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EP0468969A1 - Anti-angiogenique topique a usage d'inhibiteur de croissance capillaire - Google Patents

Anti-angiogenique topique a usage d'inhibiteur de croissance capillaire

Info

Publication number
EP0468969A1
EP0468969A1 EP90903703A EP90903703A EP0468969A1 EP 0468969 A1 EP0468969 A1 EP 0468969A1 EP 90903703 A EP90903703 A EP 90903703A EP 90903703 A EP90903703 A EP 90903703A EP 0468969 A1 EP0468969 A1 EP 0468969A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
composition
formula
aryl
compound
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.)
Withdrawn
Application number
EP90903703A
Other languages
German (de)
English (en)
Inventor
J. Michael Holland
Duane B. Lakings
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.)
Pharmacia and Upjohn Co
Original Assignee
Upjohn Co
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
Application filed by Upjohn Co filed Critical Upjohn Co
Publication of EP0468969A1 publication Critical patent/EP0468969A1/fr
Withdrawn legal-status Critical Current

Links

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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • 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
    • A61K8/63—Steroids; Derivatives thereof
    • 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
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00—Preparations for affecting hair growth
    • A61Q7/02—Preparations for inhibiting or slowing hair growth

Definitions

  • the present invention is a method for inhibiting hair growth through the use of angiostatic steroids.
  • the angiostatic steroid is used in an anti-angiogenesis effective amount.
  • Angiogenesis is the development of blood vessels which typically would lead to a vascular bed capable of sustaining viable tissue. Angiogenesis is a necessary process in the establishment of embryonic tissue and development of a viable embryo. Similarly angiogenesis is a necessary step in the establishment and development of tumor tissue as well as certain inflammatory conditions. The inhibition of angiogenesis is therefore useful in the control of embryogenesis, inflammatory conditions, and tumor growth, as well as numerous other conditions.
  • the present invention demonstrates that conversion of a hair follicle from its resting (telogen) into its active (anagen) state can be inhibited by the topical application of angiostatic steroids.
  • telogen resting
  • anagen active
  • One possible explanation is that the conversion of a follicle from the telogen to anagen state required for hair growth is not initiated or possibly that hair growth is stopped in active hair follicles when capillary neogenesis is inhibited.
  • U.S. Patent 4,771,042 describes a novel class of solution stable non-glucocorticoid steroids (angiostatics) which are useful in the inhibition of angiogenesis.
  • the present invention is a method for preventing hair growth through the use of topical angiostatic steroids.
  • the method of the present invention utilizes angiostatic steroids of general Formula I (see Formula Chart) wherein the various substitutions have the following meanings:
  • R 1 is CH 3 or C 2 H 5 ;
  • R 2 is H and R 3 is in the ⁇ -position and is -OH, -O-alkyl(C 1 -C 1 2 ), -O-COalkyl(C 1 -C 12 ), -O-COaryl, -O-CON(R) 2 , or OCOOR 7 wherein aryl is phenyl wherein f is 0 to 2 and wherein the phenyl ring is -(exceptionally substituted with from 1 to 3 groups selected from Cl, F, Br, alkyl(C 1 -C 3 ), alkoxy(C 1 -C 3 ), thioalkoxy(C 1 -C 3 ), i.e., -S-alkyl-(C 1 -C 3 ) , CI 3 C-, F 3 C, NH2' and -NHCOCH 3 , i.e., acetamido, or aryl is furyl, thienyl, pyrrolyl or pyridy
  • R 2 is ⁇ -Cl and R 3 is ⁇ -Cl;
  • R 2 and R 3 taken together form an oxygen (-O-) bridging positions C-9 and C-11; or
  • R 2 and R 3 taken together form a second or a double bond between positions C-9 and C-11;
  • R 4 is H, CH 3 , Cl or F
  • R 5 is H, OH, F, Cl, Br, CH 3 , phenyl, vinyl or allyl;
  • R 6 is H or CH 3 ;
  • R 9 is H, OH, CH 3 , F or -CH 2 ;
  • R 10 is H, OH, CH 3 or R 10 forms a second or double bond between positions C-16 and C-17.
  • the present invention provides a method of inhibiting hair growth in mammals and more preferably in a humans which comprises the topical administration of a composition comprising an angiostatic steroid of Formula I.
  • the compound of Formula I is present in an anti-angiostatic effective amount, preferably at least 1 mg/ml or from about 1 mg/ml to about 10 mg/ml.
  • the present invention is directed toward a method for preventing hair growth by the topical administration of an effective amount of an angiostatic steroid.
  • the angiostatic steroid is present in an anti-angiogenic "effective amount" which is an amount effective to prevent the development of capillary blood vessels in the hair follicle.
  • This method provides an easy means to prevent hair growth in a hair follicle of a mammal including humans .
  • the method is effective as long as the topical administration is continued and therefore discontinued use will allow normal hair regrowth.
  • Medical indications include hereditary and acquired hyper- trichotic disorders such as hypertrichosis lanuginosa, virilizing and nonvirilizing hirsutism and postmenopausal hypertrichosis. Cosmetic indications would appear to be almost limitless, restricted only by safety and efficacy considerations.
  • R 1 through R 4 and R 6 are hydrogen, R 5 is fluorine, R 9 is methyl and R 10 is hydroxyl.
  • R 1 is alkyl(C 1 - -C 3 ), preferably CH 3 or C 2 H 5 ;
