Classifications

• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic 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
  • A61K8/49—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
  • A61K8/492—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 having condensed rings, e.g. indol
• • 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

Definitions

• the present invention relates to methods for treating hair loss in mammals, including arresting hair loss, reversing hair loss and / or promoting hair growth.
• the methods comprise administering a composition wherein the composition comprises an indoline compound.
• 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. Such baldness is cosmetically unappealing, and is particularly distressing to the person experiencing the hair loss.
• hair growth occurs by a cycle of activity which involves alternating periods of growth and rest. This cycle is often divided into three main 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.
• the next phase, telogen is often characterized as the resting stage during which the regressed follicle contains a germ with tightly packed dermal papilla cells. At telogen, the initiation of a new anagen phase is caused by rapid cell proliferation in the germ, expansion of the dermal papilla, and elaboration of basement membrane components. This cycle is repeated throughout hair growth. Wherein 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.
• Propecia ® may be more effective than Rogaine ®
• patients using Propecia ® are experiencing limited hair growth.
• potential side effects of Propecia ® are serious.
• Propecia ® may cause impotence, decreased sexual drive, decreased volume of ejaculate, breast tenderness and enlargement, and hypersensitivity reactions, including lip swelling and skin rash.
• Propecia ® is not indicated for women and children. In fact, women who are pregnant or potentially pregnant should not even handle crushed or broken tablets containing the drug. See Physician's Desk Reference ® . 52 th Ed. (1998), p. 1737 and The New England Journal of Medicine. Vol. 338, No. 9, February 26, 1998.
• indoline compounds are effective for treating hair loss in mammals, including arresting hair loss, reversing hair loss and / or promoting hair growth. See Duranton et al.. EP 0,648,488, assigned to L'Oreal, published April 19, 1995. Such treatment may be either alone or in combination with one or more other agents useful for treating hair loss. Certain of these compounds will have anti-inflammatory properties as well, including cyclooxygenase inhibition, which has been heretofore described as being detrimental for treatment of hair loss.
• tenidap (5-chloro-3-(2-thenoyl)-2-oxindole-l-carboxamide), which has been extensively studied for various properties including, for example, anti-inflammation and use for treatment of Alzheimer's Disease, is surprisingly useful for treating hair loss.
• hair loss may be associated with activation of cytokines (including, for example, IL-1), tumor necrosis factors, and T-cell proliferation.
• cytokines including, for example, IL-1
• T-cell proliferation T-cell proliferation.
• indoline compounds having structures as defined herein, are useful for treating hair loss in mammals, including arresting and / or reversing hair loss and promoting hair growth. Accordingly, the present inventor provides herein compounds, compositions, and methods of their use for effectively treating hair loss.
• the present invention relates to methods for treating hair loss comprising administering a compound which have been found by the present inventor to be particularly useful for treating hair loss in mammals, including arresting and / or reversing hair loss and promoting hair growth.
• the compounds which may be utilized in the present method have the structure:
• the present invention relates to methods of using compounds and compositions which are particularly useful for treating hair loss in mammals (preferably humans), including arresting and / or reversing hair loss and promoting hair growth.
• alkanamido is a -NHC(0)U radical wherein U is an alkyl, alkenyl, or alkynyl, preferably an alkyl or alkenyl, and most preferably an alkyl substituent.
• alkanamidos have from 2 to about 15 carbon atoms (C 2 - C ⁇ 5 ); preferably from 2 to about 10 carbon atoms (C 2 - o); more preferably from 2 to about 8 carbon atoms (C 2 - C 8 ), even more preferably from 2 to about 6 carbon atoms (C 2 - C 6 ), and most preferably from 2 to about 4 carbon atoms (C 2 - C 4 ).
• alkanoyl is a -C(0)U radical wherein U is an alkyl, alkenyl, or alkynyl, preferably an alkyl or alkenyl, and most preferably an alkyl substituent.
• alkanoyls have from 2 to about 15 carbon atoms (C 2 - C ⁇ 5 ); preferably from 2 to about 10 carbon atoms (C 2 - o); more preferably from 2 to about 8 carbon atoms (C 2 - C 8 ), even more preferably from 2 to about 6 carbon atoms (C 2 - C 6 ), and most preferably from 2 to about 4 carbon atoms (C 2 - C 4 ).
• alkenyl is an unsaturated hydrocarbon chain radical. Alkenyls have at least one olefinic double bond. Unless otherwise specified, alkenyls have from 2 to about 15 carbon atoms (C 2 - 5 ); preferably from 2 to about 10 carbon atoms (C 2 - o); more preferably from 2 to about 8 carbon atoms (C 2 - C 8 ), and most preferably from about 2 to about 6 carbon atoms (C 2 - C 6 ).
• 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. Unless otherwise specified, alkoxys have from 1 to about 15 carbon atoms (Ci - C 15 ); preferably from 1 to about 10 carbon atoms ( - do); more preferably from 1 to about 8 carbon atoms (Ci - C 8 ), even more preferably from 1 to about 6 carbon atoms ( - C 6 ), and most preferably from 1 to about 4 carbon atoms (Ci - C 4 ). Examples of alkoxy radicals include -O-alkyl and -O-alkenyl.
• alkoxycarbonyl is -C(0)OK, wherein K is an alkyl. Unless otherwise specified, alkoxycarbonyls having from 2 to about 10 carbon atoms; preferably from 2 to about 8 carbon atoms, more preferably from 2 to about 5 carbon atoms, even more preferably from 2 to about 3 carbon atoms, and most preferably 2 carbon atoms.
