JP2003500431A - How to treat hair loss - Google Patents

Abstract

  (57) [Summary] The present invention relates to a method for treating hair loss in a mammal, including stopping and / or reversing hair loss and promoting hair growth. The method includes administering a cardiac inactive compound having a structure described herein and a pharmaceutically acceptable carrier.

Description

Detailed Description of the Invention

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

[0002] Loss BACKGROUND hair invention is a common problem, for example, whether caused by natural processes or is often chemically by the use of certain therapeutic drugs designed to alleviate conditions such as cancer, Be encouraged by. Often such hair loss is accompanied by a lack of hair regrowth, which leads to partial or complete alopecia.

As is well known in the art, hair growth occurs by a cycle of activity that includes alternating periods of growth and rest. This cycle is often
And three major stages known as telogen. Growth is the growth phase of the cycle and can be characterized by the entry of hair follicles deep into the dermis, with rapid proliferation of cells that are undergoing differentiation to form hair. The next phase is the interphase, which is a transitional phase characterized by arrest of cell division, during which the hair follicles regress through the dermis and hair growth ends. The next phase, telogen, is often characterized as telogen, during which regressed hair follicles develop embryos (ge) with densely packed dermal papilla cells.
rm) is included. During the telogen, the onset of a new growth phase is the rapid proliferation of cells in the embryo,
It is caused by swelling of the dermal papilla and elaboration of basement membrane components. Where the hair has finished growing, the majority of hair follicles are at rest and anagen is not involved, thus causing the onset of complete or partial alopecia.

Many attempts have been made in the literature to cause hair regrowth, for example by promoting or prolonging the anagen. Currently for the treatment of male pattern baldness 2
Two drugs have been approved by the US Food and Drug Administration, which is topical minoxidil (sold as Rogaine® by Pharmacia & Upjohn)
, And finasteride for oral use (sold as Propecia® by Merck & Co., Inc.). However, the search for effective hair growth inducers is ongoing for several reasons, including safety concerns and / or lack of efficacy.

Interestingly, the thyroid hormone known as thyroxine (“T4”)
It is well known to be converted to thyronine ("T3") in human skin by the selenium-containing protein deiodinase I. Depletion of selenium causes a decrease in T3 levels due to a decrease in deiodinase I activity. This decrease in T3 level
Strongly associated with hair loss. Consistent with this observation, hair growth is a reported side effect of T4 administration. For example, Berman , "Peripheral Effects of L-Thyro
xine on Hair Growth and Coloration in Cattle ", Journal of Endocrinology,
Vol. 20, pp. 282-292 (1960); and Gunaratnam , "The Effects of Thyroxine.
on Hair Growth in the Dog ", J. Small Anim. Pract., Vol. 27, pp. 17-29
(1986). Moreover, T3 and T4 have been the subject of several patent publications relating to the treatment of hair loss. For example, 1970 January Fischer et al of the public to 8 days DE 1,617,477; GB of published October 24, 1984 the Mortim er 2,138,286;. And Life Medical Sciences, transfer pre-1996 Inc. 8 See Lindenbaum , WO 96/25943, published 29th March.

Unfortunately, however, the administration of T3 and / or T4 to treat hair loss is not feasible. These thyroid hormones are also known to induce significant cardiotoxicity. For example , 19 transferred to Syntex
Walker et al. , US Pat . No. 5,284,971, issued Feb. 8, 1994, and Smit.
See Emmett et al. , US Pat . No. 5,061,798, issued Oct. 29, 1991, assigned to h Kline & French Laboratories. However, surprisingly, the inventors have discovered compounds that promote hair growth without inducing cardiotoxicity. Consistent with this finding, but not limited by theory,
The inventors have surprisingly found that compounds useful in the present invention interact strongly with the hair-selective thyroid hormone receptor, but less strongly with the cardiac-selective hormone receptor, or at all. I found that it did not work. These unique properties are of course not shared with T3 and / or T4. Therefore,
The compounds described herein for use in the methods and compositions are useful for the treatment of hair loss, including arresting and / or reversing hair loss and promoting hair growth. Don't strain the heart (cardiac-sparing
) Compound.

SUMMARY OF THE INVENTION The present invention involves stopping and / or reversing hair loss and promoting hair growth and is particularly useful for treating hair loss in mammals. To a method for treating hair loss comprising administering a compound found by et al. The compound utilized in this method has the structure:

[0008]

[Chemical 6]

[Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₁₈ , R ₁₉ , and X are defined herein. ] And its pharmaceutically acceptable salts, hydrates and biohydrolyzable
lyzable) amides, esters, and imides.

[0010] DETAILED DESCRIPTION OF THE INVENTION The invention comprises to promote stopping hair loss and / or reverse the causes and growth of hair, particularly useful is the compounds and compositions for treating hair loss in a mammal How to use things.

In addition to discovering that the compounds are useful for treating hair loss, the inventors have also surprisingly found that the preferred compounds do not stress the heart. . Preferred compounds useful in the methods of the invention are therefore those that do not stress the heart, as defined herein below.

Publications and patents are referenced throughout this disclosure. All documents cited herein are incorporated herein by reference. All percentages, ratios, and ratios used herein are by weight unless otherwise noted.

In the description of the invention various embodiments and / or individual features are disclosed. All combinations of such embodiments and features can result in preferred practice of the invention, as will be apparent to those of ordinary skill in the art.

As used herein, when any variable, moiety, group, or the like, occurs more than once in any variable or structure, its definition at each occurrence is Is independent of its definition in all occurrences of.

Definitions and Uses of Terms The following is a list of definitions of terms used in this specification. As used herein, "alkanoyl" is an alkyl substituted with oxo (C = O).

“Alkoxy”, as used herein, is an oxygen radical having an alkyl, alkenyl, or alkynyl, preferably alkyl or alkenyl, most preferably an alkyl substituent. Examples of alkoxy radicals include -O-alkyl and -O-alkenyl. Alkoxy radicals may be substituted or unsubstituted.

As used herein, “alkyl” is 1 to about 15 carbon atoms; preferably 1 to about 10 carbon atoms; more preferably 1 to about 6 carbon atoms; most preferably 1 To unsubstituted or substituted saturated hydrocarbon chain radicals having about 4 carbon atoms. Preferred alkyls include, for example, methyl, ethyl, propyl, isopropyl, and butyl.

“Aryl” as used herein is an aromatic ring radical that is carbocyclic or heterocyclic. Preferred aryl groups include, for example, phenyl, benzyl, tolyl, xylyl, cumenyl, naphthyl, biphenyl, thienyl, furyl,
Pyrrolyl, pyridinyl, pyrazinyl, thiazolyl, pyrimidinyl, quinolinyl,
Triazolyl, tetrazolyl, benzothiazolyl, benzofuryl, indolyl,
Examples include indenyl, azulenyl, fluorenyl, anthracenyl, oxazolyl, isoxazolyl, isotriazolyl, imidazolyl, pyraxolyl, oxadiazolyl, indolizinyl, indolyl, isoindolyl, purinyl, quinolidinyl, quinolinyl, isoquinolinyl, cinnolinyl, and the like. The aryl may be substituted or unsubstituted.

“Arylalkyl” as used herein is an alkyl radical substituted with an aryl group or an aryl radical substituted with an alkyl group. Preferred arylalkyl groups include benzyl, phenylethyl, and phenylpropyl. The arylalkyl may be substituted or unsubstituted.

As used herein, “biohydrolyzable amides” refers to a compound that does not interfere with the activity of the compound or that is readily converted in vivo by a mammalian patient to give the active compound. The amides of the compounds used in the invention.

As used herein, a “biohydrolyzable ester” refers to a compound that does not interfere with the activity of the compound or is readily converted in vivo by a mammalian patient to give the active compound. The esters of the compounds used in the invention.

“Biohydrolyzable imides” as used herein refers to those compounds that do not interfere with the activity of the compound or are readily transformed in vivo by a mammalian patient to give the active compound. The imides of the compound used in the invention.

“Cycloalkyl” as used herein is a saturated carbocycle or heterocycle radical. Preferred cycloalkyl groups include, for example, cyclobutyl, cyclopentyl, and cyclohexyl. The cycloalkyl may be substituted or unsubstituted.

As used herein, preferred “halogen” (or “halo” or the like) is bromine, chlorine, iodine, and fluorine, more preferably bromine,
Chlorine and iodine, even more preferably bromine and chlorine, most preferably chlorine.

