JP2002538092A - Method of treating hair loss using a non-immunosuppressant - Google Patents

Abstract

  (57) [Summary] The present disclosure describes a method of treating hair loss in a mammal, including inhibiting and / or reversing hair loss and promoting hair growth. The method comprises administering a non-immunosuppressive compound having the structure described herein and a pharmaceutically acceptable carrier.

Description

DETAILED DESCRIPTION OF THE INVENTION

FIELD OF THE INVENTION The present invention relates to a method for treating hair loss in a mammal, comprising inhibiting and / or reversing hair loss and promoting hair growth.

BACKGROUND Hair Loss invention, for example, a natural consequence or common problems that arise are often chemically promoted through the use of certain therapeutic drugs designed to alleviate conditions such as cancer. Such hair loss is often accompanied by a lack of recurrent hair causing partial or total hair loss.

[0003] As is known in the art, hair growth occurs through a cycle of activity during alternating periods of growth and rest. This cycle often occurs during growth, regression,
And is divided into three major phases, known as rest periods. Growing phase is the proliferative phase of the cycle and can be characterized by deep penetration of hair follicles into the dermis, with rapid proliferation of cells that differentiate into hair. The next period is the catagen, which is characterized as a transitional phase indicated by a cessation of cell division, during which the follicles regress through the dermis and hair growth ceases. In the next period,
The telogen is often characterized as a telogen, during which the regressed hair follicles contain the roots with closely packed dermal papilla cells. During telogen, rapid cell growth in the hair root, enlargement of the dermal papilla, and synthesis of basement membrane components trigger the onset of a new anagen. When hair growth ceases, most of the hair follicles enter a telogen phase and the anagen phase does not begin, thus causing the onset of complete or partial hair loss.

[0004] There are many efforts in the literature to assist in recurrent hair, for example, by promoting or prolonging anagen. At this time, there are two drugs approved by the US Food and Drug Administration for the treatment of male pattern baldness: topical minoxidil (Pharmaci)
a & Upjohn, marketed as Rogaine®), and oral finasteride (Merck & Co.,
Inc. Commercially available as Propecia®). However, the search for effective hair growth inducers continues for several reasons, including safety concerns and / or lack of efficacy.

[0005] Interestingly, cyclosporin A aids significant hair-induced side effects
It is known. However, unfortunately, cyclosporin A does not
Due to its potent immunosuppressive activity, it is not practical for use as a hair growth agent.Y amamoto etc. "Hair Growth-Stimulating Ef
facts of Cyclosporin A and FK506, Pot
ent Immunosuppressants ”, Journal of D
ermatological Science, Vol. 7 (suppl.),
pp. S47-S54 (1994);Maurer, etc., “Hair Growth
h Modulation by Topical Immunophilin
 "Ligands", American Journal of Pathol
ogy, Vol. 150, no. 4, pp. 1433-1441 (1997); Paus, etc. "Hair Growth Control by Immuno."
suppression ”, Archives of Dermatologic
cal Research, Vol. 288, pp. 408-410 (1996)
);Paus, etc."Cyclosporin A, PSC 833 and FK.
506, but not Cyclosporin H and Rapamy
cin, Induce Anagen and Inhibit Catalog
n in Murine Skin ", The Journal of Inv
estimative Dermatology, Vol. 101, p. 420
(1994);Paus, etc."Cyclosporin A, FK506 an
d Related Drugs as Tools for Hair Re
search ”, Archives of Dermatological R
esearch, Vol. 285, p. 80 (1993); andTraber, etc. "Cyclosporins-New Analogies by Prec.
ursor Directed Biosynthesis ", The Jou
rnal of Antibiotics, Vol. 42, no. 4, pp. 5
91-597 (1988).

[0006] It has been reported that PSC833, a non-immunosuppressive analog of cyclosporin D, induces mouse hair anagen at a lower level than cyclosporin A. P aus, etc., "Cyclosporin A, PSC833 and FK506
, But not cyclosporin H and Rapamyci
n, Induce Anagen and Inhibit Catalogen
in Murine Skin ", The Journal of Inves
Tigative Dermatology, Vol. 101, p. 420 (1
994); Paus et al. , "Cyclosporin A, FK506 and
Related Drugs as Tools for Hair Rese
arch ", Archives of Dermatological Res
earch, Vol. 285, p. 80 (1993).

[0007] Based on PSC833, which has a weaker effect compared to cyclosporin A, a challenge has been made to provide non-immunosuppressive analogues of cyclosporin A that exhibit hair growth induction approaching that of cyclosporin A itself. Surprisingly, a cyclosporin A analog has been found which has no immunosuppressive activity and induces a level of hair growth comparable to cyclosporin A. Thus, provided herein are potential methods of treating hair loss using cyclosporin A analogs that are practical for use.

SUMMARY OF THE INVENTION The present invention has been found by the present invention, which is particularly useful for treating hair loss in mammals, including inhibiting and / or reversing hair loss and promoting hair growth. And administering a non-immunosuppressive compound to a mammal. The compound used in the method of the present invention has the following structure:

[0009]

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And pharmaceutically acceptable salts, hydrates, and biologically hydrolyzable amides, esters, and imides, wherein R ₁ , R ₁ ′,
R ₁ ″, R ₂ , R ₃ , R ₄ , R ₅ , R ₅ ′, R ₆ , R ₇ , and R ₈ are as defined herein.

[0011] DETAILED DESCRIPTION OF THE INVENTION The present invention is a mammal, preferably suppresses hair loss in humans and / or inverted, and involves promoting hair growth, particularly compounds useful for the treatment of hair loss And methods of using the composition.

In addition to finding that the compounds of the present invention are useful in treating hair loss, it has surprisingly been found that immune stimulation is not required for stimulation of hair growth. In addition, the compounds found have not only been useful in treating hair loss, but have also been surprisingly found to be non-immunosuppressive. Thus, compounds useful in the methods of the present invention are non-immunosuppressive as defined herein.

[0013] Publications and patents are referenced throughout the disclosure. All references cited herein are hereby incorporated by reference. All percentages, ratios, and ratios used herein are by weight unless otherwise specified.

Definitions and Uses of Terms The following is a list of definitions of terms used herein: "Salt" as used herein is formed with any acidic (eg, carboxyl) group. Or an anionic salt formed with any basic (eg, amino) group. Many such salts are known in the art. Preferred cationic salts include alkali metal salts (such as sodium and potassium), alkaline earth metal salts (such as magnesium and calcium), and organic salts. Preferred anionic salts include halides (eg, chloride salts). Such acceptable salts, when administered, must be suitable for use on mammals.

“Alkenyl” as used herein is an unsaturated hydrocarbon chain radical. Al
Kenyl has at least one double bond. Unless otherwise specified, alkenyl
Can have from 2 to about 15 carbon atoms (C_Two-C_Fifteen); Preferably 2 to about 10
Carbon atom (C_Two-C_Ten); More preferably from 2 to about 8 carbon atoms (C_Two-C ₈ ), And most preferably from 2 to about 6 carbon atoms (C_Two-C₆).
Non-limiting examples of alkenyl include vinyl, allyl, and butenyl.

“Alkoxy” as used herein is an oxygen radical having an alkyl, alkenyl, or alkynyl, preferably an alkyl or alkenyl, and most preferably an alkyl substituent. Examples of the alkoxy group include -O-methyl and -O-ethyl.

“Alkyl” as used herein is a saturated hydrocarbon chain radical. Unless otherwise specified, alkyl is 1 to about 15 carbon atoms (C ₁ -C ₁₅ ); preferably 1 to about 10 carbon atoms (C ₁ -C ₁₀ ); more preferably 1 to about 6 carbon atoms (C ₁ -C ₁₀ ). number of carbon atoms (C ₁ -C _6); and most preferably 1 to about 4 carbon atoms (C ₁ -C _4). Preferred alkyls include, for example, methyl, ethyl, propyl, iso-propyl, and butyl.

“Alkynyl” as used herein is an unsaturated hydrocarbon chain radical. Al
Quinyl has at least one triple bond. Unless otherwise specified, alkini
Can have from 2 to about 15 carbon atoms (C_Two-C_Fifteen); Preferably 2 to about 10
Carbon atom (C_Two-C_Ten); More preferably from 2 to about 8 carbon atoms (C_Two-C ₈ ), And most preferably from 2 to about 6 carbon atoms (C_Two-C₆).

As used herein, a “biologically hydrolysable amide” does not inhibit the activity of the compound, or is easily converted in vivo by a mammalian patient to give the active compound. An amide of the compound used in the present invention.

