JP2002525302A - Method of treating hair loss using ketoamides - Google Patents

Abstract

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

Description

DETAILED DESCRIPTION OF THE INVENTION

FIELD OF THE INVENTION [0001] The present invention relates to a method of treating hair loss in mammals, including inhibiting and / or reversing hair loss and promoting hair growth (hair growth).

RELATED APPLICATIONS This application claims priority under Title 35, United States Code §119 (e), based on provisional application Ser. No. 60 / 102,458, filed Sep. 30, 1998.

BACKGROUND OF THE INVENTION Hair loss is a common problem that occurs, for example, by natural changes or is often chemically advanced by the use of some therapeutic agents designed to alleviate symptoms such as cancer. It is. Such hair loss is often accompanied by insufficient regeneration of the hair causing partial or total alopecia. Such alopecia lacks aesthetic appeal and is very painful for people who have hair loss.

[0004] As is well known in the art, hair growth occurs through a cycle of activity that involves alternating periods of growth and rest. This cycle is often divided into three main phases, known as anagen, catagen, and telogen. The anagen is the growth stage of this cycle, characterized by the rapid proliferation of cells different from the formation of hair, which causes the hair follicle to penetrate deep into the dermis. The next phase is the regression phase, a transition phase characterized by a cessation of cell division, during which the hair follicles regress through the dermis and hair growth stops. The next stage, telogen, is often characterized as a rest period, in which the regressed hair follicles contain hair roots with tightly packed dermal papilla cells. During telogen, a new growth phase is initiated by rapid cell proliferation in the hair root, dermal papilla swelling, and assimilation of basement membrane components. This cycle is repeated throughout the hair growth. When hair growth ceases, most of the rest of the hair follicle during the telogen and anagen phase is not fixed, resulting in total or partial alopecia.

According to the literature, many attempts have been made to promote hair regeneration, for example by promoting or prolonging the anagen. Currently, the U.S. Food and Drug Administration provides topical minoxidil (sold by Pharmacia & Upjohn as Rogaine®), and oral finasteride (Propecia) for the treatment of male pattern baldness. (Registered trademark) sold by Merck & Co., Inc.)
Has approved two chemicals.

However, there are conflicting reports on the hair growth effect of minoxidil. In fact, early clinical studies examining blood pressure lowering with the use of minoxidil did not show hirsutism (hair growth) as a side effect. Dormois et al., Minoxidil in Severe Hypertension: Minoxidil in Severe H
ypertension: Value When Conventional Drugs Have Failed), American
American Heart Journal, Vol. 90, pp. 360-368 (1
975). In fact, minoxidil manufacturers have reported poor hair growth in some patients using minoxidil. See Physician's Desk Reference®, 49th Edition (1995), p. In addition, serious side effects of minoxidil may include vasodilation (causing pericardial fluid retention and increased heart rate), dyspnea, and weight gain. Physician Desk Reference (registered trademark), 49th edition (1995), 25
See page 81.

[0007] Furthermore, in an early indicator, Propecia.RTM.
ne) (registered trademark), but patients using Propecia (registered trademark) have poor hair growth. The New England Journal of Medicine, 338, No
. 9, Feb. 26, 1998. Furthermore, the strong side effects of Propecia® are severe. Propecia® can cause hypersensitivity reactions, such as impotence, decreased sexual impulses, reduced ejaculation, breast softening and enlargement, and lip swelling and rough skin. In addition, Propecia (
® is not indicated for women and children. Indeed, pregnant or potential pregnant women should not use tablets containing this drug, even if ground or cracked. Physician's Desk Reference (registered trademark), 52nd edition (1998), 17
P. 37 and The New England Journal of Medicine (The N
ew England Journal of Medicine), volume 338, no. 9, February 26, 1998
See day.

[0008] Interestingly, the immunosuppressants cyclosporin A and FK506 are known to cause significant hirsutism as a side effect. Iwabuchi et al., Of an immunosuppressive peptidyl-prolyl cis-trans isomerase (PPIase) inhibitor, cyclosporin A, FK506, ascomycin, and rapamycin,
Effect on hair growth initiation in mice: no immunosuppression required for new hair growth (E
ffects of Immunosuppressive Peptidyl-Prolyl cis-trans Isomerase (PPIase)
Inhibitors, Cyclosporin A, FK506, Ascomycin, and Rapamycin, on Hair Gro
wth Initiation in Mouse: Immunosuppression is not Required for New Hair G
rowth) ", Journal of Dermatological Science
9: 64-69 (1995); Yamamoto et al., "Hair growth stimulating effect of cyclosporin A and FK506, which are potent immunosuppressants, (Hair)
Growth-Stimulating Effects of Cyclosporin A and FK506, Potent Immunosupp
ressants) '', Journal of Derological Science
Matological Science), Volume 7 (supplement), S47-S54 (1994); Yamamoto et al., "Stimulation of hair growth by topical application of FK506, a potent immunosuppressant (S
timulation of Hair Growth by Topical Application of FK506, a Potent Immu
nosuppressive Agent), Journal of Investigational Dermatology, Vol. 102, 160-
164 (1994); FK50, a potent immunosuppressant, by Jiang et al.
Induction of Anag in resting mouse skin by topical application of No. 6
en in Telogen Mouse Skin by Topical Application of FK506, a Potent Immun
osuppressant), Journal of Investigational Dermatology, Vol. 104, 523-525.
(1995); McElwee et al., "Topical FK506: an Effective Immunotherapy for Alopecia Areata? A Study Using the Dundee Trial Hair Loss Rat Model (T
opical FK506: A Potent Immunotherapy for Alopecia Areata? Studies Using t
he Dundee Experimental Bald Rat Model), British Journal of Dermatology, 137, 491-
497 (1997); Maurer et al., "Hair Growth Modulation by Topical Immunophilin Liga
nds), American Journal of Patology
Hology), Vol. 4, No. 150, pages 1433-1441 (1997); and Paus et al., "Hair Growth Control by Immunosuppression.
Suppression), Arch. Dermatol. Res., 288, 408-410 (19
96). However, the use of these compounds as hair growth (hair growth) actives is undesirable because of their significant efficacy as immunosuppressants.

[0009] FK506 is a complex polycyclic molecule having the following structure:

[0010]

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[0011] Stocks et al., "The Contribution to Binding of the Pyrano in the Truncated Binding Domain of FK-506"
side Substituents in the Excised Binding Domain of FK-506), Bioorganic & Medicinal Chemis
try Letters), Vol. 4, No. 12, pp. 1457-1460 (1994). Analogs very similar to this complex polycycle have been disclosed as having hair growth properties, for example, in the formation of alopecia areata and / or androgenetic alopecia. For example, U.S. Patent No. 5,541,193 to Kawai et al., Issued July 30, 1996, assigned to Abbott Laboratories; issued March 5, 1996, assigned to Fujisawa Pharmaceutical Company. U.S. Patent No. 5,496,564 to Asakura et al.
Baumman, issued October 2, 1994, transferred to Sandoz Ltd.
ann) et al., U.S. Patent No. 5,352,671; and Merck & Co., Inc.
See U.S. Patent No. 5,550,233 to Ruprecht et al., Issued August 27, 1996, assigned to

[0012] However, the growing interest associated with the hair growth activity of cyclosporin A and FK506 is that hirsutism is caused by a variety of smaller non-polycyclic immunosuppressive and non-immunosuppressive compounds that are less complex than FK506. The lack of a report has somewhat subsided. Guilford Pharmaceut
Steiner (Stein) issued on December 19, 1996,
International Publication WO 96/40140; Hamilton et al., International Publication WO 96/40633, issued December 19, 1996, assigned to Gilford Pharmaceuticals, Inc .; GPINIL Holding (GPI NIL Holding).
U.S. Patent No. 5,696,135 to Steiner et al., issued December 9, 1997, assigned to Guildford Pharmaceuticals, Inc .; U.S. Pat. No. 5,614,547 to Hamilton et al .; International Publication No. WO9 to Steiner et al., Issued May 9, 1997, assigned to Gilford Pharmaceuticals, Inc.
7/16190; Vertex Pharmaceuticals (Vertex Pharma)
ceuticals, Inc.), issued Nov. 21, 1996, Zelle et al., International Publication WO 96/36630; issued to Vertex Pharmaceuticals, Inc., issued Oct. 9, 1997. WO 97/36869, Armistead, et al .; WO 96/36869, Zelle et al., Issued May 23, 1996, assigned to Vertex Pharmaceuticals, Inc.
/ 15101; transferred to Vertex Pharmaceuticals, Inc. 19
International Publication WO92 by Armistead et al. Issued on November 12, 1992.
/ 19593; 19 transferred to Vertex Pharmaceuticals, Inc.
International Publication WO94 / Armistead et al., Published April 14, 1994.
07858; 199 Transferred to Vertex Pharmaceuticals, Inc.
WO 95/26337 published by Zelle et al. On October 5, 5; International publication of Duffy et al. Issued on Dec. 10, 1992, transferred to Vertex Pharmaceuticals, Inc. WO92 / 21313; Armistead et al., U.S. Patent No. 5,192,773, issued March 9, 1993, assigned to Vertex Pharmaceuticals, Inc .;
Issued on July 19, 1994, transferred to Pharmaceuticals, Inc.
U.S. Patent No. 5,330,993 to Armistead et al., Issued April 22, 1997, assigned to Vertex Pharmaceuticals, Inc.
U.S. Pat. No. 5,622,970 to Armistead et al .; U.S. Pat. No. 5,654 to Armistead et al., Issued Aug. 5, 1997, assigned to Vertex Pharmaceuticals, Inc. , 332; U.S. Patent No. 5,620,971 to Armexstead et al., Issued April 15, 1997, assigned to Vertex Pharmaceuticals; assigned to Vertex Pharmaceuticals. Was issued on August 6, 1996
(Zelle) et al., U.S. Patent No. 5,543,423; Armisted, issued May 14, 1996, assigned to Vertex Pharmaceuticals, Inc.
U.S. Pat. No. 5,516,797 to Armystead, issued September 9, 1997, assigned to Vertex Pharmaceuticals, Inc.
U.S. Pat. No. 5,665,774 to Tead et al .; "Restored Polyamide Analogues of Andres et al. Trans-Prolyl Peptide Mimics"
lly Defined Analogs of Prolylamides.trans-Prolyl Peptidomimetics), Journal of Organic Chemistry,
58, 6609-6613 (1993); and Armiste
ad) et al., “Design, Synthesis and Structure of Non-polycyclic inhibitors of FKBP12, a major binding protein of the immunosuppressant FK506.
macrocyclic Inhibitors of FKBP12, the Major Binding Protein for the Immu
nosuppressant FK506), Acta Crystallograph
ica), D51, pp. 522-528 (1995).