  • R 5 is CH 3 , F, Cl, Br, H or OH, and more preferably R 5 is in the ⁇ -position and is CH 3 , H or F;
  • R 6 is H or CH 3 and more preferably is H;
  • R 9 is H, ⁇ -OH or CH 3 ; and R 10 is ⁇ -H or ⁇ -OH.
  • R 2 is hydrogen and R 3 is in the ⁇ - position and is OH, -O-alkyl(C 1 -C 12 ), preferably -O-alkyl/(C 1 -C 4 ), -O-COalkyl(C 1 -C 12 ), preferably -O-COalkyl(C 1 -C 6 ), -O-COaryl, -0-CON(R)2 or -OCOOR 7 wherein aryl, R, and R 7 have the meanings defined in Formula I and preferably aryl is phenyl and R is hydrogen or methyl.
  • the wavy bond means the group represented by R 5 may be in the alpha or beta position.
  • the aryl moiety in the R 3 group -OCOaryl is attached to the carbonyloxy moiety through any of the available ring carbon atoms of said aryl moiety.
  • Any reference herein to compounds of Formula I includes pharmacologically acceptable salts thereof.
  • the steroids of Formula I-VI are topically administered to an area on the body where hair growth is to be inhibited.
  • the topical administration of the angiostatic steroid composition is typically done by routine applications to the hair follicles where hair growth is undesirable.
  • the angiostatic steroid is generally present in an amount effective to have an anti- angiostatic result, preferably at least 1 mg/ml or from about 1 mg/ml to about 10 mg/ml.
  • the dosage is, of course, dependent upon the circumstance of treatment and particular mammal treated which can be readily determined.
  • Sterile aqueous solutions of the compounds of Formula I typically will contain other components such as preservatives, anti-oxidants, chelating agents, or other stabilizers.
  • Suitable preservatives can include benzyl alcohol, the parabens, benzalkonium chloride, or benzoic acid.
  • Anti-oxidants such as sodium bisulfite, ascorbic acid, propyl 3,4,5-trihydroxy benzoate, and the like may be employed.
  • Chelating agents such as citrate, tartrate, or ethylenediaminetetraacetic acid (EDTA) may be vised.
  • Other additives useful as stabilizers of corticosteroid prodrugs e.g., creatinine, polysorbate 80, and the like
  • Sterile aqueous solutions of compounds of Formula I can be administered to the patent being treated, or various topical formulations can be prepared.
  • Typical topical compositions include those pharmaceutical forms in which can be applied externally by direct contact with the surface to be treated.
  • Conventional pharmaceutical forms for this purpose include ointments, waxes, lotions, pastes, jellies, sprays, aerosols, and the like in aqueous or nonaqueous formulations.
  • the term "ointment” embraces formulations (including creams) having oleaginous, absorption, water-soluble and emulsion-type bases, e.g., petrolattim, lanolin, polyethylene glycols, as well as mixtures of these.
  • the composition can be applied to the area to be treated, such as the scalp, face, arms, legs or other areas where hair growth is undesirable, by spraying, dabbing or swabbing. Other less specific methods can be employed provided the active ingredient, angiostatic steroid is delivered to the region of the hair follicle.
  • the composition is periodically applied to the treatment area on a routine basis prior to , during and subsequent to the inhibitions of hair growth.
  • the routine treatment would be to apply the composition at least daily, preferably twice daily. When hair growth is desired the treatment can be discontinued.
  • the compounds of Formula I are known in the art or are prepared by procedures known in the art, such as described in U.S. Patent 4,771,042 herein incorporated by reference.
  • Illustrative examples of the compounds of Formula I include: 17 ⁇ ,21-dihydroxy-4,9(11)pregnadiene-3 , 20-dione; 6 ⁇ -methylcortisone;
  • the compound selected from Formula I was 6 ⁇ -fluoro-17 ⁇ -hydroxy-21-hydroxy-160-methylpregna-4,9(11)-diene-- 3,20-dione (Formula I wherein R 1 through R 4 and R 6 are hydrogen, R 5 is fluorine, R 9 is methyl and R 10 is hydroxyl).
  • This compound was topically applied to the mouse's shaved back once daily, commencing at 22 days of age and continuing through 35 days of age, an interval corresponding to the first rest and second anagen in this species. Control groups received either the vehicle or nothing.
  • the timing, extent and pattern of hair growth was evaluated subjectively and by sequential photographs. A treatment related inhibition of hair growth was observed that corresponded with the area of drug applica tion.
  • the inhibitory effect occurred without clinical evidence of dermatitis, suggesting that inhibition was follicle specific and not due to local or systemic toxicity.
  • the effect was fully reversible, in that with cessation of treatment, follicles slowly entered anagen from skin areas that had been previously without visible hair growth.
  • Example 2 A study was conducted as in Example 1, using varying amounts of 6 ⁇ -fluoro-17 ⁇ -hydroxy-21-hydroxy-16 ⁇ -methylpregna-4,9(11)-diene-- 3,20-dione. The results are shown in Table 1 which scores the mice each day for evidence of hair growth on the treated area. The scores are number of mice in group with regrowth in treatment area per number of mice in treatment group.
  • Example 2 Since the study in Example 2 showed hair inhibition at all levels a similar study was conducted to determine a minimum dosage. The same compound was evaluated and the results are shown in Table 2.
  • Example 2 The same hair growth study as used in Example 1 was employed to compare three steroid compounds. Two compounds were selected from

