EP1185229A1 - Methode de traitement de la perte des cheveux - Google Patents

Methode de traitement de la perte des cheveux

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Publication number
EP1185229A1
EP1185229A1 EP00913675A EP00913675A EP1185229A1 EP 1185229 A1 EP1185229 A1 EP 1185229A1 EP 00913675 A EP00913675 A EP 00913675A EP 00913675 A EP00913675 A EP 00913675A EP 1185229 A1 EP1185229 A1 EP 1185229A1
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EP
European Patent Office
Prior art keywords
alkyl
group
hydrogen
compound
independently
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.)
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EP00913675A
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German (de)
English (en)
Inventor
Lixin Lilly Zhang
Robert Scott Youngquist
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UT Southwestern Medical Center
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UT Southwestern Medical Center
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Publication of EP1185229A1 publication Critical patent/EP1185229A1/fr
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    • 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
    • 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
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • 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
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • A61K31/09—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon having two or more such linkages
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • 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
    • A61K8/365—Hydroxycarboxylic acids; Ketocarboxylic acids
    • 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
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
    • 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
    • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A61K8/4926—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having six membered rings
    • 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 pe ⁇ ods of growth and rest.
  • This cycle is often divided mto three mam stages which are known as anagen, catagen, and telogen.
  • Anagen is the growth phase of the cycle and may be characterized by penetration of the hair follicle deep mto 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 du ⁇ ng which the hair follicle regresses through the dermis and hair growth is ceased.
  • telogen is often characte ⁇ zed as the resting stage du ⁇ ng 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
  • 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 Lindenbaum, 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. U.S. Patent No. 5,061,798, 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 surprisingly 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 m the methods and compositions herein are cardiac-sparing 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 administering 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 in 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-spa ⁇ ng.
  • any variable, moiety, group, or the like occurs more than one time in any va ⁇ able or structure, its definition at each occurrence is independent of its definition at every other occurrence.
  • alkoxy is an oxygen radical having an alkyl, alkenyl, or alkynyl, preferably an alkyl or alkenyl, and most preferably an alkyl substituent.
  • alkoxy radicals include -O-alkyl and -O-alkenyl.
  • An alkoxy radical may be substituted or unsubstituted.
  • alkyl is an unsubstituted or substituted saturated hydrocarbon chain radical having from 1 to about 15 carbon atoms; preferably from 1 to about 10 carbon atoms; more preferably from 1 to about 6 carbon atoms; and most preferably from 1 to about 4 carbon atoms.
  • Preferred alkyls include, for example, methyl, ethyl, propyl, zs ⁇ -propyl, and butyl.
  • aryl is an aromatic ⁇ ng radical which is either carbocychc or heterocychc.
  • Preferred aryl groups include, for example, phenyl, benzyl, tolyl, xylyl, cumenyl, napthyl, biphenyl, thienyl, furyl, pyrrolyl, pyridmyl, pyrazmyl, thiazolyl, pyrimidmyl, quinohnyl, triazolyl, tetrazolyl, benzothiazolyl, benzofuryl, mdolyl, indenyl, azulenyl, fluorenyl, anthracenyl, oxazolyl, isoxazolyl, isotriazolyl, imidazolyl, pyraxolyl, oxadiazolyl, mdolizmyl, mdolyl, isoindolyl, pu ⁇ nyl,
  • arylalkyl is an alkyl radical substituted with an aryl group or an aryl radical substituted with an alkyl group.
  • Preferred arylalkyl groups include benzyl, phenylethyl, and phenylpropyl.
  • Arylalkyls may be substituted or unsubstituted.
  • biohydrolyzable amides are amides of the compounds used m 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 m 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 m 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 saturated carbocychc or heterocychc ⁇ ng radical.
  • Preferred cycloalkyl groups include, for example, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyls may be substituted or unsubstituted.
  • halogens are bromine, chlorine, iodine, and fluorine, more preferably, bromine, chlorine, and iodine, even more preferably bromine and chlo ⁇ ne, and most preferably chlorine.
