CA2345079A1 - Tocopherols, tocotrienols, other chroman and side chain derivatives and uses thereof - Google Patents

Tocopherols, tocotrienols, other chroman and side chain derivatives and uses thereof Download PDF

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CA2345079A1
CA2345079A1 CA002345079A CA2345079A CA2345079A1 CA 2345079 A1 CA2345079 A1 CA 2345079A1 CA 002345079 A CA002345079 A CA 002345079A CA 2345079 A CA2345079 A CA 2345079A CA 2345079 A1 CA2345079 A1 CA 2345079A1
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chroman
yloxy
tetramethyl
trimethyltridecyl
acetic acid
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CA002345079A
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CA2345079C (en
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Kimberly Kline
Bob G. Sanders
Laurence Hurley
Robb Gardner
Marla Menchaca
Weiping Yu
Puthucode N. Ramanan
Shengquan Liu
Karen Israel
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Research Development Foundation
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Research Development Foundation
Kimberly Kline
Bob G. Sanders
Laurence Hurley
Robb Gardner
Marla Menchaca
Weiping Yu
Puthucode N. Ramanan
Shengquan Liu
Karen Israel
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/66—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
    • C07D311/72—3,4-Dihydro derivatives having in position 2 at least one methyl radical and in position 6 one oxygen atom, e.g. tocopherols

Abstract

The present invention provides an antiproliferative compound having structur al formula (I), wherein X is oxygen, nitrogen or sulfur; R1 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, carboxylic acid, carboxylate, carboxamide, ester, thioamide, thiolacid, thiolester, saccharide, alkoxy-linked saccharide, amin e, sulfonate, sulfate, phosphate, alcohol, ethers and nitriles; R2 is hydrogen, methyl, benzyl carboxylic acid, benzyl carboxylate, benzyl carboxamide, benzylester, saccharide and amine; R3 is selected from the group consisting of hydrogen, methyl, benzyl carboxylic acid, benzyl carboxilate, benzyl carboxamide, benzylester, saccharide and amine; R4 is of methyl, benzyl carboxylic acid, benzyl carboxylate, benzyl carboxamide, benzylester, saccharide and amine; and R5 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, carboxyl, amide and ester. Also provided is a method for inducing apoptosis in a cell comprising administering a composition comprising a compound.

Claims (20)

1. A compound having a structural formula wherein X is selected from the group consisting of oxygen, nitrogen or sulfur; Y is oxygen or sulfur; wherein when Y is oxygen, n is 1; when Y is sulfur, n is 0;
R1 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, carboxylic acid, carboxylate, carboxamide, ester, thioamide, thiolacid, thiolester, saccharide, alkoxy-linked saccharide, amine, sulfonate, sulfate, phosphate, alcohol, ethers and nitriles;
R2 is selected from the group consisting of hydrogen, methyl, benzyl carboxylic acid, benzyl carboxylate, benzyl carboxamide, benzylester, saccharide and amine;
R3 is selected from the group consisting of hydrogen, methyl, benzyl carboxylic acid, benzyl carboxylate, benzyl carboxamide, benzylester, saccharide and amine;
R4 is selected from the group consisting of methyl, benzyl carboxylic acid, benzyl carboxylate, benzyl carboxamide, benzylester, saccharide and amine; and R5 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, carboxyl, amide and ester;
wherein when X is oxygen, R2 is methyl, R3 is methyl, R4 is methyl and R5 is phytyl, R1 is not a carboxylate selected from the group consisting of butyrate, succinate, retinoate, nicotinoate and phosphate.