• alkyl is a saturated hydrocarbon chain radical. Unless otherwise specified, alkyls have from 1 to about 15 carbon atoms (Ci - C 15 ); preferably from 1 to about 10 carbon atoms (Cj - C ]0 ); more preferably from 1 to about 6 carbon atoms (Q - C 6 ); and most preferably from 1 to about 4 carbon atoms ( - C 4 ). Preferred alkyls include, for example, methyl, ethyl, propyl, iso-propyl, and butyl.
• alkylene refers to an alkyl, alkenyl, or alkynyl which is a diradical.
• methylene is -CH2-.
• alkylsulfonyl is a -S(0)U or a -S(0) 2 U radical wherein U is an alkyl, alkenyl, or alkynyl, preferably an alkyl or alkenyl, and most preferably an alkyl substituent.
• alkylsulfonyls have from 1 to about 15 carbon atoms ( - 5 ); preferably from 1 to about 10 carbon atoms ( - C ⁇ 0 ); more preferably from 1 to about 8 carbon atoms (Ci - C 8 ), even more preferably from 1 to about 6 carbon atoms ( - C 6 ), and most preferably from 1 to about 4 carbon atoms ( - C ).
• alkylthio is a sulfur radical having an alkyl, alkenyl, or alkynyl, preferably an alkyl or alkenyl, and most preferably an alkyl substituent. Unless otherwise specified, alkylthios have from 1 to about 15 carbon atoms (Ci - C 1 5); preferably from 1 to about 10 carbon atoms ( - C ⁇ 0 ); more preferably from 1 to about 8 carbon atoms (Ci - C 8 ), even more preferably from 1 to about 6 carbon atoms (Ci - C 6 ), and most preferably from 1 to about 4 carbon atoms (Ci - C ). Examples of alkoxy radicals include -S-alkyl and -S-alkenyl.
• alkynyl is an unsaturated hydrocarbon chain radical. Alkynyls have at least one triple bond. Unless otherwise specified, alkynyls have from 2 to about 15 carbon atoms (C 2 - C 15 ); preferably from 2 to about 10 carbon atoms (C 2 - Cio); more preferably from 2 to about 8 carbon atoms (C 2 - C 8 ), and most preferably from about 2 to about 6 carbon atoms (C 2 - C 6 ).
• “benzamido” is a -NHC(0)C 6 C 5 radical. As used herein, “benzoyl” is a -C(0)C6H 5 radical.
• biohydrolyzable amides are amides of the compounds used in the present invention which do not interfere with the activity of the compound, or that are readily converted in vivo by a mammalian subject to yield an active compound.
• biohydrolyzable esters are esters of the compounds used in the present invention which do not interfere with the activity of the compound, or that are readily converted in vivo by a mammalian subject to yield an active compound.
• carbocyclic ring As used herein, “carbocyclic ring”, “carbocycle”, or the like is a hydrocarbon ring radical.
• Carbocyclic rings are monocyclic or are fused, bridged, or spiro polycyclic rings. Unless otherwise specified, monocyclic rings contain from 3 to about 9 atoms, preferably from about 4 to about 7 atoms, and most preferably 5 or 6 atoms. Polycyclic rings contain from about 7 to about 17 atoms, preferably from about 7 to about 14 atoms, and most preferably 9 or 10 atoms.
• cycloalkyl is a saturated carbocyclic or heterocyclic ring radical.
• the cycloalkyl has from 3 to 7 carbon atoms.
• Preferred cycloalkyl groups include, for example, cyclobutyl, cyclopentyl, and cyclohexyl.
• cycloalkenyl is a saturated carbocyclic or heterocyclic ring radical having at least one olefinic bond.
• the cycloalkenyl has from 4 to 7 carbon atoms.
• 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.
• 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.
• heterocyclic 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 monocyclic or are fused, bridged, or spiro polycyclic 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.
• Heterocyclic rings may be substituted or unsubstituted.
• the term "inhibitor" with reference to lipoxygenase and / or cyclooxygenase means that the compound limits (inhibits) the enzymatic activity of one or more lipoxygenases and / or cyclooxygenases.
• the indoline compound utilized herein inhibits one or more lipoxygenases and / or cyclooxygenases.
• Such compounds may be referred to as lipoxygenase inhibitors and cyclooxygenase inhibitors, respectively.
• Lipoxygenase inhibitors may be either selective or non-selective for inhibition of lipoxygenase relative to cyclooxygenase.
• cyclooxygenase inhibitors may be either selective or non-selective for inhibition of cyclooxygenase relative to lipoxygenase.
• the indoline compound utilized herein is a cyclooxygenase inhibitor.
• a “lower” moiety is a moiety having 1 to about 6, preferably 1 to about 4, carbon atoms.
• N,N-dialkylsulfamoyl is a -S0 2 NUV radical wherein U and V are each, independently, alkyls having from one to four carbon atoms ( - C 4 ).
• pharmaceutically acceptable means suitable for use in a human or other mammal.
• phenoxyalkyl is an oxygen radical bearing a phenyl substituent which bears an alkyl substituent.
• phenoxycarbonyl is -C(0)0-phenyl.
• phenylalkanoyl is an alkanoyl radical substituted with a phenyl ring. Unless otherwise specified, phenylalkanoyls have from 7 to 10 carbon atoms.
• phenylalkyl is an alkyl radical bearing a phenyl substituent or a phenyl radical bearing an alkyl substituent.
