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WO2002062422A1 - Nouvelles compositions d'activateurs de canaux potassiques et inhibiteurs de la proteine kinase c et leur utilisation - Google Patents

Nouvelles compositions d'activateurs de canaux potassiques et inhibiteurs de la proteine kinase c et leur utilisation Download PDF

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Publication number
WO2002062422A1
WO2002062422A1 PCT/SE2002/000105 SE0200105W WO02062422A1 WO 2002062422 A1 WO2002062422 A1 WO 2002062422A1 SE 0200105 W SE0200105 W SE 0200105W WO 02062422 A1 WO02062422 A1 WO 02062422A1
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WIPO (PCT)
Prior art keywords
composition
anyone
minoxidil
hair loss
inhibitors
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/SE2002/000105
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English (en)
Inventor
Jan Rundegren
Bo Kreilgård
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Health AB
Original Assignee
Pharmacia AB
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Filing date
Publication date
Application filed by Pharmacia AB filed Critical Pharmacia AB
Priority to JP2002562427A priority Critical patent/JP2004518701A/ja
Priority to EP02715944A priority patent/EP1357974A1/fr
Publication of WO2002062422A1 publication Critical patent/WO2002062422A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00—Preparations for affecting hair growth
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
    • A61K8/4953—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom containing pyrimidine ring derivatives, e.g. minoxidil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
    • A61K8/498—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom having 6-membered rings or their condensed derivatives, e.g. coumarin
    • 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
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/74—Biological properties of particular ingredients
    • A61K2800/78—Enzyme modulators, e.g. Enzyme agonists
    • A61K2800/782—Enzyme inhibitors; Enzyme antagonists

