JP2003500483A - Biaryl compounds - Google Patents

Abstract

(57) SUMMARY The present invention relates to compounds and compositions that are particularly useful for treating hair loss in an animal, including stopping hair loss and / or reversing hair loss and promoting hair growth. The compounds of the present invention have the structure: And pharmaceutically acceptable salts, hydrates, and biohydrolyzable amides, esters and imides thereof, provided that R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R _{6 , R 6 ', R 7,} R 8, R 9, R 10, Y, X, R 11, and R ₁₂ are defined herein.

Description

Detailed Description of the Invention

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

BACKGROUND OF THE INVENTION Hair loss is a common problem that occurs through natural processes, for example, or is often chemically promoted through the use of certain therapeutic agents designed to reduce symptoms such as cancer. To be done. Often, such hair loss is achieved by the lack of hair regrowth that causes partial or complete baldness.

As is well known in the art, hair growth occurs through a cycle of activity that involves alternating cycles of growth and dormancy. This cycle is often divided into three major stages: anagen, catagen and telog.
En). The anagen is the anagen of the circulation and may be characterized by a deep penetration of the hair follicles into the skin with a rapid proliferation of cells that differentiate to form hair. The next phase is the interphase, a transitional phase characterized by the arrest of cell division, during which cell vesicles regress through the skin to arrest hair growth. The next stage, telogen, is often characterized as dormancy, during which
Regressed vesicles contain tightly packed germs of lactose dendritic cells.
In the telogen phase, the onset of a new anagen is caused by rapid cell proliferation in the germ, elongation of the dermal papilla cells, and synthesis of basement membrane components. When hair growth ceases, most of the hair follicles are telogen and not during anagen, ie causing the onset of complete or partial baldness.

Many attempts have been made in the literature to provoke hair regrowth, for example by promoting and prolonging the anagen. There are currently two drugs approved by the US Food and Drug Administration for the treatment of male pattern baldness: topical minoxidil (marketed as Rogaine® by Pharmacia & Upjohn).
And oral finasteride (marketed as Propecia® by Merck & Co.). However, studies of effective hair growth inducers are ongoing for several reasons, including safety concerns and / or lack of efficacy.

Interestingly, the thyroid hormone known as thyroxine (“T4”) is thyronine (“T4”) in human skin by the selenoprotein deiodinase I.
3 "). The selenium defect is deionase I.
It causes a decrease in T3 levels due to decreased activity; this decrease in T3 levels is highly associated with hair loss. Consistent with this observation, hair growth is a reported side effect of T4 administration. Berman, "Peripheral Effec
ts of L-Thyroxine on Hair Growth and
Coloration in Castle ”, Journal of En
docology, Vol. 20, pp. 282-292 (1960);
And Gunaratnam, "The Effects of Thyroxi.
ne on Hair Growth in the Dog ", J. Small
l Anim. Pract. , Vol. 27, pp. 17-29 (1986). In addition, T3 and T4 have been the subject of several patent publications relating to the treatment of hair loss. For example, Fischer et al. , DE 1,617,477, 1
Published January 8, 970; Mortimer, GB 2,138,286,198.
See October 24, 1996; and Lindenbaum, WO 96/25943, assigned to Life Medical Sciences, Inc., published August 29, 1996.

Unfortunately, however, administration of T3 and / or T4 to treat hair loss is not practical because these thyroid hormones are also known to induce significant cardiopathic effects. Because it was. For example, Walker et al
． , US Pat. No. 5,284,971, assigned to Syntex, February 8, 1994
Sun and Emmett et al. , U.S. Pat. No. 5,061,798, assigned to Smith Kline and French Laboratories, October 29, 1991. Surprisingly, the inventors of the present invention have discovered a compound that strongly initiates hair growth without inducing cardiotoxicity. Consistent with this finding, but not intended to be bound by theory, the inventors of the present invention have surprisingly found that the preferred compounds of the present invention strongly interact with hair-selective thyroid hormone receptors. However, it has been found that it interacts with little or no cardiac selective hormone receptors. These unique properties are of course not common with T3 and / or T4. Thus, the compounds and compositions herein are useful in treating hair loss, including stopping hair loss and / or reversing hair loss and promoting hair growth.

SUMMARY OF THE INVENTION The present invention relates to compounds and compositions that are particularly useful for treating hair loss in an animal, including arresting hair loss and / or reversing hair loss, and promoting hair growth.

