JP2002525305A - Hair loss treatment method using sulfonamide - Google Patents

Abstract

  (57) [Summary] The present disclosure describes methods for treating hair loss in a mammal, including stopping and / or overturning hair loss and promoting hair growth. The method comprises administering a compound having the structure of Formula (I) and a pharmaceutically acceptable carrier.

Description

DETAILED DESCRIPTION OF THE INVENTION

FIELD OF THE INVENTION The present invention relates to methods for treating hair loss in a mammal, including stopping and / or overturning hair loss and promoting hair growth.

[0002] This application claims priority to provisional application number 60 / 102,437, filed September 30, 1998, under 35 USC 119 (e).

BACKGROUND OF THE INVENTION Hair loss is a common problem that often occurs, for example, as a natural phenomenon or is enhanced by the use of certain therapeutic agents designed to alleviate conditions such as cancer. It is. Such hair loss is often accompanied by a lack of hair regeneration that causes partial or complete alopecia. Such alopecia is superficially unattractive and particularly annoys those who are experiencing hair loss. 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 stages, known as the anagen, catagen and telogen. The anagen is the growth phase of the cycle and may be characterized by a hair follicle with rapid proliferation of cells that are differentiating to form hair penetrate deep into the dermis. The next phase is catagen, a transient phase characterized by a pause in cell division, during which the hair follicles regress through the dermis and hair growth ceases. The next phase, resting phase, is often characterized as a resting phase during which the regressed hair follicles contain embryos packed with dermal papillary cells. In the telogen phase, rapid cell proliferation, dermal papillary proliferation and synthesis of basement membrane components result in the initiation of a new anagen. This cycle is repeated throughout the hair growth.
When hair growth ceases, most of the hair follicles in the telogen and anagen are not involved, causing the development of complete or partial alopecia.

According to the literature, many attempts have been made to trigger hair regeneration, for example by promoting or prolonging the anagen. There are currently two drugs approved by the US Food and Drug Administration for the treatment of androgenetic alopecia: minoxidil for application (launched as Logaine® by Pharmacia & Upjohn) and oral finasteride (Merck) On the market as Propecia (registered trademark).

[0005] However, there are conflicting reports regarding the ability of minoxidil to cause hair growth. In fact, previous clinical trials that reduced blood pressure through the use of minoxidil did not even mention hirsutism (hair growth) as a side effect. Dormoi et al. (Dormoi
s), "Minoxidil in severe hypertension: value when unsuccessful as a customary drug", (American Heart Journal, Vol. 90, pp. 360-368 (1
975)). In fact, minoxidil manufacturers reported that hair growth was limited to some patients who used minoxidil. See Physician's Desk Reference® 49th Edition, (1995) p.
In addition, the serious side effects of minoxidil can occur, including vasodilation (
Fluid retention around the heart and increased heart rate), dyspnea and weight gain. Physician's Desk Reference (registered trademark) 49th edition, (1995) p. 2581.

[0006] Further, while previous guidelines suggest that Propecia® may be more effective than Logaine®, patients using Propecia® may have limited hair growth. Have experienced. The New England Journal of Medicine, 33
See Vol. 8, No. 9, February 26, 1998. Furthermore, the potential side effects of Propecia® are severe. Propecia® is impotence,
It can cause hypersensitivity reactions, including decreased energy, decreased ejaculation volume, chest tenderness and thickening, lip swelling and rash. Furthermore, Propecia® is not indicated for women and children. In fact, pregnant or potential pregnant women should not even handle crushed or broken tablets containing the drug. Physician Desk Reference (registered trademark) 52nd edition, (1998) 1373 pages,
And The New England Journal of Medicine (338, No. 9, February 26, 1998).

Interestingly, the immunosuppressants cyclosporin A and FK506 are known to cause significant hirsutism side effects. See, Iwabuchi et al., "Effects of the immunosuppressive peptidyl-prolyl cis-trans isomerase (PPIase) inhibitor, cyclosporin A, FR506, ascomycin and rapamycin on initiating hair growth in mice: Does not require immunosuppression. "Journal of Dermatological Science, 9, pp. 64-69 (1995)
Yamamoto et al., "The hair growth stimulating effect of a potent immunosuppressant, cyclosporin A and FK506", Journal of Dermatological Science, Vol. 7, S47-S54 (1994); Yamamoto et al., "A potent immunosuppressant, FK506. Stimulation of hair growth by topical application ", Journal of Investigational Dermatology, Vol. 102, 160
１６ 164 (1994); Jiang et al., “PK, a potent immunosuppressant.
Induction of the anagen and telogen of mouse skin by topical application of 506 ", Journal of I
nvestigational Dermatology, vol. 104, pp. 523-525 (1995); McElwee et al. (McElwee) "Local FK506: a potent immunotherapy for alopecia areata? A study using a dandy experimental bald rat model", British Journal of Der.
matology, 137, 491-497 (1997); Mahler et al.
urer) "Regulation of hair growth by local immunophilin ligands", American Journal
of Pathology, Vol. 150, No. 4, pp. 1433-1441 (1997); and Paus et al., "Control of Hair Growth by Immunosuppression," Arch. Dermatol.
Res., 288, 408-410 (1996). However, the use of such compounds may be undesirable due to their strong ability as immunosuppressants. FK506 is a complex of a macrocyclic molecule having the following structure:

[0008]

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[0009] Stocks et al., "Contribution to Binding of Pyranoside Substituents in Truncated Binding Domains of FK506," (Bioorganic & Medicinal Chemistry Let
Ters, Vol. 4, No. 12, pp. 1457-1460, 1994) Analogs that are very similar to this complex macrocycle may have hair growth properties in the form of, for example, alopecia areata and / or androgenetic alopecia. It has been disclosed. See below. U.S. Pat. No. 5,541,193 (Kwai et al.), Assigned to Abbott Laboratories and issued on July 30, 1996; U.S. Pat. 496,564 (Asakura et al.); Assigned to Sandoz Pharmaceuticals, U.S. Pat. No. 5,352,671 (Baumann) issued Oct. 4, 1994; and assigned to Merck, U.S. Patent No. 5,550,233, issued August 27, 1996 (Rupprecht et al.).

However, the excitement associated with the hairy activity of cyclosporin A and FK506 is
It has been somewhat tempered by the lack of reports on hair loss due to various, smaller, non-macrocyclic immunosuppressants and non-immunosuppressive compounds that are less structurally complex than FK506. See below. Transferred to Guildford Pharmaceutical, 1996
WO 96/40140 published on December 19, 2001 (Steiner et al.
WO), transferred to Guildford Pharmaceuticals and published on December 19, 1996
96/40633 (Hamilton et al.); U.S. Pat. No. 5,696,13, assigned to GPI NIL Holding, and issued on Dec. 9, 1997.
No. 5, (Stainer et al.); Assigned to 1997 Guildford Pharmaceuticals, U.S. Pat. No. 5,614,547 (Hamilton et al.), Issued Mar. 25, 1997; WO97 / 16190 released on the 9th
No. WO96 / 36630 (Zelle); assigned to Vertex Pharmaceuticals and published on November 21, 1996; assigned to Vertex Pharmaceuticals and published on October 9, 1997. WO 97/36869 (Armistead et al.); Assigned to Vertex Pharmaceuticals, March 2, 1996
WO96 / 15101 (Zele et al.) Published on March 3; assigned to Vertex Pharmaceutical Co., Ltd .; WO92 / 19593 (Armisted et al.) Published on November 12, 1992; assigned to Vertex Pharmaceuticals, 1994 WO 94/07858 published on April 14 (Armisted et al.); Transferred to Vertex Pharmaceuticals;
WO95 / 26337 (Zele et al.) Published on October 5, 1995; WO92 / 213 transferred to Vertex Pharmaceuticals and published on December 10, 1992
No. 13; Duffy et al .; assigned to Vertex Pharmaceuticals, U.S. Pat. No. 5,192,773 issued Mar. 9, 1993) Armisted et al .; assigned to Vertex Pharmaceuticals, Jul. 19, 1994. U.S. Patent No. 5,330,993 issued.
No. 5,622,970 (Armstead et al.); Assigned to Vertex Pharmaceuticals, Inc., and issued on Apr. 22, 1997; assigned to Vertex Pharmaceuticals, Inc., Aug. 5, 1997. US Patent No. 5,654, issued to
No. 332 (Armisted et al.); Assigned to Vertex Pharmaceuticals, U.S. Pat. No. 5,620,971 (Armstead et al.) Issued Apr. 15, 1997; assigned to Vertex Pharmaceuticals, Aug. 6, 1996. US Patent No. 5,5 issued
No. 43,423 (Zele et al.); Transferred to Vertex Pharmaceuticals, March 14, 1996
U.S. Pat. No. 5,516,797 issued to U.S. Pat. No. 5,716,797 (Armisted et al.); U.S. Pat. No. 5,665, issued September 9, 1997, assigned to Vertex Pharmaceuticals.
No. 774 (Armisted et al.); Andres et al. (Structurally limited analogs of prolylamide. Trans-prolyl peptide mimetic), Journal.
of Organic Chemistry, Vol. 58, pp. 6609-4413 (1993); and Armisted et al., "FK which is the major binding protein of the immunosuppressant FK506.
Design, Synthesis and Structure of Non-macrocyclic Inhibitors of BP12 "Acta Crystallographica, D51, 522-528 (1995).