A “biologically hydrolysable ester” as used herein does not inhibit the activity of the compound, or is readily converted in vivo by a mammalian patient to give the active compound. It is an ester of the compound used in the present invention.

As used herein, “biologically hydrolyzable imide” does not inhibit the activity of the compound, or is readily converted in vivo by a mammalian patient to give the active compound. It is an imide of the compound used in the present invention.

As used herein, a “lower” moiety (eg, a “lower” alkyl) is a moiety having 1 to about 6, preferably 1 to about 4, carbon atoms. "Pharmaceutically acceptable" as used herein means suitable for use in humans or other mammals.

As used herein, “a safe and effective amount of a compound (or composition, etc.)” means an amount effective to exhibit biological activity, where biological The activity is preferably at the active site of the mammalian patient, without undue side effects (such as toxicity, irritation, or allergic reactions) and a reasonable benefit when used in the methods of the invention Inhibiting or reversing hair loss or promoting hair growth, balanced by risk ratio.

As used herein, a substituent may itself be substituted. Such substitutions may also be made by one or more substituents. Such substituents are described in C.I. Hansch and A.H. Leo , Substudent
Constants for Correlation Analysis i
n Chemistry and Biology (1979). "Substituted" as used herein with respect to groups, moieties, etc.
The term is preferably hydrogen, alkyl, alkenyl, unless otherwise specified.
Alkoxy, hydroxy, oxo, nitro, amino, alkylamino, cyano,
Halo, carboxy, alkoxyacyl (eg, carbethoxy), thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl (eg, piperidinyl, morpholinyl, pyrrolidinyl), imino, thioxo, hydroxyalkyl, aryloxy, and arylalkyl, more preferably Is hydrogen, alkyl, alkenyl, alkoxy, hydroxy, oxo, nitro, amino, alkylamino, halo, thiol, and aryloxy, even more preferably hydrogen, alkyl, alkenyl, alkoxy, hydroxy, nitro, amino, alkylamino,
And halo, even more preferably hydrogen, alkyl, and alkoxy, and most preferably having one or more substituents each independently selected from alkoxy.

As used herein, when any variant, moiety, group, etc. occurs one or more times in any variant or structure, its definition in each case, each definition in another case, etc. And independent.

Method of the Invention The invention has the following structure:

[0027]

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[0028] Hair loss comprising administering to a mammal a compound comprising and a pharmaceutically acceptable salt, hydrate, and composition comprising a biologically hydrolyzable amide, ester, and imide. relates to a method of treating, wherein: (a) R ₁ is 1-propenyl, propyl, 3-hydroxy-1-propenyl, -O- methyl, selected -O-p-benzoyl benzyl, and from the group consisting of hydroxy (B) R ₁ ′ is selected from hydroxy, oxo, and acyloxy; (c) R ₁ ″ is selected from hydrogen and methyl; (d) R ₂ is ethyl, n-butyl, 2-hydroxy Propyl, 2-methoxypropyl, 1-methylpropyl, and 2-acyloxy-propyl; (e) R ₃ is hydrogen, methyl, benzyl, 1-propenyl , And 2-methyl-
(F) R ₄ is a substituted or unsubstituted C ₁ -C ₉ straight or branched chain alkyl; (g) R ₅ is substituted or be a C ₁ -C ₆ straight-chain or branched-chain alkyl unsubstituted; (h) R ₅ 'is hydrogen, methyl, benzyl, p- fluorobenzyl, 1-propenyl, and 1-phenyl-1-propenyl (I) R ₆ is 2-methylpropyl, 2-methyl-3-hydroxypropyl,
(J) R ₇ is selected from methyl and phenyl; and (k) R ₈ is selected from methyl and hydroxymethyl.

The R ₁ moiety The R ₁ moiety is 1-propenyl, propyl, 3-hydroxy-1-propenyl,
Selected from -O-methyl, -Op-benzoylbenzyl, and hydroxy. More preferably, R ₁ is 1-propenyl, propyl, and 3-hydroxy-1
Selected from -propenyl, most preferably R ₁ is 1-propenyl.

R ₁ 'Moiety The R ₁ ' moieties are selected from hydroxy, oxo, and acyloxy. As used herein, the term "oxo" refers to a double bonded oxygen group. The term "acyloxy" as used herein refers to an oxygen radical having an acyl substituent. “Acyl” means a group (ie, X—C (＝ O) —) that can be formed by removing a hydroxy from a carboxylic acid, wherein X is
Any substituent, but preferably alkyl, alkenyl, alkynyl,
And aryl, most preferably alkyl. Thus, for example,
Acyloxy "is exemplified by -OC (= O) -alkyl.

While both hydroxy and oxo are both highly preferred, the most preferred R ₁ 'moiety is oxo. The R ₁ "part R ₁ " part is selected from hydrogen and methyl. Most preferably, R ₁ ″ is hydrogen.

These R ₁ , R ₁ ′, and R ₁ ″ moieties are further disclosed in US Pat. No. 5,767,0 to Ko et al. , For example, issued Jun. 16, 1998 and assigned to Novartis.
No. 96; published on May 29, 1997, Guilford Pharmaceutical
utils, Inc. International Patent Application Publication WO 97/18828 to Steiner et al ., Assigned to Bartz et al. , "Inhibition of H."
uman Immunodeficiency Virus Replicat
ion by Nonimmunosuppressive Analogs
of Cyclosporin A ", Proceedings of the
National Academy of Sciences U.S.A. S. A.
, Vol. 92, pp. 5381-5385 (1995).

R ₂ Portion The R ₂ portion is selected from ethyl, n-butyl, 2-hydroxypropyl, 2-methoxypropyl, 1-methylpropyl, and 2-acyloxy-propyl. The term "acyloxy" as used herein refers to an oxygen radical having an acyl substituent. “Acyl” means a group (ie, X—C (ＸO) —) that can be formed by removing the hydroxy from a carboxylic acid, where X is preferably alkyl, alkenyl, alkynyl, and aryl Is selected from Thus, 2-acyloxy-propyl has the formula:

[0034]

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Wherein X is any substituent, but is preferably selected from alkyl, alkenyl, alkynyl, and aryl, and is most preferably alkyl.

R ₂ is preferably ethyl, n-butyl, 2-hydroxypropyl, and 2-
Selected from methoxypropyl. Most preferably, R ₂ is ethyl. These R ₂ moiety is issued for example on June 16, 1998 Novarti
U.S. Patent No. 5,767,096 to Ko et al .; May 2, 1997.
Published Guilford Pharmaceuticals Inc.
Are further described in International Patent Application Publication WO 97/18828 to Steiner et al.

The R ₃ moiety R ₃ is selected from hydrogen, methyl, benzyl, 1-propenyl, and 2-methyl-3-hydroxy-propyl. Preferably R ₃ moiety is selected from hydrogen, methyl and benzyl. Most preferably, R ₃ is hydrogen or benzyl.

These R_ThreePortions are published, for example, on June 16, 1998, Novarti
assigned to sKo etc.U.S. Patent No. 5,767,096; May 2, 1997.
Published Guilford Pharmaceuticals Inc.
Transferred toSteiner, etc.International Patent Application Publication No. WO 97/18828; Hu etc. "Cyclosporin Analogs Modified in
 the 3,7,8-Positions: Substitute Eff
ects on Peptidylprolyl Isomerase Inh
ibition and Immunosuppressive Active
ty Are Nonadditive ”, Journal of Medic
al Chemistry, Vol. 38, pp. 4164-4170 (199
It is further described in 5).

[0039] For the configuration at R ₃ position, R ₃ moieties can be L or D configuration, but preferably is D configuration. The R ₄ moiety R ₄ is a substituted or unsubstituted C ₁ -C ₉ straight or branched chain alkyl,
Preferably it is a substituted or unsubstituted C ₁ -C ₆ straight or branched alkyl, and more preferably a substituted or unsubstituted C ₁ -C ₄ straight or branched alkyl. is there.

Preferably, R ₄ is selected from 2-methylpropyl, 2-methyl-3-hydroxypropyl, 2-methylbutyl, iso-propyl, 2-hydroxypropyl, and methyl. Most preferably R ₄ is 2-methylpropyl.

These R_FourPortions are published, for example, on June 16, 1998, Novarti
assigned to sKo etc.U.S. Patent No. 5,767,096; May 2, 1997.
Published Guilford Pharmaceuticals Inc.
Transferred toSteiner, etc.International Patent Application Publication No. WO 97/18828; Bartz, etc. "Inhibition of Human Immunomode
ficiency Virus Replication by Nonimm
unosuppressive Analogs of Cyclospori
n A ", Proceedings of the National Aca
demy of Sciences U.S.A. S. A. , Vol. 92, pp. 53
81-5385 (1995).

