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
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
  • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
  • A61K8/4913—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having five membered rings, e.g. pyrrolidone carboxylic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
  • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
  • A61K8/4926—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having six membered rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/14—Drugs for dermatological disorders for baldness or alopecia

Definitions

• the present invention relates to methods for treating hair loss m mammals, including arresting and / or reversing hair loss and promoting hair growth.
• Hair loss is a common problem which occurs, for example, through natural processes or is often chemically promoted through the use of certain therapeutic drugs designed to alleviate conditions such as cancer. Often such hair loss is accompanied by lack of hair regrowth which causes partial or full baldness. Such baldness is cosmetically unappealing, and is particularly distressing to the person expe ⁇ encing 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 mam stages which are known as anagen, catagen, and telogen. Anagen is the growth phase of the cycle and may be characte ⁇ zed by penetration of the hair follicle deep into the dermis with rapid proliferation of cells which are differentiating to form hair. The next phase is catagen, which is a transitional stage marked by the cessation of cell division, and du ⁇ ng which the hair follicle regresses through the dermis and hair growth is ceased.
• anagen is the growth phase of the cycle and may be characte ⁇ zed by penetration of the hair follicle deep into the dermis with rapid proliferation of cells which are differentiating to form hair.
• catagen is a transitional stage marked by the cessation of cell division, and du ⁇ ng which the hair follicle regresses through the dermis and hair growth is ceased.
• telogen is often characte ⁇ zed as the resting stage during which the regressed follicle contains a germ with tightly packed dermal papilla cells
• the initiation of a new anagen phase is caused by rapid cell proliferation 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 m telogen and anagen is not engaged, thus causing the onset of full or partial baldness.
• mmoxidil has reported only limited hair growth in a portion of patients using mmoxidil. See, e ⁇ , Physician's Desk Reference ® . 49 th Ed. (1995), p. 2580. Furthermore, serious side effects of mmoxidil are possible, including vasodilation (which leads to retention of fluid around the heart and increased heart rate), difficulty in breathing, and weight gam. Physician's Desk Reference ® . 49* Ed. (1995), p. 2581.
• 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.
• FK506 is a complex, macrocyclic molecule having the following structure:
• the present inventors have discovered a class of compounds which arrest and / or reverse hair loss or promote hair growth but do not share the complex, macrocyclic structure of FK506.
• the present inventors have further discovered compounds among this class which invoke hair growth yet are surprisingly non-immunosuppressive or are nominally immunosuppressive.
• the minimized and / or absent immunosuppressive activity of these hypertrichotic compounds are distinct advantages as compared to the immunosuppressive compounds cyclosporin A and FK506.
• the present inventors therefore provide methods of treating hair loss by administering compositions comprising the compounds described herein.
• the present invention relates to methods for treating hair loss comprising administering compounds which have been found by the present inventors to be particularly useful for treating hair loss in mammals, including arresting and / or reversing hair loss and promoting hair growth.
• the compounds utilized in the present method have the structure:
• the present invention relates to methods of using compounds and compositions which are particularly useful for treating hair loss in mammals, including arresting and / or reversing hair loss and promoting hair growth.
• the present inventors have also surprisingly discovered that immunosuppression is not required for hair growth stimulation.
• the present inventors have further discovered compounds that are useful for treating hair loss but are surprisingly non-immunosuppressive.
• Preferred compounds useful in the method of the present invention are therefore, as defined herein, non- immunosuppressive.
• salt is a cationic salt formed at any acidic (e.g., carboxyl) group, or an anionic salt formed at any basic (e.g., amino) group. Many such salts are known in the art.
• Preferred cationic salts include the alkali metal salts (such as, for example, sodium and potassium), alkaline earth metal salts (such as, for example, magnesium and calcium), and organic salts.
• Preferred anionic salts include the hahdes (such as, for example, chloride salts). Such acceptable salts must, when administered, be appropriate for mammalian use.