2. The compound of claim 1, wherein said compound is selected from the group consisting of 2,5,7,8-tetramethyl-(2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy) acetic acid, 2,5,7,8-tetramethyl-(2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy)propionic acid, 2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy) valeric acid, 2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy) hexanoic acid, 2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy) octanoic acid, 2,5,8-trimethyl-(2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy)acetic acid, 2,7,8-trimethyl-(2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy)acetic acid, 2,8-dimethyl-(2R-(4R,8R,12-trimethyltridecyl) chroman-6-yloxy) acetic acid, 2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy) acetamide, methyl 12,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl) chroman-6-yloxy) acetate, 2-(N,N-(carboxymethyl)-2(2,5,7,8-tetramethyl-(2R-(4R,8R,12-trimethyltridecyl) chroman-6-yloxy) acetic acid, 2-(2,5,7,8-tetramethyl-(2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy))ethan-1-ol, 2-(2,5,7,8-pentamethylchroman-6-yloxy)acetic acid, 2,5,7,8-tetramethyl-(2RS-(4RS,8RS,12-trimethyltridecyl)chroman-6-yloxy)acetic acid, 2,5,7,8-tetramethyl-(2R-(carboxy)chroman-6-yloxy))acetic acid, 2,5,7,8-tetramethyl-2R-(2RS,6RS,10-trimethylundecyl)chroman-6-yloxy) acetic acid, 2,5,7,8,-tetramethyl-2R-(2,6,10-trimethyl-1,3,5,9 E:Z
decatetraen)chroman-6-yloxy)acetic acid, 3-(2,5,7,8-tetramethyl-(2R-(4R,8,12-trimethyltridecyl)chroman-6-yloxy)propyl-1-ammonium chloride, 2,5,7,8-tetramethyl-(2R-(4R,8R,12-trimethyltridecyl)chroman-3-ene-6-yloxy) acetic acid, 6-(2,5,7,8-tetramethyl-(2R-(4R,8,12-trimethyltridecyl)chroman)acetic acid, 2,5,7,8,-tetramethyl-(2R-(heptadecyl)chroman-6-yloxy) acetic acid 2,5,7,8-tetramethyl-(2R-(heptyl)chroman-6-yloxy)acetic acid, 2,5,7,8,-tetramethyl-(2R-(tridecyl)chroman-6-yloxy) acetic acid, 2,5,7,8,-tetramethyl-(2R-(heptadecyl)chroman-6-yloxy) acetic acid, 2,5,7,8,-tetramethyl-2R-(4,8,-dimethyl-1,3,7 E:Z
nonotrien)chroman-6-yloxy) acetic acid, E,Z,RS,RS-(phytyltrimethylbenzenethiol-6-yloxy)acetic acid, (R)-2((2,5,7,8-tetramethyl-2-(3 propene methyl ester)chroman-6-yloxy)acetic acid, and 2,5,7,8-tetramethyl-(2R-(propionate)chroman-6-yloxy)acetic acid.
3. A method for the treatment of a cell proliferative disease comprising administering to an animal a pharmacologically effective dose of a compound having a structural formula wherein X is selected from the group consisting of oxygen, nitrogen or sulfur; Y is oxygen or sulfur; wherein when Y is oxygen, n is 1; when Y is sulfur, n is 0;
R1 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, carboxylic acid, carboxylate, carboxamide, ester, thioamide, thiolacid, thiolester, saccharide, alkoxy-linked saccharide, amine, sulfonate, sulfate, phosphate, alcohol, ethers and nitriles;

R2 is selected from the group consisting of hydrogen, methyl, benzyl carboxylic acid, benzyl carboxylate, benzyl carboxamide, benzylester, saccharide and amine;
R3 is selected from the group consisting of hydrogen, methyl, benzyl carboxylic acid, benzyl carboxylate, benzyl carboxamide, benzylester, saccharide and amine;
R4 is selected from the group consisting of methyl, benzyl carboxylic acid, benzyl carboxylate, benzyl carboxamide, benzylester, saccharide and amine; and R5 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, carboxyl, amide and ester;
wherein when X is oxygen, R1 is methyl, R3 is methyl, R4 is methyl and R5 is phytyl, R1 is not a carboxylate selected from the group consisting of succinate, retinoate, nicotinoate and phosphate.
