WO2000072813A1 - Methode de traitement de la perte des cheveux a l'aide de derives de diphenylmethane - Google Patents

Methode de traitement de la perte des cheveux a l'aide de derives de diphenylmethane Download PDF

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Publication number
WO2000072813A1
WO2000072813A1 PCT/US2000/005254 US0005254W WO0072813A1 WO 2000072813 A1 WO2000072813 A1 WO 2000072813A1 US 0005254 W US0005254 W US 0005254W WO 0072813 A1 WO0072813 A1 WO 0072813A1
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Prior art keywords
hydrogen
compound
group
compounds
lower alkyl
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PCT/US2000/005254
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English (en)
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Lixin Lilly Zhang
Robert Scott Youngquist
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The University Of Texas Southwestern Medical Center
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Priority to MXPA01012495A priority Critical patent/MXPA01012495A/es
Priority to AU35078/00A priority patent/AU3507800A/en
Priority to CA002374266A priority patent/CA2374266A1/fr
Priority to JP2000620925A priority patent/JP2003500433A/ja
Priority to US09/980,407 priority patent/US6680344B1/en
Priority to EP00913678A priority patent/EP1185231A1/fr
Publication of WO2000072813A1 publication Critical patent/WO2000072813A1/fr

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    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/36—Carboxylic acids; Salts or anhydrides 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
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • 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

Definitions

  • the present invention relates to methods for treating hair loss in mammals, including arresting and / or reversing hair loss and promoting hair growth
  • Hair loss is a common problem which occurs, for example, through natural processes or is often chemically promoted through the use of certain therapeutic drugs designed to alleviate conditions such as cancer. Often such hair loss is accompanied by lack of hair regrowth which causes partial or full baldness.
  • hair growth occurs by a cycle of activity which involves alternating periods of growth and rest. This cycle is often divided into three mam stages which are known as anagen, catagen, and telogen. Anagen is the growth phase of the cycle and may be characte ⁇ zed by penetration of the hair follicle deep into the dermis with rapid proliferation of cells which are differentiating to form hair The next phase is catagen, which is a transitional stage marked by the cessation of cell division, and during which the hair follicle regresses through the dermis and hair growth is ceased.
  • anagen is the growth phase of the cycle and may be characte ⁇ zed by penetration of the hair follicle deep into the dermis with rapid proliferation of cells which are differentiating to form hair
  • catagen is a transitional stage marked by the cessation of cell division, and during which the hair follicle regresses through the dermis and hair growth is ceased.
  • telogen is often characte ⁇ zed as the resting stage during which the regressed follicle contains a germ with tightly packed dermal papilla cells.
  • the initiation of a new anagen phase is caused by rapid cell proliferation m the germ, expansion of the dermal papilla, and elaboration of basement membrane components.
  • hair growth ceases, most of the hair follicles reside m telogen and anagen is not engaged, thus causing the onset of full or partial baldness.
  • T4 thyroid hormone
  • T3 thyronme
  • Selenium deficiency causes a decrease in T3 levels due to a decrease in deiodmase I activity; this reduction in T3 levels is strongly associated with hair loss
  • hair growth is a reported side effect of administration of T4. See, e.g.. Berman. "Peripheral Effects of L-Thyroxme on Hair Growth and Coloration in Cattle", Journal of Endocrinology, Vol. 20, pp. 282 - 292 (1960); and Gunaratnam.
  • T3 and T4 have been the subject of several patent publications relating to treatment of hair loss. See, e.g.. Fischer et al.. DE 1,617,477, published January 8, 1970; Mortimer. GB 2,138,286, published October 24, 1984; and Lmdenbaum. WO 96/25943, assigned to Life Medical Sciences, Inc., published August 29, 1996.
  • T3 and / or T4 to treat hair loss is not practicable because these thyroid hormones are also known to induce significant cardiotoxicity.
  • U.S. Patent No. 5,284,971 assigned to Syntex, issued February 8, 1994
  • Emmett et al. assigned to Smith Kline & French Laboratories, issued October 29, 1991.
  • the present inventors have discovered compounds which promote hair growth without inducing cardiotoxicity.
  • the present inventors have surpnsmgly discovered that the compounds useful in the present invention interact strongly with hair- selective thyroid hormone receptors but interact less strongly, or not at all, with heart-selective hormone receptors. These unique properties are, of course, not shared with T3 and / or T4. Accordingly, the compounds described for use in the methods and compositions herein are cardiac-sparmg compounds useful for treating hair loss, including arresting and / or reversing hair loss and promoting hair growth.
  • the present invention relates to methods for treating hair loss comprising admmiste ⁇ ng a compound which has been found by the present inventors to be particularly useful for treating hair loss m mammals, including arresting and / or reversing hair loss and promoting hair growth.
  • the compounds utilized in the present method have the structure:
  • the present invention relates to methods of using compounds and compositions which are particularly useful for treating hair loss mammals, including arresting and / or reversing hair loss and promoting hair growth
  • the present inventors have also surprisingly discovered that the preferred compounds are cardiac-sparing
  • the preferred compounds useful in the method of the present invention are therefore, as defined herein below, cardiac-sparmg.