• alkenyl is an unsaturated hydrocarbon chain radical. Alkenyls have at least one olefimc double bond. Unless otherwise specified, alkenyls have from 2 to about 15 carbon atoms (C 2 - C 15 ); preferably from 2 to about 10 carbon atoms (C 2 - C 10 ); 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-hmitmg 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.
• alkyl is a saturated hydrocarbon chain radical. Unless otherwise specified, alkyls have from 1 to about 15 carbon atoms (C, - C 15 ); preferably from 1 to about 10 carbon atoms (C, - C 10 ); more preferably from 1 to about 6 carbon atoms (C X - C 6 ); and most preferably from 1 to about 4 carbon atoms (C, - C 4 ). Preferred alkyls include, for example, methyl, ethyl, propyl, wo-propyl, and butyl.
• alkylene refers to an alkyl, alkenyl, or alkynyl which is a diradical.
• methylene is -CH2-.
• 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 I5 ); preferably from 2 to about 10 carbon atoms (C 2 - C 10 ); 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 ).
• biohydrolyzable amides are amides of the compounds used in the present invention which do not interfere with the activity of the compound, or that are readily converted in vivo by a mammalian subject to yield an active compound.
• biohydrolyzable esters are esters of the compounds used in the present invention which do not interfere with the activity of the compound, or that are readily converted in vivo by a mammalian subject to yield an active compound.
• biohydrolyzable imides are imides of the compounds used in the present invention which do not interfere with the activity of the compound, or that are readily converted in vivo by a mammalian subject to yield an active compound.
• Carbocychc ring As used herein, "carbocychc ring”, “carbocycle”, or the like is a hydrocarbon ring radical. Carbocychc rings are monocychc or are fused, bridged, or spiro polycychc rings. Unless otherwise specified, monocychc rings contain from 3 to about 9 atoms, preferably from about 4 to about 7 atoms, and most preferably 5 or 6 atoms. Polycychc 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 carbocychc or heterocychc ring radical.
• Preferred cycloalkyl groups include, for example, cyclobutyl, cyclopentyl, and cyclohexyl.
• 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.
• heterocyclychc ⁇ ng is a ring radical comp ⁇ sed of carbon atoms and one or more heteroatoms m the ring wherein the heteroatoms are selected from the group consisting of oxygen, sulfur, nitrogen, and phosphorous, more preferably, oxygen, sulfur, and nitrogen.
• Heterocycles are monocychc or are fused, bridged, or spiro polycychc rings. Unless otherwise specified, monocycles contain from 3 to about 9 atoms, preferably from about 4 to about 7 atoms, and most preferably 5 or 6 atoms. Polycycles contain from about 7 to about 17 atoms, preferably from about 7 to about 14 atoms, and most preferably 9 or 10 atoms.
• Heterocychc rings may be substituted or unsubstituted.
• 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.
• safe and effective amount of a compound means an amount that is effective to exhibit biological activity, preferably wherein the biological activity is arresting and / or reversing hair loss or promoting hair growth, at the s ⁇ te(s) of activity m a mammalian subject, without undue adverse side effects (such as toxicity, irritation, or allergic response), commensurate with a reasonable benefit / risk ratio when used in the manner of this invention.
• 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.
