WO2008079328A2 - Omega-5-fatty acids useful in lipoxygenase 5 inhibition and in the treatment of cancer - Google Patents

Omega-5-fatty acids useful in lipoxygenase 5 inhibition and in the treatment of cancer Download PDF

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Publication number
WO2008079328A2
WO2008079328A2 PCT/US2007/026152 US2007026152W WO2008079328A2 WO 2008079328 A2 WO2008079328 A2 WO 2008079328A2 US 2007026152 W US2007026152 W US 2007026152W WO 2008079328 A2 WO2008079328 A2 WO 2008079328A2
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cooh
omega
fatty acid
pharmaceutically acceptable
solvate
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PCT/US2007/026152
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French (fr)
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WO2008079328A3 (en
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Thomas E. Adrian
Richard F. Murphy
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Creighton University
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Publication of WO2008079328A3 publication Critical patent/WO2008079328A3/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
    • A61K31/185—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
    • A61K31/202—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 having three or more double bonds, e.g. linolenic

Definitions

  • the subject invention is directed generally to omega-5-fatty acids and, more particularly, to the use of omega-5-fatty acids in lipoxygenase 5 inhibition and in the treatment of cancer.
  • Pancreatic cancer is one of the most enigmatic and aggressive malignant diseases facing oncologists (Parker et al . , "Cancer Statistics. 1996,” CA Cancer J. Clin. , 46:5-27 (1996) (“Parker”)). It is now the fourth leading cause of cancer death in both men and women in the United States, and the incidence of this disease has significantly increased over the past 20 years (Parker; Trede et al . , "Survival After Pancreaticoduodenectomy: 118 Consecutive Resections Without an Operative Mortality," Ann . Surg .. 211:447-458 (1990); Cameron et al .
  • Pancreatic cancer is responsible for 27,000 deaths per year in the United States. Because of lack of early diagnosis and poor therapeutic responsiveness of pancreatic cancer, less than 2% of patients survive beyond five years, and the median expectation of life after diagnosis of pancreatic cancer is less than 6 months (Horward; Poston; and Black) .
  • Colonic cancer is the second most common form of cancer in the United States (Doll et al . , "Mortality in Relation to Smoking: 20 Years' Observations on Male British Doctors," BMJ, 2:1525-1536 (1976); Hruban et al . , “Molecular Diagnosis of Cancer and Micrometastases, " Adv. Anat . Pathol.. 5:175-178 (1998) ("Hruban”) ; Figueredo et al . , "Adjuvant Therapy for Stage II Colon Cancer After Complete Resection. Provincial Gastrointestinal Disease Site Group, " Cancer Prev.
  • Colonic cancer occurs in more than 138,000 patients and is responsible for more than 55,000 deaths in the United States each year (Wingo) . Up to 70 % of patients with colonic cancer develop hepatic metastasises by the time of death, indicating that non- detectable micro-metastases are present at the time of surgery (Hruban,- Figueredo; and Ness) . Furthermore, metastatic cancer is often not responsive to standard chemotherapeutic regimens, resulting in treatment failure (Figueredo and Ness) . The overall response of advanced or non-resectable colorectal cancer patients to chemotherapeutic agents varies from 26 to 44 percent.
  • the present invention also relates to a pharmaceutical composition.
  • the present invention relates to a method of inhibiting 5-lipoxygenase activity.
  • the present invention also relates to a method of decreasing proliferation of adenocarcinoma cells, or of inducing apoptosis of adenocarcinoma cells, or of inducing differentiation of adenocarcinoma cells into non-cancerous cells.
  • the present invention also relates to a method of treating adenocarcinoma in a subject.
  • omega-5 fatty acids of the present invention are capable of forming salts and that the salt forms of pharmaceuticals are commonly used, often because they are more readily crystallized and purified than are the free acids .
  • Suitable salts of the aforementioned omega-5 fatty acids include pharmaceutically acceptable salts.
  • pharmaceutically acceptable salt refers to salts of the subject omega-5 fatty acids which are substantially non-toxic to living organisms.
  • Typical pharmaceutically acceptable salts include those salts prepared by reaction of the omega-5 fatty acids of the present invention with a pharmaceutically acceptable organic or inorganic base. Such salts are known as base addition salts.
  • Suitable base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates , and the like.
  • Bases useful in preparing such salts include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like.
  • any pharmaceutically acceptable salt of this invention is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole.
  • esters and amides such as pharmaceutically acceptable esters and amides, of the aforementioned omega-5 fatty acids.
  • suitable esters include alkyl, aryl , and aralkyl esters, such as methyl esters, ethyl esters, propyl esters, dodecyl esters, benzyl esters, and the like.
  • suitable amides include, unsubstituted amides, monosubstituted amides, and disubstituted amides, such as methyl amide, dimethyl aminde, methyl ethyl amide, and the like.
  • the method of the present invention can be practiced using solvate forms of the aforementioned omega-5 fatty acids or salts, esters, and/or amides thereof, such as ethanol solvates, hydrates, and the like.
  • omega-5 fatty acids or salts, esters, amides, and/or solvates thereof can be present as a single species. Alternatively, two or more of the present invention's omega-5 fatty acids or salts, esters, amides, and/or solvates thereof can be present as a mixture. Additionally or alternatively, the omega-5 fatty acids or salts, esters, amides, and/or solvates thereof can be present with other materials (i.e., other than the present invention's omega- 5 fatty acids or salts, esters, amides, and/or solvates thereof) .
  • the omega-5 fatty acids of the present invention can be isolated.
  • isolated when referring to a compound, means that the compound is present alone or is present as part of a composition that is not found in nature. For example, in the case where the compound is one that is naturally found in the presence of other chemical components (e.g., in an organism, a cell, a tissue, or some other portion thereof) , the compound is to be deemed to be “isolated” when the compound is partially, substantially, of wholly free of one or more of the other chemical components with which it is naturally found.
  • other chemical components e.g., in an organism, a cell, a tissue, or some other portion thereof
  • the omega-5 fatty acids used in the method of the present invention can be substantially pure, i.e., substantially free from other fatty acids or esters, amides, and solvates thereof; from other unsaturated fatty acids or esters, amides, and solvates thereof; from other polyunsaturated fatty acids or esters, amides, and solvates thereof; from omega-3 fatty acids or esters, amides, and solvates thereof; from omega-3 polyunsaturated fatty acids or esters, amides, and solvates thereof; from other biologically active materials; and/or from other materials.
  • compound A is to be deemed to be substantially free from compound B if the weight ratio of compound A to compound B is greater than about 1.3 (e.g., greater than about 1.5, greater than about 2, greater than about 3, greater than about 5, greater than about 10, greater than about 20, greater than about 30, greater than about 50, and/or greater than about 100) .
  • a compound which is the predominant species present in a mixture is, for the purposes of the present invention, to be considered substantially pure.
  • omega-5 fatty acids of the present invention can be synthetically produced; or they can be isolated from naturally occurring plants, animals, or other organisms or portions thereof; or they can be isolated from mixtures produced by the in vivo or ex vivo action of one or more enzymes on other fatty acids .
  • the omega-5 fatty acids of the present invention can also be prepared by any suitable synthetic, biological, or other method.
  • Reagents and conditions (i) LiBH 4 , TMSCl, THF; (ii) pTsCl , Et 3 N; (iii) LiBr, (CH 3 ) 2 C0; (iv) PDC, DMF; (v) P(Ph) 3 , PhCH 3 , heat; (vi) nBuLi then C 5 H 10 O, THF, RT.
  • (1) is reduced to the diol by treatment with lithium borohydride and trimethylsilyl chloride; and then the diol is toslyated with one equivalent of tosyl chloride to furnish (2) which is purified by chromatography.
  • Tosylate displacement by stirring with lithium bromide provides (3) which is then oxidized to acid (4) with pyridinium dichromate in N, N- dimethylformamide .
  • Reagents and conditions (i) LiBH 4 , TMSCl, THF; (ii) pTsCl , Et 3 N; (iii) LiBr, (CH 3 J 2 CO; (iv) PDC, DMF; (v) P(Ph) 3 , PhCH 3 , heat; (vi) nBuLi then C 5 H 10 O, THF, RT.
  • SCHEME 4 LiBH 4 , TMSCl, THF; (ii) pTsCl , Et 3 N; (iii) LiBr, (CH 3 J 2 CO; (iv) PDC, DMF; (v) P(Ph) 3 , PhCH 3 , heat; (vi) nBuLi then C 5 H 10 O, THF, RT.
  • Reagents and conditions (i) TBDMSCl, Et 3 N; (ii) LiCC (CH 2 ) 3 CH 3 , THF/HMPA, -78°C; (iii) TBNF, THF, RT; (iv) PCC, CH 2 Cl 2 ; then NaClO 2 , tBuOH; (v) H 2 (g) , Pd/Pb on CaCO 3 .
  • Reagents and conditions (i) LiBH 4 , TMSCl, THF; (ii) pTsCl , Et 3 N; (iii) LiBr, (CH 3 ) 2 C0; (iv) PDC, DMF; (v) P(Ph) 3 , PhCH 3 , heat; (vi) nBuLi then C 5 H 10 O, THF, RT.
  • Reagents and conditions (i) TBDMSCl, Et 3 N; (ii) LiCC(CH 2 J 3 CH 3 , THF/HMPA, -78 0 C; (iii) TBNF, THF, RT; (iv) PCC, CH 2 Cl 2 ; then NaClO 2 , tBuOH; (v) H 2 (g) , Pd/Pb on CaCO 3 .
  • Reagents and conditions (i) DHP, pTsOH, CH 2 Cl 2 ; (ii) tBu (Me) 2 SiOCH 2 CCLi, THF-HMPA, -78°C; (iii) TBNF, RT; (iv) PPh 3 Br 2 ; (v) BuLi, -78°C, CH 3 (CH 2 J 3 Br; (vi) TBNF, RT; (vii) BuLi, -78°C then compound (44) ; (viii) pTsOH, MeOH; (ix) PCC, CH 2 Cl 2 ; then NaClO 2 , tBuOH; (x) H 2 (g) , Pd/Pb on CaCO 3 .
  • Reagents and conditions (i) DHP, pTsOH, CH 2 Cl 2 ; (ii) tBu (Me) 2 SiOCH 2 CCLi, THF-HMPA, -78°C; (iii) TBNF, RT; (iv) PPh 3 Br 2 ; (v) BuLi, -78°C, CH 3 (CH 2 J 3 Br; (vi) TBNF, RT; (vii) BuLi, -78°C then compound (54) ; (viii) pTsOH, MeOH; (ix) PCC, CH 2 Cl 2 ; then NaClO 2 , tBuOH; (x) H 2 (g) , Pd/Pb on CaCO 3 .
  • Reagents and conditions (i) DHP, pTsOH, CH 2 Cl 2 ; (ii) tBu (Me) 2 SiOCH 2 CCLi, THF-HMPA, -78°C; (iii) TBNF, RT; (iv) PPh 3 Br 2 ; (v) BuLi, -78°C, CH 3 (CH 2 J 3 Br; (vi) TBNF, RT; (vii) BuLi, -78°C then compound (64) ; (viii) pTsOH, MeOH; (ix) PCC, CH 2 Cl 2 ; then NaClO 2 , tBuOH; (x) H 2 (g) , Pd/Pb on CaCO 3 .
