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WO1996039832A1 - Composes et procedes visant a stimuler la pousse des cheveux - Google Patents

Composes et procedes visant a stimuler la pousse des cheveux Download PDF

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Publication number
WO1996039832A1
WO1996039832A1 PCT/US1996/008433 US9608433W WO9639832A1 WO 1996039832 A1 WO1996039832 A1 WO 1996039832A1 US 9608433 W US9608433 W US 9608433W WO 9639832 A1 WO9639832 A1 WO 9639832A1
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WO
WIPO (PCT)
Prior art keywords
patient
pharmaceutical composition
effective amount
treating
need
Prior art date
Application number
PCT/US1996/008433
Other languages
English (en)
Inventor
Patrick C. Kung
Ze Zeng Li
Original Assignee
Kung Patrick C
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US08/484,097 external-priority patent/US5639785A/en
Application filed by Kung Patrick C filed Critical Kung Patrick C
Priority to AU59704/96A priority Critical patent/AU5970496A/en
Publication of WO1996039832A1 publication Critical patent/WO1996039832A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 

Definitions

  • the present invention relates to the use of isoflavonoid derivatives for the treatment of male pattern baldness and alopecia areata, and to promote the conversion of gray hair to the original pigment in hair follicles.
  • the invention further relates to the use of isoflavonoid derivatives to increase brain circulation, thereby alleviating symptoms associated with cardiovascular sickness resulting in decreased blood supply to the brain.
  • Also described herein are methods for the synthesis of isoflavonoid derivatives. More particularly, this invention relates to the methods of making and using substituted benzopyrany1-4-ones.
  • Minoxidil enlarges vellus hair follicles and seems to maintain terminal follicles in the scalps of mammals. After four months of treatment, approximately 25% of patients achieve minimal regrowth of hair. Rogaine®, the only compound approved to date to treat baldness, was developed because the oral administration of the drug stimulated hair growth. (Upjohn Co. Physicians Desk Ref., pp. 2578, 49th Ed (1995) . Minoxidil is a substituted pyrimidine.
  • the present invention relates to the use of daidzein, known as 7-hydroxy- 3-(4-hydroxyphenyl)-4-H-l-benzopyranyl-4-one.
  • Daidzein is an isoflavone with a variety of pharmacological effects.
  • isoflavone glycosides such as daidzin (7- glycoside daidzein)
  • isoflavones are found mostly in leguminous plants.
  • J.L. Ingham Naturally Occurring Isoflavonoids, Vol. 43, pp. 1-226, Progress in the chemistry of organic natural products, Ed, . Herz, H. Grisebach & G.W. Kirby, Springer-Verlag, Wien, New York, 1983.
  • the synthesis of daidzein & its derivatives was reviewed & reported by G. Shao et al (Yao Hsueh Hsueh Pao 15(9), 538, 1980; Q.E. Ji and Y.L.
  • Daidzein and its derivatives were also shown to have estrogenic effects (E. Farmakalidis, Food Che , Toxicol 22,237, 1984).
  • daidzein, equol and lignan were found to compete with estradiol for binding to the rat uterine type II estrogen binding site (H. Aldercreutz et al. J. Steroid Biochem. Mol. Biol. 41(3-8): 331, 1992) and to human recombinant estrogen receptor (ibid 49(2-3): 153, 1994) .
  • the estrogenic effects are very mild and become significant only with high doses or prolonged treatment.
  • G.H. Degan J.
  • Daidzein was also shown to inhibit insulin or insulin growth factor-l (IGF-1)-mediated signaling in cell cycle progression of Swiss 3T3 cells. It was suggested that the blocking of the Gl phase cell cycle was attributed to the inhibition of casein kinase II enzyme activity by daidzein. The enzyme is required for the commitment of itogenic signal by insulin or IGF-1 in Gl phase. (K. Higashi and H. Ogawara, Biochi et Biophysica Acta 1221(1): 29, 1994).
  • Isoflavones have been claimed to exhibit antifibrile, antispas odic, antihypertensive, and anti-dysrhythmic activities. Until recently, an effect of isoflavones on ethanol drinking behavior had never been demonstrated.
  • W-M Keung and B.L. Vallee published a series of studies on the implication of isoflavones, especially daidzin and daidzein, in the treatment of alcohol abuse. They found that daidzin and daidzein suppressed free choice ethanol intake, and did not significantly affect the body weight, water or food intake of Syrian Golden hamsters tested (W-M Keung and B.L. Vallee, PCT Patent Publication No.
  • the substituted isoflavonoids of this invention are useful in the treatment of hair loss, in the conversion of hair color to its original pigment, and in increasing blood supply to the brain, and are represented by the formula (I)