4. The method of claim 3, wherein said compound is selected from the group consisting of 2,5,7,8-tetramethyl-(2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy)acetic acid, 2,5,7,8-tetramethyl-(2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy) propionic acid, 2,5,7,8-tetramethyl-(2R-(4R,8R,12-trimethyltridecyl) chroman-6-yloxy)butyric acid, 2,5,8-trimethyl-(2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy)acetic acid, 2,7,8-trimethyl-(2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy) acetic acid, 2,8-dimethyl-(2R-(4R,8R,12-trimethyltridecyl) chroman-6-yloxy) acetic acid, 2-(N,N-(carboxymethyl)-2(2,5,7,8-tetramethyl-(2R-(48,8R,12-trimethyltridecyl) chroman-6-yloxy) acetic acid, 2,5,7,8-tetramethyl-(2RS-(4RS,8RS,12-trimethyltridecyl)chroman-6-yloxy)acetic acid, 2,5,7,8-tetramethyl-2R-(2RS,6RS,10-trimethylundecyl)chroman-6-yloxy) acetic acid, 3-(2,5,7,8-tetramethyl-(2R-(48,8,12-trimethyltridecyl)chroman-6-yloxy)propyl-1-ammonium chloride, 2,5,7,8-tetramethyl-(2R-(4r,8R,12-trimethyltridecyl)chroman-3-ene-6-yloxy) acetic acid, 2-(2,5,7,8-tetramethyl-(2R-(4R,8,12-trimethyltridecyl) chroman-6-yloxy)triethylammonium sulfate, 6-(2,5,7,8-tetramethyl-(2R-(48,8,12-trimethyltridecyl) chroman) acetic acid, 2,5,7,8,-tetramethyl-(2R-(heptadecyl)chroman-6-yloxy) acetic acid, 2,5,7,8,-tetramethyl-2R-(4,8,-dimethyl-1,3,7 E:Z
nonotrien)chroman-6-yloxy) acetic acid, and E,Z,RS,RS-(phytyltrimethylbenzenethiol-6-yloxy)acetic acid.
5. The method of claim 3, wherein said compound exhibits an anti-proliferative effect comprising apoptosis, DNA
synthesis arrest, cell cycle arrest, or cellular differentiation.
6. The method of claim 3, wherein said animal is a human.
7. The method of claim 3, wherein said composition is administered in a dose of from about 1 mg/kg to about 60 mg/kg.
8. The method of claim 3, wherein administration of said composition is selected from the group consisting of oral, topical, intraocular, intranasal, parenteral, intravenous, intramuscular, or subcutaneous.
9. The method of claim 3, wherein said cell proliferative disease is selected from the group consisting of neoplastic diseases and non-neoplastic disorders.
10. The method of claim 9, wherein said neoplastic disease is selected from the group consisting of ovarian cancer, cervical cancer, endometrial cancer, bladder cancer, lung cancer, breast cancer, testicular cancer, prostate cancer, gliomas, fibrosarcomas, retinoblastomas, melanomas, soft tissue sarcomas, ostersarcomas, leukemias, colon cancer, carcinoma of the kidney, pancreatic cancer, basal cell carcinoma, and squamous cell carcinoma.
11. The method of claim 9, wherein said non-neoplastic disease is selected from the group consisting of psoriasis, benign proliferative skin diseases, ichthyosis, papilloma, restinosis, scleroderma, hemangioma, viral diseases, and autoimmune diseases.
12. The method of claim 11, wherein said autoimmune diseases are selected from the group consisting of autoimmune thyroiditis, multiple sclerosis, myasthenia gravis, systemic lupus erythematosus, dermatitis herpetiformis, celiac disease, and rheumatoid arthritis.
13. The method of claim 9, wherein said non-neoplastic disorders are selected from the group consisting of viral disorders and autoimmune disorders.
14. The method of claim 13, wherein said viral disorder is Human Immunodeficiency Virus.
15. The method of claim 13, wherein said autoimmune disorders are selected from the group consisting of the inflammatory process involved in cardiovascular plaque formation, ultraviolet radiation induced skin damage and disorders involving an immune component.