As used herein, "pharmaceutically acceptable" means suitable for use in humans or other mammals. As used herein, "compound (or composition or the like)
"Safe and effective amount of" means an amount effective to exhibit bioactivity, preferably where bioactivity is at the site of activity of a mammalian patient when used in the method of the invention. Stopping and / or reversing hair loss and promoting hair growth, without excessive adverse side effects (eg, toxicity, irritation, or allergic reaction) and corresponding to a reasonable benefit / risk ratio Is.

As used herein, a “salt” is a cationic salt formed at any acidic (eg, carboxyl) group or an anion formed at any basic (eg, amino) group. It is a natural salt. 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 halides (eg chloride salts). Such acceptable salts must be suitable for use in mammals when administered.

Method of the Invention The invention has the structure:

[0028]

[Chemical 7]

[0029]   [Wherein (a) X is oxygen, sulfur, and CH₂Selected from;   (B) R₁And R₂Are each independently hydrogen, halogen, hydroxy, trifru
Oromethyl, C₁~ C₆Alkyl, C₁~ C₆Alkenyl and C₁~ C_FourAlkoxy
Selected from;   (C) R₃Is selected from hydrogen, alkyl, aryl, and arylalkyl
L;   (D) R_FourIs hydrogen, halogen, C₁~ C_FourAlkyl, C₁~ C_FourAlkenyl, hi
Droxy and C₁~ C_FourSelected from the group consisting of alkoxy;   (E) R_FiveIs hydrogen, halogen, hydroxy, alkyl, C₁~ C_FourAlkenyl
, C₁~ C_FourFrom alkoxy, cycloalkyl, aryl, and arylalkyl
Selected;   (F) R₆Is alkyl, aryl, -CH₂CH (NH₂) CO₂H, -CH₂
CH (OH) CO₂H, -CH₂CR₇R₈NR₉R_Ten, -YC (O) R₁₁,-(C
H₂)_n-OH, -CH₂C (R₁₂) (NH₂) CO₂R₁₃, -CH₂CH (COOH
) (NH) C (O) (CH₂)_mC (O) NH (CH₂)_nR₂₀, And -CH₂CR_{1 2} R₁₂C (O) OR₁₃Selected from;   (G) R₇Is hydrogen and C₁~ C_FourSelected from alkyl;   (H) R₈Is hydrogen and -C (O) R₁₁Selected from;   (I) R₉And R_TenAre each independently hydrogen, C₁~ C_FourAlkyl and C₁~ C _Four Selected from alkanoyl;   (J) Y is a bond and C₁~ C_FourSelected from alkyl;   (K) R₁₁Is hydroxy, C₁~ C_FourAlkoxy, -NR₁₄R₁₅, C₁~ C_FourA
Rukiru, C₁~ C_FourAlkenyl and C₁~ C_FourSelected from alkynyl;   (L) R₁₂Is C₁~ C₆Alkyl;   (M) R₁₃Is C₁~ C₆Alkyl, cycloalkyl, and arylalkyl
Selected from;   (N) R₁₄Is hydrogen and C₁~ C_FourSelected from alkyl;   (O) R₁₅Is hydrogen, C₁~ C_FourAlkyl and C₁~ C_FourChoose from alkanoyl
Done;   (P) R₁₈And R₁₉Are each independently hydrogen, C₁~ C₆Alkyl, C₁~ C₆A
Selected from lukenyl, hydroxy, and halogen;   (Q) m is an integer of 2 to 4;   (R) n is an integer from 1 to 4;   (S) R₂₀Is an unsaturated, non-saturated compound containing 1-2 nitrogen atoms as the only heteroatoms.
It is a substituted 5- or 6-membered monocyclic heterocycle. ] And compounds having pharmaceutically acceptable salts, hydrates, and biohydrolysis
Comprising administering a composition comprising possible amides, esters and imides
, To a method of treating hair loss.

The X moiety X is selected from oxygen (—O—), sulfur (—S—), and —CH ₂ —. Preferably X is oxygen and -CH ₂ - is selected from. Most preferably X is oxygen.

The R ₁ and R ₂ moieties R ₁ and R ₂ are each independently hydrogen, halogen, hydroxy, trifluoromethyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, and C ₁ -C. Selected from ₄ alkoxy. Preferably, R ₁ and R ₂ are each independently selected from hydrogen, halogen, trifluoromethyl, and C ₁ -C ₆ alkyl. More preferably, R ₁ and R ₂ are each independently selected from halogen, trifluoromethyl, and C ₁ -C ₆ alkyl. Most preferably, R ₁ and R ₂ are each independently selected from halogen and C ₁ -C ₆ alkyl. Preferred halogens are chlorine and iodine.

The R ₃ moiety R ₃ is selected from hydrogen, alkyl, aryl, and arylalkyl.
Preferably R ₃ is selected from hydrogen, alkyl and arylalkyl.
Preferred alkyls for R ₃ are methyl and ethyl. A preferred arylalkyl for R ₃ is benzyl.

The R ₄ moiety R ₄ is selected from the group consisting of hydrogen, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkenyl, hydroxy, and C ₁ -C ₄ alkoxy. Preferably R ₄ is
It is selected from hydrogen and halogen (most preferably iodine). Most preferably,
R ₄ is hydrogen.

[0034]   R ₅ part R_FiveIs hydrogen, halogen, hydroxy, alkyl, C₁~ C_FourAlkenyl, C₁~ C _Four Selected from alkoxy, cycloalkyl, aryl, and arylalkyl
It Preferably R_FiveIs hydrogen, halogen (especially iodine), alkyl, cycloal
Selected from alkyl, aryl, and arylalkyl. More preferably, R _Five Is from hydrogen, alkyl, cycloalkyl, aryl, and arylalkyl
To be selected. Even more preferably, R_FiveIs alkyl, cycloalkyl, ari
And arylalkyl. Most preferably R_FiveIs Archi
Selected from aryl and arylalkyl (the preferred arylalkyl is benzyl).
Is selected.

[0035]   R ₁₈ and ₁₉ parts   R₁₈And R₁₉Are each independently hydrogen, C₁~ C₆Alkyl, C₁~ C₆Archeni
Selected from ru, hydroxy, and halogen. Preferably R₁₈And R₁₉Is
Each independently hydrogen and C₁~ C₆Selected from alkyl. Most preferably R ₁₈ And R₁₉Are each hydrogen.

R ₆ moiety R ₆ is alkyl, aryl, —CH ₂ CH (NH ₂ ) CO ₂ H, —CH ₂ CH (
_{OH) CO 2 H, -CH 2} CR 7 R 8 NR 9 R 10, -YC (O) R 11, - (CH 2) n
_{-OH, -CH 2 C (R 12} ) (NH 2) CO 2 R 13, -CH 2 CH (COOH) (N
H) C (O) (CH 2) m C (O) NH (CH 2) n R 20, and -CH ₂ CR ₁₂ R ₁₂
It is selected from C (O) OR ₁₃ . Preferably, R _{6 is, -CH 2 CH (NH 2)} C
_{O 2 H, -CH 2 CH (} OH) CO 2 H, -CH 2 CR 7 R 8 NR 9 R 10, -YC (O
_{) R 11, -CH 2 C (} R 12) (NH 2) CO 2 R 13, -CH 2 CH (COOH) (N
H) C (O) (CH 2) m C (O) NH (CH 2) n R 20, and -CH ₂ CR ₁₂ R ₁₂
It is selected from C (O) OR ₁₃ R.

R ₇ is a substituent on —CH ₂ CR ₇ R ₈ NR ₉ R ₁₀ . R ₇ is hydrogen and C ₁ to
It is selected from C ₄ alkyl. R ₈ is a substituent on the _{-CH 2 CR 7 R 8 NR 9} R 10. R ₈ is hydrogen and -C (
O) selected from R ₁₁ .

R ₉ and R ₁₀ are substituents on —CH ₂ CR ₇ R ₈ NR ₉ R ₁₀ and CH ₂ CR ₇ R ₈ NR ₉ R ₁₀ . R ₉ and R ₁₀ are each independently selected from hydrogen, C ₁ -C ₄ alkyl, and C ₁ -C ₄ alkanoyl (oxo-substituted alkyl). Preferably R ₉ and R ₁₀ are each independently selected from hydrogen and C ₁ -C ₄ alkyl.

Y is a substituent on —YC (O) R ₁₁ . Y is selected from a bond and C ₁ -C ₄ alkyl. When Y is a bond, C (O) R ₁₁ of -YC (O) R ₁₁ is directly covalently bonded to each phenyl ring of the compound via a single bond.