  • any va ⁇ able, moiety, group, or the like occurs more than one time m any va ⁇ able or structure, its definition at each occurrence is independent of its definition at every other occurrence.
  • acyl refers to the group -C(0)R, where R is lower alkyl or cycloalkyl, for example, acetyl, propionyl, cyclopropionyl, butanoyl, and the like.
  • alkoxy is an oxygen radical having an alkyl substituent.
  • alkoxy radicals include -O-methyl and -O-ethyl.
  • alkyl is a saturated, straight or branched chain monovalent hydrocarbon radical. Unless otherwise specified, alkyls have from 1 to about 8 carbon atoms (Ci - C 8 ). Preferred alkyls include, for example, methyl, ethyl, propyl, zso-propyl, tert-butyl, w-butyl, sec-butyl, wo-butyl, n-hexyl, and w-octyl.
  • aryl refers to a monovalent unsaturated aromatic carbocychc radical having a single ⁇ ng (e g , phenyl) or two rings (e g , naphthyl or biphenyl), which may optionally be mono-, di-, or tri-substituted, independently, with hydroxy, -COOH, lower alkyl, lower alkoxy, nitro, amino, alkylamino, dialkylamino, trifluoromethyl, and / or cyano.
  • biohydrolyzable amides are amides of the compounds used in the present invention which do not interfere with the activity of the compound, or that are readily converted in vivo by a mammalian subject to yield an active compound.
  • biohydrolyzable esters are esters of the compounds used in the present invention which do not interfere with the activity of the compound, or that are readily converted in vivo by a mammalian subject to yield an active compound.
  • biohydrolyzable imides are imides of the compounds used in the present invention which do not interfere with the activity of the compound, or that are readily converted in vivo by a mammalian subject to yield an active compound.
  • cycloalkyl is a monovalent monocyclic hydrocarbon radical having from three to eight carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • halogen refers to chlorine, bromine, iodine, and fluorine, preferably chlorine, bromine, and iodine, more preferably chlorine and iodine, and most preferably iodine.
  • heteroaryl refers to a monovalent aromatic carbocyclic radical having from 1 to 3 heteroatoms within a single ring, (e.g., pyridyl, imidazolyl, thiazolyl, pyrimidine, oxazolyl, and the like), which may optionally be mono-, di-, or tri-substituted, independently, with hydroxy, -COOH, lower alkyl, lower alkoxy, nitro, amino, alkylamino, dialkylamino, trifluoromethyl, and / or cyano.
  • lower alkoxy means the group -OJlower alkyl) wherein lower alkyl is as defined herein.
  • lower alkyl refers to an alkyl radical having from 1 to 6 carbon atoms (Cj - C 6 ), such as, for example, methyl, ethyl, propyl, ⁇ o-propyl, tert-butyl, butyl, w-hexyl, and the like, unless otherwise indicated.
  • pharmaceutically acceptable means suitable for use in a human or other mammal.
  • safe and effective amount of a compound means an amount that is effective to exhibit biological activity, preferably wherein the biological activity is arresting and / or reversing hair loss or promoting hair growth, at the site(s) of activity in a mammalian subject, without undue adverse side effects (such as toxicity, irritation, or allergic response), commensurate with a reasonable benefit / risk ratio when used in the manner of this invention.
  • salt is a catiomc salt formed at any acidic (e g , carboxyl) group, or an amonic salt formed at any basic (e g , ammo) group Many such salts are known in the art.
  • Preferred catiomc salts include the alkali metal salts (such as, for example, sodium and potassium), alkaline earth metal salts (such as, for example, magnesium and calcium), and organic salts.
  • Preferred amonic salts include the hahdes (such as, for example, chloride salts). Such acceptable salts must, when administered, be appropriate for mammalian use.
  • the present invention relates to methods of treating hair loss comp ⁇ smg administering a composition comprising a compound having the structure:
  • n is an integer from 1 to 3;
  • R] and R 2 are each, independently, selected from hydrogen and lower alkyl; or wherein Ri is hydrogen and R 2 is hydroxy; or wherein R x is doubly-bonded oxygen and R 2 is nil; or wherein R[ is doubly-bonded sulfur and R 2 is ml;
  • (c) t is selected from hydrogen, lower alkyl, and cycloalkyl
  • Re and R 9 are each, independently, selected from hydrogen and lower alkyl
  • R ⁇ and Rg are each, independently, selected from hydrogen, lower alkyl, optionally substituted phenyl, optionally substituted benzyl, and heteroaryl; wherein at least one of R 7 and R 8 is not hydrogen;
  • (f) Rio is selected from hydrogen, lower alkyl, cycloalkyl, and acyl;
  • R ⁇ is selected from hydrogen, lower alkyl, and cycloalkyl.
  • the compounds useful m the present invention are dimethyl-substituted biphenyl compounds linked through a carbon atom linker, wherein the linker is optionally substituted with Ri and / or R 2 .
  • Each of the phenyl rings of the biphenyl compound are substituted with at least one moiety, as is described below.
  • Ri is selected from methyl, hydrogen, and doubly-bonded oxygen.
  • R 2 is selected from methyl and hydrogen More preferably, at least one of R] and R 2 is hydrogen. Most preferably, Rj and R 2 are each hydrogen.