[0008]   The compounds of the present invention have the structure:

[0009]

[Chemical 2]

And pharmaceutically acceptable salts, hydrates, and biohydrolyzable amides, esters and imides thereof, wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₆ '
, R ₇ , R ₈ , R ₉ , R ₁₀ , Y, X, R ₁₁ , and R ₁₂ are defined herein.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to compounds and compositions that are particularly useful for treating hair loss in an animal and include stopping hair loss and / or reversing hair loss and promoting hair growth. .

In addition to the discovery that the compounds of the present invention are useful in treating hair loss, the inventors of the present invention have also surprisingly found that the preferred compounds of the present invention are heart-tolerant. discovered.

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

In the description of the invention, various aspects and / or individual features are disclosed. As will be apparent to those skilled in the art, all such combinations of aspects and features are possible and can result in preferred practice of the invention.

As used herein, when any variable, moiety, group, etc. occurs more than one time in any variable or structure, its definition at each occurrence is as defined at each other occurrence. Become independent.

Definitions and Usage of Terms The following is a list of definitions for terms used herein: “Salt” as used herein is formed at any acidic (eg, carboxyl) group. Cationic salts, or anionic salts formed at any basic (eg amino) group. A preferred cationic salt is an alkali metal salt (
For example, sodium and potassium), alkaline earth metal salts (eg, magnesium and calcium), and organic salts. A preferred anionic salt is a halide (
For example, chlorine salt). Such acceptable salts must be suitable for mammalian use when administered.

As used herein, “alkenyl” refers to 2 to about 15 carbon atoms; preferably 2 to about 10 carbon atoms; more preferably 2 to about 8 carbon atoms, and most preferably about. Unsubstituted or substituted hydrocarbon chain radicals having 2 to about 6 carbon atoms. Alkenyl has at least one olefinic double bond. Non-limiting examples of alkenyl include vinyl, allyl, and butenyl.

“Alkoxy”, as used herein, is an oxygen radical having an alkyl, alkenyl, or alkynyl, preferably alkyl or alkenyl, and most preferably an alkyl substituent. Examples of alkoxy radicals include -O-alkyl and -O-alkenyl. The alkoxy radical may or may not be substituted.

“Aryloxy” as used herein is an oxygen radical having an aryl substituent. The aryloxy radical may or may not be substituted. 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, and most preferably 1 to about 4 carbon atoms. Is an unsubstituted or substituted hydrocarbon chain radical having a carbon atom of. Preferably, alkyl is, for example, methyl, ethyl, propyl, iso-
Includes propyl and butyl.

As used herein, “alkylene” refers to the diradical alkyl, alkenyl, or alkynyl. For example, "methylene" is -CH ₂ -. The alkylene may or may not be substituted.

As used herein, “alkynyl” is 2 to about 15 carbon atoms; preferably 2 to about 10 remaining carbon atoms; more preferably 2 to about 8 carbon atoms, and most preferably Unsubstituted or substituted hydrocarbon chain radicals having from about 2 to about 6 carbon atoms. Alkynyl has at least one triple bond.

“Aryl” as used herein is either a carbocyclic or heterocyclic aromatic cyclic radical. Preferred aryl groups are, for example, phenyl, benzyl, tolyl, xylyl, cumenyl, naphthyl, biphenyl, thienyl, furyl, pyrrolyl, pyridinyl, pyrazinyl, thiazolyl, pyrimidinyl, quinolinyl, triazolyl, tetrazolyl, benzothiazolyl, benzohyryl, indolyl, indenyl, zulenyl, Includes fluorenyl, anthracenyl, oxazolyl, isoxazolyl, isotriazolyl, imidazolyl, pyraxolyl, oxadiazolyl, indolizinyl, indolyl, isoindolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl and the like. Aryl may or may not be substituted.

“Arylalkenyl” as used herein is an alkenyl substituent substituted with aryl or an aryl radical substituted with an alkenyl group. The arylalkenyl may or may not be substituted.

“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 are benzyl, phenylethyl, and phenylpropyl. Arylalkyl may or may not be substituted.

As used herein, a “biohydrolyzable amide” is an amide of a compound of the invention that does not interfere with the activity of the compound, or is readily converted in vivo by a mammalian subject to yield an active compound. It is an amide of a compound of the invention.