16. A pharmaceutical composition, comprising the compound of claim 3 and a pharmaceutically acceptable carrier.
17. The pharmaceutical composition of claim 16, wherein said compound is selected from the group consisting of 2,5,7,8-tetramethyl-(2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy)acetic acid, 2,5,7,8-tetramethyl-(2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy)propionic acid, 2,5,7,8-tetramethyl-(2R-(4R,8R,12-trimethyltridecyl) chroman-6-yloxy)butyric acid, 2,5,8-trimethyl-(2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy)acetic acid, 2,7,8-trimethyl-(2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy)acetic acid, 2,8-dimethyl-(2R-(4R,8R,12-trimethyltridecyl) chroman-6-yloxy) acetic acid, 2-(N,N-(carboxymethyl)-2(2,5,7,8-tetramethyl-(2R-(4R,8R,12-trimethyltridecyl) chroman-6-yloxy) acetic acid, 2,5,7,8-tetramethyl-(2RS-(4RS,8RS,12-trimethyltridecyl)chroman-6-yloxy)acetic acid, 2,5,7,8-tetramethyl-2R-(2RS,6RS,10-trimethylundecyl)chroman-6-yloxy)acetic acid, 3-(2,5,7,8-tetramethyl-(2R-(4R,8,12-trimethyltridecyl)chroman-6-yloxy)propyl-1-ammonium chloride, 2,5,7,8-tetramethyl-(2R-(4r,8R,12-trimethyltridecyl)chroman-3-ene-6-yloxy) acetic acid, 2-(2,5,7,8-tetramethyl-(2R-(4R,8,12-trimethyltridecyl)chroman-6-yloxy)tiethylammonium sulfate, 6-(2,5,7,8-tetramethyl-(2R-(4R,8,12-trimethyltridecyl)chroman) acetic acid, 2,5,7,8,-tetramethyl-(2R-(heptadecyl)chroman-6-yloxy) acetic acid, 2,5,7,8,-tetramethyl-2R-(4,8,-dimethyl-1,3,7 E:Z
nonotrien)chroman-6-yloxy) acetic acid, and E,Z,RS,RS-(phytyltrimethylbenzenethiol-6-yloxy)acetic acid.
18. A method of inducing apoptosis of a cell, comprising the step of contacting said cell with a pharmacologically effective dose of a compound having a structural formula wherein X is selected from the group consisting of oxygen, nitrogen or sulfur; Y is oxygen or sulfur; wherein when Y is oxygen, n is 1; when Y is sulfur, n is 0;
R1 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, carboxylic acid, carboxylate, carboxamide, ester, thioamide, thiolacid, thiolester, saccharide, alkoxy-linked saccharide, amine, sulfonate, sulfate, phosphate, alcohol, ethers and nitriles;
R2 is selected from the group consisting of hydrogen, methyl, benzyl carboxylic acid. benzyl carboxylate, benzyl carboxamide, benzylester, saccharide and amine;

R3 is selected from the group consisting of hydrogen, methyl, benzyl carboxylic acid, benzyl carboxylate, benzyl carboxamide, benzylester, saccharide and amine;
R4 is selected from the group consisting of methyl, benzyl carboxylic acid, benzyl carboxylate, benzyl carboxamide, benzylester, saccharide and amine; and R5 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, carboxyl, amide and ester;
wherein when X is oxygen, R2 is methyl, R3 is methyl, R4 is methyl and R5 is phytyl, R1 is not a carboxylate selected from the group consisting of succinate, retinoate, nicotinoate and phosphate.
19. The method of claim 18, wherein said compound is selected from the group consisting of 2,5,7,8-tetramethyl-(2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy)acetic acid, 2,5,7,8-tetramethyl-(2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy) propionic acid, 2,5,7,8-tetramethyl-(2R-(4R,8R,12-trimethyltridecyl) chroman-6-yloxy)butyric acid, 2,5,8-trimethyl-(2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy)acetic acid, 2,7,8-trimethyl-(2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy) acetic acid, 2,8-dimethyl-(2R-(4R,8R,12-trimethyltridecyl) chroman-6-yloxy) acetic acid, 2-(N,N-(carboxymethyl)-2(2,5,7,8-tetramethyl-(2R-(4R,8R,12-trimethyltridecyl) chroman-6-yloxy) acetic acid, 2,5,7,8-tetramethyl-(2RS-(4RS,8RS,12-trimethyltridecyl)chroman-6-yloxy)acetic acid, 2,5,7,8-tetramethyl-2R-(2RS,6RS,10-trimethylundecyl)chroman-6-yloxy) acetic acid, 3-(2,5,7,8-tetramethyl-(2R-(48,8,12-trimethyltridecyl)chroman-6-yloxy)propyl-1-ammonium chloride, 2,5,7,8-tetramethyl-(2R-(4r,8R,12-trimethyltridecyl)chroman-3-ene-6-yloxy) acetic acid, 2-(2,5,7,8-tetramethyl-(2R-(4R,8,12-trimethyltridecyl) chroman-6-yloxy)triethylammonium sulfate, 6-(2,5,7,8-tetramethyl-(2R-(48,8,12-trimethyltridecyl) chroman) acetic acid, 2,5,7,8,-tetramethyl-(2R-(heptadecyl)chroman-6-yloxy) acetic acid, 2,5,7,8,-tetramethyl-2R-(4,8,-dimethyl-1,3,7 E:Z
nonotrien)chroman-6-yloxy) acetic acid, and E,Z,RS,RS-(phytyltrimethylbenzenethiol-6-yloxy)acetic acid.