  • R 4 may substitute at any available position on the designated phenyl ⁇ ng.
  • R is selected from hydrogen, lower alkyl, and cycloalkyl
  • R 4 is hydrogen.
  • Re and R 9 are each, independently, selected from hydrogen and lower alkyl.
  • Re and R 9 are each, independently, selected from hydrogen and n-butyl. More preferably, at least one of Re and R 9 is hydrogen. Most preferably Re and R 9 are each hydrogen.
  • R 7 and R 8 are each, independently, selected from hydrogen, lower alkyl, optionally substituted phenyl, optionally substituted benzyl, and heteroaryl; wherein at least one of R 7 and R 8 is not hydrogen.
  • R 7 and R 8 are each, independently, selected from hydrogen and zso-propyl. More preferably, R 7 is hydrogen and R 8 is ⁇ o-propyl.
  • R] 0 is selected from hydrogen, lower alkyl, cycloalkyl, and acyl.
  • Preferably Rio is selected from hydrogen and lower alkyl, preferably hydrogen and methyl. Most preferably, Rio is hydrogen.
  • the Integer n is selected from hydrogen, lower alkyl, cycloalkyl, and acyl.
  • Preferably Rio is selected from hydrogen and lower alkyl, preferably hydrogen and methyl. Most preferably, Rio is hydrogen.
  • the integer n determines the number of methylene groups m the respective moiety
  • the integer n is from 1 to 3, and is most preferably 1
  • R ⁇ moiety is selected from hydrogen, lower alkyl, and cycloalkyl
  • Rn is selected from hydrogen and lower alkyl
  • Rj is hydrogen
  • the present invention relates to methods of treating hair loss by admmistenng a compound having a structure as described herein.
  • the compound utilized in the present invention will be cardiac-sparmg
  • Compounds test compounds
  • cardiac-sparmg cardiac-sparmg
  • other methods well-known in the art may be used (but with the term "cardiac-sparing" being defined according to the method disclosed herein below).
  • the cardiotoxicity assay measures the potential of a test compound to adversely affect the cardiovascular system As thyroid hormone (T3) damages the cardiovascular system, the heart enlarges.
  • thyroid hormone T3 damages the cardiovascular system
  • the heart enlarges.
  • T3 thyroid hormone
  • the cardiotoxicity assay herein below is used to test compounds for potentially adverse cardiac effects by measuring their effect on the heart-to-body weight ratio.
  • the first group is a vehicle control group and the second group is a test compound group.
  • the length of the assay is 30 days, with treatment of vehicle or test compound in vehicle daily for 28 of those days as described below Prior to initiation of the assay, each rat is allowed to acclimate to standard environmental conditions for 5 days. Each rat receives food (standard rat chow diet) and water ad libitum 5 days prior to initiation of the assay as well as to termination of the study.
  • the vehicle is 91 :9 (v:v) propylene glycohethanol
  • the test compound is prepared at a concentration of 500 ⁇ g/mL in the vehicle
  • each rat is weighed on day 1 of the assay. Dosage calculations are then performed: each rat will be administered daily a dosing solution of vehicle or test compound m vehicle (depending on whether the rat is in the vehicle control group or the test compound group, respectively) at 500 ⁇ L of dosing solution per kg of rat. For rats in the test compound group, this corresponds to a dose of 250 ⁇ g of test compound per kg of rat.
  • Day 2 is the first day of treatment with dosmg solution for both groups. Body weights are taken for each rat on days 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26, and 29 prior to dosing for that day; for each rat, the dosing solutions are recalculated and administered accordingly upon change m body weight.
  • Treatment occurs once daily in the morning on days 2 through 29, inclusive, for each rat in each group.
  • the dosmg solution is administered subcutaneously between the shoulders of the rat such that the injection sites are rotated in this area.
  • the hearts of each rat are then excised as follows. An incision is made to expose the abdominal cavity. The rib cage is carefully cut at the sternum with small scissors, such that the heart and lungs are exposed. With small scissors and forceps, the vessels connected to the heart are cut away from the heart. These vessels include the caudal vena cava, left cranial vena cava (pulmonary trunk), right cranial vena cava, thoracic aorta, right subclavian artery, internal thoracic artery and vein, and any other small attachments. The heart is then immediately taken out intact, including the left and right auricles and left and right ventricles. Immediately thereafter, any excess tissue is t ⁇ mmed away, the heart is lightly blotted on a paper towel until no more blood is visibly left behind on the paper towel, and the heart is weighed.
  • the heart weight is divided by the body weight after euthamzation for each rat to give the heart/body ratio.
  • the heart/body ratios for each rat in the vehicle control group are added together and divided by 6 (i e. , the total number of rats in the group) to give RV (ratio for vehicle control group).
  • RV ratio for vehicle control group
  • RT ratio for test compound group
  • the index C is then calculated by dividing RT by RV As defined herein, where C is less than 1.3, the test compound is cardiac-spa ⁇ ng.
  • C is less than 1.2, more preferably less than 1.15, and most preferably less than 1.1.
  • T3 and T4 are not cardiac-sparmg.