• safe and effective amount of a compound means an amount that is effective to exhibit biological activity, preferably wherein the biological activity is arresting and / or reversing hair loss or promoting hair growth, at the site(s) of activity in a mammalian subject, without undue adverse side effects (such as toxicity, irritation, or allergic response), commensurate with a reasonable benefit / risk ratio when used in the manner of this invention.
• thenoyl is a -C(0)SC 4 H 3 radical having the structure:
• 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.
• tautomeric forms will exist in certain compounds utilized in the present invention. Wherein tautomer A of the compound is shown, it is understood to include, for example, tautomers B and C of that compound although not specifically depicted. To illustrate:
• a first embodiment of the present invention relates to methods of treating hair loss comprising administering a composition comprising a compound having the structure:
• X is selected from hydrogen, fluoro, chloro, bromo, nitro, cyano, thio, alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, trifluoromethyl, alkylsulfonyl having 1 to
• Y is selected from hydrogen, fluoro, chloro, bromo, alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, alkoxy having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, and trifluoromethyl;
• W is selected from oxygen and sulfur
• Ri is selected from alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, cycloalkenyl having 4 to 7 carbons, phenyl, substituted phenyl, phenylalkyl, (substituted phenyl)alkyl, phenoxyalkyl, (substituted phenoxy)alkyl, naphthyl, bicyclo[2.2.1]heptan-2-yl, bicyclo[2.2.1]hept-5-en-2-yl, and -(CH 2 ) n -Q-Ro; wherein there are 1 or 2 substituents on the substituted phenyl, the (substituted phenyl)alkyl, and the (substituted phenoxy)alkyl which are each, independently, selected from the group consisting of fluoro, chloro, bromo, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atom
• Q is selected from furan, thiophene, pyrrole, pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazole, 1,2,3-thiadiazole, 1,3,4-thiadiazole, 1,2,5-thiadiazole, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, tetrahydrothiopyran, pyridine, pyrimidine, pyrazine, benzo[b] furan, and benzo[b]thiophene; and
• (g) Ro is selected from hydrogen, chloro, fluoro, bromo, and alkyl having 1 to 4 carbon atoms.
• the X Moietv X is selected from hydrogen, fluoro, chloro, bromo, nitro, cyano, thio, alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, trifluoromethyl, alkylsulfonyl having 1 to 4 carbon atoms, phenyl, alkanoyl having 2 to 4 carbon atoms, benzoyl, thenoyl, alkanamido having 2 to 4 carbon atoms, benzamido, and N,N-dialkylsulfamoyl.
• X is selected from hydrogen, fluoro, chloro, bromo, nitro, trifluoromethyl, methyl, ethyl, w-propyl, iso-propyl, n-butyl, iso-butyl, -SOCH 3 (i.e., alkylsulfonyl having 1 carbon atom), -SOC 4 H 9 (i.e., alkylsulfonyl having 4 carbon atoms), - S0 2 CH 3 (i.e., alkylsulfonyl having 1 carbon atom), -S0 2 C 4 H 9 (i.e., alkylsulfonyl having 4 carbon atoms), methoxy, ethoxy, «-propoxy, ⁇ o-propoxy, w-butoxy, iso-butoxy, -SCH 3 (i.e., alkylthio having 1 carbon atom), -SC 4 H 9 (i.e., alkylthio having 4
• X substitutes at position 4, 5, or 6 of the indoline ring as defined herein above. More preferably, X substitutes at position 5 or 6 of the indoline ring as defined herein above. Most preferably, X substitutes at position 5 of the indoline ring as defined herein above.
• Y is selected from hydrogen, fluoro, chloro, bromo, alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, alkoxy having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, and trifluoromethyl.
• Y is selected from hydrogen, fluoro, chloro, bromo, methyl (i.e., alkyl having 1 carbon atom), and methoxy (i.e., alkoxy having 1 carbon atom).
• Y is hydrogen.
• Y substitutes at position 5 or 6 of the indoline ring as defined herein above. Most preferably, Y substitutes at position 6 of the indoline ring as defined herein above.
• X and Y are bonded together to form a 4,5-, 5,6-, or 6,7-methylenedioxy group or a 4,5-, 5,6-, or 6,7-ethylenedioxy group; or wherein when X and Y are bonded together and attached to adjacent carbon atoms, form a divalent radical Z, wherein Z is selected from:
• W is selected from oxygen and sulfur, preferably oxygen.
• Rj is selected from alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, cycloalkenyl having 4 to 7 carbons, phenyl, substituted phenyl, phenylalkyl, phenoxyalkyl, (substituted phenoxy)alkyl, naphthyl, bicyclo[2.2.1]heptan-2-yl, bicyclo[2.2.1]hept-5-en-2-yl, and -(CH 2 ) n -Q-Ro; wherein there are 1 or 2 substituents on the substituted phenyl, the (substituted phenyl)alkyl, and the (substituted phenoxy)alkyl which are each, independently, selected from the group consisting of fluoro, chloro, bromo, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, and trifluoromethyl.
• n is 0, 1, or 2 (wherein n is 0, then -(CH 2 ) resort-Q-Ro is -Q-Ro).
• Q is selected from furan, thiophene, pyrrole, pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazole, 1,2,3-thiadiazole, 1,3,4-thiadiazole, 1,2,5-thiadiazole, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, tetrahydrothiopyran, pyridine, pyrimidine, pyrazine, benzo[b] furan, and benzo[b]thiophene.
• Ro is selected from hydrogen, chloro, fluoro, bromo, and alkyl having 1 to 4 carbon atoms.