  • reaction of 7-bromoheptanol (61) with dihydropyran and p-toluenesulphonic acid under standard conditions provides (62) .
  • 62) treatment of t-butyldimethylsilyl protected propargyl alcohol with n-butyl lithium at -78°C makes the lithium acetylide in situ, and quenching with (62) furnishes (63) which can be purified by chromatography.
  • Reagents and conditions (i) DHP, pTsOH, CH 2 Cl 2 ; (ii) tBu (Me) 2 SiOCH 2 CCLi, THF-HMPA, -78°C; (iii) TBNF, RT; (iv) PPh 3 Br 2 ; (v) BuLi, -78°C, CH 3 (CH 2 ) 3 Br; (vi) TBNF, RT; (vii) BuLi, -78°C then compound (74) ; (viii) pTsOH, MeOH; (ix) PCC, CH 2 Cl 2 ; then NaClO 2 , tBuOH; (x) H 2 (g) , Pd/Pb on CaCO 3 .
  • Reagents and conditions (i) DHP, pTsOH, CH 2 Cl 2 ; ( ⁇ ) tBu (Me) 2 SiOCH 2 CCLi, THF-HMPA, -78°C; (iii) TBNF, RT; (iv) PPh 3 Br 2 ; (v) BuLi, -78°C, CH 3 (CH 2 J 3 Br; (vi) TBNF, RT; (vii) BuLi, -78°C then compound (84) ; (viii) pTsOH, MeOH; (ix) PCC, CH 2 Cl 2 ; then NaClO 2 , tBuOH; (x) H 2 (g) , Pd/Pb on CaCO 3 .
  • the omega-5 fatty acids of the present invention can also be prepared by biological methods, such as by the in vivo or ex vivo action of one or more enzymes on suitable precursors of the desired omega-5 fatty acid.
  • the pharmaceutical composition additionally includes one or more pharmaceutically acceptable carriers, diluents, or excipients .
  • the pharmaceutically acceptable carriers, diluents, or excipients and manner of formulation of the pharmaceutical compositions are conventional. The usual methods of formulation used in pharmaceutical science may be used here.
  • compositions may be used, including tablets, chewable tablets, capsules, solutions, parenteral solutions, intranasal sprays or powders, troches, suppositories, transdermal patches, and suspensions.
  • compositions contain from about 0.5% to about 50% of the active (omega-5 fatty acids, esters, salts, amides, or solvates), depending on the desired doses and the type of composition to be used.
  • the amount of the active is best defined as the "effective amount", that is, the amount of omega-5 fatty acids, esters, salts, amides, or solvates which provides the desired dose to the subject to whom it is to be administered.
  • omega- 5 fatty acids, esters, salts, amides, or solvates employed in the present invention are not believed to depend greatly on the nature of the composition, and, therefore, the compositions can be chosen and formulated primarily or solely for convenience and economy.
  • Capsules can be prepared by mixing the omega-5 fatty acids, esters, salts, amides, or solvates with a suitable diluent and filling the proper amount of the mixture in capsules.
  • suitable diluents include inert powdered substances (such as starches) , powdered cellulose (especially crystalline and microcrystalline cellulose) , sugars (such as fructose, mannitol and sucrose) , grain flours, and similar edible powders.
  • Tablets can be prepared by direct compression, by wet granulation, or by dry granulation.
  • Their formulations usually incorporate diluents, binders, lubricants, and disintegrators (in addition to the omega-5 fatty acids, esters, salts, amides, or solvates).
  • Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts (such as sodium chloride) , and powdered sugar. Powdered cellulose derivatives can also be used.
  • Typical tablet binders include substances such as starch, gelatin, and sugars (e.g., lactose, fructose, glucose, and the like) .
  • sugars e.g., lactose, fructose, glucose, and the like
  • Natural and synthetic gums can also be used, including acacia, alginates, methylcellulose, polyvinylpyrrolidine, and the like.
  • Polyethylene glycol, ethylcellulose, and waxes can also serve as binders.
  • Tablets can be coated with sugar, e.g., as a flavor enhancer and sealant.
  • the omega-5 fatty acids, esters, salts, amides, or solvates can also be formulated as chewable tablets, by using large amounts of pleasant- tasting substances, such as mannitol, in the formulation.
  • Instantly dissolving tablet-like formulations can also be employed, for example, to assure that the patient consumes the dosage form and to avoid the difficulty that some patients experience in swallowing solid objects.
  • a lubricant can be used in the tablet formulation to prevent the tablet and punches from sticking in the die.
  • the lubricant can be chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid, and hydrogenated vegetable oils.
  • Tablets can also contain disintegrators.
  • Disintegrators are substances that swell when wetted to break up the tablet and release the compound. They include starches, clays, celluloses, algins, and gums. As further illustration, corn and potato starches, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation-exchange resins, alginic acid, guar gum, citrus pulp, sodium lauryl sulfate, and carboxymethylcellulose can be used.
  • Compositions can be formulated as enteric formulations, for example, to protect the active ingredient from the strongly acid contents of the stomach. Such formulations can be created by coating a solid dosage form with a film of a polymer which is insoluble in acid environments and soluble in basic environments.
  • Illustrative films include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, and hydroxypropyl methylcellulose acetate succinate .
  • conventional bases can be used.
  • cocoa butter is a traditional suppository base. The cocoa butter can be modified by addition of waxes to raise its melting point slightly.
  • Water-miscible suppository bases such as polyethylene glycols of various molecular weights, can also be used in suppository formulations .
  • Transdermal delivery systems e.g., transdermal patches
  • Transdermal patches can include a resinous composition in which the omega-5 fatty acids, esters, salts, amides, or solvates will dissolve or partially dissolve; and a film which protects the composition and which holds the resinous composition in contact with the skin.
  • Other, more complicated patch compositions can also be used, such as those having a membrane pierced with a plurality of pores through which the drugs are pumped by osmotic action.
  • omega-5 fatty acids, esters, salts, amides, or solvates of present invention can also be formulated as a nutriceutical composition that can include, in addition to the omega-5 fatty acids, esters, salts, amides, or solvates, one or more materials which are conventionally used in the food processing industry, such as proteins, sugars and other carbohydrates, extenders, fillers, preservatives, and the like.
  • the omega-5 fatty acids, esters, salts, amides, or solvates of present invention can be used to decrease proliferation of adenocarcinoma cells, and/or induce apoptosis of adenocarcinoma cells, and/or induce differentiation of adenocarcinoma cells into non-cancerous cells.
  • the method can be carried out by contacting the adenocarcinoma cells with one or more of the omega-5 fatty acids, esters, salts, amides, or solvates of present invention.
  • the method can be practiced in vitro or in vivo .
  • the method of the present invention can be practiced by administering any omega-5 fatty acid or other compound under conditions effective for the omega-5 fatty acid or other compound to be metabolized or otherwise converted to an omega-5 fatty acid of the present invention prior to the latter omega-5 fatty acid's coming into contact with the adenocarcinoma cells.
  • the method of the present invention can be used in vivo to treat adenocarcinomas, such as prostate cancer, lung cancer, stomach cancer, pancreatic cancer, breast cancer, and colon cancer.
  • adenocarcinomas such as prostate cancer, lung cancer, stomach cancer, pancreatic cancer, breast cancer, and colon cancer.
  • contacting can be carried out by administering a therapeutically effective amount of the omega-5 fatty acid, ester, salt, amide, or solvate of present invention to the human subject, for example, by directly injecting the omega-5 fatty acid, ester, salt, amide, or solvate into a tumor.
  • the present invention in another aspect thereof, relates to a method of treating adenocarcinomas, such as prostate cancer, lung cancer, stomach cancer, breast, pancreatic cancer, colon cancer, esophageal cancer, uterine cancer, ovarian cancer, or other cancers involving epithelial cells.
  • the method includes administering, to the subject, an omega-5 fatty acid, ester, salt, amide, or solvate of present invention, either alone or in the form of a pharmaceutical composition.
  • Suitable subjects include, for example mammals, such as rats, mice, cats, dogs, monkeys, and humans.
  • Suitable human subjects include, for example, those which have previously been determined to be at risk of having prostate cancer, lung cancer, stomach cancer, pancreatic cancer, colon cancer, and/or breast cancer and those who have been diagnosed as having prostate cancer, lung cancer, stomach cancer, pancreatic cancer, colon cancer, and/or breast cancer.
  • the subject suffers from only one of these types of cancers, for example, from only pancreatic cancer.
  • the omega-5 fatty acids, esters, salts, amides, or solvates are administered to the subject, preferably under conditions effective to decrease proliferation and/or induce apoptosis and/or induce differentiation of the adenocarcinoma cells in the event that they develop.
  • Such preventive (which is not used in the absolute 100% sense) therapy can be useful in high risk individuals as long as the adverse side effects of the administration of these compounds are outweighed by the potential benefit of prevention.
  • omega-5 fatty acids, esters, salts, amides, or solvates of the present invention can be used in the treatment method of the present invention.
  • compounds may be administered alone or in combination with compatible carriers as a composition.
  • Compatible carriers include suitable pharmaceutical carriers, diluents, or excipients. The diluent, carrier, and excipient ingredients should be selected so that they do not diminish the therapeutic effects of the compounds used in the present invention.
  • compositions herein may be made up in any suitable form appropriate for the desired use.
  • suitable dosage forms include oral, parenteral, or topical dosage forms .
  • Suitable dosage forms for oral use include tablets, dispersible powders, granules, capsules, suspensions, syrups, and elixirs.
  • Inert diluents and carriers for tablets include, for example, calcium carbonate, sodium carbonate, lactose, and talc.
  • Tablets may also contain granulating and disintegrating agents, such as starch and alginic acid; binding agents, such as starch, gelatin, and acacia; and lubricating agents, such as magnesium stearate, stearic acid, and talc. Tablets may be uncoated or may be coated by known techniques to delay disintegration and absorption.
  • Inert diluents and carriers which may be used in capsules include, for example, calcium carbonate, calcium phosphate, and kaolin.
  • Suspensions, syrups, and elixirs may contain conventional excipients, for example, methyl cellulose, tragacanth, sodium alginate; wetting agents, such as lecithin and polyoxyethylene stearate; and preservatives, such as ethyl -p- hydroxybenzoate .
  • Dosage forms suitable for parenteral administration include solutions, suspensions, dispersions, emulsions, and the like. They may also be manufactured in the form of sterile solid compositions which can be dissolved or suspended in sterile injectable medium immediately before use . They may contain suspending or dispersing agents known in the art. Examples of parenteral administration are intraventricular, intracerebral, intramuscular, intravenous, intraperitoneal, rectal, and subcutaneous administration.
  • these formulations can include other active materials, particularly, actives which have been identified as useful in the treatment of prostate, lung, stomach, breast, colon, pancreatic cancers and/or other adenocarcinomas.
  • actives can be broad-based anti -cancer agents, such that they also are useful in treating other types of cancers (i.e., in addition to adenocarcinomas) or they may be more specific, for example, in the case where the other active is useful for treating adenocarcinomas or particular types of adenocarcinomas.
  • the other actives can also have non- anti -cancer pharmacological properties in addition to their anti -adenocarcinoma properties.
