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  • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
  • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
  • C07C217/78—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
  • C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
  • C07C217/82—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring
  • C07C217/90—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring the oxygen atom of at least one of the etherified hydroxy groups being further bound to a carbon atom of a six-membered aromatic ring, e.g. amino-diphenylethers
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
  • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
  • C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
  • C07C233/25—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
  • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
  • C07C233/67—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
  • C07C233/75—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
  • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
  • C07C271/06—Esters of carbamic acids
  • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
  • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups

Definitions

• the present invention relates to methods for treating hair loss in mammals, including arresting and / or reversing hair loss and promoting hair growth.
• Hair loss is a common problem which occurs, for example, through natural processes or is often chemically promoted through the use of certain therapeutic drugs designed to alleviate conditions such as cancer. Often such hair loss is accompanied by lack of hair regrowth which causes partial or full baldness.
• hair growth occurs by a cycle of activity which involves alternating periods of growth and rest. This cycle is often divided into three mam stages which are known as anagen, catagen, and telogen. Anagen is the growth phase of the cycle and may be 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 during which the hair follicle regresses through the dermis and hair growth is ceased.
• anagen is the growth phase of the cycle and may be characterized by penetration of the hair follicle deep mto the dermis with rapid proliferation of cells which are differentiating to form hair.
• catagen is a transitional stage marked by the cessation of cell division, and during which the hair follicle regresses through the dermis and hair growth is ceased.
• telogen is often 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 m 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 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 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.
• the present inventors have discovered compounds which strongly initiate hair growth without inducing cardiotoxicity.
• 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 , Rt, R5, R7, Rs, 9, Rio, Y, X, R11, and R ]2 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-spa ⁇ ng
• any variable, moiety, group, or the like occurs more than one time m 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 , ammo) 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 halides (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 olefimc double bond. Non-limiting examples of alkenyls include vinyl, allyl, and butenyl.
• 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.
• 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, ⁇ o-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 heterocychc.
• Preferred aryl groups include, for example, phenyl, benzyl, tolyl, xylyl, cumenyl, napthyl, biphenyl, thienyl, furyl, pyrrolyl, pyridmyl, pyrazinyl, thiazolyl, py ⁇ midinyl, quinohnyl, triazolyl, tetrazolyl, benzothiazolyl, benzofuryl, indolyl, mdenyl, azulenyl, fluorenyl, anthracenyl, oxazolyl, isoxazolyl, isot ⁇ azolyl, lmidazolyl, pyraxolyl, oxadiazolyl, lndolizinyl, indolyl, isoindolyl, pu ⁇ nyl
• Aryls may be substituted or unsubstituted.
• 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 in 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 ⁇ ngs contain from 3 to about 9 atoms, preferably from about 4 to about 7 atoms, and most preferably 5 or 6 atoms
• Polycychc rings 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
• 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 comp ⁇ sed 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. Heteroarylalkyl s may be substituted or unsubstituted.
• heterocyclychc ring is a ⁇ ng 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 (heterocycles) may be substituted or unsubstituted.
• heterocycloalkyl is a cycloalkyl having at least one heteroatom in the ring. Heterocycloalkyls may be substituted or unsubstituted
• heterocycloalkenyl is a cycloalkenyl having at least one heteroatom m the ring Heterocycloalkyls may be substituted or unsubstituted.
• a “lower” moiety 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.