Definitions

  • the present invention relates to novel compositions of potassium channel openers and protein kinase C inhibitors, methods for making the compositions, and methods for inducing and/or stimulating hair growth and/or reducing hair loss using the compositions.
  • the present invention also relates to a first composition comprising one or more potassium channel openers and a second composition comprising one or more protein kinase C inhibitors, said first and second compositions to be used in combination for inducing and/or stimulating hair growth and/or reducing hair loss.
  • PCOs potassium channel openers
  • P-1075 N-cyano-N- tertpentyl-N'-3-pyridinylguanidine
  • diazoxide cromakilim and minoxidil.
  • Buhl AE Conrad SJ, Waldon DJ, Brunden MN. Potassium channel conductance as a control mechanism in hair foUicles. J Invest Dermatol 1993; 101 (1 Suppl): pp. 148S-152S, and Harmon CS, Lutz D, Ducote J.
  • Potassium channel openers stimulate DNA synthesis in mouse epidermal keratinocyte and whole hair follicle cultures. Skin Pharmacol 1993; 6: 170-178. These PCOs have also vascular effects in that they relax smooth muscle cells of capillaries. This property has been implicated as a possible mechanism for stimulating hair growth by increasing blood supply to the hair follicles, but other mechanisms as well have been suggested for the hair growth stimulant minoxidil. Such mechanisms are anti-fibrotic effect by its inhibition of lysyl hydroxylase (Murad S,
  • Minoxidil being 2,4-diamino-6-piperidinylpyrimidine-3-oxide
  • Loniten and Rogaine which are marketed by Pharmacia as a treatment for hypertension, and as a treatment and preventative for androgenic alopecia (male and female pattern baldness), respectively.
  • the preparation and antihypertensive use of minoxidil is described in US Patent No 3,461,461.
  • Methods and topical preparations for using the compound to grow hair and to treat male and female pattern baldness are described and claimed in US Patents No 4,139,619 and 4,596,812.
  • proanthocyanidins are polymers or oligomers of flavan-3-ol units, such as catechin, epicatechin, gallocatechin, epigallocatechin, achalelechin, and epiafzelechin; whose molecules occasionally incorporate gallic acid.
  • Epicatechin dimers such as procyanidin Bl, B2, and B3 as well as the epicatechin trimer Cl but not the monomer show stimulation of hair keratinocytes and hair growth stimulation in the C3H mouse. See Takahashi T, Kamiya T, Hasegawa A, Yokoo Y. Procyanidin ohgomers selectively and intensively promote proliferation of mouse hair epithelial cells in vitro and activate hair follicle growth in vivo. J Invest Dermatol 1999; 112: 310-316.
  • proanthocyanidine as hair growth promoter is disclosed in WO 9600561.
  • combination products comprising a potassium channel opener and some other hair promoting agent, e g minoxidil and the 5-alpha reductase inhibitor finasteride, US 5,578,599, and minoxidil and the androgen receptor RU 58841, US 5,411,981.
  • the present invention is directed to first novel compositions of one or more potassium channel openers and one or more protein kinase C inhibitors. Specifically, in one embodiment, there is provided a composition comprising minoxidil and procyanidin B2. Other embodiments of the invention relate to first compositions comprising combinations of other potassium channel openers and other protein kinase C inhibitors.
  • compositions comprising one or more potassium channel openers and a third composition comprising one or more protein kinase C inhibitors, said first and second compositions to be used in combination for inducing and/or stimulating hair growth and/or reducing hair loss.
  • Methods for treating and/or preventing hair loss in a region of a patient, wherein the methods comprise topically administering to the region compositions as described herein, are also provided by the present invention.
  • the present invention is directed, in part, to novel first compositions of one or more potassium channel openers and one or more protein kinase C inhibitors, to methods for making the compositions, and to methods for inducing and/or stimulating hair growth and/or reducing hair loss using the compositions.
  • the present invention also relates to a second composition comprising one or more potassium channel openers and a third composition comprising one or more protein kinase C inhibitors, said second and third compositions to be used in combination for inducing and/or stimulating hair growth and/or reducing hair loss.
  • compositions of the present invention may take a variety of forms including, for example, solutions, emulsions, suspensions or mixture thereof in a wide range of viscosities, including semi-solids, in gelled or non-gelled form, for direct topical application or for topical application by spraying, and different forms of patches for topical application.
  • the respective concentration of the one or more potassium channel openers and the one or more protein kinase C inhibitors in the present compositions may vary within a wide range depending on the specificity for the respective compound and the pharmaceutical formulation used. Useful concentrations are though from around 0.5% (w/w) to around 10% (w/w) when the potassium channel opener minoxidil and from around 0.1% (w/w) to around 10% (w/w) when the protein kinase C inhibitor is procyanidin B2.
  • the solvent is a polar solvent. Preferred among these are polar, protic solvents.
  • the solvent is water or a hydroxy compound, i e, a compound containing at least one hydroxy (OH) group.
  • hydroxy compounds are alcohols (i e, compounds containing one hydroxy group) or polyols (i e, compounds containing two or more hydroxy groups) or mixtures of alcohols and/or polyols.
  • exemplary alcohols include, for example, ethanol, propanol and butanol. Reference herein to "ethanol” includes absolute alcohol, as well as “alcohol USP” and all denatured forms of 95% ethanol.
  • propanol refers to all isomeric forms, including n-propanol and isopropanol
  • butanol refers to all isomeric forms, including, for example, n-butanol, iso-butanol and sec-butanol.
  • Preferred among these alcohols are ethanol and propanol, with ethanol being more preferred.
  • Exemplary polyols include, for example propylene glycol, dipropylene glycol, hexylene glycol, 1,3-butylene glycol, liquid polyethylene glycols, such as polyethylene glycol 200 (PEG- 200) and polyethylene glycol 400 (PEG-400), and glycerol (the latter also referred to sometimes as glycerine).
  • PEG- 200 polyethylene glycol 200
  • PEG-400 polyethylene glycol 400
  • glycerol the latter also referred to sometimes as glycerine
  • Preferred among these polyols is propylene glycol.
  • the solvent employed may be a mixture of water, an alcohol and a polyol.
  • compositions of the present invention may be topically administered to a region of a patient for the prevention or treatment of hair loss.
  • the compositions may optionally comprise additional pharmaceutically acceptable additives and ingredients such as, for example, pH modifiers, chemical stabilizers, including antioxidants, hair conditioners, such as vitamin B5/panthenol, calcium pantothenate or other panthenol derivatives, colorants, fragrances, fragrance modifiers, other vitamins such as vitamin E, penetration modifiers, such as azone and DEET, surfactants, such as Cremophor (BASF), cosmetic agents for the skin or scalp, such as fatty acids and fatty acid esters, herbal extracts, such as henna, other viscosity enhancing or thickening agents, oils, emulsifiers, wetting agents, sunscreens and anti- irritants.