  • the other actives can have anti -inflammatory properties, or, alternatively, they can have no such anti -inflammatory properties .
  • omega- 5 fatty acids, esters, salts, amides, or solvates of the present invention may be naturally occurring.
  • the omega-5 fatty acids, esters, salts, amides, or solvates of the present invention used in the treatment methods of the present invention can be isolated, substantially pure, or both.
  • omega- 5 fatty acids, esters, salts, amides, or solvates of the present invention will vary according to the particular omega-5 fatty acids, esters, salts, amides, or solvates of the present invention being employed, the particular composition formulated, and the mode of administration. Many factors that may modify the action of the compound (e.g., body weight, sex, diet, time of administration, route of administration, rate of excretion, condition of the subject, drug combinations, and reaction sensitivities and severities) can be taken into account by those skilled in the art. Administration can be carried out continuously or periodically within the maximum tolerated dose.
  • omega-5 fatty acids, esters, salts, amides, or solvates of the present invention can also be used to inhibit 5 -lipoxygenase activity, either in vivo or ex vivo.
  • 5 -lipoxygenase activity is inhibited by contacting 5 -lipoxygenase with omega-5 fatty acids, esters, salts, amides, or solvates of the present invention.
  • an omega-5 fatty acid, ester, salt, amide, or solvate thereof of the present invention is administered to the subject.
  • Methods and compositions for effecting the aforementioned "contacting” and “administering” steps include those discussed above in the context of treating adenocarcinomas.
  • the present invention is further illustrated with the following examples.
  • Hard gelatin capsules are prepared using the following ingredients:
  • the above ingredients are mixed and filled into hard gelatin capsules weighing about 1.4 g each.
  • a tablet is prepared using the ingredients set forth below:
  • An aerosol solution is prepared containing the following components:
  • Propellant 22 70.00 (Chlorodifluoromethane)
  • the active compound is mixed with ethanol and the mixture added to a portion of the Propellant 22, cooled to -30 0 C and transferred to a filling device. The required amount is then fed to a stainless steel container and diluted with the remainder of the propellant. Valve units are then fitted to the container.
  • Tablets each containing 600 mg of active ingredient are made as follows:
  • the active ingredient, starch, and cellulose are passed through a No . 45 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve.
  • the granules so produced are dried at 50 0 C. and passed through a No . 18 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate, and talc previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing about 1 g.
  • the active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 45 sieve, and filled into hard gelatin capsules in 1280 mg quantities.
  • Suppositories each containing 550 mg of active ingredient may be made as follows:
  • the active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2.5 g capacity and allowed to cool.
  • the medicament is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste.
  • the benzoic acid solution, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.
  • Formulation 8 An intravenous formulation containing 500 mg of medicament per 20 ml dose can be prepared as follows: Active Ingredient 500 mg Mannitol 500 mg

Abstract

Disclosed are omega-5 fatty acids having one of the following formulae: CH3- (CH2) 3-CH=CH- (CH2) 9-COOH, CH3- (CH2) 3-CH=CH- (CH2) 11-COOH, CH3- (CH2) 3-CH=CH- (CH2) 13-COOH, CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2) 6-COOH, CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2) 8-COOH, CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2) 10-COOH, CH3- (CH2) 3-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) 5-COOH, CH3- (CH2) 3-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) 7-COOH, and CH3- (CH2)3-CH=CH-CH2-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2)4-COOH and pharmaceutically acceptable esters, salts, amides, and solvates thereof, as well as pharmaceutical compositions which include one or more of aforementioned omega-5 fatty acids and pharmaceutically acceptable esters, salts/ amides, and solvates thereof. Also disclosed are methods of inhibiting 5 -lipoxygenase activity; methods of decreasing proliferation of adenocarcinoma cells, or of inducing apoptosis of adenocarcinoma cells, or of inducing differentiation of adenocarcinoma cells into non-cancerous cells; and methods of treating adenocarcinoma in a subject using one or more of aforementioned omega-5 fatty acids and pharmaceutically acceptable esters, salts, amides, and solvates thereof.

Description

OMEGA-5 -FATTY ACIDS USEFUL IN LIPOXYGENASE 5 INHIBITION AND IN THE TREATMENT OF CANCER
The present application claims the benefit of U.S. Provisional Patent Application Serial No. 60/876,712, filed December 22, 2006, which provisional patent application is hereby incorporated by reference.
FIELD OF THE INVENTION
The subject invention is directed generally to omega-5-fatty acids and, more particularly, to the use of omega-5-fatty acids in lipoxygenase 5 inhibition and in the treatment of cancer.
BACKGROUND OF THE INVENTION
Pancreatic cancer is one of the most enigmatic and aggressive malignant diseases facing oncologists (Parker et al . , "Cancer Statistics. 1996," CA Cancer J. Clin. , 46:5-27 (1996) ("Parker")). It is now the fourth leading cause of cancer death in both men and women in the United States, and the incidence of this disease has significantly increased over the past 20 years (Parker; Trede et al . , "Survival After Pancreaticoduodenectomy: 118 Consecutive Resections Without an Operative Mortality," Ann . Surg .. 211:447-458 (1990); Cameron et al . , "One Hundred and Forty-five Consecutive Pancreaticoduodenectomies Without Mortality," Ann . Surg .. 217:430- 438 (1993) ; Horward, "Pancreatic Adenocarcinoma, " Curr . Prob. in Cancer. 20:286-293 (1996) ("Horward"); Poston et al., Gut. Biology of Pancreatic Cancer. 32:800-812 (1991) ("Poston"); and Black et al . , "Treatment of Pancreatic Cancer: Current Limitations, Future Possibilities," Oncology. 10:301-307 (1996) ("Black")). Pancreatic cancer is responsible for 27,000 deaths per year in the United States. Because of lack of early diagnosis and poor therapeutic responsiveness of pancreatic cancer, less than 2% of patients survive beyond five years, and the median expectation of life after diagnosis of pancreatic cancer is less than 6 months (Horward; Poston; and Black) .
Colonic cancer is the second most common form of cancer in the United States (Doll et al . , "Mortality in Relation to Smoking: 20 Years' Observations on Male British Doctors," BMJ, 2:1525-1536 (1976); Hruban et al . , "Molecular Diagnosis of Cancer and Micrometastases, " Adv. Anat . Pathol.. 5:175-178 (1998) ("Hruban") ; Figueredo et al . , "Adjuvant Therapy for Stage II Colon Cancer After Complete Resection. Provincial Gastrointestinal Disease Site Group, " Cancer Prev.
Control . 1:379-92 (1997) ("Figueredo"); Ness et al . , "Outcome States of Colorectal Cancer: Identification and Description Using Patient Focus Groups, " Am. J. Gastroenterol .. 93:1491-7 (1998) ("Ness"); Trehu et al . , "Cost of Screening for Colorectal Cancer: Results of a Community Mass Screening Program and Review of Literature," South Med. J.. 85:248-253 (1992); and Wingo et al., "Cancer Statistics," CA Cancer J. Clin.. 45:8-30 (1995) ("Wingo")). Colonic cancer occurs in more than 138,000 patients and is responsible for more than 55,000 deaths in the United States each year (Wingo) . Up to 70 % of patients with colonic cancer develop hepatic metastasises by the time of death, indicating that non- detectable micro-metastases are present at the time of surgery (Hruban,- Figueredo; and Ness) . Furthermore, metastatic cancer is often not responsive to standard chemotherapeutic regimens, resulting in treatment failure (Figueredo and Ness) . The overall response of advanced or non-resectable colorectal cancer patients to chemotherapeutic agents varies from 26 to 44 percent. For example, less than one third of colorectal cancer patients with liver metastases respond to treatment with agents such as 5-FU and leucovorin (JEd.) . Breast cancer has the highest incidence of any cancer in women with the diagnosis being made in more than 275,000 per year in the USA (Richards et al . , "Influence of Delay on Survival in Patients with Breast Cancer: A Systematic Review," Lancet , 353:1119-26 (1999); Norton, "Adjuvant Breast Cancer Therapy: Current Status and Future Strategies -- Growth Kinetics and the Improved Drug Therapy of Breast Cancer," Semin. Oncol . , 26:1-4 (1999); Morrow et al . , "Current Controversies in Breast Cancer Management," Curr . Probl . Surg .. 36:163-216 (1999); and Ruppert et al . , "Gene Therapy Strategies for Carcinoma of the Breast," Breast Cancer Res. Treatment. 44:93-114 (1997)). Even though five year survival has increased to more than 80%, more than 77,000 women still die from this disease each year (JEd.) . Thus, another dimension in chemotherapeutic agents for pancreatic, colonic, and breast cancer would be extremely beneficial, especially to control metastatic and unresectable disease.
SUMMARY OF THE INVENTION
The present invention relates to an omega-5 fatty acid having one of the following formulae: CH3- (CH2) 3-CH=CH- (CH2) 9-COOH, CH3- (CH2) 3-CH=CH- (CH2) ^-COOH, CH3- (CH2) 3-CH=CH- (CH2) 13-COOH, CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2) 6-COOH, CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2) 8-COOH, CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2) 10-COOH, CH3- (CH2) 3-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) 5-COOH,
CH3- (CH2) 3-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) ,-COOH, and CH3- (CH2) 3-CH=CH-CH2-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) 4-COOH or a pharmaceutically acceptable ester, salt, amide, or solvate thereof. The present invention also relates to a pharmaceutical composition. The pharmaceutical composition includes an omega-5 fatty acid having one of the following formulae: CH3- (CH2) 3-CH=CH- (CH2) 9-COOH, CH3- (CH2) 3-CH=CH- (CH2) ^-COOH, CH3- (CH2) 3-CH=CH- (CH2) 13-COOH, CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2) 6-COOH, CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2) 8-COOH, CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2) 10-COOH, CH3- (CH2) 3-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) 5-COOH, CH3- (CH2) 3-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) 7-COOH, and CH3- (CH2) 3-CH=CH-CH2-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) 4-C00H or a pharmaceutically acceptable ester, salt, amide, or solvate thereof or a combination thereof. The pharmaceutical composition also includes one or more pharmaceutically acceptable carriers, diluents, or excipients.
The present invention relates to a method of inhibiting 5-lipoxygenase activity. The method includes contacting 5 -lipoxygenase with an omega-5 fatty acid having one of the following formulae: CH3- (CH2) 3-CH=CH- (CH2J9-COOH, CH3- (CH2) 3-CH=CH- (CH2) ^-COOH, CH3- (CH2) 3-CH=CH- (CH2) 13-COOH, CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2) 6-COOH, CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2) 8-COOH, CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2) 10-COOH, CH3- (CH2) 3-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) 5-COOH, CH3- (CH2) 3-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) 7-COOH, and CH3- (CH2J3-CH=CH-CH2-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) 4-COOH or a pharmaceutically acceptable ester, salt, amide, or solvate thereof or combinations thereof.