• substituted in reference to a group, moiety, or the like, means having one or more substituent groups each independently selected from hydrogen, alkyl, alkenyl, alkoxy, hydroxy, nitro, ammo, alkylammo, cyano, halo, thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl (e g , pipe ⁇ dmyl, morpholmyl, pyrrohdmyl), lmmo, hydroxyalkyl, aryloxy, and arylalkyl, preferably hydrogen, alkyl, alkenyl, alkoxy, hydroxy, nitro, ammo, alkylamino, halo, thiol, and aryloxy, more preferably hydrogen, alkyl, alkenyl, alkoxy, hydroxy, nitro, ammo, alkylamino, and halo, even more preferably hydrogen, alkyl, alkenyl, alkoxy, hydroxy,
• the compounds of the present invention have the structure:
• R b R 2 , R 5 , R 7 , and R 10 are each, independently, selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl
• R 4 is selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarylalkyl, and heteroarylalkenyl; wherein when R 2 is hydrogen, Y is -CH 2 CHK ⁇ , X is selected from the group consisting of -NZ- and -NH-, and R !2 is - C 4 alkyl, wherein Ki is selected from hydrogen and Ci - C 4 alkyl and
• R 8 and R 9 are each, independently, selected from the group consisting of 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;
• 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 -O-;
• Ri 1 is selected from the group consisting of bond and -C(O)-; wherein when Y is bond and X is -O- then R n is -C(O)-; and wherein when Y is alkyl and X is -O- then R n ⁇ s not -C(O)-;
• R 12 is selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, and heteroarylalkenyl; or wherein when R ⁇ is bond, then R 12 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 ]2 is heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarylalkyl, or heteroarylalkenyl, then a heteroatom of R ⁇ 2 is not directly coval
• the present compounds are substituted biphenyl ether compounds.
• the substituents are described in further detail below.
• R l5 R 2 , R 5 , R 7 , and R ⁇ 0 are each, independently, selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl.
• Ri, R 2 , R5, R7, and R 10 are preferably each, independently, selected from hydrogen, halogen, alkyl, alkenyl, heteroalkyl, and heteroalkenyl.
• R,, R 2 , R 5 , R 7 , and R ⁇ 0 are more preferably each, independently, selected from hydrogen, halogen, and lower alkyl.
• Rj, R 2 , R 5 , R 7 , and R 10 are each hydrogen.
• the substituent P IS selected from halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarylalkyl, and heteroarylalkenyl; wherein when R 2 is hydrogen, Y is -CH 2 CHK ⁇ , X is selected from the group consisting of -NZ- and -NH-, and R I2 is C] - C 4 alkyl, wherein K] is selected from hydrogen and d - C alkyl and Z is Ci - C 4 alkyl, then Rt is not arylalkyl is preferably selected from halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroalkyl, heteroalkenyl,
• 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. 4 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.
• R 4 The most preferred lower alkyls for R 4 are methyl, ethyl, ..sO-propyl, and tert-butyl, preferably methyl, zs ⁇ -propyl, and tert-butyl, more preferably .s ⁇ -propyl or tert-butyl. Most preferably, R 4 is lower alkyl, particularly zs ⁇ -propyl or tert-butyl.
• Rg 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 8 and R 9 are even 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 chlo ⁇ ne.
• R 8 and R 9 are methyl, ethyl, wo-propyl, and tert-butyl, preferably methyl, zso-propyl, and tert-butyl, more preferably methyl and zs ⁇ -propyl.
• R 8 and R 9 are each, independently, selected from lower alkyl and halogen, particularly methyl and chlo ⁇ ne, 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 3 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 3 is selected from hydrogen and lower alkyl. The most preferred lower alkyl for R 3 is methyl.
• Y is selected from bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl
• Y is bond
• X is directly bonded to the phenyl ring bearing R 7 , R 8 , R 9 , and R I0
• 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.
• the Substituent X 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 u is bond, then R !2 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] 2 and Z are bonded together to form a cycle selected cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl.
• Z is - C 3 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-.
• X is -NH-, -N(CH 3 )-, or -NZ- wherein R !2 and Z are bonded together to form a cycle selected from 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.
• Non- hmitmg examples of these cycles include pipe ⁇ dinyl, morpholmyl, piperazmyl, pyrrolidinyl, indolinyl, succmimidyl, and hydantomyl.
• R u is selected from bond and -C(O)-. However, wherein when Y is bond and X is -O- then Rn is -C(O)-; and wherein Y is alkyl and X is -O- then Rn is not -C(O)- (but rather is bond).