  • additional pharmaceutically acceptable additives and ingredients such as, for example, pH modifiers, chemical stabilizers, including antioxidants, hair conditioners, such as vitamin B5/panthenol, calcium pan
  • compositions of the present invention may be prepared by combining together the components of the compositions, as described herein, at a temperature and for a time sufficient to preferably provide a pharmaceutically elegant composition.
  • combining together means that all of the components of the compositions may be combined and mixed together at about the same time.
  • combining together means that the various components may be combined in one or more preferential sequences to provide the desired product.
  • compositions of the present invention may be advantageously employed to treat and/or prevent a region of hair loss or alopecia in a patient.
  • the methods may comprise topically administering to the region a composition as described herein.
  • the life of a hair is subjected to a cycle, called the pilar cycle, during which the hair grows (anagen), transitions (catagen), and falls out (telogen), before being replaced by a new hair which appears in the same follicle and the cycle is repeated.
  • This constant renewal process undergoes a natural change during ageing.
  • the hair cycles become shorter, resulting in finer, shorter hairs. Hair loss results when this process is accelerated or disturbed, i.e.
  • the growth phases become shorter, the passage of hair into the telogen phase is earlier and hairs fall out in larger numbers. Successive shortening growth cycles may result in increasingly fine and short hair, which is slowly converted into fluff. This phenomenon may lead to progressive hair thinning and may eventually lead to baldness.
  • Dermatologists recognize many different types of hair loss, the most common by far being androgenetic alopecia (also known as male or female "pattern baldness"), wherein humans begin losing scalp hair as they get older. While this type of hair loss is more common in males, it also occurs in women.
  • This male type of alopecia may be characterized by progressive thinning, as discussed above, or may be characterized by hair loss with little diffuse hair thinning, such as frontal hair loss, mid-anterior balding, bitemporal recession, and/or vertex balding.
  • the androgenetic alopecia is generally characterized by a diffuse thinning of the top of the scalp but with preservation of a frontal hairline.
  • Alopecia areata, anagen hair loss, and diffuse alopecia, such as telogen effluvium are other presentations of hair loss, which may be distinguished from androgenetic alopecia. These other forms of hair loss may also be treated with the present compositions.
  • compositions according to the present invention have a better hair growing effect than compositions comprising either only potassium channel openers or only protein kinase C inhibitors it is possible, in order to achieve the same effect, to administer the present compositions less frequently than had instead been administered a composition comprising either only potassium channel openers or only protein kinase C inhibitors.
  • Useful administration of the present compositions hence includes administration once daily or even less often.
  • At least additive effect Use of compositions according to the present invention preferably, but not exclusively, provides for an effect being at least additive in relation to separate use of potassium channel openers and protein kinase C inhibitors respectively. Such additive effect is far from obvious.
  • Minoxidil is a potassium channel opener. It has been shown that certain other potassium channel openers also have a hair growth stimulation effect. Thus, if minoxidil would be combined with a substance having a similar mode of action no added effect would be expected as the upper limit for this effect would have been reached through the use of minoxidil only.
  • minoxidil it might though be possible to achieve an at least additive effect if minoxidil be combined with a substance having another mode of action.
  • This other substance should neither inhibit minoxidil in the formulation, nor counteract minoxidil as to absorption, receptor binding and metabolism.
  • a non-obvious and inventive process has been performed in order to secure that the necessary conditions are fulfilled in order to preferably achieve an at least additive effect by combined use of potassium channel openers and protein kinase C inhibitors.
  • a batch of 100 ml was obtained by mixing 0.3% (w/w) procyanidin B2, 2.0% (w/w) minoxidil, 70% (w/w) ethanol, 10% (w/w) 1,3-butylene glycol and 18% (w/w) purified water was mixed and stirred at room temperature to obtain a clear reddish-brown solution.
  • Example 3
  • a second composition comprising one or more potassium channel openers and a third composition comprising one or more protein kinase C inhibitors, said first and second compositions to be used in combination for inducing and/or stimulating hair growth and/or reducing hair loss.
  • Said second and third compositions are manufactured essentially according to Examples 1, 2 or 3.
  • Said second and third compositions may be administered in many different dosage regimes, e g concomitantly or irrespective of one another. For example a patient may administer one dose from each composition in the morning and one dose from each composition in the evening. Alternatively a patient may administer one dose from the second composition in the morning and one dose from the third composition in the evening. Also other regimes are envisageable, such as different number of doses per day for the second and the third composition respectively. The most suitable administration regime depends on the factual therapeutic situation.
  • the quantitative determination of minoxidil was performed by means of a HPLC method using a column (Symmetry ), C18, 3.5 ⁇ m, 100 A, 150 x 4.6 mm and a water/ methanol/glacial acid (30/70/1) mobile phase with 3 g/1 of docusate sodium and adjusted to pH 3.0 using perchloric acetic acid.
  • the flow was 1.0 ml min. the injection volume 20 ⁇ l and detection was done at 254 nm using an UN-detector.
  • procyanidin B2 was performed by means of a HPLC method using a column (Symmetry ), C18, 3.5 ⁇ m, 100 A, 150 x 4.6 mm and a water/ acetonitrile/glacial acid (93:5.2) mobile phase. The flow was 1.0 ml/min. the injection volume 10 ⁇ l and detection was done at 280 nm using an UV-detector.
  • Example 7 Stability of Solution 1 and Solution 2 is disclosed below in Table 1 and Table 2 respectively.
  • the stumptail macaque monkey is used for testing effect of the substances on hair growth.
  • This species show general androgenetic alopecia of the frontal area of the scalp already from the age of two years and has been shown to respond with hair growth to both topical minoxidil and oral finasteride.
  • mice stumptail macaque monkeys are the most universal model animals in this therapeutic area responding both to hormonal and non-hormonal hair growth promoting substances.
  • a one square inch test area is marked by tattooing dots at the corners of the square. At baseline the test area is shaved and after each month for 4 months the test area is shaved and the weight of the hair is measured. The hair weight is a measure of hair growth.
  • the monkeys are studied in three groups with at least 5 animals in each group. The products tested in the three arms are a) 5% topical minoxidil, b) 1% topical procyanidin B2, c) a mixture of 5% minoxidil and 1% procyanidin B2 manufactured in the same way as Solution 1 of Example 1.