  • 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 s ⁇ te(s) of activity m a mammalian subject, without undue adverse side effects (such as toxicity, irritation, or allergic response), commensurate with a reasonable benefit / ⁇ sk ratio when used m the manner of this invention.
  • salt is a catiomc salt formed at any acidic (e.g , carboxyl) group, or an anionic salt formed at any basic (e g., ammo) group.
  • 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 anionic salts include the halides (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 comprising administering a composition comprising a compound having the structure
  • X is selected from oxygen, sulfur, and CH 2 ;
  • R, and R 2 are each, independently, selected from hydrogen, halogen, hydroxy, t ⁇ fluoromethyl, Cj - C 6 alkyl, - C 6 alkenyl, and - C 4 alkoxy;
  • R 3 is selected from hydrogen, alkyl, aryl, and arylalkyl
  • R is selected from R 4 is selected from the group consisting of hydrogen, halogen, Ci - C 4 alkyl, - C 4 alkenyl, hydroxy, and - C 4 alkoxy;
  • R 5 is selected from hydrogen, halogen, hydroxy, alkyl, - C 4 alkenyl, Ci - C 4 alkoxy, cycloalkyl, aryl, and arylalkyl;
  • Re is selected from alkyl, aryl, -CH 2 CH(NH 2 )CO 2 H, -CH 2 CH(OH)CO 2 H, - CH 2 CR 7 R 8 NR 9 R 10 , -YC(O)Rnova, -(CH 2 ) n -OH, -CH 2 C(R 12 )(NH 2 )CO 2 R 13 , - CH 2 CH(COOH)(NH)C(O)(CH 2 ) m C(O)NH(CH 2 ) n R 20 , and -CH 2 CR 12 R I2 C(O)OR 13 ;
  • R 7 is selected from hydrogen and C] - C 4 alkyl
  • R 8 is selected from hydrogen and -C(O)R ⁇
  • R 9 and R 10 are each, independently, selected from hydrogen, - C 4 alkyl, and Ci -
  • R 13 is selected from C] - C 6 alkyl, cycloalkyl, and arylalkyl;
  • R !4 is selected from hydrogen and C] - C 4 alkyl;
  • Ri 5 is selected from hydrogen, C] - C 4 alkyl, and Cj - C alkanoyl;
  • Rig and R )9 are each, independently, selected from hydrogen, - C 6 alkyl, Ci - C 6 alkenyl, hydroxy, and halogen;
  • m is an integer from 2 to 4;
  • (r) n is an integer from 1 to 4; and
  • R 20 is an unsaturated, unsubstituted five- or six-membered monocyclic heterocycle containing from one to two nitrogen atoms as the only heteroatoms.
  • X is selected from oxygen (-O-), sulfur (-S-), and -CH 2 -.
  • X is selected from oxygen and -CH 2 -.
  • Ri and R 2 are each, independently, selected from hydrogen, halogen, hydroxy, frifluoromethyl, C - C 6 alkyl, C ⁇ - C 6 alkenyl, and - C 4 alkoxy.
  • R, and R 2 are each, independently, selected from hydrogen, halogen, frifluoromethyl, and d - C 6 alkyl.
  • R] and R 2 are each, independently, selected from halogen, trifluoromethyl, and Ci - C 6 alkyl.
  • Rj and R 2 are each, independently, selected from halogen and Cj - C 6 alkyl.
  • Preferred halogens are chlorine and iodine.
  • R 3 is selected from hydrogen, alkyl, aryl, and arylalkyl.
  • R 3 is selected from hydrogen, alkyl, and arylalkyl.
  • Preferred alkyls for R 3 are methyl and ethyl.
  • a preferred arylalkyl for R 3 is benzyl.
  • R 4 is selected from the group consisting of hydrogen, halogen, C] - C 4 alkyl, - C 4 alkenyl, hydroxy, and Ci - C 4 alkoxy.