  • R 1 represents hydrogen, hydroxy, alkoxy of 1-6 carbon atoms, alkyl of 1-6 carbon atoms, OCOR where R is alkyl of 1-6 carbon atoms or phenyl
  • R 2 is hydrogen, hydroxy, alkoxy of 1-6 carbon atoms, alkyl of 1-6 carbon atoms, OCOR where R is alkyl of 1-6 carbon atoms or phenyl
  • R 3 is hydrogen; and pharmaceutically acceptable salts thereof.
  • ketone (3.) As shown in Scheme I below, p-hydroxy phenylacetic acid (2.) is reduced with resorcinol ( !) in the presence of anhydrous zinc chloride to produce the ketone (3.) .
  • suitable catalysts include, but are not limited to, aluminum chloride, boron trifluoride etherate, boron trifluoride, antimony chloride and ferric chloride.
  • the ketone (3.) is treated with N,N-dimethylformamide dimethyl acetal in dimethylformamide to afford daidzein (4.) .
  • the cyclization of the ketone (3.) to daidzein (4 can also be effected with N,N- dimethylformamide di-tert-butyl acetal, N,N-dimethylformamide di-cyclohexyl acetal, N,N-dimethylformamide di-ethyl acetal, N,N-dimethylformamide diisopropyl acetal, and N,N- dimethylformamide di-neopentyl acetal.
  • isoflavonoid derivatives of the type of formula (I) exhibiting the hair growth promoting, gray hair converting, and brain blood supply increasing activities of daidzein may be prepared by the approach of a multiple component combinatorial array synthesis by adding side chains to the daidzein core structure (R.W. Armstrong, PCT Patent Publication No. WO95/02566, published January 26, 1995), and are hereby incorporated by reference.
  • the present invention includes pharmaceutically acceptable salts of the compounds of formula (I) .
  • Non-toxic salts of the compounds of the above-identified formulas formed with organic or inorganic bases are also included within the scope of this invention and they include, for example, those of alkali metals, such as sodium, potassium and lithium.
  • the salts are prepared by conventional means as, for example, by treating a compound of formula (I) with an appropriate base. Illustrative examples of compounds of this invention are shown in Table I.
  • an extract of Pueraria lobata containing a sufficient concentration of daidzein may also be used for the practice of the present invention.
  • the compounds of this invention are useful as agents to treat male pattern baldness, to promote the conversion of gray hair to the original pigment in hair follicles, and in the treatment of brain circulatory deficiencies.
  • the present invention is directed to a method of increasing blood flow to the brain by the administration of an effective amount of daidzein or mixture of compounds of formula I.
  • the compounds may be administered with suitable pharmaceutical carriers and can be in solid or liquid dosage form such as tablets, capsules, powders, soft gels, solutions, suspensions, emulsions, creams or ointments.
  • a further object of this invention is to supply the compounds of this invention in a controlled-release formulation.
  • the compounds of this invention can be administered orally, parenterally, for example, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation or by application to mucous membranes via an aerosol spray or by application to the scalp or skin by ointment or a cream.
  • the quantity of compound administered will vary depending on the patent and the mode of administration and can be any effective amount.
  • the quantity of compound administered may vary over a wide range to provide in a unit dosage an effective amount from about 0.001 to 20 mg/kg of body weight of the patient per day to achieve the desired effect.
  • the desired affect can be obtained by consumption of a unit dosage form such as a tablet containing 1-200 mg of a compound of this invention taken 1-3 times daily.
  • a further object of this invention relates to a method of producing tablets of 7-hydroxy-3-(4-hydroxy-phenyl)-4-H-l- benzopyranyl-4-one.
  • Tablets of 7-hydroxy-3-(4-hydroxy-phenyl)-4-H-l- benzopyranyl-4-one have various clinical applications in treating central nervous system and hypertension diseases such as faintness, dizziness, stress, hand and leg numbness. They can also reduce whole blood viscosity, and reduce resistance in peripheral blood vessels. They also increases blood transport capacity and improve blood supply to certain organs.
  • the active ingredient, 7-hydroxy-3-(4-hydroxy- phenyl)-4-H-l-benzopyranyl-4-one is non-toxic.
  • An object of the present invention is to provide a method of producing tablets of 7-hydroxy-3-(4-hydroxy- phenyl)-4-H-l-benzopyranyl-4-one.