R ₁₁ is selected from hydroxy, C ₁ -C ₄ alkoxy, —NR ₁₄ R ₁₅ , C ₁ -C ₄ alkyl, C ₁ -C ₄ alkenyl, and C ₁ -C ₄ alkynyl. Preferably,
R ₁₁ is hydroxy, C ₁ -C ₄ alkoxy, and -NR ₁₄ R _15.
Most preferably R ₁₁ is selected from hydroxy and C ₁ -C ₄ alkoxy.

R ₁₂ is —CH ₂ C (R ₁₂ ) (NH ₂ ) CO ₂ R ₁₃ and —CH ₂ CR ₁₂ R ₁₂ C (O
) A substituent on OR ₁₃ . R ₁₂ is a C ₁ -C ₆ alkyl. R _{13 is, -CH 2 CR 12 R 12 C} (O) OR 13 and _{-CH 2 C (R 12) (} NH 2)
It is a substituent on CO ₂ R ₁₃ . R ₁₃ is selected from C ₁ -C ₆ alkyl, cycloalkyl, and arylalkyl. Preferably R ₁₃ is C ₁ -C ₆ alkyl.

R ₁₄ and R ₁₅ are each (optionally) substituents on R ₁₁ . R ₁₄ is selected from hydrogen and C ₁ -C ₄ alkyl, preferably methyl or ethyl. R ₁₅ is selected from hydrogen, C ₁ -C ₄ alkyl, and C ₁ -C ₄ alkanoyl (oxo (C═O) substituted alkyl). Preferably R ₁₅ is selected from hydrogen and C ₁ -C ₄ alkyl.

The integers m and n are —CH ₂ CH (COOH) (NH) C (O) (CH ₂ ) _m C (
O) NH (CH ₂ ) _n R ₂₀ . The integer m is 2-4, preferably 2.
The integer n is 1 to 4, preferably 1. R ₂₀ is also --CH ₂ CH (COOH)
(NH) is of _{C (O) (CH 2)} m C (O) NH (CH 2) n R 20. R ₂₀ is an unsaturated, unsubstituted 5- or 6-membered monocyclic heterocycle containing 1-2, preferably 1 nitrogen atom as the only heteroatom. Non-limiting examples of preferred heterocycles are:
Pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl, more preferably imidazolyl, most preferably 5-imidazolyl.

Preferred compounds useful in the methods of the invention are described by Yokoyama et al. , "Synthesi
s and Structure-Activity Relationships of Oxamic Acid and Acetic Acid
Derivatives Related to L-Thyronine ", Journal of Medicinal Chemistry, Vol
. 38, pp. 695-707 (1995). Such compounds are further described in Table 1 below.

[0045]

[Table 1]

Other preferred compounds useful in the methods of the invention are those assigned to Karo Bio
It is described in WO 99/00353 of Li et al. , Published Jan. 7, 999.
Particularly preferred of these compounds have the structure:

[0047]

[Chemical 8]

Wherein R ₅ is selected from C ₁ -C ₆ alkyl and C ₃ -C ₇ cycloalkyl; R ₁ and R ₂ are each independently hydrogen, halogen, and C ₁ -C ₆ alkyl, wherein at least one of R ₁ and R ₂ is not hydrogen; R ₁₁ is selected from the group consisting of hydroxy and C ₁ -C ₄ alkoxy. ]. Preferred compounds of this structure are submitted in Table 2 below.

[0049]

[Table 2]

Other preferred compounds for use in the method of the present invention are described in WO 97/46228 of Kun et al. , Published Dec. 11, 1997, assigned to Octamer, Inc. Of these, particularly preferred are the structures:

[0051]

[Chemical 9]

Wherein R ₃ is selected from methyl and ethyl; R ₄ is selected from hydrogen and iodine; R ₅ is selected from hydrogen, iodine and alkyl; R ₁₈ and R ₁₉ are Each independently selected from hydrogen and C ₁ -C ₆ alkyl; X is oxygen, sulfur,
And CH ₂ ; R ₁ and R ₂ are each independently selected from hydrogen, halogen, and C ₁ -C ₄ alkyl. ].

Other preferred compounds useful in the methods of the invention are those described in Kun et al. , WO 99/20263, published Apr. 29, 1999, assigned to Octamer, Inc.

Other preferred compounds useful in the methods of the invention are Ciba Corning Diagnosti
It is described in Feinberg et al. , U.S. Pat . No. 4,711,855 issued Dec. 8, 1987, assigned to cs Corp. Particularly preferred of these compounds have the structure:

[0055]

[Chemical 10]

[Wherein m is an integer of 2 to 4; n is an integer of 1 to 4; R ₂₀ is an unsaturated and unsubstituted group containing 1 to 2 nitrogen atoms as the only heteroatoms. Is a 5- or 6-membered monocyclic heterocycle. ]. Examples of such heterocycles include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl, more preferably imidazolyl, most preferably 5-imidazolyl.

Other preferred compounds useful in the method of the invention are Wechter et al. , US Pat . No. 3,449,419 issued June 10, 1969, assigned to The Upjohn Co.
It is explained in the issue. Particularly preferred of these compounds have the structure:

[0058]

[Chemical 11]

[0059]   [In the formula, R₃Is hydrogen and C₁~ C_FourSelected from alkyl; R_FourIs hydrogen and yo
Selected from silicon; R_FiveIs hydrogen, iodine, and C₁~ C_FourSelected from alkyl
; R₁₈And R₁₉Are each independently hydrogen and C₁~ C_FourSelected from alkyl; R ₁ And R₂Are each independently halogen; Y is a bond and C₁~ C₃Alkyl?
Selected from; R₁₁Is -NR₁₄R₁₅And R₁₄And R₁₅Are each independently hydrogen
And C₁~ C_FourSelected from alkyl. ] Have.

Other preferred compounds useful in the methods of the invention are those described in Kummer et al. , US Pat . No. 3,930,017, issued Dec. 30, 1975. Particularly preferred of these compounds have the structure:

[0061]

[Chemical 12]

[0062]   [In the formula, R_FourIs selected from hydrogen and iodine; R₁And R₂Are each independently
, Hydrogen and iodine; each R₁₂Is independently C₁~ C₆Alkyl; R ₁₃ Is C₁~ C₆Selected from alkyl, cycloalkyl, and arylalkyl
It ] Have.

Other preferred compounds useful in the method of the invention are Smith Kline & French L
Ellis et al. , U.S. Pat . No. 4,766,121, issued Aug. 23, 1988, assigned to Aboratories Ltd .. Particularly preferred of these compounds have the structure:

[0064]

[Chemical 13]

[0065]   [Wherein, X is oxygen, sulfur, and CH₂Selected from; R₁And R₂Are each German
Upright, hydrogen, halogen, and C₁~ C_FourSelected from alkyl; R₆Is -CH₂ CR₇R₈NR₉R_TenAnd -YC (O) R₁₁Selected from; R₁₆Is aryl
; R₁₇Is hydrogen and C₁~ C_FourSelected from alkyl. ] Have. Preferably X is oxygen; R₁₇Is hydrogen; R₆Is -CH₂CR ₇ R₈NR₉R_TenAnd R₈Is -C (O) R₁₁And R₁₁Is hydroxy;
And / or R₉Is C₁~ C_FourAlkyl and R_TenIs hydrogen. Also preferably
Is R₆Is -YC (O) R₁₁And Y is C₁~ C_FourAlkyl; and / or
Is R₁And R₂Are each independently halogen. R₁₆A particularly preferred group for
, 4-hydroxyphenyl, 5-hydroxy-2-pyridyl, 6-oxo-3 (
1H) pyridyl, and 6-oxo-3 (1H) pyridazinyl.

Other preferred compounds useful in the methods of the invention are described by Leeson et al. , "Select
ive Thyromimetics. Cardiac-Sparing Thyroid Hormone Analogues Containing
3'-Arylmethyl Subsituents ", Journal of Medicinal Chemistry, Vol. 32, pp.
320-336 (1989). Particularly preferred among these compounds are those shown in Table 3 below.

[0067]

[Table 3]

[0068]

[Table 4]

[0069]

[Table 5]

[0070]

[Table 6]

[0071]

[Table 7]

Analytical Methods The present invention relates to methods of treating hair loss by administering a compound having the structure described herein. Preferably, the compounds utilized in the present invention do not stress the heart. The following method can be used to test compounds (test compounds) for their ability to induce anagen and their lack of cardiotoxicity (without stressing the heart). Alternatively, other methods known in the art may be used (however, the term "heart-free" is defined according to the methods disclosed herein below).