Surprisingly, the inventors have discovered a class of compounds that stop and / or overturn hair loss or promote hair growth, but do not share the complex macrocyclic structure of FK506. The inventors have further discovered that, within its new class, compounds that cause hair growth are surprisingly not or only marginally immunosuppressive. It is a distinct advantage that such a compound with a hirsutism effect has as little and / or no immunosuppressive activity as 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 inventors have found that the present invention is particularly useful for treating hair loss in mammals, including stopping and / or overturning hair loss and promoting hair growth. A method of treating hair loss, comprising administering a compound of choice. The compound utilized in this method has the following structure:

[0013]

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And pharmaceutically acceptable salts, hydrates, and biohydrolyzable amides, esters, and imides, wherein G, J, K, A, B, D, and m are Defined in the specification.

DETAILED DESCRIPTION OF THE INVENTION The present invention uses compounds and compositions that are particularly useful for treating hair loss in mammals, including stopping and / or overturning hair loss and promoting hair growth. About the method.

[0016] In addition to discovering that the present compounds are useful for treating hair loss, the present inventors have surprisingly discovered that immune suppression is not required for hair growth stimulation.
The present inventors have further discovered compounds that are useful in treating hair loss, but are surprisingly not immunosuppressive. Preferred compounds useful in the methods of the invention are therefore non-immunosuppressive, as defined herein.

[0017] Publications and patents are cited throughout this disclosure. All references cited herein are hereby incorporated by reference.

[0018] All percentages, ratios and parts used herein are by weight unless otherwise specified.

Definitions and Usage of Terms The following is a list of definitions for the terms used herein: "Salt" as used herein is formed by any acidic group (eg, a carboxyl group). A cationic salt or an anionic salt formed with any basic group (for example, an amino group). Many such salts are well-known in the art. Preferred cationic salts include alkali metal salts (eg, sodium and potassium)
, Alkaline earth metal salts (eg, magnesium and calcium), and organic salts. Preferred anionic salts include halogen compounds (eg, chloride groups). Such acceptable salts, when administered, must be suitable for use in mammals.

As used herein, “alkenyl” is an unsaturated hydrocarbon chain radical. Alkenyls have at least one olefinic double bond. Unless otherwise specified, alkenyl has 2 to about 15 carbon atoms (C ₂ -C ₁₅ ); preferably 2 to about 10 carbon atoms (C ₂ -C ₁₀ ); more preferably 2 to about 8 carbon atoms. carbon atoms (C ₂ ~C _8), and most preferably about 2 to about 6 carbon atoms (C ₂ ~C _6). Non-limiting examples of alkenyls include vinyl, allyl and butenyl.

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

As used herein, “alkyl” is a saturated hydrocarbon chain radical.
Unless otherwise specified, alkyl is from 1 to about 15 carbon atoms (C ₁ -C ₁₅ ); preferably from 1 to about 10 carbon atoms (C ₁ -C ₁₀ ); more preferably from 1 to about 6 carbon atoms. (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 divalent group, alkyl, alkenyl, or alkynyl. For example, "methylene" is, -CH ₂ - is.

As used herein, “alkynyl” is an unsaturated hydrocarbon chain radical. Alkynyl has at least one triple bond. Unless otherwise specified,
Alkynyl has 2 to about 15 carbon atoms (C ₂ -C ₁₅ ); preferably 2 to about 10 carbon atoms (C ₂ -C ₁₀ ); more preferably 2 to about 8 carbon atoms (C ₂ -C ₁₀ ). _{2 to} C ₈
), And most preferably from about 2 to about 6 carbon atoms (C ₂ -C _6).

As used herein, a “biohydrolysable amide” is a compound of the present invention that does not interfere with the activity of the compound or is readily converted in vivo by a test mammal to produce the active compound. Is an amide of the compound

As used herein, a “biohydrolysable ester” is a compound of the present invention that does not interfere with the activity of the compound or is readily converted in vivo by a test mammal to yield the active compound. Is an ester of the compound

As used herein, a “biohydrolyzable imide” is a compound of the present invention that does not interfere with the activity of the compound or is readily converted in vivo by a test mammal to yield the active compound. Is an imide of the compound

As used herein, “carbocyclic ring”, “carbocycle”, or the like, is a hydrocarbon ring radical. The carbocyclic ring is a monocyclic, fused or bridged, or spiro polycyclic ring. Unless otherwise specified, a monocyclic ring contains 3 to about 9 atoms, preferably about 4 to about 7 atoms, and most preferably 5 or 6 atoms. The polycyclic ring has about 7 to about 17 atoms, preferably about 7 to about 1
It contains 4 atoms, most preferably 9 or 10 atoms.

“Cycloalkyl,” as used herein, is a saturated carbocyclic or heterocyclic ring radical. Preferred cycloalkyl groups include, for example, cyclobutyl, cyclopentyl, and cyclohexyl.

As used herein, “heteroalkenyl” is an alkenyl radical consisting of carbon atoms and one or more heteroatoms, where heteroatoms are oxygen, sulfur, nitrogen, and phosphorus, and also Preferably, it is selected from the group consisting of oxygen, sulfur, and nitrogen.

As used herein, “heteroalkyl” is an alkyl radical consisting of carbon atoms and one or more heteroatoms, where heteroatoms are oxygen, sulfur, nitrogen, and phosphorus, and also Preferably, it is selected from the group consisting of oxygen, sulfur, and nitrogen.

As used herein, “heterocyclic ring”, “heterocycle” or equivalent is a cyclic radical consisting of carbon atoms and one or more heteroatoms in the ring, wherein the heteroatoms Is selected from the group consisting of oxygen, sulfur, nitrogen and phosphorus, more preferably oxygen, sulfur and nitrogen. Heterocycle is monocyclic or fused,
Or a crosslinked or spiro polycyclic ring. Unless otherwise specified,
Monocyclic compounds contain about 3 to about 9 atoms, preferably about 4 to about 7 atoms, and most preferably 5 or 6 atoms. Polycyclic compounds contain about 7 to about 17 atoms, preferably about 7 to about 14 atoms, and most preferably 9 or 10 atoms. The heterocyclic ring (heterocycle) may be substituted or unsubstituted.

As used herein, a “lower” moiety (eg, a “lower” alkyl) is
Moieties having from about to about 6, preferably from about 1 to about 4, carbon atoms.

As used herein, “pharmaceutically acceptable” means suitable for use in humans or other animals.

As used herein, “safe and effective amount of a compound (or composition, or analog)” means an amount effective to exhibit biological activity, preferably biological activity. When used in the method of the invention, a reasonable ratio of effect / risk is balanced in the active site of the test mammal, without excessive harmful side effects (such as toxicity, irritation or allergic reactions) and stopping hair loss And / or overturning or promoting hair growth. As used herein, a variable, moiety, group or analog is a variable or structure that has one or more occurrences.
In the event that it occurs more than once, the definition in each is independent of the definition in all others.

The present invention relates to a method for treating hair loss comprising administering a composition comprising: (a) a compound having the structure:

[0037]

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And pharmaceutically acceptable salts, hydrates, and biohydrolyzable amides, esters, and imides thereof, wherein:

