WO2000073265A1 - Derives de thyroxane contenant du soufre et leur utilisation en tant que promoteurs de croissance capillaire - Google Patents

Derives de thyroxane contenant du soufre et leur utilisation en tant que promoteurs de croissance capillaire Download PDF

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WO2000073265A1
WO2000073265A1 PCT/US2000/005252 US0005252W WO0073265A1 WO 2000073265 A1 WO2000073265 A1 WO 2000073265A1 US 0005252 W US0005252 W US 0005252W WO 0073265 A1 WO0073265 A1 WO 0073265A1
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group
alkyl
heteroalkyl
heterocycloalkyl
alkenyl
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PCT/US2000/005252
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English (en)
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Robert Scott Youngquist
John Mcmillan Mciver
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The University Of Texas Southwestern Medical Centre
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Priority to MXPA01012497A priority Critical patent/MXPA01012497A/es
Priority to CA002375667A priority patent/CA2375667A1/fr
Priority to EP00914768A priority patent/EP1194405A1/fr
Priority to AU36115/00A priority patent/AU3611500A/en
Priority to JP2000621332A priority patent/JP2003500471A/ja
Priority to US09/980,404 priority patent/US6723717B1/en
Publication of WO2000073265A1 publication Critical patent/WO2000073265A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • 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
    • A61K8/46—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing sulfur
    • 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
    • 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
    • A61K8/4913—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having five membered rings, e.g. pyrrolidone carboxylic acid
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C317/34—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
    • C07C317/38—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atom of at least one amino group being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfones
    • C07C317/40—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/31—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/33—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to a carbon atom of the same non-condensed six-membered aromatic ring
    • C07C323/35—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to a carbon atom of the same non-condensed six-membered aromatic ring the thio group being a sulfide group
    • C07C323/37—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to a carbon atom of the same non-condensed six-membered aromatic ring the thio group being a sulfide group the sulfur atom of the sulfide group being further bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
    • C07C323/40—Y being a hydrogen or a carbon atom
    • C07C323/41—Y being a hydrogen or an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
    • C07C323/40—Y being a hydrogen or a carbon atom
    • C07C323/42—Y being a carbon atom of a six-membered aromatic ring

Definitions

  • the present invention relates to methods for treating hair loss m 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 dmded into 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 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.
  • telogen is often characterized 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 the germ, expansion of the dermal papilla, and elaboration of basement membrane components.
  • hair growth ceases, most of the hair follicles reside in telogen and anagen is not engaged, thus causing the onset of full or partial baldness.
  • T4 thyroid hormone
  • T3 thyronine
  • 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 See, e.g . Walker et al., U.S. Patent No. 5,284,971, assigned to Syntex, issued February 8, 1994 and Emmett et al.. U.S. Patent No.
  • the present inventors have discovered compounds which strongly initiate hair growth without inducing cardiotoxicity Consistent with this discovery, but without intending to be limited by theory, the present inventors have surprisingly discovered that the preferred compounds of 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 and compositions herein are useful for treating hair loss, including arresting and / or reversing hair loss and promoting hair growth.
  • the present invention relates to compounds and compositions which are particularly useful for treating hair loss m mammals, including arresting and / or reversing hair loss and promoting hair growth.
  • the compounds of the present invention have the structure:
  • R, R 2 , R 3 , R4, R 5 , R 6 , Re', R7, Rt,, RQ, I O, Y. X, R11. and R 12 are defined herein
  • the present invention relates to 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 of the present invention are cardiac-sparing.
  • variable, moiety, group, or the like occurs more than one time in any variable or structure, its definition at each occurrence is independent of its definition at every other occurrence.
  • salt is a cationic salt formed at any acidic (e g . carboxyl) group, or an anionic salt formed at any basic (e g , amino) group.
  • Preferred cationic 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 hahdes (such as, for example, chloride salts). Such acceptable salts must, when administered, be appropriate for mammalian use.
  • alkenyl is an unsubstituted or substituted hydrocarbon chain radical having from 2 to about 15 carbon atoms; preferably from 2 to about 10 carbon atoms: more preferably from 2 to about 8 carbon atoms, and most preferably from about 2 to about 6 carbon atoms.
  • Alkenyls have at least one olefinic double bond
  • Non-hmitmg examples of alkenyls include vinyl, allyl, and butenyl.
  • alkoxy is an oxygen radical having an alky 1, 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.
  • aryloxy is an oxygen radical having an aryl substituent.
  • An aryloxy 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, wo-propyl, and butyl
  • alkylene refers to an alkyl, alkenyl, or alkynyl which is a diradical.
  • methylene is -CH2-.
  • Alkylenes may be substituted or unsubstituted.
  • alkynyl is an unsubstituted or substituted hydrocarbon chain radical having from 2 to about 15 carbon atoms; preferably from 2 to about 10 carbon atoms; more preferably from 2 to about 8 carbon atoms, and most preferably from about 2 to about 6 carbon atoms. Alkynyls have at least one triple bond.
  • aryl is an aromatic ring radical which is either carbocychc or heterocyclic.