The present invention also relates to a method of decreasing proliferation of adenocarcinoma cells, or of inducing apoptosis of adenocarcinoma cells, or of inducing differentiation of adenocarcinoma cells into non-cancerous cells. The method includes contacting a sample comprising adenocarcinoma cells with an omega- 5 fatty acid having one of the following formulae: CH3- (CH2) 3-CH=CH- (CH2) 9-COOH, CH3- (CH2) 3-CH=CH- (CH2) U-COOH, CH3- (CH2) 3-CH=CH- (CH2) 13-COOH, CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2) 6-COOH, CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2) 8-COOH, CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2) 10-COOH, CH3- (CHJ)3-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) 5-COOH, CH3- (CH2) 3-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) 7-COOH, and CH3- (CH2) 3-CH=CH-CH2-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) 4-COOH or a pharmaceutically acceptable ester, salt, amide, or solvate thereof or combinations thereof.
The present invention also relates to a method of treating adenocarcinoma in a subject. The method includes administering to the subject an effective amount of an omega- 5 fatty acid having one of the following formulae: CH3- (CH2) 3-CH=CH- (CH2J9-COOH,
CH3- (CH2) 3-CH=CH- (CH2) ^-COOH, CH3- (CH2) 3-CH=CH- (CH2) 13-COOH, CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2) 6-COOH, CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2) 8-COOH, CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2) 10-COOH, CH3- (CH2) 3-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) 5-COOH, CH3- (CH2) 3-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) 7-COOH, and CH3- (CH2) 3-CH=CH-CH2-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) 4-COOH or a pharmaceutically acceptable ester, salt, amide, or solvate thereof or combinations thereof.
DETAILED DESCRIPTION OF THE INVENTION
The present invention, in one aspect thereof, relates to an omega- 5 fatty acid having one of the following formulae: CH3- (CH2) 3-CH=CH- (CH2) 9-COOH, CH3- (CH2) 3-CH=CH- (CH2) n-COOH, CH3- (CH2) 3-CH=CH- (CH2) 13-COOH, CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2) 6-COOH, CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2) 8-COOH, CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2) 10-COOH, CH3- (CH2) 3-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) S-COOH, CH3- (CH2) 3-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) 7-COOH, and CH3- (CH2) 3-CH=CH-CH2-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) 4-COOH or an ester, salt, amide, or solvate thereof.
It will be appreciated by the skilled reader that the omega-5 fatty acids of the present invention are capable of forming salts and that the salt forms of pharmaceuticals are commonly used, often because they are more readily crystallized and purified than are the free acids .
Suitable salts of the aforementioned omega-5 fatty acids include pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" as used herein, refers to salts of the subject omega-5 fatty acids which are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the omega-5 fatty acids of the present invention with a pharmaceutically acceptable organic or inorganic base. Such salts are known as base addition salts.
Suitable base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates , and the like. Bases useful in preparing such salts include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like.
It should be recognized that the particular counterion forming a part of any pharmaceutically acceptable salt of this invention is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole.
As alluded to above, the present invention also relates to esters and amides, such as pharmaceutically acceptable esters and amides, of the aforementioned omega-5 fatty acids. Examples of suitable esters include alkyl, aryl , and aralkyl esters, such as methyl esters, ethyl esters, propyl esters, dodecyl esters, benzyl esters, and the like. Examples of suitable amides include, unsubstituted amides, monosubstituted amides, and disubstituted amides, such as methyl amide, dimethyl aminde, methyl ethyl amide, and the like.
In addition, the method of the present invention can be practiced using solvate forms of the aforementioned omega-5 fatty acids or salts, esters, and/or amides thereof, such as ethanol solvates, hydrates, and the like.
The omega-5 fatty acids or salts, esters, amides, and/or solvates thereof can be present as a single species. Alternatively, two or more of the present invention's omega-5 fatty acids or salts, esters, amides, and/or solvates thereof can be present as a mixture. Additionally or alternatively, the omega-5 fatty acids or salts, esters, amides, and/or solvates thereof can be present with other materials (i.e., other than the present invention's omega- 5 fatty acids or salts, esters, amides, and/or solvates thereof) . The omega-5 fatty acids of the present invention can be isolated. The phrase "isolated", when referring to a compound, means that the compound is present alone or is present as part of a composition that is not found in nature. For example, in the case where the compound is one that is naturally found in the presence of other chemical components (e.g., in an organism, a cell, a tissue, or some other portion thereof) , the compound is to be deemed to be "isolated" when the compound is partially, substantially, of wholly free of one or more of the other chemical components with which it is naturally found. Additionally or alternatively, the omega-5 fatty acids used in the method of the present invention can be substantially pure, i.e., substantially free from other fatty acids or esters, amides, and solvates thereof; from other unsaturated fatty acids or esters, amides, and solvates thereof; from other polyunsaturated fatty acids or esters, amides, and solvates thereof; from omega-3 fatty acids or esters, amides, and solvates thereof; from omega-3 polyunsaturated fatty acids or esters, amides, and solvates thereof; from other biologically active materials; and/or from other materials. For the purposes of the present invention compound A is to be deemed to be substantially free from compound B if the weight ratio of compound A to compound B is greater than about 1.3 (e.g., greater than about 1.5, greater than about 2, greater than about 3, greater than about 5, greater than about 10, greater than about 20, greater than about 30, greater than about 50, and/or greater than about 100) . A compound which is the predominant species present in a mixture is, for the purposes of the present invention, to be considered substantially pure. "Purified" and "isolated" omega-5 fatty acids of the present invention can be synthetically produced; or they can be isolated from naturally occurring plants, animals, or other organisms or portions thereof; or they can be isolated from mixtures produced by the in vivo or ex vivo action of one or more enzymes on other fatty acids . The omega-5 fatty acids of the present invention can also be prepared by any suitable synthetic, biological, or other method.
Illustratively, CH3- (CH2) 3-CH=CH- (CH2) 1X-COOH can be prepared according to the sequence of reactions shown in either Scheme 1 or Scheme 2 below.
SCHEME 1
HO2C ( CH2 ) J-1CO2H (l) > HO ( CH L 22 )> 1133OV Ts (lll) * HO ( CH2 ) 13Br
(ϋ)
(D (2) (3)
(iv)
BrCH2 (CH2) HCO2H
Figure imgf000011_0001
Br" +
(vi)
H,C(CH 2J' 3 (CH LJ2> 1 l1lCvO7H Ph3PCH2 (CH2) J1CO2H
(6) (5)
Reagents and conditions: (i) LiBH4, TMSCl, THF; (ii) pTsCl , Et3N; (iii) LiBr, (CH3) 2C0; (iv) PDC, DMF; (v) P(Ph)3 , PhCH3, heat; (vi) nBuLi then C5H10O, THF, RT.
SCHEME 2
(i)
HO (CH2) 12Br tβu (Me)2SiO (CH2) 12Br (7) (8)
(ii)
CH3 (CH2) 3C.≡ C (CH2J12OSi (Me)2 fcBu
(9)
(iii) , (iv)
H,C (CH5 2)' 3 (CHJ11CO2H _ (v) CH3 ( CH2 ) 3C ^≡ C ( CH2 ) HCO2H
(6: (10)
Reagents and conditions: (i) TBDMSCl, Et3N; (ii) LiCC (CH2) 3CH3, THF/HMPA, -78°C; (iii) TBNF, THF, RT; (iv) PCC, CH2Cl2; then NaClO2, tBuOH; (v) H2 (g) , Pd/Pb on CaCO3. Following Scheme 1, commercially available undecanedicarboxylic acid (1) (Aldrich Chemical Co., Milwaukee, WI) is converted to 13-bromotridecanoic acid (4) by the procedure of Peseckis et al . , J. Biol . Chem. , 268 (7) : 5107-5114 (1993), which is hereby incorporated by reference. Briefly, (1) is reduced to the diol by treatment with lithium borohydride and trimethylsilyl chloride; and then the diol is toslyated with one equivalent of tosyl chloride to furnish (2) which is purified by chromatography. Tosylate displacement by stirring with lithium bromide provides (3) which is then oxidized to acid (4) with pyridinium dichromate in N, N- dimethylformamide . Using methods described in Carballeira et al . , J. Nat Prod.. 64:1426-1429 (2001), which is hereby incorporated by reference, treatment of (4) with triphenylphospine provides phosphonium salt (5) which is then treated with n-butyl lithium to form the phosphonium ylid. Subsequent Wittig reaction with valeraldehyde provides the desired compound (6) . Alternatively, as shown in Scheme 2, commercially available 12-bromododecanol (7) (Aldrich Chemical Co., Milwaukee, WI) is treated with t-butyl- dimethylsilyl chloride in the presence of triethylamine to provide (8) . Treatment of commercially available 1- hexyne (Aldrich Chemical Co., Milwaukee, WI) with n-butyl lithium at -78°C followed by addition of compound (8) then provides compound (9) . Deprotection of (9) with tetrabutylammonium fluoride and then successive oxidations with pyridinium chlorochromate and sodium chlorite/t-butanol according to methods described in Carballeira et al . , J. Nat Prod.. 65:1715-1718 (2002), which is hereby incorporated by reference, provides alkyne (10) . Finally, hydrogenation of (10) using Lindlar's catalyst (for example, following the procedures set forth in Lindlar et al . , Orα Synth. ,46 :89 (1966) and Stork et al . , J. Am. Chem. Soc .. 97:3258 (1975), which are hereby incorporated by reference) provides the 5 desired compound (6) .
Methods that are analogous to those set forth in Schemes 1 and 2, can be used to prepare CH3- (CH2) 3- CH=CH- (CH2) 9-COOH and CH3- (CH2) 3-CH=CH- (CH2) 13-COOH . For example, CH3- (CH2) 3-CH=CH- (CH2) 9-COOH can be prepared using 10 the reactions shown in either Scheme 3 or Scheme 4 below. In Scheme 3, the desired compound (16) is produced from a nonanedicarboxylic acid (11) starting material. In Scheme 4, the desired compound (16) is produced from a 10-bromodecanol (17) starting material.
15
SCHEME 3
HO2C ( CH2 ) 9CO2H (l) > HO ( CH2 ) xlOTs (lll) > HO ( CH2 ) xlBr
(ii) (11) (12) (13)
(iv)
BrCH2 (CH2) 9CO2H
(14)
(v)
. . , Br" +
H3C (CH2) ζ ^(CH2J9CO2H -* — — Ph3IPCH2 (CH2J9CO2H
(16) (15)
Reagents and conditions: (i) LiBH4, TMSCl, THF; (ii) pTsCl , Et3N; (iii) LiBr, (CH3J2CO; (iv) PDC, DMF; (v) P(Ph)3 , PhCH3, heat; (vi) nBuLi then C5H10O, THF, RT. SCHEME 4
HO (CH2) 10Br (i) ^u(Me)2SiO (CH2) 10Br (17) (18)
(ϋ)
CH3 (CH2) 3C^ C (CH2) 10OSi (Me)^Bu
(19)
(iii) , (iv)
(V)
H3C (CH2) ζ (CHJqCO,H -*- CH3 ( CH2 ) 3C E= C ( CH, ) qCOPH
(16) (20)
Reagents and conditions: (i) TBDMSCl, Et3N; (ii) LiCC (CH2) 3CH3 , THF/HMPA, -78°C; (iii) TBNF, THF, RT; (iv) PCC, CH2Cl2; then NaClO2, tBuOH; (v) H2 (g) , Pd/Pb on CaCO3.