Surprisingly, the present inventors have discovered a group of compounds that prevent and / or reverse hair loss and promote hair growth (hair growth), but do not have the complex polycyclic structure of FK506. . We have further discovered from this group of compounds that cause hair growth but are surprisingly non-immunosuppressive or superficially immunosuppressive. The fact that these polychaete compounds have minimal immunosuppressive activity and / or no immunosuppressive activity is clearly advantageous compared to the immunosuppressive compounds cyclosporin A and FK506. Accordingly, we provide a method of treating hair loss by administering a composition comprising a compound described herein.

SUMMARY OF THE INVENTION The present invention provides for the administration of compounds found by the present inventors to be particularly useful in the treatment of hair loss in mammals, including the prevention and / or reversal of hair loss and the promotion of hair growth. And a method of treating hair loss. The compound used in the method of the present invention has the following structure:

[0015]

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And pharmaceutically acceptable salts, hydrates, and biohydrolyzable amides, esters and imides, wherein X, J, A, B, D, Q, and m Is defined herein.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to methods of using compounds and compositions that are particularly useful for treating hair loss, such as preventing and / or reversing hair loss and promoting hair growth (hair growth) in mammals. In addition to finding that the compounds of the present invention are useful in treating hair loss, the inventors have also surprisingly discovered that immunosuppression is not required for stimulation of hair growth (hair growth). In addition, the present inventors have discovered compounds that are useful in treating hair loss, but are surprisingly non-immunosuppressive. Accordingly, preferred compounds useful in the methods of the invention are as defined herein and are non-immunosuppressive.

Throughout this disclosure, reference is made to publications and patents. All references cited herein are hereby incorporated by reference. All percentages, ratios and proportions used herein are by weight unless otherwise specified.

Definitions and Uses of Terms The following is a list of definitions of terms used herein. As used herein, “salt” refers to a cationic salt formed with any of the acidic groups (eg, carboxyl groups) or an anionic formed with any of the basic groups (eg, amino groups). 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:
Halide (eg, chloride). Such an acceptable salt is
When administered, it must be suitable for use in mammals.

As used herein, “alkenyl” is an unsaturated hydrocarbon chain group. Alkenyl has at least one olefinic double bond. Unless otherwise specified, alkenyl has 2 to about 15 carbon atoms (C _{2 to} C ₁₅ ), preferably 2 to about 10 carbon atoms (C _{2 to} C ₁₀ ), and more preferably 2 to about 8 carbon atoms. (C ₂ -C ₈ ), and most preferably C ₂ -C ₆ (C ₂ -C ₆ ). Non-limiting examples of alkenyl include vinyl, allyl, and butenyl.

As used herein, “alkoxy” is an oxygen radical having an alkyl, alkenyl, or alkynyl substituent, preferably an alkyl or alkenyl substituent, most preferably an alkyl substituent. Examples of the alkoxy group include-
O-alkyl and -O-alkenyl groups are mentioned.

As used herein, “alkyl” is a saturated hydrocarbon chain group. Unless otherwise specified, alkyl has 1 to about 15 carbon atoms (C ₁ -C ₁₅ );
It preferably has 1 to about 10 carbon atoms (C _{1 to} C ₁₀ ), and more preferably ₁ to ₁₀ carbon atoms.
It has about 6 (C ₁ -C ₆ ), and most preferably has 1 to about 4 carbon atoms (C ₁ -C ₄ ).
Preferred alkyls include, for example, methyl, ethyl, propyl, isopropyl, and butyl.

As used herein, “alkylene” refers to a two-terminal radical of alkyl, alkenyl, or alkynyl. For example, "methylene" is -CH ₂ -.

As used herein, “alkynyl” is an unsaturated hydrocarbon chain group. Alkynyl has at least one triple bond. Unless otherwise specified, alkynyl has 2 to about 15 carbon atoms (C _{2 to} C ₁₅ ) and preferably has 2 to about 15 carbon atoms.
It has about 10 (C ₂ -C ₁₀ ), more preferably 2 to about 8 (C _{2 to} C ₈ ), and most preferably about 2 to about 6 (C _{2 to} C ₆ ). .

As used herein, a “biohydrolyzable amide” is an amide of a compound used in the present invention, which does not interfere with the activity of the compound or is readily in vivo in a test mammal. Into an active compound. As used herein, a "biohydrolyzable ester" is an ester of a compound used in the present invention that does not interfere with the activity of the compound or is readily converted in vivo in a test mammal. To give the active compound. As used herein, a "biohydrolyzable imide" is an imide of a compound used in the present invention that does not interfere with the activity of the compound or is readily converted in vivo in a test mammal. To give the active compound.

As used herein, “carbocyclic ring, carbocycle”
"Is a hydrocarbon ring group. Carbocycles are monocyclic or polycyclic with fused, bridged or spiro. Unless otherwise specified, a monocycle contains from 3 to about 9 atoms, preferably from about 4 to about 7, most preferably 5 or 6 atoms. The polycycle contains about 7 to about 17 atoms, preferably about 7 to about 14, and most preferably 9 or 10 atoms.

As used herein, “cycloalkyl” is a saturated carbocyclic or heterocyclic group. Preferred cycloalkyl groups include, for example, cyclobutyl,
Cyclopentyl, and cyclohexyl.

As used herein, “heteroalkenyl” is an alkenyl group consisting of carbon atoms and one or more heteroatoms, wherein the heteroatoms are oxygen, sulfur, nitrogen, and It is selected from the group consisting of phosphorus, preferably the group consisting of oxygen, sulfur and nitrogen.

As used herein, “heteroalkyl” refers to carbon and 1
An alkyl group consisting of one or more heteroatoms, wherein said heteroatoms are selected from the group consisting of oxygen, sulfur, nitrogen and phosphorus, preferably the group consisting of oxygen, sulfur and nitrogen is there.

As used herein, “heterocycle” and the like are ring groups consisting of carbon atoms and one or more heteroatoms, wherein the heteroatoms are oxygen, sulfur, nitrogen, It is selected from the group consisting of phosphorus, preferably the group consisting of oxygen, sulfur and nitrogen. A heterocycle is a monocycle or a polycycle having fused, bridged or spiro. Unless otherwise specified, a monocycle contains from 3 to about 9 atoms, preferably from about 4
From about 7 to most preferably 5 or 6 atoms. The polycycle contains about 7 to about 17 atoms, preferably about 7 to about 14, and most preferably 9 or 10 atoms. Heterocycles may be substituted or unsubstituted.

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. As used herein, "pharmaceutically acceptable" means used as appropriate for a human or other mammal.

As used herein, a “safe and effective amount of a compound (or composition or the like)” is an amount effective to exhibit biological activity at the active site of a test mammal, and is preferably The activity is the prevention and / or reversal of hair loss or the promotion of hair growth, without undue side effects (toxicity, irritation, or allergic reactions, etc.) and a reasonable benefit / risk ratio when used in the method of the invention. Amount. When used in the present invention, one or more variables, moieties, groups, etc., are present in any variable or structure in the present invention, and the definition at each occurrence is
Independent of its definition in each of the other entities.

[0033] The present invention of the present invention is directed to a method for treating hair loss, (a) Structure:

[0034]

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And a pharmaceutically acceptable salt, hydrate, and biohydrolyzable amide, ester, and imide thereof, wherein: (i) Q is a first heteroatom, The first heteroatom is nitrogen; (ii) A is selected from CH ₂ , O, S and NR ₁ ; (iii) R ₁ is selected from the group consisting of hydrogen and alkyl;

(Iv) J is hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ alkenyl, benzyl,
Ar substituted C ₁ -C ₆ alkyl, Ar-substituted C ₃ -C ₆ alkenyl, selected from Ar substituted C ₃ -C ₆ alkynyl; K is, C ₁ -C ₆ alkyl, Ar-substituted C ₁ -C ₆ alkyl,
Ar substituted C ₂ -C ₆ alkenyl, Ar-substituted C ₂ -C ₆ alkynyl, and is selected from cyclohexylmethyl; or, J and K are joined together, 5-, 6-, or 7
May form a membered heterocycle, which ring is O, S, S (O), S (O) ₂ ,
NH and NE may optionally include additional heteroatoms, and when B and D are linked together to form a substituted or unsubstituted tetrahydronaphthalene moiety, J and K are optionally both Linked to and fused to the phenyl ring
May form a membered carbocycle;

(V) X is hydrogen, C ₁ -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, are selected [C ₁ -C ₄ alkyl] -Y, [C ₂ -C ₄ alkenyl] -Y, Y, and from -NR ₃ R _4;

(Vi) R_Two, R_Three, R_Four, B, D, and E are each independently nil (
Absent), oxygen, hydrogen, Ar, C₁-C₆Alkyl, C_Two-C₆Alkenyl, C_Two
-C₆Alkynyl, C_Five-C₇Cycloalkyl-substituted C₁-C₆Alkyl, C_Five-C₇Shi
Chloroalkyl-substituted C_Three-C₆Alkenyl, C_Five-C₇Cycloalkyl-substituted C_Three-C₆A
Lucinyl, C_Five-C₇Cycloalkenyl-substituted C₁-C₆Alkyl, C_Five-C₇Cycloa
Lucenyl-substituted C_Three-C₆Alkenyl, C_Five-C₇Cycloalkenyl-substituted C_Three-C₆Al
Quinyl, Ar substituted C₁-C₆Alkyl, Ar substituted C_Three-C₆Alkenyl and Ar
Exchange C_Three-C₆Alkynyl; provided that the alkyl, alkenyl, and alkynyl are selected from
One or more CH of quinyl_TwoThe parts are O, S, S (O), S (O)_Two, And NR
May be optionally substituted with a heteroatom selected from: wherein R is hydrogen, C ₁ -C_FourAlkyl, C_Three-C_FourAlkenyl, C_Three-C_FourAlkynyl, and C₁-C_FourCrosslinking
Alkyl, wherein the bridge is N of NR and a heteroatom containing alkyl, alkenyl.
Or a carbon atom of alkynyl to form a bridged ring, wherein the bridged ring is
5 optionally fused to Ar; B and D also bound together, optionally fused to allyl
B and D may also form-, 6- or 7-membered carbocycles;
And may independently be:

[0039]

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Wherein Z is selected from hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, and C ₂ -C ₆ alkynyl, and V is Ar and oxo, hydrogen, hydroxyl, O- (
B is also selected from substituted 5-, 6-, or 7-membered carbocycles having substituents independently selected from C ₁ -C ₄ alkyl) and O- (C ₂ -C ₄ alkenyl); It may be T, wherein T has the following structure:

[0041]

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Wherein X ₂ is selected from O and NR ₁₀ , wherein R ₁₀ is hydrogen, C ₁ -C ₆ alkyl,
And it is selected from C ₁ -C ₆ alkenyl; R ₉ is phenyl, benzyl, C ₁ -C ₅
Alkyl, C ₁ -C ₅ alkenyl, C ₁ -C ₅ alkyl substituted with phenyl, and C ₁ -C ₅ alkenyl substituted with phenyl; when B is T,
Is R ₈ , wherein R ₈ is selected from C ₁ -C ₈ alkyl optionally substituted with C ₃ -C ₈ cycloalkyl, and Ar; R ₃ and R ₄ are also linked together to form 5 -, 6-
Or may form a 7-membered heterocyclic aliphatic or aromatic ring;