  • Preferred aryl groups include, for example, phenyl, benzyl, tolyl. xylyl, cumenyl, napthyl, biphenyl, thienyl, furyl, pyrrolyl, pyridmyl, pyrazinyl, thiazolyl, py ⁇ midinyl, quinohnyl, t ⁇ azolyl, tetrazolyl, benzo thiazolyl, benzofuryl, indolyl, indenyl, azulenyl, fluorenyl, anthracenyl, oxazolyl, isoxazolyl, isotriazolyl, lmidazolyl, pyraxolyl, oxadiazolyl, mdohzmyl, mdolyl, isoindolyl, pu ⁇ n
  • arylalkenyl is an alkenyl radical substituted with an aryl group or an aryl radical substituted with an alkenyl group.
  • Arylalkenyls may be substituted or unsubstituted.
  • 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 of 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 of the present invention which do not interfere with the activity of the compound, or that are readily converted ... vivo by a mammalian subject to yield an active compound
  • biohydrolyzable imides are imides of the compounds of 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
  • Carbocychc ring As used herein, "carbocychc ring”, “carbocycle”, or the like is a hydrocarbon ring radical Carbocychc rings are monocychc or are fused, bridged, or spiro polycychc rings. Unless otherwise specified, monocychc rings contain from 3 to about 9 atoms, preferably from about 4 to about 7 atoms, and most preferably 5 or 6 atoms. Polycychc ⁇ ngs contain from about 7 to about 17 atoms, preferably from about 7 to about 14 atoms, and most preferably 9 or 10 atoms Carbocychc rings (carbocycles) may be substituted or unsubstituted.
  • cycloalkyl is a saturated carbocychc or heterocychc ring radical.
  • Preferred cycloalkyl groups include, for example, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyls may be substituted or unsubstituted.
  • cycloalkenyl is an unsaturated carbocychc or heterocychc ring radical having at least one double bond. Cycloalkenyls may be substituted or unsubstituted.
  • halogens are bromine, chlorine, iodine, and fluorine, more preferably, bromine, chlorine, and iodine, even more preferably bromine and chlorine, and most preferably chlorine
  • heteroalkenyl is an alkenyl radical comprised of carbon atoms and one or more heteroatoms wherein the heteroatoms are selected from the group consisting of oxygen, sulfur, nitrogen, and phosphorous, more preferably, oxygen, sulfur, and nitrogen. Heteroalkenyls may be substituted or unsubstituted
  • heteroalkyl is an alkyl radical comprised of carbon atoms and one or more heteroatoms wherein the heteroatoms are selected from the group consisting of oxygen, sulfur, nitrogen, and phosphorous, more preferably, oxygen, sulfur, and nitrogen. Heteroalkyls may be substituted or unsubstituted.
  • heteroalkynyl is an alkynyl radical comprised of carbon atoms and one or more heteroatoms wherein the heteroatoms are selected from the group consisting of oxygen, sulfur, nitrogen, and phosphorous, more preferably, oxygen, sulfur, and nitrogen. Heteroalkynyls may be substituted or unsubstituted.
  • heteroaryl is an aryl radical comprised of carbon atoms and one or more heteroatoms wherein the heteroatoms are selected from the group consisting of oxygen, sulfur, nitrogen, and phosphorous, more preferably, oxygen, sulfur, and nitrogen. Heteroaryls may be substituted or unsubstituted.
  • heteroarylalkenyl is an arylalkenyl radical wherein the aryl group and / or the alkenyl group is comprised of carbon atoms and one or more heteroatoms wherein the heteroatoms are selected from the group consisting of oxygen, sulfur, nitrogen, and phosphorous, more preferably, oxygen, sulfur, and nitrogen. Heteroarylalkenyls may be substituted or unsubstituted.
  • heteroarylalkyl is an arylalkyl radical wherein the aryl group and / or the alkyl group is comprised of carbon atoms and one or more heteroatoms wherein the heteroatoms are selected from the group consisting of oxygen, sulfur, nitrogen, and phosphorous, more preferably, oxygen, sulfur, and nitrogen. Heteroarylalkyls may be substituted or unsubstituted.
  • heterocyclychc ring is a ring radical comprised of carbon atoms and one or more heteroatoms in the ring wherein the heteroatoms are selected from the group consisting of oxygen, sulfur, nitrogen, and phosphorous, more preferably, oxygen, sulfur, and nitrogen.
  • Heterocycles are monocychc or are fused, bridged, or spiro polycychc rings. Unless otherwise specified, monocycles contain from 3 to about 9 atoms, preferably from about 4 to about 7 atoms, and most preferably 5 or 6 atoms Polycycles contain from about 7 to about 17 atoms, preferably from about 7 to about 14 atoms, and most preferably 9 or 10 atoms.
  • Heterocychc rings may be substituted or unsubstituted.
  • heterocycloalkyl is a cycloalkyl having at least one heteroatom m the nng. Heterocycloalkyls may be substituted or unsubstituted.
  • heterocycloalkenyl is a cycloalkenyl having at least one heteroatom in the ring. Heterocycloalkyls may be substituted or unsubstituted
  • a “lower” moiety e g , "lower” alkyl is moiety having 1 to about 6, preferably 1 to about 4. carbon atoms
  • 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 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
  • substituted means having one or more substituent groups each independently selected from hydrogen, alkyl, alkenyl, alkoxy, hydroxy, nitro, amino, alkylam o, cyano, halo, thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl (e g , pipe ⁇ dinyl, morphol yl, pyrrohdmyl), lmmo, hydroxyalkyl, aryloxy, and arylalkyl, preferably hydrogen, alkyl, alkenyl, alkoxy, hydroxy, nitro, ammo, alkylammo, halo, thiol, and aryloxy, more preferably hydrogen, alkyl, alkenyl, alkoxy, hydroxy, nitro, ammo, alkylammo, and halo, even more preferably hydrogen,
  • Rj, R 2 , Rs. R 7 . and R 10 are each, independently, selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl. heteroalkeml, and heteroalkynyl;
  • R- is selected from the group consisting of halogen, alkyl, alkenyl, alkynyl. cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl. heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarylalkyl.