• Ri is -(CH 2 ) ceremoni-Q-Ro.
• Q is preferably selected from furan, thiophene, and pyrrole. Most preferably, Q is thiophene.
• Rj is -(CH 2 ) n -Q-Ro, then n is preferably 0 or 1, most preferably 0.
• Ro is hydrogen.
• Examples of preferred moieties for X ⁇ include trifluoromethyl, 2-furyl, (2-furyl)methyl, 3- methyl-2-furyl, 5-propyl-2-furyl, 3-furyl, (2-thienyl)methyl, (3-thienyl)methyl, 3-methyl-2-thienyl, 5-propyl-2-thienyl, 3-(3-thienyl)propyl, l-(2-furyl)ethyl, 3-(2-furyl)propyl, 2-thienyl, 3-thienyl, methyl, wo-propyl, w-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobut-1-en-l-yl, cyclohep-1-en-l-yl, phenyl, 2-fluorophenyl, 3 -fluorophenyl, 4-chlorophenyl
• a particularly preferred compound for use in the present invention is known as tenidap (5- chloro-3-(2-thenoyl)-2-oxindole-l-carboxamide) (including salts, hydrates tautormers, and biohydrolyzable amides and esters thereof), having the structure:
• pro-forms of the above described compounds are utilized (the term "pro-drug” is also commonly used in the art; as used herein, the terms “pro-form” and “pro-drug” should be considered synonymous).
• the pro-forms are, for example, enol ethers and esters of the above described compounds. Without intending to be limited by theory, it is contemplated that the pro-forms are precursors which, following administration, release a biologically active compound in vivo through, for example, hydrolysis of an ether or ester of the pro-form.
• the pro-forms have the structure:
• X is selected from hydrogen, fluoro, chloro, bromo, nitro, cyano, thio, alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, trifluoromethyl, alkylsulfonyl having 1 to 4 carbon atoms, phenyl, alkanoyl having 2 to 4 carbon atoms, benzoyl, thenoyl, alkanamido having 2 to 4 carbon atoms, benzamido, and N,N-dialkylsulfamoyl;
• Y is selected from hydrogen, fluoro, chloro, bromo, alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, alkoxy having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, and trifluoromethyl; (c) or wherein X and Y are bonded together to form a 4,5-, 5,6-, or 6,7-methylenedioxy group or a 4,5-, 5,6-, or 6,7-ethylenedioxy group; or wherein when X and Y are bonded together and attached to adjacent carbon atoms, form a divalent radical Z, wherein Z is selected from:
• W is selected from oxygen and sulfur
• Ri is selected from alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, cycloalkenyl having 4 to 7 carbons, phenyl, substituted phenyl, phenylalkyl, (substituted phenyl)alkyl, phenoxyalkyl, (substituted phenoxy)alkyl, naphthyl, bicyclo[2.2.1]heptan-2-yl, bicyclo[2.2.1]hept-5-en-2-yl, and -(CH 2 ) n -Q-Ro; wherein there are 1 or 2 substituents on the substituted phenyl, the (substituted phenyl)alkyl, and the (substituted phenoxy)alkyl which are each, independently, selected from the group consisting of fluoro, chloro, bromo, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atom
• n is an integer selected from 0, 1, and 2;
• Q is selected from furan, thiophene, pyrrole, pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazole, 1,2,3-thiadiazole, 1,3,4-thiadiazole, 1,2,5-thiadiazole, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, tetrahydrothiopyran, pyridine, pyrimidine, pyrazine, benzofb] furan, and benzo[b]thiophene;
• (g) Ro is selected from hydrogen, chloro, fluoro, bromo, and alkyl having 1 to 4 carbon atoms;
• R is selected from alkanoyl having 2 to 10 carbon atoms, phenylalkanoyl having 7 to 10 carbon atoms, alkoxycarbonyl having 2 to 10 carbon atoms, phenoxycarbonyl, alkylsulfonyl having 1 to 4 carbon atoms, and alkyl having 1 to 4 carbon atoms. All isomers of the exocyclic double bond depicted for the above pro-forms are contemplated within the methods of the present invention (including cis, trans, and mixtures thereof).
• X is selected from hydrogen, fluoro, chloro, bromo, nitro, cyano, thio, alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, trifluoromethyl, alkylsulfonyl having 1 to 4 carbon atoms, phenyl, alkanoyl having 2 to 4 carbon atoms, benzoyl, thenoyl, alkanamido having 2 to 4 carbon atoms, benzamido, and N,N- dialkylsulfamoyl.
• X is selected from hydrogen, fluoro, chloro, bromo, nitro, trifluoromethyl, methyl, ethyl, w-propyl, /s ⁇ -propyl, M-butyl, ⁇ o-butyl, -SOCH 3 (i.e., alkylsulfonyl having 1 carbon atom), -SOC 4 H 9 (i.e., alkylsulfonyl having 4 carbon atoms), -S0 2 CH 3 (i.e., alkylsulfonyl having 1 carbon atom), -S0 2 C 4 H 9 (i.e., alkylsulfonyl having 4 carbon atoms), methoxy, ethoxy, «-propoxy, iso-propoxy, /z-butoxy, wo-butoxy, -SCH 3 (i.e., alkylthio having 1 carbon atom), -SC 4 H 9 (i.e., alkylthio having 1 carbon
• X substitutes at position 5 or 6 of the indoline ring as defined herein above. Most preferably, X substitutes at position 5 of the indoline ring as defined herein above.
• Y is selected from hydrogen, fluoro, chloro, bromo, alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, alkoxy having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, and trifluoromethyl.