R _{5 The} moiety R ₅ is a substituted or unsubstituted C ₁ -C ₆ straight or branched chain alkyl,
And more preferably C ₁ -C ₄ linear or branched alkyl not or substituted substituted.

Preferably, R ₅ is selected from 2-methylpropyl, n-butyl and iso-propyl. Most preferably R ₅ is iso - propyl. These R ₅ moiety is issued for example on June 16, 1998 Novarti
U.S. Patent No. 5,767,096 to Ko et al .; May 2, 1997.
Published Guilford Pharmaceuticals Inc.
Are further described in International Patent Application Publication WO 97/18828 to Steiner et al.

R ₅ ′ Moiety The R ₅ ′ moieties are selected from hydrogen, methyl, benzyl, p-fluorobenzyl, 1-propenyl, and 1-phenyl-1-propenyl. For clarity,
1-propenyl has the following formula:

[0045]

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Is exemplified as follows. For further clarity, 1-phenyl-1-propenyl has the following formula:

[0047]

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Is exemplified as follows. Furthermore, Papageorgiou et al. , “Conforma
Tional Control of Cyclosporin Thong
h Substitution of the N-5 Position. A
New Class of Cyclosporin Antagonist
s ", Bioorganic & Medicinal Chemistry,
Vol. 5, No. 1, pp. 187-192 (1997).

Preferably R ₅ ′ is selected from hydrogen, methyl and 1-propenyl, more preferably hydrogen and 1-propenyl. Most preferably, R ₅ ′ is hydrogen. R ₆ moiety The R ₆ moiety is 2-methylpropyl, 2-methyl-3-hydroxypropyl, methyl and ethyl, more preferably 2-methylpropyl and 2-methyl-3.
-Selected from hydroxypropyl. Most preferably R ₆ is 2-methylpropyl.

These R ₆ moieties can be found, for example, on Nov. 16, 1998, Novarti.
U.S. Patent No. 5,767,096 to Ko et al .; May 2, 1997.
Published Guilford Pharmaceuticals Inc.
Are further described in International Patent Application Publication WO 97/18828 to Steiner et al.

R ₇ Part The R ₇ part is selected from methyl and phenyl. Preferably R ₇ is methyl.

These R ₇ moieties are disclosed, for example, in Guilfor published May 29, 1997.
d Pharmaceuticals Inc. International Patent Application Publication Nos. WO 97/18828 to Steiner et al . And "Cyclospori" to Hu et al .
n Analogs Modified in the 3,7,8-Posi
points: Substitute Effects on Peptidy
lprolyl Isomerase Inhibition and Imm
unosuppressive Activity Are Nonaddit
ive ”, Journal of Medical Chemistry, Vo
l. 38, pp. 4164-4170 (1995).

The R ₈ moiety The R ₈ moiety is selected from methyl and hydroxymethyl. Preferably R ₈ is
Methyl.

These R ₈ moieties are disclosed, for example, in Guilfor published May 29, 1997.
d Pharmaceuticals Inc. International Patent Application Publication Nos. WO 97/18828 to Steiner et al . And "Cyclospori" to Hu et al .
n Analogs Modified in the 3,7,8-Posi
points: Substitute Effects on Peptidy
lprolyl Isomerase Inhibition and Imm
unosuppressive Activity Are Nonaddit
ive ”, Journal of Medical Chemistry, Vo
l. 38, pp. 4164-4170 (1995).

Preferred compounds useful in the method of the invention include the following:

[0056]

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[0057]

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[0058]

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Are shown below. Analytical Methods The present invention relates to a method of treating hair loss in a mammal by administering to the mammal a non-immunosuppressive compound having the structure described herein. Compounds (test compounds) can be tested for their ability to induce anagen and their immunosuppressive activity (or lack thereof) using the following methods. Alternatively, other methods known in the art can be used, but according to the term "non-immune" as defined by the methods disclosed herein below.

Resting Phase Transition Assay The resting phase transition assay is the ability of a test compound to convert a mouse that is in the resting phase of the hair growth cycle (“resting phase”) to the growth phase of the hair growth cycle (“growth phase”). Is measured.

Without wishing to be bound by theory, there are three main periods of the hair growth cycle: anagen, catagen, and telogen. C3H mouse (Hall
an Sprague Dawley, Inc. , Indianapolis,
IN), it is believed that there is a prolonged rest period from about 40 days to about 75 days after birth, when hair growth is synchronized. It is believed that hair growth is no longer synchronized after 75 days of age. Mice with dark (brown or black) hair, about 40 days old, are used in hair growth experiments, with the growth of hair (hair) where local application of a hair growth inducer is evaluated. Thus, melanin formation occurs.
The telogen turnover assay described below is used to screen for potential hair growth compounds by measuring melanogenesis.

Three groups of C3H mice at 44 days of age are used: a vehicle control group, a positive control group and a test compound group, where the test compound group is administered the compound used in the method of the invention. The duration of the assay is at least 19 days including 15 treatment days (where the treatment date is Monday to Friday). Day 1 is the first day of treatment. Most experiments end at day 19, but if the melanogenesis reaction appears positive but occurs slowly, some can be performed up to day 24. A typical experimental design is shown in Table 1 below.

[0063]

[Table 1]

^** Vehicle is 60% ethanol, 20% propylene glycol, and 20% dimethyl isosorbide (Sigma Chemical Co., St.
. Commercially available from Louis, MO).

The mice are treated locally from Monday to Friday on the lower back (from the base of the tail to the lower ribs). Place a titrator and tip on the back of each mouse.
Used to release 00 μL. The 400 μL application is applied slowly, moving the mouse hair and allowing the application to reach the skin.

While each treatment is applied topically to the mice, each mouse is given a visual rating of 0 to 4 for the color of the skin where it was applied. When the mouse is converted from telogen to anagen, its skin color becomes more bluish black. As shown in Table 2, grades 0 to 4 indicate the following visual observations when the skin changes from white to bluish black.

[0067]

[Table 2]

Immunosuppressive Assays The immunosuppressive assays described herein predict the immunosuppressive activity (or non-immunosuppressive activity) of the compounds used in the methods of the present invention. The assay is performed as follows: Mature male C ranging from 7 to 16 weeks old after euthanasia (CO ₂ asphyxiation).
The spleen is removed from the 3H mouse (the live mouse is Harlan Sprague).
e Dawley, Inc. , Indianapolis, IN). The spleen was immediately cooled with Hanks solution (HBSS, Gibco-BRL).
, Gaithersburg, MD). The spleen is then ground between frosted glass slides and filtered through a sterile screen to remove tissue debris. The obtained cell suspension is mixed with an equal volume of Ficoll-P.
aque Plus (Pharmacia Biotech, Piscataw
ay, NJ) (commercially available from NJ)
And centrifuge at 20 ° C. for about 40 minutes to collect splenocytes. Splenocytes are collected from the interface using a disposable pipette and washed twice with HBSS, followed by centrifugation at 100 xg for 10 minutes at 20 ° C. Splenocytes were prepared from 10% heat-inactivated fetal bovine serum (Gibco-BRL), penicillin (50 units / mL), streptomycin (100 μg / mL), L-glutamine (2 mM), 2-mercaptoethanol (10 ⁻⁵ M). And N-2-hydroxyethylpiperazine-N'-2-
Resuspend in 5-10 mL of cell culture medium consisting of RPMI 1640 without phenol red (culture medium commercially available from Gibco-BRL) containing ethanesulfonic acid (HEPES) (10 mM). Cells are counted and examined for viability using, for example, trypan blue. Spleen cells in medium
0 ⁶ resuspended in cells / mL, and pipetted into 96-well round-bottom plates placed at 10 ⁵ cells / well. Splenocytes were harvested with 50 μL / well of conconavalin (conc
Activation with and without the presence of the test compound by the addition of onavalin) A (final assay concentration = 5 μg / ml). Test compounds are prepared as stock solutions in methyl sulfoxide (DMSO), then diluted in vehicle and added at 50 μL / well so that the final concentration of DMSO in the assay is less than 0.05%. Plates are incubated for 48 hours at 37 ° C. with 5% CO ₂ .
After 48 hours, cells were treated with 1 μCi / well of methyl- ³ H-thymidine (Amersh).
am, Buckinghamshire, England) is applied and incubated for an additional 24 hours.