Cardiotoxicity Assay: The cardiotoxicity assay measures the potential adverse effects of test compounds on the cardiovascular system. The heart enlarges as thyroid hormone (T3) damages the circulatory system. For example, Gomberg-Maitland et al. , "Thyroid hormone and Card
iovascular Disease ", American Heart Journal, Vol. 135 (2), pp. 187-196
(1998); Klein and Oiamaa , "Thyroid Hormone and the Cardiovascular System
", Current Opinion in Endocrinology and Diabetes, Vol. 4, pp. 341-346
(1997); and Klemperer et al. , "Thyroid Hormone Therapy and Cardiovascular.
Disease ", Progress in Cardiovascular Diseases, Vol. 37 (4), pp. 329-3
36 (1996). This increases the weight of the heart based on total body weight. Compounds are tested for potential adverse effects on the heart by measuring their effect on the heart-to-body weight ratio using the cardiotoxicity assay described below herein.

Six male Sprague Dawley rats each (Harlan Sprague Dawley, Inc., I
ndianapolis, IN), each weighing approximately 220 grams to 235 grams. The first group is the vehicle control group and the second group is the test compound group. The length of the assay is 30 days and treatment of vehicle or test compound in vehicle is performed daily for 28 of these 30 days, as described below.

Prior to the start of the assay, each rat is acclimated to standard environmental conditions for 5 days.
Each rat receives food (standard rat chow diet) and water ad libitum until 5 days before the start of the assay and until the end of the study.

The vehicle is 91: 9 (v: v) propylene glycol: ethanol. Test compounds are made up at a concentration of 500 μg / ml in vehicle. Each rat is weighed on day 1 of the assay. Dose calculation is then performed.
Each rat is dosed daily with vehicle or a dosing solution of the test compound in the vehicle (depending on whether the rat belongs to the vehicle control group or the test compound group, respectively) at 500 μL dosing solution per kg rat. In the case of rats in the test compound group, this corresponds to a dose of 250 μg of test compound per kg of rat.

Day 2 is the first day of treatment with the dosing solution for both groups. Each rat was weighed at 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26, and 29 days prior to dosing on that day, and the dosing solution was given to each rat. Recalculate and administer as appropriate based on changes in body weight.

Treatment is carried out once daily in the morning for each rat in each group from day 2 to day 29. For each treatment, the dosing solution is administered subcutaneously between the shoulders of the rat and the injection site is rotated within this area.

On the morning of day 30, rats in each group are euthanized with CO ₂ on dry ice. The total body weight is immediately measured for each rat. The heart of each rat is then excised as follows. An incision is made to expose the abdominal cavity. Carefully cut the rib cage with small scissors in the sternum to expose the heart and lungs. Using small scissors and forceps, the blood vessels that connect to the heart are cut from the heart. These vessels are the caudal vena cava, the left cranial vena cava (main trunk of the lung), the right cranial vena cava,
Includes the thoracic aorta, right subclavian artery, internal mammary artery and vein, and any other small appendages. The heart is then immediately undamaged and includes the left and right atrial appendages and the left and right ventricles. Immediately after this, any excess tissue is removed and the heart is lightly blotted on the paper towel until no more blood is visibly left on the paper towel and the heart is weighed.

For each rat, after euthanasia, the heart weight is divided by the body weight to give the heart / body ratio. The heart / body ratio of each rat in the vehicle control group is added together and divided by 6 (ie the total number of rats in this group) to give the RV (ratio for the vehicle control group). Similarly, the heart / body ratios of each rat in the test compound group are added together and divided by 6 to give RT (ratio for the test compound group).

To calculate the index C next, RT is divided by RV. If C is less than 1.3, as defined herein, the test compound is cardiac inactive. Preferably, C is less than 1.2, more preferably less than 1.15, most preferably less than 1.1. According to this method, T3 and T4 are not cardiac inactive.

Resting phase inversion assay: In the resting phase inversion assay, mice in which the test compound is in the resting phase of the hair growth cycle (“resting phase”) are transferred to the growth phase of the hair growth cycle (“growing phase”). It measures the likelihood of conversion.

Without being limited by theory, there are three major phases in the hair growth cycle: anagen, interphase, and telogen. C3H mice (Harlan Sprague Dawley, Inc., Indianapolis, IN) from about 40 days to about 75 days after birth have a longer telogen period during which hair growth is thought to be synchronized. There is. It is believed that after 75 days of age, hair growth is no longer synchronous.
About 40 after birth with a dark coat (brown or black) in hair growth experiments
When using day mice, melanogenesis occurs with the growth of hair (hair coat), at which point topical application of hair growth inducers is evaluated. The compounds are screened for hair growth potential by measuring melanogenesis using the telogen conversion assay described below herein.

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 was administered the compound used in the method of the present invention. To do. Assay length is at least 19 days, treatment is 1
Perform 5 days (procedure days are Monday to Friday). Day 1 is the first day of treatment. Most studies end on day 19, although melanogenic reactions appear positive, but some may be performed up to day 24 if they occur slowly. A typical study design is shown in Table 4 below. Typical dosing concentrations are set forth in Table 4, but the skilled artisan will readily appreciate that such concentrations may be modified.

[0085]

[Table 8]

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

Mice are treated topically on the waist (base of tail or lower ribs) Monday-Friday. Use a pipettor and tip to deliver 400 μL to the back of each mouse. 400 μL are applied slowly while the hair of the mouse is moved, allowing the application to reach the skin.

Each treatment is applied topically to the mice, while the skin color in the application area of each animal is given a visual rating of 0-4. As the mouse transitions from telogen to anagen, its skin color will become more bluish black. As shown in Table 5, grades 0-4 represent the following visual observations as the skin progresses from white to bluish black.

[0089]

[Table 9]

[0090] Production method The compounds used in the methods of the present invention, to those skilled in the art are prepared by known procedures. The starting material used for producing the present compound is a known compound, a compound produced by a known method, or a compound which is commercially available as a starting material.

It is recognized that one of ordinary skill in the art of organic chemistry can readily perform standard manipulations of organic compounds without further instruction. Examples of such manipulations are discussed in standard texts such as J. March, Advanced Organic Chemistry, John Wiley & Sons (1992).

When masking or protecting other functional groups within a compound, it is appropriate that certain reactions are performed at their best, thus increasing reaction yields and / or avoiding undesired side reactions. It is clear to the industrial engineers. Often, technicians use protecting groups to increase the reaction yield and avoid unwanted side reactions. These reactions have been found in the literature and are within the scope of those skilled in the art. Many examples of such operations are given, for example, in T. Greene, Protecting Groups in Or.
ganic Synthesis, John Wiley & Sons (1981).

The compounds of this invention possess one or more chiral centers. As a result, one optical isomer, including diastereomers and optical antipodes, may be selectively prepared separately from the other, for example by chiral starting materials, catalysts or solvents, or compatible isomers, Alternatively, both optical isomers, including diastereomers and optical antipodes, can be prepared in one go (racemic mixture). Since the compounds of the present invention can exist as racemic mixtures, mixtures of optical isomers, including diastereomers and optical antipodes, are:
Separation may be done by known methods such as by using chiral salts and chiral chromatography.

Furthermore, one optical isomer, including diastereomers and optical antipodes, or one stereoisomer, has been found to possess more promising properties than the others. That is, when disclosing and claiming the present invention, when disclosing one racemic mixture, both optical isomers including diastereomers and optical antipodes, or stereoisomers substantially free of the other It is to be disclosed and claimed.