• X is selected from -NZ- and -NH-, then both bond and -C(O)- are highly preferred for R u , but most preferably, Rn is -C(O)- Wherein X is -O-, R n is most preferably - C(O)-.
• R 12 is selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, and heteroarylalkenyl; or wherein when R n is bond, then R 12 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 12 is heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarylalkyl, or heteroarylalkenyl, then a heteroatom of R 12 is not directly covalently bonded to Rn- Accordingly,
• Y is bond or hydroxy-substituted ethyl (i.e., -CHOHCH 2 -)
• X is - NH-
• R n is bond
• R ] is not methyl. More preferably, wherein Y is bond or alkyl, X is - NH-, and Rn is bond, then R 1 is not methyl. Also, wherein Y is bond, X is -0-, and R ⁇ is - C(O)- then R ]2 is not aryl.
• R 12 is selected from alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, 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.
• R !2 is selected from alkyl, alkenyl, heteroalkyl, heteroalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, and heteroarylalkenyl, 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, heterocycloalkenyl, aryl, and heteroaryl.
• R ⁇ 2 is lower alkyl, or is bonded to Z to form a cycle selected from cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl.
• the most preferred lower alkyls for R ]2 are methyl, ethyl, «-propyl, zs ⁇ -propyl, n-butyl, tert-butyl, and w-pentyl, particularly methyl, z-propyl, zs ⁇ -propyl, n-butyl, and tert-butyl.
• 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.
• Non- hmiting examples of these cycles include pipe ⁇ dinyl, morpholmyl, piperazmyl, pyrrohdmyl, mdolmyl, succinimidyl, and hydantomyl.
• the present invention relates to compounds and methods for treating hair loss.
• the compound utilized in the present invention will be cardiac-spa ⁇ ng.
• 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 m the art may be used (but with the term “cardiac-spa ⁇ ng” being defined according to the method disclose •Hd "I htterrrppe-iimnn HK bppelllrrow ⁇ ).
• the cardiotoxicity assay measures the potential of a test compound to adversely affect the cardiovascular system.
• thyroid hormone T3 damages the cardiovascular system, the heart enlarges.
• T3 thyroid hormone
• Klem and Oiamaa "Thyroid Hormone and the Cardiovascular System", Current Opinion in Endocrinology and Diabetes, Vol. 4, pp.341-346 (1997)
• Klemperer et al. "Thyroid Hormone Therapy and Cardiovascular Disease", Progress in Cardiovascular 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 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 m vehicle daily for 28 of those days as described below.
• each rat is allowed to acclimate to standard environmental conditions for 5 days.
• Each rat receives food (standard rat chow diet) and water ad libitum 5 days prior to initiation of the assay as well as to termination of the study.
• the vehicle is 91 :9 (v:v) propylene glycohethanol.
• the test compound is prepared at a concentration of 500 ⁇ g/mL in the vehicle.
• each rat is weighed on day 1 of the assay. Dosage calculations are then performed: each rat will be administered daily a dosing solution of vehicle or test compound 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 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 dosmg for that day; for each rat, the dosing 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. For each treatment, the dosmg solution is administered subcutaneously between the shoulders of the rat such that the injection sites are rotated in this area.
• the hearts of each rat are then excised as follows. An incision is made to expose the abdominal cavity. The rib cage is carefully cut at the sternum with small scissors, such that the heart and lungs are exposed. With small scissors and forceps, the vessels connected to the heart are cut away from the heart. These vessels include the caudal vena cava, left cranial vena cava (pulmonary trunk), ⁇ ght 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 euthanization for each rat to give the heart/body ratio.
• the heart/body ratios for each rat in the vehicle control group are added together and divided by 6 (i e , the total number of rats in the group) to give RV (ratio for vehicle control group).
• RV ratio for vehicle control group
• RT ratio for test compound group
• the index C is then calculated by dividing RT by RV.
• 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 ⁇ ne
• 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 period 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 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 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 2 below. Typical dosage concentrations are set forth in Table 2, however 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 in 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.
• one optical isomer including diastereomers and enantiomers
• another optical starting materials, catalysts or solvents or may prepare 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, or stereoisomers 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.