• the present invention relates to methods of treating hair loss comprising administering a composition comprising (a) a compound having the structure:
• Q is a first heteroatom, wherein the first heteroatom is nitrogen;
• A is selected from CH 2 , O, S, and NR,;
• R] is selected from the group consisting of hydrogen and alkyl;
• J is selected from hydrogen, - C 6 alkyl, C 3 - C 6 alkenyl, benzyl, Ar substituted Ci - C 6 alkyl, Ar substituted C 3 - C 6 alkenyl, Ar substituted C 3 - C 6 alkynyl;
• K is selected from C] - C 6 alkyl, Ar substituted - C 6 alkyl, Ar substituted C 2 - C 6 alkenyl, Ar substituted C 2 - C 6 alkynyl, and cyclohexylmethyl; or J and K may be bonded together to form a 5-, 6-, or 7- membered heterocychc ring wherein the ring may optionally contain an additional heteroatom selected from O, S, S(O), S(0) 2 , NH, and NE, wherein when B and D are bonded together to form a substituted or unsubstituted tetrahydronapthal
• R 2 , R 3 , R 4 , B, D, and E are each, independently, selected from nil, hydrogen,
• X 2 is selected from O and NRio, wherein R !0 is selected from hydrogen, - C ⁇ alkyl, and Cj - C 6 alkenyl; and R 9 is selected from phenyl, benzyl, - C 5 alkyl, - C 5 alkenyl, Ci - C 5 alkyl substituted with phenyl, and Ci - C 5 alkenyl substituted with phenyl; wherein when B is T, then D is R 8 , wherein R 8 is selected from Ci - C 8 alkyl optionally substituted with C 3 - C 8 cycloalkyl, and Ar; and wherein R 3 and R may also be bonded together to form a 5-, 6-, or 7-membered heterocychc aliphatic or aromatic ring; (vii) Ar and Y are each, independently, selected from phenyl, benzyl, 1-napthyl, 2-napthyl, indenyl, azulenyl, fluor
• the compounds used in the present method comprise a moiety attached to the diketoamide moiety which is referred to herein as the X Moiety, or X.
• X is selected from hydrogen, Ci - C 9 alkyl, C 2 - C 9 alkenyl, C 5 - C 7 cycloalkyl, C 5 - C 7 cycloalkyl, C 5 - C 7 cycloalkenyl, C 5 - C 7 cycloalkenyl, Ar, -OR 2 , [C, - C 4 alkyl]-Y, [C 2 - C 4 alkenyl]-Y, Y, and - NR 3 P .
• the preferred Ar moieties are selected from phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, and 1,2,3,4-tetrahydroquinolinyl.
• moieties may be unsubstituted or substituted, but wherein X is substituted Ar then preferred substituents include hydroxyl, nitro, trifluoromethyl, - C 6 alkyl, O-[C ⁇ - C 6 alkyl], halogen, -S0 3 H, and -NRsR ⁇ , wherein R 5 and Re are described herein above.
• the more preferred X moieties are selected from 3,4,5- trimethoxyphenyl, «o-propyl, phenyl, tert-butyl, thiophenyl-2-yl, 3-benzyloxyphenyl, 3- allyloxyphenyl, 2-furyl, and 3-isopropoxyphenyl.
• the most preferred X moiety is 3,4,5- trimethoxyphenyl.
• J and K moieties may be independent of each other having the above described structures or, as stated, may be bonded together to form a 5-, 6-, or 7-membered heterocychc ring optionally containing an additional heteroatom selected from O, S, S(O), S(0) 2 , NH, and NE.
• B and D are bonded together to form a substituted or unsubstituted tetrahydronapthalene moiety
• J and K may be optionally bonded together to form a 5- or 6-membered carbocychc ring which is fused to a phenyl ring.
• substituted or unsubstituted tetrahydronapthalene moiety is:
• R ⁇ h R ⁇ s 2 , and R 63 are each, independently, selected from hydrogen, halogen, alkyl, O- alkyl, (CH 2 ) b -aryl, and R 50 (CH 2 ) b -aryl, wherein R 50 is selected from O, S, and NR 5] ; wherein R 5J is selected from alkyl and hydrogen; b is an integer from 0 to 4; and R ⁇ is selected from hydrogen and (CH2) C -R 52 , wherein R 52 is selected from aryl and NR 53 R 54 , wherein R 53 and R 54 are each, independently, selected from hydrogen, alkyl, and (CH 2 )-aryl, or wherein R 53 and R 54 are bonded together to form a 5- or 6-membered heterocychc ring; and c is an integer from 1 to 3.
• the ring is preferably 5- or 6-membered. Wherein J and K form the heterocychc ring, the ring preferably does not contain any additional heteroatoms other than the Q nitrogen required at the 1 -position of the cycle as shown herein.
• A is selected from CH 2 , O, S, and NR wherein Ri is described herein.
• A is selected from O and NRi.
• Most preferably A is NR].
• Ri is most preferably hydrogen.
• B and D are side chains which are selected from a variety of moieties described herein above.
