4 and R5 must be F3

where R is COOH, CH₃, or CHO;

where R is COOH, CH₃ or CHO;

where R is COOH, CH₃ or CHO;

where R is COOH, CH₃ or CHO; and pharmaceutically acceptable salts thereof.

14. Method of Claim 13 in which the treatment is administered for the purpose of reducing the size of a psoriatic lesion in a patient.

15. The method of Claim 14 in which the preparation also contains zinc chloride in an amount of between about 0.5 and about 30 weight percent.

16. Method of Claim 15 in which the preparation is applied to a patient for the alleviation of skin allergies, psoriasis and other skin disorders involving sealing and epidermal cell proliferation, insect bites, allergic rhinitis, conjunctivitis, hay fever, bronchial asthma, allergic gastroenteritis, uterine contractions. hyperactivity of the colon and bronchospasms.

17. The method of Claim 16 in which the preparation is applied topically to treat skin allergies, skin or subcitaneous cell proliferation, or insect bites, and other skin inflammation, and the preparation also contains zinc chloride in an amount between anout 0.5 and about 30 weight percent.

18. The method for treating psoriatic lesions in a host in need of such treatment comprising topically applying to said lesions an effective amount of pahrmaceutical preparation comprising a suitable pharmaceutical carrier and a compound selected from the compounds of the formulae:

where R1 is (OC)n (CH₂)m, COOR and where n is 0 or 1, m is 1-4, and R is H, -CH₃ or -C₂H₅; or an acid moiety, including an amino acid moiety;

R2, R3 and R4 are, independently, H or R1; and R5 and R6 are, independently, H or -CH₃;

wherein R1, R2, R3 and R4, are, independently, H or -CH; or R1 and R2 and/or R3 and R4 taken together are -CH₂-;

R5 and R6 are, independently, H or -CH3; and R7 and R8 are, independently, H, -SO₃H or -SO₃Na; and

wherein there are, independently, double or single bonds in the 1-2 and 3-4 positions; and

R1, R2, R3 and R4 are, independently, H, -CH₃, or R1 and R2 and/or R3 and R4 taken together are CH₂-; and

R5 and R6 are, independently, a 2-12 dienoic fatty acid moiety, a 1-12 mono-or dialkene, -CHO, -COOH or taken together are succinic anhydride.--

19. The method of claim 18 in which said pharmaceutical preparation also contains zinc chloride in an amount of between about 0.5 and about 30 weight percent.--