• the compounds of the present invention may be prepared using a va ⁇ ety of procedures known to those ordinarily skilled in the art.
• Non-limitmg general preparations include the following.
• the compounds of the invention may 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 , acylatmg or alkylating) a compound of the structure:
• R l5 R 2 , R 3 , R,, R 5 , R 7 , R 8 , R 9 , R I0 , 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 activated esters such as, for example, 1 -hydroxybenzot ⁇ azole esters, mixed anhydrides with organic or inorganic acids such as hydrochloric acid and sulfomc acids, and symmet ⁇ cal anhydrides of the acids of structure U
• Activated derivatives of structure III include t ⁇ fluromethane sulfonyl esters and other activated derivatives known to those ordinarily skilled in the art
• Compounds of structure IV are generally appropriately reactive without further modification; however, it may be necessary to convert a less reactive halogen to a more reactive halogen such as bromine or iodine as is known by those ordinarily skilled m the art.
• 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 Examples 7b and 15 to afford a secondary or tertiary am e, alkylation of an amide as described in Example 7a and alkylation of the aromatic ⁇ ngs using F ⁇ edel-Crafts conditions similar to those described in Example 10b.
• Compounds of structure I may be prepared from a biaryl ether intermediate of structure V wherein P is an electron-withdrawing functionality, for example, a nitro, cyano or acyl group.
• Compounds of structure V can be prepared by conversion of an anisole of structure VI to a symmet ⁇ cal bis-aryl lodonium salt as m Example lb herein followed by condensation in a copper catalyzed reaction with a phenol of structure VI
• Appropriately substituted amsoles of structure VI are commercially available or may be prepared from their corresponding phenols as described, for example, in Example la herein, or may be synthesized using methods known to those ordinarily skilled m the art
• Appropriately substituted phenols of structure VII are commercially available or may be prepared using methods known to those ordinarily skilled in the art
• compounds of structure V may be prepared by condensing a 4- halomtrobenzene of structure LX with an appropriately substituted phenol of structure VIE in a base catalyzed reaction as described in Examples 2a, 10a, and 11a herein.
• Compounds of the structure V can be converted to compounds of the structure I by further transformation.
• P is nitro
• the resulting compound of structure V can be converted mto a compound of structure I by reduction to the amme using standard chemical reactions utilizing, for example, palladium on carbon or tm chloride.
• P is acyl
• such compounds may be converted to compounds of structure I using, for example, peracetic acid to convert the acetophenone to an acetyl ester.
• the compounds of structure I may be prepared by reductive alkylation of the ketone using a primary or secondary amme and a borohyd ⁇ de reducing reagent.
• P is cyano
• such compounds may be converted a compound of structure I by reduction to an alkylamino compound using conditions known to those ordma ⁇ ly skilled in the art.
• the pH is made slightly basic (pH about 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 and dried over MgS0 4 and filtered. The filtrate is evaporated to provide 2b
• iY-[3,5-dimethyl-4-(4'-hydroxy-3'- ⁇ so-propylphenoxy)phenyl]butyramide iV-[3,5- d ⁇ methyl-4-(4'-methoxy-3'-z5 ⁇ -propylphenoxy)phenyl]butyram ⁇ de) (Example 4, 0.5 g) is dissolved 5 mL dichloromethane and cooled m a dry lce/zs ⁇ -propylphenoxy)phenyl]butyram ⁇ de) (Example 4, 0.5 g) is dissolved 5 mL dichloromethane and cooled m a dry lce/zs ⁇ -propanol bath. To this solution is added dropwise 1 M boron t ⁇ bromide (4.6 mL) in dichloromethane. After 30 minutes, the reaction is poured over ice (10 g) and is stirred an additional 30 minutes.