• Preferred B moieties are selected from hydrogen, alkyl, alkenyl, 3-(2-pyridyl)propyl, 3- phenylpropyl, 2-phenoxyphenyl, 3-phenoxyphenyl, phenyl, benzyl, 2-(3-pyridyl)ethyl, E-3-[trans- (4-hydroxycyclohexyl)]-2-methyl-prop-2-enyl, E-3-[trans-(4-hydroxycyclohexyl)]-2-methyl-eth- 2-enyl, 3-(3-pyridyl)propyl, 2-phenylethyl, 2-(4-methoxyphenyl)ethyl, 3-(N- benzimidazolyl)propyl, 3-(4-methoxyphenyl)propyl, 3-[N-(7-azaindolyl)propyl, 3-(N-
• the Integer m is from 0 to 3, preferably from 0 to 1.
• Ar moiety is defined herein above.
• Preferred Ar moieties are selected from phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, 1,2,3,4- tetrahydroisoquinolinyl, 2-furyl, and 1,2,3,4,-tetrahydroquinolinyl, wherein Ar has one or more substituents each independently selected from the group consisting of hydrogen, hydroxyl, nitro, trifluoromethyl, C, - C 6 alkyl, 0-[C ⁇ - C 6 alkyl], halogen, -S0 3 H, and -NR 5 R 6 , wherein R 5 and Re are described herein above.
• Preferred compounds useful in the methods of the present invention are shown in the tables below:
• R 8 , R 9 , and X 2 are defined herein above.
• Other preferred compounds useful in the present method include those wherein B and D are bonded together to form a 5-, 6-, or 7-membered carbocychc ring which is fused with an aromatic ring, such as:
• R ]2 is selected from hydrogen and -(CH 2 ) t -R ⁇ 6 , wherein t is an integer from 1 to 3 and Ri6 is selected from the group consisting of Ar and NR 17 R ⁇ s, wherein R 17 and R ⁇ 8 are each, independently, selected from hydrogen, d - C 5 alkyl, and -(CH 2 )-Ar, or R ]7 and Ris may be bonded together to form a 5- or 6-memberedheterocyclic ring; and
• R ]3 , R 14 , and R 15 are each, independently, selected from hydrogen, halogen, Cj - C 6 alkyl, 0-(C ⁇ - C 6 alkyl), -(CH 2 ) e -Ar, and -G(CH 2 ) e -Ar, wherein e is an integer from 0 to 4; and G is selected from the group consisting of O, S, and NR 19 , wherein R ⁇ 9 is selected from the group consisting of hydrogen and - C 6 alkyl; and
• (c) A is selected from -O- and -NH-.
• Ri 3 are R] 5 are each, independently, selected from -OCH 2 -4-pyridine, -O-propyl, and hydrogen;
• R 14 is selected from -OCH 2 -4-pyridine, methyl, and hydrogen;
• R 12 is selected from -CH 2 -3-pyridine and hydrogen
• the present invention relates to methods of treating hair loss by administering a compound having a structure as described herein.
• the preferred compounds are non-immunosuppressive.
• Compounds (test compounds) may be tested for their ability to induce anagen and their immunosuppressive activity (or lack thereof) using the following methods.
• other methods well-known in the art may be used (but with the term "non-immunosuppressive" being defined according to the method disclosed herein below).
• the Telogen Conversion Assay measures the potential of a test compound to convert mice in the resting stage of the hair growth cycle ("telogen"), to the growth stage of the hair growth cycle (“anagen").
• telogen there are three principal phases of the hair growth cycle: anagen, catagen, and telogen. It is believed that there is a longer telogen period in C3H mice (Harlan Sprague Dawley, Inc., Indianapolis, IN) from approximately 40 days of age until about 75 days of age, when hair growth is synchronized. It is believed that after 75 days of age, hair growth is no longer synchronized. Wherein about 40 day-old mice with dark fur (brown or black) are used in hair growth experiments, melanogenesis occurs along with hair (fur) growth wherein the topical application of hair growth promoters are evaluated.