(I) Q is a 1-position heteroatom and the 1-position heteroatom is nitrogen; (ii) G is C₁~ C₆Alkyl, C₁~ C₆Alkenyl, C_Five~ C₇No
Chloroalkyl, C₁~ C_FourC substituted with alkyl_Five~ C₇A cycloalkenyl of C_Two
~ C_FourC substituted with an alkenyl of_Five~ C₇Substituted with a cycloalkenyl or alkyl
Selected from Ar, Ar substituted with alkenyl, and Ar; (iii) Ar is phenyl, 1-naphthyl, 2-naphthyl, 2-furyl,
3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, and
4-pyridyl, piperazinyl, piperidinyl, monocyclic heterocycle, and bicyclic heterocycle
Wherein Ar is optionally hydrogen, halogen, hydroxyl, nitro
, Trifluoromethyl, trifluoromethoxy, C₁~ C₆Alkyl, C_Two~ C₆A
Lucenyl, C₁~ C_FourAlkoxy, benzyloxy, phenoxy, 1,2-methylene
Independently selected from the group consisting of dioxy, amino, carboxy, and phenyl
Substituted with one or more selected substituents; (iv) J is hydrogen, C₁~ C_TwoK, and benzyl;
Is C₁~ C_FourFrom the group consisting of alkyl, benzyl, and cyclohexylmethyl
Or J and K are linked together to form a 5-, 6-, 7-membered heterocyclic ring
May be formed, wherein the rings are optionally O, S, S (O) and S (O)_TwoGroup consisting of
(V) A is CH_Two, O, and NR₁From R, in which case R₁Is hydrogen and
C₁~ C_Four(Vi) B and D are each independently hydrogen, Ar, C₁~ C₆An alkyl,
C_Two~ C₆Alkenyl, C_Five~ C₇Substituted with cycloalkyl of₁~ C₆Al
Kill, C_Five~ C₇Substituted with cycloalkyl of_Two~ C₆Alkenyl, C_Five~ C₇ Substituted with cycloalkenyl of₁~ C₆Alkyl, C_Five~ C₇The cycloalket of
C substituted with nyl_Two~ C₆Alkenyl, C₁~ C₆Ar substituted with an alkyl
, C₁~ C₆Ar, C substituted with alkenyl of₁~ C₆A heteroalkyl, C_Two~
C₆A heteroalkenyl, C_Five~ C₇Substituted with cycloalkyl of₁~ C₆Of
Teloalkyl, C_Five~ C₇Substituted with cycloalkyl of_Two~ C₆Heteroarche
Nil, C_Five~ C₇Substituted with cycloalkenyl of the formula₁~ C₆A heteroalkyl, C _Five ~ C₇Substituted with cycloalkenyl of the formula_Two~ C₆A heteroalkenyl, C₁~ C₆ Ar, C substituted with a heteroalkyl_Two~ C₆Substituted with a heteroalkenyl of
Ar, and selected from the following formulas:

[0040]

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Wherein Z is selected from hydrogen, C ₁ -C ₆ alkyl, and C ₂ -C ₆ alkenyl, wherein T is Ar and hydrogen, hydroxyl, C ₁ -C ₄ alkoxy, And 5-, 6-, or 7-membered cycloalkyl substituted with at least one substituent selected from and oxo; at least one of B and D is not hydrogen; (vii) m Is an integer from 0 to 3; and (b) a pharmaceutically acceptable carrier.

G Part The G part is directly linked to the sulfonamide moiety as shown herein. Preferred G moieties are saturated or unsaturated phenyl, 4-methylphenyl, 2-thienyl, 2,4,6-triisopropylphenyl, 4-fluorophenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,5- Dimethoxyphenyl, 3,4
5-trimethoxyphenyl, methyl, 1-naphthyl, 8-quinolyl, 1- (5-
(N, N-dimethylamino) naphthyl, 4-methoxyphenyl, 4-iodophenyl, 2,4,6-trimethylphenyl, benzyl, 2-naphthyl, 4-nitrophenyl, 3-nitrophenyl, 4-chlorophenyl, and E -Styrenyl. The most preferred G moiety is 3,4,5-trimethoxyphenyl.

The J and K Portions The J and K portions may be independent of each other having the structure described above and, as described above, are joined together to form O, S, S (O), and S ( O) A 5-, 6-, or 7-membered heterocyclic ring optionally containing an additional heteroatom selected from ₂ may be formed. Preferred J and K are linked together to form O, S, S (O), and S (O) ₂
A 5-, 6-, or 7-membered heterocyclic ring optionally containing an additional heteroatom selected from: When J and K form a heterocyclic ring, the ring is preferably a 5- or 6-membered ring. When J and K form a heterocyclic ring, the ring is preferably
It 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, and NR ₁ , where R ₁ is hydrogen and C ₁ -C ₄
A is preferably selected from O and NR ₁ . Most preferred A is NR ₁ . R ₁ is most preferably hydrogen.

[0045]B and D side chains B and D are selected from various parts as described herein above
It is a side chain. Preferred B moieties are hydrogen, C₁~ C₆Alkyl, C₁~ C₆Alkenyl of 3-
(2-pyridyl) propyl, 3-phenylpropyl, 2-phenoxyphenyl,
3-phenoxyphenyl, phenyl, benzyl, 2- (3-pyridyl) ethyl,
E-3- [trans- (4-hydroxycyclohexyl)]-2-methyl-propyl
P-2-enyl, E-3- [trans- (4-hydroxycyclohexyl)]-2
-Methyl-es-2-enyl, 3- (3-pyridyl) propyl, 2-phenylethyl
Tyl, 2- (4-methoxyphenyl) ethyl, 3- (N-benzimidazolyl) p
Ropyl, 3- (4-methoxyphenyl) propyl, 3- [N- (7-azaindo
Ril) propyl, 3- (N-purinyl) propyl, 3- (3-pyridyl) -N-
Oxide, 3- (4-hydroxymethylphenyl) propyl, 3- (2-thienyl
Le) propyl, 3- (4-carboxyphenyl) propyl, 4-phenylbutyl
, 2-hydroxymethylphenyl, 2-allyloxyphenyl, 3- (3-hydrido
Loxymethylphenyl) propyl, 3- (3-carboxyphenyl) propyl,
3-hydroxymethylphenyl, 2-hydroxyphenyl, 3-pyridyl, 5-
Phenylpentyl, 4- (4-methoxyphenyl) butyl, 4-cyclohexyl
Butyl, 3-cyclohexylpropyl, 3-cyclopentylpropyl, 3-fe
Selected from nonoxybenzyl and 3- (3-indolyl) propyl. Preferred D moieties are nil, hydrogen, 3-phenylpropyl, 2-phenoxyf
Phenyl, 3- (3-indolyl) -propyl, 2-phenylethyl, 4-phenyl
Rubutyl, 3,5-bis (benzyloxy) phenyl, C₁~ C₆Alkyl, C ₁ ~ C₆Alkenyl, phenyl, and 3- (4-methoxyphenyl) propyl
Selected from

Integer m The integer m is 0 to 3, preferably 0 to 1. Preferred compounds useful for use in the method of the invention are shown below in the following table:

[0047]

[Table 1]

[0048]

[Table 2]

[0049]

[Table 3]

[0050]

[Table 4]

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

Resting Phase Assay : The resting phase assay is a test compound that converts mice in the resting phase of the hair growth cycle ("telogen") to the growing phase of the hair growth cycle ("anagen"). Measure your ability. Without intending to be limited by theory, the hair growth cycle has three basic phases: anagen, catagen, and telogen. In C3H mice (Harlan Sprague Dawley, Inc., Indianapolis, Ind., USA), it is believed that synchronizing hair growth has a long rest period from about 40 days to about 75 days. It is believed that after 75 days of age hair growth is no longer synchronized. When approximately 40-day-old mice with dark coat (brown or black) are used in hair growth experiments, melanin formation occurs along with the growth of hair (hair), thereby evaluating the topical application of a hair growth promoter. . The telogen conversion assay described below was used to screen compounds for hair growth by measuring melanogenesis. Three groups of 44-day-old C3H mice were utilized: a vehicle control group, a positive control group, and a test compound group, where the test compound group receives the compounds used in the method of the present invention. The duration of the assay is at least 19 days and the treatment is for 15 days (treatment date is Monday to Friday). The first day is the first day of treatment. Most tests end on day 19, but may be performed up to day 24 if melanogenesis is positive but slowly forms. A typical test plan is shown in Table 5 below:

[0053]

[Table 5]

^** Solvent is 60% ethanol, 20% propylene glycol, and 20% dimethyl isosorbide (commercially available from Sigma Chemical Company, St. Louis, Mo., USA).

The mice are treated locally from Monday to Friday on the lower back of the mouse (from the base of the tail to the lower ribs). Drain 400 μL into the back of each mouse using a pipette and tip. While moving the coat of the mouse, a 400 μL application is slowly applied to reach the skin.

As each treatment is applied to the mice, a 0 to 4 visual rating is given to the color of the skin at the application site of each animal. As the mouse transitions from telogen to anagen,
Its skin color becomes more bluish black. As shown in Table 6, the grades from 0 to 4 are:
Represents the following changes in skin from white to bluish black by visual observation.