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Birds (AREA)
  • Steroid Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Cosmetics (AREA)

Abstract

Est décrit un procédé pour inhiber la croissance capillaire chez des mammifères, qui comporte l'administration topique d'une composition renfermant une quantité efficace anti-angiogénique d'un composé angiostatique de formule (I). Ce composé est présent dans une quantité d'au moins 1 mg/ml, de préférence comprise entre environ 1 mg/ml et environ 10 mg/ml.
EP90903703A 1989-04-18 1990-02-20 Anti-angiogenique topique a usage d'inhibiteur de croissance capillaire Withdrawn EP0468969A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US33983689A 1989-04-18 1989-04-18
US339836 1989-04-18

Publications (1)

Publication Number Publication Date
EP0468969A1 true EP0468969A1 (fr) 1992-02-05

Family

ID=23330825

Family Applications (1)

Application Number Title Priority Date Filing Date
EP90903703A Withdrawn EP0468969A1 (fr) 1989-04-18 1990-02-20 Anti-angiogenique topique a usage d'inhibiteur de croissance capillaire

Country Status (5)

Country Link
EP (1) EP0468969A1 (fr)
JP (1) JPH04504572A (fr)
KR (1) KR920700035A (fr)
AU (1) AU5154990A (fr)
WO (1) WO1990012577A2 (fr)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4063868B2 (ja) * 1995-02-28 2008-03-19 ザ ジレット カンパニー 毛髪成長を抑制するための脈管形成抑制剤の使用
US6596703B1 (en) 1997-07-11 2003-07-22 Jagotec Ag Promotion of wound healing utilizing steroids having reduced deteriorous systemic side effects typical of glucocorticoids, mineralocorticoids and sex steroids
FR2872040B1 (fr) * 2004-06-23 2006-09-22 Centre Nat Rech Scient Cnrse Utilisation cosmetique d'au moins un tetrapeptide naturel ac-n-ser-asp-lys-pro- ou un de ses analogues en tant qu'agent antivieillissement et restructurant de la peau
EP1726297B1 (fr) * 2005-05-23 2010-08-18 Reckitt Benckiser (UK) Limited Composition comprenant de la wortmannine et son utilisation pour inhiber la croissance capillaire
BRPI0909564B8 (pt) 2008-05-28 2021-05-25 Reveragen Biopharma Inc uso de um composto
WO2011127048A2 (fr) 2010-04-05 2011-10-13 Validus Biopharma MODULATEURS STÉROÏDES NON HORMONAUX DE NF-ĸB POUR LE TRAITEMENT DE MALADIES
WO2017004205A1 (fr) 2015-06-29 2017-01-05 Reveragen Biopharma, Inc. Modulateurs stéroïdiens non hormonaux de nf-κb pour le traitement de maladies
US11382922B2 (en) 2019-03-07 2022-07-12 Reveragen Biopharma, Inc. Aqueous oral pharmaceutical suspension compositions

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9012577A2 *

Also Published As

Publication number Publication date
KR920700035A (ko) 1992-02-19
AU5154990A (en) 1990-11-16
JPH04504572A (ja) 1992-08-13
WO1990012577A2 (fr) 1990-11-01
WO1990012577A3 (fr) 1992-03-19

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