• the Telogen Conversion Assay herein below is used to screen compounds for potential hair growth by measuring melanogenesis.
• Three groups of 44 day-old C3H mice are utilized: a vehicle control group, a positive control group, and a test compound group, wherein the test compound group is administered a compound used in the method of the present invention.
• the length of the assay is at least 19 days with 15 treatment days (wherein the treatment days occur Mondays through Fridays). Day 1 is the first day of treatment. Most studies will end on Day 19, but a few may be carried out to Day 24 if the melanogenesis response looks positive, but occurs slowly.
• a typical study design is shown in Table 16 below:
• 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.
• Immunosuppression Assay The immunosuppression assay herein predicts the immunosuppressive activity of a compound used in the method of the present invention.
• the assay is performed as follows:
• Spleens are excised from euthanized (C0 2 asphyxiation) adult male C3H mice ranging in age from seven to sixteen weeks old (live mice commercially available from Harlan Sprague Dawley, Inc., Indianapolis, IN). The spleens are placed immediately in cold Hanks Balanced Salt Solution (HBSS, commercially available from Gibco-BRL, Gaithersburg, MD). The spleens are then ground up between frosted glass slides and filtered through a sterile screen to remove tissue debris.
• HBSS Hanks Balanced Salt Solution
• the resulting cell suspension is underlayed with an equal volume of Ficoll-Paque Plus (commercially available from Pharmacia Biotech, Piscataway, NJ) and centrifuged at 400 x g for approximately forty minutes at 20 °C in order to collect the splenocytes.
• the splenocytes are collected from the interface using a disposable pipet and are washed twice with HBSS, followed by centrifugation at 100 x g for ten min at 20 °C.
• Splenocytes are resuspended in five to ten mL of cell culture media consisting of phenol red-free RPMI 1640 (culture media commercially available from Gibco-BRL) containing 10% heat-inactivated fetal bovine serum (Gibco-BRL), penicillin (50 U/mL), streptomycin (100 ⁇ g/mL), L-glutamine (2 mM), 2-mercaptoethanol (10 "5 M), and N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES) (10 mM). The cells are counted and checked for viability using, for example, trypan blue.
• DMSO methyl sulfoxide
• the cells are pulsed with 1 ⁇ Ci/well of methyl- 3 H- thymidine (commercially available from Amersham, Buckinghamshire, England) and incubated an additional 24 hours. After 24 hours, the cells are harvested onto GF/C filter plates (commercially available from Packard, Downers Grove, IL), solubilized in Microscint 20 (Packard), and counted on a TopCount microplate scintillation and luminescence plate counter (Packard). Activity is measured as a percentage of control activity in the absence of test compound and plotted versus test compound concentration. The data are fit to a 4-parameter curve fit (Sigmaplot) and IC50 values are calculated.
• Sigmaplot 4-parameter curve fit
• test compounds are considered non-immunosuppressive if, by using this method, the ratio of (cyclosporin A IC 50 /test compound IC 50 ) x 100 is less than or equal to 0.02, i.e., a non-immunosuppressive test compound has ⁇ 2% of the immunosuppressive activity of cyclosporin A.
• MTT 3-[4,5-dimethyl-thiazoyl-2-yl]2,5-diphenyl- tetrazolium bromide
• MTT 3-[4,5-dimethyl-thiazoyl-2-yl]2,5-diphenyl- tetrazolium bromide
• the assay is carried out in serum-free, phenol red- free RPMI 1640 and the dye is solubilized in 100 ⁇ L/well DMSO and read at an OD of 540 nm with a background correction at 650 nm on a SpectraMax Plus microplate reader (Molecular Devices, Menlo Park, CA).
• the compounds used in the methods of the present invention are prepared according to methods which are well-known to those 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.
• 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.
• This product is diluted in ether (1.2 L) and acidified by slow addition of 1M HCI (1.2 L). The mixture stirs for one hour and is concentrated in vacuo. The resulting precipitate is diluted with acetonitrile and is stirred for 16 hours. The desired l,7-Diphenyl-4-aminoheptane is collected by filtration.