[0057]

[Table 6]

Immunosuppressive Assay : The immunosuppressive assay herein predicts the immunosuppressive activity of the compounds used in the method of the present invention. Assay is performed as follows: adult male C3H mice 7-16 weeks old were euthanized (CO ₂ asphyxiation) to remove the spleen (live mice Indianapolis, Harlan Sprague Dawley, Inc. More commercially available). The spleens are immediately placed in chilled Hanks balanced salt solution (HBSS, commercially available from Gibco BRL, Gaithersburg, MD, USA). The spleen is then broken between frosted glass slides and filtered through a sterile sieve to remove tissue debris. To recover spleen cells, the resulting cell suspension is overlaid with an equal volume of Ficoll-Pac Plus (commercially available from Pharmacia Biotech, Piscataway, NJ) and approximately 40 × g at 20 ° C. at 400 × g. Centrifuge for minutes. Harvest splenocytes from the interface using a disposable pipette
Wash twice with BSS and centrifuge at 100 xg for 10 minutes at 20 ° C. 10%
Heat-inactivated fetal calf serum (Gibco BRL), penicillin (50 U / mL), streptomycin (100 μg / mL), L-glutamine (2 mM), 2-mercaptoethanol (10 ⁻⁵ M), and N-2-hydroxyethyl Piperazine-N'-
The splenocytes are resuspended in 5-10 mL of cell culture medium consisting of RPMI 1640 without Phenol Red (culture medium commercially available from Gibco BRL) containing 2-ethanesulfonic acid (HEPES) (10 mM). For example, cells are counted using trypan blue and the viability is confirmed. To the culture medium at 10 ⁶ cells / mL were resuspended splenocytes is pipetted into a 96 well round bottom plates at 10 ⁵ cells / well. Splenocytes are activated by adding 50 μL / well Concanavalin A (final concentration = 5 μg / mL) in the presence or absence of the test compound. Test compounds were made up in stock with methyl sulfoxide (DMSO), then diluted in medium and added at 50 μL / well to give a final DMSO concentration in the assay of 0.05%.
Less than. Incubate the plate at 37 ° C. with 5% CO ₂ for 48 hours. After 48 hours, 1 [mu] Ci / well of methyl - Cells were pulsed with ³ H- thymidine (England, commercially available from Amersham, Buckinghamshire), further incubated for 24 hours.

Twenty-four hours later, cells are harvested on GF / C filter plates (commercially available from Packard, Donners Grove, Illinois), solubilized in Microscinti 20 (Packard), top-count microplate scintillation and chemiluminescent plates. Count with a counter (Packard). Activity is measured as a ratio of control activity in the absence of test compound and plotted against test compound concentration. Fitting the data to the 4-parameter curve fitting (Sigma Plot) to calculate IC ₅₀ values. As used herein, using this method, (I of cyclosporin A
If the ratio of C ₅₀ / IC _{50 of} test compound) × 100 is less than or equal to 0.02, ie the non-immunosuppressive test compound is 2% of the immunosuppressive activity of cyclosporin A
Is considered non-immunosuppressive.

The viability of the cells was measured using MTT (3- [4,5-dimethyl-thiazoyl-2-yl] 2
, 5-diphenyl-tetrazolium bromide) dye assay. This is because the assay is serum free, phenol red free RPMI 1640.
The dye was solubilized in 100 μL / well of DMSO and background corrected at 650 nm with a SpectraMax Plus plate reader (Molecular Devices, Menlo Park, Calif.), Followed by O 2 at 540 nm.
Other than reading D, Nelson et al. (Nelson) published the Journal of Immunology,
150, No. 6, pages 2139-2147 (1993).

Preparation Methods The compounds used in the method of the present invention are prepared according to methods well known to those skilled in the art.
Starting materials used to prepare the compounds are known, are prepared by known methods, or are commercially available as starting materials. The skilled artisan in the field of organic chemistry recognizes that standard operations on organic compounds can be readily performed without further instructions. Examples of such operations are described in It is discussed in standard textbooks such as March by Higher Organic Chemistry (John Wiley & Sons, 1992). Skilled technicians will recognize that other functionality is covered or protected within the compound,
As the reaction yield increases and / or side reactions are avoided, one will readily recognize that a particular reaction is best performed. Skilled technicians often utilize protecting groups to achieve such increased yields or to avoid unwanted reactions. Such reactions are found in the literature and are within the skill of the artisan. Examples of such operations are described, for example, in T.W. It is found among the protecting groups in the organic synthesis of Greene (John Wiley & Sons, 1981).

The compounds of the present invention have one or more chiral centers. As a result, one of the optical isomers, including diastereomers and enantiomers, may be selectively prepared, for example, with a chiral starting material, catalyst or solvent, or may include diastereomers and enantiomers simultaneously (racemic Mixtures), both stereoisomers or both optical isomers may be prepared. Since the compounds of the present invention may exist as a racemic mixture, mixtures of diastereomers and optical isomers, including enantiomers, or stereoisomers, for example, are known in the art, such as using chiral salts or chiral chromatography. It may be separated by a method.

Further, one optical isomer, including diastereomers and enantiomers, or stereoisomers, may have desirable properties over others. Thus, when disclosing and claiming the invention, if a racemic mixture is disclosed, both optical isomers, including diastereomers and enantiomers, or stereoisomers substantially free of others, are similarly disclosed and claimed. It is clearly contemplated that The following is a more specific description of the methods for making the various compounds of the present invention, but is not limited to these examples. As used herein, the following abbreviations are used:

[0064]

[Table 7]

Embodiment 1

[0066]

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1a. (S) -3-Phenylbutyl pipecolate: In a 50 mL anhydrous benzene suspension of (S) -pipecolic acid tartrate (5.0 g, 17.9 mmol) was added 4-phenyl-1-butanol (13.8 g, 89.5 mmol) and p-toluenesulfonic acid monohydrate (3.8 g, 19.8 mmol) are added and the resulting mixture is heated to reflux overnight under a Dean-Stark trap. The resulting solution is concentrated and 1
Dissolve in 00 mL of 4: 1 ether: ethyl acetate and extract with 0.5 N HCl. Wash the acidic aqueous layer with 100 mL of 4: 1 ether: ethyl acetate and add 8 mL of 3
Basify by adding 0% NH ₄ OH and extract in ethyl acetate. Wash the combined organic extracts with brine, dry over MgSO ₄ and concentrate to give the free amine.

1b. (S)-3-phenylbutyl N-(4-methylsulfonyl) Pipekoreto: Amine 1a (30 mg, 0.12 mmol) in 0.5mL of dichloromethane was added _{i-Pr 2 EtN (22mL,} 0.13mmoL) and p- Toluenesulfonyl chloride (24 mg, 0.13 mmol) is added. The resulting mixture is stirred at room temperature for 1 hour. Concentrate the reaction mixture and chromatograph to obtain the desired sulfonamide.

Embodiment 2

[0070]

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2a. 4-phenyl-1-butyraldehyde: 4-phenyl-1-butanol (
3.2 mL, 20.8 mmol) of 20 mL of dichloromethane solution at 0 ° C. in powder 3A molecular sieve (3.2 g) followed by pyridinium chlorochromate (PCC) (5.
37 g, 24.9 mmol). The resulting suspension is stirred at 0 ° C. for 1 hour, during which time additional PCC (2.16 g, 10 mmol) is added. Warm the reaction mixture to room temperature. After stirring for 0.5 hour, the reaction mixture is diluted with ether and filtered through celite to give a crude product.

2b. 3-Phenyl-1-propylmagnesium bromide: A suspension of magnesium turnings (736 mg, 30.3 mmol) in THF (50 mL) at room temperature was added.
2-Dibromoethane (50 mL) is added, followed by dropwise addition of 1-bromo-3-phenylpropane (5.5 g, 25.1 mmol). After stirring at room temperature for 0.5 hours, the suspension is transferred by cannula to a storage container (100 mL) and subsequently used as a 0.5 M solution of the Grinul reagent in THF.

2C. 1,7-diphenyl-4-heptanol: A solution of 4-phenyl-1-butanal (700 mg, 4.7 mmol) in THF (5.0 mL) was added at 0 ° C. to 3-phenyl-0-propylmagnesium bromide (10 mL). , 5 mmol) and the resulting mixture is stirred at 0 ° C. for 0.5 h. The mixture is quenched by the dropwise addition of saturated NH ₄ Cl and diluted with ether. The phases were separated, the organic layer was washed with water and brine, dried over MgSO _4. Concentration gives the desired alcohol.

2d. (S) -BOC-Pipecolyl-1,7-diphenyl-4-heptanyl ester: In a 5 mL dichloromethane solution of (S) -BOC-L-pipecolic acid (164 mg, 0.72 mmol) was added alcohol 2c (174 mg) at room temperature. , 0.65
mmoL), EDAC (140 mg, 0.72 mmol) and catalytic amounts of N, N
-Add dimethylaminopyridine. The reaction mixture was stirred at room temperature for 0.5 hour,
It is then applied directly to a silica gel column. Elution gives the desired ester.

2e. (S) -1,7-diphenyl-4-heptanyl pipecolate: ester 2
c (47 mg, 0.10 mmol) in 1 mL dichloromethane solution at room temperature
Add FA (1 mL). After stirring at room temperature for 0.5 hours, the resulting solution is neutralized by dropwise addition of saturated K ₂ CO ₃ . The phases are separated, the organic phase is washed with water and
MgSO ₄ dried over to give the desired product were concentrated.