(Vii) Ar and Y are each independently phenyl, benzyl, 1-na
Futyl, 2-naphthyl, indenyl, azulenyl, fluorenyl, anthraceni
2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3
-Pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazoly
, Pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isoto
Liazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,
3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3
5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl,
Isoindolyl, 3H-indolyl, indolinyl, benzo [b] furanyl,
Benzo [b] thiophenyl, 1H-indazolyl, benzimidazolyl, benzti
Azolyl, purinyl, 4H-quinolizinyl, quinolinyl, 1,2,3,4-tetra
Lahydroquinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroisoquino
Linyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8
-Naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl
, Phenothiazinyl, phenoxazinyl, 2-pyrolinyl, 3-pyrolinyl, pi
Loridinyl, 1,3-dioxolyl, imidazolidinyl, 2H-pyranyl, 4H
-Pyranyl, piperidyl, 1,4-dioxanyl, morpholinyl, 1,4-dithi
Selected from anil, thiomorpholinyl, piperazinyl, and quinuclidinyl;
Ar is hydrogen, halogen, hydroxyl, nitro, -SO_ThreeH, trifluorome
Chill, trifluoromethoxy, C₁-C₆Alkyl, C_Two-C₆Alkenyl, O- [
C₁-C₆Alkyl], O- [C_Two-C_FourAlkenyl], O-benzyl, O-phenyl
1,2-methylenedioxy, -NR_FiveR₆, Carboxyl, N- [C₁-C_FiveA
Alkyl] carboxamide, N- [C_Three-C_FiveAlkenyl] carboxamide, N, N
-Di- [C₁-C_FiveAlkyl] carboxamide, N, N-di- [C_Three-C_FiveAlkene
Ru] carboxamide, N-morpholinocarboxamide, N-benzylcarboxa
Amide, N-thiomorpholinocarboxamide, N-picolinoylcarboxamide,
Morpholinyl, piperidinyl, OM, CH_Two− (CH_Two)_q-M, O- (CH_Two) _q -M, (CH_Two)_q-OM, and CH = CH-M.
Has two or more substituents; R_FiveAnd R₆Is independently hydrogen, C₁-C₆A
Luquil, C_Three-C₆Alkenyl, C_Three-C₆Selected from alkynyl, and benzyl
Or R_FiveAnd R₆May be linked together to form a 5- or 6-membered heterocyclic ring
M: M is 4-methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl
, Pyrazyl, quinolyl, 3,5-dimethylisoxazoyl, isoxazoyl, 2
-Methylthiazoyl, thiazoyl, 2-thienyl, 3-thienyl, and pyrimidi
Q is an integer from 0 to 2; Y is hydrogen, halogen, hydroxy
, Nitro, trifluoromethyl, trifluoromethoxy, C₁-C₆Alkyl,
C₁-C₆Alkenyl, O- [C₁-C_FourAlkyl], O- [C_Two-C_FourAlkenyl]
, O-benzyl, O-phenyl, 1,2-methylenedioxy, amino, and
(Viii) m is an integer from 0 to 3), and (b) a composition comprising: (b) a pharmaceutically acceptable carrier. And a method of treating hair loss.

[0044]X part The compound used in the method of the invention may be X moiety or X moiety
And a moiety that binds to the diketoamide moiety. X is hydrogen, C₁-C₉Al
Kill, C_Two-C₉Alkenyl, C_Five-C₇Cycloalkyl, C_Five-C₇Cycloalkyl
, C_Five-C₇Cycloalkenyl, C_Five-C₇Cycloalkenyl, Ar, -OR_Two, [
C₁-C_FourAlkyl] -Y, [C_Two-C_FourAlkenyl] -Y, Y, and -NR_ThreeR_FourOr
Selected from As described herein above, all moieties are unsubstituted or substituted
X may be substituted cycloalkyl or cycloalkenyl
Preferred substituents on such X moieties are C₁-C_FourAlkyl or hydroxy or C _Two -C_FourAlkenyl. Ar, R_Two, Y, R_Three, And R_FourIs the other part in this specification
Describe in minutes. When X is Ar, preferred Ar moieties are phenyl, 2-pyri
Jill, 3-pyridyl, 4-pyridyl, imidazolyl, indolyl, isoindori
Quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroisoquinolini
And 1,2,3,4-tetrahydroquinolinyl. In this specification
As noted above, all portions may be unsubstituted or substituted,
When X is a substituted Ar, preferred substituents include hydroxyl, nitro, tri
Trifluoromethyl, C₁-C₆Alkyl, O- [C₁-C₆Alkyl], halogen,
-SO_ThreeH, -NR_FiveR₆And R_FiveAnd R₆Is described herein above.
. More preferred X moieties are 3,4,5-trimethoxyphenyl, isopropyl,
Phenyl, tert-butyl, thiophenyl-2-yl, 3-benzyloxyphenyl
, 3-allyloxyphenyl, 2-furyl, and 3-isopropoxyphenyl
Is selected from The most preferred X moiety is 3,4,5-trimethoxyphenyl.
You.

The J and K Portions The J and K portions may have the above-described structures independently of each other, or, as described above, are joined together to form O, S, S (O), S (O ) May form a 5-, 6- or 7-membered heterocycle optionally containing additional heteroatoms selected from the group consisting of ₂ , NH and NE. When B and D are joined together to form a substituted or unsubstituted tetrahydronaphthalene moiety, J and K may optionally be joined together to form a 5- or 6-membered carbocycle fused to a phenyl ring. Good. The substituted or unsubstituted tetrahydronaphthalene moieties as used in the present invention are as follows.

[0046]

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In the formula, R ₆₁ , R ₆₂ and R ₆₃ are each independently hydrogen, halogen, alkyl, O-alkyl, (CH ₂ ) _b -aryl, and R ₅₀ (CH ₂ ) _b -aryl R ₅₀ is selected from O, S, and NR ₅₁ ; R ₅₁ is selected from alkyl and hydrogen; b is an integer from 0 to 4; R ₆₄ is hydrogen and (CH ₂ ) is selected from _c -R _52, R ₅₂ is selected from aryl and NR ₅₃ R _54, R ₅₃ and R ₅₄ are each independently hydrogen, alkyl, and (CH ₂₎ - is selected from aryl Or R ₅₃ and R ₅₄ are linked together to form a 5- or 6-membered heterocycle; c is an integer from 1 to 3.

When J and K form a heterocycle, the ring is preferably 5- or 6-membered. J
When and K form a heterocycle, the ring preferably does not contain any additional heteroatoms other than the Q nitrogen required at position 1 of the ring, as shown herein.

The A moiety A is selected from CH ₂ , O, S, and NR ₁ , wherein R ₁ is described herein. Preferably, A is selected from O and NR _1. Most preferred A is NR ₁ . In such a case, R ₁ is most preferably hydrogen.

B and D Portions B and D are side chains selected from the various moieties described herein above. Preferred B moieties are 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-propen-2-yl, E-
3- [trans- (4-hydroxycyclohexyl)]-2-methyl-ethene-
2-yl, 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-purinyl) propyl, 3- (3-pyridyl) -N-oxide, 3- (
4-hydroxymethylphenyl) propyl, 3- (2-thienyl) propyl, 3
-(4-carboxyphenyl) propyl, 4-phenylbutyl, 2-hydroxymethylphenyl, 2-allyloxyphenyl, 3- (3-hydroxymethylphenyl) propyl, 3- (3-carboxyphenyl) propyl, 3-hydroxy Methylphenyl, 2-hydroxyphenyl, 3-pyridyl, 5-phenylpentyl, 4- (4-methoxyphenyl) butyl, 4-cyclohexylbutyl, 3-cyclohexylpropyl, 3-cyclopentylpropyl, 3-phenoxybenzyl,
And 3- (3-indolyl) propyl.

Preferred D moieties are nil, oxygen, hydrogen, 3-phenylpropyl, 2-phenoxyphenyl, 3- (3-indolyl) -propyl, 2-phenylethyl, 4-
Selected from phenylbutyl, 3,5-bis (benzyloxy) phenyl, alkyl, alkenyl, phenyl, and 3- (4-methoxyphenyl) propyl.

Integer m The integer m is 0 to 3, preferably 0 to 1.

[0053]Preferred Ar moiety The Ar moiety is defined herein above. Preferred Ar moieties are phenyl
, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, indolyl,
Isoindolyl, quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydro
Isoquinolinyl, 2-furyl and 1,2,3,4-tetrahydroquinolinyl
Ar is hydrogen, hydroxyl, nitro, trifluoromethyl, C₁
-C₆Alkyl, O- [C₁-C₆Alkyl], halogen, -SO_ThreeH, and -NR _Five R₆Having one or more substituents each independently selected from the group consisting of:
R_FiveAnd R₆Is described herein above. Preferred compounds useful in the method of the invention are shown in the table below.

[0054]

[Table 1]

[0055]

[Table 2]

Other preferred compounds useful in the method of the present invention include:
B and D may be joined together to form a 5-, 6-, or 7-membered carbocycle fused to an aromatic ring.

[0057]

Embedded image

Wherein (a) R ₁₂ is selected from hydrogen and — (CH ₂ ) _t —R ₁₆ , where t is an integer from 1 to 3, and R ₁₆ comprises Ar and NR ₁₇ R ₁₈ R ₁₇ and R ₁₈ are selected from the group
Each independently selected from hydrogen, C ₁ -C ₅ alkyl, and — (CH ₂ ) —Ar, or R ₁₇ and R ₁₈ are bonded together to form a 5- or 6-membered heterocyclic ring; (B) R ₁₃ , R ₁₄ and R ₁₅ are each independently hydrogen, halogen, C ₁ -C ₆ alkyl, O- (C ₁ -C ₆ alkyl), — (CH ₂ ) _e − Ar, and -G (CH ₂
) Is selected from _e -Ar, where e is an integer from 0 to 4; G is O, S, and is selected from the group consisting of NR _19, R _19, from hydrogen and C ₁ -C ₆ alkyl (C) A is selected from -O- and -NH-.

[0059]

[Table 3]

Wherein preferably: (a) R ₁₃ and R ₁₅ are each independently —OCH ₂ -4-pyridine, —O—
Propyl, and it is selected from hydrogen; (b) R ₁₄ is -OCH _{2-4-pyridine,} is selected from methyl, and more hydrogen; (c) R ₁₂ is selected from -CH _2-3-pyridine and hydrogen (D) X is 3,4,5-trimethoxyphenyl.