After 24 hours, cells were plated on GF / C filter plates (Packard, Down)
ers Grove, IL) (commercially available from Microsci, Inc.).
nt 20 (Packard) and dissolve in TopCount micropre
And counting with a fluorescent plate counter (Packard)
You. Activity is measured as the percent of control activity in the absence of test compound,
It is then plotted against the concentration of the test compound. The data is approximated by a 4-variable curve approximation method (
Sigmaplot) and IC₅₀Calculate the value. In this specification
In use, the test compound is prepared using this method (IC of cyclosporin A). ₅₀ / IC of test compound₅₀) X 100 ratio equal to or less than 0.02
Where the non-immunosuppressive test compound is ≦ 2% cyclos, as defined herein.
If it has the immunosuppressive activity of porin A, it is considered non-immunosuppressive.

Cell viability was determined by the method of Nelson et al. , Journal of Immunolog.
y, Vol. 150, no. 6, pp. MTT (3- [4,5-dimethyl-thiazoyl-bromide-bromide) as described by 2139-2147 (1993).
2-yl] 2,5-diphenyl-tetrazolium) staining assay, except that the assay was serum-free and phenol red-free RPMI 1640
And the dye is dissolved in 100 μL / well of DMSO and
pectraMax Plus microplate reader (Molecular
Devices, Menlo Park, Calif.) By reading at an OD of 540 nm with background correction at 650 nm.

Preparation Methods The compounds used in the method of the present invention are prepared by methods known to those skilled in the art. The starting materials used to prepare this compound are known, are prepared by known methods, or are commercially available as starting materials.

It will be appreciated that those skilled in organic chemistry can readily perform standard manipulations of organic compounds without further guidance. Examples of such operations are described in Mar
ch, Advanced Organic Chemistry , John W.
Considered in standard textbooks such as iley & Sons (1992).

Certain reactions are best performed when other functional groups in the compound are blocked or protected, thus increasing the yield of the reaction and / or avoiding any undesired side reactions. It will be readily appreciated by those skilled in the art. Often, those skilled in the art will use protecting groups to achieve such increased yields or avoidance of undesired reactions. These reactions are found in the literature and are well within the skill of the art. Examples of many such operations are described, for example, by T.W. Greene, Protecting Groups in Organic Synthesis , John
Wiley & Sons (1981).

The compounds of the present invention can have one or more chiral centers. As a result, one optical isomer, including diastereomers and enantiomers, can be prepared selectively over another, for example, by a chiral starting material, catalyst or solvent, or both stereoisomers Or both optical isomers (racemic mixtures), including diastereomers and enantiomers, can be prepared at one time. Since the compounds of the present invention can exist as a racemic mixture, mixtures of optical isomers, including diastereoisomers and enantiomers, can be prepared by known methods, such as by using chiral salts and chiral chromatography. Can be used to separate.

It is further recognized that one of the optical isomers or stereoisomers, including diastereomers and enantiomers, may have more favorable properties than the other. Thus, when disclosing and claiming the present invention, when one racemic mixture is disclosed, it is intended that both optical isomers, including diastereomers and enantiomers, be substantially free of the other Or, it is expressly contemplated that stereoisomers are also disclosed and claimed.

The synthesis of compounds useful in the present invention has been described in the art. Therefore,
Those skilled in the art will be able to prepare the compounds described herein. Change
For guidance, the following references describe the synthesis of the compounds used in the methods of the present invention.
Listed:Bartz, etc., “Inhibition of Human Im
munodeficiency Virus Replication by
Nonimmunosuppressive Analogs of Cycl
osporin A ”, Proceedings of the Nation
al Academy of Sciences U.S.A. S. A. , Vol. 92
Pp. 5381-5385 (1995); published July 2, 1998;
hone-PoulencBarriere, etc.WO98 / 28
328; issued July 1, 1997; Sandoz Ltd. Transferred to Boelsterli, etc. U.S. Patent No. 5,643,870; June 1, 1996.
Published on Sunday, Sandoz Ltd. Transferred toBollinger, etc.of
U.S. Patent No. 5,525,590; issued May 26, 1992;
oz Ltd. Transferred toDreyfuss etc.U.S. Pat. No. 5,116,81
No. 6; issued on February 8, 1994, and issued by Sandoz Ltd. Transferred toE berle U.S. Pat. No. 5,284,826 issued Sep. 15, 1998.
Was transferred to NovartisEliasU.S. Pat. No. 5,807,820
issue;Hu etc."Cyclosporin Analogs Modified
in the 3,7,8-Positions: Substitute E
effects on Peptidylprolyl Isomerase I
nhibition and Immunosuppressive Acti
"Vity Are Nonadditive", Journal of Med
icinal Chemistry, Vol. 38, pp. 4164-4170
(1995); issued on June 16, 1998 and transferred to Novartis
WasKo etc.U.S. Pat. No. 5,767,069;Papageorgiou, etc.of"
Conformal Control of Cyclospori
n through Substitution of the N-5 Po
site. A New Class of Cyclosporin An
tagonists ", Bioorganic & Medicinal Ch
emistry, Vol. 5, pp. 187-192 (1997);Rich et al. "Synthsis, Biological Activity, and C
informational Analysis of (2S, 3R, 4S)
-MeBmt¹-Cyclosporin, a Novel 1-Positi
on Epimer of Cyclosporin A ", Journal
of Medicinal Chemistry, Vol. 32, pp. 198
2-1987 (1989); published September 17, 1986, Sandoz.
Ltd. Transferred toSeebachEuropean Patent Application EP 0,194,97
2: October 27, 1987, Sandoz Ltd. Transferred to Seebach U.S. Patent No. 4,703,033; issued September 13, 1988.
And Sandoz Ltd. Transferred toSeebachU.S. Pat.
No. 771,122; published May 29, 1997, Guilford Ph.
armaceuticals, Inc. Transferred toSteiner, etc.WO9
7/18828;Sun, etc."Synthesis, Conformation
, And Immunosuppressive Activity of C
yclosporins That Container ε-Oxygen (4R
) -4-[(E) -Butenyl] -4, N-dimethyl-L-Thr
eonine Analogs in the 1-Position ", Jo
urnal of Medicinal Chemistry, Vol. 33,
pp. 1443-1452 (1990); issued September 15, 1981;
andoz Ltd. Transferred toTraber, etc.U.S. Pat. No. 4,289,8
No. 51;Traber, etc."Cyclosporins-New Analog"
us by Precursor Directed Biosyntheses
is ", The Journal of Antibiotics, Vol.
2, No. 4, pp. 591-597 (1988); departs on August 16, 1988
And Sandoz Ltd. Transferred toWengerU.S. Pat.
64, 503; and published September 2, 1993, and Sandoz Ltd.
Transferred toWengerInternational Patent Application Publication No. WO 93/17039.

As a further guide, the following non-limiting examples illustrate methods for making the preferred compounds used in the present invention. Example 1

[0078]

Embedded image

(3′-Keto) cyclosporin A: Dess-Martin periodinane (
periodinane) (2.12 g, 5 mmol; Ireland et al. , "A
n Improved Procedure for the Prepara
Tion of the Dess-Martin Periodinane "
, Journal of Organic Chemistry, Vol. 58
, P. 2899 (prepared by the method reported in 1993) is mixed with dichloromethane (20 mL) and stirred for 10 minutes at ambient temperature. Solution at 5 ° C
And cyclosporin A (2 g, 1.66 mmol; Alexis
(Commercially available from Corporation, San Diego, CA) in dichloromethane (40 mL) is added dropwise over 10 minutes. The mixture was stirred at 5 ° C. for 1 hour, followed by sodium thiosulfate (5.53 g, 35
mmol), sodium bicarbonate (5.03 g, 60 mmol) and water (100 m
Add the solution of L). The resulting mixture is stirred rapidly for 20 minutes, while warming from 5 ° C. to ambient temperature. The mixture is extracted with dichloromethane (3 × 75 mL), then the combined extracts are dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The residue obtained is purified by preparative chromatography (silica gel; ethyl acetate saturated with water) to give the desired (3′-keto) cyclosporin A.