  • R 4 is selected from hydrogen and halogen (most preferably iodine).
  • t is hydrogen.
  • R 5 is selected from hydrogen, halogen, hydroxy, alkyl, Ci - C 4 alkenyl, Ci - C alkoxy, cycloalkyl, aryl, and arylalkyl.
  • R5 is selected from hydrogen, halogen (particularly iodine), alkyl, cycloalkyl, aryl, and arylalkyl. More preferably, R 5 is selected from hydrogen, alkyl, cycloalkyl, aryl, and arylalkyl. Even more preferably, R 5 is selected from alkyl, cycloalkyl, aryl, and arylalkyl. Most preferably, R 5 is selected from alkyl and arylalkyl (a preferred arylalkyl is benzyl).
  • Ri 8 and R ]9 are each, independently, selected from hydrogen, C] - C 6 alkyl, C ⁇ - C 6 alkenyl, hydroxy, and halogen.
  • R ]8 and R 19 are each, independently, selected from hydrogen and - C 6 alkyl.
  • R 18 and R 19 are each hydrogen.
  • Re is selected from alkyl, aryl, -CH 2 CH(NH 2 )CO 2 H, -CH 2 CH(OH)CO 2 H, - CH 2 CR 7 R 8 NR 9 R 10j -YC(O)R,tician -(CH 2 ) n -OH, -CH 2 C(R 12 )(NH 2 )CO 2 R 13 ,
  • Re is selected from -CH 2 CH(NH 2 )CO 2 H, -CH 2 CH(OH)CO 2 H, -CH 2 CR 7 R 8 NR 9 R 10 , -YC(O)R u , - CH 2 C(R 12 )(NH 2 )CO 2 R ⁇ 3 , -CH 2 CH(COOH)(NH)C(O)(CH 2 ) m C(O)NH(CH 2 ) n R 20 , and CH 2 CR 12 R 12 C(O)OR 13 .
  • R 7 is a substituent on -CH 2 CR 7 R 8 NR 9 R 10 .
  • R 7 is selected from hydrogen and Q - C alkyl.
  • R 8 is a substituent on -CH 2 CR 7 R 8 NR 9 R ]0 .
  • R 8 is selected from hydrogen and -C(O)R ⁇ .
  • Preferably R 8 is hydrogen.
  • R 9 and R ⁇ 0 are substituents on -CH 2 CR 7 R 8 NR 9 R 10 and CH 2 CR 7 R 8 NR 9 R 10 .
  • R 9 and R 10 are each, independently, selected from hydrogen, C] - C 4 alkyl, and Ci - C 4 alkanoyl (oxo substituted alkyl).
  • R 9 and R ]0 are each, independently, selected from hydrogen and Ci - C 4 alkyl.
  • Y is a substituent on -YC(O)R ⁇ .
  • Y is selected from a bond and Q - C 4 alkyl.
  • Rii is selected from hydroxy, C] - C 4 alkoxy, -NR 14 R ⁇ 5 , - C 4 alkyl, Cj - C 4 alkenyl, and Ci - C 4 alkynyl
  • R n is selected from hydroxy, - C 4 alkoxy, and -NR 14 R 15 .
  • R n is selected from hydroxy and Q - C 4 alkoxy.
  • R, 2 is a substituent on -CH 2 C(R 12 )(NH 2 )CO 2 R, 3 and -CH 2 CR, 2 R 12 C(O)OR 13 R 12 is C, - C 6 alkyl.
  • R, 3 is a substituent on -CH 2 CR, 2 R 12 C(O)OR 13 and -CH 2 C(R 12 )(NH 2 )CO 2 R 13 .
  • R, 3 is selected from Q - C 6 alkyl, cycloalkyl, and arylalkyl.
  • R !3 is Ci - C 6 alkyl.
  • Ru and R ]5 are each (optionally) substituents on R u .
  • R 14 is selected from hydrogen and - C 4 alkyl, preferably methyl or ethyl.