[0061]

[Table 4]

[0062]

[Table 5]

Other preferred compounds useful in the method of the present invention include: (a) 3-phenyl-1-propyl (2S) -1- (3,3-dimethyl-1, 2
-Dioxopentyl) -2-pyrrolidine carboxylate; (b) 3-phenyl-1-propen-2- (E) -yl (2S) -1- (3,3
-Dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarboxylate;
(C) 3- (3,4,5-trimethoxyphenyl) -1-propyl (2S) -1
-(3,3-dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarboxylate; (d) 3- (3,4,5-trimethoxyphenyl) -1-propene-2- (E)
-Yl (2S) -1- (3,3-dimethyl-1,2-dioxopentyl) -2-
(E) 3- (4,5-dichlorophenyl) -1-propyl (2S) -1- (3,
3-dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarboxylate; (f) 3- (4,5-dichlorophenyl) -1-propen-2- (E) -yl (
2S) -1- (3,3-Dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarboxylate; (g) 3- (4,5-methylenedioxyphenyl) -1-propyl (2S)- 1
-(3,3-dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarboxylate; (h) 3- (4,5-methylenedioxyphenyl) -1-propene-2- (E)
-Yl (2S) -1- (3,3-dimethyl-1,2-dioxopentyl) -2-
(I) 3-cyclohexyl-1-propyl (2S) -1- (3,3-dimethyl-
(1,2-dioxopentyl) -2-pyrrolidine carboxylate; (j) 3-cyclohexyl-1-propen-2- (E) -yl (2S) -1- (
3,3-dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarboxylate; (k) (1R) -1,3-diphenyl-1-propyl (2S) -1- (3,3-
Dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarboxylate; (1) (1R) -1,3-diphenyl-1-propen-2- (E) -yl (2S
) -1- (3,3-Dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarboxylate; (m) (1R) -1-cyclohexyl-3-phenyl-1-propyl (2S)-
1- (3,3-dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarboxylate; (n) (1R) -1-cyclohexyl-3-phenyl-1-propene-2- (E
) -Yl (2S) -1- (3,3-dimethyl-1,2-dioxopentyl) -2
-Pyrrolidinecarboxylate; (o) (1R) -1- (4,5-dichlorophenyl-3-phenyl-1-propyl (2S) -1- (3,3-dimethyl-1,2-dioxopentyl)- (P) 3-phenyl-1-propyl (2S) -1- (1,2-dioxo-2-cyclohexyl) ethyl-2-pyrrolidinecarboxylate; (q) 3-phenyl-1-carboxylate Propyl (2S) -1- (1,2-dioxo-4-cyclohexyl) butyl-2-pyrrolidinecarboxylate; (r) 3-phenyl-1-propyl (2S) -1- (1,2-dioxo-2 − [
(Furanyl]) ethyl-2-pyrrolidinecarboxylate; (s) 3-phenyl-1-propyl (2S) -1- (1,2-dioxo-2- [
Thienyl]) ethyl-2-pyrrolidinecarboxylate; (t) 3-phenyl-1-propyl (2S) -1- (1,2-dioxo-2- [
2-thiazolyl]) ethyl-2-pyrrolidinecarboxylate; (u) 3-phenyl-1-propyl (2S) -1- (1,2-dioxo-2-phenyl) ethyl-2-pyrrolidinecarboxylate; ) 1,7-Diphenyl-4-heptyl (2S) -1- (3,3-dimethyl-
(W) 3-phenyl-1-propyl (2S) -1- (3,3-dimethyl-1,2,1; 2-dioxopentyl) -2-pyrrolidinecarboxylate;
-Dioxo-4-hydroxybutyl) -2-pyrrolidinecarboxylate; (x) 3-phenyl-1-propyl (2S) -1- (3,3-dimethyl-1,2
-(Dioxopentyl) -2-pyrrolidinecarboxylate; (y) 1- [1-3,3-dimethyl-1,2-dioxopentyl) -L-proline] -L-phenylalanine ethyl ester; (z) 1 -[1-3,3-dimethyl-1,2-dioxopentyl) -L-proline] -L-leucine ethyl ester; (aa) 1- [1-3,3-dimethyl-1,2-dioxo (Pentyl) -L-proline] -L-phenylglycine ethyl ester; (bb) 1- [1-3,3-dimethyl-1,2-dioxopentyl) -L-proline] -L-phenylalanine phenyl ester; cc) 1- [1-3,3-dimethyl-1,2-dioxopentyl) -L-proline] -L-phenylalanine benzyl ester; and (dd) 1- [1-3,3-dimethyl) 1,2 dioxopentyl) -L- proline] -L- isoleucine ethyl ester.

[0064]

[Table 6A]

[0065]

[Table 6B]

[0066]

[Table 6C]

[0067]

[Table 7A]

[0068]

[Table 7B]

[0069]

[Table 7C]

[0070]

[Table 8A]

[0071]

[Table 8B]

[0072]

[Table 8C]

[0073]

[Table 8D]

[0074]

[Table 9A]

[0075]

[Table 9B]

[0076]

[Table 9C]

[0077]

[Table 10]

[0078]

[Table 11]

[0079]

[Table 12]

[0080]

[Table 13]

[0081]

[Table 14]

[0082]

[Table 15]

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

Resting Phase Analysis: In the resting phase analysis, the test compound is exposed to the resting phase of the hair growth cycle ("resting period").
) Is measured for its potential to convert the mouse in the growth phase of the hair growth cycle ("growth phase").

Without intending to be limited by theory, the C3H mouse, about 40 to about 75 days old, has three main phases in the hair growth cycle: anagen, catagen, and telogen.
In Harlan Sprague Dawley, Inc., Indianapolis, Indiana, it is believed that synchronizing hair growth will extend the rest period. It is believed that hair growth is no longer synchronized after 75 days of age. In a hair growth test, when a mouse of about 40 days of dark hair (brown or black) is used to evaluate the topical application of a hair restorer, melanin generation occurs with hair growth. The following telogen turnover assay is used to screen the hair growth potential of compounds by measuring melanogenesis.

[0086] Three groups of 44-day-old C3H mice are used: a solvent control group, a positive control group, and a test compound group to which the compound used in the method of the present invention is administered as a test compound. The analysis period includes at least one treatment day of 15 days (treatment is performed Monday to Friday).
9 days. Day 1 is the first day of treatment. Most tests end on day 19, but the melanogenesis reaction appears to be positive, but if development is slow, some tests may be performed up to day 24. A representative test plan is shown in Table 16 below.

[0087]

[Table 16]

The lower back of the mouse (from the base of the tail to the lower ribs) is topically treated Monday through Friday. Apply 400 L to the back of each mouse using a pipettor and tip. When applying 400 L, apply slowly while moving the hair of the mouse to reach the skin. While each treatment is applied locally to the mouse, the skin color at the application area of each animal is visually graded from 0 to 4. As mice transition from telogen to anagen,
The skin color becomes darker. As shown in Table 17, a rating of 0-4 represents the following visual observation as the skin progresses from white to blue-black.

[0089]

[Table 17]

Immunosuppressive assay: The immunosuppressive assay herein predicts the immunosuppressive activity of the compounds used in the method of the present invention. This analysis is performed as follows. 7 to 16-week-old adult male C3H mice (live mice Harlan Sprague-Dawley, Inc. ((Harlan Sprague Dawley, Inc.) , Indiana, USA, has been sold by Indianapolis)) euthanasia (CO ₂ Death by suffocation)
The spleen is removed. The spleen was cooled in Hanks buffered saline (HBSS, Gibco
co) -BRL (sold by Geysersburg, MD)
insert. The spleen is then ground between frosted glass slides and filtered through a sterile screen to remove tissue debris. An equal volume of Ficoll-Paque Plus (sold by Pharmacia Biotech (Piscataway, NJ, USA)) is placed on top of the resulting cell suspension. Centrifuge at 400 × g for about 40 minutes at 20 ° C. to collect splenocytes. Splenocytes are collected from the interface using a disposable pipette, washed twice with HBSS, and centrifuged at 100 xg for 10 minutes at 20 ° C. Splenocytes were 10% heat-inactivated fetal bovine serum (Gibco-BRL), penicillin (50 U / mL), streptomycin (100 μg / mL), L-glutamine (2 mM), 2-mercaptoethanol (10-5 M) ) And N-2-hydroxyethylpiperazine-N
Resuspend in 5-10 mL of cell culture medium consisting of phenol red-free RPMI 1640 (media sold by Gibco-BRL) containing '-2-ethanesulfonic acid (HEPES) (10 mM). The cells are counted and checked for viability using, for example, trypan blue. The splenocytes are resuspended at 10 ⁶ cells / mL in medium and pipetted to a 96-well round bottom plate at 10 ⁵ cells / well. 50 μL / well of concanavalin A is added in the presence or absence of the test compound (final assay concentration = 5 μg / ml) to activate splenocytes. Test compounds are prepared as stock solutions in methyl sulfoxide (DMSO), then diluted in media,
Add 50 μL / well to bring the final concentration of DMSO in this analysis to 0.05% or less. Plates are incubated for 48 hours at 37 ° C. with 5% CO ₂ .
After 48 hours, cells were harvested at 1 μCi / well of methyl-3H-thymidine (Amersham
Pulse label with (Amersham) (sold by Buckinghamshire, UK) and incubate for an additional 24 hours.

Twenty-four hours later, cells were harvested on GF / C filter plates (sold by Packard (Downers Grove, Ill.), USA) and microscint 20 (Microscint 20). (Packard) and dissolved in a TopCount microplate scintillation and luminescence plate counter.
Count with an inescence plate counter (Packard). Activity is measured as a percentage of control activity in the absence of test compound and plotted against test compound concentration. The data was fit to a 4-parameter curve
e fit) (Sigmaplot) and calculate IC ₅₀ values. As used herein, using this method, (cyclosporin AIC ₅₀ /
A test compound is considered non-immunosuppressive if the ratio of test compound IC ₅₀ ) × 100 is 0.02 or less, ie, the non-immunosuppressive test compound has 2% of the immunosuppressive activity of cyclosporin A. .

The viability of cells is described in Nelson et al., Journal of Immunology (J.
ournal of Immunology), Volume 150, No. 6, 2139-2147 (19
93), except that the analysis was performed in serum-free, phenol red-free RPMI 1640, the dye was dissolved in 100 μL / well of DMSO, and the SpectraMax Plus microplate reader (SpectraMax) was used.
Plus microplate reader) (Molecular Devices)
MTT (3- [4,5-dimethyl-thiazoyl-2-yl] 2,5-diphenyl-bromide, background corrected at 650 nm in Menlo Park, CA, USA) and read at OD 540 nm. Evaluate by (tetrazolium) dye analysis.

Preparation Method The compounds used in the method of the present invention are prepared by methods well known to those skilled in the art. Starting materials used for the production of the compounds are known, produced by known methods, or sold as starting materials. One skilled in the art of organic chemistry will recognize that standard handling of organic compounds is straightforward without further instructions. Examples of such handling are described in March (M
arch), Advanced Organic Chemi
stry), John Wiley & Sons, 1992 and others.