Embodiment 2

[0081]

Embedded image

[0082] (N ⁵ -1- propenyl) cyclosporin A: Cyclosporin A (2g, 1
. 66 mmol; Alexis Corporation, San Diego
, CA, commercially available) are dissolved in tetrahydrofuran (40 mL) at ambient temperature in an inert atmosphere. The reaction solution was cooled to −78 ° C. and 1N phosphazene base in P4-tert-butyl (8.4 mL, 8.32 mmol; Fluka
(Commercially available from Chemika AG, Buchs, Switzerland)) is added dropwise over 5 minutes. The solution is stirred for a further 5 minutes at -78 C, followed by the dropwise addition of allyl bromide (1.16 mL, 13.3 mmol) over 1 minute. The solution is stirred for 90 minutes at -78 [deg.] C, followed by the addition of 1N aqueous citric acid (20 mL). Pour the mixture into a solution of 1N aqueous citric acid (80 mL) and brine (20 mL), then extract with ethyl acetate (3 × 50 mL). The combined organic extracts were dried (MgSO _4), filtered, and concentrated under reduced pressure. The residue was separated by preparative chromatography (silica gel; 1: 1 to 1: 0 (
Ethyl acetate: Purification by gradient elution) in dichloromethane), the desired (N ⁵ - obtain allyl) cyclosporin A.

Embodiment 3

[0084]

Embedded image

(N-Me-D-Phe) ³ -CsA: Cyclosporin A (5.0 g, 4.
Alexis Corporation, San Diego, 16 mmol;
(Commercially available from CA) are dissolved in tetrahydrofuran (250 mL) at ambient temperature under an inert atmosphere. The reaction was cooled to −78 ° C. and 1N lithium bis (trimethylsilyl) amide in tetrahydrofuran (41.6 mL)
, 41.6 mmol; Aldrich Chemical Co. , Milwa
ukee, WI) is added dropwise over 5 minutes. After stirring at −78 ° C. for about 1.5 hours, benzyl bromide (14.2 g, 83.2 m
mol; Aldrich Chemical Co. , Milwaukee, W
(Commercially available from I) is added dropwise over 5 minutes. The reaction mixture is stirred at -78 ° C for about 1 hour, then at 0 ° C for about 1.5 hours, and finally at ambient temperature for about 45 minutes. Water (50 mL) is added and the reaction mixture is concentrated under reduced pressure to remove tetrahydrofuran. Then the mixture is poured onto water (150 mL) and extracted with diethyl ether (3 × 200 mL). Wash the combined ether extracts with 1: 1 water: brine (100 mL), dry over MgSO ₄ , filter, and concentrate under reduced pressure. The crude product obtained is separated by chromatography for separation (
Silica gel; gradient elution of dichloromethane: methanol from 99: 1 to 96: 4)
To give the desired (N-Me-D-Phe) ^3- CsA.

Embodiment 4

[0087]

Embedded image

(3′-keto) ¹ (N-Me-D-Phe) ³ -CsA: Dess-Mart
in periodinane (6.50 g, 15.33 mmol; Ireland et al. , "A
n Improved Procedure for the Prepara
Tion of the Dess-Martin Periodinane "
, Journal of Organic Chemistry, Vol. 58
, P. 2899 (prepared by the method reported in 1993) is mixed with dichloromethane (20 mL) and stirred for 10 minutes at ambient temperature. Solution at 0 ° C
And then (N-Me-D-Phe) ^{3 in} dichloromethane (40 mL)
-CsA (2.20 g, 1.70 mmol; prepared according to Example 3 herein) is added dropwise over 10 minutes. After stirring the mixture at 0 ° C. for about 2.5 hours, additional Dess-Martin periodinane (2.16 g, 5.1 mmole) was added.
l) is added to the reaction. The reaction mixture is stirred for a further 5 hours at 0 ° C. Sodium thiosulfate (17 g, 107.3 mmol), sodium bicarbonate (15.45 g,
183.9 mmol) and a solution of water (300 mL). The resulting mixture is rapidly stirred at ambient temperature for about 20 minutes. The mixture was diluted with dichloromethane (3 × 100
mL) and the combined organic extracts were dried (MgSO ₄ ), filtered,
Then, it is concentrated under reduced pressure. The resulting residue is purified by preparative chromatography (silica gel; gradient elution from 99: 1 to 96: 4 dichloromethane: methanol) to give the desired (3′-keto) ¹ (N-Me-D- Phe) ³ -CsA is obtained.

Use of the Compounds of the Invention The method of the invention is effected by the administration of a compound having the structure described herein and preferably a pharmaceutically or cosmetically acceptable carrier.

The compounds described herein are useful for treating conditions such as treating hair loss in mammals, including inhibiting and / or reversing hair loss and promoting hair growth. Can be used. Such conditions are manifest themselves in alopecia, including, for example, male pattern baldness and female pattern baldness.

The compounds of the present invention are non-immunosuppressive, as defined herein. Preferably, in the methods of the present invention, the compound is formulated in a pharmaceutical or cosmetic composition for use in treating or preventing a condition as described above. Remi ngton's Pharmaceutical Sciences, Mack
Publishing Company, Easton, PA. (1990)
Standard pharmaceutical formulation techniques are used, such as those disclosed therein.

Typically, from about 5 mg to about 3000 mg, more preferably from about 5 mg to about 1000 mg, more preferably from about 10 mg to about 100 mg of a compound having a structure described herein is administered in systemic administration. Administered daily.
It is understood that these dosage ranges are exemplary only, and that daily dosages may be adjusted by various factors. The particular dosage of the compound to be administered, as well as the duration of the treatment and whether the treatment is topical or systemic, are independent. The dosage and treatment regimen will depend on the particular compound used, the application of the treatment, the potency of the compound, the personal characteristics of the patient (eg, weight, age, gender, and the medical condition of the patient),
It also depends on factors such as adherence to treatment management, and the presence and severity of side effects of treatment.

According to the present invention, the compounds of the present invention are co-administered with a pharmaceutically acceptable or cosmetically acceptable carrier (collectively referred to herein as “carriers”). The term "carrier" as used herein refers to one or more compatible solid or liquid fillers, diluents or encapsulating materials, suitable for administration to a mammal. As used herein, the term "compatible" refers to a behavior in which the components of the composition do not interact under normal conditions of use to substantially reduce the potency of the composition. It means that it is possible to mix with the compounds of the invention and with each other.
Carriers must of course be of sufficiently high purity and of sufficiently low toxicity that they are suitable for administration to the animal to be treated, preferably mammals (most preferably humans). The carrier may be inert itself, or may retain its own pharmaceutical and / or cosmetic benefits.

The compositions of the present invention can be in any of a variety of dosage forms suitable for (for example) oral, rectal, topical, nasal, ophthalmic, or parenteral administration. Of these, topical and / or oral administration is particularly preferred, and topical is most preferred. Various carriers known in the art can be used depending on the particular route of administration desired. These include solid or liquid fillers, diluents, suspensions (hydrotropes), surfactants, and encapsulating agents. An optional pharmaceutically or cosmetically active substance that does not substantially inhibit the activity of the compounds of the present invention can also be included. The amount of carrier used with the compound is an amount sufficient to provide a practical amount of the substance to administer the compound per unit dose. Techniques and compositions for producing dosage forms useful in the methods of the invention are described in the following references: Modern Pharmaceuticals , Chapter 9 and 10, Banker & Rho.
des, eds. (1979); Lieberman et al., Pharmaceutical dental Dosage Forms: Tablets (1981); and An.
sel, Introduction to Pharmaceutical D osage Forms , 2 nd Ed. , (1976).

Some examples of substances that can be used as carriers or components thereof include sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; sodium carboxymethylcellulose, ethylcellulose, and methylcellulose. 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 theobroma oil. ;Propylene glycol,
Polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers such as TWEENS; humectants such as sodium lauryl sulfate; coloring agents; fragrances; tableting agents, stabilizers; ;
Pyrogen-free water; isotonic saline; and phosphate buffered saline.

[0096] The choice of carrier to be used with the compounds of the invention is typically dictated by the method by which the compound is to be administered. In particular, carriers for systemic administration include sugar, starch, cellulose and derivatives thereof, 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. Preferably, the carrier in a parenterally administered composition comprises at least 90% by weight of the total composition.

A variety of oral dosage forms can be used, including solid dosage forms such as tablets, capsules, granules and loose powders. These oral dosage forms contain a safe and effective amount, usually at least about 5%, and preferably from about 25% to about 50% of the compound used in the present invention. Tablets may contain suitable binders, lubricants, diluents, disintegrants, colorants, fragrances, flow inducers, and melting agents, compressed tablets, rub-in tablets, enteric-coated tablets, sugar-coated tablets, film-coated tablets. Or it can be a multiple compressed tablet. Liquid oral dosage forms are prepared from aqueous solutions, emulsions, suspensions, non-effervescent granules, including suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavors. Includes reconstituted solutions and / or suspensions and effervescent preparations reconstituted from effervescent granules.