As used herein, a “biohydrolyzable ester” is an ester of a compound of the invention that does not interfere with the activity of the compound, or is readily converted in vivo by a mammalian subject to give an active compound. An ester of a compound of the invention.

As used herein, a “biohydrolyzable imide” is an imide of a compound of the invention that does not interfere with the activity of the compound, or is readily converted in vivo by a mammalian subject to give an active compound. It is an imide of the compound of the present invention.

As used herein, “carbocyclic ring”, “carbocycle” and the like are hydrocarbon rings. The carbocyclic ring is monocyclic or fused,
It is a bridged or spiropolycyclic ring. Unless otherwise specified, a monocycle contains 3 to about 9 atoms, preferably about 4 to about 7 atoms, and most preferably 5 or 6 atoms. The polycyclic ring contains about 7 to about 17, preferably about 7 to about 14, and most preferably 9 or 10 atoms. The carbocyclic ring (carbocycle) may or may not be substituted.

“Cycloalkyl” as used herein is a saturated carbocyclic or heterocyclic ring radical. Preferred cycloalkyl groups include, for example, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl may or may not be substituted.

“Cycloalkenyl” as used herein is an unsaturated carbocyclic or heterocyclic ring radical having at least one double bond.

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

As used herein, “heteroalkenyl” is an alkenyl radical composed of carbon atoms and one or more heteroatoms, provided that the heteroatoms are from the group consisting of oxygen, sulfur, nitrogen, and phosphorus. Selected, more preferably oxygen, sulfur and nitrogen. Heteroalkenyl may be substituted or unsubstituted.

As used herein, “heteroalkyl” is an alkyl radical composed of carbon atoms and one or more heteroatoms, provided that the heteroatoms are from the group consisting of oxygen, sulfur, nitrogen, and phosphorus. Selected, more preferably oxygen, sulfur and nitrogen. Heteroalkyl may or may not be substituted.

As used herein, “heteroalkynyl” is an alkynyl radical composed of carbon atoms and one or more heteroatoms, provided that the heteroatoms are from the group consisting of oxygen, sulfur, nitrogen, and phosphorus. Selected, more preferably oxygen, sulfur and nitrogen. Heteroalkynyl may be substituted or unsubstituted.

As used herein, “heteroaryl” is an aryl radical consisting of a carbon atom and one or more heteroatoms, provided that the heteroatoms are oxygen, sulfur,
It is selected from the group consisting of nitrogen and phosphorus, more preferably oxygen, sulfur and nitrogen. Heteroaryl may be substituted or unsubstituted.

As used herein, “heteroarylalkenyl” is an arylalkenyl radical, provided that the aryl and / or alkenyl groups consist of carbon atoms and one or more heteroatoms, provided that the heteroatoms are It is selected from the group consisting of oxygen, sulfur, nitrogen and phosphorus, more preferably oxygen, sulfur and nitrogen. Heteroarylalkenyl may be substituted or unsubstituted.

As used herein, “heteroarylalkyl” is an arylalkyl radical provided that the aryl and / or alkyl groups consist of carbon atoms and one or more heteroatoms, provided that the heteroatoms are It is selected from the group consisting of oxygen, sulfur, nitrogen and phosphorus, more preferably oxygen, sulfur and nitrogen. Heteroarylalkyl may or may not be substituted.

As used herein, “heterocyclic ring”, “heterocycle” and the like are cyclic radicals consisting of carbon atoms and one or more heteroatoms in the ring, provided that the heteroatoms are oxygen. , Sulfur, nitrogen and phosphorus, more preferably oxygen, sulfur and nitrogen. Heterocycles are monocycles or are fused, bridged, or spiropolycyclic rings. Unless otherwise specified, a monocycle contains 3 to about 9 atoms, preferably about 4 to about 7 atoms, and most preferably 5 or 6 atoms. The polycyclic ring contains about 7 to about 17, preferably about 7 to about 14, and most preferably 9 or 10 atoms. The heterocycle may or may not be substituted.

“Heterocycloalkyl” as used herein is a cycloalkyl having at least one heteroatom in the ring. Heterocycloalkyl may be substituted or unsubstituted.

“Heterocycloalkenyl” as used herein is a cycloalkenyl having at least one heteroatom in the ring. Heterocycloalkenyl may be substituted or unsubstituted.