2f. (S) -1,7-diphenyl-4-heptanyl N- (4-methoxysulfonyl) pipecolate: To a solution of amine 2e (12.1 mg, 0.031 mmol) in dichloromethane (1 mL) was added i-Pr ₂ EtN (6 mL, 0.035 mmol),
And 4-methoxybenzenesulfonyl chloride (7.1 mg, 0.034 mmol). The resulting mixture is stirred at room temperature for 1 hour. Concentrate the reaction mixture and chromatograph to obtain the desired sulfonamide.

Embodiment 3

[0078]

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3a. (S)-(N-tert-butoxycarbonyl) -pipecolate 1,7-diphenyl-4-heptylamide: (S)-(N-tert-butoxycarbonyl)
-Dissolve pipecolic acid (4.0 g, 17.7 mmol) in 160 mL DMF. 1,7-Diphenyl-4-aminoheptane (4.30 g, 16.1 mmol) and N, N-diisopropylethylamine (4.16 g, 32.2 mmol) were added, followed by PyBOP (8.80 g, 16.9 mmol). Add. 18. at room temperature.
Stir the reaction for 5 h, then pour into ice cold 0.1 N HCl (600 mL) and extract with ethyl acetate (600 mL). Bring the organic layer to brine (100 mL)
, Saturated NaHCO ₃ solution (300 mL), and brine (2 × 200 mL). Dry the organic solution over MgSO ₄ , filter and concentrate under reduced pressure.
Purification by chromatography on silica gel gives the desired amide 3a.

3b. (S) -Pipecolic acid 1,7-diphenyl-4-heptylamide: Amide 3a (7.3 g, 15.3 mmol) is dissolved in 150 mL of anhydrous dichloromethane. Trifluoroacetic acid (120 mL) is added dropwise over 5 minutes. After 2 hours, cool the mixture in an ice water bath and add saturated K ₂ CO ₃ solution until the pH is about 8. Transfer the mixture to a separatory funnel containing dichloromethane (200 mL) and water (200 mL) and shake. Wash the organic layer with water (200 mL) before drying over MgSO ₄ . The mixture is filtered and concentrated under reduced pressure to give the desired amine 3b.

3C. (S) -N- (3 ', 4'-dimethoxyphenylsulfonyl) -pipecolic acid 1,7-diphenyl-4-heptylamide: amide 3b (4.4 g,
11.7 mmol) in anhydrous methylene chloride (100 mL). N, N-diisopropylethylamine (2.55 mL, 14.7 mmOL) was added and the solution was added to 5 mL.
Cool to ° C. 3 ′, 4′-Dimethoxyphenylsulfonyl chloride (3.47 g, 1
(4.7 mmol) at once. The reaction mixture is stirred at room temperature for 18 hours and concentrated to half volume. Pour the concentrate over ethyl acetate (300 mL) and add 0.1 M HCl (
100 mL), saturated sodium bicarbonate solution (100 mL), and brine (50 mL).
mL). Dry the organic solution over MgSO ₄ , filter and concentrate under reduced pressure. Purify the crude product by preparative chromatography on silica gel to obtain the desired sulfonamide 3c.

Embodiment 4

[0083]

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4a. (N-tert-butoxycarbonyl) -pyrrolidine-2 (S) -carboxylic acid 1,7-diphenyl-4-heptylamide: (N-tert-butoxycarbonyl) -pyrrolidine-2 (S) -carboxyl Add acid (3.8 g, 17.7 mmol) to 16
Dissolve in 0 mL DMF. 1,7-diphenyl-4-aminoheptane (4.3
0 g, 16.1 mmol) and N, N-diisopropylethylamine (4.16 g)
, 32.2 mmol) and PyBOP (9.20 g, 17.1 mmol).
Add. The reaction was stirred at room temperature for 20.5 hours, then ice cold 0.1 N H
Pour into Cl (600 mL) and extract with ethyl acetate (600 mL). The layers were separated and the organic layer was washed with brine (100 mL), saturated NaHCO ₃ solution (300 mL).
), And brine (2 × 200 mL). MgSO ₄
Dry over, filter and concentrate under reduced pressure. Purification on silica gel gives the desired amide 4a.

4b. The pyrrolidine-2 (S) -carboxylic acid 1,7-diphenyl-4-heptylamide: amide 4a (7.4 g, 16.5 mmol) is dissolved in 160 mL of anhydrous dichloromethane. Add trifluoroacetic acid (130 mL) dropwise over 5 minutes.
After 45 minutes, cool the mixture in an ice-water bath and add saturated K ₂ CO ₃ solution until the pH is about 8. Transfer the mixture to a separatory funnel containing dichloromethane (300 mL) and water (300 mL) and shake. Wash the organic layer with water (100 mL) before drying over MgSO ₄ . The mixture is filtered and concentrated under reduced pressure to give the desired amine 4b.

4C. N- (3 ', 4'-dimethoxyphenylsulfonyl) -pyrrolidine-2 (S
) -Carboxylic acid 1,7-diphenyl-4-heptylamide: amine 4b at room temperature
(4.38 g, 12.0 mmol) is dissolved in anhydrous dichloromethane (100 mL). N, N-diisopropylethylamine (2.6 g, 15 mmol) was added,
Cool the solution to 5 ° C. 3 ', 4'-Dimethoxyphenylsulfonyl chloride (3.5
g, 15 mmol) at once. At room temperature, the reaction mixture was stirred for 18 hours,
It is then concentrated to half. Pour the concentrate over ethyl acetate (300 mL) and add 0.1 M
(100 mL), saturated sodium bicarbonate solution (100 mL), and brine (50 mL). Dry the organic solution, filter and concentrate under reduced pressure. Purification of the crude product by preparative chromatography gives the desired sulfonamide 4c.

Embodiment 5

[0088]

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5a. Magnesium (40.2 g, 1.65 mol) and anhydrous ether (3.2 L)
Is mixed in the reaction vessel with stirring. 1-bromo-3-phenylpropane 1
. Add 6 L anhydrous ether solution to the addition funnel. The bromide solution is added dropwise to the reaction vessel with stirring over 1 hour. The mixture is stirred for 1-2 hours until the addition is complete. 4
-Anhydrous ether of phenylbutyronitrile (160 g, 1.1 mmol) (2.
4L) Put solution in addition funnel. Add the solution to the reaction vessel over 1 hour. When the addition is complete, warm the solution to reflux for 10 hours and stir for 6 hours at room temperature.

5b. 1,7-Diphenyl-4-aminoheptane: Dilute the reaction mixture of 5a with methanol (3.2 L) using an addition funnel. Sodium borohydride (83.4
g, 2.2 mol) at once. When the addition is complete, stir the reaction at room temperature for 6 hours. The reaction is stopped by slow addition of water (3.2 L) to the reaction mixture. Dilute the mixture with ether (3.2 L) and water (1.6 L). Separate the ether layer and extract the aqueous layer twice with ether (3.2 Lx2). The combined ether extracts are washed once with sodium chloride solution, dried, filtered and concentrated under reduced pressure to give the crude product. Dilute the product with ether (1.2 L) and add 1M
Acid (1.2 L) by slow addition. 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 5b is recovered by filtration.

Uses of the Compounds The methods of the present invention are practiced by administering a compound having the structure herein and a pharmaceutically acceptable carrier. The compounds of the present invention may be used in treating hair loss in mammals, including stopping and / or overturning hair loss, and in treating conditions such as promoting hair growth. Such conditions are manifested, for example, in hair loss, including male pattern baldness and female pattern baldness.

While some of the compounds may exhibit immunosuppressive activity, preferred compounds of the present invention are non-immunosuppressive as defined herein. Preferably, in the methods of the invention, the compounds of the invention are formulated into pharmaceutical compositions for use in treating or preventing a condition as described above. Remington's Pharmaceutical Sciences (Mack Publishing Company, Easton, PA)
(1990) using standard formulation techniques.

Compounds having a structure as described herein typically comprise from about 5 mg to about 30 mg.
00 mg, preferably about 5 mg to about 1000 mg, more preferably about 10 mg to
Approximately 100 mg administered daily for systemic administration. It is understood that such dosage ranges are for illustration purposes only and daily administration may be adjusted based on various factors. The specific dosage of the compound to be administered will depend on the duration of the treatment and whether the treatment is local or systemic, as well as on one another. The dosage and treatment regimen will also depend on the particular compound used, the indication of the treatment, the efficacy of the compound, the subject's personal characteristics (eg, the subject's weight, age, sex and medical condition), the treatment. It also depends on factors such as compliance with the regimen and the existence and side-effects of the treatment.