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Abstract

L'invention concerne de nouvelles compositions comprenant un ou plusieurs activateurs de canaux potassiques, tels que le minoxidil, et un ou plusieurs inhibiteurs de la protéine kinase C, tels que la procyanidine B2. L'invention concerne en outre des procédés permettant d'utiliser lesdites compositions pour traiter ou prévenir l'alopécie sur une zone corporelle d'un patient.
PCT/SE2002/000105 2001-02-07 2002-01-23 Nouvelles compositions d'activateurs de canaux potassiques et inhibiteurs de la proteine kinase c et leur utilisation Ceased WO2002062422A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2002562427A JP2004518701A (ja) 2001-02-07 2002-01-23 カリウムチャネル開口薬およびプロテインキナーゼｃ阻害薬の新規な組成物ならびにそれらの使用
EP02715944A EP1357974A1 (fr) 2001-02-07 2002-01-23 Nouvelles compositions d'activateurs de canaux potassiques et inhibiteurs de la proteine kinase c et leur utilisation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE0100374A SE0100374D0 (sv) 2001-02-07 2001-02-07 Novel compositions of potassium channel openers and protein kinase c inhibitors and use thereof
SE0100374-8 2001-02-07

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WO2002062422A1 true WO2002062422A1 (fr) 2002-08-15

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EP (1) EP1357974A1 (fr)
JP (1) JP2004518701A (fr)
SE (1) SE0100374D0 (fr)
WO (1) WO2002062422A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004033448A3 (fr) * 2002-10-11 2004-06-03 Proteotech Inc Isolation, purification et synthese de procyanidine b2, et ses utilisations
EP1921076A1 (fr) * 2002-10-11 2008-05-14 Proteotech Inc. synthèse de procyanidine B2
US7514583B2 (en) 2002-05-31 2009-04-07 Proteotech, Inc. Compounds, compositions and methods for the treatment of amyloid diseases and synucleinopathies such as alzheimer's disease, type 2 diabetes, and parkinson's disease
US8754133B2 (en) 2001-11-02 2014-06-17 Proteotech, Inc. Compounds, compositions and methods for the treatment of inflammatory diseases