As further illustration, CH3- (CH2) 3-CH=CH- (CH2) 13-COOH can be prepared using the reactions shown in either Scheme 5 or Scheme 6 below. In Scheme 5, the desired compound
(26) is produced from a tridecanedicarboxylic acid (21) 5 starting material. In Scheme 6, the desired compound
(26) is produced by from a 14-bromotetradecanol (27) starting material. SCHEME 5
HO ^,2C^— ( \ C v<Hii2, ) ' .1 ,3CO 23H (l) > HO ( CH X22 )' .1 ,5OV Ts (lll) » HO ( CH2 ) 15Br
(ii)
(21) (22) (23)
(iv)
BrCH2 (CH2J13CO2H
(24)
(v)
Br" +
(vi)
H3C(CH ■2 ' 3 (CHJ 13CO2H Ph3PCH2 (CH2J13CO2H
(26) (25)
Reagents and conditions: (i) LiBH4, TMSCl, THF; (ii) pTsCl , Et3N; (iii) LiBr, (CH3) 2C0; (iv) PDC, DMF; (v) P(Ph)3 , PhCH3, heat; (vi) nBuLi then C5H10O, THF, RT.
SCHEME 6
HO (CH2J14Br (i) -*- fcBu (Me)2SiO (CH2J14Br (27) (28)
(ii)
CH3 (CH2) 3C^ C (CH2) 140Si (Me)^Bu
(29)
(iii) , (iv)
(v)
H3C(CH2J3" " (CH2) 13CO2H -*■ CH3 ( CH2 ) 3C = C ( CH2 ) 13CO2H
(26) (30)
Reagents and conditions: (i) TBDMSCl, Et3N; (ii) LiCC(CH2J3CH3, THF/HMPA, -780C; (iii) TBNF, THF, RT; (iv) PCC, CH2Cl2; then NaClO2, tBuOH; (v) H2 (g) , Pd/Pb on CaCO3. A suitable method for preparing CH3- (CH2) 3- CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) 7-COOH is set forth in the following Scheme 7.
SCHEME 7
Br(CH2J8OH (i) (ϋ)
Br(CH2J8OTHP cBu (Me) 2Si0CH2C._≡C (CH2) 8OTHP (41) (42) (43)
(iii) , (iv)
BrCH2C ^≡C ( CH2 ) 80THP (44)
(V)
HC ^≡CCH2C^≡ CSiMe3 H3C (CH2) 3C^≡ CCH2C^ CSiMe3 (45) (46)
(vi) , (vii)
H3C ( CH2 ) 3C^≡ CCH2C^≡ CCH2C ^≡C ( CH2 ) 80THP (47;
(viii) , (ix)
H3C ( CH2 ) 3C.≡ CCH2C_≡ CCH2C ^≡C ( CH2 ) 7CO2H (48)
(X)
H.C(CH A2' 3 v( CH2 J7CO2H
(49)
Reagents and conditions: (i) DHP, pTsOH, CH2Cl2; (ii) tBu (Me)2SiOCH2CCLi, THF-HMPA, -78°C; (iii) TBNF, RT; (iv) PPh3Br2; (v) BuLi, -78°C, CH3(CH2J3Br; (vi) TBNF, RT; (vii) BuLi, -78°C then compound (44) ; (viii) pTsOH, MeOH; (ix) PCC, CH2Cl2; then NaClO2, tBuOH; (x) H2 (g) , Pd/Pb on CaCO3. Briefly, reaction of commercially available, 8- bromooctanol (41) (Aldrich Chemical Co., Milwaukee, WI) with dihydropyran and p-toluenesulphonic acid under standard conditions (such as those described in Bernady et al . , J. Org. Chem.. 44:1438 (1979), which is hereby incorporated by reference) provides (42) . Treatment of t-butyldimethylsilyl protected propargyl alcohol with n- butyl lithium at -78°C makes the lithium acetylide in situ, and quenching with (42) furnishes (43) which can be purified by chromatography. Removal of the silyl protecting group with tetrabutylammonium fluoride and reaction of the resulting propargyl alcohol with triphenylphosphine dibromide (for example, as described in Schaefer et al . , Org Synth. , V:249 (1973), which is hereby incorporated by reference) provides bromo derivative (44) . Similarly, reaction of commercially available, 1-trimethylsilyl-l , 4-pentadiyne (45) (GFS Chemicals, Powell, OH) with n-butyl lithium at low temperature followed by quenching with 1-iodobutane provides (46) . Next, treatment of (46) with tetrabutylammonium fluoride to remove the trimethylsilyl protecting group (for example, as described in Cai et al., HeIv. Chim. Acta. 78:732 (1995), which is hereby incorporated by reference) and reaction with n-butyl lithium at low temperature followed by quenching with compound (44) provides (47) . The tetrahydropyran protecting group is removed from (47) under standard conditions (such as those described in Corey et al . , J. Am. Chem. Soc .. 100:1942 (1978), which is hereby incorporated by reference) , and the alcohol is oxidized to acid (48), for example as described in Figure 2. Finally, all 3 triple bonds are hydrogenated using Lindlar's catalyst (for example, following the procedures set forth in Lindlar et al . , Org . Synth..46:89 (1966) and Stork et al . , J. Am. Chem. Soc .. 97:3258 (1975), which are hereby incorporated by reference) to provide the desired compound (49) . Methods that are analogous to those set forth in Scheme I1 can be used to prepare CH3- (CH2) 3-CH=CH-CH2- CH=CH-CH2-CH=CH- (CH2) s-COOH, for example, by using the reactions sequence shown in Scheme 8 below, starting with 6-bromohexanol (51) .
SCHEME 8
Br (CH2) 6OH — — *- Br(CH2J6OTHP (ll) *■ fcBu (Me) 2Si0CH2CΞEΞ≡C (CH2) 6OTHP (51) (52) (53)
(iii) , (iv)
BrCH2C Ξ≡C ( CH2 ) 6OTHP (54)
(v)
HC^Ξ≡ CCH2CEEE≡ CSiMe3 →- H3C(CH2J3CEEEEEECCH2CEE-EEECSiMe3 (55) (56)
(vi) , (vii)
H3C ( CH2 ) 3CEΞΞΞ≡ CCH2CΞΞ≡ CCH2C ≡≡ΞC ( CH2 ) 6OTHP (57)
(viii) , (ix)
H3C ( CH2 ) 2C= CCH2CEΞ≡ CCH2C ≡EE≡C ( CH2 ) 5CO2H (58)
(x)
H3C(CH 2> 3 ~(CH,).CO?H
(59)
Reagents and conditions: (i) DHP, pTsOH, CH2Cl2; (ii) tBu (Me)2SiOCH2CCLi, THF-HMPA, -78°C; (iii) TBNF, RT; (iv) PPh3Br2; (v) BuLi, -78°C, CH3(CH2J3Br; (vi) TBNF, RT; (vii) BuLi, -78°C then compound (54) ; (viii) pTsOH, MeOH; (ix) PCC, CH2Cl2; then NaClO2, tBuOH; (x) H2 (g) , Pd/Pb on CaCO3.
The synthetic manipulations set forth in Schemes 1-8 can be used to prepare CH3-(CH2J3-CH=CH-CH2- CH=CH- (CH2) S-COOH, CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2) 8-COOH, CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2J10-COOH, and CH3- (CH2J3- 5 CH=CH-CH2-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2J4-COOH. For example, CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2) 6- COOH can be prepared using the following Scheme 9.
SCHEME 9
Br (CHJ7OH (l) > Br (CHJ7OTHP (ll) » fcBui Me)2SiOCH2C^ C (CH2) 70THP (61) (62) (63)
;iii) , (iv)
BrCH2C^C (CH2) 70THP (64)
(V)
HC! ICSiMe3 ■*- H3C (CH2) 3C≡ CS iMe|
(65) (66)
(vi) , (vii)
H3C ( CH2 ) 3C≡ CCH2C ^C ( CH2 ) 70THP (67)
(viii) , (ix)
H3C (CH2) 3C≡ CCH2C^C (CH2J6CO2H (68)
(x)
H3C(CH2)^ / ^(CH2J6CO2H
(69)
Reagents and conditions: (i) DHP, pTsOH, CH2Cl2; (ii) tBu (Me)2SiOCH2CCLi, THF-HMPA, -78°C; (iii) TBNF, RT; (iv) PPh3Br2; (v) BuLi, -78°C, CH3 (CH2J3Br; (vi) TBNF, RT; (vii) BuLi, -78°C then compound (64) ; (viii) pTsOH, MeOH; (ix) PCC, CH2Cl2; then NaClO2, tBuOH; (x) H2 (g) , Pd/Pb on CaCO3. Briefly, reaction of 7-bromoheptanol (61) with dihydropyran and p-toluenesulphonic acid under standard conditions (such as those described in Bernady et al . , J. Org. Chem.. 44:1438 (1979), which is hereby incorporated by reference) provides (62) . Treatment of t-butyldimethylsilyl protected propargyl alcohol with n-butyl lithium at -78°C makes the lithium acetylide in situ, and quenching with (62) furnishes (63) which can be purified by chromatography. Removal of the silyl protecting group with tetrabutyl- ammonium fluoride and reaction of the resulting propargyl alcohol with triphenylphosphine dibromide (for example, as described in Schaefer et al . , Org Synth.. V:249 (1973), which is hereby incorporated by reference) provides bromo derivative (64) . Similarly, reaction of commercially available, trimethylsilylacetylene (65) (Aldrich Chemical Co., Milwaukee, WI) with n-butyl lithium at low temperature followed by quenching with 1-iodobutane provides (66) . Next, treatment of (66) with tetrabutylammonium fluoride to remove the trimethylsilyl protecting group (for example, as described in Cai et al . , HeIv. Chim. Acta. 78:732 (1995), which is hereby incorporated by reference) and reaction with n-butyl lithium at low temperature followed by quenching with compound (64) provides (67) . The tetrahydropyran protecting group is removed from (67) under standard conditions (such as those described in Corey et al . , J. Am. Chem. Soc .. 100:1942 (1978), which is hereby incorporated by reference) , and the alcohol is oxidized to acid (68), for example as described in Figure 2. Finally, both triple bonds are hydrogenated using Lindlar's catalyst (for example, following the procedures set forth in Lindlar et al . , Org Synth..46:89 (1966) and Stork et al . , J. Am. Chem. Soc .. 97:3258 (1975), which are hereby incorporated by reference) to provide the desired compound (69) . As further illustration, CH3- (CH2) 3 -CH=CH-CH2- CH=CH- (CH2) 8-COOH can be prepared using the following Scheme 10, starting with 9-bromononanol (71) .
SCHEME 10
Br(CHJ9OH (l) > Br(CHj9OTHP-^^tBu(Me)2SiOCH,C==C(CH2)9OTHP
(71) (72) (73)
(iii) , (iv)
BrCH2C^C (CH2) 9OTHP (74)
(V)
HC = CSiMβj -*- H3C (CH2J3C = CSiMq1 (75) (76)
(vi) , (vii)
H3C (CH2) 3C≡ CCH2C =C (CH2) 9OTHP (77)
(viii) , (ix)
H3C (CH2) 3C≡ CCH,C≡C(CH,)8CO2H (78)
(x)
H3C(CH2)' ^(CH2J8CO2H
(79)
Reagents and conditions: (i) DHP, pTsOH, CH2Cl2; (ii) tBu (Me)2SiOCH2CCLi, THF-HMPA, -78°C; (iii) TBNF, RT; (iv) PPh3Br2; (v) BuLi, -78°C, CH3 (CH2) 3Br; (vi) TBNF, RT; (vii) BuLi, -78°C then compound (74) ; (viii) pTsOH, MeOH; (ix) PCC, CH2Cl2; then NaClO2, tBuOH; (x) H2 (g) , Pd/Pb on CaCO3. As still further illustration, CH3- (CH2) 3-CH=CH- CH2-CH=CH- (CH2) 10-COOH can be prepared using the following Scheme 11, starting with 11-bromoundecanol (81) .
