WO2000044757A1 - Hesperitin pro-forms with enhanced bioavailability - Google Patents
Hesperitin pro-forms with enhanced bioavailability Download PDFInfo
- Publication number
- WO2000044757A1 WO2000044757A1 PCT/US2000/001923 US0001923W WO0044757A1 WO 2000044757 A1 WO2000044757 A1 WO 2000044757A1 US 0001923 W US0001923 W US 0001923W WO 0044757 A1 WO0044757 A1 WO 0044757A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- acid salt
- pro
- moiety
- hesperetin
- group
- Prior art date
Links
- 0 *c1c(*=C)cc([C@](C2)Nc3cc(O*)cc(N)c3C2=O)cc1 Chemical compound *c1c(*=C)cc([C@](C2)Nc3cc(O*)cc(N)c3C2=O)cc1 0.000 description 1
Classifications
-
- 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
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/32—2,3-Dihydro derivatives, e.g. flavanones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- 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
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- This invention relates generally to the field of bioflavanoids, and more specifically to forms of bioflavanoids that increase their bioavailability, and to the use of these compounds for the treatment of disease.
- Hesperidin and the a glycone of hesperidin, hesperetin, are flavonoids found in lemons, grapefruits, tangerines, and oranges, and have the following structures:
- bioflavonoids from citrus fruits, known as bioflavonoids exhibit beneficial effects, suppressing oxidative stress, inhibit breast cancer and have anti-inflammatory function.
- Hesperidin has been used for the prevention and treatment of cerebral anemia, and pelioma. Recently has been found that hesperidin and hesperetin are effective inhibitors of 3-hydroxy-3-methylglutaryl CoA (U.S. Patent 5, 763,414, herein incorporated by reference). Moreover, hesperetin has topical application for sebum control and treatment of acne in mammalian skin and scalp (U.S. Patent 5,587,176, herein incorporated by reference).
- flavonoids The bioavailability of flavonoids is an important problem in physiological effects, statistically; less than 20% of administered flavonoid is absorbed to blood which subsequently is metabolized to glucuronides and sulfates. Only free flavonoids without sugar molecule, the so-called aglycones are able to pass through the gut wall. Hydrolysis of flavonoid glycosides only occurs in the colon by microorganisms, which in the same time degrade released flavonoids.
- a hesperitin pro-form is provided.
- the invention provides both a hydrophilic and a lipophilic hesperetin pro-form.
- a pharmaceutical composition which is suitable for topical or oral administration in an individual, the composition comprising a hydrophilic hesperetin pro-form and a pharmaceutically acceptable carrier.
- a pharmaceutical composition is also provided which is suitable for topical or oral administration in an individual, the composition including a lipophilic hesperetin pro-form and a pharmaceutically acceptable carrier.
- a method is provided for treating a subject having or at risk of having a cell proliferative disorder, including administering to the subject a therapeutically effective amount of a hesperetin pro-form.
- a method for decreasing oxidative stress in a subject having a disorder associated with oxidative stress including administering to the subject a therapeutically effective amount of a hesperitin pro-form.
- a method is further provided for treating a subject having or at risk of having a disorder associated with sebacous gland activity, including administering to the subject a therapeutically effective amount of a hesperetin pro-form.
- a method for treating a subject having or at risk of having a cardiovascular disorder including administering to the subject a therapeutically effective amount of a hesperetin pro-form.
- a “hesperetin pro-form” is hydrophilic or a lipophilic pro-form of hesperetin of the general formula:
- hydrophilic hesperetin pro-form is a compound of the formula indicated above wherein:
- R is H and R, is an organic or an inorganic salt of phosphoric or sulfuric acid residue.
- R is H and R is an organic or an inorganic salt of phosphoric or sulfuric acid residue.
- a “lipophilic hesperetin pro-form” is a compound of the formula indicated above, wherein:
- R and R is a saturated or unsaturated fatty acid moiety.
- One of R and R ! is an acid moiety selected from the group consisting of a straight or branched aliphatic chain, including an alkyl, alkenyl, alkynyl, alkoxyalkyl, alkythioalkyl, aminoalkyl group, including substituted or non- substitued cycloalkyl, and an aromatic group, including aryl, aryalkyl, and substitued derivatives such as where a ring contains one or more nitrogen, sulfer, or oxygens.