  • R ]5 is selected from hydrogen and Ci - C 4 alkyl.
  • the integers m and n are of -CH 2 CH(COOH)(NH)C(O)(CH 2 ) m C(O)NH(CH 2 ) n R 20 .
  • the integer m is from 2 to 4, preferably 2.
  • the integer n is from 1 to 4, preferably 1.
  • R 20 is also of - CH 2 CH(COOH)(NH)C(O)(CH 2 ) m C(O)NH(CH 2 ) n R 20 .
  • R 20 is an unsaturated, unsubstituted five- or six-membered monocyclic heterocycle containing from one to two, preferably one, nitrogen atoms as the only heteroatoms.
  • Non-hmitmg examples of preferred heterocycles are pyrrolyl, pyrazolyl, imidazolyl, pyridyl, py ⁇ dazmyl, pyrimidmyl, and pyrazmyl, more preferably imidazolyl, most preferably 5- ⁇ m ⁇ dazolyl.
  • R 5 is selected from C] - C 6 alkyl and C 3 - C 7 cycloalkyl
  • R ⁇ and R 2 are each, independently, selected from hydrogen, halogen, and d - C 6 alkyl, wherein at least one of Ri and R 2 is not hydrogen
  • Rn is selected from the group consisting of hydroxy and - C 4 alkoxy.
  • R 3 is selected from methyl and ethyl
  • R 4 is selected from hydrogen and iodine
  • R 5 is selected from hydrogen, iodine, and alkyl
  • R ⁇ 8 and R 19 are each, independently, selected from hydrogen and d - 6 alkyl
  • X is selected from oxygen, sulfur, and CH 2
  • R] and R 2 are each, independently, selected from hydrogen, halogen, and Ci - C 4 alkyl.
  • n is an integer from 1 to 4
  • R 20 is an unsaturated, unsubstituted five- or six-membered monocyclic heterocycle containing from one to two nitrogen atoms as the only heteroatoms.
  • heterocycles include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, py ⁇ dazmyl, pyrimidmyl, and pyrazmyl, more preferably imidazolyl, most preferably 5- ⁇ m ⁇ dazolyl.
  • R 3 is selected from hydrogen and Ci - C 4 alkyl
  • R 4 is selected from hydrogen and iodine
  • R 5 is selected from hydrogen, iodine, and d - C 4 alkyl
  • R )8 and R 19 are each, independently, selected from hydrogen and Ci - C 4 alkyl
  • R] and R 2 are each, independently, halogen
  • Y is selected from bond and Ci - C 3 alkyl
  • Rn is -NR ⁇ 4 R ]5
  • R ]4 and R 15 are each, independently, selected from hydrogen and Ci - C 4 alkyl
  • R is selected from hydrogen and iodine
  • R, and R 2 are each, independently, selected from hydrogen and iodine
  • each R [2 is, independently, Ci - C 6 alkyl
  • Rn is selected from Ci - C 6 alkyl, cycloalkyl, and arylalkyl.
  • X is selected from oxygen, sulfur, and CH 2 ; Ri and R 2 are each, independently, selected from hydrogen, halogen, and Ci - C 4 alkyl; Re is selected from -CH 2 CR 7 R 8 NR 9 R, 0 and - YC(O)R n ; Ri 6 is aryl; and R !7 is selected from hydrogen and Ci - C 4 alkyl.
  • X is oxygen; R ]7 is hydrogen; R, is -CH 2 CR 7 R 8 NR9R 10 ; R 8 is -C(O)R H ; R u is hydroxy; and / or R 9 is Ci - C 4 alkyl and R ⁇ 0 is hydrogen.
  • R 6 is -YC(O)Rn; Y is Ci - C 4 alkyl; and / or R] and R 2 are each, independently, halogen.
  • Particularly preferred groups for R ⁇ 6 are selected from 4-hydroxyphenyl, 5-hydroxy-2 -pyridyl, 6-oxo-3(lH)pyr ⁇ dyl, and 6-oxo-3(lH)pyr ⁇ dazmyl.