  • the tablets made by the method of the present invention may manifest improved bioavailability and demonstrate a significant clinical effect.
  • a method of the present invention comprises pulverizing the raw material of the active ingredient, such as a powder of 7-hydroxy-3-(4-hydroxy-phenyl)-4-H-l-benzopyranyl-4-one produced by the synthetic process described herein, to a macrocrystalline product with a particle size not greater than 4 microns (Table II) , mixing with an appropriate amount of carrier such as lactose, vitamins, starch, macrocrystalline cellulose, disintegrant (dicalcium phosphate) , inorganic salts, solubilizer and a surfactant (e.g. Tween 80) , agglomerating and drying the mixture, adding magnesium stearate (lubricant) , and forming tablets as described in Modern Pharmaceutics, G.S. Barber and CT. Rhodes (1979) (Marcel Dekker, Inc. New York, NY).
  • carrier such as lactose, vitamins, starch, macrocrystalline cellulose, disintegrant (dicalcium phosphate) , inorganic salt
  • Airjet Pulverizer (Model QS 50: 0.85/10) used to downsize the daidzein crystals was purchased from the No. 3 Chemical Engineering Mechanical Instrument Factory, Shanghai, China.
  • Pulverizing the raw material of 7-hydroxy-3-(4-hydroxy- phenyl)-4-H-l-benzopyranyl-4-one produces a microcrystal with a particle size of no more than 4 microns.
  • the tablets are formed by adding to the pulverized or untreated daidzein the appropriate amount of fillers, solubilizer, disintegrating agents or binding agents, such as, lactose, vitamins, starch, inorganic salts, microcrystalline cellulose and a trace of surfactant to make a soft product, agglomerating the soft product, drying the agglomerated product at 80° to 90°C, adding magnesium stearate (lubricant) to the dried product which results in the formation of tablets.
  • the newly grown hairs in the affected area are mostly dark brown.
  • the response to the medicine is more sensitive in areas with most recent hair loss.
  • the overall increase of the hair density in the affected area is very significant.
  • Example 5 A healthy Chinese male (age 47) with normal blood pressure volunteered to take the medicine for the same observation as in Example 4 at the dose described above. His hair condition is normal with no baldness. During the six month testing period, he collected in intervals the hair samples from regular daily combing. Before the testing and during the first month of testing, the hair samples collected had two types, namely completely dark brown or completely gray. At around 50 days into the testing period, a new type of hair, partly dark brown and partly gray, began to appear in the hair samples; they represented about 3% of the gray hairs. In this subject, the gray hairs represented about 25% of his total hairs in the samples collected. It is noted that the dark brown part of the new type of hair is always associated with the lower part of the hair shaft.
  • the quality and thickness of the new type of hair is very similar to the other types of hairs of this subject.
  • the ratio of length of the dark brown part to that of the gray part of the new type of hair varies from 1:5 to 4:1 in the samples collected during the five-month period. This varying ratio may reflect the stages of the growth cycle of each hair follicle examined. The observation was discontinued at the end of five months. No untoward effects were reported.
  • Table IV Each patient also experienced significant improvement (Table IV) of several symptoms, such as headaches, giddiness, chest tightness, mental alertness and vertigo, which are frequently associated with cardiovascular sickness; some of these improvements may be attributed to increased and equalized blood supply via the neck arteries to the brain during treatment with daidzein.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention porte sur de nouvelles compositions pharmaceutiques de dérivés d'isoflavonoïde efficaces dans le traitement de la calvitie hippocratique et de la pelade. Ces compositions facilitent la conversion du pigment des cheveux gris en pigment d'origine dans les follicules capillaires et accroissent l'apport sanguin en direction du cerveau. Cette invention porte également sur des procédés thérapeutiques de la calvitie hippocratique, de la pelade, des cheveux gris et des défaillances circulatoires cérébrales. Il est également fait état de procédés permettant la synthèse de dérivés d'isoflavonoïde.
PCT/US1996/008433 1995-06-07 1996-06-03 Composes et procedes visant a stimuler la pousse des cheveux WO1996039832A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU59704/96A AU5970496A (en) 1995-06-07 1996-06-03 Compounds and methods for promoting hair growth