  • the Telogen Conversion Assay measures the potential of a test compound to convert mice in the resting stage of the hair growth cycle ("telogen"), to the growth stage of the hair growth cycle (“anagen").
  • telogen there are three principal phases of the hair growth cycle: anagen, catagen, and telogen It is believed that there is a longer telogen period m C3H mice (Harlan Sprague Dawley, Inc., Indianapolis, IN) from approximately 40 days of age until about 75 days of age, when hair growth is synchronized. It is believed that after 75 days of age, hair growth is no longer synchronized. Wherein about 40 day-old mice with dark fur (brown or black) are used in hair growth expe ⁇ ments, melanogenesis occurs along with hair (fur) growth wherein the topical application of hair growth mducers are evaluated.
  • the Telogen Conversion Assay herein below is used to screen compounds for potential hair growth by measuring melanogenesis.
  • Three groups of 44 day-old C3H mice are utilized' a vehicle control group, a positive control group, and a test compound group, wherein the test compound group is administered a compound used m the method of the present invention.
  • the length of the assay is at least 19 days with 15 treatment days (wherein the treatment days occur Mondays through Fridays).
  • Day 1 is the first day of treatment. Most studies will end on Day 19, but a few may be carried out to Day 24 if the melanogenesis response looks positive, but occurs slowly.
  • a typical study design is shown in Table 1 below. Typical dosage concentrations are set forth in Table 1, however the skilled artisan will readily understand that such concentrations may be modified.
  • the vehicle is 60% ethanol, 20% propylene glycol, and 20% dimethyl isosorbide (commercially available from Sigma Chemical Co , St. Louis, MO).
  • mice are treated topically Monday through Friday on their lower back (base of tail to the lower rib).
  • a pipettor and tip are used to deliver 400 ⁇ L to each mouse's back.
  • the 400 ⁇ L application is applied slowly while moving hair on the mouse to allow the application to reach the skin.
  • the compounds used in the methods of the present invention are prepared according to procedures which are well-known to those ordinarily skilled in the art.
  • the starting materials used m preparing the compounds are known, made by known methods, or are commercially available as a starting mate ⁇ al.
  • the compounds of the present invention may have one or more chiral centers.
  • one optical isomer including diastereomers and enantiomers
  • another optical starting materials for example by chiral starting materials, catalysts or solvents
  • both stereoisomers or both optical isomers including diastereomers and enantiomers at once (a racemic mixture).
  • the compounds of the invention may exist as racemic mixtures, mixtures of optical isomers, including diastereomers and enantiomers, may be separated using known methods, such as through the use of, for example, chiral salts and chiral chromatography.
  • one optical isomer including a diastereomer and enantiomer, or a stereoisomer
  • both optical isomers including diastereomers and enantiomers, or stereoisomers substantially free of the other are disclosed and claimed as well.
  • syntheses of the compounds useful in the present invention are described m the art. Accordingly, the ordinarily stalled artisan will be able to prepare the compounds desc ⁇ bed herein.
  • the syntheses of the present compounds are desc ⁇ bed m Scanlan et al., WO 98/57919, assigned to The Regents of the University of California, published December 23, 1998 and Scanlan et al..
  • U.S. Patent No. 5,883,294 assigned to The Regents of the University of California, issued March 16, 1999.
  • non-hmitmg syntheses of the compounds used herein are set forth m the examples below.
  • phenol of Formula 1 is protected by conversion to, for example, the methoxy derivative, for example by reacting 1 with methyl iodide m the presence of a base such as, for example, potassium carbonate, a polar solvent such as N,N-d ⁇ methylformam ⁇ de (DMF)
  • a base such as, for example, potassium carbonate
  • a polar solvent such as N,N-d ⁇ methylformam ⁇ de (DMF)
  • DMF N,N-d ⁇ methylformam ⁇ de
  • other protecting groups may be utilized instead of methoxy such as, for example, a silyl protecting group (e g , tert-butyldimethylsilyloxy)
  • the compound of Formula 2 may be brommated using potassium bromide m the presence of a crown ether such as, for example, 18-Crown-6, and an oxidizing agent such as, for example, 3-chloroperoxy benzoic acid
  • a crown ether such as, for example, 18-Crown-6
  • an oxidizing agent such as, for example, 3-chloroperoxy benzoic acid
  • the reaction is carried out in an inert solvent such as, for example, dichloromethane
  • the 4-bromo derivative of Formula 3 is isolated and purified by conventional means such as, for example, flash chromatography.
  • the bromo moiety of 5 is then converted to a formyl group.
  • the reaction is carried out conventionally, adding t-butylhthium to a solution of 5 in an inert solvent at about -78°C, preferably tetrahydrofuran (THF), and adding DMF to the cold solution After stir ⁇ ng, the mixture is allowed to warm to room temperature.
  • the 4-formyl de ⁇ vative of Formula 6 is isolated and purified by conventional means, preferably by flash chromatography.
  • Example 3 The compounds utilized in the present invention are prepared as shown below.