20. The method of claim 18, wherein said method is useful in the treatment of a cell proliferative disease.
CA2345079A 1998-09-23 1999-09-23 Tocopherols, tocotrienols, other chroman and side chain derivatives and uses thereof Expired - Fee Related CA2345079C (en)

Applications Claiming Priority (3)

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US10154298P 1998-09-23 1998-09-23
US60/101,542 1998-09-23
PCT/US1999/021778 WO2000016772A1 (en) 1998-09-23 1999-09-23 Tocopherols, tocotrienols, other chroman and side chain derivatives and uses thereof

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CA2345079C CA2345079C (en) 2011-06-21

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US (2) US6417223B1 (en)
EP (1) EP1115398B1 (en)
JP (1) JP2002526446A (en)
KR (1) KR100712383B1 (en)
CN (2) CN1195513C (en)
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Families Citing this family (55)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6703384B2 (en) 1998-09-23 2004-03-09 Research Development Foundation Tocopherols, tocotrienols, other chroman and side chain derivatives and uses thereof
US6048891A (en) 1998-12-17 2000-04-11 Loma Linda University Medical Center Use of γ-tocopherol and its oxidative metabolite LLU-α in the treatment of natriuretic disease
KR20010055765A (en) * 1999-12-13 2001-07-04 이경하 3-Methyl-chromane or thiochromane derivatives
EP1241165A4 (en) * 1999-12-13 2003-03-19 Chugai Pharmaceutical Co Ltd Optically active chroman and thiochroman derivatives
EP1241167A4 (en) * 1999-12-13 2003-03-26 Chugai Pharmaceutical Co Ltd 3-ethyl-, 3-propyl- or 3-butyl-chroman and -thiochroman derivatives
KR20010055766A (en) * 1999-12-13 2001-07-04 이경하 Metal salts of 3-methyl-chromane or thiochromane derivative
WO2001058889A1 (en) * 2000-02-11 2001-08-16 Research Development Foundation Tocopherols, tocotrienols, other chroman and side chain derivatives and uses thereof
US7144919B1 (en) * 2000-08-23 2006-12-05 Youngdae Kim Polyoxyethylene-polyoxypropylene vitamin E and process for preparation thereof
KR100612398B1 (en) * 2000-11-14 2006-08-16 바이탈 헬스 사이언시즈 피티와이 리미티드 Complexes of phosphate derivatives
AUPR549901A0 (en) * 2001-06-06 2001-07-12 Vital Health Sciences Pty Ltd Topical formulation containing tocopheryl phosphates
EP1420797A4 (en) * 2001-07-27 2005-03-02 Vital Health Sciences Pty Ltd Dermal therapy using phosphate derivatives of electron transfer agents
JP2005505586A (en) * 2001-10-04 2005-02-24 ワイス Chroman derivatives as 5-hydroxytryptamine-6 ligands
ATE487456T1 (en) * 2001-12-13 2010-11-15 Vital Health Sciences Pty Ltd TRANSDERMAL TRANSPORT OF COMPOUNDS
US20030236301A1 (en) * 2001-12-19 2003-12-25 Bob Sanders Liposomal delivery of vitamin E based compounds
CA2470920C (en) * 2001-12-19 2013-04-02 Research Development Foundation Liposomal delivery of vitamin e based compounds
US20040034093A1 (en) * 2002-05-30 2004-02-19 Hensley Kenneth L. Methods for enhancing motor performance and/or endurance
AU2002950713A0 (en) * 2002-08-09 2002-09-12 Vital Health Sciences Pty Ltd Carrier
AU2003900200A0 (en) * 2003-01-17 2003-01-30 Vital Health Sciences Pty Ltd Compounds having antiproliferative properties