• V-[3,5-dimethyl-4-(4'-benzyloxy-3'-wo-propylphenoxy)phenyl]butyramide 7V-[3,5- d ⁇ methyl-4-(4'-hydroxy-3'-z5 ⁇ -propylphenoxy)phenyl]butyram ⁇ de) (Example 5, 173 mg) is dissolved in 5 mL acetone To this solution is added 96 mg potassium carbonate and 51 microhters benzyl bromide. The reaction is refluxed overnight. At this time, it is filtered through cehte and concenfrated under reduced pressure. The product is crystallized from hexanes to afford 6.
• the organic layer is extracted twice with IN hydrochloric acid (25 mL), twice with water (25 mL), twice with IN sodium hydroxide (25 mL), twice with water (25 mL), dried with magnesium sulfate, and concentrated under reduced pressure.
• the remaining residue is dissolved in 40 mL of DMF followed by addition of lithium bromide (4.1 g).
• the mixture is refluxed for 17 hours at 150°C.
• the mixture is concentrated under high vacuum.
• 60 mL water and 60 mL ethyl acetate is added and stirred. This mixture is filtered, the organic layer separated and dried with magnesium sulfate.
• the organic layer is concentrated under high vacuum and the remaining residue presorbed to silica gel using dichloromethane.
• the presorbed residue is then purified by chromatography on silica gel and subsequently crystallized from hexanes to afford 10a.
• the organic layer is extracted twice with 50 mL IN hydrochloric acid, twice with 50 mL water, twice with 50 mL IN sodium hydroxide, twice with 50 mL water, dried with magnesium sulfate, filtered, and concentrated under reduced pressure.
• the residue is dissolved in 160 mL of 1- methyl-2-pyrrohdmone followed by addition of lithium chloride (3.6 g). The mixture is refluxed for 17 hours at 120 °C. The mixture is concentrated under reduced pressure. To this residue, 100 mL water and 100 mL ethyl acetate is added and stirred. This mixture is filtered, the organic layer separated, and dried with magnesium sulfate. The organic layer is concenfrated under high vacuum to afford 11a.
• reaction is diluted with 75 mL diethyl ether and the organic layer is washed with 2M potassium hydrogen sulfate (25 mL x 3), once with water, 1 N sodium hydroxide (50 mL x 2), and once with 50 mL brme.
• 2M potassium hydrogen sulfate 25 mL x 3
• 1 N sodium hydroxide 50 mL x 2
• the organic layer is d ⁇ ed over sodium sulfate, filtered and the filtrate is concentrated under reduced pressure and purified by chromatography on silica gel to afford 16.
• 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 in mammals, including arresting and / or reversing hair loss and promoting hair growth. Such conditions may manifest themselves in, for example, alopecia, including male pattern baldness and female pattern baldness.
• the compounds of the present invention may be useful for weight control, including the freatment and / or prevention of obesity
• Other uses for the compounds of the present invention include stimulation of nail growth, treatment of sk conditions, prevention of hair discoloration, obesity, cholesterol lowering, treatment of thyroid disorders, and freatment 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 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-administered 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.
• topical and / or oral administration are especially preferred with topical being most preferred
• earners 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 mate ⁇ als may be included which do not substantially interfere with the activity of the compound of the present invention
• the amount of earner 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 earners or components thereof are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stea ⁇ c acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as the TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tabletmg agents, stabilizers; antioxidants; preservatives; pyrogen-free water; l
• 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, lsotomc salme, and pyrogen- free water.
• Preferred earners for parenteral administration include propylene glycol, ethyl oleate, pyrrohdone, 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- mducmg 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, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; dismtegrants such as starch, algmic acid and croscarmelose; lub ⁇ cants 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, can be added for appearance.
• 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
• lub ⁇ cants such as magnesium stearate, stea ⁇ c acid and talc.
• 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. The selection of carrier 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 ordinarily skilled in the art.
• Orally administered 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 algmate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate.
• Peroral liquid compositions may also contain one or more components such as sweeteners, flavoring 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 sublmgual, buccal and nasal dosage forms.
• Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalhne 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 earner of the topical composition preferably aids penefration of the present compounds mto the skin 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, skm patches, and the like.