Suitable carriers for preparing unit dosage forms for oral administration are known in the art. Tablets typically contain inert diluents such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; starches such as alginic acid and croscarmellose. Disintegrant; magnesium stearate,
Lubricants such as stearic acid and talc; and conventional pharmaceutically compatible adjuvants. Glidants such as silicon dioxide can be used to improve the flow properties of the dust mixture. Coloring agents, such as Food and Drug Administration approved dyes, can be added for appearance. Sweetening and flavoring agents such as aspartate, saccharin, menthol, peppermint, and fruit flavors are useful adjuvants for chewable tablets. Capsules (including time release and sustained release) typically contain one or more of the solid diluents disclosed above. The choice of carrier component depends on secondary considerations that are not important for the purposes of the present invention, such as taste, price, and storage stability, and can be readily made by one skilled in the art.

Compositions for oral administration further include liquid solutions, emulsions, suspensions, powders, granules, elixirs, tinctures, syrups, and the like. Suitable carriers for preparing such compositions are known in the art. Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerin, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. Typical suspending agents for suspensions include methylcellulose, sodium carboxymethylcellulose, AVICEL RC-591, tragacanth and sodium alginate; typical humectants are lecithin and polysorbate 80
And typical preservatives include methyl paraben and sodium benzoate. The oral liquid composition can further include one or more ingredients such as sweeteners, flavors and colorants disclosed above.

Such compositions are typically prepared such that the compounds of the invention are released in the gastrointestinal tract near the desired topical application or at various times to prolong the desired effect. Can be coated by pH or time dependent coatings by conventional methods. Such dosage forms are typically, but not limited to, one or more of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethyl cellulose phthalate, ethyl cellulose, Eudragit coating, wax and Including shellac.

Other compositions useful for achieving systemic release of the compounds of the present invention include sublingual, buccal and nasal dosage forms. Such compositions typically include one or more soluble filler materials such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethylcellulose and hydroxypropylcellulose. It may further include the slip agents, lubricants, sweeteners, colorants, antioxidants and fragrances disclosed above.

The compounds of the present invention can be further administered topically. The carrier of the topical composition preferably helps the compound of the present invention penetrate into the skin to reach around the hair follicles. The topical compositions of the present invention include, for example, solutions, oils, creams, ointments, gels, lotions, shampoos, leave and wash hair conditioners, milks, detergents, humectants, sprays, skin patches. , And the like.

[0103] Topical compositions containing the active ingredient include, for example, water, alcohol, genuine aloe gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol,
It can be mixed with various carrier materials known in the art, such as PPG-2 myristyl propionate, and the like.

Other substances suitable for use in topical carriers include, for example, emollients, solvents, humectants, thickeners and powders. Examples of each of these types of substances, which can be used alone or as a mixture with one or more substances, are as follows: emollients such as stearyl alcohol, glyceryl monoricinoleate, Glycerin monostearate, propane-1,2-diol, butane-1,3-diol, mink oil, cetyl alcohol, iso-propyl isostearate, stearic acid, iso-butyl palmitate, isocetyl stearate, oleyl alcohol, laurin Isopropyl acid, hexyl laurate, decyl oleate, octadecane-2-ol, isocetyl alcohol, cetyl palmitate, dimethylpolysiloxane, di-n-butyl sebacate, iso-propyl myristate, iso-propyl palmitate, stearin Acid So-propyl, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, peanut oil, castor oil, acetylated lanolin alcohol, petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, Lauryl lactate, myristyl lactate, decyl oleate, and myristyl myristate; propellants, such as propane, butane, iso-butane, dimethyl ether, carbon dioxide, and nitrous oxide; solvents, such as ethyl alcohol, methylene chloride, iso -Propanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulfoxide, dimethylformamide, Trahydrofuran; wetting agents, for example, glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, and gelatin; and dusts, for example, chalk, talc, acid clay, kaolin, starch, gum Colloidal silicon dioxide, sodium polyacrylate, tetraalkylammonium smectite, trialkylarylammonium smectite, chemically modified magnesium aluminum silicate, organically modified montmorillonite clay, hydrated silicic acid Aluminum, fumed silica, carboxyvinyl polymer, sodium carboxymethylcellulose, and ethylene glycol monostearate.

The compounds used in the present invention include smaller unilamellar vesicles, larger unilamellar vesicles and multilayers.
It can be administered in the form of a liposome release system such as a vesicle. Liposomes are
Various phosphorous such as resterol, stearylamine or phosphatidylcholine
It can be formed from lipids. Preferred Treatments for Local Release of Compounds of the Invention
For example, Dowton et al., “Influence of Liposomal C
composition on Topical Delivery of En
Capsulated Cyclosporin A: I. An in vit
ro Study Using Hairless Mouse Skin ", S. T. P. Pharma Science , Vol. 3, pp. 404-40
7 (1993);Wallach and Philippott, “New T
type of Lipid Vehicle: Novasome (R) ",Li Posome Technology , Vol. 1, pp. 141-156 (1
993); issued March 27, 1990, and published by Micro-Pak, Inc. To
TransferredWallachU.S. Patent No. 4,911,928; and 1998
Published on November 10th, the University of Michigan and
Micro-Pak, Inc. Transferred toWeiner, etc.US Patent No. 5,8
Use liposomes as described in US Pat. No. 34,014 (Weiner, etc. With the compounds as described herein, together with the replacement of minoxidil
Instead or in addition).

The compounds of the present invention can be further administered by iontophoresis. For example, Internet site www. unipr. it / arpa / dipfa
rm / erasmus / erasm14. html; Banga et al. , "Hygr
ogel-based Iontotherapeutic Delivery
Devices for Transaction Delivery of
Peptide / Protein Drugs ", Pharm. Res., V
ol. 10 (5), pp. 697-702 (1993); Ferry , "The.
original Model of Iontophoresis Util
size in Transdermal Drug Delivery ”, P
harmonica Acta Helvetiae, Vol. 70,
pp. 279-287 (1995); Gangorosa et al. , "Modern.
Iontophoresis for Local Drug Deliver
y ", Int. J. Pharm, Vol. 123, pp. 159-171 (19)
95); Green et al. , "Iontophoretic Delivery o.
fa Series of Triptetide Across the
Skin in vitro ", Pharm. Res., Vol 8, pp. 1
121-1127 (1991); Jadoul et al. , " Quantiticati.
on and Localization of Fentanyl and
TRH Delivered by Iontophoresis in th
e Skin ", Int. J. Pharm., Vol. 120, pp. 221-
8 (1995); O'Brien et al. , "An Updated Review.
of it's Antiviral Activity, Pharmacoki
netic Properties and Therapeutic Eff
icacy ", Drugs, Vol. 37, pp. 233-309 (1989).
Parry et al. , "Acyclovir Bioavailability in.
Human Skin ", J. Invest. Dermatol., Vol.
98 (6) pp. 856-63 (1992); Santi et al. , "Drug R.
esservoir Composition and Transport o
f Salmon Calcitonin in Transdermal I
ontophoresis ", Pharm. Res., Vol 14 (1), p.
p. 63-66 (1997); Santi et al. , "Reverse Iontop."
horesis-Parameters Determining Elect
loosmotic Flow: I. pH and Ionic Strength
th ", J. Control. Release, Vol. 38, pp. 159-
165 (1996); Santi et al. , "Reverse Iontophore."
sis-Parameters Determining Electroros
matic Flow: II. Electrode Chamber Form
ulation ", J. Control. Release, Vol. 42, pp.
. 29-36 (1996); Rao et al. , "Reverse Iontophor."
ess: Noninvasive Glucose Monitoring
in vivo in Humans ", Pharm. Res., Vol.
(12), p. 1869-1873 (1995); Thysmsn et al. , "Hu.
man Calcitinin Delivery in Rats by I
ontophoresis ", J. Pharm. Pharmacol., Vol.
. 46, pp. 725-730 (1994); and Volpato et al. , "Ion.
tophoresis Enhances the Transport of
Acyclovir through Nude Mouse Skin b
y Electrorepulsion and Electroosmosi
s ", Pharm. Res., Vol. 12 (11), pp. 1623-162.
7 (1995).

The composition of the present invention may further contain an activity promoter, if desired. The activity enhancer can be selected from a wide range of molecules that can function in different ways to enhance the hair growth effect of the compounds of the present invention. Particular types of activity enhancers include other hair growth stimulants and penetration enhancers.