  • R is hydrogen
  • Y is -CTLCHK
  • X is selected from the group consisting of -NZ- and -NH-
  • R ]2 is Cj - C 4 alkyl
  • Ki is selected from hydrogen and C, - C 4 alkyl and Z is C, - C_, alkyl, then R-, is not arylalkyl
  • R s and R are each, independently, selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalk l, heterocycloalkenyl, heteroaryl, heteroarylalkyl, and heteroarylalkenyl; wherein at least one of Rs and R 9 is not hydrogen;
  • R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarylalkyl and heteroarylalkenyl ;
  • R 6 and R 6 ' are each, independently, selected from the group consisting of ml and oxo;
  • Y is selected from the group consisting of bond, alkyl, alkenyl. alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl;
  • X is selected from the group consisting of -NZ-, -NH- and -0-;
  • R] ! is selected from the group consisting of bond and -C(O)-; wherein when Y is bond and X is -0-, then R, , is -C(O)-;
  • R, 2 is selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl.
  • R i2 and Z may be optionally bonded together to form a cycle selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl; wherein when R I2 is heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkem l. heteroaryl, heteroarylalk l. or heteroarylalkenyl, then a heteroatom of R ]2 is not directly covalently bonded to R n ; wherein when R ]2 is heteroalkyl.
  • the present compounds are sulfur-bridged compounds linked through a carbon atom which is substituted with substituents R 6 and / or R 6 '.
  • substituents R 6 and / or R 6 ' are described in further detail below.
  • R R 2 , R 5 , R7, and R 10 each substitute on one of the phenyl rings of the structure shown herein.
  • Rj, R 2 , R 5 , R 7 , and R ]0 are each, independently, selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl.
  • 0 are preferably each, independently, selected from hydrogen, halogen, alkyl, alkenyl, heteroalkyl, and heteroalkenyl.
  • R,, R 2 , R 5 , R 7 . and R I0 are more preferably each, independently, selected from hydrogen, halogen, and lower alkyl. Most preferably, R,, R 2 , R 5 , R 7 , and R ]0 are each hydrogen.
  • the substituent R is selected from halogen, alkyl, alkenyl. alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl. heterocycloalkyl.
  • R 2 is hydrogen, Y is -CT CHK,, X is selected from the group consisting of -NZ- and -NH-, and R, 2 is C] - C 4 alkyl, wherein K] is selected from hydrogen and C, - C 4 alkyl and Z is - C alkyl, then R-t is not arylalkyl.
  • R- 4 is preferably selected from halogen, alkyl. alkenyl, alkym l.
  • R 4 is more preferably selected from halogen, alkyl, alkenyl. heteroalkyl, and heteroalkenyl.
  • R 4 is even more preferably selected from halogen, alkyl. alkenyl. and heteroalkyl.
  • R- ⁇ is most preferably selected from halogen and lower alkyl.
  • the most preferred halogens for R-» are chlorine, bromine, and iodine, preferably chlorine and iodine, and most preferably iodine.
  • the most preferred lower alky s for R- are methyl, ethyl, /s ⁇ -propyl, and tert-butyl, preferably methyl, zso-propyl, and tert-butyl, more preferably ..vo-propyl or tert-butyl.
  • R ⁇ is lower alkyl, particularly ..so-propyl or tert-butyl.
  • R 8 and R 9 are each, independently, selected from hydrogen, halogen, alkyl, alkenyl. alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroalkyl, heteroalkenyl. heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarylalkyl, and heteroarylalkenyl; wherein at least one of R 8 and R 9 is not hydrogen.
  • each of R 8 and R 9 are not hydrogen.
  • R 8 and R 9 are preferably each, independently, selected from halogen, alkyl, alkenyl, heteroalkyl, and heteroalkenyl.
  • R 8 and R 9 are more preferably each, independently, selected from halogen, alkyl, alkenyl, and heteroalkyl.
  • R s and R 9 are e ⁇ en more preferably each, independently, selected from halogen and lower alkyl.
  • the most preferred halogens for R 8 and R 9 are chlorine and bromine, preferably chlorine.
  • R 8 and R 9 are methyl, ethyl, /so-propyl, and tert-butyl, preferably methyl, /s ⁇ -propyl, and tert-butyl, more preferably methyl and vo-propyl. Most preferably, R 8 and R 9 are each, independently, selected from lower alkyl and halogen, particularly methyl and chlorine, respectively.
  • R 3 substitutes on the oxygen moiety of the biphenyl structure as shown above.
  • R 3 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarylalkyl and heteroarylalkenyl.
  • R 3 is selected from hydrogen, alkyl, alkenyl, cycloalkyl, aryl, arylalkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, heteroaryl, and heteroarylalkyl.
  • R 3 is selected from hydrogen, alkyl, alkenyl, aryl, arylalkyl, heteroalkyl, heteroaryl, and heteroarylalkyl. Still more preferably, R-, is selected from hydrogen, alkyl, alkenyl, arylalkyl (preferably benzyl), heteroalkyl, and heteroarylalkyl. Even more preferably. R 3 is selected from hydrogen, lower alkyl. and lower alkenyl. Most preferably. R-> is selected from hydrogen and lower alkyl. The most preferred lower alkyl for R 3 is methyl.