  • the present invention relates to methods of treating hair loss by administering a compound having a structure as described herein.
  • the compound utilized m the present invention will be cardiac-sparing.
  • Compounds (test compounds) may be tested for their ability to induce anagen and their lack of cardiotoxicity (cardiac-sparmg) using the following methods.
  • other methods well-known in the art may be used (but with the term "cardiac-sparmg" being defined according to the method disclosed herein below).
  • Cardiotoxicity Assay :
  • 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.
  • each rat 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 p ⁇ or 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 dosmg solutions are recalculated and administered accordingly upon change in 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 rats of each group are euthanized with CO 2 from dry ice
  • Each rat is immediately weighed for total body weight.
  • 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 ⁇ ght ventricles. Immediately thereafter, any excess tissue is trimmed 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 euthanization for each rat to give the heart/body ratio.
  • the heart/body ratios for each rat m the vehicle control group are added together and divided by 6 (i.e., the total number of rats m 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.
  • the test compound is cardiac-sparmg.
  • 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-spa ⁇ ng.
  • 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 pe ⁇ od m C3H mice Harlan Sprague Dawley, Inc., Indianapolis, IN mice 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 in 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 4 below. Typical dosage concentrations are set forth in Table 4, 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 in preparing the compounds are known, made by known methods, or are commercially available as a starting material.
  • the compounds of the present invention may have one or more chiral centers.
  • one optical isomer including diastereomers and enantiomers
  • another optical isomer including diastereomers and enantiomers
  • 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 desc ⁇ bed in the art. Accordingly, the ordinarily skilled artisan will be able to prepare the compounds described herein.
  • the syntheses of va ⁇ ous of the present compounds are desc ⁇ bed m, for example, Ellis et al., U.S. Patent No. 4,910,305, assigned to Smith Kline & French Laboratories, issued March 20, 1990, Ellis et al., U S. Patent No 4,826,876, assigned to Smith Klme & French Laboratories, issued May 2, 1989; Ellis et al., U.S Patent No 4,766,121 assigned to Smith Klme & French Laboratories, issued August 23, 1988; Emmett et al., U.S Patent No.
  • the benzoic acid (2 g) is demethylated with boron t ⁇ bromide (1M, 26 mL) in dichloromethane at 0 °C.
  • the mixmre is stirred overnight at room temperamre before quenching with a water/ice mixmre.
  • the layers are separated and the water layer is extracted with dichloromethane.
  • the combined organic extracts are dried, filtered and concentrated. The resulting residue is recrystallized to give 3,5-d ⁇ bromo-4-(4-hydroxy-3- ⁇ sopropylphenoxy)benzo ⁇ c acid.
  • Bromine (35.2 g) is added dropwise to a suspension of methyl 4-hydroxy-phenylacetate (16.6 g) in water (500 mL). After 1 day of stirring, the mixture is partitioned between water and ethyl acetate. The organic layer is washed with aqueous sodium thiosulfate, dried, filtered and concentrated. The residue is recrystallized from methanol to give methyl 3,5-d ⁇ bromo-4- hydroxyphenylacetate .
  • Methyl 3,5-d ⁇ chloro-4-hydroxybenzoate (10 g) is coupled with b ⁇ s(3- ⁇ sopropyl-4- methoxyphenyl) ⁇ odon ⁇ um tetrafluoroborate (35 g) using the method described in Example 1.
  • Pu ⁇ fication by column chromatography followed by recrystalhzation from methanol affords methyl 3,5-d ⁇ chloro-4-(4-methoxy-3- ⁇ sopropylphenoxy) benzoate.
  • Methyl 3,5-d ⁇ chloro-4-(4-methoxy-3- ⁇ sopropylphenoxy)benzoate (see Example 3) (3.0 g) is treated with a IM solution of dusobutyl aluminium hydride (DIBAL) in tetrahydrofuran (32.5 mL) at 0 °C and then warmed to room temperamre and stirred overnight.