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

As used herein, a “safe and effective amount of a compound” (or composition, etc.) is
By an amount effective to exhibit biological activity is preferred, provided that the biological activity is in accordance with the modes of the present invention without undue side effects (eg, damaging, inflammatory or allergic response) at the active site of a mammalian subject. Prevents and / or reverses hair loss or promotes hair growth on the same basis with reasonable benefits / risk factors when used.

The term “substituted” when referring to groups, moieties, etc., as used herein, unless otherwise specified, is hydrogen, alkyl, alkenyl, alkoxy, hydroxy, nitro, amino, alkylamino. , Cyano, halo, thio, aryl, cycloaryl, cycloalkyl, heteroaryl, heterocycloalkyl (eg piperidinyl, morphonylyl, pyrrolidinyl), imino, hydroxyalkyl, aryloxy, and arylalkyl, preferably hydrogen, alkyl, Alkenyl, alkoxy, hydroxy, nitro, amino, alkylamino, halo,
Thio, and arylalkyl, more preferably hydrogen, alkyl, alkenyl,
It is meant to have one or more substituents each independently selected from alkoxy, hydroxy, nitro, amino, alkylamino and halo, more preferably hydrogen, alkyl and alkoxy, and most preferably alkoxy.

[0044]                             Compounds of the invention   The compounds of the present invention have the structure:

[0045]

[Chemical 3]

And pharmaceutically acceptable salts, hydrates, and biohydrolyzable amides, esters and imides thereof, wherein (a) R ₁ , R ₂ , R ₅ , R ₇ and R ₁₀ is each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl and heteroalkynyl; (b) R ₄ is halogen, alkyl, alkenyl, alkynyl, cycloalkyl, Selected from the group consisting of cycloalkenyl, aryl, arylalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarylalkyl, and heteroarylalkenyl; provided that R ₂ is H , Y is —CH ₂ CHK ₁ and X
Is selected from the group consisting of -NZ- and -NH-, and R ₁₂ is C ₁ -C ₄ alkyl, where K ₁ is selected from hydrogen and C ₁ -C ₄ alkyl, and Z is C _1-.
When a C ₄ alkyl, R ₄ is not arylalkyl; (c) R ₈ and R ₉ are each independently hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl Alkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl,
Selected from the group consisting of heterocycloalkenyl, heteroaryl, heteroarylalkyl, and heteroarylalkenyl; provided that at least one of R ₈ and R ₉ is not hydrogen; (e) R ₃ is hydrogen, alkyl, alkenyl , Alkynyl, cycloalkyl,
Cycloalkenyl, aryl, arylalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl,
(E) R ₆ and R ₆ ′ are each independently hydrogen, halogen, hydroxy, amino, or a group selected from the group consisting of heteroaryl, heteroarylalkyl, and heteroarylalkenyl;
(F) selected from the group consisting of cyano, thio, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroarikinyl; provided that R ₆ and R ₆ 'are both selected from the group consisting of oxo and thioxo; Y is selected from the group consisting of a bond, alkyl, alkenylalkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl; (g) X is selected from the group consisting of -NZ-, -NH- and -O-; h) R ₁₁ is selected from the group consisting of a bond and -C (O)-; provided that Y is a bond and X is -O-, then R ₁₁ is -C (O)-; (I) R ₁₂ is alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, heterocyclo Selected from the group consisting of alkyl, heterocycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, and heteroarylalkenyl; provided that when R ₁₁ is a bond, R ₁₂ and Z are optionally a bond together. To form a ring selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl; R ₁₂ is heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocyclo When alkenyl, heteroaryl, heteroarylalkyl, or heteroarylalkenyl, the heteroatom of R ₁₂ is not directly covalently bonded to R ₁₁ ; and Y is a bond, X is —O—, and R ₁₁ is -C (O
)-, R ₁₂ is not alkyl; and (j) Z is selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl; provided that R ₁₁ is a bond, R ₁₂ and Z are optionally joined together to form a ring selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl.

The compounds of the present invention are biphenyl compounds linked through carbon atoms substituted by the substituents R ₆ and R ₆ '. The remaining substituents and R ₆ and R ₆ 'are described in the following odor detail.

Substituents R ₁ , R ₂ , R ₅ , R ₇ and R ₁₀ Substituents R ₁ , R ₂ , R ₅ , R ₇ and R ₁₀ are one of the phenyl rings of the structures shown herein. Replace each above. R ₁ , R ₂ , R ₅ , R ₇ and R ₁₀ are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl and heteroalkynyl.