  • Compounds of Formula 7 are prepared by reaction of compounds 3 and 6. Generally, the p-b ⁇ omo compound 3 is dissolved in an inert solvent, preferably tetrahydrofuran, cooled to about -78 °C, and tert-butyllithium is added. The mixture is stirred for about 10 minutes and compound 6 is added. After stirring, the mixture is allowed to warm to room temperature. When the reaction is substantially complete, the compound of Formula 7 is isolated and purified by conventional means, preferably by flash chromatography. The compound of Formula 7 is then hydrogenated to remove the hydroxy group. Generally, a platinum or palladium catalyst is used, preferably palladium on carbon. The reaction is carried out m an acidic medium, preferably acetic acid in ethanol, under an atmosphere of hydrogen and room temperature and pressure. The compound of Formula 8 is isolated by conventional means, and preferably used with no further purification.
  • an inert solvent preferably tetrahydrofuran
  • tert-butyllithium is added.
  • the compound of Formula 8 is then demethylated
  • the reaction is carried out conventionally, using boron t ⁇ bromide in dichloromethane
  • the compound of Formula 9 is isolated and purified by conventional means, preferably by flash chromatography.
  • the compound of Formula 9 is converted to I wherein R 10 is hydrogen by reaction with a halo ester of formula X-(CH 2 )nC0 2 Rn, wherein X is chloro, bromo, or lodo, n is 1, 2, or 3, and Rn is lower alkyl, for example, tert-butyl.
  • the compound 9 is dissolved in an inert solvent, for example tetrahydrofuran, cooled to about -25 °C, and cesium carbonate is added followed by the halo ester. The mixture is stirred for about 1 hour, then allowed to warm to room temperature.
  • the ester of compound I is isolated and pu ⁇ fied by conventional means, preferably by flash chromatography.
  • the ester is then dissolved m a protic solvent, preferably methanol, and hydrolyzed with a base, preferably sodium hydroxide.
  • a base preferably sodium hydroxide
  • the ketones of Formula 10 are prepared from the compounds of Formula 7 by oxidation. Generally, 7 is dissolved in an inert solvent, preferably dichloromethane, cooled to about 0 °C, and an oxidizing agent such as pyridinium dichromate is added. The mixture is stirred about 4 hours and then 11 is isolated and purified by conventional means, preferably by flash chromatography.
  • an inert solvent preferably dichloromethane
  • the compound 10 is then reacted with an organo cerium complex to give 11.
  • anhydrous cerium chloride is stirred in an inert solvent, preferably tetrahydrofuran, at room temperature for about 2 hours in an inert atmosphere.
  • the resultant suspension is cooled to about -78 °C and an organolithium complex of formula RiLi is added. Stirring continues for about thirty minutes, after which time the compound 10 is added in an inert solvent, preferably tetrahydrofuran.
  • the mixture is stirred about three hours at -78 °C, and then warmed to about 0 °C.
  • the compound 11 is isolated by conventional means, preferably through column chromatography.
  • the compound 11 is then hydrogenated to the compound 12 in the same manner as shown for the conversion of 7 to 8 above
  • the compound 12 is then treated with boron t ⁇ bromide as shown above for the conversion of 8 to 9 above to give a 4 4'-d ⁇ hydroxy derivative, which is converted to a compound of Formula I as shown above for the conversion of 9 to a compound of Formula I wherein R 10 is hydrogen, by reaction with an ester of formula X(CH 2 ) n C0 2 R ⁇ .
  • the ketone 10, prepared as shown above, is treated with boron t ⁇ bromide in the same manner as shown above for the conversion of 8 to 9.
  • a mixture of compounds is obtained, a 4,4'-d ⁇ hydroxy compound 14, and a 4-hydroxy-4' -methoxy de ⁇ vative 13.
  • the 4-hydroxy-4' -de ⁇ vative 13 is then converted to a compound of Formula I wherein Rio is methyl by reaction with an ester of formula X(CH 2 ) n C0 2 R, m the same manner as shown above for the conversion of 9 to a compound of Formula I.
  • the 4,4'-d ⁇ hydroxy compound 14 when subjected to the same conditions, gives a mixture of two compounds a 4'-hydroxy-4- oxyalkanoic acid of Formula I and a 4-hydroxy-4'-oxyalkano ⁇ c acid of Formula I.
  • a compound for use m the present invention is prepared wherein Re is lower alkyl.
  • Anhydrous cerium chloride is reacted with an alkyl lithium, for example «-butylhth ⁇ um, at about room temperature m an inert solvent such as tetrahydrofuran, to obtain a lithium ce ⁇ um complex.
  • the suspension obtained is cooled to about -78 °C, and the ketone 10 (prepared as described above) is added. The reaction stirs about 3 hours at this temperature, followed by stirring about 2 hours at 0 °C.
  • the compound 15 is isolated by conventional means and is preferably purified by flash chromatography.
  • the compound 15 is treated with boron t ⁇ bromide in the same manner as shown above for the conversion of 8 to 9, to yield a 4,4'-d ⁇ hydroxy compound, which is converted to a compound of Formula I wherein ⁇ is lower alkyl by reaction with an ester of formula X(CH 2 ) n C0 2 R, in the same manner as shown above for the conversion of 9 to a compound of Formula I, to give a mixture of three compounds: a 4'-hydroxy-4-oxyalkano ⁇ c acid of Formula I, a 4-hydroxy-4'-oxyalkano ⁇ c acid of Formula I, and a 4,4'-b ⁇ s(oxyalkano ⁇ c acid) of Formula I.