  • R 6 and R 6 ' are each, independently, selected from l and oxo. Wherein both R 6 and R 6 ' are nil, then the sulfur-bridge of the compound is -S-. Wherein R 6 is nil and R 6 ' is oxo (or wherein R 6 is oxo and R 6 ' is nil), then the sulfur-bridge of the compound is a sulfoxide (-S(O)-). Wherein R 6 and R 6 ' are both oxo, then the sulfur-bridge of the compound is a sulfone (-S(0)(0)- )•
  • Y is selected from bond, alkyl, alkenyl. alkynyl. heteroalkyl, heteroalkenyl, and heteroalkynyl. Wherein Y is bond, X is directly bonded to the phenyl ring bearing R 7 , R 8 , R 9 , and R ]0 .
  • Y is preferably selected from bond, alkyl. alkenyl, heteroalkyl, and heteroalkenyl. More preferably, Y is selected from bond and lower alkyl. Most preferably, Y is bond.
  • X is selected from -NZ-, -NH-, and -0-.
  • Z substitutes on the nitrogen of -NZ- and is selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl. and heteroalkynyl; or wherein when R n is bond, then R 12 and Z may be optionally bonded together to form a cycle selected from cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl.
  • Z is selected from alkyl, alkenyl, heteroalkyl, and heteroalkenyl, or R ]2 and Z are bonded together to form a cycle selected from cycloalkyl, cycloalkenyl, heterocycloalkyl. heterocycloalkenyl, aryl, and heteroaryl. More preferably, Z is lower alkyl, or R ] and Z are bonded together to form a cycle selected from cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl.
  • Z is C, - d alkyl, particularly methyl, or R 12 and Z are bonded together to form a cycle selected from cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl.
  • X is selected from -NH- and -NZ-. Most preferably. X is -NH-, -N(CH 3 )-, or -NZ- wherein R ]2 and Z are bonded together to form a cycle selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl. aryl. and heteroaryl.
  • the cycle is preferably selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, more preferably from cycloalkyl. heterocycloalkyl. and aryl. even more preferably from cycloalkyl and heterocycloalkyl, and most preferably heterocycloalkyl.
  • the cycle may also optionally bear one or more oxo (i e , doubly bonded oxygen) substituents
  • oxo i e , doubly bonded oxygen
  • Non- hmit g examples of these cycles include pipe ⁇ dmyl, morphohnyl, piperazmyl, pyrrohdmyl, lndolmyl, succinimidyl. and hydantoinyl.
  • Rn is selected from bond and -C(O)-. wherein when Y is bond and X is -0-, then Rn is - C(O)-. Wherein R n is bond, R )2 is directly bonded to X. While both bond and -C(O)- are both highly preferred for R, ,, most preferably, R ⁇ , is -C(O)-
  • R 12 is selected from alkyl, alkenyl. alkynyl. heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl. heterocycloalkenyl, aryl.
  • R ]2 and Z may be optionally bonded together to form a cycle selected from the group consisting of cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl, wherein when R n is heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarylalkyl, or heteroarylalkenyl, then a heteroatom of R ⁇ is not directly covalenth bonded to R n - Accordingly, carbamates and ureas at the -Y-X-R n -Ri 2 linkage are not contemplated withm the present invention.
  • R is heteroalkyl, it is not, e.g , -0-CH 2 - CH 3 , but could be, e
  • R )2 is selected from alkyl, alkenyl, heteroalkyl, heteroalkenyl, cy cloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, and heteroarylalkenyl, or is bonded to Z to form a cycle selected from cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl. More preferably, R 12 is selected from alkyl, alkenyl.
  • R. 2 is selected from alkyl, heteroalkyl, arylalkyl, and heteroarylalkyl, or is bonded to Z to form a cycle selected from cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl.
  • R. 2 is selected from alkyl, heteroalkyl, arylalkyl, and heteroarylalkyl, or is bonded to Z to form a cycle selected from cycloalkyl, cycloalkenyl, heterocycloalkyl.
  • R 12 is lower alkyl. or is bonded to Z to form a cycle selected from cy cloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl
  • the most preferred lower alkyis for R ]2 are methyl, ethyl, ⁇ -propyl, .so-propyl, /.-butyl, tert-butyl, and ..-pentyl, particularly methyl, /.-propyl, zso-propyl, /.-butyl, and tert-butyl
  • the cycle is preferably selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, more preferably from cycloalkyl, heterocycloalkyl, and aryl.
  • the cycle may also optionally bear one or more oxo (z e., doubly bonded oxygen) substituents.
  • oxo z e., doubly bonded oxygen
  • Non- limitmg examples of these cycles include pipe ⁇ dmyl, morphohnyl, piperazmyl, pyrrohdinyl, mdolmyl, succimmidyl. and hydantomyl.
  • R 6 and R 6 ' are each nil:
  • R 6 is nil and R 6 ' is oxo (or R 6 is oxo and R 6 ' is nil): 17
  • the present invention relates to compounds and methods for treating hair loss.
  • the compound utilized 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-sparing) using the following methods.