[0049]   R₁, R₂, R_Five, R₇And R_TenAre preferably hydrogen, halogen, and
Selected from alkyl, alkenyl, heteroalkyl, and heteroalkenyl.
R₁, R₂, R_Five, R₇And R_TenIs more preferably each independently hydrogen, halogen,
And lower alkyl. Most preferably R₁, R₂, R_Five, R₇And R _Ten Are each halogen.

Substituent R _{4 The} substituent R ₄ is halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, hetero. Selected from aryl, heteroarylalkyl, and heteroarylalkenyl; provided that R ₂ is hydrogen, Y is —CH ₂ CHK ₁ , and X is —NZ.
--And --NH--, and R ₁₂ is C ₁ -C ₄ alkyl, where K ₁ is selected from hydrogen and C ₁ -C ₄ alkyl, and Z is C ₁ -C ₄ alkyl. And R ₄ is not arylalkyl.

R ₄ is preferably halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroalkyl, heteroalkenyl,
Selected from heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarylalkyl, and heteroarylalkenyl. R ₄ is more preferably selected from halogen, alkyl, alkenyl, heteroalkyl and heteroalkenyl. R ₄ is more preferably selected from halogen, alkyl, alkenyl, and heteroalkyl. R ₄ is most preferably selected from halogen and lower alkyl. The most preferred halogens for R ₄ are chlorine, bromine, and iodine, preferably chlorine and iodine, and most preferably iodine. Most preferred lower alkyl for R ₄ is methyl, ethyl, iso-propyl, and tertiary butyl, preferably methyl, iso-propyl and tertiary butyl, more preferably iso-propyl or tertiary. Butyl. Most preferably R ₄ is lower alkyl, especially iso-propyl or tertiary butyl.

Substituents R ₈ and R ₉ R ₈ and R ₉ are each independently hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, Selected from heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarylalkyl, and heteroarylalkenyl; provided that at least one of R ₈ and R ₉ is not hydrogen.

R ₈ and R ₉ are preferably each independently selected from halogen, alkyl, alkenyl, heteroalkyl and heteroalkenyl. R ₈ and R ₉ are more preferably each independently selected from halogen, alkyl, alkenyl and heteroalkyl. R ₈ and R ₉ are more preferably each independently selected from halogen and lower alkyl. The most preferred lower alkyls for R ₈ and R ₉ are methyl, ethyl, iso-propyl, and tertiary butyl, preferably methyl, iso-
Propyl and tertiary butyl, more preferably iso-propyl or tertiary butyl. Most preferably, R ₈ and R ₉ are each independently selected from lower alkyl and halogen, especially methyl and chlorine.

The substituent R ₃ R ₃ substitutes on the oxygen moiety of the biphenyl structure as shown above. R ₃ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarylalkyl, and heteroaryl. Selected from alkenyl. Preferably R ₃ is hydrogen, alkyl, alkenyl, cycloalkyl, aryl,
It is selected from arylalkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, heteroaryl, and heteroarylalkyl. More preferably, R ₃ is hydrogen, alkyl, alkenyl, aryl, aryl alkyl, heteroaryl, and heteroarylalkyl. Even more preferably, R ₃ is hydrogen, alkyl, alkenyl, arylalkyl (preferably benzyl), are selected heteroalkyl, and heteroaryl alkyl. Even more preferably, R ₃ is selected from hydrogen, lower alkyl, and lower alkenyl. Most preferably selected from hydrogen and lower alkyl. The most preferred lower alkyl for R ₃ is methyl.

The substituents R ₆ and R ₆ ′ R ₆ and R ₆ ′ are each independently a hydrogen, halogen, hydroxy, amino, cyano, thio, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroarikinyl. Or R ₆ and R ₆ 'are both oxo and thioxo. Preferably, R ₆ and R ₆ 'is, each independently, hydrogen, is selected from halogen, hydroxy, amino, and lower alkyl; or R ₆ and R _6' are both oxo. Even more preferably, R ₆ and R ₆ 'are each independently
Hydrogen, halogen, hydroxy, and (most preferably C ₁ -C ₃ alkyl) lower alkyl is selected from; or R ₆ and R ₆ 'are both oxo. Most preferably, R ₆ and R ₆ 'are each hydrogen.