• Y is preferably selected from hydrogen, fluoro, and chloro. Most preferably, Y is hydrogen for the pro-form compounds herein.
• Y substitutes at position 5 or 6 of the indoline ring as defined herein above. Most preferably, Y substitutes at position 6 of the indoline ring as defined herein above.
• W is selected from oxygen and sulfur, preferably oxygen.
• Ri is selected from alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, cycloalkenyl having 4 to 7 carbons, phenyl, substituted phenyl, phenylalkyl, phenoxyalkyl, (substituted phenoxy)alkyl, naphthyl, bicyclo[2.2.1]heptan-2-yl, bicyclo[2.2.1]hept-5-en-2-yl, and -(CH 2 ) n -Q-Ro; wherein there are 1 or 2 substituents on the substituted phenyl, the (substituted phenyl)alkyl, and the (substituted phenoxy)alkyl which are each, independently, selected from the group consisting of fluoro, chloro, bromo, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, and trifluor
• n is 0, 1, or 2 (wherein n is 0, then -(CH 2 ) n -Q-Ro is - Q-Ro).
• Q is selected from furan, thiophene, pyrrole, pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazole, 1,2,3-thiadiazole, 1,3,4-thiadiazole, 1,2,5- thiadiazole, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, tetrahydrothiopyran, pyridine, pyrimidine, pyrazine, benzofb] furan, and benzo[b]thiophene.
• Ro is selected from hydrogen, chloro, fluoro, bromo, and alkyl having 1 to 4 carbon atoms.
• Ri is -(CH 2 ) n -Q-Ro or benzyl for the pro-form compounds herein.
• Q is preferably selected from furan, thiophene, and pyrrole. Most preferably, Q is thiophene.
• Ri is -(CH 2 ) n -Q-Ro, then n is preferably 0 or 1, most preferably 0.
• Ro is hydrogen.
• Rj is most preferably -(CH 2 ) n -Q-Ro.
• examples of preferred moieties for Ri include trifluoromethyl, 2-furyl, (2-furyl)methyl, 3-methyl-2-furyl, 5-propyl-2-furyl, 3-furyl, (2- thienyl)methyl, (3-thienyl)methyl, 3-methyl-2-thienyl, 5-propyl-2-thienyl, 3-(3-thienyl)propyl, 1- (2-furyl)ethyl, 3-(2-furyl)propyl, 2-thienyl, 3-thienyl, methyl, is ⁇ -propyl, «-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobut-1-en-l-yl, cyclohep-1-en-l-yl, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-chloropheny
• R is selected from alkanoyl having 2 to 10 carbon atoms, phenylalkanoyl having 7 to 10 carbon atoms, alkoxycarbonyl having 2 to 10 carbon atoms, phenoxycarbonyl, alkylsulfonyl having 1 to 4 carbon atoms, and alkyl having 1 to 4 carbon atoms.
• R is selected from alkanoyl having 2 to 10 carbon atoms, phenylalkanoyl having 7 to 10 carbon atoms, alkoxycarbonyl having 2 to 10 carbon atoms, phenoxycarbonyl, and alkyl having 1 to 3 carbon atoms.
• R is selected from alkanoyl having 2 to 4 carbon atoms, phenylalkanoyl having 7 to 10 carbon atoms, and alkyl having 1 to 3 carbon atoms. Most preferably, R is selected from alkanoyl having 2 to 4 carbon atoms and alkyl having 1 to 3 carbon atoms.
• Non-limiting examples of R include acetyl, propionyl, z-butyryl, phenylacetyl, methoxycarbonyl, ethoxycarbonyl, n-hexoxycarbonyl, and methylsulfonyl.
• pro-forms utilized in the present invention include the pro-forms of tenidap (5-chloro-3-(2-thenoyl)-2-oxindole-l-carboxarnide) (and salts, hydrates, and tautomers thereof).
• pro-forms will have the structure:
• pro-form compounds suitable for use in the present invention are set forth in Table 5 below: Table 5 - Preferred Compounds for Use in the Present Invention
• Such salts may be administered as one or more salts. Many such salts are known in the art. Such acceptable salts must, when administered, be appropriate for mammalian use. Such salts may be formed as described in Kadin. U.S. Patent No. 4,556,672, assigned to Pfizer Inc., issued December 3, 1985. Such salts include, for example, both organic and inorganic salts.
• Non-limiting examples of suitable salts include salts formed with ammonia, organic amines, alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydrides, alkali metal alkoxides, alkaline earth metal hydroxides, alkaline earth metal carbonates, alkaline earth metal hydrides, and alkaline earth metal alkoxides.
• bases which may form such salts include ammonia, primary amines such as tt-propylamine, H-butylamine, aniline, cyclohexylamine, berrzylamine, * »-toluidine, ethanolamine, and glucamine; secondary amines such as diethylamine diethanolamine, N-methylglucamine, N-methylaniline, morpholine, pyrrolidine, and piperidine; teriary amines such as triethylamine, triethanolamine, N,N-dimethylaniline, N-ethylpiperidine, and N-methylmorpholine; hydroxides such as sodium hydroxide; alkoxides such as sodium ethoxide and potassium methoxide; hydrides such as calcium hydride and sodium hydride; and carbonates such as potassium carbonate and sodium carbonate.
• Preferred salts are those of sodium, potassium, ammonium, ethanolamine, diethanolamine, and triethanolamine. Particularly preferred are
• the present invention relates to methods of treating hair loss by administering a compound having a structure as described herein.