SCHEME 11
Br (CHJ lχOH (l) > Br (CHj ^OTHP (ll) > fcBu (Me)2SiOCISC=C (CH2) ^OTHP
(81) (82) (83)
(iii) , (iv)
BrCH2CEEEEEEEC(CHJ11OTHP (84)
(v)
HC-ΞΞΞ≡ CSiM^ H3C (CHj)3C = CSiMe^ (85) (86)
(vi) , (vii)
H3C (CH2) 3CΞ≡ CCH2C Ξ≡C (CH2) 13_OTHP (87)
(viii) , (ix)
H3C(CH2J3C^ CCH2CE-E-EC (CH2) !QCO2H (88)
(x)
H3C (CH2); ^CHJ10CO2H
(89)
Reagents and conditions: (i) DHP, pTsOH, CH2Cl2; (ϋ) tBu (Me)2SiOCH2CCLi, THF-HMPA, -78°C; (iii) TBNF, RT; (iv) PPh3Br2; (v) BuLi, -78°C, CH3(CH2J3Br; (vi) TBNF, RT; (vii) BuLi, -78°C then compound (84) ; (viii) pTsOH, MeOH; (ix) PCC, CH2Cl2; then NaClO2, tBuOH; (x) H2 (g) , Pd/Pb on CaCO3. The omega-5 fatty acids of the present invention can also be prepared by biological methods, such as by the in vivo or ex vivo action of one or more enzymes on suitable precursors of the desired omega-5 fatty acid. For example, CH3- (CH2) 3-CH=CH-CH2-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) 4-COOH can be produced enzymatically from CH3-(CH2J3- CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) 7-COOH. CH3- (CH2) 3-CH=CH-CH2- CH=CH-CH2-CH=CH- (CH2) 7-COOH can be produced enzymatically from CH3- (CH2) 3-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) 5-COOH. CH3- (CH2)3-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) 5-COOH can be produced enzymatically from CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2) 8-COOH. CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2J8-COOH can be produced enzymatically from CH3-(CH2J3-CH=CH-(CH2J11-COOH. CH3- (CH2) 3- CH=CH-(CH2J11-COOH can be produced enzymatically from CH3- (CH2J3-CH=CH- (CH2J9-COOH. CH3-(CH2)3-CH=CH-(CH2)9-COOH can be produced enzymatically from CH3-(CH2)3-CH=CH-(CH2)7-COOH. CH3-(CH2J3-CH=CH-(CH2J7-COOH is commercially available, for example, from Aldrich (Milwaukee, Wisconsin); or it can be prepared by known methods, such as those described in Beilstein Handbook of Organic Chemistry, 2(2) :423, which is hereby incorporated by reference. CH3- (CH2) 3-CH=CH-CH2- CH=CH- (CH2) 8-COOH can also be prepared enzymatically from CH3- (CH2)3-CH=CH-CH2-CH=CH- (CH2J6-COOH; and CH3- (CH2) 3-CH=CH- CH2-CH=CH-(CH2J6-COOH can be prepared enzymatically from CH3- (CH2J3-CH=CH-(CH2J9-COOH, which, in turn, can be prepared as discussed above. CH3-(CH2)3-CH=CH-CH2-CH=CH-(CH2)10-COOH can be prepared enzymatically from CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2) 8-C00H, which, in turn, can be prepared as discussed above. CH3-(CH2J3-CH=CH-CH2-CH=CH-(CH2J10-COOH can also be prepared enzymatically from CH3-(CH2J3-CH=CH-(CH2J13-COOH. CH3-(CH2J3-CH=CH-(CH2J13-COOH can be prepared enzymatically from CH3-(CH2J3-CH=CH-(CH2)H-COOH, which, in turn, can be prepared as discussed above. The present invention also relates to a pharmaceutical composition that includes an omega- 5 fatty acid having one of the following formulae: CH3- (CH2) 3-CH=CH- (CH2) 9-COOH, CH3- (CH2) 3-CH=CH- (CH2) ^-COOH, CH3- (CH2) 3-CH=CH- (CH2) 13-C00H,
CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2) 6-COOH,
CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2) 8-COOH,
CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2) 10-COOH,
CH3- (CH2) 3-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) 5-COOH, CH3- (CH2)3-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) 7-COOH, and
CH3- (CH2J3-CH=CH-CH2-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2J4-COOH or a pharmaceutically acceptable ester, salt, amide, or solvate thereof or combinations thereof (e.g., as in the case where the pharmaceutical composition comprises two or more of the aforementioned omega- 5 fatty acids, esters, salts, amides, or solvates) . The pharmaceutical composition additionally includes one or more pharmaceutically acceptable carriers, diluents, or excipients . The pharmaceutically acceptable carriers, diluents, or excipients and manner of formulation of the pharmaceutical compositions are conventional. The usual methods of formulation used in pharmaceutical science may be used here. All of the usual types of compositions may be used, including tablets, chewable tablets, capsules, solutions, parenteral solutions, intranasal sprays or powders, troches, suppositories, transdermal patches, and suspensions. In general, compositions contain from about 0.5% to about 50% of the active (omega-5 fatty acids, esters, salts, amides, or solvates), depending on the desired doses and the type of composition to be used. The amount of the active, however, is best defined as the "effective amount", that is, the amount of omega-5 fatty acids, esters, salts, amides, or solvates which provides the desired dose to the subject to whom it is to be administered. The activity of the omega- 5 fatty acids, esters, salts, amides, or solvates employed in the present invention are not believed to depend greatly on the nature of the composition, and, therefore, the compositions can be chosen and formulated primarily or solely for convenience and economy.
Capsules can be prepared by mixing the omega-5 fatty acids, esters, salts, amides, or solvates with a suitable diluent and filling the proper amount of the mixture in capsules. The usual diluents include inert powdered substances (such as starches) , powdered cellulose (especially crystalline and microcrystalline cellulose) , sugars (such as fructose, mannitol and sucrose) , grain flours, and similar edible powders.
Tablets can be prepared by direct compression, by wet granulation, or by dry granulation. Their formulations usually incorporate diluents, binders, lubricants, and disintegrators (in addition to the omega-5 fatty acids, esters, salts, amides, or solvates). Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts (such as sodium chloride) , and powdered sugar. Powdered cellulose derivatives can also be used. Typical tablet binders include substances such as starch, gelatin, and sugars (e.g., lactose, fructose, glucose, and the like) . Natural and synthetic gums can also be used, including acacia, alginates, methylcellulose, polyvinylpyrrolidine, and the like. Polyethylene glycol, ethylcellulose, and waxes can also serve as binders.
Tablets can be coated with sugar, e.g., as a flavor enhancer and sealant. The omega-5 fatty acids, esters, salts, amides, or solvates can also be formulated as chewable tablets, by using large amounts of pleasant- tasting substances, such as mannitol, in the formulation. Instantly dissolving tablet-like formulations can also be employed, for example, to assure that the patient consumes the dosage form and to avoid the difficulty that some patients experience in swallowing solid objects.
A lubricant can be used in the tablet formulation to prevent the tablet and punches from sticking in the die. The lubricant can be chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid, and hydrogenated vegetable oils.
Tablets can also contain disintegrators.
Disintegrators are substances that swell when wetted to break up the tablet and release the compound. They include starches, clays, celluloses, algins, and gums. As further illustration, corn and potato starches, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation-exchange resins, alginic acid, guar gum, citrus pulp, sodium lauryl sulfate, and carboxymethylcellulose can be used. Compositions can be formulated as enteric formulations, for example, to protect the active ingredient from the strongly acid contents of the stomach. Such formulations can be created by coating a solid dosage form with a film of a polymer which is insoluble in acid environments and soluble in basic environments.
Illustrative films include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, and hydroxypropyl methylcellulose acetate succinate . When it is desired to administer the omega-5 fatty acids, esters, salts, amides, or solvates as a suppository, conventional bases can be used. Illustratively, cocoa butter is a traditional suppository base. The cocoa butter can be modified by addition of waxes to raise its melting point slightly. Water-miscible suppository bases, such as polyethylene glycols of various molecular weights, can also be used in suppository formulations . Other suitable pharmaceutical compositions include those which can be used in conjunction with transdermal delivery systems (e.g., transdermal patches) for transdermal delivery of the omega-5 fatty acids, esters, salts, amides, or solvates of the present invention. Transdermal patches can include a resinous composition in which the omega-5 fatty acids, esters, salts, amides, or solvates will dissolve or partially dissolve; and a film which protects the composition and which holds the resinous composition in contact with the skin. Other, more complicated patch compositions can also be used, such as those having a membrane pierced with a plurality of pores through which the drugs are pumped by osmotic action.
The omega-5 fatty acids, esters, salts, amides, or solvates of present invention can also be formulated as a nutriceutical composition that can include, in addition to the omega-5 fatty acids, esters, salts, amides, or solvates, one or more materials which are conventionally used in the food processing industry, such as proteins, sugars and other carbohydrates, extenders, fillers, preservatives, and the like.
The omega-5 fatty acids, esters, salts, amides, or solvates of present invention can be used to decrease proliferation of adenocarcinoma cells, and/or induce apoptosis of adenocarcinoma cells, and/or induce differentiation of adenocarcinoma cells into non-cancerous cells. The method can be carried out by contacting the adenocarcinoma cells with one or more of the omega-5 fatty acids, esters, salts, amides, or solvates of present invention. The method can be practiced in vitro or in vivo .
The meaning of the terms "proliferation",
"apoptosis", and "differentiation" are readily understood in the art. Illustrative methods for assaying for proliferation, apoptosis, or differentiation are described in U.S. Patent Application Publication No. US2004/0053962 , which is hereby incorporated by reference. "Adenocarcinoma cells", as used herein, are meant to include cancerous epithelial cells, such as prostate cancer cells, lung cancer cells, stomach cancer cells, breast cancer cells, pancreatic cancer cells, and colon cancer cells.