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012504135A (ja) * 2008-09-27 2012-02-16 ジャイナ ファーマシューティカルズ，インコーポレーテッド 経口適用および局所適用のための脂質系薬学的調製物、ならびにそれらの組成物、方法、および使用

Citations (5)

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US4596812A (en) * 1976-05-24 1986-06-24 The Upjohn Company Methods and solutions for treating male pattern alopecia
US5578599A (en) * 1990-08-10 1996-11-26 The Upjohn Company Stimulation of hair growth with minoxidil and a 5α-reductase inhibitor
EP0797978A2 (fr) * 1996-03-29 1997-10-01 Kyowa Hakko Kogyo Co., Ltd. Composition pour la croissance des cheveux contenant un inhibiteur de la protéine-kinase C
US5907038A (en) * 1995-07-05 1999-05-25 Hoffmann-La Roche Inc. Azepanes
US5914406A (en) * 1994-01-12 1999-06-22 Hoffman-La Roche Inc. Azepanes and their ring homologues having protein kinase inhibiting activity

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US6126940A (en) * 1994-06-30 2000-10-03 Kyowa Hakko Kogyo Co., Ltd. Hair-growing agent comprised of proanthocyanidins

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US4596812A (en) * 1976-05-24 1986-06-24 The Upjohn Company Methods and solutions for treating male pattern alopecia
US5578599A (en) * 1990-08-10 1996-11-26 The Upjohn Company Stimulation of hair growth with minoxidil and a 5α-reductase inhibitor
US5914406A (en) * 1994-01-12 1999-06-22 Hoffman-La Roche Inc. Azepanes and their ring homologues having protein kinase inhibiting activity
US5907038A (en) * 1995-07-05 1999-05-25 Hoffmann-La Roche Inc. Azepanes
US6136969A (en) * 1995-07-05 2000-10-24 Hoffmann-La Roche Inc. Azepanes
EP0797978A2 (fr) * 1996-03-29 1997-10-01 Kyowa Hakko Kogyo Co., Ltd. Composition pour la croissance des cheveux contenant un inhibiteur de la protéine-kinase C

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Title
HARMON CHARLES S. ET AL.: "Bisindolylmaleimidine protein-kinase-C inhibitors delay the decline in DNA dynthesis in mouse hair follicle organ cultures", SKIN PHARMACOL., vol. 10, 1997, pages 71 - 78, XP002968012 *
TOMOYA TAKAHASHI ET AL.: "Proanthocyanidins from grape seeds promote proliferation of mouse hair follicle cells in vitro and convert hair cycle in vivo", ACTA DERM. VENEREOL., vol. 78, 1998, STOCKHOLM, pages 428 - 432, XP009002006 *
TOMOYA TAKAHASHI ET AL.: "Several selective protein kinase C inhibitors including procyanidins promote hair growth", SKIN PHARMACOL. APPL. SKIN PHYSIOL., vol. 13, 2000, pages 133 - 142, XP009001663 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8754133B2 (en) 2001-11-02 2014-06-17 Proteotech, Inc. Compounds, compositions and methods for the treatment of inflammatory diseases
US7514583B2 (en) 2002-05-31 2009-04-07 Proteotech, Inc. Compounds, compositions and methods for the treatment of amyloid diseases and synucleinopathies such as alzheimer's disease, type 2 diabetes, and parkinson's disease
US8163957B2 (en) 2002-05-31 2012-04-24 Proteotech, Inc. Compounds, compositions and methods for the treatment of amyloid diseases and synucleinopathies such as alzheimer's disease, type 2 diabetes and parkinson's disease
WO2004033448A3 (fr) * 2002-10-11 2004-06-03 Proteotech Inc Isolation, purification et synthese de procyanidine b2, et ses utilisations
EP1921076A1 (fr) * 2002-10-11 2008-05-14 Proteotech Inc. synthèse de procyanidine B2

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SE0100374D0 (sv) 2001-02-07
EP1357974A1 (fr) 2003-11-05
JP2004518701A (ja) 2004-06-24

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