• the method of the present invention is performed by administration of a compound having a structure herein and a pharmaceutically-acceptable carrier.
• the compounds herein may be used for the treatment of such conditions as treating hair loss in mammals, including arresting and / or reversing hair loss and promoting hair growth. Such conditions may manifest themselves in, for example, alopecia, including male pattern baldness and female pattern baldness. While certain of the present compounds may exhibit immunosuppressive activity, the preferred compounds of the present invention are, as defined herein, non-immunosuppressive.
• the compounds are formulated into pharmaceutical 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 carrier ("carrier").
• pharmaceutically-acceptable 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, being treated.
• the carrier can itself be inert or it can possess pharmaceutical benefits of its own.
• compositions of this invention may be in any of a variety of forms, suitable (for example) for oral, rectal, topical, nasal, ocular or parenteral administration. Of these, topical or oral administration is especially preferred.
• a variety of pharmaceutically-acceptable 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 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 pharmaceutically-acceptable 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;
• pharmaceutically-acceptable 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 pharmaceutically-acceptable 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 of the present invention. Tablets can be compressed, tablet triturates, enteric- coated, sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents.
• Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.
• suitable solvents preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.
• the pharmaceutically-acceptable carrier suitable for the preparation of unit dosage forms for oral administration are well-known in the art.
• 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. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets.
• 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 croscar
• 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 pu ⁇ oses 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 pharmaceutically-acceptable 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, microcrystalhne 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 earner 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 m any form including, for example, solutions, creams, ointments, gels, lotions, shampoos, leave- on and rinse-out hair conditioners, milks, cleansers, moisturizers, sprays, skin patches, and the like.
• Topical compositions containing the active compound can be admixed with a variety of carrier materials well known in the art, such as, for example, water, alcohols, aloe vera gel, allantom, glycerine, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, and the like.
• carrier materials such as, for example, water, alcohols, aloe vera gel, allantom, glycerine, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, and the like.
• Other materials suitable for use in topical carriers include, for example, emollients, solvents, humectants, thickeners and powders. Examples of each of these types of matenals, which can be used singly or as mixtures of one or more materials, are as follows:
• Emollients such as stearyl alcohol, glyceryl mono ⁇ cmoleate, glyceryl monostearate, propane- 1,2-d ⁇ ol, butane- 1,3-d ⁇ ol, mink oil, cetyl alcohol, zso-propyl isostearate, stearic acid, iso- butyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, dimethylpolysiloxane, d ⁇ - «-butyl sebacate, isopropyl myristate, wo-propyl palmitate, wo-propyl stearate, butyl stearate, polythylene glycol, t ⁇ ethylene glycol, lanolin, sesame oil, coconut oil, arachis oil, castor oil,
• the compounds used in the present invention may also be administered in the form of hposome delivery systems, such as small umlamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
• Liposomes can be formed from a variety of phosphohpids, such as cholesterol, stearylam e or phosphatidylchohnes.
• a preferred formulation for topical delivery of the present compounds utilizes liposomes such as described in Dowton et al., "Influence of Liposomal Composition on Topical Delivery of Encapsulated Cyclospo ⁇ n 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.. www.un ⁇ pr. ⁇ t/a ⁇ a/d ⁇ pfarm erasmus/erasml4.html, Banga et al., "Hydrogel-based Iontotherapeutic Delivery Devices for Transdermal Delivery of Peptide/Protem Drugs", Pharm. Res.. Vol. 10 (5), pp. 697-702 (1993), Ferry L.L., "Theoretical Model of Iontophoresis Utilized in Transdermal Drug Delivery", Pharmaceutical Acta Helvetiae. Vol 70, pp.
• compositions of the present invention may also optionally comprise an activity enhancer.
• the activity enhancer can be chosen from a wide variety of molecules which can function in different ways to enhance hair growth effects of a compound of the present invention
• Particular classes of activity enhancers include other hair growth stimulants and penetration enhancers.