The synthesis of compounds useful in the present invention has been described in the literature. Accordingly, one of ordinary skill in the art would be able to prepare the compounds described herein. Details on the synthesis of various of the present compounds can be found, for example, in the following description: US Pat. No. 4,910,305 to Ellis et al. Smith Kline & French, published May 2, 1989
Ellis et al., U.S. Pat. No. 4,826,876; 19 assigned to Laboratories;
Elli transferred to Smith Kline & French Laboratories, issued August 23, 1988
U.S. Pat. No. 4,766,121; Smith, issued Oct. 29, 1991.
US Pat. No. 5,061 to Emmett et al. Assigned to Kline & French Laboratories
, 798; Smith Kline & French Laboratories, issued September 15, 1964
Assigned to Blank et al., U.S. Pat. No. 3,149,153; November 2, 1966.
Blank et al., U.S. Pat. No. 3,287,396, assigned to Smith Kline & French Laboratories, issued on 2nd; Smith Kline & French, published 23 July 1986.
Leeson et al. EP 0,188,351 assigned to Laboratories; assigned to The Regents of the University of California published July 12, 1990
Stearns et al. WO 90/07330; Yu et al. U.S. Pat. No. 4,363,815 issued Dec. 14, 1982; Kummer et al. U.S. Pat. No. 3,930,017 issued Dec. 30, 1975; U.S. Pat. No. 4,110,470 to Kummer et al., Issued August 29, 2010; The Upjohn Company issued June 10, 1969.
No. 3,449,419 assigned to Wechter et al .; U.S. Pat. No. 4,711,855 to Feinberg assigned to Ciba Corning Diagnostics Corp. issued Dec. 8, 1987; Dec. 1997; Kun et al. WO 97/46228 assigned to Octamer, Inc. published on 11th; Li et al WO 99/00353 assigned to Karo Bio published Jan. 7, 1999; and Leeson et al., “Selective Thyrom”.
imetics. Cardiac-Sparing Thyroid Hormone Analogues Containing 3′−Arylm
ethyl Substituents '', Journal of Medicinal Chemistry, Vol.32, pp.320-336.
(1989).

The following examples further illustrate, but are not limited to, the preparation of compounds used in this method.

Example 1

[0098]

[Chemical 14]

Bis (3-isopropyl-4-methoxyphenyl) iodonium tetrafluoroborate (Yokoyama et al., "Synthesis and Structure-Activity Relation"
ships of Oxamic Acid and Acetic Acid Derivatives Related to L-Thyronine
, Journal of Medicinal Chemistry, Vol.38, pp.695-707 (1995)) and copper bronze (6.1 g) in a suspension in dichloromethane (150 mL).
Methyl dibromo-4-hydroxybenzoate (15 g) and triethylamine (
A solution of 5.4 g) in dichloromethane (100 mL) is added dropwise at room temperature. The mixture is stirred overnight and filtered through Celite. After concentration, the obtained residue is passed through a short silica gel column. The pure fractions are combined and concentrated to dryness. The residue is recrystallized from methanol to give methyl 3,5-dibromo-4- (4'-methoxy-3'-isopropylphenoxy) -benzoate.

The above ester (6.5 g) was hydrolyzed by treatment with 1M aqueous NaOH (60 mL) and methanol (150 mL) to give 3,5-dibromo-4- (4.
′ -Methoxy-3′-isopropylphenoxy) -benzoic acid is obtained.

Benzoic acid (2 g) was added to boron tribromide (1M, 26 mL) in dichloromethane at 0 ° C.
) Demethylate. The mixture is stirred overnight at room temperature and then quenched with a water / ice mixture. Separate the layers and extract the aqueous layer with dichloromethane. The combined organic extracts are dried, filtered and concentrated. The obtained residue was recrystallized to give 3,5-dibromo-4.
-(4-Hydroxy-3-isopropylphenoxy) -benzoic acid is obtained.

Example 2

[0103]

[Chemical 15]

Bromine (35.2 g) was added to methyl 4-hydroxy-phenylacetate (16.6 g).
Is added dropwise to the suspension in water (500 mL). After stirring for 1 day, the mixture is partitioned between water and ethyl acetate. The organic layer was washed with aqueous sodium thiosulfate, dried,
Filter and concentrate. The residue was recrystallized from methanol to give 3,5-dibromo-4.
-Methyl hydroxyphenylacetate is obtained.

The above phenol (5 g) was combined with bis (3-isopropyl-4-methoxyphenyl) iodonium tetrafluoroborate as described in Example 1 (9.5 g).
Bind to. Purify by column chromatography and recrystallize from methanol to give 3
, Methyl 5-dibromo-4- (4-methoxy-3-isopropylphenoxy) phenylacetate is obtained.

The above ester (2.4 g) is demethylated with boron tribromide. The crude product was recrystallized from dichloromethane and light petroleum ether to give 3,5-dibromo-4- (
4'-Hydroxy-3'-isopropylphenoxy) phenylacetic acid is obtained.

Example 3

[0108]

[Chemical 16]

Methyl 3,5-dichloro-4-hydroxybenzoate (10 g) was converted to bis (3-isopropyl-4-methoxyphenyl) iodonium tetrafluoroborate (35 g) using the method described in Example 1. Join. Purify by column chromatography and recrystallize from methanol to give methyl 3,5-dichloro-4- (4-methoxy-3-isopropylphenoxy) phenylacetate.

The above methoxy compound (100 mg) was demethylated and hydrolyzed using the method described in Example 1 to give 3,5-dichloro-4- (4-hydroxy-3-).
Isopropylphenoxy) benzoic acid is obtained.

Example 4

[0112]

[Chemical 17]

Methyl 3,5-dichloro-4- (4-methoxy-3-isopropylphenoxy) benzoate (see Example 3) (3.0 g) was added to diisobutylaluminum hydride (DIBAL) in tetrahydrofuran (0 ° C.). 32.5 mL) and then warmed to room temperature and stirred overnight. The reaction mixture was ice-cooled 1M-HC
1 solution and extract three times with ethyl acetate. Wash the organic layer (brine),
Dry, filter and concentrate to dryness to obtain 3,5-dichloro-4- (4-methoxy-3-isopropylphenoxy) benzyl alcohol.

Using the method described in Example 1, the above alcohol (200 mg) 3,5
-Dichloro-4- (4-hydroxy-3-isopropylphenoxy) benzyl alcohol is obtained.

Example 5

[0116]

[Chemical 18]

Borrows et al., “The Synthesis of Thyroxine and Related Substances. Part
I. The Preparation of Thyrosine and Some of its Derivatives, and New Rou
te to Thyroxine '', Journal of The Chemical Society, Supp .. Issue No. 1, S
Using the general methodology of 185-S190 (1949), 3,5-diiodo-4- (4'-
Methyl ethoxyphenoxy) benzoate is synthesized.

Example 6

[0119]

[Chemical 19]

Borrows et al., “The Synthesis of Thyroxine and Related Substances. Part
I. The Preparation of Thyrosine and Some of its Derivatives, and New Rou
te to Thyroxine '', Journal of The Chemical Society, Supp .. Issue No. 1, S
Using the general methodology of 185-S190 (1949), 3,5-diiodo-4- (4'-
Methoxyphenoxy) benzoic acid is synthesized.

Example 7

[0122]

[Chemical 20]

3,3 ′, 5-triiodotyroacetic acid is commercially available from Sigma Chemical Co. (St. Louis, Mo.).

Example 8

[0125]

[Chemical 21]

3,3 ′, 5-Triiodothyropropionic acid is commercially available from Sigma Chemical Co. (St. Louis, Mo.).

Example 9

[0128]

[Chemical formula 22]

9a. Isopropyl anisole: potassium hydroxide (5.6 g) 13.4
Add to mL of acetone then 2-isopropylphenol (13.6 g). After dissolving the potassium hydroxide, methyl iodide (14.2 g) is added. The reaction mixture is refluxed for about 16 hours. Add 150 mL of water. 100 parts of this reaction mixture
Extract 3 times with mL of diethyl ether. The organic layer is extracted twice with 100 mL 10% sodium hydroxide in water, once with 100 mL water, and once with saturated ammonium chloride. After drying over magnesium sulphate, the organic solution is dried over MgSO ₄ , filtered and concentrated under reduced pressure. The material is fractionally distilled under reduced pressure to give 9a.

9b. Bis (3-isopropyl-4-methoxyphenyl) iodonium tetrafluoroborate: Acetic anhydride (7 mL) is cooled to -15 ° C in a dry ice / acetone bath. Fuming nitric acid (5.4 mL) is added dropwise. Iodine (2.5g)
Is added at once and then 4.7 mL of trifluoroacetic acid are added dropwise. 20 minutes later,
The reaction mixture is removed from the bath and stirred at room temperature for 30 minutes. After the iodine has dissolved
The reaction mixture is sparged to remove nitric oxide and concentrated under vacuum. This material is then taken up in 15 mL acetic anhydride and cooled to -10 ° C. In this cooling solution, 2-
35 mL acetic anhydride and 5 mL of isopropylanisole (9a; 7.43 g)
The solution in trifluoroacetic acid is added dropwise. The reaction mixture is left in the refrigerator for about 16 hours. The reaction mixture is allowed to come to room temperature for 3 hours and then concentrated under high vacuum. 25 residues
Take up in mL of methanol, 25 mL of 10% sodium bisulfite and 188 mL of 2M sodium tetrafluoroborate. The mixture is stirred vigorously for 30 minutes and the supernatant decanted. Add 200 mL of hexane to the residue and stir for another 30 minutes. At this point the solid is collected, washed with hexane and dried under vacuum to give 9b.