EP1589964B1 (en) * 2003-01-17 2011-11-23 Vital Health Sciences Pty Ltd. Compounds having anti-proliferative properties
US6716873B1 (en) * 2003-03-20 2004-04-06 Yasoo Health Inc. Tocopherol ester compounds
AU2003901815A0 (en) * 2003-04-15 2003-05-01 Vital Health Sciences Pty Ltd Phosphate derivatives
ITTO20030140U1 (en) * 2003-09-16 2005-03-17 Interfila Srl COSMETIC PENCIL
US20050065099A1 (en) 2003-09-19 2005-03-24 Gail Walkinshaw Treatment of mitochondrial diseases
US20050080109A1 (en) * 2003-10-09 2005-04-14 Papas Andreas M. Gamma-tocopherol and gamma-tocotrienol therapy for multiple sclerosis
DE602004027936D1 (en) * 2003-10-29 2010-08-12 Sonus Pharmaceutical Inc TOCOPHEROL-MODIFIED THERAPEUTIC DRUG COMPOUND
US20080045559A1 (en) * 2003-10-29 2008-02-21 Sonus Pharmaceuticals, Inc. Tocopherol-modified therapeutic drug compounds
NZ549567A (en) 2004-03-03 2009-10-30 Vital Health Sciences Pty Ltd Formulations comprising a tocopheryl phosphate tertiary amine alkaloid complex
US20060165769A1 (en) * 2004-09-30 2006-07-27 Hyatt John A Pharmaceutical formulations containing vitamin E TPGS molecules that solubilize lipophilic drugs without significant efflux inhibition, and use of such formulations
CA2599424A1 (en) * 2005-03-03 2006-09-08 Vital Health Sciences Pty Ltd Compounds having anti-cancer properties
CN100334080C (en) * 2005-06-01 2007-08-29 华东理工大学 Benzo-dihydropyran glycoside derivatives
WO2006133506A1 (en) * 2005-06-17 2006-12-21 Vital Health Sciences Pty Ltd A carrier comprising one or more di and/or mono-(electron transfer agent) phosphate derivatives or complexes thereof
KR20080085839A (en) * 2005-12-23 2008-09-24 바이탈 헬스 사이언시즈 피티와이 리미티드 Compounds having cytokine modulating properties
WO2007098139A2 (en) * 2006-02-21 2007-08-30 The Ohio State University Research Foundation Anticancer agents
US8318812B2 (en) * 2006-06-02 2012-11-27 The Ohio State University Research Foundation Therapeutic agents for the treatment of lymphoid malignancies
US8288369B2 (en) * 2006-06-27 2012-10-16 University Of South Florida Delta-tocotrienol treatment and prevention of pancreatic cancer
WO2009012096A2 (en) * 2007-07-18 2009-01-22 Research Development Foundation Improved therapeutic methods and compositions comprising chroman ring compounds
WO2010051664A1 (en) * 2008-11-05 2010-05-14 沈阳中海药业有限公司 7h-imidazo[1,20-a]pyrano[2,3-c]pyridine derivations and the use thereof
JP2012523458A (en) * 2009-04-13 2012-10-04 ザ オハイオ ステート ユニバーシティー リサーチ ファウンデーション Protein phosphatase 2A activator
US8362071B2 (en) * 2009-04-17 2013-01-29 The Ohio State University Research Foundation Antiadhesion agents
KR20120034649A (en) * 2009-05-11 2012-04-12 버그 바이오시스템즈, 엘엘씨 Methods for treatment of disease using an epimetabolic shifter (coenzyme q10)
US10071030B2 (en) 2010-02-05 2018-09-11 Phosphagenics Limited Carrier comprising non-neutralised tocopheryl phosphate
RU2553350C2 (en) 2010-03-30 2015-06-10 Фосфейдженикс Лимитед Transdermal plaster
US8309768B2 (en) 2010-11-29 2012-11-13 The Ohio State University Research Foundation FTY720-derived anticancer agents
WO2012122586A1 (en) 2011-03-15 2012-09-20 Phosphagenics Limited New composition
CN102516258B (en) * 2011-11-11 2014-06-25 正大天晴药业集团股份有限公司 Water-soluble vitamin E derivative modified fat-soluble anti-cancer drug compound and preparation, preparation method and application of compound
