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WO1988003800A1 - Inhibiteurs de lipoxygenase - Google Patents

Inhibiteurs de lipoxygenase Download PDF

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Publication number
WO1988003800A1
WO1988003800A1 PCT/US1986/002548 US8602548W WO8803800A1 WO 1988003800 A1 WO1988003800 A1 WO 1988003800A1 US 8602548 W US8602548 W US 8602548W WO 8803800 A1 WO8803800 A1 WO 8803800A1
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WIPO (PCT)
Prior art keywords
independently
taken together
compounds
lipoxygenase
preparation
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PCT/US1986/002548
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English (en)
Inventor
Russell T. Jordan
Larry M. Allen
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Chemex Pharmaceuticals, Inc.
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Priority to KR1019880700848A priority Critical patent/KR890700023A/ko
Priority to PCT/US1986/002548 priority patent/WO1988003800A1/fr
Priority to EP19870900421 priority patent/EP0289506A4/en
Priority to JP62500248A priority patent/JPH01501790A/ja
Publication of WO1988003800A1 publication Critical patent/WO1988003800A1/fr
Priority to AU68116/90A priority patent/AU6811690A/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to the use of certain organic compounds as inhibitors of the lipoxygenase pathway of the arachidonic acid.
  • Lipoxygenase and cyclo-oxygenase pathway inhibitors 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.
  • Panganamala 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.
  • 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.
  • 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.
  • the catecholic butanes useful in the compositions of the instant invention are of the formula
  • 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;
  • R 1 -R 6 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; CF 3 ; Halo; carboxy; carbalkoxy; cyano; hydroxymethyl; sulfonic acid; sulfonamido; aminosulfonyl (i.e. - NHSO 2 R); 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 R 1 to R 6 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 R 3 to R 6 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 the ⁇ position on ring A to form a 5, 6, or 7 membered ring.
  • R 1 and R 2 are independently H, lower alkyl or lower acyl
  • R 3 , R 4 , R 5 and R 6 are independently H or lower alkyl; R 7 , R 8 and R 9 are independently H, hydroxy, lower alkoxy or lower acyloxy; R 10 , H 11 , R 12 , and R 13 are independently H or lower alkyl.
  • Lower alkyl is intended to generally mean C 1 -C 6 alkyl, and preferably R 3 and R 4 are C 1 - C 3 alkyl.
  • Lower acyl is intended to generally mean [C 1 -C 6 ] acyl, with [C 2 - C 6 ] 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.
  • R 10 , R 12 , and R 13 are H, e.g., those wherein R 5 is H, R 5 and R 6 are H or R 5 , R 6 and R 7 are H and R 8 and R 9 are OH or OR 1 ;
  • R 3 and R 4 each are CH 3 or C 2 H 5 including those of a), especially those wherein R 5 , R 6 , and R 7 are H and/or R 8 and R 9 are OH and OR 1 ;
  • R 1 and R 2 are lower acyl, e.g., hydrocarbonacyl, preferably, alkanoyl, e.g., acetyl, propionyl, etc., including those of a) and b);
  • R 1 and R 2 are alike and R 8 and R 9 are OR 1 including those of a), b) and c); and
  • 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).
  • 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 (CH 3 CO-), propionyl (CH 3 CH 2 CO-), butyryl (CH 3 CH 2 CH 2 CO-), and the like.
  • RCO- acetyl
  • propionyl CH 3 CH 2 CO-
  • butyryl CH 3 CH 2 CH 2 CO-
  • the corresponding groups are acetoxy (CH 3 CO 2 -), propionyloxy (CH 3 CH 2 CO 2 -), and butyroyloxy (CH 3 CH 2 CH 2 CO 2 -).
  • 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:
  • 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
  • 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;
  • R 1 is H and R 2 is not H; where R 2 is H and R 1 is not H; and where R 1 and R 2 are independently CH 3 , 1-5 alkyl, 2-5 alkenyl, acetoxy, propionoxy, and R 1 and R 2 taken together are methylene; and R 3 -R 10 are as described above.
  • compositions 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.
  • 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:
  • R1 is -OC n (CH2)m-COOR where n is 0 or 1, m is 1- 4, and R is H, CH 3 or C 2 ⁇ 5 ; sugar acid moieties, amino acid moieties, fatty acid moieties, and saccharide moieties;
  • R2-R4 are, independently, H or R1 and
  • R5 and R6 are independently H and CH 3 .
  • 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 CH 3 .
  • R1-R4 are independently H and CH 2 , or R1 and R2 and/or R3 and R4 taken together are CH 2 ; R5 and R6 are independently H or methyl; and R7 and R8 are, independently H, HSO 3 , and NaSO 3 .
  • R1-R4. are H, R5 and R6 are CH 3 and both R7 and R8 are HSO 3 , or R7 is H and R8 is NaSO 3 .
  • R1-R4 are independently H, CH 3 , or R1 and R2 and/or R3 and R4 taken together are CH 2 ; 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.
  • 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.
  • R1-R4 are, independently, H, CH 3 or R1 and R2 and/or R3 and R4 taken together are CH 2 .
  • R1-R4 are H or CH 3 .
  • R1 and R2 are, independently, H and CH 3 , or taken together, are CH 2 ; 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.
  • 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.
  • R1 is CH 2 , 0, NH, CF 2 or CHF; and where R2, R3, R4 and R5 are, independently, F and H.
  • R1 is CH 2 and R2 and R3 are F and R4 and R5 are H; or R1 is CH 2 and R2 and R3 are H and R4 and R5 are F; or R1 is CF 2 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.
  • this fluorine be such as to form an L--fluoro-compound.
  • R is COOH, CH 3 , or CHO.
  • R is COOH, CH 3 or CHO.
  • R is COOH, CH 3 or CHO
  • 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.
  • 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 .
  • the compounds of this invention can be administered by any means that effects inhibition of the lipoxygenase pathway in warm-blooded animals.
  • 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.
  • 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.
  • ointments include agents to provide the necessary tackiness for adherence to the skin.
  • concentration of the compounds will be between about 0.1 and about 10 weight percent.
  • 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.
  • the curative effects thereof are enhanced by the addition of zinc chloride.
  • 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.
  • 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.
  • 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.
  • NGDA-tetra-spermidiny ⁇ carbonate NGDA-tetra-0-methyl- histidine; 1,4-bis-(3-arachidonyl,4-hydroxyphenyl),
  • 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.
  • a shampoo e.g. Johnson & Johnson Baby Shampoo
  • Spectrophotometer temperature was set at 25°C, chart speed at 24 nm/min., and wavelength at' 234 nm.
  • reference and sample the following was pipetted:
  • Buffer used was 0.1 M borate, pH9.
  • Substrate was soybean lipoxidase type V, 1.47 x 10 6 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.
  • 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 A 234 /min. was calculated from the linear portion of the graph which typically began after four minutes of reaction.
  • Example 1 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.
  • 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.
  • 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 IC 50 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).