In accordance with the present invention, the subject compounds are co-administered with a pharmaceutically acceptable carrier ("carrier"). The term pharmaceutically acceptable carrier, as used herein, means one or more compatible solid or liquid filler diluents or encapsulating materials suitable for administration to mammals. . The term "compatible", as used herein, refers to a compound of the present invention such that the components of the composition do not interact in a manner that would substantially reduce the effectiveness of the composition under normal conditions of use. It means that the compounds of the invention can be further mixed with each other. The carrier must, of course, be sufficiently pure and sufficiently toxic to be suitable for administration to the animal being treated, preferably to a mammal. The carrier may be inert per se, or may have its own pharmaceutical advantages.

The compositions of the present invention may be in any of a variety of forms suitable for (for example) oral, rectal, topical, nasal, ocular or parenteral administration. Of these, topical or oral administration is particularly preferred. Various pharmaceutically acceptable carriers well known in the art may be used depending on the particular route of administration desired. These include solid or liquid fillers, diluents, hydrotropes, surfactants, and encapsulating materials. Any pharmacologically active substance that does not substantially interfere with the activity of the compound of the present invention may be included. The amount of carrier used in combination with the compound of the present invention is sufficient to provide a practical amount of the substance for administration per unit dose of compound. Techniques and compositions for making dosage forms useful in the methods of the present invention are described in the following references: "Modern Preparations", Chapters 9 and 10 (Banker & Road, Ed.
& Rhodes) (1979); Lieberman et al., "Pharmaceutical Forming: Tablets"(1981); and Ansel, "Introduction to Pharmaceutical Forming I," Second Edition (19).
76 years).

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; sodium carboxymethylcellulose; Cellulose and its derivatives such as ethylcellulose and methylcellulose; powdered tragacanth; malt; gelatin; talc; solid lubricating oils such as stearic acid and magnesium stearate; calcium sulphate; Vegetable oils such as cocoa oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers such as Tween; Wetting agents such as lium; coloring agents; flavoring agents; tablet formers, stabilizers; antioxidants; preservatives, preservatives; pyrogen-free water; isotonic saline; .

The choice of pharmaceutically acceptable carrier to be used in conjunction with the subject compounds will basically be determined by the purpose of the compound to be administered.

In particular, pharmaceutically acceptable carriers for systemic administration include sugar, starch, cellulose and derivatives thereof, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginates, phosphate buffers Liquids, emulsifiers, isotonic saline, and pyrogen-free water are included. Preferred carriers for parenteral administration include propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil. Preferably, the pharmaceutically acceptable carrier comprises at least about 90% of the total composition weight of the composition for parenteral administration.

Various oral dosage forms can be used, including solid forms such as tablets, capsules, granules and powders. Such oral dosage forms will generally contain a safe and effective amount of a compound of the present invention of at least about 5%, preferably about 25% to about 50%. Tablets contain suitable binders, lubricants, diluents, disintegrants, coloring agents, flavoring agents, rheological agents, and melting agents, tablet powders, enteric coatings, sugar coatings, film coats, or composites. It may be compressed. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, non-effervescent granules containing suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, melting agents, coloring and flavoring agents. Reconstituted solutions and / or suspensions and effervescent preparations reconstituted from effervescent granules are included.

Pharmaceutically acceptable carriers suitable for the preparation of unit dosage forms for oral administration are well-known to those of skill in the art. Tablets typically contain calcium carbonate, sodium carbonate, mannitol,
Inert diluents such as lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmellose; lubricants such as magnesium stearate, stearic acid and talc. Various conventional pharmaceutically compatible auxiliaries are included. Glidants such as silicon dioxide can be used to improve the flow properties of the powder mixture. Colorants such as FD & C dyes can be added for appearance. Sweetening agents and flavoring agents such as aspartame, saccharin, menthol, peppermint, and fruit flavors are useful adjuvants for chewable tablets. Capsules (including time release and sustained release dosage forms) typically contain one or more of the solid diluents disclosed above. The choice of carrier component depends on secondary considerations such as taste, price and storage stability, is not critical for the purposes of the present invention, and is readily made by those skilled in the art.

Compositions for oral administration also include liquid solutions, emulsions, suspensions, powders, granules, elixirs, tinctures, syrups and the like. Pharmaceutically acceptable carriers suitable for the preparation of such compositions are well-known to those skilled in the art. Typical components of carriers suitable for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. With respect to suspensions, typical suspensions include:
Methylcellulose, sodium carboxymethylcellulose, Avicel
) RC-591, tragacanth and sodium alginate; typical humectants include lecithin and polysorbic acid 80; typical preservatives include methyl paraben and sodium benzoate. Oral liquid compositions also include
One or more of the sweetening, flavoring and coloring agents disclosed above may be included.

The compositions may be prepared by conventional methods so that the compounds of the present invention are released in the gastrointestinal tract near the desired topical application or at various times to prolong the desired effect. , Typically a pH or time dependent coating. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethylcellulose, eudragit coating, wax and shellac. Not done.

Other compositions useful for achieving systemic administration of the compounds of the present invention include sublingual, buccal and nasal dosage forms. Such compositions typically include one or more soluble fillers such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethylcellulose and hydroxypropylmethylcellulose. . Glidants, lubricants, sweeteners, coloring agents, antioxidants and flavoring agents disclosed above may also be included. The compounds of the present invention may be administered topically. The carrier of the topical composition is preferably intended to allow the compound of the invention to penetrate the skin such that it reaches the periphery of the hair follicle. Topical compositions of the invention include, for example, solutions, creams, ointments, gels, lotions, shampoos, leave-on and rinse-off hair conditioners,
It can be in any form, including milk, cleansers, moisturizers, sprays, skin patches and the like.

[0104] Topical compositions containing the active ingredient are suitable for use in the art, for example, water, alcohol, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, and the like. May be mixed with various carrier materials known in the art.

Other substances suitable for use in topical carriers include, for example, emollients,
Solvents, wetting agents, thickeners and powders can be mentioned. Each example of such a type of substance, some of which can be used alone or as a mixture of one or more substances, is as follows: stearyl alcohol, Glyceryl monoricinoleate, glyceryl monostearate, propane-1,2-diol, butane-1,3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl Alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol,
Isocetyl alcohol, cetyl palmitate, dimethylpolysiloxane, di-n
-Butyl sebacate, isopropyl myristate, isopropyl palmitate,
Isopropyl stearate, 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 lactic acid, myristyl lactic acid,
Emollients such as decyl oleate and myristyl myristate; high pressure gases such as propane, butane, isobutane, dimethyl ether, carbon dioxide, and laughter; ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl Ether, diethylene glycol monobutyl ether,
Solvents such as diethylene glycol monoethyl ether, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran; glycerin, sorbitol,
Wetting agents such as sodium pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate and gelatin; and lime powder, talc, fuller's earth,
Kaolin, starch, rubber, colloidal silicon dioxide, sodium polyacrylate, tetraalkylammonium smectite, trialkylarylammonium smectite, chemically-modified magnesium silicate, organically-modified montmorillonite clay, hydroxyaluminate silicate, Powders such as fumed silica, carboxyvinyl polymer, sodium carboxymethylcellulose, and ethylene glycol monostearate.

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 various phospholipids, such as cholesterol, stearylamine or phosphatidylcholine. Preferred formulations for topical delivery of the compounds of this invention include those described in Dowton et al., "Encapsulated Cyclosporin A.
Of liposome composition on local delivery of liposomes: In using a hairless mouse
vitro test ", (STP Pharma Science), vol. 3, 404-4.
Page 07 (1993), Wallach and Philippo
t) "New Type of Lipid Membranes: Novassam (R)", Liposome Technology, Vol. 141, pages 141-156 (1993), and transferred to Wallac Micropack and emitted light on March 27, 1990. U.S. Pat. No. 4,911,928.