Those skilled in the art will recognize that certain reactions are best performed when other functional groups in the compound are masked or protected, thus improving reaction yield and / or avoiding unwanted side reactions. Will be easily understood. Those skilled in the art often utilize protecting groups to achieve such increased yields or to avoid undesired reactions. These reactions are described in the literature and are within the skill of the art. Many examples of such handling are described, for example, by T.W. Green, protecting group in organic synthesis (Prote
cting Groups in Organic Synthesis), John Willie and Sons (Joh
n Wiley & Sons), 1981.

The compounds of the present invention may have one or more chiral centers. As a result, one optical isomer such as a diastereomer and an enantiomer can be selectively produced from the other, for example, by a chiral starting material, a catalyst or a solvent, or both stereoisomers or diastereomers can be produced. It is also possible to prepare both optical isomers, such as a mer and an enantiomer at once (racemic mixture). Since the compounds of the present invention may exist as a racemic mixture, optical isomers such as diastereomers and enantiomers, or mixtures of stereoisomers may be separated using known methods, for example, using chiral salts and chiral chromatography. May be. In addition, it is recognized that one isomer, such as a diastereomer and an enantiomer, or a stereoisomer may have more favorable properties than the other. Accordingly, when disclosing and claiming the present invention, if one racemic mixture is disclosed, it is substantially free of the other, optical isomers such as diastereomers and enantiomers, or stereoisomers Are equally considered to be disclosed and claimed as well.

The following are non-limiting examples that more specifically illustrate the methods for making the various compounds of the present invention. As used herein, the following abbreviations are used:

[0097]

[Table 18]

Embodiment 1

[0099]

Embedded image

The above compound was obtained from Guilford Pharmaceuticals, Inc.
Armaceuticals Inc.) issued on March 25, 1997, Hamilton (Ha
milton) et al., US Pat. No. 5,614,547. Example 2

[0101]

Embedded image

The above compounds were obtained from Guilford Pharmaceuticals, Inc.
maceuticals Inc., issued on March 25, 1997,
(lton) et al., US Pat. No. 5,614,547. Example 3

[0103]

Embedded image

3a. (S)-(N-tert-butoxycarbonyl) pipecolic acid 1,7-
Diphenyl-4-heptylamide: Dissolve (S)-(N-tert-butoxycarbonyl) pipecolic acid (4.7 g, 20.3 mmol) in 200 mL of DMF. 1,7-diphenyl-4-aminoheptane (5.44 g, 20.3 mm
ol) (which can be produced as in Example 4 below) and i-Pr ₂ EtN (7
. 1 mL, 40.7 mmol), followed by PyBOP (10.6 g, 20
. 3 mmol) are added. The reaction solution was stirred at room temperature for 18 hours and then cooled on ice.
Pour into 1N hydrochloric acid (800 mL) and extract with ethyl acetate (800 mL). After liquid separation, the organic layer was washed with a saline solution (200 mL) and a saturated sodium hydrogen carbonate solution (400 mL).
And brine (200 mL). Dry the organic solution over magnesium sulfate, filter, and concentrate under reduced pressure. The product is purified by silica gel chromatography to give the desired amide 3a.

3b. (S) -Picolic acid 1,7-diphenyl-4-heptylamide: Amide 1a (8.74 g, 18.3 mmol) is dissolved in 150 mL of anhydrous dichloromethane. TFA (100 mL) is added dropwise over 5 minutes. After 2 hours, the mixture is cooled in an ice bath and a saturated potassium carbonate solution is added until the pH is about 8. Transfer the mixture to a separatory funnel containing dichloromethane (200 mL) and (200 mL) and shake. Separate the organic layer, wash with water (200 mL) and dry over magnesium sulfate. The mixture is filtered and concentrated under reduced pressure to give the desired amine 3b.

3c. (S) -N- (3 ', 4', 5'-trimethoxyphenylglyoxy)
Pipecolic acid 1,7-diphenyl-4-heptylamide: amine 3b (0.6
(5 g, 1.72 mmol) are dissolved in 35 mL of anhydrous DMF. 3 ', 4', 5
After adding '-trimethoxyphenylglyoxylic acid (0.4 g, 1.72 mmol) and i-Pr ₂ EtN (0.44 g, 3.43 mmol), PyBOP (
0.9 g, 1.72 mmol). After stirring the reaction at room temperature for 21 hours,
Pour into ice-cooled 0.1N hydrochloric acid (150 mL) and extract with ethyl acetate (150 mL). The layers were separated and the organic layer was washed with a saline solution (50 mL) and a saturated sodium hydrogen carbonate solution (1
(50 mL) and brine (50 mL). Dry the organic solution over magnesium sulfate, filter, and concentrate under reduced pressure. The product is purified by silica gel chromatography to give the desired amide 3c. Example 4

[0107]

Embedded image

4a. Magnesium (40.2 g, 1.65 mol) and anhydrous ether (3.
2L) are mixed in a reaction vessel with stirring. A 1.6 L anhydrous solution of 1-bromo-3-phenylpropane in ether is placed in a separate container. The bromide solution is added dropwise to the stirred reaction vessel over 1 hour. After the addition is complete, the mixture is stirred for 1-2 hours. 4
-Phenylbutyronitrile (160 g, 1.1 mol) in anhydrous ether (2.4
L) Put the solution in another container. This solution is added dropwise to the reaction vessel over 1 hour. After completion of the dropwise addition, the solution is heated under reflux for 10 hours and then stirred at room temperature for 6 hours.

4b. The reaction mixture of 1,7-diphenyl-4-aminoheptane: 4a is diluted with another container with methanol (3.2 L). Sodium borohydride (83.
4 g, 2.2 mol) are added in portions. After the addition is completed, the reaction solution is stirred at room temperature for 6 hours. The reaction mixture is slowly added with water (3.2 L) and cooled. The mixture is diluted with ether (3.2L) and water (1.6L). Separate the ether layer and extract the aqueous layer twice with ether (3.2 L × 2). The combined ether extracts are washed once with sodium chloride, dried, filtered and concentrated under reduced pressure to give the crude product. The product is diluted with ether (1.2 L) and acidified by slow addition of 1 M hydrochloric acid (1.2 L). The mixture is stirred for 1 hour and concentrated under reduced pressure. The precipitate obtained is diluted with acetonitrile and stirred for 16 hours. The desired 1,7-diphenyl-4-aminoheptane is collected by filtration. Example 5

[0110]

Embedded image

[0111] Vertex Pharmaceuticals, Inc.
The compounds are prepared as described in Armistead et al., U.S. Pat. No. 5,620,971, issued Apr. 15, 1997, assigned to U.S. Pat. Example 6

[0112]

Embedded image

[0113] Vertex Pharmaceuticals, Inc.
The compounds are prepared as described in Armistead et al., U.S. Pat. No. 5,620,971, issued Apr. 15, 1997, assigned to U.S. Pat. Example 7

[0114]

Embedded image

[0115] Vertex Pharmaceuticals, Inc.
The compounds are prepared as described in Armistead et al., U.S. Pat. No. 5,620,971, issued Apr. 15, 1997, assigned to U.S. Pat. Example 8

[0116]

Embedded image

[0117] Vertex Pharmaceuticals, Inc.
Zelle, U.S. Patent No. 5,7, issued March 10, 1998, assigned to
As described in No. 26,184, a compound having the above structure can be produced.

Use of the Compounds of the Invention The methods of the invention are practiced by administering a compound having the structure herein and a pharmaceutically acceptable carrier. The compounds herein can be used in mammals to treat conditions such as the treatment of hair loss, such as preventing and / or reversing hair loss, and promoting hair growth. Such a situation can be manifested, for example, in alopecia such as male and female alopecia.

While some compounds of the invention may exhibit immunosuppressive activity, preferred compounds of the invention are non-immunosuppressive, as defined herein. Preferably, in the methods of the invention, the compound is formulated into a pharmaceutical composition for use in treating or preventing a condition as described above. Remington's Pharmaceutical Sciences (Mack Publishi
Standard pharmaceutical preparation techniques are used, such as those disclosed in ng Company, Easton, Pa., 1990).

Typically, a compound having a structure as described herein, about 5 per day
mg to about 3000 mg, more preferably about 5 mg to about 1000 mg, more preferably about 10 mg to about 100 mg, are administered systemically. It is understood that these dosage ranges are merely exemplary, and that the daily dosage may be adjusted by various factors. The particular dosage of the compound administered will be interdependent, as will the duration of the treatment, and whether the treatment is local or systemic. Dosage and treatment regimen
The specific compound used, therapeutic indication, efficacy of the compound, personal characteristics of the subject (eg, subject's weight, age, gender, and medical condition, etc.), compliance with treatment regimen, and the presence and severity of side effects of treatment It will also depend on factors such as gender.

According to the present invention, the subject compounds are co-administered with a pharmaceutically acceptable carrier ("carrier"). As used herein, the term pharmaceutically acceptable carrier means one or more compatible solid or liquid filled diluents or encapsulating materials, suitable for administration to a mammal. The term "compatible", as used herein, means that the components of the composition are combined with a compound of the present invention in a manner that eliminates, under normal conditions of use, substantially reducing the efficacy of the composition; and It means that they can be mixed with each other. Of course, the carrier must be of sufficiently high purity and sufficiently low toxicity to be suitable for administration to the animal, preferably mammal, being treated. The carrier may be inert itself, or may have its own pharmaceutical benefits.

The compositions of the present invention may be in any of a variety of dosage forms suitable for (for example) oral, rectal, topical, nasal, ocular or parenteral administration. Of these, topical or oral administration is particularly preferred. Depending on the particular route of administration desired, pharmaceutically acceptable carriers well known in the art can be used.
These carriers include solid or liquid fillers, diluents, suspending agents, surfactants,
And encapsulating materials. Does not substantially interfere with the activity of the compound of the invention,
Any pharmaceutically active substance can be mentioned. The amount of carrier employed with the compound is an amount sufficient to provide a practical amount of the substance for administration per unit dose of the compound. Techniques and compositions for producing dosage forms useful in the methods of the invention include:
It is described in the following reference books: Modern Pharmaceutics, 9th and 1st.
Ver. 0, written by Banker and Rhodes, (1979);
ieberman) et al, Pharmaceutical Dosage Forms: Tablets
(1981); and Ansel, Introduction to Pharmaceutical Dosage Forms (Introduction to
Pharmaceutical Dosage Forms), Second Edition, (1976).

Some examples of substances that can act as pharmaceutically acceptable carriers or components thereof include:
Sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; celluloses such as sodium carboxymethylcellulose, ethylcellulose and methylcellulose and derivatives thereof; powdered tragacanth; malt; gelatin; talc; stearic acid and magnesium stearate Calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and cocoa oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; Alginic acid; emulsifiers such as TWEENs; wetting agents such as sodium lauryl sulfate; coloring agents; fragrances; tableting; stabilizers; antioxidants; preservatives; depyrogenic water; isotonic saline; There is.