  • 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 ad ⁇ ersely affect the cardiovascular system As thyroid hormone (T3) damages the cardiovascular system the heart enlarges See, e g , Gomberg-Maitland et al "Thyroid hormone and Disease", American Heait Journal Vol 135(2), pp 187-196 (1998), Klein and Oiamaa "Thyroid Hormone and the Cardiovascular System", Cm rent Opinion in Endocrinology and Diabetes Vol 4, pp 341-346 ( 1997) and Klemperer et al "Thyroid Hormone Therapy and Cardiovascular Disease", Piogress in Caidioxasculai Diseases Vol 37 (4), pp 329-336 (1996) This increases the weight of the heart relative to whole body weight
  • the cardiotoxicity assay herein below is used to test compounds for potentially ad ⁇ erse 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 prior to initiation of the assay as well as to termination of the study
  • the vehicle is 91 9 (v v) propylene glycol ethanol
  • 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 or test compound in 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 dosing solution for both groups Bod ⁇ 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. For each treatment, the dosing solution is administered subcutaneously between the shoulders of the rat such that the injection sites are rotated m 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 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 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 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-sparme.
  • 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 in 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 experiments, melanogenesis occurs along with hair (fur) growth w herein 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 and a test compound group wherein the test compound group is administered a compound according to 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, howe ⁇ er the ordinarily 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 of the present invention are prepared according to methods which are well-known to those ordinarily skilled m the art
  • the starting materials used in preparing the compounds of the invention 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 center
  • the compounds of the invention may exist as racemic mixtures, mixtures of optical isomers, including diastereomers and enantiomers.
  • optical isomer including a diastereomer and enantiomer. or a stereoisomer. may have favorable properties over the other.
  • optical isomers including diastereomers and enantiomers, or stereoisomers substantially free of the other are disclosed and claimed as well
  • the compounds of the present invention may be prepared using a variety of procedures known to those ordinarily skilled in the art Non-hmitmg general preparations include the following.
  • the compounds of the invention can be prepared, after removal of temporary protection groups (see, e.g.. T. Greene, Protecting Groups in Organic Synthesis, John Wiley & Sons, 1981 ) by condensing (e g . acylating or alkylating) a compound of the structure'
  • R,, R 2 , R 3 , R.,, R 5 , R 7 , R 8 , R 9 , R, 0 , Y, and X are defined herein above and are in an appropriately protected form if necessary, with a reactive derivative of the structure:
  • R 12 is defined herein above and is in an appropriately protected form if necessary and Q is halogen, preferably bromine or iodine, and most preferably iodine.
  • Reactive derivatives of structure II include, for example, activated esters such as 1 -hydroxybenzotriazole esters, mixed anhydrides of organic or inorganic acids such as hydrochloric acid and sulfonic acids, and symmetrical anhydrides of the acids of structure II
  • Activated derivatives of structure III include trifluoromethane sulfonyl esters and other activated derivatives known to those ordinarily skilled
  • appropriately protected compounds resulting from the condensation of a compound of structure I with a compound of structure II, III or IV may be further modified to afford additional compounds of the invention after removal of temporary protection groups
  • modifications include, but are not limited to, reduction of an amide to an amme as described in Example 6 to afford a secondary or tertiary amine, and alkylation of an amide as described in Example 6
  • compounds of the invention in an appropriately protected form if necessary and having the thioether linkage, may be oxidized using conditions known to those ordinarily skilled in the art to afford sulfones of the structure V and sulfoxides of the structure VI (see structures below), also compounds of the invention after removal of temporary protection groups
  • a specific example of the oxidation of a thioether to the sulfone using tert- butylhydroperoxide is described m
  • Example 13 specific examples of the oxidation of a thioether to the sulfoxide using 3-chloroperoxybenzo ⁇ c acid are described in Examples 1 1 and 12.
  • compounds of the structure I may be prepared from a biaryl thioether intermediate of structure VII wherein P is, for example, a nitro, cyano, or acyl group
  • Compounds of the structure VII may be prepared by condensing a 4-halon ⁇ trobenzene of structure VIII with an appropriately substituted phenol of structure DC in a base catalyzed reaction as described in Examples 1, 7 and 8 below wherein Q is preferably chlorine or bromine
  • Compounds of the structure VII can be converted to compounds of the structure I by further transformation
  • P is nitro
  • the resulting compound of structure VII may be converted into a compound of structure I by reduction to the am e using standard chemical reactions
  • P is an acyl group
  • the compounds may be converted to compounds of structure I having secondary or tertiary amines by reductive alkylation of the ketone with a primary or secondary amine and a borohydnde reducing reagent m a solvent such as t ⁇ methylorthoformate using conditions known to those ordinarily skilled in the art
  • Copper (I) thiobenzoate Copper (II) acetate (3 g) is dissolved m 100 mL glacial acetic acid Thiobenzoic acid (1.25 g) is dissolved in 25 mL glacial acetic acid and this is poured into the copper (II) acetate solution. Precipitate is formed and is isolated by filtration. The solid is washed with acetic acid, water, and ethanol, and then dried under reduced pressure to afford lc.
  • 3,5-d ⁇ methyl-4-(4'- methoxyth ⁇ ophenoxy)-n ⁇ trobenzene (lg; 0.33 g) is dissolved m 5 mL of 49' 1 ethanohethyl acetate by heating on a water bath (40 °C) and to this solution, tin chloride dihydrate (1 g) is added. The reaction is heated to 70 °C and stirred for about 2 hours. The reaction is allowed to cool to room temperature, then poured onto ice. The pH is made slightly basic (pH 7-8) by addition of 5% aqueous sodium bicarbonate (50 mL) and then extracted with ethyl acetate (50 mL). The organic phase is washed with brine (50 mL), treated with charcoal, dried over MgS0 , and filtered. The filtrate is evaporated to provide lh Alternative preparation of 1 e
  • the reaction is stirred for 1 hour and poured into a separator funnel.