  • DIBAL dusobutyl aluminium hydride
  • tetrahydrofuran 32.5 mL
  • the reaction mixmre is poured mto an ice-cold IM HC1 solution and extracted with ethyl acetate three times.
  • the organic layer is washed (b ⁇ ne), dried, filtered and concentrated to dryness to afford 3,5- d ⁇ chloro-4-(4-methoxy-3- ⁇ sopropylphenoxy) benzylalcohol.
  • 3,5-dnodo-4-(4'-methoxyphenoxy)benzo ⁇ c acid is synthesized using the general methodology of Borrows et al., "The Synthesis of Thyroxme and Related Substances. Part I. The Preparation of Tyrosme and Some of its Derivatives, and a New Route to Thyroxme", Journal of the Chemical Society, Supp. Issue No. 1, S185 - S190 (1949).
  • the material is then taken up in 15 mL acetic anhydride and cooled to -10 °C. To this cooled solution is added dropwise a solution of 2- lsopropyl anisole (9a; 7.43 g) in 35 mL acetic anhydride and 5 mL t ⁇ fluoroacetic acid The reaction is allowed to stand in a refrigerator for about 16 hours. After allowing the reaction to return to room temperature for 3 hours, the reaction is concentrated under high vacuum. The residue is taken up in 25 mL methanol, 25 mL 10% sodium bisulfite, and 188 mL 2M sodium tetrafluoroborate The mixture is stirred vigorously for 30 minutes and the supernatant is decanted off. To the residue is added 200 mL hexane and it is stirred for an additional 30 minutes. At that time, the solid is collected, washed with hexane, and d ⁇ ed under vacuum to afford 9b.
  • the methods of the present invention are performed by administering to a mammal (preferably a human) a compound having a structure as described herein and, preferably, a pharmaceutically-acceptable or cosmetically-acceptable earner.
  • the compounds herein may be used for the treatment of such conditions as treating hair loss m 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- spa ⁇ ng.
  • the compounds are formulated mto 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 "carrier”).
  • 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.
  • Car ⁇ ers must, of course, be of sufficiently high purity 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 prefe ⁇ ed 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 car ⁇ ers or components thereof are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its de ⁇ vatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lub ⁇ cants, 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, mannitol, and polyethylene glycol; algmic acid; emulsifiers, such as the TWEENS; wetting agents, such sodium lauryl sulfate; colo ⁇ ng agents; flavo ⁇ ng agents; tabletmg agents, stabilizers; antioxidants; preservative
  • car ⁇ ers 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, isotonic salme, and pyrogen- free water.
  • Preferred earners for parenteral administration include propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil.
  • the ca ⁇ ier, 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 in 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 comp ⁇ se conventional pharmaceutically-compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; dismtegrants such as starch, algmic acid and croscarmelose; lubricants such as magnesium stearate, stea ⁇ c acid and talc. Ghdants such as silicon dioxide can be used to improve flow characte ⁇ stics of the powder mixture.
  • Colo ⁇ ng agents such as the FD&C dyes, can be added for appearance.
  • Sweeteners and flavo ⁇ ng agents such as aspartame, saccha ⁇ n, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets.
  • Capsules typically comp ⁇ se one or more solid diluents disclosed above. The selection of earner components depends on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of the subject invention, and can be readily made by a person skilled m the art.
  • Orally administered compositions also include liquid solutions, emulsions, suspensions, powders, granules, elixirs, tinctures, syrups, and the like.
  • 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 various 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 subhngual, buccal and nasal dosage forms.
  • Such compositions typically compnse one or more of soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystallme cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose.
  • Ghdants, lubricants, sweeteners, colorants, antioxidants and flavonng 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, moistunzers, sprays, skm patches, and the like.
  • Topical compositions containing the active compound can be admixed with a va ⁇ ety of earner materials well known m 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.
  • a va ⁇ ety of earner materials well known m 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.