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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Procédés d'utilisation de plusieurs composés pour l'inhibition de lipoxygénase dans des animaux à sang chaud. Des états pathologiques pouvant être traités par les composés ci-décrits comprennent le psoriasis et autres maladies de la peau y compris l'écaillement et la prolifération cellulaire épidermique, les troubles inflammatoires, les morsures et piqûres d'insectes, la rhinite allergique, la conjonctivite, le rhume des foins, l'asthme bronchique, la gastro-entérite allergique, les contractions utérines, l'hyperactivité du côlon et les bronchospasmes.
PCT/US1986/002548 1986-11-19 1986-11-19 Inhibiteurs de lipoxygenase WO1988003800A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
KR1019880700848A KR890700023A (ko) 1986-11-19 1986-11-19 리폭시게나제 저해제
PCT/US1986/002548 WO1988003800A1 (fr) 1986-11-19 1986-11-19 Inhibiteurs de lipoxygenase
EP19870900421 EP0289506A4 (en) 1986-11-19 1986-11-19 Lipoxygenase inhibitors
JP62500248A JPH01501790A (ja) 1986-11-19 1986-11-19 リポキシゲナーゼ阻害剤
AU68116/90A AU6811690A (en) 1986-11-19 1990-12-17 Lipoxygenase inhibitors

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US1986/002548 WO1988003800A1 (fr) 1986-11-19 1986-11-19 Inhibiteurs de lipoxygenase

Publications (1)

Publication Number Publication Date
WO1988003800A1 true WO1988003800A1 (fr) 1988-06-02

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1986/002548 WO1988003800A1 (fr) 1986-11-19 1986-11-19 Inhibiteurs de lipoxygenase

Country Status (5)

Country Link
EP (1) EP0289506A4 (fr)
JP (1) JPH01501790A (fr)
KR (1) KR890700023A (fr)
AU (1) AU6811690A (fr)
WO (1) WO1988003800A1 (fr)