- a hesperetin pro-form has increased metabolic resistance and improved absorption as compared to hesperetin.
- Metal resistance refers to a decreased ability of an enzyme, normally found in a metabolic pathway, to degrade the compound, as compared to a control compound.
- Improved absorption refers to an increased ability of an organism to absorb a compound, via any route (e.g. dermal absorption, intestinal absorption) as compared to a control compound.
- Methods and compositions of the present invention provide increased bioavailability of hesperetin by converting this flavanone into pro- compound. This is preferably accomplished by attaching leaving group, which can be readily hydrolyzed under physiologic conditions to produce the starting flavanone.
- hydroxyl groups at 7 and 3' positions are converted to carboxylic, phosphoric and sulfuric acid esters.
- enzymatic or spontaneous hydrolysis of the pro-compounds in gastrointestinal tract or skin release free hesperetin as a function of time.
- Kinetics of this process can be controlled by appropriate formulation of the pro-compounds to decrease metabolic transformation and increase absorption of hesperetin in the target cells.
- the pro-compounds may advantageously be employed therapeutically or prophylactically for variety conditions, provided as a dietary supplement, drug or bioactive component of cosmetics.
- the molecule of hesperetin has three hydroxyl groups, which differ from each other with different reactivity to acylating reagent. High reactivity of 7-hydroxyl group made possible direct formation of hesperetin-7-esters using activated carboxylic acids or acyl chlorides at the presence of base. Synthesis of hesperetin-3'-eters, required prior esterification of 3'-OH conversion of 7-OH group to benzylformyl or t- butyldimethylsilyl derivatives.
- PHARMACEUTICAL COMPOSITIONS The invention also contemplates various pharmaceutical compositions containing a hesperetin pro-form that are effective in treating a variety of disorders. These disorders include "cell proliferative disorders” , “disorders associated with oxidative stress”, “skin disorders”, and “cardiovascular disorders”.
- Neoplasia refers to a disease of inappropriate cell proliferation.
- cell proliferative disorder denotes malignant as well as nonmalignant cell populations which often appear to differ from the surrounding tissue both morphologically and genotypically.
- Malignant cells i.e., tumors or cancer
- Concepts describing normal tissue growth are applicable to malignant tissue because normal and malignant tissues can share similar growth characteristics, both at the level of the single cell and at the level of the tissue. Tumors are as much a disease of disordered tissue growth regulation as of disordered cellular growth regulation.
- the growth characteristics of tumors are such that new cell production exceeds cell death; a neoplastic event tends to produce an increase in the proportion of stem cells undergoing self-renewal and a corresponding decrease in the proportion progressing to maturation (McCulloch, E.A., et ah, 1982, "The contribution of blast cell properties to outcome variation in acute myeloblastic leukemia (AML),” Blood 59:601 -608).
- the cells treated by the method of the invention are neoplastic cells.
- cardiovascular disorder refers to any coronary or cardio-circular disease, including atherosclerosis and hypercholesterolemia.
- disorder associated with sebaceous gland activity refers to a disorder of the pilosebaceous glands of the mammalian skin and scalp. Examples are disorders of sebum secretin such as acne.
- “Acne” is a pilosebaceous disease characterized by comedo, papules, inflamed nodules and superficial pus-filled cysts. The course and severity of the disease is determined by the interaction between hormones, keratinization, sebum formation and bacteria.
- treating sebaceous gland activity as used herein means preventing, retarding, and/or arresting the production of sebum.
- the tern “treating acne” refers to preventing, retarding, and/or arresting the process of acne formation.
- compositions according to the invention are prepared by bringing a pro-form of hesperetin of the present invention into a form suitable for administration (e.g., a pharmaceutically acceptable carrier) to a subject using carriers, excipients and additives or auxiliaries.
- a pharmaceutically acceptable carrier e.g., a pharmaceutically acceptable carrier
- carriers or auxiliaries include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, vitamins, cellulose and its derivatives, animal and vegetable oils, polyethylene glycols and solvents, such as sterile water, alcohols, glycerol and polyhydric alcohols.
- Intravenous vehicles include fluid and nutrient replenishers.
- Preservatives include antimicrobial, anti-oxidants, chelating agents and inert gases.