The choice of a pharmaceutically acceptable carrier to be used with the subject compound is basically determined by the way the compound is to be administered. In particular, pharmaceutically acceptable carriers for systemic administration include sugars, starches, cellulose and derivatives thereof, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffer. , Emulsifier, isotonic saline,
And exothermic substances include water. Preferred carriers for parenteral administration include propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil. In compositions for parenteral administration, the pharmaceutically acceptable carrier preferably comprises at least about 90% by weight of the total composition.

A variety of oral dosage forms can be used, including solid forms such as tablets, capsules, granules and bulk powders. These oral forms contain a safe and effective amount, usually at least about 5%, preferably from about 25% to about 50%, of a compound of the present invention. Tablets contain suitable binders, lubricants, diluents, disintegrants, colorants, fragrances, glidants, and melting agents, and can be compressed, tablet micronized, enteric-coated, sugar-coated, film-coated, Alternatively, it is possible to perform multiple compression. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, non-cellular granules, including suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, melting agents, coloring agents and fragrances. Solutions and / or suspensions, which are reconstituted from agents, and effervescent formulations, which are reconstituted from effervescent granules.

Pharmaceutically acceptable carriers suitable for the manufacture of unit dosage forms for oral administration are well-known in the art. Tablets typically contain, as inert diluents, conventional pharmaceutically compatible auxiliaries such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; starch, Disintegrants such as alginic acid and croscarmellose; lubricants such as magnesium stearate, stearic acid and talc. In order to improve the flow properties of the powder mixture, direct-running lubricants such as silicon dioxide can be used. Colorants such as FD & C dyes can be added for appearance. For chewable tablets, sweeteners and flavoring agents such as aspartame, saccharin, menthol, peppermint, and fruit flavors are useful adjuvants. Capsules (including time release and sustained release formulations) typically include one or more diluents disclosed above. The choice of carrier components depends on taste,
Depending on secondary considerations such as cost and storage stability, these are not critical to the purpose of the subject invention and can be readily selected by one skilled in the art.

The composition for oral administration also includes liquid solutions, emulsions, suspensions, powders, granules, elixirs, tinctures, syrups and the like. Pharmaceutically acceptable carriers suitable for the manufacture of such compositions are well-known in the art. Representative components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. Representative suspending agents used for suspending agents include methylcellulose, sodium carboxymethylcellulose, Avicel RC-
591, tragacanth and sodium alginate; typical preservatives include methyl paraben and sodium benzoate. The oral liquid composition may also include one or more components such as the sweeteners, flavors, and colorants disclosed above.

Such compositions may also be coated in a conventional manner, and typically include various compounds in which the subject compound exerts the desired effect in the gastrointestinal tract, near the desired topical application, or It may be coated with a pH or time dependent coating, such that it is released over time. Such dosage forms typically include one or more of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac. ,
It is not limited to these.

Other compositions useful for systemic delivery of the subject compounds include sublingual, buccal, and nasal dosage forms. Such compositions are typically
It contains one or more soluble filler materials such as sucrose, sorbitol and mannitol; and one or more binders such as gum arabic, microcrystalline cellulose, carboxymethylcellulose and hydroxypropylmethylcellulose. Lubricants for direct hitting, lubricants, sweeteners, coloring agents, antioxidants and fragrances disclosed above may also be included.

The compounds of the present invention can also be administered topically. The carrier of the topical composition preferably helps the compound of the present invention to penetrate the skin and reach around the hair follicle. The topical compositions of the present invention include, for example, solutions, creams, ointments, gels, lotions, shampoos, leave-on or rinse-out hair conditioners, emulsions, cleaners, moisturizers, sprays And any form such as a skin patch and the like.

Topical compositions containing the active compound include, for example, water, alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, and the like. It can be mixed with various carrier materials known in the art.

Other materials suitably used for topical carriers include, for example, emollients, solvents, humectants, thickeners and powders. These types of materials can be used alone or as a mixture of one or more materials, examples of which are as follows.

Relaxants, for example, stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane-1,2-diol, butane-1,3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, palmitin Isobutyl acid, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecane-2-ol, isocetyl alcohol, cetyl palmitate, dimethylpolysiloxane, di-n-butyl sebacate, myristic acid Isopropyl, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, peanut oil Il, castor oil, acetylated lanolin alcohols, petrolatum, mineral oil,
Butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate and the like; propellants such as propane, butane, isobutane, dimethyl ether,
Carbon dioxide, nitrogen oxides and the like; solvents such as ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran and the like;
Humectants such as glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate and gelatin; and dusts such as chalk, talc, fuller's earth, kaolin, starch, gum, colloidal dioxide. Silicon, sodium polyacrylate, tetraalkylammonium smectite, trialkylarylammonium smectite, chemically modified magnesium ammonium silicate, organically modified montmorillonite clay, aluminum silicate hydrate, fumed silica, carboxyvinyl polymer, sodium carboxymethylcellulose, and ethylene glycol mono Stearate and the like.

The compounds used in the present invention may be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. In a preferred formulation for topical delivery of the compound of the present invention,
"Effect of liposome composition on local delivery of encapsulated cyclosporin A: I. In vitro studies using hairless mouse skin"
of Liposomal Composition on Topical Delivery of Encapsulated Cyclospori
n A: I. An in vitro Study Using Hairless Mouse Skin) ", S.M. T. P. Pharma Sciences, Vol. 3, pp. 404-407 (1993).
Wallach and Philippot, "New Type of Lipid Vesicle: Novasome", Liposomes,
Technology (Liposome Technology), Vol. 1, 141-156 (1993)
And the liposomes described in Wallach U.S. Pat. No. 4,911,928, issued March 27, 1990, assigned to Micro-Pak, Inc., and the like. .

The compounds of the present invention can also be administered by ionization therapy. For example, ww
w.unipr.it/arpa/dipfarm/erasmus/erasm14.html, Banga et al., "Hydrogel-based ionotherapy delivery device for transdermal delivery of peptide / protein drugs.
(Hydrogel-based Iontotherapeutic Delivery Devices for Transdermal Deliv
ery of Peptide / Protein Drugs) ", Pharm. Res., 10 (5), 697-7.
02 (1993); Ferry L.L. L. , `` Theoretical Model of Iontophoresis Utilized in Tr
ansdermal Drug Delivery), Pharmaceutical Acta Helvetier
(Pharmaceutical Acta Helvetiae), Vol. 70, pages 279-287 (1995).
, Gangarosa et al., "Modern Ionization Therapy for Local Drug Delivery (Modern
Iontophoresis for Local Drug Delivery) ", Int. J. Pharm, Vol. 123, 1
59-171 (1995), Green et al., "Iontophoretic Delivery of a Series of Tripeptides in vitro.
peptides Across the Skin in vitro) ", Pharm. Res., Vol. 8, 1121-1.
127 (1991), Jadoul et al., "Quantification and localization of fentanyl and TRH delivered by ionization therapy in the skin.
(Localization of Fentanyl and TRH Delivered by Iontophoresis in the Skin)
Int. J. Pharm., 120, 221-8 (1995), O'Brien (O.
'Brien) et al., "A recent report on antimicrobial activity, pharmacokinetic properties and therapeutic efficacy (An Updated R
eview of its Antiviral Activity, Pharmacokinetic Properties and Therapeu
tic Efficacy ", Drugs, 37, 233-309 (1989), Parry et al.," Bioavailability of acyclovir in human skin.
Acyclovir Biovailability in Human Skin), J. Invest. Dermatol., 98th.
(6), 856-63 (1992), Santi et al., "Drug Reservoir Compos for Drug Container Composition and Delivery of Salmon Calcitonin in Transcutaneous Ionization Therapy.
ition and Transport of Salmon Calcitonin in Transdermal Iontophoresis)
Pharm. Res., 14 (1), 63-66 (1997), Santi.
Et al., "Reverse-phase ionization therapy-electroosmotic flow measurement parameters: I. pH and ionic strength (Rev.
erse Iontophoresis-Parameters Determining Electroosmotic Flow: I. pH an
d Ionic Strength, ”J. Control. Release, 38, 159-165 (1
996), Santi et al., "Reverse Phase Ionization Therapy-Electroosmotic Measurement Parameters:
II. Electrode chamber composition (Reverse Iontophoresis-Parameters Determining Electroos
motic Flow: II. Electrode Chamber Formulation), J. Control. Release,
42, 29-36 (1996); Rao et al., "Reverse-phase ionization therapy: human.
Non-invasive glucose monitoring in vitro (Reverse Iontophoresis: Noni
nvasive Glucose Monitoring in vivo in Humans) ", Pharm. Res., Vol. 12 (
12), 1869-1873 (1995), Thysman et al., "Human Calcitonin Delivery in Rats by Ionization Therapy (Human Calcitonin Delivery i).
n Rats by Iontophoresis) ", J. Pharm. Pharmacol., 46, 725-73.
0 (1994), Volpato et al., "Ionization therapy enhances transdermal delivery of acyclovir to nude mice by electrorepulsion and electroosmosis (Iontophoresis Enhan).
ces the Transport of Acyclovir through Nude Mouse Skin by Electrorepulsi
on and Electroosmosis) ", Pharm. Res., Vol. 12 (11), 1623-16.
See page 27 (1995).

The compositions of the present invention may optionally include an activity enhancer. 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. Activity enhancers of this class include other hair growth stimulants and penetration enhancers.

Additional hair growth stimulants 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. If any of these other hair growth stimulants are present, they will typically be present in the compositions of the invention at about 0% by weight of the composition.
. 01% to about 15%, preferably about 0.1% to about 10%, most preferably about 0.1% to about 15%.
About 5% to about 5% is used.

Additional hair growth stimulants in the compositions of the present invention include, for example, Aminxil and US Pat. No. 3,382,247, US Pat. No. 5,756,092 issued May 26, 1998, U.S. Patent No. 5,772,9, issued June 30, 1998
No. 90, U.S. Pat. No. 5,760,043, issued Jun. 2, 1998, 1994.
U.S. Pat. No. 328,914 issued Jul. 12, 1995, U.S. Pat. No. 5,466,694 issued Nov. 14, 1995, and 5,438, issued Aug. 1, 1995.
No. 058 and US Pat. No. 4,973,474, issued Nov. 27, 1990, all of which are incorporated herein by reference, and minoxidil and minoxidil derivatives, and cromakaline and diazoxide. including,
Vasodilators such as potassium channel agonists can be used.

One suitable type of additional hair growth stimulant for use in the present invention is an antiandrogen. Examples of suitable anti-androgens include, but are not limited to, finasteride and US Pat. No. 5,516,779, issued May 14, 1996, which is incorporated herein by reference, and Nane et al. Cancer Research 58, "Effects of Some Novel Inhibitors of the In Vitro and In Vivo Effects of Novel Inhibitors of C17,20-Lyase and 5-Reductase, and Their Potential Role in the Treatment of Prostate Cancer." C17, 20-Lyase an
d 5-Reductase in vitro and in vivo and Their Potential Role in the Tre
atment of Prostate Cancer), α- and cyproterone acetate, azelaic acid and its derivatives, and 1996.
No. 5,480,913, issued on Jan. 2, 1995, and flutamide, and US Pat. No. 5,411,981 issued on May 2, 1995, issued on Oct. 15, 1996. Examples include compounds described in U.S. Patent No. 5,565,467 and U.S. Patent No. 4,910,226, issued March 20, 1990, all of which are incorporated herein by reference.