  • the methods of the present invention are performed by admimste ⁇ ng to a mammal (preferably a human) a compound having a structure as described herein and, preferably, a pharmaceutically-acceptable or cosmetically-acceptable carrier.
  • the compounds herein may be used for the treatment of such conditions as treating hair loss in mammals, including arresting and / or reversing hair loss and promoting hair growth. Such conditions may manifest themselves in, for example, alopecia, including male pattern baldness and female pattern baldness.
  • the compounds of the present invention are, as defined herein, cardiac- sparmg.
  • the compounds are formulated into pharmaceutical or cosmetic compositions for use in treatment or prophylaxis of conditions such as the foregoing.
  • Standard pharmaceutical formulation techniques are used, such as those disclosed in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. (1990).
  • a compound having a structure as described herein is administered per day for systemic administration. It is understood that these dosage ranges are by way of example only, and that daily administration can be adjusted depending on various factors. The specific dosage of the compound to be administered, as well as the duration of treatment, and whether the treatment is topical or systemic are interdependent.
  • the dosage and treatment regimen will also depend upon such factors as the specific compound used, the treatment indication, the efficacy of the compound, the personal attributes of the subject (such as, for example, weight, age, sex, and medical condition of the subject), compliance with the treatment regimen, and the presence and severity of any side effects of the treatment.
  • the subject compounds are co-admmistered with a pharmaceutically-acceptable or cosmetically-acceptable carrier (herein collectively described as “earner”).
  • carrier means one or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for administration to a mammal.
  • compatible means that the components of the composition are capable of being commingled with a compound of the present invention, and with each other, in a manner such that there is no interaction which would substantially reduce the efficacy of the composition under ordinary use situations.
  • Carriers must, of course, be of sufficiently high pu ⁇ ty and sufficiently low toxicity to render them suitable for administration to the animal, preferably mammal (most preferably human), being treated.
  • the carrier can itself be inert or it can possess pharmaceutical and / or cosmetic benefits of its own.
  • compositions of this invention may be in any of a variety of forms, suitable (for example) for oral, rectal, topical, nasal, ocular or parenteral administration. Of these, topical and / or oral administration are especially preferred with topical being most preferred.
  • a variety of carriers well-known m the art may be used These include solid or liquid fillers, diluents, hydrotropes, surface-active agents, and encapsulating substances.
  • Optional pharmaceutically-active or cosmetically-active materials may be included which do not substantially interfere with the activity of the compound of the present invention.
  • the amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound.
  • substances which can serve as carriers or components thereof are sugars, such as lactose, glucose and sucrose, starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stea ⁇ c acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glyce ⁇ ne, sorbitol, manmtol, and polyethylene glycol; algmic acid; emulsifiers, such as the TWEENS; wetting agents, such sodium lauryl sulfate; colo ⁇ ng agents; flavoring agents; tabletmg agents, stabilizers; antioxidants; preservatives; pyrogen-free water;
  • the choice of a carrier to be used m conjunction with the subject compound is typically determined by the way the compound is to be administered.
  • carriers for systemic administration include sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, algmic acid, phosphate buffer solutions, emulsifiers, lsotomc saline, and pyrogen- free water.
  • Preferred earners for parenteral administration include propylene glycol, ethyl oleate, pyrrohdone, ethanol, and sesame oil.
  • the earner, in compositions for parenteral administration comprises at least about 90% by weight of the total composition.
  • oral dosage forms can be used, including such solid forms as tablets, capsules, granules and bulk powders. These oral forms comprise a safe and effective amount, usually at least about 5%, and preferably from about 25% to about 50%, of a compound used m the present invention. Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow- inducing agents, and melting agents.
  • Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents
  • Tablets typically comprise conventional pharmaceutically-compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, manmtol, lactose and cellulose; binders such as starch, gelatin and sucrose, dismtegrants such as starch, algmic acid and croscarmelose, lubricants such as magnesium stearate, stearic acid and talc Glidants such as silicon dioxide can be used to improve flow characteristics of the powder mixture Colo ⁇ ng agents, such as the FD&C dyes, can be added for appearance
  • Sweeteners and flavoring agents such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets
  • Capsules typically compnse one or more solid diluents disclosed above.
  • the selection of carrier components depends on secondary considerations like taste, cost, and
  • Orally administered compositions also include liquid solutions, emulsions, suspensions, powders, granules, elixirs, tinctures, syrups, and the like.
  • the earners suitable for preparation of such compositions are well known in the art
  • Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water
  • typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, AVICEL RC-591, tragacanth and sodium algmate
  • typical wetting agents include lecithin and polysorbate 80
  • typical preservatives include methyl paraben and sodium benzoate.
  • Peroral liquid compositions may also contain one or more components such as sweeteners, flavo ⁇ ng agents and colorants disclosed above.
  • compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that the subject compound is released in the gastrointestinal tract in the vicinity of the desired topical application, or at vanous times to extend the desired action
  • dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvmylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac.