The additional hair growth stimulants can be selected from a wide range of molecules that can function in different ways to promote the hair growth effects of the compounds of the present invention. These optional other hair growth stimulants, when present, are typically present in the compositions herein at from about 0.01% to about 15%, preferably from about 0.1% to about 15%, of the composition.
It is used in an amount ranging from 1% to about 10%, most preferably from about 0.5% to about 5% by weight.

For example, potassium channel agonists including minoxidil and minoxidil derivatives such as aminexil, and US Pat. No. 3,382,247, US Pat. , 75
U.S. Patent No. 5,772,99, issued June 30, 1998.
0, U.S. Patent No. 5,760,043, issued June 2, 1998;
U.S. Pat. No. 328,914 issued Jul. 12, 1994; U.S. Pat. No. 5,466,694 issued Nov. 14, 1995; No. 4,438,058, and U.S. Pat. No. 4,973,474, issued Nov. 27, 1990, all of which are incorporated herein by reference. Vasodilators, such as those, and cromakalin and diazoxide can be used as additional hair growth stimulating agents in the compositions herein.

One suitable class of additional hair growth stimulants for use herein is
It is an anti-androgen. Examples of suitable androgens include, but are not limited to, finasteride and US Pat. No. 5,516, issued May 14, 1996.
, (Incorporated by reference herein) 779, and Nane etc., Ca ncer Research 58, "Effects of Some No
vel Inhibitors of C17,20-Lyase and 5
α-Reductase in vitro and in vivo and
Their Potential Role in the Treatme
5-alpha-reductase inhibitors, such as those described in nt of Prostate Cancer, and cyproterone acetate, azelaic acid and its derivatives and U.S. Pat. No. 5,480,913 issued Jan. 2, 1996.
No. 5,411,981, issued May 2, 1995, Oct. 15, 1996.
And US Pat. No. 5,910,226 issued Mar. 20, 1990, all of which are incorporated herein by reference. Incorporated by reference in the specification.

[0111] Another suitable class of optional hair growth stimulant, filed on September 21, US patent application Ser. No. 09 / 400,681 1999 issue of such McIver, filed on September 21, 1999 US patent application Ser. No. 09 / 400,682, such as McIver; US patent application of McIver, etc., which was filed on September 21, 1999 09/40
0,679 No.; September 1999 Tiesman such filed 21 days U.S. Patent Application 09 / 400,021 Patent; US Patent Application 09 / 400,425 No. of such September 1999 Fulmer filed 21 days ; August 1999 D Egenhardt like filed on 5th U.S. provisional Patent application No. 60 / 147,279; 1999 8
U.S. Provisional Application 60 / 147,3, filed December 5, filed by Degenhardt et al.
No. 13; August 1999 U.S. Provisional Patent Application No. 60 / 147,280 of 5 days Degenhardt etc. filed; August 1999, such Degenha rdt filed 5th U.S. Provisional Patent Application 60 / 147,278 No .: FK506 analogs as described in US Provisional Application No. 60 / 147,276 to Eickhoff et al. , Filed August 5, 1999, all of which are incorporated herein by reference. Incorporated as.

Another suitable type of optional hair growth stimulant is selenium sulfide, ketoconazole, triclocarbon, triclosan (tr
iclosan, pyrithione zinc, itraconazole, asiatic acid, hinokitiol, mipirocin and European Patent Application Publication E
Antimicrobial agents such as those described in PA 0,680,745 (incorporated herein by reference), clinacycin hydrochloride, benzoyl peroxide, benzyl peroxide and minocycline. It is.

Anti-inflammatory agents can also be incorporated into the compositions herein as optional hair growth stimulating agents. Examples of suitable anti-inflammatory agents are hydrocortisone, mometasone furoate, and glucocorticoids such as prednisolone, those described in US Pat. No. 5,756,092, and cyclooxygenases such as benzidamine. Or a lipoxygenase inhibitor,
Salicylic acid and European Patent Application Publication EPA 0, published May 2, 1997.
770,399, International Patent Application Publication WO94 published March 31, 1994.
/ 06434 and French Patent Application F published on November 21, 1975
Non-steroidal anti-inflammatory agents can be included, including the compounds described in R2,268,523, all of which are incorporated herein by reference.

Another suitable class of optional hair growth stimulating agents are thyroid hormones and derivatives and analogs thereof. Examples of thyroid hormones suitable for use herein can include triiodothyrionine. Examples of thyroid hormone analogs that may be suitable for use herein are described in U.S. Provisional Application No. 60 / 136,996 to Zhang et al., Filed June 1, 1999; U.S. Provisional Patent Application No. 60 / 137,024, filed on January 1, Zhang et al., Filed on June 1, 1999,
US Provisional Application No. 60 / 137,022 to Hhang et al., US Provisional Application No. 60 / 137,023 to Zhang et al.
U.S. Provisional Application 60 / 137,0, filed on January 1, filed with Youngquist et al.
No. 52, U.S. Provisional Patent Application No. 60 / 137,063 filed on June 1, 1999, by Youngquist et al., Youngqu filed on June 1, 1999.
including those described in US Provisional Patent Application No. 60 / 136,958 to ist et al.

A prostaglandin agonist or antagonist can be used as an optional hair growth stimulant in the compositions herein as well. An example of a suitable prostaglandin agonist or antagonist is latanoprost (latanprost).
opstone) and Johnstone's WO published August 6, 1998.
98/33497, published by Stjernshant on April 27, 1995.
z WO95 / 11003, Ueno's Japanese Patent Application Publication, JP-A-9-1000
No. 91 and Nakamura's Japanese Patent Application Publication, and JP-A-8-134242.

Another class of optional hair growth stimulants for use herein is
It is a retinoid. Suitable retinoids include isotretinoin, acitretin (a
citretin) and tazarotene.

Another type of optional hair growth stimulant for use herein is
See, for example, Bradbury et al., U.S. patent application Ser. No. 09 / 353,408, filed Jul. 15, 1999, entitled "Method for Regulating Ha."
ir Growth "and Bradbury, filed July 15, 1999.
Et al., U.S. patent application Ser. No. 09 / 353,409, "Compositions Whi."
ch Container Triterpenes for Regulatin
g Hair Growth ", each of which is incorporated herein by reference in its entirety.

Other types of optional hair growth stimulants for use herein are flavonoids, ascomycin derivatives and analogs, histamine antagonists such as diphenhydramine hydrochloride And other triterpenes such as oleanolic acid and ursone, as well as U.S. Pat. No. 5,529,769, Japanese Patent Application Publication No. 10-017431, International Patent Application Publication No. No., Japanese Patent Application Publication, JP-A-9-067253, International Patent Application Publication WO92 / 09262, Japanese Patent Application Publication, JP-A-62-09321.
5, U.S. Pat. No. 5,631,282, U.S. Pat. No. 5,679,705, Japanese Patent Application Publication, and JP-A-8-193094, published on Sep. 8, 1993. European Patent Application Publication No. EP 0558,509 to Bonte et al. And International Patent Application Publication No. WO 9/1986 published on January 16, 1997.
7/01346, both of which are hereby incorporated by reference in their entirety, US Pat. No. 5,015,470 issued May 14, 1991. US Patent No. 5,3, issued April 5, 1994.
No. 00,284 and U.S. Pat. No. 5,185,3, issued Feb. 9, 1993.
No. 25, all of which are incorporated herein by reference, proteoglycanase or glycosaminoglycanase inhibitors, estrogen agonists and antagonists, pseudoterin (ps
analogs or inhibitors, such as cytokines and growth factor promoters, interleukin-1 inhibitors, interleukin-6 inhibitors, interleukin-10 promoters and tumor necrosis factor inhibitors, vitamin D analogs and epithelium Body hormone antagonists, vitamins such as vitamin B12 analogs and panthenol, interferon agonists and antagonists, US Pat. No. 5,550,
No. 158, including hydroxy acids, benzophenones, and hydantoin anticonvulsants such as phenytoin.