Another suitable class of optional hair growth stimulants is 1) US Patent Provisional Application No. 60 / 122,925 to Fulmer et al., Filed March 5, 1999, which is hereby incorporated by reference. Cyclosporins and cyclosporin analogs, including those described in US Patent Provisional Application No. 60 / 147,279 to Degenhardt et al., Filed August 5, 1999; U.S. Provisional Application No. 60 / 147,313 to Degenhardt et al.
US Provisional Application No. 6 of Degenhardt et al., Filed August 5, 1999.
No. 0 / 147,280; Degenhardt filed on Aug. 5, 1999.
U.S. Provisional Application No. 60 / 147,278; and Eickhoff et al., U.S. Provisional Application No. 60 / 147,276, filed August 5, 1999.
All of which are incorporated herein by reference), such as those described in
Immunosuppressive or non-immunosuppressive agents, such as 6 analogs.

Another suitable type of any hair growth stimulant is selenium sulfide, ketoconazole, tricrocarbon, triclosan, zinc pyrithione, itraconazole, asiatic acid, hinokitiol, mipirocin, and EPA0,
680, 745 (incorporated herein by reference), antibacterial agents such as clinacycin hydrochloride (clinacycin), benzoyl peroxide, benzyl peroxide and minocycline.

As an optional hair growth stimulant, an anti-inflammatory agent can also be incorporated into the compositions herein. Examples of suitable anti-inflammatory agents include glucocorticoids such as hydrocortisone, mometasone furoate and prednisolone, US Pat. No. 5,756,092
Cyclooxygenase or lipoxygenase inhibitors such as those described in US Pat.
EPA 0,770,399 issued on March 31, 1994, WO94 / 0 issued on March 31, 1994
6434, and the compounds described in FR 2,268,523 issued on November 21, 1975 (all of which are incorporated herein by reference).

Another suitable class of optional hair growth stimulants is thyroid hormones, and derivatives and analogs thereof. Examples of thyroid hormones suitable for use in the present invention include triiodothyronine. Examples of thyroid hormone analogs suitable for use herein include Zhang et al., U.S. Provisional Patent Application No. 60 / 136,996, filed June 1, 1999; U.S. Provisional Application No. 60 / 137,024 to Zhang et al.
Zhang et al., U.S. Provisional Application No. 60/13, filed June 1, 1999.
7,022, Zhang et al., U.S. Provisional Patent Application No. 60 / 137,023, filed June 1, 1999;
ngquist) et al., US Provisional Application No. 60 / 137,052, June 1, 1999.
US Patent Provisional Application No. 60/137 to Youngquist et al.
No. 6,063, and U.S. Provisional Application No. 60 / 136,958 to Youngquist et al., Filed June 1, 1999.

In the compositions herein, a prostaglandin agonist or antagonist can also be used as an optional hair growth stimulating agent. Examples of suitable prostaglandin agonists or antagonists include latanoprost and WO 98/33497 of Johnstone, issued Aug. 6, 1998, and Szelnschants, published on Apr. 27, 1995 ( Stjernschantz), WO 95/11003, Ueno JP 97-100901, and Nakamura JP 96-134242.
Nos. 1 to 3 are mentioned.

Another class of optional hair growth stimulants for use in the present invention are retinoids. Suitable retinoids include isotretinoin, acitretin, and tazarotene.

Another class of any hair growth stimulant used herein is the triterpenes;
See, for example, US Patent Application No. 09 / 353,408 to Bradbury et al., Filed July 15, 1999, entitled "Method for Regulating Hair Gr
No. 09 / 353,409, filed Jul. 15, 1999, entitled "Compositions Which Contain Triterpenes for Regulating Hair." Growth)
", All of which are incorporated by reference.

Another class of any hair growth stimulant used herein includes flavinoids
(flavinoids), ascomycin derivatives and analogs, histamine antagonists such as diphenhydramine hydrochloride, oleanolic acid and ursolic acid and US Pat. No. 5,529
, 769, Japanese Patent No. 10017431, WO95 / 35103, US Pat. No. 5,468,888, Japanese Patent No. 09067253, WO92 / 0926.
2, such as those described in Japanese Patent No. 6,209,215, US Patent No. 5,631,282, US Patent No. 5,679,705, Japanese Patent No. 08193,094,
Other Triterpenes, European Patent 0 to Bonte et al. Issued September 8, 1993.
No. 5,558,509 and WO9 of Bonte et al., Published Jan. 16, 1997.
Saponins, US Pat. No. 5,015,470 issued May 14, 1991, such as those described in US Pat. No. 7/01346, both of which are incorporated herein by reference.
No. 5,300,284, issued Apr. 5, 1994, and 1993.
Proteoglycanase or glycosaminoglycanase inhibitors, estrogen agonists, such as those described in U.S. Patent No. 5,185,325, issued February 9, 2016, all of which are incorporated herein by reference. Drugs and antagonists, pseudoterins (p
seudoterins), interleukin 1 inhibitors, interleukin-6 inhibitors, interleukin-10 promoters, and tumor necrosis factor inhibitors, such as cytokine and growth factor promoters, analogs or inhibitors, vitamin D analogs and Vitamins such as parathyroid hormone antagonists, vitamin B12 analogs and panthenol, interfuron agonists and antagonists, hydroxy acids such as those described in US Pat. No. 5,550,158, benzophenones And hydantoin anticonvulsants such as phenytoin.

Other additional hair growth stimulants are, for example, Tsuji et al., Japanese Patent No. 09-157,139 issued June 17, 1997; Miraview issued August 10, 1988.
eau) EP 0277455 A1; Cabo Soler et al., WO 97/05878, issued February 20, 1997; Bont, issued March 13, 1992.
WO92 / 16186 to Bonte et al .; Japanese Patent No. 62-93215 to Okazaki et al. Issued on April 28, 1987; US Patent No. 4,987,150 to Kurono et al. Issued January 22, 1991. No. 290811 issued on October 15, 1992 by Ober et al .; Japanese Patent No. 05-286,835 issued by Tanaka et al. Issued on Nov. 2, 1993; Greff) FR2
723,313, Gibson U.S. Pat. No. 5, issued May 14, 1991;
U.S. Patent No. 5,559,09, issued September 24, 1996.
2, U.S. Patent No. 5,536,751, issued July 16, 1996, 1998.
U.S. Pat. No. 5,714,515 issued Feb. 3, 1988; EPA 0,319,991 issued Jun. 14, 1989; EPA 0,357, issued Oct. 6, 1988.
630, EPA 0,573,253, issued December 8, 1993, January 1986
Japanese Patent No. 61-260010 issued on Jan. 18, U.S. Pat. No. 5,772,990 issued on Jun. 30, 1998, and US Pat. No. 5 issued on Oct. 1, 1991.
U.S. Pat. No. 4,761,4, issued Aug. 2, 1988.
No. 01, all of which are incorporated herein by reference.

[0149] Non-limiting examples of penetration enhancers that may 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-hydroxy Propionic 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, dioctyl adipate, dicapry adipate, diisopropyl adipate,
Diisopropyl sebacate, dibutyl sebacate, diethyl sebacate, dimethyl sebacate, dioctyl sebacate, dibutyl suberate, dioctyl azelate, dibenzyl sebacate, dibutyl phthalate, dibutyl azelate, ethyl myristate, dimethyl azelate, myristate Butyl, dibutyl succinate, didecyl phthalate, decyl oleate, ethyl caprate, ethyl salicylate, isopropyl palmitate, ethyl laurate, 2-ethyl-hexyl pelargonate, isopropyl isostearate, butyl laurate, benzyl benzoate, benzoate Butyl acid, hexyl laurate, ethyl caprate, ethyl caprylate, butyl stearate, benzyl salicylate, 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 oxides, sugar esters, tetrahydrofurfural alcohol, urea, diethyl-m-toluamide, and 1-dodecylazacycloheptan-2-one.

In all of the foregoing, the compounds employed in the methods of the invention may, of course, be administered alone or as a mixture, and the composition may further comprise additional agents or excipients appropriate for the indication.

[0151] The following examples Examples of the composition administered is not intended to limit the present invention, those skilled in the art to provide an indication for carrying out the method of the present invention. In each of the examples, "compounds" other than those described may be replaced in the examples with those having a structure as described herein, with similar results.

Example A A composition for topical administration is prepared comprising the following ingredients:

[0153]

[Table 19]

A male male subject with androgenetic alopecia is treated according to the methods of the present invention. In particular,
The composition is administered topically to the subject daily for 6 weeks.

Example B The method of Dowton et al., "Effect of liposome composition on local delivery of encapsulated cyclosporin A: I. Influence of Liposomal Composition on Topical Delivery of Encapsulate.
d Cyclosporin A: I. An in vitro Study Using Hairless Mouse Skin) "
T. P. Pharma Sciences, Vol. 3, 404-40
According to page 7 (1993), a composition for topical administration is prepared using the compound of Example 2 in place of cyclosporin A and Novasome 1 in a non-ionic liposome formulation. A human male subject with androgenetic alopecia is treated daily with the composition. Specifically, the above composition is locally administered to a subject for 6 weeks.

Example C A shampoo containing the following ingredients is prepared.