  • mate ⁇ als suitable for use m topical carriers include, for example, emollients, solvents, humectants, thickeners and powders.
  • Emollients such as stearyl alcohol, glyceryl mononcmoleate, glyceryl monostearate, propane- 1,2-d ⁇ ol, butane-l,3-d ⁇ ol, mink oil, cetyl alcohol, z_O-propyl isostearate, stea ⁇ c acid, iso- butyl palmitate, lsocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, lsocetyl alcohol, cetyl palmitate, dimethylpolysiloxane, di-M-butyl
  • the compounds used in the present invention may also be administered in the form of hposome delivery systems, such as small umlamellar vesicles, large umlamellar vesicles, and multilamellar vesicles.
  • Liposomes can be formed from a variety of phosphohpids, such as cholesterol, stearylarmne or phosphatidylchohnes
  • 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 Cyclosporm A: I. An in vitro Study Using Hairless Mouse Skm", S TP Pharma Sciences, Vol. 3, 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 in 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-limiting examples of other hair growth stimulants which may be used in the compositions herein, including both systemic and topical compositions, include, for example, benzalkonium chloride, benzethonium chloride, phenol, estradiol, diphenhydramine hydrochloride, chlorpheniramine maleate, chlorophyllin derivatives, cholesterol, salicylic acid, cysteine, methionine, red pepper tincture, benzyl nicotinate, D,L - menthol, peppermint oil, calcium pantothenate, panthenol, castor oil, hinokitiol, prednisolone, resorcinol, monosaccharides and esterified monosaccharides, chemical activators of protein kinase C enzymes, glycosaminoglycan chain cellular uptake inhibitors, inhibitors of glycosidase activity, glycosaminoglycanase inhibitors, esters of pyroglutamic acid, hexo
  • Non-hmitmg examples of penetration enhancers which may be used m 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-hydroxypropiomc 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-isoprop
  • 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 comp ⁇ smg 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 in mammals (particularly humans) including, for example, arresting and / or reversing hair loss and / or promoting hair growth.
  • the kit may compnse 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.
  • compositions for topical administration comprising:
  • a human male subject suffe ⁇ ng 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.
  • 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 Sk “, S.T.P. Pharma Sciences, Vol. 3, pp. 404 - 407 (1993), using the compound of Example 2 in lieu of cyclospo ⁇ n A and using the Novasome 1 for the non-ionic liposomal 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 is made, comp ⁇ smg:
  • a human subject suffering 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 telle que décrite dans la description ainsi qu'un excipient acceptable sur le plan pharmaceutique.
EP00913675A 1999-06-01 2000-03-01 Methode de traitement de la perte des cheveux Withdrawn EP1185229A1 (fr)

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US6664291B2 (en) 2000-03-31 2003-12-16 Pfizer, Inc. 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
ES2253495T3 (es) 2001-09-26 2006-06-01 Pfizer Products Inc. Acidos indol carboxilicos como ligandos de receptores tiroideos.
US6979750B1 (en) 2003-04-18 2005-12-27 The Regents Of The University Of California Thyronamine derivatives and analogs and methods of use thereof
US7321065B2 (en) 2003-04-18 2008-01-22 The Regents Of The University Of California Thyronamine derivatives and analogs and methods of use thereof
JP4849213B2 (ja) * 2005-12-15 2012-01-11 ライオン株式会社 育毛養毛剤
JP2010519250A (ja) * 2007-03-20 2010-06-03 ザ プロクター アンド ギャンブル カンパニー アミンオキシド界面活性剤又は汚れ浸透剤を含有する組成物
US8143424B2 (en) 2007-06-06 2012-03-27 Torrent Pharmaceuticals Ltd. Thyroid like compounds
DK2695611T3 (en) 2012-08-06 2015-01-05 Wolff August Gmbh & Co Kg Arzneimittel Dr Eprotirome for use in the prevention and / or treatment of hair disorders and their compositions

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