For example, an omega-5 fatty acid of the present invention (e.g., having the formula CH3- (CH2) 3-CH=CH-CH2- CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) 4-COOH) can be used to decrease proliferation of adenocarcinoma cells, and/or to induce apoptosis of adenocarcinoma cells, and/or to induce differentiation of adenocarcinoma cells into non-cancerous cells by administering the omega-5 fatty acid of the present invention (i.e., having the formula CH3-(CH2J3- CH=CH-CH2-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) 4-COOH) under conditions effective for the omega-5 fatty acid of the present invention (i.e., having the formula CH3-(CH2)3- CH=CH-CH2-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) 4-COOH) to contact the adenocarcinoma cells. This can be achieved, for example, by directly injecting the omega-5 fatty acid of the present invention (e.g., having the formula CH3-(CH2J3- CH=CH-CH2-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2J4-COOH) into a tumor or other sample containing the adenocarcinoma cells. Alternatively, an omega-5 fatty acid of the present invention having the formula CH3- (CH2) 3-CH=CH-CH2- CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) 4-COOH can be used to decrease proliferation of adenocarcinoma cells, and/or to induce apoptosis of adenocarcinoma cells, and/or to induce differentiation of adenocarcinoma cells into non-cancerous cells by administering a second omega-5 fatty acid of the present invention (e.g., one having the formula CH3-(CH2)3- CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) 7-COOH) under conditions effective for the second omega-5 fatty acid (i.e., having the formula CH3- (CH2) 3-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) 7-C00H) to be metabolized or otherwise converted to the omega-5 fatty acid of the present invention having the formula CH3- (CHJ)3-CH=CH-CH2-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) 4-COOH prior to the latter omega-5 fatty acid's coming into contact with the adenocarcinoma cells.
It will thus be appreciated that the method of the present invention can be practiced by administering any omega-5 fatty acid or other compound under conditions effective for the omega-5 fatty acid or other compound to be metabolized or otherwise converted to an omega-5 fatty acid of the present invention prior to the latter omega-5 fatty acid's coming into contact with the adenocarcinoma cells. In one embodiment, the method of the present invention does not involve administration of a compound having the formula CH3- (CH2) 3-CH=CH- (CH2) n-COOH, where n is 7, 9, 11, or 13 or a pharmaceutically acceptable ester, salt, amide, or solvate thereof.
As mentioned above, the method of the present invention can be used in vivo to treat adenocarcinomas, such as prostate cancer, lung cancer, stomach cancer, pancreatic cancer, breast cancer, and colon cancer. In the case where the method of the present invention is carried out in vivo, for example, where the adenocarcinoma cells are present in a human subject, contacting can be carried out by administering a therapeutically effective amount of the omega-5 fatty acid, ester, salt, amide, or solvate of present invention to the human subject, for example, by directly injecting the omega-5 fatty acid, ester, salt, amide, or solvate into a tumor. Details with regard to administering omega-5 fatty acids, esters, salts, amides, or solvates in accordance with the method of the present invention are described below. The present invention, in another aspect thereof, relates to a method of treating adenocarcinomas, such as prostate cancer, lung cancer, stomach cancer, breast, pancreatic cancer, colon cancer, esophageal cancer, uterine cancer, ovarian cancer, or other cancers involving epithelial cells. The method includes administering, to the subject, an omega-5 fatty acid, ester, salt, amide, or solvate of present invention, either alone or in the form of a pharmaceutical composition.
Suitable subjects include, for example mammals, such as rats, mice, cats, dogs, monkeys, and humans.
Suitable human subjects include, for example, those which have previously been determined to be at risk of having prostate cancer, lung cancer, stomach cancer, pancreatic cancer, colon cancer, and/or breast cancer and those who have been diagnosed as having prostate cancer, lung cancer, stomach cancer, pancreatic cancer, colon cancer, and/or breast cancer. Preferably, the subject suffers from only one of these types of cancers, for example, from only pancreatic cancer. In subjects who are determined to be at risk of having adenocarcinoma, the omega-5 fatty acids, esters, salts, amides, or solvates are administered to the subject, preferably under conditions effective to decrease proliferation and/or induce apoptosis and/or induce differentiation of the adenocarcinoma cells in the event that they develop. Such preventive (which is not used in the absolute 100% sense) therapy can be useful in high risk individuals as long as the adverse side effects of the administration of these compounds are outweighed by the potential benefit of prevention.
Any of the omega-5 fatty acids, esters, salts, amides, or solvates of the present invention can be used in the treatment method of the present invention. For example, compounds may be administered alone or in combination with compatible carriers as a composition. Compatible carriers include suitable pharmaceutical carriers, diluents, or excipients. The diluent, carrier, and excipient ingredients should be selected so that they do not diminish the therapeutic effects of the compounds used in the present invention.
The compositions herein may be made up in any suitable form appropriate for the desired use. Examples of suitable dosage forms include oral, parenteral, or topical dosage forms .
Suitable dosage forms for oral use include tablets, dispersible powders, granules, capsules, suspensions, syrups, and elixirs. Inert diluents and carriers for tablets include, for example, calcium carbonate, sodium carbonate, lactose, and talc. Tablets may also contain granulating and disintegrating agents, such as starch and alginic acid; binding agents, such as starch, gelatin, and acacia; and lubricating agents, such as magnesium stearate, stearic acid, and talc. Tablets may be uncoated or may be coated by known techniques to delay disintegration and absorption. Inert diluents and carriers which may be used in capsules include, for example, calcium carbonate, calcium phosphate, and kaolin. Suspensions, syrups, and elixirs may contain conventional excipients, for example, methyl cellulose, tragacanth, sodium alginate; wetting agents, such as lecithin and polyoxyethylene stearate; and preservatives, such as ethyl -p- hydroxybenzoate . Dosage forms suitable for parenteral administration include solutions, suspensions, dispersions, emulsions, and the like. They may also be manufactured in the form of sterile solid compositions which can be dissolved or suspended in sterile injectable medium immediately before use . They may contain suspending or dispersing agents known in the art. Examples of parenteral administration are intraventricular, intracerebral, intramuscular, intravenous, intraperitoneal, rectal, and subcutaneous administration.
In addition to the above, generally non-active components of the above-described formulations, these formulations can include other active materials, particularly, actives which have been identified as useful in the treatment of prostate, lung, stomach, breast, colon, pancreatic cancers and/or other adenocarcinomas. These actives can be broad-based anti -cancer agents, such that they also are useful in treating other types of cancers (i.e., in addition to adenocarcinomas) or they may be more specific, for example, in the case where the other active is useful for treating adenocarcinomas or particular types of adenocarcinomas. The other actives can also have non- anti -cancer pharmacological properties in addition to their anti -adenocarcinoma properties. For example, the other actives can have anti -inflammatory properties, or, alternatively, they can have no such anti -inflammatory properties .
It is understood that some of the omega- 5 fatty acids, esters, salts, amides, or solvates of the present invention (i.e., some of the compounds that are useful in the methods of the present invention) may be naturally occurring. The omega-5 fatty acids, esters, salts, amides, or solvates of the present invention used in the treatment methods of the present invention can be isolated, substantially pure, or both.
It will be appreciated that the actual preferred amount of omega- 5 fatty acids, esters, salts, amides, or solvates of the present invention to be administered according to the present invention will vary according to the particular omega-5 fatty acids, esters, salts, amides, or solvates of the present invention being employed, the particular composition formulated, and the mode of administration. Many factors that may modify the action of the compound (e.g., body weight, sex, diet, time of administration, route of administration, rate of excretion, condition of the subject, drug combinations, and reaction sensitivities and severities) can be taken into account by those skilled in the art. Administration can be carried out continuously or periodically within the maximum tolerated dose. Optimal administration rates for a given set of conditions can be ascertained by those skilled in the art using conventional dosage administration tests. The omega-5 fatty acids, esters, salts, amides, or solvates of the present invention can also be used to inhibit 5 -lipoxygenase activity, either in vivo or ex vivo. In one illustrative method, 5 -lipoxygenase activity is inhibited by contacting 5 -lipoxygenase with omega-5 fatty acids, esters, salts, amides, or solvates of the present invention. In another illustrative method that is particularly well adapted for use in vivo to inhibit 5- lipoxygenase activity in a subject, an omega-5 fatty acid, ester, salt, amide, or solvate thereof of the present invention is administered to the subject. Methods and compositions for effecting the aforementioned "contacting" and "administering" steps include those discussed above in the context of treating adenocarcinomas. The present invention is further illustrated with the following examples.
EXAMPLES
The following examples provides an illustrative list of formulations suitable for use with the omega- 5 fatty acids employed in the treatment methods and compositions of the present invention. These examples are provided only to illustrate the invention and should not be interpreted as limiting the present invention in any way.
Formulation 1
Hard gelatin capsules are prepared using the following ingredients:
Quantity (mg/capsule)
Active Ingredient 1000
Starch, dried 400
Magnesium stearate 20
Total 1420 mg
The above ingredients are mixed and filled into hard gelatin capsules weighing about 1.4 g each.
Formulation 2
A tablet is prepared using the ingredients set forth below:
Quantity (mg/tablet)
Active Ingredient 1000
Cellulose, microcrystalline 800
Silicon dioxide, fumed 20
Stearic acid 10
Total 1830 mg The components are blended and compressed to form tablets each weighing about 1.8 g.
Formulation 3
An aerosol solution is prepared containing the following components:
Weight %
Active Ingredient 0.50
Ethanol 29.50
Propellant 22 70.00 (Chlorodifluoromethane)
Total 100.00
The active compound is mixed with ethanol and the mixture added to a portion of the Propellant 22, cooled to -300C and transferred to a filling device. The required amount is then fed to a stainless steel container and diluted with the remainder of the propellant. Valve units are then fitted to the container.
Formulation 4
Tablets each containing 600 mg of active ingredient are made as follows:
Active Ingredient 600 mg
Starch 180 mg
Microcrystalline cellulose 140 mg
Polyvinylpyrrolidone 16 mg Sodium carboxymethyl starch 18 mg
Magnesium stearate 2 mg
Talc 4 mg
Total 960 mg
The active ingredient, starch, and cellulose are passed through a No . 45 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 500C. and passed through a No . 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing about 1 g.
Formulation 5
Capsules each containing 800 mg medicament are made as follows:
Active Ingredient 800 mg
Starch 236 mg Microcrystalline cellulose 236 mg
Magnesium stearate 8 mg
Total 1280 mg
The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 45 sieve, and filled into hard gelatin capsules in 1280 mg quantities.
Formulation 6
Suppositories each containing 550 mg of active ingredient may be made as follows:
Active Ingredient 550 mg Saturated fatty acid glycerides 2,000 mg
Total 2,550 mg
The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2.5 g capacity and allowed to cool.
Formulation 7
Suspensions each containing 500 mg of medicament per 10 ml dose are made as follows:
Active Ingredient 500 mg Sodium carboxymethyl cellulose 500 mg
Syrup 6 ml
Benzoic acid solution 0.4 ml Flavor q.v.
Color q.v.
Purified water to total 10 ml
The medicament is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste. The benzoic acid solution, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.
Formulation 8 An intravenous formulation containing 500 mg of medicament per 20 ml dose can be prepared as follows: Active Ingredient 500 mg Mannitol 500 mg
5 N sodium hydroxide q.s. Purified water to total 20 ml
The amount of sodium hydroxide solution used is that amount sufficient to yield a pH of approximately 9.5 when reconstituted with 20 ml of sterile water for injections. Although the invention has been described in detail for the purpose of illustration, it is understood that such detail is solely for that purpose, and variations can be made therein by those skilled in the art without departing from the spirit and scope of the invention which is defined by the claims that are set forth below.