[0056] Substituent Y   Y is a bond, alkyl, alkenylalkynyl, heteroalkyl, heteroar
It is selected from alkenyl and heteroalkynyl. When Y is a bond, X is R ₇ , R₈, R₉, And R_TenIs directly attached to the phenyl ring having. Y is preferably
Bonds, alkyl, alkenylalkynyls, heteroalkyls, and heteroalkenyls
Selected from Most preferably Y is selected from a bond and lower alkyl
. Most preferably Y is a bond.

[0057] Substituent X   X is selected from -NZ-, -NH- and -O-. Z is on the -NZ- nitrogen
And alkyl, alkenyl, alkynyl, heteroalkyl, hetero
Selected from alkenyl and heteroalkynyl; provided that R₁₁When is a bond, R ₁₂ And Z are optionally linked together to form cycloalkyl, cycloalkenyl
, Heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl
Form a ring selected from Preferably Z is alkyl, alkenyl, het
Selected from lower alkyl and heteroalkenyl, or R₁₂And Z join together
By combining, cycloalkyl, cycloalkenyl, heterocycloalkyl
Form a ring selected from heterocycloalkenyl, aryl and heteroaryl
To achieve. More preferably Z is lower alkyl or R₁₂And Z join together
By combining, cycloalkyl, cycloalkenyl, heterocycloalkyl
Form a ring selected from heterocycloalkenyl, aryl and heteroaryl
To achieve. Most preferably Z is C₁-C₃Alkyl, especially methyl, or R ₁₂ And Z are linked together to form cycloalkyl, cycloalkenyl, het
From cycloalkyl, heterocycloalkenyl, aryl and heteroaryl
Form the ring of choice.

Preferably X is selected from —NH— and —NZ—. Most preferably,
X is, -NH -, - N (CH 3) -, or a -NZ-, however, by R ₁₂ and Z are to be joined together, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, Form a ring selected from the group consisting of aryl and heteroaryl.

When R ₁₂ and Z are optionally joined together to form a ring, the ring is cycloalkyl, heterocycloalkyl, aryl and heteroaryl, more preferably cycloalkyl, heterocycloalkyl and aryl. , Even more preferably selected from cycloalkyl and heterocycloalkyl, and most preferably heterocycloalkyl. In addition to any of the above substituents, the ring may optionally have one or more oxo (ie, double bond oxygen) substituents. Non-limiting examples of these rings include piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, indolinyl, succinimidyl and hydantoinyl.

The substituent R ₁₁ R ₁₁ is selected from a bond and —C (O) — provided that Y is a bond and X is —O—, then R ₁₁ is —C (O) —. is there. When R ₁₁ is a bond, R ₁₂ is directly bonded to X, the compound is an amine (X is —NZ— or —NH—) or an ether (X is —O—, and Y is a bond). No).

The substituent R ₁₂ R ₁₂ is alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, arylalkyl, heteroaryl, heteroaryl. Alternatively, when R ₁₁ is a bond, R ₁₂ and Z are optionally bonded together to form a cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl. May form a ring selected from the group consisting of aryl;
However, when R ₁₂ is heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarylalkyl, or heteroarylalkenyl, the heteroatom of R ₁₂ is not directly covalently bonded to R ₁₁ . Therefore, carbamates and ureas with —Y—X—R ₁₁ —R ₁₂ bonds are not contemplated in the present invention. For example, when R ₁₂ is heteroalkyl, it can be, for example, —CH ₂ —O—CH ₃ , but not, for example, —O—CH ₂ —CH ₃ .

Further, when Y is a bond, X is —O—, and R ₁₁ is —C (O) —, then R ₁₂ is not alkyl.