• Topical compositions containing the active compound can be admixed with a variety of carrier materials well known in the art, such as, for example, water, alcohols, aloe vera gel, allantom, glyce ⁇ ne, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 my ⁇ styl propionate, and the like.
• carrier materials such as, for example, water, alcohols, aloe vera gel, allantom, glyce ⁇ ne, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 my ⁇ styl propionate, and the like.
• compositions suitable for use in topical earners include, for example, emollients, solvents, humectants, thickeners and powders. Examples of each of these types of materials, which can be used singly or as mixtures of one or more materials, are as follows:
• Emollients such as stearyl alcohol, glyceryl mononcinoleate, glyceryl monostearate, propane- 1,2-d ⁇ ol, butane- 1, 3 -diol, mink oil, cetyl alcohol, zso-propyl isostearate, stea ⁇ c acid, iso- butyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, dimethylpolysiloxane, di-n-butyl sebacate, isopropyl my ⁇ state, zso-propyl palmitate, zs ⁇ -propyl stearate, butyl stearate, polyethylene glycol, t ⁇ ethylene glycol, lanolin, sesame oil, coconut oil, arachis oil, castor
• Liposomes can be formed from a va ⁇ ety 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 Skm", S.TP Pharma Sciences, Vol. 3, pp. 404 - 407 (1993); Wallach and Phihppot, "New Type of Lipid Vesicle: Novasome ® ", Liposome Technology, Vol. 1, pp. 141 - 156 (1993); Wallach, U.S. Patent No.
• the compounds of the present invention may also be administered by iontophoresis. See, e.g., internet site www.un ⁇ pr. ⁇ t/a a/d ⁇ pfarm 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 Transdermal Drug Delivery", Pharmaceutical Ada Helvetiae, Vol 70, pp.
• 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, benzalkomum chlo ⁇ de, benzethomum chloride, phenol, esfradiol, diphenhydramine hydrochlo ⁇ de, chlorphemramme maleate, chlorophyllm derivatives, cholesterol, salicylic acid, cysteme, methionme, red pepper tincture, benzyl nicotmate, D,L - menthol, peppermint oil, calcium pantothenate, panthenol, castor oil, hmokitiol, predmsolone, resorcmol, monosaccha ⁇ des and este ⁇ fied monosaccha ⁇ des, chemical activators of protein kmase C enzymes, glycosammoglycan chain cellular uptake inhibitors, inhibitors of glycosidase activity, glycosammoglycanase inhibitors, esters of pyrog
• Non-limitmg 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-hydroxyprop ⁇ on ⁇ c acid, 2-hydroxyoctano ⁇ c acid, propan-1-ol, 1,4-d ⁇ oxane, tetrahydrofuran, butan-l,4-d ⁇ ol, propylene glycol dipelargonate, polyoxypropylene 15 stearyl ether, octyl alcohol, POE ester of oleyl alcohol, oleyl alcohol, lauryl alcohol, dioctyl adipate, dicapryl adipate, di-isopropy
• the compounds used in the present methods can be administered alone or as mixtures, and the compositions may further include additional drugs or excipients as appropriate for the indication.
• kits comprising a compound and / or composition 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 in 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 in 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 cyclospo ⁇ n A and using the Novasome 1 for the non-ionic liposomal formulation.
• a human male subject suffe ⁇ ng 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:

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• 2000
  • 2000-03-01 WO PCT/US2000/005251 patent/WO2000072920A1/en not_active Application Discontinuation
  • 2000-03-01 MX MXPA01012491A patent/MXPA01012491A/es unknown
  • 2000-03-01 EP EP00913676A patent/EP1183074A1/en not_active Withdrawn
  • 2000-03-01 AU AU35076/00A patent/AU3507600A/en not_active Abandoned
  • 2000-03-01 AR ARP000100917A patent/AR018472A1/es not_active Application Discontinuation
  • 2000-03-01 CA CA002375822A patent/CA2375822A1/en not_active Abandoned
  • 2000-03-01 JP JP2000621024A patent/JP2003500459A/ja active Pending

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