- Other pharmaceutically acceptable carriers include aqueous solutions, non-toxic excipients, including salts, preservatives, buffers and the like, as described, for instance, in Remington's Pharmaceutical Sciences. 15th ed. Easton: Mack Publishing Co., 1405-1412, 1461-1487, 1975, and The National Formulary XIV.. 14th ed. Washington: American Pharmaceutical Association, 1975, the contents of which are hereby incorporated by reference.
- the pH and exact concentration of the various components of the pharmaceutical composition are adjusted according to routine skills in the art. See Goodman and Gilman's The Pharmacological Basis for Therapeutics. 7th ed.
- the invention in another embodiment, relates to a method of treating a cell proliferative disorder, a disorder associated with oxidative stress, a skin disorder, and a cardiovascular disorder.
- administering involves administering to a subject a therapeutically effective dose of a pharmaceutical composition containing the compounds of the present invention and a pharmaceutically acceptable carrier.
- administering the pharmaceutical composition of the present invention may be accomplished by any means known to the skilled artisan.
- subject is meant any mammal, preferably a human.
- the pharmaceutical compositions are preferably prepared and administered in dose units.
- Solid dose units are tablets, capsules and suppositories.
- different daily doses are necessary. Under certain circumstances, however, higher or lower daily doses may be appropriate.
- the administration of the daily dose can be carried out both by single administration in the form of an individual dose unit or else several smaller dose units and also by multiple administration of subdivided doses at specific intervals.
- the dosage should not be so large as to cause adverse side effects, such as unwanted cross-reactions, anaphylactic reactions and the like.
- the dosage will vary with the age, condition, sex, and extent of the disease in the patient and can be determined by one skilled in the art.
- the dosage can be adjusted by the individual physician in the event of any contraindications and can be readily ascertained without resort to undue experimentation.
- the pharmaceutical compositions according to the invention are in general administered topically, intravenously, orally or parenterally or as implants, but even rectal use is possible in principle.
- Suitable solid or liquid pharmaceutical preparation forms are, for example, granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, aerosols, drops or injectable solution in ampule form and also preparations with protracted release of active compounds, in whose preparation excipients and additives and/or auxiliaries such as disintegrants, binders, coating agents, swelling agents, lubricants, flavorings, sweeteners or solubilizers are customarily used as described above.
- the pharmaceutical compositions are suitable for use in a variety of drug delivery systems. For a brief review of present methods for drug delivery, see Langer, Science, 249: 1527-1533, 1990, which is incorporated herein by reference.
- compositions according to the invention may be administered locally or systemically.
- therapeutically effective dose is meant the quantity of a compound according to the invention necessary to prevent, to cure or at least partially arrest the symptoms of the disease and its complications. Amounts effective for this use will, of course, depend on the severity of the disease and the weight and general state of the patient.
- dosages used in vitro may provide useful guidance in the amounts useful for in situ administration of the pharmaceutical composition, and animal models may be used to determine effective dosages for treatment of particular disorders.
- Various considerations are described, e.g., in Gilman et al, eds., Goodman and Gilman's: the Pharmacological Bases of Therapeutics. 8th ed., Pergamon Press, 1990; and Remington's Pharmaceutical
- the obtained product was dissolved in ethyl acetate and hydrogenated at the presence of 10% palladium on charcoal. After filtration and removal of the solvent the residue was crystallized from hexane.
- Electrospray mass spectrum showed: m/z 567 [M-H].
- Electrospray spectrum showed: m/z 381 [M-H].
- Electrospray spectrum showed: m/z 381 [M-H].