Other additional hair growth stimulants are described, for example, in Japanese Patent Application Publication No. 9-157,139 to Tsuji et al., Published June 17, 1997;
Mirabeau published European Patent Application EP 0277455 published on Oct. 10.
No. A1; WO97 published by Cabo Soler et al.
WO92 / 1, published on March 13, 1992 by Bonte et al.
6186; Japanese Patent Application Publication by Okazaki et al. Published on April 28, 1987, JP-A-62-93215; Kuro published on January 22, 1991.
US Patent No. 4,987,150 to No. et al .; Japanese Patent Application Publication No. 290811 to Ohba et al. published October 15, 1992; Japanese Patent Application Publication No. Tanaka et al. JP-A-5-286835, 19
Greff published French Patent Application FR 2,723 published August 2, 1994.
Gibbson, U.S. Pat. No. 5,313,313 issued May 14, 1991.
015,470, U.S. Pat. No. 5,559, September 24, 1996.
No. 092, U.S. Pat. No. 5,536,751 issued Jul. 16, 1996; U.S. Pat. No. 5,714,515 issued Feb. 3, 1998, 1989.
European Patent Application Publication No. EPA 0,319,991, published on June 14, 1919.
European Patent Application Publication No. EPA 0,357,630 published on Oct. 6, 1988,
European Patent Application Publication EPA 0,573,253 published December 8, 1993.
No., Japanese patent application published on November 18, 1986, Japanese Patent Application Laid-Open No. 61-26.
No. 0010, US Pat. No. 5,772,990, issued Jun. 30, 1998.
No. 5,053,410 issued Oct. 1, 1991, and US Pat. No. 4,761,401 issued Aug. 2, 1988, All of which are incorporated herein by reference.

Non-limiting examples of penetration enhancers that can be used in the compositions herein include, for example, 2-methylpropan-2-ol, propan-2-ol, ethyl 2-hydroxypropanoate Hexane-2,5-diol, POE (2) ethyl ether, di (2-hydroxypropyl) ether, pentane-2,4-diol, acetone, POE (2) methyl ether, 2-hydroxypropionic acid, 2- Hydroxyoctanoic acid, propan-1-ol, 1,4-dioxane, tetrahydrofuran, butane-1,4-diol, propylene glycol diperargonate, polyoxypropylene 15 stearyl ether, octyl alcohol, POE ester of oleyl alcohol, oleyl alcohol, Lauryl alcohol, adipic acid di Cutyl, dicapryl adipate, di-isopropyl adipate, di-isopropyl sebacate, dibutyl sebacate, diethyl sebacate, dimethyl sebacate, dioctyl sebacate, dibutyl sebacate, dioctyl azelate, dibenzyl sebacate, dibutyl phthalate, dibutyl phthalate, Dibutyl azelate, ethyl myristate, dimethyl azelate, butyl myristate, dibutyl succinate, didecyl phthalate, decyl oleate, ethyl caproate, ethyl salicylate, iso-propyl palmitate, ethyl laurate, 2-ethylhexyl pelargonate , Iso-propyl isostearate, butyl laurate, benzyl benzoate, butyl benzoate, hexyl laurate, ethyl caprate, ethyl caprylate, butyl stearate, Benzyl lithate, 2-hydroxypropanoic acid, 2-hydroxyoctanoic acid, dimethyl sulfoxide, N, N-dimethylacetamide, N, N-dimethylformamide, 2-pyrrolidone, 1-methyl-2-pyrrolidone, 5-methyl-2 -Pyrrolidone, 1,5-dimethyl-2-pyrrolidone,
1-ethyl-2-pyrrolidone, phosphine oxide, sugar ester, tetrahydrofurfural alcohol, urea, diethyl-m-toluamide
, And 1-dodecylazacycloheptan-2-one.

In all of the above, of course, the compounds of the present invention can be administered alone or as a mixture, and the composition further comprises additional drugs or excipients as appropriate for the application. be able to.

Examples of Composition Administration The following examples, which do not limit the invention, but are provided as guidance to those skilled in the art of practicing the methods of the invention. In each example, compounds other than the ones described can be replaced by another having the structure described herein.

Example A A composition for topical administration is prepared comprising:

[0124]

[Table 3]

A human male patient with androgenetic alopecia is treated by the method of the present invention. Specifically, the composition is administered topically to the patient daily for 6 weeks. Example B A composition for topical administration is described in Dowton et al., "Influence of Li.
poposal Composition on Topical Deliv
ery of Encapsulated Cyclosporin A: I.
An in vitro Study Using Hairless Mou
se Skin ", STP Pharma Sciences , Vol.
Pp. 404-407 (1993), using the compound of Example 1 in place of cyclosporin A and using Novasome 1 as a nonionic liposome formulation.

A human male patient with androgenetic alopecia is treated daily with the composition described above. Specifically, the composition is administered topically to the patient for 6 weeks. Example C Four different shampoos are prepared as follows:

[0127]

[Table 4]

A human patient with androgenetic alopecia is treated by the method of the present invention. Specifically, patients use the shampoo described above daily for 12 weeks.

────────────────────────────────────────────────── ─── Continuing the front page (72) Inventor Ticeman, Jay Patrick 45014, Ohio, USA, Fairfield, Delcrest Drive 6353 (72) Inventor Degenhart, Charles Raymond, 45240, Ohio, USA Cincinnati, Welling Wood Court 10555 (72) Inventor Eckhoff, David Joseph 41017, Kentucky, United States of America 410, Edgwood, Garden Way 505 (72) Inventor McKever, John McMillan 45241, Ohio, United States of America, Cincinnati, Indian Springs de Live 9999 F term (reference) 4C084 AA01 AA02 BA01 BA09 BA18 BA24 CA59 DA11 MA02 NA07 NA14 ZA92 4C086 AA01 AA02 BC42 DA12 MA01 MA02 MA04 NA07 NA14 ZA92

Claims (10)

[Claims] 1. The following structure: Administering to a mammal a non-immunosuppressive compound having the formula: and a pharmaceutically acceptable salt, hydrate, and a biologically hydrolyzable amide, ester, and imide thereof. A method for treating hair loss, characterized by: (a) R ₁ is 1-propenyl, propyl, 3-hydroxy-1-propenyl, —O-methyl, —O-p-benzoylbenzyl (B) R ₁ ′ is selected from the group consisting of hydroxy, oxo, and acyloxy; (c) R ₁ ″ is selected from the group consisting of hydrogen and methyl; d) R ₂ is ethyl, n- butyl, 2-hydroxypropyl, 2-methoxypropyl, 1-methylpropyl, and 2-acyloxy - ne propyl Is selected from the group; (e) R ₃ is hydrogen, methyl, benzyl, 1-propenyl, and 2-methyl -
3-hydroxy - is selected from the group consisting of propyl; (f) R ₄ is an C ₁ -C ₉ straight or branched chain alkyl which are not or substituted substituted; (g) R ₅ is a substituted (H) R ₅ ′ is hydrogen, methyl, benzyl, p-fluorobenzyl, 1-propenyl, and 1-phenyl-, which is substituted or unsubstituted C ₁ -C ₆ linear or branched alkyl; Selected from the group consisting of 1-propenyl; (i) R ₆ is 2-methylpropyl, 2-methyl-3-hydroxypropyl,
Methyl, and are selected from the group consisting of ethyl; (j) R ₇ is selected from the group consisting of methyl and phenyl; and (k) R ₈ is selected from the group consisting of methyl and hydroxymethyl; said method . 2. (a) R ₁ ′ is selected from the group consisting of hydroxy and oxo; (b) R ₁ ″ is hydrogen; (c) R ₂ is ethyl, n-butyl, 2- It is selected from hydroxypropylmethylcellulose, and the group consisting of 2-methoxypropyl; and (d) R ₃ is hydrogen, methyl, and is selected from the group consisting of benzyl; the method of claim 1. (A) R ₄ is 2-methylpropyl, 2-methyl-3-hydroxypropyl,
2-methylbutyl, iso - propyl, 2-hydroxypropyl, and is selected from the group consisting of methyl; is (b) R _5, 2-methyl-propyl, n- butyl and iso - is selected from the group consisting of propyl; and (c) R ₅ 'is hydrogen, methyl, and 1 is selected from the group consisting of propenyl; method according to any one of claims 1 or 2. 4. The method according to any one of claims 1 to 3, wherein R ₂ is ethyl and R ₃ is selected from the group consisting of hydrogen and benzyl. 5. R ₅ ′ is selected from the group consisting of hydrogen and 1-propenyl, and R ₄ is 2
The method according to any one of claims 1 to 4, which is -methylpropyl. 6. The method of claim 1, wherein R ₅ is iso-propyl and R ₆ is 2-methylpropyl.
The method according to any one of claims 1 to 5. 7. The method according to claim 1, wherein R ₇ is methyl and R ₈ is methyl. 8. The method according to claim 11, wherein R ₁ is 1-propenyl and R ₁ ′ is oxo. 9. The method according to claim 1, wherein the administration is topical. 10. A composition useful for treating hair loss, comprising the non-immunosuppressive compound according to any one of claims 1 to 9 and a second compound selected from the group consisting of minoxidil and finasteride. object.