• Compounds test compounds
• Compounds may be tested for their ability to treat hair loss using the following method. Alternatively, other methods well-known in the art may be used.
• Alopecia Areata Mouse Model The compounds used in the methods of the present invention may be tested for ability to treat hair loss according to the mouse model set forth in McElwee et al.. "Experimental Induction of Alopecia Areata-Like Hair Loss in C3H/HeJ Mice Using Full-Thickness Skin Grafts", The Journal of Investigative Dermatology, Vol. 111, pp. 797 - 803 (1998).
• the mouse model may be modified by once-daily or twice-daily dosing a control group and a test compound group throughout the period of the study.
• the control group is dosed vehicle while the test compound group is dosed from about 0.0001% to about 10%, preferably from about 0.0001% to about 1%, of the test compound in vehicle.
• the vehicle may be any cosmetically or pharmaceutically acceptable vehicle, however, acetone and methyl sulfoxide (DMSO) are each (independently) preferred vehicles.
• the compounds used in the methods of the present invention are prepared according to procedures which are well-known to those ordinarily skilled in the art.
• the starting materials used in preparing the compounds are known, made by known methods, or are commercially available as a starting material.
• the compounds of the present invention may have one or more chiral centers. As a result, one may selectively prepare one optical isomer, including diastereomers and enantiomers, over another, for example by chiral starting materials, catalysts or solvents, or may prepare both stereoisomers or both optical isomers, including diastereomers and enantiomers at once (a racemic mixture). Since the compounds of the invention may exist as racemic mixtures, mixtures of optical isomers, including diastereomers and enantiomers, may be separated using known methods, such as through the use of, for example, chiral salts and chiral chromatography.
• one optical isomer including a diastereomer and enantiomer, or a stereoisomer
• both optical isomers including diastereomers and enantiomers, or stereoisomers substantially free of the other are disclosed and claimed as well.
• Example 1 l-phenoxycarbonyl-2-phenoxycarbonyloxy-5-chloro-indole: A mixture of 5-chloro-oxindole (16.7 g, 0.10 mol), triethylamine (22.2 g, 0.22 mol), phenylchloroformate (34.4 g, 0.22 mol), and tetrahydrofuran (360 mL) is stirred at 20 °C for about one hour. The solvent is removed in vacuo, the residue is poured into water, and the precipitate is filtered and collected.
• the crude precipitate is filtered and collected.
• the crude precipitate is dissolved in hot methanol (635 mL).
• 2-amino-ethanol (6.35 g) is added and the solution is clarified with activated charcoal and filtered.
• Hydrochloric acid (cone. 37%) (18.75 mL) is added dropwise to the filtrate at 40 - 50 °C.
• the suspension is stirred at 20 - 30 °C for two hours and dried to provide the desired compound.
• Example 2 Tenidap Calcium Salt Dihydrate: Tenidap (64.15 g, 200 mmol) is combined with 98% calcium hydroxide (7.94 g, 105 mmol) in dimethylacetamide (160 mL). The resulting mixture is heated to 65 °C for 15 minutes. The mixture is cooled to about 25 °C and filtered. Precipitation is accomplished by the addition of a 50/50 (v/v) mixture of zs ⁇ -propanol and water (480 mL). The resulting mixture is granulated at ambient temperature for about one hour. The partially crystalline product is collected by filtration. The product is charged to about 1240 mL of a 9/1 (v/v) mixture of ⁇ -propanol and water. The resulting mixture is heated to reflux for one hour. The mixture is cooled to 60 °C and filtered at that temperature. The resulting product is dried in vacuo at 45 °C.
• the methods of the present invention are performed by administering to a mammal (preferably a human) a composition comprising a compound having a structure as described herein and, preferably, a pharmaceutically-acceptable or cosmetically-acceptable carrier.
• compositions of the present invention may be administered in a variety of manners including, for example, oral, rectal, topical, nasal, ocular or parenteral administration. Of these, topical and / or oral administration are especially preferred with topical being most preferred. Preferably, the topical administration is administration to the scalp.
• the topical administration is administration to those areas of the mammal's scalp which is exhibiting lack of hair or thin hair (i.e., bald or balding).
• the amount of the composition and frequency of application may vary widely, depending on the desired effect and / or the mammal's needs.
• the composition is applied from 1 to about 70 times per week, more typically from 7 to about 40 times per week, and most typically about 7 to 21 times per week (i.e., about 1 to 3 times per day).
• 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).
• compositions comprise a safe and effective amount, usually at least 0.0001% to about 99.9999%, preferably from about 0.001% to about 50%, more preferably from about 0.01% to about 25%, even more preferably from about 0.1% to about 10%, and most preferably from about 0.1% to about 5% of a compound used in the present invention.
• 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 as a composition 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.
• the carrier may be present in the composition at a level of from about 0.00001% to about 99.99999%, preferably from about 1% to about 99.999%, more preferably from about 10% to about 99.999%, still more preferably from about 25% to about 99.9%, even more preferably from about 50% to about 99.9%, and most preferably from about 75% to about 99.9%, all by weight of the composition.
• 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 stearic 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; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic sugars,
• carriers for systemic administration include sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffer solutions, emulsifiers, isotonic 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 0.001% to about 99.999%, preferably from about 0.01% to about 50%, more preferably from about 0.1% to about 25%), even more preferably from about 0.1% to about 10%), and most preferably from about 0.1% to about 5% of a compound used in the present invention.
• Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, f ⁇ lm- coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents.
• Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preserva- tives, 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; disintegrants such as starch, alginic acid and croscarmelose; lubricants such as magnesium stearate, stearic acid and talc. Glidants such as silicon dioxide can be used to improve flow characteristics of the powder mixture. 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
• disintegrants such as starch, alginic acid and croscarmelose
• lubricants such as magnesium stearate, stearic acid and talc.
• Glidants such as silicon dioxide can be used to improve flow characteristics
• 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 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 alginate; 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, polyvinylacetate 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 mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. Glidants, 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 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, skin patches, and the like. Such compositions may be administered using standard methods.
• the topical compositions may be topically delivered from a variety of delivery devices.
• the compositions can be incorporated into a medicated cleansing pad.
• these pads comprise form about 50% to about 75% of a substrate and from about 25%) to about 50% of a liquid composition deliverable from the substrate.
• Suitable pads are described, for example, in U.S. Patent 4,891,228; Thurman et al.; issued January 2, 1990; and U.S. Patent 4,891 ,227; Thaman et al.; issued January 2, 1990.
• compositions useful herein can be incorporated into and delivered from a soft-tipped or flexible dispensing device.
• These devices are useful for the controlled delivery of the compositions to the skin surface and have the advantage that the treatment composition itself never need be directly handled by the user.
• Non-limiting examples of these devices comprise a fluid container including a mouth, an applicator, means for holding the applicator in the mouth of the container and a normally closed pressure-responsive valve for permitting the flow of fluid from the container to the applicator upon the application of pressure to the valve.
• the fluid preferably contains from about 0.01% to about 20%, preferably from about 0.1% to about 10%, and most preferably from about 1% to about 5% of an indoline compound as described herein, all by weight of the fluid (composition).
• the valve can include a diaphragm formed from an elastically fluid impermeable material with a plurality of non-intersecting acruate slits therein, where each slit has a base which is intersected by at least one other slit, and where each slit is out of intersecting relation with its own base, and wherein there is a means for disposing the valve in the container inside of the applicator. Examples of these applicator devices are described in U.S.
• Patents 4,693,623 to Schwartzman issued September 25, 1987; 3,669,323; Harker et al.; issued June 13, 1972; 3,418,055;Schwartzman; issued December 24, 1968; and 3,410,645; Schwartzman; issued November 12, 1968; all of which are herein incorporated by reference.
• Examples of applicators useful herein are commercially available from Dab-O-Matic, Mount Vernon, N.Y.
• 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, allantoin, glycerine, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, and the like.
• carrier materials such as, for example, water, alcohols, aloe vera gel, allantoin, glycerine, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, and the like.
• Emollients such as stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane- 1,2-diol, butane- 1,3-diol, mink oil, cetyl alcohol, iso-propy ⁇ isostearate, stearic acid, iso- butyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, dimethylpolysiloxane, di- «-butyl sebacate, isopropyl myristate
• Emollients such as stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane- 1,2-diol, butane- 1,3-diol, mink oil, cetyl alcohol, iso
• the compounds used in the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
• Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
• 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 Cyclosporin A: I. An in vitro Study Using Hairless Mouse Skin", S.T.P. Pharma 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 Helvetiae, Vol 70, pp. 279-287 (1995); Gangarosa et al..
• the methods of the present invention may also further comprise administering a compound as set forth herein and an activity enhancer.
• “further comprising administering” means either administering the compound and the activity enhancer separately (e.g., administration of compound followed by activity enhancer or administration of activity enhancer followed by compound) or wherein the compound and the activity enhancer are administered in the same composition.
• compositions comprising a compound as set forth herein and an activity enhancer.
• the activity enhancer can be chosen from a wide variety of molecules which can function in different ways to enhance hair growth effects of a compound of the present invention.
• Particular classes of activity enhancers include other hair growth stimulants and penetration enhancers.
• Additional hair growth stimulants can be chosen from a wide variety of molecules which can function in different ways to enhance the hair growth effects of the compositions and methods of the present invention.
• These optional other hair growth stimulants, when present, are typically employed in the compositions herein at a level ranging from about 0.001% to about 15%, preferably from about 0.01% to about 10%, even more preferably from about 0.1% to about 10%, and most preferably from about 0.5% to about 5%, all by weight of the composition.
• Vasodilators such as potassium channel agonists including, for example, minoxidil and minoxidil derivatives such as aminexil and such as those described in U.S. Patent 3,382,247, U.S. Patent 5,756,092, issued May 26, 1998, U.S. Patent 5,772,990, issued June 30, 1998, U.S. Patent 5,760,043, issued June 2, 1998, U.S. Patent 328,914, issued July 12, 1994, U.S. Patent 5,466,694, issued November 14, 1995, 5,438,058, issued August 1, 1995, and U.S. Patent 4,973,474, issued November 27, 1990, (all of which are herein incorporated by reference), and cromakalin and diazoxide can be used as an additional hair growth stimulant in the compositions herein.
• Particularly preferred methods herein comprise administration of a compound as set forth herein above and minoxidil.
• particularly preferred compositions herein comprise a compound as set forth herein above and minoxidil.
• antiandrogens include, but are not limited 5- ⁇ -reductase inhibitors such as finesteride and those described in U.S. Patent 5,516,779, issued May 14, 1996 (herein incorporated by reference) and in Nane et al., Cancer Research 58. "Effects of Some Novel Inhibitors of C17,20-Lyase and 5 -Reductase in vitro and in vivo and Their Potential Role in the Treatment of Prostate Cancer," as well as cyproterone acetate, azelaic acid and its derivatives and those compounds described in U.S.