[0157]

[Table 20]

A human male subject with androgenetic alopecia is treated by the method of the present invention. In particular,
Subjects use the shampoo described above daily for 12 weeks.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61K 31/4545 A61K 31/4545 A61P 17/14 A61P 17/14 C07D 207/16 C07D 207/16 211/34 211/34 401/12 401/12 405/12 405/12 (71) Applicant ONE PROCTER & GANBLE PLAZA, CINCINNATI, OHIO, UNITED STATES OF AMERICA (72) Inventor Fulmer, Andrew Wayne West, Ohio, United States of America Chester, Wilderness, Trail 6452 (72) Inventor McIver, John Macmillan Cincinnati, Indians, Springs, Ohio, USA 9999 (72) Inventor's Day Genhardt, Charles Raymond Cincinnati, Ohio, USA Wellingwood, Court 10555 (72) Inventor Aikoff, David Joseph Kentucky, United States, Edgwood, Garden, Way 505 F-term (reference) 4C054 AA02 CC04 DD38 EE01 FF01 4C063 AA01 BB08 CC12 CC81 DD03 DD10 EE01 4C069 AA17 BB54 BD06 4C083 AB332 AC072 AC102 AC122 AC172 AC392 AC542 AC562 AC642 AC712 AC782 AC842 AC851 AC852 AD132 AD152 AD222 CC37 CC38 DD23 EE22 4C086 AA01 BC07 BC21 GA02 GA07 GA08 MA05

Claims (10)

[Claims] 1. A method for treating hair loss, comprising: (a) a structure:A non-immunosuppressive compound having the formula: and pharmaceutically acceptable salts, hydrates and raw materials thereof.
Hydrolyzable amides, esters and imides, wherein (i) Q is a first heteroatom, wherein said first heteroatom is nitrogen
(Ii) A is CH_Two, O, S and NR₁Selected from the group consisting of: (iii) R₁Is selected from the group consisting of hydrogen and alkyl; (iv) J is hydrogen, C₁-C₆Alkyl, C_Three-C₆Alkenyl, benzyl,
Ar substitution C₁-C₆Alkyl, Ar substituted C_Three-C₆Alkenyl, Ar substituted C_Three-C₆A
K is selected from the group consisting of₁-C₆Alkyl, Ar substituted C₁-C₆ Alkyl, Ar substituted C_Two-C₆Alkenyl, Ar substituted C_Two-C₆Alkynyl and
Selected from the group consisting of clohexylmethyl; or J and K are linked together;
It may form a 5-, 6- or 7-membered heterocyclic ring, which ring may be O, S, S
(O), S (O)_TwoAn additional heteroatom selected from the group consisting of, NH, and NE
And B and D may be bonded together to form a substituted or unsubstituted tetra
When forming a hydronaphthalene moiety, J and K are optionally linked together to form phenyl
(V) X is hydrogen, C₁-C₉Alkyl, C_Two-C₉Alkenyl, C_Five-C₇Shiku
Lower alkyl, C_Five-C₇Cycloalkyl, C_Five-C₇Cycloalkenyl, C_Five-C₇Shi
Chloroalkenyl, Ar, -OR_Two, [C₁-C_FourAlkyl] -Y, [C_Two-C_FourAl
Kenyl] -Y, Y, and -NR_ThreeR_FourSelected from the group consisting of: (vi) R_Two, R_Three, R_Four, B, D, and E are each independently nil,
Hydrogen, Ar, C₁-C₆Alkyl, C_Two-C₆Alkenyl, C_Two-C₆Alkynyl, C _Five -C₇Cycloalkyl-substituted C₁-C₆Alkyl, C_Five-C₇Cycloalkyl-substituted C_Three
-C₆Alkenyl, C_Five-C₇Cycloalkyl-substituted C_Three-C₆Alkynyl, C_Five-C₇
Cycloalkenyl-substituted C₁-C₆Alkyl, C_Five-C₇Cycloalkenyl-substituted C_Three−
C₆Alkenyl, C_Five-C₇Cycloalkenyl-substituted C_Three-C₆Alkynyl, Ar substitution
C₁-C₆Alkyl, Ar substituted C_Three-C₆Alkenyl and Ar-substituted C_Three-C₆Archi
Selected from the group consisting of nil; provided that the alkyl, alkenyl, and alkynyl
One or more CH_TwoThe parts are O, S, S (O), S (O)_Two, And NR
R may be optionally substituted with a heteroatom selected from the group consisting of ₁ -C_FourAlkyl, C_Three-C_FourAlkenyl, C_Three-C_FourAlkynyl, and C₁-C_FourCrosslinking
Selected from the group consisting of alkyl, where the bridge is N of NR and heteroatom containing
Formed between a carbon atom of an alkyl, alkenyl, or alkynyl to form a bridged ring
Wherein the bridged ring is optionally fused to an Ar moiety; B and D are also linked together to form
May form a 5-, 6-, or 7-membered carbocycle fused to an allyl;
And D may also each independently be the following groups:Wherein Z is hydrogen, C₁-C₆Alkyl, C_Two-C₆Alkenyl and C_Two-C₆Al
Is selected from the group consisting of quinyl, wherein V is Ar and oxo, hydrogen, hydroxy
, O- (C₁-C_FourAlkyl) and O- (C_Two-C_FourAlkenyl)
Consisting of a substituted 5-, 6-, or 7-membered carbocycle having independently selected substituents
B may also be T, wherein T has the following structure:Where X_TwoAre O and NR_TenSelected from the group consisting of_TenIs hydrogen, C₁-C₆
Alkyl, and C₁-C₆R is selected from the group consisting of alkenyl;₉Is phenyl
, Benzyl, C₁-C_FiveAlkyl, C₁-C_FiveAlkenyl, phenyl substituted C₁-C_FiveA
Alkyl and phenyl substituted C₁-C_FiveB is selected from the group consisting of alkenyl;
D is R₈Where R₈Is C_Three-C₈Arbitrary with cycloalkyl
C being replaced₁-C₈R is selected from the group consisting of alkyl, and Ar;_ThreeAnd R_Four May also be bonded together to form a 5-, 6-, or 7-membered heterocyclic aliphatic or aromatic ring.
(Vii) Ar and Y are each independently phenyl, benzyl, 1-na
Futyl, 2-naphthyl, indenyl, azulenyl, fluorenyl, anthraceni
2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3
-Pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazoly
, Pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isoto
Liazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,
3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3
5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl,
Isoindolyl, 3H-indolyl, indolinyl, benzo [b] furanyl,
Benzo [b] thiophenyl, 1H-indazolyl, benzimidazolyl, benzti
Azolyl, purinyl, 4H-quinolizinyl, quinolinyl, 1,2,3,4-tetra
Lahydroquinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroisoquino
Linyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8
-Naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl
, Phenothiazinyl, and phenoxazinyl, 2-pyrolinyl, 3-pyrolinyl
, Pyrrolidinyl, 1,3-dioxolyl, imidazolidinyl, 2H-pyranyl,
4H-pyranyl, piperidyl, 1,4-dioxanyl, morpholinyl, 1,4-
Group consisting of dithianyl, thiomorpholinyl, piperazinyl and quinuclidinyl
Where Ar is hydrogen, halogen, hydroxyl, nitro, -SO _Three H, trifluoromethyl, trifluoromethoxy, C₁-C₆Alkyl, C_Two-C ₆ Alkenyl, O- [C₁-C₆Alkyl], O- [C_Two-C_FourAlkenyl], O-
Benzyl, O-phenyl, 1,2-methylenedioxy, -NR_FiveR₆, Carboxy
, N- [C₁-C_FiveAlkyl] carboxamide, N- [C_Three-C_FiveAlkenyl]
Ruboxamide, N, N-di- [C₁-C_FiveAlkyl] carboxamide, N, N-di
− [C_Three-C_FiveAlkenyl] carboxamide, N-morpholinocarboxamide, N
-Benzylcarboxamide, N-thiomorpholinocarboxamide, N-picolino
Ilcarboxamide, morpholinyl, piperidinyl, OM, CH_Two− (CH_Two) _q -M, O- (CH_Two)_q-M, (CH_Two)_q-OM, and CH = CH-M
Having one or more substituents independently selected from the group_FiveAnd R₆Is it
Each independently hydrogen, C₁-C₆Alkyl, C_Three-C₆Alkenyl, C_Three-C₆Archi
Or R is selected from the group consisting of_FiveAnd R₆Are joined together
M may form a 5- or 6-membered heterocycle; M is 4-methoxyphenyl,
2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazyl, quinolyl, 3,5-di
Methyl isoxazoyl, isoxazoyl, 2-methylthiazoyl, thiazoyl,
Q is selected from the group consisting of 2-thienyl, 3-thienyl, and pyrimidyl;
And Y is hydrogen, halogen, hydroxyl, nitro,
Trifluoromethyl, trifluoromethoxy, C₁-C₆Alkyl, C₁-C₆Al
Kenyl, O- [C₁-C_FourAlkyl], O- [C_Two-C_FourAlkenyl], O-benzyl
, O-phenyl, 1,2-methylenedioxy, amino, and carboxyl
And (viii) m is an integer of 0 to 3; and (b) a pharmaceutically acceptable carrier. A method for treating hair loss, comprising administering an object. 2. The method of claim 1, wherein J and K are linked together to form a 5-, 6-, or 7-membered heterocycle, and m is an integer from 0 to 1. 3. J and K are joined together to form a 5-, 6-, or 7-membered heterocycle containing an additional heteroatom selected from the group consisting of S, O, NH, and NE. The method according to claim 1 or 2, wherein 4. The compound according to claim 1, wherein Has a structure selected from the group consisting more, wherein, G, L, and M are each independently, CH _2, S, O, chosen NH, and from the group consisting of NE, claim 1 Or the method of 2. 5. The compound according to claim 1, wherein Has a structure selected from the group consisting more, wherein, G, L, and M are each independently, CH _2, S, O, chosen NH, and from the group consisting of NE, claim 1 Or the method of 2. 6. The method according to claim 1, wherein said compound has the following structure: Wherein (a) R ₁₂ is selected from the group consisting of hydrogen and — (CH ₂ ) _t —R ₁₆ , where t is 1 to
An integer of 3 wherein R ₁₆ is selected from the group consisting of Ar and NR ₁₇ R ₁₈ , wherein R ₁₇ and R ₁₈ are each independently hydrogen, C ₁ -C ₅ alkyl, and — (CH ₂ ) -A
is selected from the group consisting of r, or R ₁ 7 and R ₁₈ may form a heterocyclic ring together bonded to a 5- or _{6-membered; (b) R 13, R} 14, and R ₁₅ is each, independently, hydrogen, halogen, C ₁ -C ₆ alkyl, O- (C ₁ -C _{6 alkyl), - (CH 2) e} -Ar, and -G (CH ₂
G) is selected from the group consisting of _e- Ar, wherein e is an integer from 0 to 4;
, S, and NR ₁₉ , wherein R ₁₉ is selected from the group consisting of hydrogen and C ₁ -C ₆ alkyl; (c) A is selected from the group consisting of —O— and —NH— You. 7. (a) R ₁₃ and R ₁₅ are each independently —OCH ₂ -4-pyridine, —O—
Propyl, and it is selected from the group consisting of hydrogen; (b) R ₁₄ is, -OCH _{2-4-pyridine,} methyl, and is selected from the group consisting of hydrogen; (c) R ₁₂ is, -CH _2-3- it is selected from pyridine and the group consisting of hydrogen; (d) a is, O, NH _2, and is selected from the group consisting of N- benzyl; (e) X is 3,4,5-trimethoxyphenyl, wherein Item 7. The method according to Item 6. 8. (a) R ₁₃ and R ₁₅ are each independently —OCH ₂ -4-pyridine, —O—
Propyl, and it is selected from the group consisting of hydrogen; (b) R ₁₄ is, -OCH _{2-4-pyridine,} methyl, and is selected from the group consisting of hydrogen; (c) R ₁₂ is, -CH _2-3- it is selected from pyridine and the group consisting of hydrogen; (d) a is, O, NH _2, and is selected from the group consisting of N- benzyl; (e) X is 3,4,5-trimethoxyphenyl, wherein Item 8. The method according to Item 7. 9. The method of claim 1, wherein the administration is topical. 10. The method of claim 1, wherein the administration is oral.