The compounds of the present invention may be administered by iontophoresis. See below.
www.unipr.it/arpa/dipfarm/erasmus/erasm14.html; Banga et al., Banga et al., "Hydrogel-Based Ion Therapy Delivery Device for Transdermal Delivery of Peptide / Protein Drugs," (Pharm. Res., No. 10). Volume (5) pages 697-702 (1993
Year)); L. Ferry, "A Theoretical Model of Iontophoresis Used in Transdermal Drug Delivery", Pharmaceutical Acta Helvetiae, Vol. 70, 279.
-287 (1995)); Gangarosa et al., "Latest Ion Osmosis Therapy for Local Drug Delivery," (Int. J. Pharm, 123, 159-1).
71 (1995)); Green et al., "Iontophoretic delivery of a series of tripeptides across the skin in vitro," (Pharma. Re.
s., Vol. 8, pp. 1121-1127 (1991)); Jadoul et al.
ul) "Fentanyl and TRH delivered by iontophoresis in the skin
Quantitative and localization ", (Int. J. Pham., Vol. 120, pp. 221-228 (19)
1995)); O'Brien et al., "The Latest Review of Antiviral Activity, Pharmacokinetic Properties and Therapeutic Effects", Drugs, 37, 233-309 (198).
Parry et al., "Bioavailability of Acyclovir in Human Skin," (J. Invest. Dermatl., 98 (6), 856-63 (1992)).
Santi) "Transport of drug container composition and salmon calcitonin in transdermal iontophoresis", (Pharm. Res., 14 (1), 63-66).
Santi et al., "Reverse-Phase Ion Osmosis Therapy-Parameters for Measuring Electroosmotic Flow: I. pH and Ionic Strength," (J. Control. Releases).
e, Vol. 38, pp. 159-165 (1996); Santi et al., Santi, "Reverse-phase iontophoresis-Parameters for measuring electroosmotic flow: II. Electrode chamber formulation", (J. Control. Release). 42, 29-36 (1996)
Rao, et al., Rao, "Reverse-phase iontophoresis: Monitoring noninvasive glucose in humans in vivo", (Pharm. Res., 12 (12), 18).
69-1873 (1995)); Thysman et al., "Delivery of human calcitonin in rats by iontophoresis", (J. Pharm. Pharmacol.
Vol. 46, pages 725-730 (1994)); Volpato et al.
"Ion-osmotic therapy enhances the transport of acyclovir through the skin of nude mice by reciprocity and electro-osmosis," (Pharm. Res., (12 (11), 162
3-1627 (1995)).

The compositions of the present invention may also optionally include an activity enhancer. The activity enhancer can be selected from a wide variety of molecules that can function in different ways to enhance the hair growth effect of the compounds of the present invention. Particular classes of activity enhancers include other hair growth stimulants and penetration enhancers.

Additional hair growth stimulating agents can be selected from a wide variety of molecules that can function in different ways to enhance the hair growth effect of the compounds of the present invention. Any such other hair growth stimulating agent, when present, is present in the compositions herein at from about 0.01% to about 15%, preferably from about 0.1% to about 10%, by weight of the composition. %, More preferably at a concentration in the range of about 0.5% to about 5%.

For example, such as Aminexil and US Pat. No. 3,382,247, US Pat. No. 5,756,092 (issued May 26, 1998), US Pat. No. 5,72
No. 2,990 (issued on June 30, 1998), US Pat. No. 5,760,043 (issued on June 2, 1998), and US Pat. No. 328,914 (issued on Jul. 1, 1994).
US Patent No. 5,466,694 (issued November 14, 1995)
No. 4,438,058, issued Aug. 1, 1995, and U.S. Pat.
No. 3,474 (issued Nov. 27, 1990), all of which are incorporated herein by reference. Dilators can be used as additional hair growth stimulating agents in the compositions herein.

One preferred class of additional hair growth stimulating agents for use herein is antiandrogens. Examples of suitable antiandrogens include 5-, such as finasteride
-Reductase inhibitors and U.S. Patent No. 5,516,779 (May 1, 1996
4th) (incorporated herein by reference) and Cancer r of Nane et al.
esearch 58, "In vitro and in vivo effects of novel inhibitors of C17,20-lyase and 5α-reductase and their possible role in the treatment of prostate cancer", as well as cyproterone acetate,
Azelaic acid and its derivatives and compounds as described in U.S. Pat. No. 5,480,913 (issued Jan. 2, 1996), flutamide, and U.S. Pat. No. 411,981 (1995, May
No. 5,565,467 (issued on October 15, 1996) and U.S. Pat. No. 4,910,226 (issued on March 20, 1990). It may include, but is not limited to.

Another suitable class of optional hair growth stimulants is 1) US Provisional Patent Application Ser. No. 60 / 122,925 (Fulm et al., Incorporated herein by reference).
er) cyclosporin and cyclosporin analogs, including those described in US Patent Application Serial No. 60 / 147,279 (filed March 5, 1999), and all of which are incorporated herein by reference. Degenhar et al.
dt), filed August 5, 1999); US Provisional Patent Application No. 60 / 147,313.
No. 60 (Dejanhard et al., Filed on Aug. 5, 1999); US Provisional Patent Application No. 60
U.S. Provisional Patent Application No. 60 / 147,278 (Dejanhard et al., Filed August 5, 1999); and U.S. Provisional Patent Application No. 60 / 147,278 (filed August 5, 1999). Patent Application No. 60 / 147,276 (Eick et al.
hoff), filed August 5, 1999), or immunosuppressive or non-immunosuppressive agents such as FK506 analogs.

Another suitable class of optional hair growth stimulants is selenium sulfide, ketoconazole, triclocarban, triclosan, zinc pyrithione, itraconazole, asianic acid, hinokitiol, mipirocin and EPO 0,680,745 (hereby incorporated by reference). And antimicrobial agents such as clinacincin hydrochloride, benzoyl peroxide, benzyl peroxide and minocycline.

[0114] Anti-inflammatory agents can also be incorporated into the compositions herein as optional hair growth stimulating agents. Examples of suitable anti-inflammatory agents include glucocorticoids such as hydrocortisone, mometasone furoate and prednisolone, or US Pat.
No. 092, cyclooxygenase or lipoxygenase inhibitors and benzydamine, salicylic acid, and EPA 0,770,399 (published May 2, 1997), WO 94/0, all incorporated herein by reference.
6434, WO 94/06434 (published March 31, 1994), and FR2
268,523 (published November 21, 1975) and may include non-steroidal anti-inflammatory agents comprising such compounds.

Another suitable class of optional hair growth stimulants are thyroid hormone and its derivatives and analogs thereof. Examples of thyroid hormones suitable for use herein may include triiodothyronine. Examples of thyroid hormone analogs that may be suitable for use herein include US Provisional Patent Application No. 60 / 136,9
No. 96 (filed on June 1, 1999 by Zhang et al.), U.S. Provisional Patent Application No. 60 / 137,024 (Chang et al., Filed on June 1, 1999), U.S. Provisional Patent Application No. 60/137. No. 137,022 (Chang et al., Filed on June 1, 1999); U.S. Provisional Patent Application No. 60 / 137,023 (Chang et al., Filed June 1, 1999)
U.S. Provisional Patent Application No. 60 / 137.052 (Youngquist et al.
st) filed on June 1, 1999), US Provisional Patent Application No. 60 / 137,063 (Youngquist et al., filed on June 1, 1999), and US Provisional Patent Application No. 6
No. 0 / 136,958 (Youngquist et al., Filed Jun. 1, 1999).

A prostaglandin agonist or antagonist can be used as an optional hair growth stimulant in the compositions herein. Examples of suitable prostaglandin agonists or antagonists include latanoprost and WO 98/33497 (Johnstone
stone), published on August 6, 1998), WO 95/11003 (Stjernschantz, published on April 27, 1995, Japanese Patent Publication No. 9-100091)
Ueno) and Japanese Patent Publication No. 8-134242 (Nakamura).

Another class of optional hair growth stimulating agents for use herein are retinoids. Suitable retinoids may include isotretinoin, acitretin and tazarotene. Another class of optional hair growth stimulating agents for use herein include, for example,
U.S. Patent Application Serial No. 09 / 353,408 "Method of Hair Growth Regulation" (Bradbury et al., Filed July 15, 1999) and U.S. Patent Application Serial No. 09 / 353,409. Compositions Containing Triterpenes For Hair Control "
(Bradbury et al., Filed July 15, 1999), each of which is incorporated by reference in its entirety, and is a triterpene such as those disclosed therein.

Another class of optional hair growth stimulating agents for use herein includes flavinoids, ascomycin derivatives and analogs, histamine antagonists such as diphenylhydramine hydrochloride, oleic acid and ursolic acid And other triterpenes such as US Pat. No. 5,529,769, JP10017431, WO 95/351.
03, U.S. Pat. No. 5,468,888, JP09067253, O92 /
No. 09262, JP62093215, U.S. Pat. No. 5,631,282, U.S. Pat. No. 5,679,705, JP08193094, EPO0,558,509 (Bonte et al., September 1993) (Released on March 8)
And saponins such as those described in WO 97/01346 (Bonte et al., Published Jan. 16, 1997), both of which are incorporated herein by reference, U.S. Pat. No. 5,015,470 (1991). U.S. Pat. No. 5,300,284 (issued on Apr. 5, 1994) and U.S. Pat. No. 5,185.
No. 3,325, issued Feb. 9, 1993, all of which are incorporated herein by reference in their entirety and which antagonize proteoglycanase or glycosaminoglycanase inhibitors, estrogen agonists. Analogs or inhibitors such as drugs, pseudotellins, cytokines and growth factor promoters, interleukin 1 inhibitors, interleukin 6 inhibitors, interleukin 10 promoters and tumor necrosis factor inhibitors, vitamin D analogs and parathyroid hormone antagonism Agents, vitamins such as vitamin B12 analogs and panthenol, interferon agonists and antagonists, hydroxy acids such as those described in US Pat. No. 5,550,158, benzophenones, and hydantoins such as phenytoin Anticonvulsants.