  • compositions useful for attaining systemic delivery of the subject compounds include sublmgual, buccal and nasal dosage forms
  • Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and manmtol; and binders such as acacia, microcrystallme cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included
  • Topical compositions of the present invention may be in any form including, for example, solutions, oils, creams, ointments, gels, lotions, shampoos, leave-on and ⁇ nse-out hair conditioners, milks, cleansers, moisturizers, sprays, skm patches, and the like.
  • Topical compositions containing the active compound can be admixed with a variety of carrier materials well known in the art, such as, for example, water, alcohols, aloe vera gel, allantom, glyce ⁇ ne, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 my ⁇ styl propionate, and the like.
  • carrier materials such as, for example, water, alcohols, aloe vera gel, allantom, glyce ⁇ ne, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 my ⁇ styl propionate, and the like.
  • mate ⁇ als suitable for use in topical carriers include, for example, emollients, solvents, humectants, thickeners and powders Examples of each of these types of materials, which can be used singly or as mixtures of one or more materials, are as follows:
  • Emollients such as stearyl alcohol, glyceryl mono ⁇ cmoleate, glyceryl monostearate, propane- 1,2-d ⁇ ol, butane-l,3-d ⁇ ol, mink oil, cetyl alcohol, zso-propyl isostearate, stearic acid, iso- butyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, dimethylpolysiloxane, di-w-butyl sebacate, iso- propyl mynstate, zs ⁇ -propyl palmitate, zso-propyl stearate, butyl stearate, polyethylene glycol, t ⁇ ethylene glycol, lanolm, sesame oil, coconut oil, arachis oil
  • the compounds used m the present invention may also be administered in the form of hposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles
  • Liposomes can be formed from a variety of phosphohpids, such as cholesterol, stearylamme or phosphatidylcholmes.
  • a preferred formulation for topical delivery of the present compounds utilizes liposomes such as described in Dowton et al., "Influence of Liposomal Composition on Topical Delivery of Encapsulated Cyclosponn A- I.
  • the compounds of the present invention may also be administered by iontophoresis. See, e.g., internet site www.unipr.it arpa/dipfarm/erasmus/erasml4.html; Banga et al., "Hydrogel-based Iontotherapeutic Delivery Devices for Transdermal Delivery of Peptide/Protem Drugs", Pharm Res , Vol. 10 (5), pp. 697-702 (1993), Ferry, "Theoretical Model of Iontophoresis Utilized in Transdermal Drug Delivery", Pharmaceutical Acta Helvetiae, Vol 70, pp.
  • compositions used in the present invention may also optionally comprise an activity enhancer
  • the activity enhancer can be chosen from a wide variety of molecules which can function different ways to enhance hair growth effects of a compound of the present invention.
  • Particular classes of activity enhancers include other hair growth stimulants and penetration enhancers
  • Non-hmitmg examples of other hair growth stimulants which may be used in the compositions herein, including both systemic and topical compositions, include, for example, benzalkomum chloride, benzethomum chloride, phenol, estradiol, diphenhydramine hydrochlo ⁇ de, chlorphemramine maleate.
  • chlorophyll derivatives cholesterol, salicylic acid, cysteme, methionme, red pepper tincture, benzyl nicotmate, D,L - menthol, peppermint oil, calcium pantothenate, panthenol, castor oil, hmotatiol, predmsolone, resorcmol, monosaccha ⁇ des and este ⁇ fied monosaccha ⁇ des, chemical activators of protein tanase C enzymes, glycosaminoglycan chain cellular uptake inhibitors, inhibitors of glycosidase activity, glycosaminoglycanase inhibitors, esters of pyroglutamic acid, hexosacchanc acids or acylated hexosacchanc acids, aryl-substituted ethylenes, N-acylated ammo acids, and, of course, mmoxidil or finaste ⁇ de.
  • the most preferred activity enhancers are mmoxidil and fmas
  • Non-hmitmg examples of penetration enhancers which may be used in the compositions herein include, for example, 2-methyl propan-2-ol, propan-2-ol, ethyl-2-hydroxypropanoate, hexan-2,5-d ⁇ ol, POE(2) ethyl ether, d ⁇ (2-hydroxypropyl) ether, pentan-2,4-d ⁇ ol, acetone, POE(2) methyl ether, 2-hydroxyprop ⁇ omc acid, 2-hydroxyoctano ⁇ c acid, propan-1-ol, 1,4-d ⁇ oxane, tetrahydrofuran, butan-l,4-d ⁇ ol, propylene glycol dipelargonate, polyoxypropylene 15 stearyl ether, octyl alcohol, POE ester of oleyl alcohol, oleyl alcohol, lauryl alcohol, dioctyl adipate, dicapryl adipate, di-isopropy
  • the compounds used in the present methods can be administered alone or as mixtures, and the compositions may further include additional drugs or excipients as appropriate for the indication
  • kits comprising a compound and / or composition herein and information and / or instructions by words, pictures, and / or the like, that use of the kit will provide treatment for hair loss m mammals (particularly humans) including, for example, arresting and / or reversing hair loss and / or promoting hair growth.