• Another suitable class of optional hair growth stimulants are immunosuppressants or non- immunosuppressants such as 1) cyclosporin and cyclosporin analogs including those described in U.S. Provisional Patent Application No. 60/122,925, Fulmer et al., "Method of Treating Hair Loss Using Non-Immunosuppressive Compounds", filed March 5, 1999, herein incorporated by reference, and 2) FK506 analogs such as those described in U.S. Provisional Patent Application No. 60/102,449, Mclver et al., "Heterocyclic 2-Substituted Ketoamides", filed September 30, 1998, U.S. Provisional Patent Application No.
• Another suitable class of optional hair growth stimulants are antimicrobials such as selenium sulfide, ketoconazole, triclocarbon, triclosan, zinc pyrithione, itraconazole, asiatic acid, hinokitiol, mipirocin and those described in EPA 0,680,745 (herein incorporated by reference), clinacycin hydrochloride, benzoyl peroxide, benzyl peroxide and minocyclin.
• antimicrobials such as selenium sulfide, ketoconazole, triclocarbon, triclosan, zinc pyrithione, itraconazole, asiatic acid, hinokitiol, mipirocin and those described in EPA 0,680,745 (herein incorporated by reference), clinacycin hydrochloride, benzoyl peroxide, benzyl peroxide and minocyclin.
• anti-inflammatories can also be incorporated into the compositions herein as an optional hair growth stimulant.
• suitable anti-inflammatories may include glucocorticoids such as hydrocortisone, mometasone furoate and prednisolone, nonsteroidal anti- inflammatories such as those described in U.S. Patent 5,756,092, and benzydamine, salicylic acid, and those compounds described in EPA 0,770,399, published May 2, 1997, WO 94/06434, published March 31, 1994, and FR 2,268,523, published November 21, 1975, all of which are herein incorporated by reference.
• thyroid hormones and derivatives and analogs thereof are thyroid hormones and derivatives and analogs thereof.
• suitable thyroid hormones for use herein may include triiodothyrionine.
• suitable thyroid hormone analogs which may be suitable for use herein include those described in U.S. Provisional Patent Application No. 60/136,996, Zhang et al.,
• Prostaglandin agonists or antagonists can also be used as optional hair growth stimulants in the compositions herein.
• suitable prostaglandins agonists or antagonists include latanoprost and those described in WO 98/33497, Johnstone, published August 6, 1998, WO
• retinoids Another class of optional hair growth stimulants for use herein are retinoids.
• Suitable retinoids may include isotretinoin, acitretin, and tazarotene.
• triterpenes such as, for example, those disclosed in Bradbury et al., U.S. Patent Application Serial No. 09/353,408, "Method for Regulating Hair Growth", filed July 15, 1999 and Bradbury et al., U.S. Patent Application Serial No. 09/353,408, "Method for Regulating Hair Growth", filed July 15, 1999 and Bradbury et al., U.S. Patent Application Serial No. 09/353,408, "Method for Regulating Hair Growth", filed July 15, 1999 and Bradbury et al., U.S. Patent
• optional hair growth stimulants for use herein include flavinoids, ascomycin derivatives and analogs, histamine antagonists such as diphenhydramine hydrochloride, other triterpenes such as oleanolic acid and ursolic acid and those described in U.S. Patent 5,529,769, JP 10017431, WO 95/35103, U.S. Patent 5,468,888, JP 09067253, WO 92/09262, JP 62093215, U.S. Patent 5,631,282, U.S.
• Patent 5,679,705, JP 08193094, saponins such as those described in EP 0,558,509 to Bonte et al., published September 8, 1993 and WO 97/01346 to Bonte et al, published January 16, 1997 (both of which are herein incorporated by reference in their entirety), proteoglycanase or glycosaminoglycanase inhibitors such as those described in U.S. Patents 5,015,470, issued May 14, 1991, U.S. Patent 5,300,284, issued April 5, 1994 and U.S.
• Patent 5,714,515 issued February 3, 1998, EPA 0,319,991, published June 14, 1989, EPA 0,357,630, published October 6, 1988, EPA 0,573,253, published December 8, 1993, JP 61- 260010, published November 18, 1986, U.S. Patent 5,772,990, issued June 30, 1998, U.S. Patent 5,053, 410, issued October 1, 1991, and U.S. Patent 4,761,401, issued August 2, 1988, all of which are herein incorporated by reference.
• 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-diol, POE(2) ethyl ether, di(2-hydroxypropyl) ether, pentan-2,4-diol, acetone, POE(2) methyl ether, 2-hydroxypropionic acid, 2-hydroxyoctanoic acid, propan-1-ol, 1,4-dioxane, tetrahydrofuran, butan-l,4-diol, propylene glycol dipelargonate, polyoxypropylene 15 stearyl ether, octyl alcohol, POE ester of oleyl alcohol, oleyl alcohol, lauryl alcohol, dioctyl adipate, dicapryl adipate, di-isopropyl adipate, di-
• kits comprising a compound and / or composition herein and information and / or instructions by words, pictures, and / or the like, that use of the kit will provide treatment for hair loss 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 herein and information and / or instructions regarding methods of application of the compound and / or composition, preferably with the benefit of treating hair loss in mammals.
• compositions for topical administration comprising:
• a human male subject 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 Cyclosporin A: I. An in vitro Study Using Hairless Mouse Skin", S.T.P. Pharma Sciences. Vol. 3, pp. 404 - 407 (1993), using tenidap 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:
• the above shampoo is used daily by the subject.

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