Claims

What Is Claimed Is:
1. A method of inhibiting 5-lipoxygenase activity, said method comprising: contacting 5 -lipoxygenase with an omega-5 fatty acid having one of the following formulae:
CH3- (CH2) 3-CH=CH- (CH2) 9-COOH
CH3- (CH2) 3-CH=CH- (CH2) ^-COOH
CH3- (CH2) 3-CH=CH- (CH2) 13-COOH
CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2) 6-COOH
CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2) 8-COOH
CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2) 10-COOH
CH3- (CH2) 3-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) 5-COOH
CH3- (CH2) 3-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) 7-COOH
CH3- (CH2)3-CH=CH-CH2-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2J4-COOH
or a pharmaceutically acceptable ester, salt, amide, or solvate thereof or combinations thereof.
2. A method according to claim 1, wherein each double bond in the omega-5 fatty acid is in the cis configuration.
3. A method according to claim 1, wherein the 5- lipoxygenase is present in a human subject and wherein said contacting comprises administering an effective amount of the omega-5 fatty acid to the human subject.
4. A method according to claim 1, wherein the adenocarcinoma cells are present in a human subject and wherein said contacting does not involve administration of a compound having the formula CH3- (CH2) 3-CH=CH- (CH2) n-COOH, where n is 7, 9, 11, or 13 or a pharmaceutically acceptable ester, salt, amide, or solvate thereof.
5. A method of decreasing proliferation of adenocarcinoma cells, or of inducing apoptosis of adenocarcinoma cells, or of inducing differentiation of adenocarcinoma cells into non-cancerous cells, said method comprising: contacting a sample comprising adenocarcinoma cells with an omega-5 fatty acid having one of the following formulae :
CH3- (CH2) 3-CH=CH- (CH2) 9-COOH
CH3- (CH2) 3-CH=CH- (CH2) J1-COOH
CH3- (CH2) 3- CH=CH- (CH2) 13-COOH
CH3- (CH2)3-CH=CH-CH2-CH=CH- (CH2) 6-COOH
CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2) 8-COOH
CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2) 10-COOH
CH3- (CH2) 3-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) 5-COOH
CH3- (CH2) 3-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) 7-COOH
CH3- (CH2)3-CH=CH-CH2-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2J4-COOH
or a pharmaceutically acceptable ester, salt, amide, or solvate thereof or combinations thereof.
6. A method according to claim 5, wherein each double bond in the omega-5 fatty acid is in the cis configuration.
7. A method according to claim 5, wherein the sample comprises prostate cancer cells, lung cancer cells, stomach cancer cells, breast cancer cells, pancreatic cancer cells, colon cancer cells, or combinations thereof.
8. A method according to claim 5, wherein the adenocarcinoma cells are present in a human subject and wherein said contacting comprises administering a therapeutically effective amount of the omega-5 fatty acid to the human subject.
9. A method according to claim 5, wherein the adenocarcinoma cells are present in a human subject and wherein said contacting does not involve administration of a compound having the formula CH3- (CH2) 3-CH=CH- (CH2) n-COOH, where n is 7, 9, 11, or 13 or a pharmaceutically acceptable ester, salt, amide, or solvate thereof .
10. A method of treating adenocarcinoma in a subject, said method comprising: administering to the subject an effective amount of an omega-5 fatty acid having one of the following formulae:
CH3- (CH2) 3-CH=CH- (CH2) 9-COOH
CH3- (CH2) 3-CH=CH- (CH2) ^-COOH
CH3- (CH2) 3-CH=CH- (CH2) 13-COOH
CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2) 6-COOH
CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2) 8-COOH
CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2) 10-COOH
CH3- (CH2) 3-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) 5-COOH
CH3- (CH2) 3-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) 7-COOH
CH3- (CHJ)3-CH=CH-CH2-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) 4-COOH or a pharmaceutically acceptable ester, salt, amide, or solvate thereof .
11. A method according to claim 10, wherein the subject is a human subject.
12. A method according to claim 10, wherein the amount is effective to decrease proliferation of cancer cells in the subject.
13. A method according to claim 10, wherein the amount is effective to induce apoptosis of cancer cells in the subject .
14. A method according to claim 10, wherein the amount is effective to induce differentiation of cancer cells in the subject into non-cancerous cells.
15. A method according to claim 10, wherein each double bond in the omega- 5 fatty acid is in the cis configuration .
16. A method according to claim 10, wherein the adenocarcinoma is selected from the group consisting of prostate cancer, lung cancer, stomach cancer, breast cancer, colon cancer, pancreatic cancer, and combinations thereof.
17. An omega-5 fatty acid having one of the following formulae :
CH3- (CH2) 3-CH=CH- (CH2) 9-COOH
CH3- (CH2) 3-CH=CH- (CH2) ^-COOH
CH3- (CH2) 3-CH=CH- (CH2) 13-COOH
CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2) 6-COOH
CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2J8-COOH
CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2) 10-COOH
CH3- (CH2) 3-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) 5-COOH
CH3- (CH2) 3-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) 7-COOH
CH3- (CH2)J-CH=CH-CH2-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2J4-COOH or a pharmaceutically acceptable ester, salt, amide, or solvate thereof .
18. An omega-5 fatty acid according to claim 17, wherein each double bond in the omega-5 fatty acid is in the cis configuration .
19. An omega-5 fatty acid according to claim 17, wherein the omega-5 fatty acid has the formula
CH3- (CH2) 3-CH=CH- (CH2) g-COOH or a pharmaceutically acceptable ester, salt, amide, or solvate thereof.
20. An omega-5 fatty acid according to claim 17, wherein the omega-5 fatty acid has the formula
CH3- (CH2) 3-CH=CH- (CH2) ^-COOH or a pharmaceutically acceptable ester, salt, amide, or solvate thereof.
21. An omega-5 fatty acid according to claim 17, wherein the omega-5 fatty acid has the formula
CH3- (CH2) 3-CH=CH- (CH2) 13-COOH or a pharmaceutically acceptable ester, salt, amide, or solvate thereof.
22. An omega-5 fatty acid according to claim 17, wherein the omega-5 fatty acid has the formula
CH3- (CH2)3-CH=CH-CH2-CH=CH- (CH2) 6-COOH or a pharmaceutically acceptable ester, salt, amide, or solvate thereof.
23. An omega-5 fatty acid according to claim 17, wherein the omega-5 fatty acid has the formula
CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2J8-COOH or a pharmaceutically acceptable ester, salt, amide, or solvate thereof.
24. An omega-5 fatty acid according to claim 17, wherein the omega-5 fatty acid has the formula CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2) 10-COOH or a pharmaceutically acceptable ester, salt, amide, or solvate thereof.
25. An omega-5 fatty acid according to claim 17, wherein the omega-5 fatty acid has the formula
CH3- (CH2J3-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) 5-COOH or a pharmaceutically acceptable ester, salt, amide, or solvate thereof .
26. An omega-5 fatty acid according to claim 17, wherein the omega-5 fatty acid has the formula
CH3- (CH2) 3-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2J7-COOH or a pharmaceutically acceptable ester, salt, amide, or solvate thereof .
27. An omega-5 fatty acid according to claim 17, wherein the omega-5 fatty acid has the formula
CH3- (CH2)3-CH=CH-CH2-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2J4-COOH or a pharmaceutically acceptable ester, salt, amide, or solvate thereof .
28. An omega-5 fatty acid according to claim 17, wherein the omega-5 fatty acid is substantially pure.
29. An omega-5 fatty acid according to claim 17, wherein the omega-5 fatty acid is isolated.
30. An omega-5 fatty acid according to claim 17, wherein the omega-5 fatty acid is isolated and substantially pure .
31. A pharmaceutical composition comprising: an omega-5 fatty acid having one of the following formulae: CH3- (CH2) 3-CH=CH- (CH2) 9-COOH
CH3- (CH2) 3-CH=CH- (CH2) X1-COOH
CH3- (CH2) 3-CH=CH- (CH2) 13 -COOH
CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2) 6-C00H
CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2) 8-C00H
CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2) 10-COOH
CH3- (CH2) 3-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) 5 -COOH
CH3- (CH2) 3-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2J7-COOH
CH3- (CH^ 3-CH=CH-CH2-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) 4-C00H
or a pharmaceutically acceptable ester, salt, amide, or solvate thereof or combinations thereof; and one or more pharmaceutically acceptable carriers, diluents, or excipients.
32. A pharmaceutical composition according to claim 31, wherein each double bond in the omega-5 fatty acid is in the cis configuration.
33. A pharmaceutical composition according to claim 31, wherein the omega-5 fatty acid has the formula
CH3- (CH2) 3-CH=CH- (CH2) g-COOH or a pharmaceutically acceptable ester, salt, amide, or solvate thereof.
34. A pharmaceutical composition according to claim 31, wherein the omega-5 fatty acid has the formula
CH3- (CH2J3-CH=CH- (CH2) n-COOH or a pharmaceutically acceptable ester, salt, amide, or solvate thereof.
35. A pharmaceutical composition according to claim 31, wherein the omega-5 fatty acid has the formula
CH3- (CH2J3-CH=CH- (CH2) 13-COOH or a pharmaceutically acceptable ester, salt, amide, or solvate thereof.
36. A pharmaceutical composition according to claim 31, wherein the omega- 5 fatty acid has the formula
CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2) 6-COOH or a pharmaceutically acceptable ester, salt, amide, or solvate thereof.
37. A pharmaceutical composition according to claim 31, wherein the omega-5 fatty acid has the formula
CH3- (CH2)3-CH=CH-CH2-CH=CH- (CH2J8-COOH or a pharmaceutically acceptable ester, salt, amide, or solvate thereof.
38. A pharmaceutical composition according to claim 31, wherein the omega-5 fatty acid has the formula
CH3- (CH2) 3-CH=CH-CH2-CH=CH- (CH2) 10-COOH or a pharmaceutically acceptable ester, salt, amide, or solvate thereof.
39. A pharmaceutical composition according to claim 31, wherein the omega-5 fatty acid has the formula
CH3- (CH2J3-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) S-COOH or a pharmaceutically acceptable ester, salt, amide, or solvate thereof .
40. A pharmaceutical composition according to claim 31, wherein the omega-5 fatty acid has the formula
CH3- (CH2J3-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2) 7-COOH or a pharmaceutically acceptable ester, salt, amide, or solvate thereof .
41. A pharmaceutical composition according to claim 31, wherein the omega-5 fatty acid has the formula
CH3- (CH2J3-CH=CH-CH2-CH=CH-CH2-CH=CH-CH2-CH=CH- (CH2J4-COOH or a pharmaceutically acceptable ester, salt, amide, or solvate thereof .
PCT/US2007/026152 2006-12-22 2007-12-22 Omega-5-fatty acids useful in lipoxygenase 5 inhibition and in the treatment of cancer WO2008079328A2 (en)

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WO2017223447A1 (en) 2016-06-23 2017-12-28 The Regents Of The University Of Michigan 12(s)-hydroxyeicosatrienoic acid compounds and their use as therapeutic agents

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017223447A1 (en) 2016-06-23 2017-12-28 The Regents Of The University Of Michigan 12(s)-hydroxyeicosatrienoic acid compounds and their use as therapeutic agents
EP3475442A4 (en) * 2016-06-23 2019-12-04 The Regents of The University of Michigan 12(s)-hydroxyeicosatrienoic acid compounds and their use as therapeutic agents
US11111222B2 (en) 2016-06-23 2021-09-07 The Regents Of The University Of Michigan Hydroxyeicosatrienoic acid compounds and their use as therapeutic agents

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