  • the tat may comprise a compound and / or composition herein and information and / or instructions regarding methods of application of the compound and / or composition, preferably with the benefit of treating hair loss in mammals.
  • composition Administration do not limit the invention, but provide guidance to the stalled artisan to perform the methods of the present invention.
  • a compound other than the one mentioned may be substituted in the example by another having a structure as described herein with similar results.
  • Example A composition for topical administration comprising:
  • a human male subject suffering from male pattern baldness is treated by a method of this invention. Specifically, for 6 weeks, the above composition is daily administered topically to the subject.
  • Example B A composition for topical administration is made according to the method of Dowton et al., "Influence of Liposomal Composition on Topical Delivery of Encapsulated Cyclosponn A: I. An in vitro Study Using Hairless Mouse Skm", S.T P Pharma Sciences. Vol. 3, pp 404 - 407 (1993), using [3,5-d ⁇ methyl-4-(4'-hydroxy-3'- ⁇ sopropylbenzyl)phenoxy]acet ⁇ c acid in lieu of cyclospo ⁇ n A and using the Novasome 1 for the non-ionic hposomal formulation.
  • a human male subject suffering from male pattern baldness is treated each day with the above composition. Specifically, for 6 weeks, the above composition is administered topically to the subject.
  • a shampoo comprising:
  • a human subject suffenng from male pattern baldness is treated by a method of this invention. Specifically, for 12 weeks, the above shampoo is used daily by the subject.

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Abstract

La présente invention concerne des méthodes de traitement de la perte des cheveux chez des mammifères, permettant notamment de stopper et/ou d'inverser la perte des cheveux et de stimuler leur croissance. Les méthodes consistent à administrer un composé ménageant le coeur ayant une structure de la formule (A) telle que décrite dans l'invention ainsi qu'un excipient acceptable sur le plan pharmaceutique.
PCT/US2000/005254 1999-06-01 2000-03-01 Methode de traitement de la perte des cheveux a l'aide de derives de diphenylmethane WO2000072813A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
MXPA01012495A MXPA01012495A (es) 1999-06-01 2000-03-01 Metodo para tratar la perdida capilar con el uso de derivados de difenilmetano.
AU35078/00A AU3507800A (en) 1999-06-01 2000-03-01 Method of treating hair loss using diphenylmethane derivatives
CA002374266A CA2374266A1 (fr) 1999-06-01 2000-03-01 Methode de traitement de la perte des cheveux a l'aide de derives de diphenylmethane
JP2000620925A JP2003500433A (ja) 1999-06-01 2000-03-01 ジフェニルメタン誘導体を用いる脱毛の処置方法
US09/980,407 US6680344B1 (en) 1999-06-01 2000-03-01 Method of treating hair loss using diphenylmethane derivatives
EP00913678A EP1185231A1 (fr) 1999-06-01 2000-03-01 Methode de traitement de la perte des cheveux a l'aide de derives de diphenylmethane

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US60/137,024 1999-06-01

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US6664291B2 (en) 2000-03-31 2003-12-16 Pfizer, Inc. Malonamic acids and derivatives thereof as thyroid receptor ligands
US6723744B2 (en) 2001-09-26 2004-04-20 Pfizer, Inc. Indole carboxylic acids as thyroid receptor ligands
US7169564B1 (en) 2001-06-26 2007-01-30 Anaderm Research Corporation FKBP51/52 and CyP40-mediated mammalian hair growth
EP2695611A1 (fr) 2012-08-06 2014-02-12 Dr. August Wolff GmbH & Co. KG Arzneimittel Eprotirome pour l'utilisation dans la prévention et/ou le traitement de troubles de cheveux et compositions correspondantes

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6664291B2 (en) 2000-03-31 2003-12-16 Pfizer, Inc. Malonamic acids and derivatives thereof as thyroid receptor ligands
US6924310B2 (en) 2000-03-31 2005-08-02 Pfizer Inc. Malonamic acids and derivatives thereof as thyroid receptor ligands
US7202275B2 (en) 2000-03-31 2007-04-10 Warner Lambert Company Llc Malonamic acids and derivatives thereof as thyroid receptor ligands
US7169564B1 (en) 2001-06-26 2007-01-30 Anaderm Research Corporation FKBP51/52 and CyP40-mediated mammalian hair growth
US6723744B2 (en) 2001-09-26 2004-04-20 Pfizer, Inc. Indole carboxylic acids as thyroid receptor ligands
EP2695611A1 (fr) 2012-08-06 2014-02-12 Dr. August Wolff GmbH & Co. KG Arzneimittel Eprotirome pour l'utilisation dans la prévention et/ou le traitement de troubles de cheveux et compositions correspondantes
WO2014023698A1 (fr) 2012-08-06 2014-02-13 Dr. August Wolff Gmbh & Co. Kg Arzneimitttel Éprotirome destiné à être utilisé dans la prévention et/ou le traitement de troubles capillaires et compositions correspondantes
CN104717964A (zh) * 2012-08-06 2015-06-17 奥古斯特沃尔夫博士有限两合公司-医药 用于预防和/或治疗毛发失调的伊罗替罗及其组合物

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JP2003500433A (ja) 2003-01-07
AR018471A1 (es) 2001-11-14

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