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991005757A1 (fr) * 1989-10-19 1991-05-02 Schering Corporation Inhibiteurs de lipoxygenase
US5488135A (en) * 1991-10-16 1996-01-30 Sandoz Ltd. Bis(phenyl)ethane derivatives
US5563292A (en) * 1990-10-17 1996-10-08 Schering Corporation Lipoxygenase inhibitors
EP0954297A1 (fr) * 1996-10-07 1999-11-10 Shaman Pharmaceuticals, Inc. Utilisation de composes bisphenoliques dans le traitement du diabete de type ii
US5990116A (en) * 1995-03-14 1999-11-23 Novartis Ag Trisubstituted phenyl derivatives
WO2002009699A3 (fr) * 2000-07-28 2003-01-03 Immupharm Aps Procede pour traiter les symptomes du rhume, la rhinite allergique et les infections liees aux voies respiratoires
EP1748767A1 (fr) * 2004-05-28 2007-02-07 Unigen Pharmaceuticals, Inc. Diarylalcanes constituant des inhibiteurs puissants d'enzymes binucleaires
WO2006041902A3 (fr) * 2004-10-06 2009-04-16 Univ Johns Hopkins Utilisation de derives d'acide nordihydroguaiaretique pour traiter des cancers et des infections virales et microbiennes qui resistent aux medicaments
US7528166B2 (en) 2002-02-05 2009-05-05 Hormos Medical Corporation Lignan derivatives
US7582677B2 (en) 2002-06-19 2009-09-01 Hormos Medical Corp. Lignan formulations
EP1938819A3 (fr) * 2001-06-19 2010-04-07 Axelar AB Nouvelle utilisation de cyclolignans spécifiques
US7728036B2 (en) 2003-05-20 2010-06-01 Erimos Pharmaceuticals, Llc Methods for delivery of catecholic butanes for treatment of tumors
US8178527B2 (en) 2006-10-02 2012-05-15 Erimos Pharmaceuticals Llc Tetra-substituted NDGA derivatives via ether bonds and carbamate bonds and their synthesis and pharmaceutical use
US8362305B2 (en) 2008-07-21 2013-01-29 Unigen, Inc. Series of skin whitening (lightening) compounds
US8440648B2 (en) 2004-07-20 2013-05-14 Erimos Pharmaceuticals Llc Methods and compositions for treatment of intraepithelial neoplasia
US8586799B2 (en) 2011-03-24 2013-11-19 Unigen, Inc. Compounds and methods for preparation of diarylpropanes
US9067875B2 (en) 2006-10-02 2015-06-30 Erimos Pharmaceuticals Llc Tetra-substituted NDGA derivatives via ether bonds and carbamate bonds and their synthesis and pharmaceutical use

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2004257575A1 (en) * 2003-05-20 2005-01-27 Erimos Pharmaceuticals Llc Methods and compositions for delivery of catecholic butanes for treatment of tumors
JP5362572B2 (ja) * 2006-10-02 2013-12-11 エリモス ファーマシューティカルズ エルエルシー テトラ−ｏ−置換ブタン架橋修飾ｎｄｇａ誘導体、それらの合成および薬学的使用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4584320A (en) * 1985-01-03 1986-04-22 David Rubin Anti-asthmatic composition and method using 8,11,14,17-eicosatetraenoic acid

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR3866M (fr) * 1964-07-08 1966-01-24 Rocal Médicament a base de dérivé du pyrocatéchol.
US4530844A (en) * 1984-07-26 1985-07-23 Warner-Lambert Company Synergistic non-steroidal anti-inflammatory compounds and compositions thereof
US4695590A (en) * 1986-05-05 1987-09-22 California Health Technologies Method for retarding aging

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4584320A (en) * 1985-01-03 1986-04-22 David Rubin Anti-asthmatic composition and method using 8,11,14,17-eicosatetraenoic acid

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
See also references of EP0289506A4 *
The Merck Index, Ninth Edition issued 1976 (RAHWAY NJ) "Guaiacol" see page 4402 No. 4399. *

Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991005757A1 (fr) * 1989-10-19 1991-05-02 Schering Corporation Inhibiteurs de lipoxygenase
US5563292A (en) * 1990-10-17 1996-10-08 Schering Corporation Lipoxygenase inhibitors
US5488135A (en) * 1991-10-16 1996-01-30 Sandoz Ltd. Bis(phenyl)ethane derivatives
US5990116A (en) * 1995-03-14 1999-11-23 Novartis Ag Trisubstituted phenyl derivatives
EP0954297A1 (fr) * 1996-10-07 1999-11-10 Shaman Pharmaceuticals, Inc. Utilisation de composes bisphenoliques dans le traitement du diabete de type ii
EP0954297A4 (fr) * 1996-10-07 2002-03-27 Shaman Pharmaceuticals Inc Utilisation de composes bisphenoliques dans le traitement du diabete de type ii
WO2002009699A3 (fr) * 2000-07-28 2003-01-03 Immupharm Aps Procede pour traiter les symptomes du rhume, la rhinite allergique et les infections liees aux voies respiratoires
EA008612B1 (ru) * 2000-07-28 2007-06-29 Иммуфарм Апс Способ лечения обычной простуды, аллергического ринита и инфекций дыхательных путей
US8003688B2 (en) 2000-07-28 2011-08-23 Immupharm Aps Method of treating symptoms of common cold, allergic rhinitis and infections relating to the respiratory tract
US8389747B2 (en) 2001-06-19 2013-03-05 Axelar Ab Use of specific cyklolignans
EP2186513A1 (fr) * 2001-06-19 2010-05-19 Axelar Ab Utilisation de cyclolignans spécifiques
EP1938819A3 (fr) * 2001-06-19 2010-04-07 Axelar AB Nouvelle utilisation de cyclolignans spécifiques
EP1938818A3 (fr) * 2001-06-19 2010-04-07 Axelar AB Nouvelle utilisation de cyclolignans spécifiques
US7528166B2 (en) 2002-02-05 2009-05-05 Hormos Medical Corporation Lignan derivatives
US7582677B2 (en) 2002-06-19 2009-09-01 Hormos Medical Corp. Lignan formulations
US7728036B2 (en) 2003-05-20 2010-06-01 Erimos Pharmaceuticals, Llc Methods for delivery of catecholic butanes for treatment of tumors
US8729136B2 (en) 2004-05-28 2014-05-20 Unigen, Inc. Diarylalkanes as potent inhibitors of binuclear enzymes
US7767661B2 (en) 2004-05-28 2010-08-03 Unigen Pharmaceuticals, Inc. Diarylalkanes as potent inhibitors of binuclear enzymes
EP1748767A4 (fr) * 2004-05-28 2008-12-24 Unigen Pharmaceuticals Inc Diarylalcanes constituant des inhibiteurs puissants d'enzymes binucleaires
US10548825B2 (en) 2004-05-28 2020-02-04 Unigen, Inc. Diarylalkanes as potent inhibitors of binuclear enzymes
US9126913B2 (en) 2004-05-28 2015-09-08 Unigen, Inc. Diarylalkanes as potent inhibitors of binuclear enzymes
EP1748767A1 (fr) * 2004-05-28 2007-02-07 Unigen Pharmaceuticals, Inc. Diarylalcanes constituant des inhibiteurs puissants d'enzymes binucleaires
US8592488B2 (en) 2004-05-28 2013-11-26 Unigen, Inc. Diarylalkanes as potent inhibitors of binuclear enzymes
US8440648B2 (en) 2004-07-20 2013-05-14 Erimos Pharmaceuticals Llc Methods and compositions for treatment of intraepithelial neoplasia
WO2006041902A3 (fr) * 2004-10-06 2009-04-16 Univ Johns Hopkins Utilisation de derives d'acide nordihydroguaiaretique pour traiter des cancers et des infections virales et microbiennes qui resistent aux medicaments
US9067875B2 (en) 2006-10-02 2015-06-30 Erimos Pharmaceuticals Llc Tetra-substituted NDGA derivatives via ether bonds and carbamate bonds and their synthesis and pharmaceutical use
US8178527B2 (en) 2006-10-02 2012-05-15 Erimos Pharmaceuticals Llc Tetra-substituted NDGA derivatives via ether bonds and carbamate bonds and their synthesis and pharmaceutical use
US8658838B2 (en) 2008-07-21 2014-02-25 Unigen, Inc. Series of skin whitening (lightening) compounds
US9096507B2 (en) 2008-07-21 2015-08-04 Unigen, Inc. Series of skin whitening (lightening) compounds
US8362305B2 (en) 2008-07-21 2013-01-29 Unigen, Inc. Series of skin whitening (lightening) compounds
US9045405B2 (en) 2011-03-24 2015-06-02 Unigen, Inc. Compounds and methods for preparation of diarylpropanes
US8586799B2 (en) 2011-03-24 2013-11-19 Unigen, Inc. Compounds and methods for preparation of diarylpropanes

Also Published As

Publication number Publication date
EP0289506A1 (fr) 1988-11-09
KR890700023A (ko) 1989-03-02
EP0289506A4 (en) 1990-12-12
AU6811690A (en) 1991-03-14
JPH01501790A (ja) 1989-06-22

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