Other additional hair growth stimulating agents are, for example, JP 09-157,139 (Tsuji et al., Published June 17, 1997), EP 0277455 A1 (all incorporated herein by reference). Mirabeau, published August 10, 1988); WO 97/05878 (Cabo Soler et al., 199).
Published February 20, 1995; WO92 / 16186 (Bonte et al., Published March 13, 1992); JP62-93215 (Okazaki et al., April 2, 1987).
U.S. Pat. No. 4,987,150 (Kurono et al., Issued Jan. 22, 1991); JP2909081 (Ohba et al., Oct. 1, 1992)
5th); JP05-286-835 (Tanaka et al., Tanaka, November 1993)
Published February 2, FR 2,723,313 (Greff, published August 2, 1994), US Pat. No. 5,015,470 (Gibson, May 1991)
US Patent No. 5,559,092 (issued September 24, 1996)
U.S. Pat. No. 5,536,751 (issued on Jul. 16, 1996), U.S. Pat. No. 5,714,515 (issued on Feb. 3, 1998), EPA 0,319,991.
No. (published on June 14, 1989) EPA 0,319,991 (June 14, 1989), EPA 0,357,630 (published on October 6, 1988), EPA
No. 0,573,253 (released on December 8, 1993), JP61-260010
No. 5,772,990 (published Nov. 18, 1986).
U.S. Pat. No. 5,053,410 (Oct. 1, 1991)
And U.S. Pat. No. 4,761,401 (issued on Aug. 2, 1988).

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-hydroxypropa Noate, 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 di Pelargonate, 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, butyl myristate, dibutyl succinic acid, didecyl phthalic acid, decyl oleate, ethyl caproate, ethyl salicylate, isopropyl palmitate, ethyl laurate, 2-ethyl-hexylperargonate, isopropyl isostearate, butyl Laurate, benzyl benzoate, butyl benzoate, 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 oxide, sugar ester, tetrahydrofurfural alcohol, urea, diethyl-m -Toluamide, and 1-dodecylazacyloheptan-2-one.

Of course, in all of the foregoing, the compounds used in the methods of the present invention can be administered alone or as a mixture, and the compositions may further include suitable additional agents or enhancers.

[0122] The following examples of the composition administered is not intended to limit the invention, there is provided a guidance to the skilled technician to perform the method of the present invention. In each example, one or more "compounds" other than those mentioned may be replaced by one having a structure as described herein with similar results. Example A A composition is made for topical administration, which includes:

[0123]

[Table 8]

A male subject afflicted with androgenetic alopecia is treated by the methods of the present invention.
Specifically, the above composition is administered topically to the subject daily for 6 weeks.

Example B Compositions for topical administration are described in Dowton et al., "Effects of liposome composition on topical delivery of encapsulated cyclosporin A: I. In vitro study using hairless mouse skin. Novosam 1 for nonionic liposome formulations, using the compound of Example 2 in place of cyclosporin A, according to the method of (STP Pharma Sciences, Vol. 3, pp. 404-407). Created using A male subject suffering from androgenetic alopecia is treated daily with the above composition. Specifically, the above composition is administered topically to the subject for 6 weeks.

Example C A shampoo containing the following is prepared:

[0127]

[Table 9]

A male subject suffering from androgenetic alopecia is treated by the methods of the present invention.
Specifically, the shampoo described above is used by the subject daily for 12 weeks.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 17/14 A61P 17/14 4H039 // A61K 31/445 A61K 31/445 C07B 61/00 300 300 C07B 61 / 00 300 C07D 207/16 C07D 207/16 211/60 211/60 401/12 401/12 409/12 409/12 (71) Applicant ONE PROCTER & GANBLE PLAZA, CINCINNATI, OHIO, UNITED STATES OF AMERICA (72 Inventor Fulmer, Andrew Wayne West, Ohio, United States, Wester, Wilderness, Trail 6452 (72) Inventor McIver, John McMillan, Cincinnati, Ohio, Ohio, USA Dian, Springs, Drive 9999 (72) Inventor Degenhart, Charles Raymond Cincinnati, Ohio, USA, Wellingwood, Court 10555 (72) Inventor Aikov, David Joseph Kentucky, United States, Edgwood, Garden, Way 505F Terms (Reference) 4C054 AA02 BB01 CC08 DD33 DD38 EE01 FF01 4C063 AA01 BB08 CC14 CC92 DD10 EE01 4C069 AA23 BC18 4C083 AB332 AC072 AC102 AC122 AC172 AC352 AC392 AC562 AC642 AC712 AC782 AC851 AC852 A092ABC12ABC12ABC12A GA04 GA07 MA01 MA04 MA52 MA70 ZA92 4H039 CA66 CL25

Claims (8)

[Claims] Claims: 1. Treating hair loss comprising administering a composition comprising the following components:
(A) a compound having the following structure: And pharmaceutically acceptable salts, hydrates, and biohydrolyzable amides,
And imide, wherein: (i) Q is a heteroatom at position 1 and the heteroatom at position 1 is nitrogen; (ii) G is C₁~ C₆Alkyl, C₁~ C₆Alkenyl, C_Five~ C₇No
Chloroalkyl, C₁~ C_FourSubstituted with an alkyl of_Five~ C₇Of cycloalkenyl,
C_Two~ C_FourSubstituted with alkenyl of_Five~ C₇With cycloalkenyl, alkyl
Selected from the group consisting of substituted Ar, alkenyl substituted Ar, and Ar
(Iii) Ar is phenyl, 1-naphthyl, 2-naphthyl, 2-furyl,
3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, and
4-pyridyl, piperazinyl, piperidinyl, monocyclic heterocyclic compound, and bicyclic
Selected from heterocyclic compounds, where Ar is optionally hydrogen, halogen, hydroxy.
Sil, nitro, trifluoromethyl, trifluoromethoxy, C₁~ C₆Alkyl
, C_Two~ C₆Alkenyl, C₁~ C_FourAlkoxy, benzyloxy, phenoxy, 1,
From the group consisting of 2-methylenedioxy, amino, carboxy, and phenyl
Each substituted with one or more independently selected substituents; (iv) J is hydrogen, C₁~ C_TwoSelected from the group consisting of alkyl and benzyl
Selected; K is C₁~ C_FourFrom alkyl, benzyl, and cyclohexylmethyl
Or J and K are linked together to form a 5-, 6-, 7-membered ring
Heterocyclic rings may be formed, which are optionally O, S, S (O) and S (O)_TwoOr
(V) A is CH_Two, O and NR₁Selected from the group consisting of₁Is
, Hydrogen and C₁~ C_Four(Vi) B and D are each independently hydrogen, Ar, C₁~ C₆An alkyl,
C_Two~ C₆Alkenyl, C_Five~ C₇Substituted with cycloalkyl of₁~ C₆Al
Kill, C_Five~ C₇Substituted with cycloalkyl of_Two~ C₆Alkenyl, C_Five~ C₇ Substituted with cycloalkenyl of the formula₁~ C₆Alkyl, C_Five~ C₇The cycloalket of
C substituted with nyl_Two~ C₆Alkenyl, C₁~ C₆Ar substituted with an alkyl
, C₁~ C₆Ar, C substituted with alkenyl of₁~ C₆A heteroalkyl, C_Two~
C₆A heteroalkenyl, C_Five~ C₇Substituted with cycloalkyl of₁~ C₆Of
Teloalkyl, C_Five~ C₇Substituted with cycloalkyl of_Two~ C₆Heteroarche
Nil, C_Five~ C₇Substituted with cycloalkenyl of the formula₁~ C₆A heteroalkyl, C _Five ~ C₇Substituted with cycloalkenyl of the formula_Two~ C₆A heteroalkenyl, C₁~ C₆ Ar, C substituted with a heteroalkyl_Two~ C₆Substituted with a heteroalkenyl of
And Ar is selected from the group consisting of: Wherein Z is hydrogen, C₁~ C₆Alkyl and C_Two~ C₆Consisting of alkenyl
Selected from the group where T is Ar and hydrogen, hydroxyl, C₁~ C_FourThe alkoxy of
And at least one substituent selected from the group consisting of oxo
B, 6-, or 7-membered cycloalkyl;
And (v) m is an integer from 0 to 3; and (b) a pharmaceutically acceptable carrier. 2. The method according to claim 1, wherein J and K are linked together to form a 5-, 6- or 7-membered ring. 3. The method according to claim 1, wherein J and K are combined with each other to form a 5-membered ring. 4. The method according to claim 1, wherein J and K are combined with each other to form a 6-membered ring. 5. The method according to claim 1, wherein A is —O—. 6. The method according to claim 1, wherein A is —NH—. 7. The method according to claim 1, wherein the administration is topical. 8. The method according to any one of claims 1 to 6, wherein the administration is oral.