  • the aqueous layer is extracted with 250 mL hexanes.
  • the organic layer is separated and the aqueous layer is extracted two more times with 100 mL hexanes.
  • N-[3,5-dimethyl-4-(4'-methoxy-3'-/so-propylthiophenoxy)phenyl]pyrrolidine 2',6'- d ⁇ methyl-3-;-sO-propyl-4-methoxy-4'-am ⁇ nod ⁇ phenylth ⁇ oether (lh, 1 58 g) is dissolved m 2 mL ethanol and 0.75 mL 1 ,4-dnodobutane is added The sample is refluxed overnight.
  • N-[3,5-dimethyl-4-(4'- ethox ⁇ -3'-/4 ⁇ -propylthiophenoxy)phenyI]benza ide 2 ,6 - d ⁇ methyl-3-. ⁇ -propyl-4-methoxy-4'-am ⁇ nod ⁇ phenylth ⁇ oether (lh; 0.245 g) is suspended in pyridine (1 mL). To this solution is added 0.24 mL benzoyl chloride and the reaction is stirred 1 hour. The sample is concentrated under reduced pressure and dissolved in ethyl acetate This is washed with water and brme then dried over magnesium sulfate and concentrated under reduced pressure. The residue is recrystalhzed from ethyl acetate:hexanes to afford 4.
  • butyramide In a dry flask under nitrogen. 0.32 g sodium hydride is suspended in 5 mL THF and stirred 10 minutes. To this solution is added dropwise N-(3,5- d ⁇ methyl-4-(4'-methoxy-3'-/5O-propylth ⁇ ophenoxy)phenyl)butyram ⁇ de (2; 1 g) in 5 mL THF. The reaction is stirred for 15 minutes and methyl iodide (0.28 mL) is added dropwise.
  • N-methyl-N-[3,5-dimethyl-4-(4'-methoxy-3'-/s ⁇ - propylthiophenoxy)phenyl]butyla ine In a dry flask under nitrogen is placed lithium aluminum hydride (1 g). To this is added 30 mL THF dropwise. After stirring 10 minutes, a solution of N-methyl-N-[3,5-d ⁇ methyl-4-(4'-methoxy-3'-/5 - propylth ⁇ ophenoxy)phenyl)butyram ⁇ de (6a, 1.36 g) in 6 mL THF is added dropwise and the reaction is refluxed for about 16 hours.
  • the reaction is allowed to cool to room temperature, then poured onto ice
  • the pH is made slightly basic (pH 7-8) by addition of 5% aqueous sodium bicarbonate (50 mL) and then extracted with ethyl acetate (50 mL)
  • the organic phase is washed with brme (50 mL), treated with charcoal, dried over MgS0 4 , and filtered.
  • the filtrate is evaporated to provide 7b.
  • 3-tert-butyl-4-methoxythiophenol 3-tert-butyl-4-methoxyth ⁇ ophenol (8a) is prepared analogously to the synthesis of 3-;->o-propyl-4-methoxyth ⁇ ophenol (le), which is described above, by substituting 2-tert-butyl phenol as a starting material for 2-z-?o-propyl phenol.
  • 3,4-dichloro-5-methyl-nitrobenzene 3,4-d ⁇ chloro-5-methyl-mtrobenzene (8b) is prepared analogously to the synthesis of 4-chloro-3,5-d ⁇ methyl-n ⁇ trobenzene (If), which is described above, by substituting 2-chloro-4-n ⁇ tro-6-methylphenol for 2,6-d ⁇ methyl-4-n ⁇ trophenol.
  • N-(3-chloro-5-methyl-4-(4'-methoxy-3'-tert-butylthiophenoxy)phenyl)acetamide Acetic anhydride (4 mL) is added to 2'-chloro-6'-methyl-3-tert-butyl-4-methoxy-4'- aminodiphenylthioether (8d, 0.25 g) and the reaction is stirred overnight. At this time, 20 mL water and 20 mL ethyl acetate are added and the reaction mixture is extracted with 1 N NaOH until the aqueous layer has a pH above 10. After extracting once with brine, drying over magnesium sulfate and filtering, the organic layer is concentrated under reduced pressure and purified by chromatography on silica gel (hexane:ethyl acetate) to afford 9.
  • N-[3,5-dimethyl-4-(4'-methoxy-3'-/so-propylphenylsulf ⁇ n>l)phenyl]butyramide A mixture of N-[3,5-dimethyl-4-(4'-methoxy-3 , -wo-propylthiophenoxy)phenyl]butyramide (2, 1.1 g), 1.2 mL 5M tert-butylhydroperoxide in nonane, and 70 mg camphor sulphonic acid are taken up in 15 mL dichloromethane and stirred for 20 hours. At this time, the reaction mixture is poured directly onto a silica gel column and the product is isolated by chromatography with hexanes: ethyl acetate
  • a compound having a structure as described herein is administered, most preferably with a pharmaceutically-acceptable or cosmetically-acceptable carrier.