9c. 2 ', 6'-diiodo-3-isopropyl-4-methoxy-4'-nitrile diphenyl ether: Weighing bis (3-isopropyl-4-methoxyphenyl) iodonium tetrafluoroborate (9b; 1g), 3 m
Take up in L of dichloromethane and add 0.17 g of copper bronze. The mixture is cooled in an ice water bath. A solution of 2,6-diiodo-4-nitrilephenol (0.48g) and triethylamine (0.28g) in 3mL dichloromethane is added dropwise. The reaction mixture is placed in the dark and stirred for 5 days. At this point, the reaction mixture is filtered through Celite and concentrated under reduced pressure. The product is purified by chromatography on silica gel to give 9c.

9d. 2 ', 6'-diiodo-3-isopropyl-4-methoxy-4'-nitrile diphenyl ether: 2', 6'-diiodo-3-isopropyl-4-
Methoxy-4'-nitrile diphenyl ether (9c; 280 mg) is dissolved in 4 mL dichloromethane and cooled in a dry ice / acetone bath. To this solution, 1.6 mL of boron tribromide (1M in dichloromethane) is added dropwise. The reaction mixture is stirred overnight and brought to room temperature. At this point, the reaction mixture is poured onto 10 mL ice and water. To this mixture is added 10 mL of ethyl acetate. Separate the organic layer and extract the aqueous layer twice with 10 mL ethyl acetate. The organic layers are combined, washed with saturated sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The product is purified by chromatography on silica gel to give 9d.

9e. 3,5-Diiodo-4- (4'-hydroxy-3'-isopropylphenoxy) benzoic acid: in 2 ', 6'-diiodo-3-isopropyl-4-methoxy-4'-nitrile diphenyl ether (9d; 95 mg) Add 1 mL of 3N sodium hydroxide. Bring sample to homogenization. At this point, the reaction mixture is cooled and neutralized with 1N HCl. A precipitate forms. It is filtered and washed with hexane to give 9e.

Uses of the Compounds The methods of the present invention include the preparation of a compound comprising a compound having the structure described herein, and preferably a pharmaceutically acceptable or cosmetically acceptable carrier, in a mammal, preferably Person).

The formulations may be used for the treatment of hair loss in mammals, including inhibiting and / or reversing hair loss and promoting hair growth. Such conditions are present in, for example, alopecia, including androgenetic baldness and female baldness.

Preferably, the compounds of the invention are cardioactive as defined herein. Preferably, in the method of the present invention, the present compound is incorporated into a pharmaceutical or cosmetic composition for treating or preventing the above-mentioned conditions. Remington's Pharmaceutical S
ciences, Mack Publishing Company, Easton, PA (1990)
Standard drug formulation techniques such as those disclosed in US Pat.

Generally, from about 5 to about 3000 mg per day, more preferably from about 5 to about 100.
0 mg, more preferably about 10 to about 100 mg of a compound having the structure described herein is administered systemically. These dosage ranges are exemplary only, and the daily dosage can be adjusted according to a variety of factors. The specific dose of the compound, and the duration of treatment, and whether the treatment is local or systemic, will depend on each other. Dosage and treatment will also depend on the particular compound used, the indication of treatment, the effect of the compound, the individual characteristics of the patient (eg patient weight, age, sex and medical condition), cooperation with treatment, and therapeutic side effects. Depends on the existence and severity of.

In the present invention, the present compounds are administered with a pharmaceutically acceptable or cosmetically acceptable carrier (collectively referred to herein as “carrier”). As used herein, the term "carrier" means one or more compatible solid or liquid fillers, diluents or encapsulating substances which are suitable for administration to mammals. As used herein, the term "compatibility" means that the ingredients are combined with the compounds of this invention and with each other such that there are no interactions that substantially diminish the efficacy of the composition under normal conditions of use. It means that you can do it. The carrier must, of course, be sufficiently pure and sufficiently low in toxicity to be suitable for administration to the animal to be treated, preferably a mammal (most preferably a human). The carrier may be inert per se,
Alternatively, it may itself have pharmaceutical and / or cosmetic benefits.

The compositions of the invention may take a variety of forms suitable for oral, rectal, topical, nasal, ocular or parenteral administration. Of these, topical and / or oral administration is particularly preferred,
Topical administration is most preferred. Various carriers well known in the art may be used, depending on the particular route of administration desired. Examples thereof are solid or liquid fillers, diluents, hydrotropes, surfactants and encapsulating substances. Any pharmaceutically or cosmetically active substance that does not substantially affect the activity of the compounds of the present invention may be included. The amount of carrier used with the present compounds is an amount sufficient to provide a practical amount of material for administration per unit dose of the present compound. Techniques and compositions for making dosage forms useful in the methods of the invention are described in the following references: Modern Pharmaceutics, Chapters 9 and 10, Banker &
Edited by Rhodes (1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (
1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, Second Edition
, (1976).

Some examples of substances that can serve as their carrier or ingredient are sugars,
For example lactose, glucose and saccharose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose; powder tragacanth; malt; gelatin; talc; solid lubricants such as stearic acid and magnesium stearate. Calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and cocoa butter; polyols such as propylene glycol, glycerin, sorbitol, mannitol and polyethylene glycol; alginic acid; emulsifiers such as TWEENS; wetting agents such as lauryl. Sodium Sulfate; Colorant; Flavoring Agent; Tablet Forming Agent; Stabilizer; Antioxidant; Preservative; Non-Pyrogen Arimizu; a and phosphate buffer solutions; isotonic saline.

The choice of carrier for use with the present compounds is generally determined by the method of administration of the compound. In particular, carriers for systemic administration include sugar, starch, cellulose and its derivatives,
Included are malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffer solutions, emulsifiers, isotonic saline, and pyrogen-free water. Preferred carriers for parenteral administration include propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil. Preferably, the carrier in the composition for parenteral administration is 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 dosage forms contain a safe and effective amount, usually at least about 5%, preferably about 25 to about 50% of a compound of the invention. Tablets may be compressed, powdered tablet, enteric-coated, sugar-coated, film-coated or multi-staged with suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents,
It contains a flow-inducing agent and a melting agent. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, suitable solvents, preservatives, emulsifying agents, suspending agents, diluting agents. Contains agents, sweeteners, melting agents, colorants and flavoring agents.

Suitable carriers for unit dosage formulations for oral administration are well known in the art. Tablets usually contain conventional pharmaceutically compatible auxiliaries as inert diluents, examples of which are calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and saccharose. Disintegrants such as starch, alginic acid and croscarmellose; lubricants such as magnesium stearate, stearic acid and talc. Glidants such as silicon dioxide can also be used to improve the flow properties of the powder mixture. Colorants, for example
FD & C dyes may be added for appearance. Sweetening agents and flavoring agents such as aspartame, saccharin, menthol, peppermint, and fruit flavors are useful as useful adjuncts for chewing tablets. Capsules (including time release and sustained release formulations) generally contain one or more of the above solid diluents. The choice of carrier components is not important for the purposes of the present invention due to taste, cost and shelf life and can be readily selected by a person skilled in the art.

Orally administered compositions also include solutions, emulsions, suspensions, powders, granules, elixirs, tinctures, syrups and the like. Suitable carriers for the production of such compositions are well known in the art. Common ingredients for carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid saccharose, sorbitol and water. In the case of suspensions, typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, AVICEL RC-591, tragacanth and sodium alginate; common wetting agents include lecithin and polysorbate 80. And common preservatives include methylparaben and sodium benzoate. Oral liquid compositions may also include one or more ingredients such as sweeteners, flavoring agents and coloring agents described above.

Such compositions may also be coated by a conventional method with a pH- or time-dependent coating to release the compound in the gastrointestinal tract near the local location where it is desirable, or at various times when the desired effect lasts. You may do it. Such dosage forms generally include one or more of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethyl cellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac,
It is not limited to these.

Other compositions useful for systemic release of the compound include sublingual, buccal and nasal dosage forms. Such compositions generally include one or more soluble filler materials such as sucrose, sorbitol and mannitol; and binders such as acacia.
Includes microcrystalline cellulose, carboxymethyl cellulose and hydroxymethyl cellulose. Lubricants, lubricants, sweeteners, colorants, antioxidants and flavoring agents mentioned above may also be included.