US20130309202A1 (en) * 2012-05-18 2013-11-21 The Ohio State University Methods for Improving Liver Function
EP2991488A4 (en) * 2013-05-02 2016-12-21 The Chancellor Masters And Scholars Of The Univ Of Oxford Glycolipid inhibition using iminosugars
JP6675985B2 (en) * 2013-09-06 2020-04-08 リサーチ ディベロップメント ファウンデーション Alpha-TEA salt forms: compositions and uses for treating disease
CA2924126C (en) 2013-09-13 2023-05-02 The Board Of Trustees Of The University Of Arkansas Preparation and use of a composition for prevention and mitigation of the effects of radiation
PT2953938T (en) * 2014-02-07 2017-10-09 Novogen ltd Functionalised benzopyran compounds and use thereof
RU2571094C1 (en) * 2015-02-11 2015-12-20 Федеральное государственное бюджетное образовательное учреждение высшего профессионального образования "Омский государственный университет им. Ф.М. Достоевского" METHOD OF PRODUCING 4-ALKOXY-4H-THIENO[3,2-c]CHROMEN-2-CARBALDEHYDES HAVING ANTIULCER ACTIVITY
US20160324914A1 (en) 2015-05-05 2016-11-10 Tocol Pharmaceuticals, Llc Use of rice bran oil distillate extract for prevention and mitigation of the effects of radiation
CN108601732A (en) 2015-12-09 2018-09-28 磷肌酸有限公司 pharmaceutical preparation
US20190330260A1 (en) 2016-12-21 2019-10-31 Avecho Biotechnology Limited Process
US20210230134A1 (en) * 2018-05-04 2021-07-29 Exact Delivery Inc. Vitamin e derivatives and their use as multi-scale imaging agents

Family Cites Families (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5118954B2 (en) * 1972-02-04 1976-06-14
CS172015B1 (en) * 1974-05-12 1976-12-29
EP0008573A1 (en) * 1977-12-16 1980-03-05 Nisshin Flour Milling Co., Ltd. Anti-tumor agent
JPS6056155B2 (en) * 1978-12-04 1985-12-09 エーザイ株式会社 Chromanyloxy fatty acid congeners
US4457918A (en) 1982-05-12 1984-07-03 The General Hospital Corporation Glycosides of vitamins A, E and K
DE3309159A1 (en) * 1983-03-15 1984-09-20 Basf Ag, 6700 Ludwigshafen NEW OPTICALLY ACTIVE CHROME DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND NEW INTERMEDIATE PRODUCTS
US4617317A (en) * 1984-10-31 1986-10-14 Bennet Justin D Method of treating ulcerative colitis
US4665204A (en) * 1985-06-27 1987-05-12 Henkel Corporation Diester derivatives of tocopherol
JPS63303049A (en) * 1987-06-04 1988-12-09 Shinagawa Refract Co Ltd Fiber-reinforced vitreous thermal spraying material
JPS6441727A (en) * 1987-08-07 1989-02-14 Toshiba Corp Cooking unit
US5610180A (en) * 1988-01-29 1997-03-11 Virginia Commonwealth University Ionizable congeners of aromatic and aliphatic alcohols as anti-leukemia agents
US5260294A (en) * 1988-08-09 1993-11-09 Hoffman-La Roche Inc. Chromanes and their pharmaceutical compositions and methods
JPH03206089A (en) * 1990-01-05 1991-09-09 Eisai Co Ltd New vitamin e derivative and production thereof
US5114957A (en) * 1990-05-08 1992-05-19 Biodor U.S. Holding Tocopherol-based antiviral agents and method of using same
DE4014708C2 (en) * 1990-05-08 1994-03-10 Heidelberger Druckmasch Ag Procedure for determining register errors
FR2672601B1 (en) * 1991-02-08 1994-10-14 Synthelabo BENZO-1,5-THIAZEPINE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION.