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrane Compounds (AREA)
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2000596013A JP2002535410A (en) | 1999-01-27 | 2000-01-26 | Hesperetin proform with enhanced bioavailability |
EP00904573A EP1155021A1 (en) | 1999-01-27 | 2000-01-26 | Hesperitin pro-forms with enhanced bioavailability |
US09/890,479 US6831098B1 (en) | 1999-01-27 | 2000-01-26 | Hesperetin pro-forms with enhanced bioavailablility |
AU26309/00A AU764186B2 (en) | 1999-01-27 | 2000-01-26 | Hesperitin pro-forms with enhanced bioavailability |
CA002358967A CA2358967A1 (en) | 1999-01-27 | 2000-01-26 | Hesperitin pro-forms with enhanced bioavailability |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11756799P | 1999-01-27 | 1999-01-27 | |
US11819899P | 1999-02-01 | 1999-02-01 | |
US60/117,567 | 1999-02-01 | ||
US60/118,198 | 1999-02-01 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2000044757A1 true WO2000044757A1 (en) | 2000-08-03 |
Family
ID=26815410
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2000/001923 WO2000044757A1 (en) | 1999-01-27 | 2000-01-26 | Hesperitin pro-forms with enhanced bioavailability |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP1155021A1 (en) |
JP (1) | JP2002535410A (en) |
CN (1) | CN1337966A (en) |
AU (1) | AU764186B2 (en) |
CA (1) | CA2358967A1 (en) |
WO (1) | WO2000044757A1 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2003102430A (en) * | 2001-09-27 | 2003-04-08 | Pokka Corp | Fermented citrus and method for producing the same |
JP2003102429A (en) * | 2001-09-27 | 2003-04-08 | Pokka Corp | Fermented lemon and method for producing the same |
EP1856085A1 (en) * | 2005-03-11 | 2007-11-21 | Howard Florey Institute of Experimental Physiology and Medicine | Flavonoid compounds and uses thereof |
US7947733B2 (en) | 2007-07-31 | 2011-05-24 | Limerick Biopharma | Phosphorylated pyrone analogs and methods |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102746264A (en) * | 2012-08-06 | 2012-10-24 | 西南大学 | 7-benzyloxy hesperetin, preparation method and application thereof |
CN106565657A (en) * | 2016-11-23 | 2017-04-19 | 陕西科技大学 | Hesperetin cinnamate compound with anti-tumor activity and synthetic method thereof |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5587176A (en) * | 1993-04-20 | 1996-12-24 | The Procter & Gamble Company | Methods of using hesperetin for sebum control and treatment of acne |
US5763414A (en) * | 1996-10-14 | 1998-06-09 | Korea Institute Of Science And Technology | Hesperidin and hesperetin as 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitor |
-
2000
- 2000-01-26 WO PCT/US2000/001923 patent/WO2000044757A1/en active Search and Examination
- 2000-01-26 JP JP2000596013A patent/JP2002535410A/en active Pending
- 2000-01-26 CA CA002358967A patent/CA2358967A1/en not_active Abandoned
- 2000-01-26 EP EP00904573A patent/EP1155021A1/en not_active Withdrawn
- 2000-01-26 AU AU26309/00A patent/AU764186B2/en not_active Ceased
- 2000-01-26 CN CN00803072A patent/CN1337966A/en active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5587176A (en) * | 1993-04-20 | 1996-12-24 | The Procter & Gamble Company | Methods of using hesperetin for sebum control and treatment of acne |
US5763414A (en) * | 1996-10-14 | 1998-06-09 | Korea Institute Of Science And Technology | Hesperidin and hesperetin as 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitor |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2003102430A (en) * | 2001-09-27 | 2003-04-08 | Pokka Corp | Fermented citrus and method for producing the same |
JP2003102429A (en) * | 2001-09-27 | 2003-04-08 | Pokka Corp | Fermented lemon and method for producing the same |
JP4522624B2 (en) * | 2001-09-27 | 2010-08-11 | 株式会社ポッカコーポレーション | Lemon fermented product and method for producing the same |
JP4522625B2 (en) * | 2001-09-27 | 2010-08-11 | 株式会社ポッカコーポレーション | Citrus fermented product and method for producing the same |
EP1856085A1 (en) * | 2005-03-11 | 2007-11-21 | Howard Florey Institute of Experimental Physiology and Medicine | Flavonoid compounds and uses thereof |
EP1856085A4 (en) * | 2005-03-11 | 2010-11-03 | Florey Howard Inst | Flavonoid compounds and uses thereof |
US8017649B2 (en) | 2005-03-11 | 2011-09-13 | Howard Florey Institute Of Experimental Physiology And Medicine | Flavonoid compounds and uses thereof |
US7947733B2 (en) | 2007-07-31 | 2011-05-24 | Limerick Biopharma | Phosphorylated pyrone analogs and methods |
Also Published As
Publication number | Publication date |
---|---|
AU2630900A (en) | 2000-08-18 |
CN1337966A (en) | 2002-02-27 |
AU764186B2 (en) | 2003-08-14 |
CA2358967A1 (en) | 2000-08-03 |
EP1155021A1 (en) | 2001-11-21 |
JP2002535410A (en) | 2002-10-22 |
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