The compounds of this invention may also be administered topically. The carrier of the topical composition is preferably
Helps the compound penetrate the skin and reach the environment of hair follicles. Topical compositions of the present invention include, for example, solutions, oils, creams, ointments, gels, lotions, shampoos, residual and rinse-off hair conditioners, emulsions, detergents, moisturizers,
It can be in the form of a spray, skin patch, etc.

Topical compositions containing the active compounds may be formulated with various carrier materials well known in the art, such as water, alcohols, aloe vera gel, allantoin, glycerin, vitamin A.
And E oil, mineral oil, propylene glycol, PPG-2 myristyl propionate and the like.

Other substances suitable for use as topical carriers are, for example, emollients, solvents, humectants, thickeners and powders. Examples of each of these substances, which may be used alone or as a mixture of one or more substances, are: emollients such as stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane-1,2- Diol, butane-1,3-diol, milk oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecane-2- All, 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 lactate, myristyl lactate, decyl oleate, and myristyl myristate; propellants such as propane, butane, isobutane, dimethyl ether,
Carbon dioxide, and nitrous oxide; 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; humectants such as glycerin. , Sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, and gelatin; and powders such as chalk, talc, fuller's earth, kaolin, starch, gums, colloidal silicon dioxide, sodium polyacrylate, Tetraalkylammonium smectite, trialkylarylammonium smectite, chemically modified magnesium aluminum silicate, organic Sex montmorillonite clay, hydrated aluminum silicate,
Fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, and ethylene glycol monostearate.

The compounds used in the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from various phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. Preferred formulations for topical administration of the compounds of this invention are described by Dowton et al., "Influence of Liposomal Composition on Topical D".
delivery of Encapsulated Cyclosporin A: I. An in vitro Study Using Hairle
ss Mouse Skin '', STP Pharma Sciences, Vol.3, pp.404-407 (1993); Wall
ach and Philippot, “New Type of Lipid Vesicle: Novasome (registered trademark)”,
Liposome Technology, Vol.1, pp.141-156 (1993); Wallach, US Pat. No. 4,911,928, issued Mar. 27, 1990, assigned to Micro-Pack, Inc .; and University of Michigan and Micro-. Weiner et al., US Pat. No. 5,834,014, issued Nov. 10, 1998, assigned to Puck, Inc. (for Weiner et al., Compounds described herein are administered in place of or in addition to minoxidil). ).

The compounds of the present invention may also be administered by iontophoresis. For example, internet site www.unipr.it/arpa/dipfarm/erasmus/erasm14.html; Banga etc.
, `` Hydrogel-based Iontotherapeutic Delivery Devices for Transdermal Del
ivery of Peptide / Protein Drugs '', Pharm. Res., Vol.10 (5), pp.679-702 (19
93); Ferry, `` Theoretical Model of Iontophoresis Utilized in Transdermal
Drug Delivery '', Pharmaceutical Acta Helvetiae, Vol.70, pp.279-287 (199
5); Gangarosa et al., `` Modern Ionophoresis for Local Drug Delivery '', Int.
J. Pharm, Vol.123, pp.159-171 (1995); Green et al., `` Ionophoretic Delivery
of a Series of Tripeptides Across the Skin in vitro '', Pharm. Res., Vol.
8, pp.1121-1127 (1991); Jadoul et al., `` Quantification and Localization of
Fentanyl and TRH Delivered by Ionophoresis in the Skin, '' Int. J. Pharm.
, Vol.120, pp.221-8 (1995); O'Brien et al., `` An Updated Review of its Antiv
iral Activity, Pharmacokinetic Properties and Therapeutic Efficacy '', Dr
ugs, Vol.37, pp.233-309 (1989); Parry et al., `` Acycovir Biovailability in H
uman Skin '', J. Invest. Dermatol., Vol.98 (6), pp.856-63 (1992); Santi et al.
, `` Drug Reservoir Composition and Transport of Salmon Calcitoninn in Tr
ansdermal Iontophoresis '', Pharm. Res. Vol.14 (1), pp.63-66 (1997); Santi
`` Reverse Iontophoresis-Parameters Determining Electroosmotic Flo
w: I. pH and Ionic Strength '', J. Countrol. Release, Vol.38, pp.159-165
(1996); Santi et al., `` Reverse Iontophoresis-Parameters Determining Electr
oosmotic Flow: II. Electrode Chamber Formulation '', J. Countrol. Release
, Vol.42, pp.29-36 (1996); Rao et al., `` Reverse Iontophoresis: Noninvasive
Glucose Monitoring in vivo in Humans '' Pharm. Res., Vol.12 (12), pp.1869-1
873 (1995); Thysman et al., `` Human Calcitonin Delivery in Rats by Iontophor.
esis, J. Pharm. Pharmacol., Vol.46, pp.725-730 (1994); and Volpato.
`` Iontophoresis Enhances the Transport of Acyclovir through Nude Mou
se Skin by Electrorepulsion and Electroosmosis '', Pharm. Res., Vol. 12 (11
), pp. 1623-1627 (1995).

The composition used in the present invention may also include an activity enhancer. The activity enhancer may 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 invention. Specific types of activity enhancers include other hair growth stimulants and penetration enhancers.

Examples of other hair growth-stimulating agents that may be used in the present compositions, including both systemic and topical compositions, are benzalkonium chloride, benzethonium chloride, phenol, estradiol, diphenhydramine hydrochloride, chlorpheniramine maleate, Chlorophyllin derivative, cholesterol, salicylic acid, cysteine, methionine, red pepper tincture, benzyl nicotinate, D, L-menthol, peppermint oil,
Calcium pantothenate, panthenol, castor oil, hinokitiol, prednisolone, resorcinol, monosaccharides and esterified monosaccharides, chemical activator of protein kinase C enzyme, glycosaminoglycan chain cell uptake inhibitor, inhibition of glycosidase activity Agents, glycosaminoglycanase inhibitors, esters of pyroglutamic acid, hexosugar acids or acylated hexosugar acids, aryl-substituted ethylenes, N-acylated amino acids and, of course, minoxidil or finasteride. Not limited. The most preferred activity enhancers are minoxidil and finasteride, with minoxidil being the most preferred.

Examples of penetration enhancers that may be used in the composition are 2-methylpropan-2-ol, propan-2-ol, ethyl-2-hydroxypropanoate, hexane-2,5-diol, POE ( 2) Ethyl ether, di (2-hydroxypropyl) ether, pentane-2,4-diol, acetone, POE (2) methyl ether, 2-hydroxypropionic acid, 2-hydroxyoctanoic acid, propane-
POE ester of 1-ol, 1,4-dioxane, tetrahydrofuran, butane-1,4-diol, propylene glycol dipelargonate, polyoxypropylene 15 stearyl ether, octyl alcohol, oleyl alcohol,
Oleyl alcohol, lauryl alcohol, dioctyl adipate, dicapryl adipate, di-isopropyl adipate, di-isopropyl 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 succinate, didecyl phthalate, decyl oleate, ethyl caproate, ethyl salicylate, isopropyl palmitate, ethyl laurate, pelargonic acid 2 -Ethyl-hexyl, isopropyl isostearate, butyl laurate, benzyl benzoate, butyl benzoate, hexyl laurate, ethyl caprate, ethyl caprylate, butyl stearate, benzyl salicylate, 2-hydroxypropanoic acid, 2-hydroxyoctane Acid, dimethyl sulfoxide, N, N-dimethylacetamide, N, N-dimethylformamide, 2-pyrrolidone, 1-methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone, 1,5-dimeme Ru-2-pyrrolidone, 1-ethyl-2-pyrrolidone, phosphine oxide, sugar ester, tetrahydrofurfural alcohol, urea, diethyl-m-toluamide, and 1-dodecylazacycloheptan-2-one. Not limited to.

In all of the above, of course, the compounds used in the method can be administered alone or as a mixture, and the composition can optionally further comprise additional agents or excipients. .

The invention further relates to a kit comprising a compound and / or the composition and verbal, pictorial, etc. information and / or instructions, wherein the kit comprises prevention and / or reversal of hair loss and / or promotion of hair growth, Used in the treatment of hair loss in mammals, especially humans. Additionally or alternatively, the kit comprises information and / or instructions regarding how to apply the compound and / or the composition, and preferably how to apply the compound and / or the composition, including the benefits of treating hair loss in a mammal. including.