  • the compounds of the present invention may be used for the treatment of such conditions as treating hair loss mammals, including arresting and / or reversing hair loss and promoting hair growth. Such conditions may manifest themselves m, for example, alopecia, including male pattern baldness and female pattern baldness hi addition, the compounds of the present invention may be useful for weight control, including the treatment and / or prevention of obesity
  • Other uses for the compounds of the present invention include stimulation of nail growth, treatment of skm conditions, prevention of hair discoloration, obesity, cholesterol lowering, treatment of thyroid disorders, and treatment of osteoporosis.
  • 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 m 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-admimstered 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 Carriers 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 preferred with topical being most preferred.
  • a variety of carriers well-known in 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.
  • 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 gelatin
  • talc solid lubricants, such as stea ⁇ c acid and magnesium stearate
  • calcium sulfate such as peanut oil.
  • cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma polyols such as propylene glycol, glycerine, sorbitol, manmtol, and polyethylene glycol
  • algmic acid such as the TWEENS
  • emulsifiers such as the TWEENS
  • wetting agents such sodium lauryl sulfate
  • coloring agents such as flavoring agents; tableting agents, stabilizers; antioxidants; preservatives: pyrogen-free water: isotomc saline; and phosphate buffer solutions.
  • a carrier to be used in 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, isotomc saline, and pyrogen- free water.
  • Preferred carriers for parenteral administration include propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil.
  • the carrier, 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- mducing 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, stea ⁇ c acid and talc. Ghdants such as silicon dioxide can be used to improve flow characteristics of the powder mixture.
  • 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, stea ⁇ c acid and talc.
  • Ghdants such as silicon dioxide can be used to improve flow characteristics of the powder mixture.
  • Coloring agents such as the FD&C dyes
  • Sweeteners and flavoring agents such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets.
  • Capsules typically comprise one or more solid diluents disclosed above.
  • compositions also include liquid solutions, emulsions, suspensions, powders, granules, elixirs, tinctures, syrups, and the like
  • the carriers 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 alginate
  • 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
  • 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 m 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 sublingual, 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 Ghdants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included
  • the compounds of the present invention may also be topically administered.
  • the carrier of the topical composition preferably aids penetration of the present compounds into the skm to reach the environment of the hair follicle.
  • Topical compositions of the present invention may be in any form including, for example, solutions, oils, creams, ointments, gels, lotions, shampoos, leave-on and rinse-out hair conditioners, milks, cleansers, moisturizers, sprays, skin 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, glycerine, 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, glycerine, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 my ⁇ styl propionate, and the like.
  • emollients such as stearyl alcohol, glyceryl mono ⁇ cmoleate, glyceryl monostearate, propane-l J-diol, butane- 1.3-d ⁇ ol, mink oil, cetyl alcohol, ⁇ o-propyl isostearate, stea ⁇ c acid, iso- butyl palmitate.
  • d ⁇ -//-butyl sebacate iso- propyl my ⁇ state, wo-propyl palmitate, Z5O-propyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolm, sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolin alcohols, petroleum, mineral oil, butyl my ⁇ state, lsostea ⁇ c acid, palmitic acid, zso-propyl hnoleate, lauryl lactate, my ⁇ styl lactate, decyl oleate, and myristyl my ⁇ state; propellants, such as propane, butane, /so-butane, dimethyl ether, carbon dioxide, and nitrous oxide; solvents, such as ethyl alcohol, methylene chloride, -so-propanol, castor oil, ethylene glycol monoethyl ether, diethylene glyco
  • the compounds used in the present invention may also be administered in the form of l posome 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 Cyclospo ⁇ n A: I. An in vitro Study Using Hairless Mouse Skin", S T.P Pliarma Sciences, Vol. 3, pp.
  • 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/Protein Drugs", Pharm Res , Vol. 10 (5), pp. 697-702 (1993); Ferry, "Theoretical Model of Iontophoresis Utilized in Transdermal Drug Delivery", Pharmaceutical Ada He etiae, Vol 70, pp 279-287 (1995).
  • 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, benzalkonium chloride, benzethomum chloride, phenol, estradiol, diphenhydramme hydrochlo ⁇ de, chlorpheniramme maleate, chlorophylhn derivatives, cholesterol, salicylic acid, cysteme, methionme, red pepper tincture, benzyl nicotinate, D,L - menthol, peppermint oil, calcium pantothenate, panthenol, castor oil, hinokitiol, pred solone, resorcinol, monosaccha ⁇ des and este ⁇ fied monosaccha ⁇ des, chemical activators of protein kinase C enzymes, glycosaminoglycan chain cellular uptake inhibitors, inhibitors of glycosidase activity, glycosammoglycanase inhibitors, esters of pyroglutamic
  • Non-limiting 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 ⁇ on ⁇ c acid.
  • 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 of the present invention and information and / or instructions by words, pictures, and / or the like, that use of the kit will provide treatment for hair loss mammals (particularly humans) including, for example, arresting and / or reversing hair loss and / or promoting hair growth.
  • the kit may comprise a compound and / or composition of the present invention and information and / or instructions regarding methods of application of the compound and / or composition, preferably with the benefit of treating hair loss m mammals.
  • 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.