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US484,097 1990-02-22
US08/484,097 US5639785A (en) 1995-06-07 1995-06-07 Methods for the treatment of baldness and gray hair using isoflavonoid derivatives
US65946696A 1996-05-31 1996-05-31
US08/659,466 1996-05-31

Publications (1)

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WO1996039832A1 true WO1996039832A1 (fr) 1996-12-19

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998048790A1 (fr) * 1997-04-28 1998-11-05 Anticancer, Inc. Utilisation de la genisteine et de composes associes pour traiter certains etats lies aux hormones sexuelles
JP2002537295A (ja) * 1999-02-15 2002-11-05 ノボゲン リサーチ ピーティーワイ リミテッド イソフラボン誘導体の製造方法
WO2004014886A1 (fr) * 2002-08-07 2004-02-19 University Of Mississippi Agents anti-giardiase et leur utilisation
EP1047420A4 (fr) * 1998-01-20 2004-04-14 Gillette Co Modulation de la croissance des poils
JP2009102342A (ja) * 1996-08-30 2009-05-14 Novogen Research Pty Ltd イソフラボン類を含有する治療方法及び組成物
JP2015166458A (ja) * 2008-10-29 2015-09-24 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ 液晶ディスプレイ
KR101824497B1 (ko) 2016-09-27 2018-03-14 주식회사 스템모어 피토에스트로겐을 유효성분으로 포함하는 탈모방지 및 모발 성장 촉진용 조성물
WO2021256233A1 (fr) * 2020-06-15 2021-12-23 国立大学法人東海国立大学機構 Inhibiteur de grisonnement des cheveux

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS58225004A (ja) * 1982-06-23 1983-12-27 Ichimaru Fuarukosu Kk イソフラボン化合物含有美白化粧料
JPH0578347A (ja) * 1991-09-18 1993-03-30 Lion Corp プテロカルペン化合物、イソフラバノン化合物および抗男性ホルモン剤

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS58225004A (ja) * 1982-06-23 1983-12-27 Ichimaru Fuarukosu Kk イソフラボン化合物含有美白化粧料
JPH0578347A (ja) * 1991-09-18 1993-03-30 Lion Corp プテロカルペン化合物、イソフラバノン化合物および抗男性ホルモン剤

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, issued 1982, FARUKOSU, "Cosmetics Containing Isoflavone Derivatives", Abstract No. 100:126730; & JP,A,58 225 004. *
CHEMICAL ABSTRACTS, issued 1993, HAKAMATA et al., "Isolation of Pterocarpene and Isoflavonone Derivatives from Platymiscium sp. and Swarzia sp. and Anti-Male Hormone Agents Containing Them", Abstract No. 119:146570; & JP,A,05 078 347. *
THE MERCK INDEX, M. WINDHOLZ et al., "DIADZEIN", 10th Edition, Published 1983, by MERCK & CO., INC., (N.J.), page 2795. *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009102342A (ja) * 1996-08-30 2009-05-14 Novogen Research Pty Ltd イソフラボン類を含有する治療方法及び組成物
WO1998048790A1 (fr) * 1997-04-28 1998-11-05 Anticancer, Inc. Utilisation de la genisteine et de composes associes pour traiter certains etats lies aux hormones sexuelles
EP1047420A4 (fr) * 1998-01-20 2004-04-14 Gillette Co Modulation de la croissance des poils
JP2002537295A (ja) * 1999-02-15 2002-11-05 ノボゲン リサーチ ピーティーワイ リミテッド イソフラボン誘導体の製造方法
WO2004014886A1 (fr) * 2002-08-07 2004-02-19 University Of Mississippi Agents anti-giardiase et leur utilisation
US7468445B2 (en) 2002-08-07 2008-12-23 University Of Mississippi Antigiardial agents and use thereof
JP2015166458A (ja) * 2008-10-29 2015-09-24 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ 液晶ディスプレイ
KR101824497B1 (ko) 2016-09-27 2018-03-14 주식회사 스템모어 피토에스트로겐을 유효성분으로 포함하는 탈모방지 및 모발 성장 촉진용 조성물
CN109689046A (zh) * 2016-09-27 2019-04-26 斯泰姆摩尔股份公司 包含植物雌激素作为有效成分的用于防止脱发及促进毛发生长的组合物
WO2021256233A1 (fr) * 2020-06-15 2021-12-23 国立大学法人東海国立大学機構 Inhibiteur de grisonnement des cheveux
CN115915970A (zh) * 2020-06-15 2023-04-04 国立大学法人东海国立大学机构 白发抑制剂

Also Published As

Publication number Publication date
AU5970496A (en) 1996-12-30

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