JPH05213982A (en) * 1991-03-26 1993-08-24 Dainippon Ink & Chem Inc Oligosaccharide tocopherol glycoside, sulfated oligosaccharide tocopherol glycoside and antiviral agent comprising the same as active ingredient
FR2676056B1 (en) 1991-05-03 1993-07-16 Adir NOVEL BENZOPYRAN DERIVATIVES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
EP0636618A1 (en) * 1991-06-04 1995-02-01 Marigen S.A. Spontaneously dispersible concentrates and microemulsions with vitamin E compounds for the preparation of medicaments with anti-tumour activity
US5135945A (en) 1991-06-05 1992-08-04 Merrell Dow Pharmaceuticals Inc. Cholesterol-lowering tocopherol analogs
HRP920935A2 (en) * 1991-10-08 1995-08-31 Astra Ab New therapeutically active compound
US5545660A (en) 1992-04-07 1996-08-13 Merrell Pharmaceuticals Inc. Hydrazide derivatives of 3,4-dihydro-2H-1-benzopyrans
FR2695387B1 (en) * 1992-09-09 1994-10-21 Adir New benzopyran compounds, process for their preparation and pharmaceutical compositions containing them.
DE4304303C2 (en) * 1993-01-22 1997-01-30 Pacific Corp Vitamin E derivatives with a quaternary nitrogen atom, process for their preparation and cosmetic compositions containing the same
CA2152693A1 (en) * 1994-08-05 1996-02-06 Kazumi Ogata Therapeutic composition for pancreatitis
US5596095A (en) * 1994-12-12 1997-01-21 Procept, Inc. Formation and utility of sulfonic acid protecting groups
US5670255A (en) * 1995-01-23 1997-09-23 Ppg Industries, Inc. Antioxidant compositions for coating substrates, substrates coated with the same and methods for inhibiting the oxidation of such compositions applied to a substrate
DE19523079A1 (en) * 1995-06-26 1997-01-02 Basf Ag Esters and amides of 9 (Z) -retinoic acid
CA2179940A1 (en) * 1995-07-18 1997-01-19 Kazumi Ogata Antiallergic composition comprising a phosphoric diester compound
US5798356A (en) * 1995-08-07 1998-08-25 Alcon Laboratories, Inc. Angiostatic compounds
CA2186654A1 (en) * 1995-10-13 1997-04-14 Masayuki Nakamura Phosphoric diester
JPH09301969A (en) * 1996-05-15 1997-11-25 Fuji Photo Film Co Ltd Chroman-based compound and heat-sensitive recording material using the same
DK0815858T3 (en) * 1996-07-01 2001-10-08 Nisshin Flour Milling Co Pharmaceutical composition containing 9-cis-retinoic acid alpha-tocopherol ester for the treatment of leukemia
US6022560A (en) 1996-08-27 2000-02-08 Clarion Pharmaceuticals Inc. Pharmaceutical compositions, novel uses, and novel form of α-tocopherylphosphocholine
FR2754713B1 (en) * 1996-10-22 1999-01-08 Roc Sa USE OF COMPLEXES FOR THE PREPARATION OF COMPOSITIONS FOR THE TREATMENT OF SENSITIVE SKIN, PREPARATION METHOD AND HYPOALLERGENIC COMPOSITIONS
BR9612753A (en) 1996-10-23 1999-10-19 Procter & Gamble Aqueous topical composition to lighten the skin and processes to lighten the skin of mammals and increase the penetrating effect of cojic acid
CA2220541A1 (en) * 1997-11-07 1999-05-07 Mcgill University Analogs of vitamin e
US5917060A (en) * 1997-12-17 1999-06-29 Basf Aktiengesellschaft Preparation of chromanyl derivatives
US5990322A (en) * 1999-03-09 1999-11-23 Sk Corporation Alpha-tocopherol cyclopropylates, the new vitamin E derivatives and method for producing the same

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