• 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 a compound of the present invention. These optional other hair growth stimulants, when present, are typically employed the compositions herein at a level ranging from about 0.01% to about 15%, preferably from about 0.1% to about 10%, most preferably from about 0.5% to about 5% by weight of the composition.
• Vasodilators such as potassium channel agonists including, for example, mmoxidil and mmoxidil derivatives such as aminexil and such as those described m 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.
• antiandrogens include, but are not limited 5- -reductase inhibitors such as f ⁇ naste ⁇ de and those desc ⁇ bed m U.S. Patent 5,516,779, issued May 14, 1996 (herein mco ⁇ orated 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 desc ⁇ bed 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.. filed March 5, 1999, herein mco ⁇ orated by reference, and 2) FK506 analogs such as those described in U.S. Provisional Patent Application No. 60/147,279, Degenhardt et al.. filed August 5, 1999; U.S. Provisional Patent Application No. 60/147,313, Degenhardt et al.. filed August 5, 1999; U.S. Provisional Patent Application No. 60/147,280, Degenhardt et al.. filed August 5.
• 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.. filed March 5,
• 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 inco ⁇ orated 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 inco ⁇ orated by reference), clinacycin hydrochloride, benzoyl peroxide, benzyl peroxide and minocyclin.
• Anti-inflammatories can also be inco ⁇ orated 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 including cyclooxygenase or lipoxygenase inhibitors 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 inco ⁇ orated 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.
• 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, filed June 1, 1999, U.S. Provisional Patent Application No. 60/137,024, Zhang et al., filed June 1, 1999, U.S. Provisional Patent Application No. 60/137,022, Zhang et al., filed June 1, 1999, U.S. Provisional Patent Application No. 60/137,023, Zhang et al., filed June 1, 1999, U.S. Provisional Patent Application No.
• 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
• Suitable retinoids may include isotretinoin, acitretin, and tazarotene.
• trite ⁇ enes 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. 09/353,409, "Compositions Which Contain Trite ⁇ enes for Regulating Hair Growth", filed July 15, 1999, each inco ⁇ orated by reference in their entirety.
• optional hair growth stimulants for use herein include flavinoids, ascomycin derivatives and analogs, histamine antagonists such as diphenhydramine hydrochloride, other trite ⁇ enes 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 inco ⁇ orated 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 5,185,325, issued February 9, 1993 (all of which are herein inco ⁇ orated in their entirety by reference) estrogen agonists and antagonists, pseudoterins, cytokine and growth factor promotors, analogs or inhibitors such as interleukinl inhibitors, interleukin-6 inhibitors, interleukin-10 promotors, and tumor necrosis factor inhibitors, vitamins such as vitamin D analogs and parathyroid hormone antagonists, Vitamin B12 analogs and panthenol, interfuron agonists and antagonists, hydroxyacids such as those described in U.S. Patent 5,550,158, benzophenones, and hydantoin anticonvulsants such as phenytoin.
• Patent 4,987,150 to Kurono et al issued January 22, 1991; JP 290811 to Ohba et al, published October 15, 1992; JP 05-286,835 to Tanaka et al, published November 2, 1993, FR 2,723,313 to Greff, published August 2, 1994, U. S. Patent 5,015,470 to Gibson, issued May 14, 1991, U.S. Patent 5,559,092, issued September 24, 1996, U.S. Patent 5,536,751, issued July 16, 1996, 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 inco ⁇ orated 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-
• the compounds used in the present method can be administered alone or as mixtures, and the compositions may further include additional drugs or excipients as appropriate for the indication.
• 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 Cyclosporin A: I. An in vitro Study Using Hairless Mouse Skin", S.T.P. Pharma Sciences. Vol. 3, pp. 404 - 407 (1993), using the compound of Example 2 in lieu of cyclosporin A and using the Novasome 1 for the non-ionic liposomal formulation.
• a human male subject suffering from male pattern baldness is treated each day with the above composition. Specifically, for 6 weeks, the above composition is administered topically to the subject.
• a shampoo comprising:
• a human male subject suffering from male pattern baldness is treated by a method of this invention. Specifically, for 12 weeks, the above shampoo is used daily by the subject.

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