Administration Examples of Compositions The following examples are not meant to limit the invention but provide guidance to those of skill in the art for carrying out the methods of the invention. In each example, a compound not stated otherwise may be replaced with another compound having the structure described herein, which in the example shows similar results.

Example A A composition for topical administration is prepared containing the following ingredients: Ingredient Amount Compound of Example 3 5% Ethanol 57% Propylene Glycol 19% Dimethylisosorbide 19% Male patient with male pattern baldness. Treated by the method of the invention. For more details, 6 weeks,
The above composition is topically administered to a patient daily.

Example B Dowton et al., "Influence of Liposomal Composition on Topical Delivery of
Encapsulated Cyclosporin A: I. An in vitro Study Using Hairless Mouse S
Kinp., STP Pharma Sciences, Vol. 3, pp.404-407 (1993), using the compound of Example 2 in place of cyclosporin A and using Novasome in a nonionic liposome formulation. A composition for use is produced.

Male patients with androgenetic alopecia are treated daily with the above compositions. Specifically, the composition is topically administered to a patient for 6 weeks.

Example C A shampoo is prepared containing the following ingredients: Example Ingredients C-1 C-2 C-3 C-4
Ammonium lauryl sulfate 11.5% 11.5% 9.5% 7.5% Ammonium laureth sulfate 4% 3% 2% 2% Cocamide MEA 2% 2% 2% 2% Ethylene glycol distearate 2% 2% 2% 2% Cetyl alcohol 2% 2% 2% 2% Stearyl alcohol 1.2% 1.2% 1.2% 1.2% Glycerin 1% 1% 1% 1% Polyquaternium 10 0.5% 0.25% − − Polyquaternium 24 − − 0.5% 0.25% Sodium chloride 0.1% 0.1% 0.1 % 0.1% Sucrose polyester of coconut fatty acid 3% 3% --- Saccharose polyester of behenate fatty acid 2% 3% --- Polydimethylsiloxane --3% 2% Cocaminopropyl betaine-1% 3% 3% Lauryl dimethylamino oxide 1.5 % 1.5% 1.5% 1.5% decyl polyglucose --1% 1% DMDM hydantoin 0.15% 0.15% 0.15% 0.15% Example 1 compound-3% 3% -Example 4 compound 6% -6% Minoxidil 3 % 2% Fe Noxyethanol 0.5% 0.5% 0.5% 0.5% Fragrance 0.5% 0.5% 0.5% 0.5% Water qsqsqsqs A patient with androgenetic alopecia is treated by the method of the present invention. Specifically, patients use the above shampoo daily for 12 weeks.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 31/4409 A61K 31/4409 31/4412 31/4412 31/50 31/50 31/513 31/513 A61P 17/14 A61P 17/14 C07D 213/30 C07D 213/30 213/64 213/64 213/65 213/65 213/68 213/68 237/14 237/14 239/36 239/36 (72) Inventor Youngkwist, Robert Scott 45040, Ohio, United States, Charleston Noor Court, Mason, 8511 F-term (reference) 4C055 AA01 AA03 AA04 AA10 BA01 BA02 BA06 BA16 BA42 BB04 BB07 BB10 BB11 CA01 CA02 CA06 CA16 CA42 CB04 CB07 DA01 CB10 CB07 DA01 CB10 DA06 DA16 DA42 DB04 DB07 DB10 DB11 4C083 AB332 AC072 AC102 AC122 AC132 AC172 AC392 AC562 AC642 AC712 AC782 AC811 AC812 AC851 AC852 AD132 AD152 AD212 AD222 CC37 CC38 DD23 EE22 4C086 AA01 AA 02 AA03 BC17 BC41 BC42 MA01 MA04 MA09 MA10 MA52 MA58 MA59 MA60 MA63 NA14 ZA92 4C206 AA01 AA02 AA03 DA19 DA23 FA53 HA14 MA01 MA04 MA12 MA72 MA78 MA79 MA80 MA83 NA14 ZA92

Claims (9)

[Claims] 1. Structure: [Wherein X is selected from the group consisting of oxygen, sulfur, and CH ₂ ; R ₁ and R ₂ are each independently hydrogen, halogen, hydroxy, trifluoromethyl, C ₁ -C ₆ alkyl, R ₁ is selected from the group consisting of C ₁ -C ₆ alkenyl, and C ₁ -C ₄ alkoxy; R ₃ is selected from the group consisting of hydrogen, alkyl, aryl, and arylalkyl; R ₄ is hydrogen, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkenyl, selected hydroxy, and C ₁ -C ₄ group consisting from the group consisting of alkoxy; R ₅ is hydrogen, halogen, hydroxy, alkyl, C ₁ -C ₄ alkenyl , C ₁ ~
Selected from the group consisting of C ₄ alkoxy, cycloalkyl, aryl, and arylalkyl; R ₆ is alkyl, aryl, —CH ₂ CH (NH ₂ ) CO ₂ H, —CH ₂ CH (
_{OH) CO 2 H, -CH 2} CR 7 R 8 NR 9 R 10, -YC (O) R 11, - (CH 2) n
_{-OH, -CH 2 C (R 12} ) (NH 2) CO 2 R 13, -CH 2 CH (COOH) (N
H) C (O) (CH 2) m C (O) NH (CH 2) n R 20, and -CH ₂ CR ₁₂ R ₁₂
R ( ₇₎ is selected from the group consisting of C (O) OR ₁₃ ; R ₇ is selected from the group consisting of hydrogen and C ₁ -C ₄ alkyl; R ₈ is selected from the group consisting of hydrogen and —C (O) R _11. R ₉ and R ₁₀ are each independently selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl, and C ₁ -C ₄ alkanoyl; Y consists of a bond and C ₁ -C ₄ alkyl R ₁₁ is selected from the group consisting of hydroxy, C ₁ -C ₄ alkoxy, —NR ₁₄ R ₁₅ , C ₁ -C ₄ alkyl, C ₁ -C ₄ alkenyl, and C ₁ -C ₄ alkynyl. R ₁₂ is C ₁ -C ₆ alkyl; R ₁₃ is selected from the group consisting of C ₁ -C ₆ alkyl, cycloalkyl, and arylalkyl; R ₁₄ is hydrogen and C ₁ -C ₄ It is selected from the group consisting of alkyl; R ₁₅ is hydrogen, C ₁ -C ₄ alkyl , And is selected from the group consisting of C ₁ -C ₄ alkanoyl; R ₁₈ and R ₁₉ are each independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, hydroxy, and the group consisting of halogen M is an integer from 2 to 4; n is an integer from 1 to 4; R ₂₀ is an unsaturated, unsubstituted 5 or 1 or 2 containing 1 to 2 nitrogen atoms as the only heteroatoms; It is a 6-membered monocyclic heterocycle. ] A non-heart-beating compound characterized by: and a pharmaceutically acceptable salt thereof,
A method of treating hair loss comprising administering to a mammal a composition comprising a hydrate and biohydrolyzable amides, esters and imides. 2. The compound has the structure: [Wherein R ₁ and R ₂ are each independently selected from the group consisting of hydrogen, halogen, and C ₁ -C ₄ alkyl; R ₆ is —CH ₂ CR ₇ R ₈ NR ₉ R ₁₀ and R Y is selected from the group consisting of —YC (O) R ₁₁ ; R ₁₆ is aryl; R ₁₇ is selected from the group consisting of hydrogen and C ₁ -C ₄ alkyl. ] The method of Claim 1 characterized by these. 3. The method according to claim 1, wherein R ₆ is —YC (O) R _11.
The method described in the section. 4. R ₁ and R ₂ are each independently halogen.
The method according to any one of 1. 5. The compound has the structure: [Wherein R ₁ and R ₂ are each independently selected from the group consisting of hydrogen and iodine. ] The method of Claim 1 characterized by these. 6. The compound has the structure: The method according to claim 1, characterized in that 7. The method of claim 6, wherein m is 3 and n is 2. 8. The compound has the structure: [Wherein R ₅ is selected from the group consisting of C ₁ -C ₆ alkyl and C ₃ -C ₇ cycloalkyl; R ₁ and R ₂ are each independently hydrogen, halogen, and C ₁ -C ₆ Is selected from the group consisting of alkyl, provided that at least one of R ₁ and R ₂ is not hydrogen; R ₁₁ is selected from the group consisting of hydroxy and C ₁ -C ₄ alkoxy. ] The method of Claim 1 characterized by these. 9. The method of any one of claims 1-8, wherein the administration is topical.