  • a composition for topical administration is made according to the method of Dowton et al., "Influence of Liposomal Composition on Topical Delivery of Encapsulated Cyclospo ⁇ n A: I. An in vitro Study Using Hairless Mouse Skm", S.T.P. Pharma Sciences, Vol. 3, pp. 404 - 407 (1993), using the compound of Example 2 in lieu of cyclosporin 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 comprising:
  • 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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
  • Birds (AREA)
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  • Dermatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Cosmetics (AREA)
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Abstract

La présente invention concerne de nouveaux composés de la formule (A) dans laquelle R1-R12, X et Y ont les définitions données dans la description, ainsi que des compositions les contenant, lesquels sont particulièrement utiles pour traiter la perte des cheveux chez des mammifères, et permettent notamment de stopper et/ou d'inverser la perte des cheveux et de stimuler leur croissance. Les composés décrits dans l'invention ménagent le coeur.
PCT/US2000/005252 1999-06-01 2000-03-01 Derives de thyroxane contenant du soufre et leur utilisation en tant que promoteurs de croissance capillaire WO2000073265A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
MXPA01012497A MXPA01012497A (es) 1999-06-01 2000-03-01 Derivados de tiroxano que contienen azufre y su uso como promotores de crecimiento capilar.
CA002375667A CA2375667A1 (fr) 1999-06-01 2000-03-01 Derives de thyroxane contenant du soufre et leur utilisation en tant que promoteurs de croissance capillaire
EP00914768A EP1194405A1 (fr) 1999-06-01 2000-03-01 Derives de thyroxane contenant du soufre et leur utilisation en tant que promoteurs de croissance capillaire
AU36115/00A AU3611500A (en) 1999-06-01 2000-03-01 Sulfur-containing thyroxane derivatives and their use as hair growth promotors
JP2000621332A JP2003500471A (ja) 1999-06-01 2000-03-01 イオウ含有チロキシン誘導体及びそれらの毛髪成長促進剤としての使用
US09/980,404 US6723717B1 (en) 1999-06-01 2000-03-01 Sulfur-containing thyroxane derivatives and their use as hair growth promotors

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US13706399P 1999-06-01 1999-06-01
US60/137,063 1999-06-01

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AR (1) AR018700A1 (fr)
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1262177A2 (fr) * 2001-05-31 2002-12-04 Pfizer Products Inc. Utilisation médicale des composés thyromimétiques pour traiter la chute des cheveux et compositions
WO2003002519A1 (fr) * 2001-06-29 2003-01-09 Bayer Aktiengesellschaft Derives phenoles et leur utilisation dans des medicaments
WO2004047827A1 (fr) * 2002-11-25 2004-06-10 Pfizer Products Inc. Procede permettant de promouvoir la croissance des ongles a l'aide de composes thyromimetiques
US6777442B2 (en) 2001-03-12 2004-08-17 Bayer Aktiengesellschaft Diphenyl derivatives
WO2012051374A2 (fr) 2010-10-15 2012-04-19 The Procter & Gamble Company Utilisation d'inhibiteurs de monoamine oxydase pour améliorer la biologie épithéliale

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1617477A1 (de) * 1967-06-22 1970-01-08 Fischer Geb Beutelschiess Alwi Biologisches Haarwuchs-Tonicum mit Garantie
GB2138286A (en) * 1983-04-19 1984-10-24 Dr Christopher Harry Mortimer Pharmaceutical composition for the treatment of hair loss
WO1996025943A1 (fr) * 1995-02-23 1996-08-29 Life Medical Sciences, Inc. Compositions et procedes pour ameliorer la croissance des cheveux et pour leur restituer leur couleur d'origine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1617477A1 (de) * 1967-06-22 1970-01-08 Fischer Geb Beutelschiess Alwi Biologisches Haarwuchs-Tonicum mit Garantie
GB2138286A (en) * 1983-04-19 1984-10-24 Dr Christopher Harry Mortimer Pharmaceutical composition for the treatment of hair loss
EP0123528A1 (fr) * 1983-04-19 1984-10-31 Christopher Harry Dr. Mortimer Composition pharmaceutique pour le traitement de la chute des cheveux
WO1996025943A1 (fr) * 1995-02-23 1996-08-29 Life Medical Sciences, Inc. Compositions et procedes pour ameliorer la croissance des cheveux et pour leur restituer leur couleur d'origine

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6777442B2 (en) 2001-03-12 2004-08-17 Bayer Aktiengesellschaft Diphenyl derivatives
EP1262177A2 (fr) * 2001-05-31 2002-12-04 Pfizer Products Inc. Utilisation médicale des composés thyromimétiques pour traiter la chute des cheveux et compositions
EP1262177A3 (fr) * 2001-05-31 2003-09-03 Pfizer Products Inc. Utilisation médicale des composés thyromimétiques pour traiter la chute des cheveux et compositions
WO2003002519A1 (fr) * 2001-06-29 2003-01-09 Bayer Aktiengesellschaft Derives phenoles et leur utilisation dans des medicaments
WO2004047827A1 (fr) * 2002-11-25 2004-06-10 Pfizer Products Inc. Procede permettant de promouvoir la croissance des ongles a l'aide de composes thyromimetiques
WO2012051374A2 (fr) 2010-10-15 2012-04-19 The Procter & Gamble Company Utilisation d'inhibiteurs de monoamine oxydase pour améliorer la biologie épithéliale

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JP2003500471A (ja) 2003-01-07
AU3611500A (en) 2000-12-18
CA2375667A1 (fr) 2000-12-07
EP1194405A1 (fr) 2002-04-10
MXPA01012497A (es) 2002-07-02
AR018700A1 (es) 2001-11-28

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