[0063]   Preferably R₁₂Is alkyl, alkenyl, heteroalkyl, heteroalk
Nyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycle
Alkenyl, aryl, arylalkyl, heteroaryl, heteroaryl
Selected from alkyl and heteroarylalkenyl, or bonded to Z
By, cycloalkyl, cycloalkenyl, heterocycloalkyl,
Form a ring selected from heterocycloalkenyl, aryl and heteroaryl
To do. More preferably, R₁₂Is alkyl, alkenyl, heteroalkyl, het
Alkenyl, aryl, arylalkyl, heteroaryl, heteroaryl
Selected from alkyl and heteroarylalkenyl, or bonded to Z
By, cycloalkyl, cycloalkenyl, heterocycloalkyl,
Form a ring selected from heterocycloalkenyl, aryl and heteroaryl
To do. Even more preferably, R₁₂Is alkyl, heteroalkyl, aryl
Selected from alkyl, heteroarylalkyl, or attached to Z
By this, cycloalkyl, cycloalkenyl, heterocycloalkyl, het
Forms a ring selected from cycloalkenyl, aryl and heteroaryl
. Most preferably R₁₂Is lower alkyl or is attached to Z
Allows cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocyclo
Form a ring selected from chloralkenyl, aryl and heteroaryl. R ₁₂ The most preferred lower alkyl for are methyl, ethyl, n-propyl, iso
-Propyl, n-butyl, tert-butyl, and n-pentyl, especially methyl, n
-Propyl, iso-propyl, n-butyl and tertiary butyl.

When R ₁₂ and Z are optionally joined together to form a ring, said ring is cycloalkyl, heterocycloalkyl, aryl and heteroaryl, more preferably cycloalkyl, heterocycloalkyl and aryl. , Even more preferably selected from cycloalkyl and heterocycloalkyl, and most preferably heterocycloalkyl. In addition to any of the above substituents, the ring may optionally have one or more oxo (ie, double bond oxygen) substituents. Non-limiting examples of these rings include piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, indolinyl, succinimidyl and hydantoinyl.

Preferred compounds of the present invention are listed in the table below. In Table 1 preferred compounds less preferred compounds of the present invention, R ₆ and R ₆ 'are each hydrogen.

[0066]

[Table 1]

[0067]

[Table 2]

[0068]

[Table 3]

[0069]

[Table 4]

Table 2-Preferred Compounds of the Invention In the following preferred compounds, R ₆ and R ₆ 'are both oxo.

[0071]

[Table 5]

[0072]

[Table 6]

[0073]

[Table 7]

[0074]

[Table 8]

[0075]

[Table 9]

[0076] In Table 3 the preferred compounds less preferred compounds of the present invention, R ₆ and R ₆ 'is hydroxy.

[0077]

[Table 10]

[0078]

[Table 11]

[0079]

[Table 12]

[0080]

[Table 13]

Analytical Methods The present invention relates to compounds and methods for treating hair loss. Preferably, the compounds utilized in the present invention will be cardiotolerant. Compounds (test compounds) may be tested for their ability to induce anagen and their lack of cardiotoxicity (cardiac tolerance) using the following method. Alternatively, other methods well known in the art may be used (although the term "cardiac tolerance" is defined according to the methods disclosed herein below).

Cardiotoxicity Assay: The cardiotoxicity assay measures the ability of a test compound to adversely affect the cardiovascular system. The heart grows as thyroid hormone (T3) damages the cardiovascular system. For example, Gomberg-Maitland et al. , "Thyr
OID HORMONE AND CARDIOVASCULAR DISEA
se ”, American Heart Journal, Vol. 135 (2
), Pp. 187-196 (1998); Klein and Ojamaa,
"Thyroid Hornone and the Cardiovascu
lar System ”, Current Opinion in Endoc
rinology and Diabetes, Vol. 4, pp. 341-3
46 (1997); and Klemperer et al. , "Thyroid
Hormone Therapy and Cardiovascular
Disease ”, Progress in Cardiovascular
Diseases, Vol. 37 (4), pp. 329-336 (196). This increases the weight of the heart relative to total body weight. Compounds are assayed for potential opposing cardiovascular effects using the following cardiotoxicity assay herein:
Test by measuring their effect on heart-to-body weight ratio.

Six Sprague Dawley rats (Harlan Sprague
e Dawley, Inc. , Indianapolis, IN) each utilizing two groups (each weighing about 220 grams to about 235 grams). Group 1 is the vehicle control group and Group 2 is the test compound group. The length of the assay is 30 days and vehicle or compound in vehicle is treated daily for 28 days as described below.

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

The medium is 91: 9 (v: v) propylene glycol: ethanol. Test compounds are prepared in the above medium at a concentration of 500 μg / mL. Each rat is weighed on day 1 of the assay. Dose calculations are then carried out: each rat receives daily a vehicle or a dose solution of the test compound in the vehicle (depending on whether the rat is a vehicle control group or a test compound group) a dose solution per kg of rat. Fifty
It is administered at 0 μL. For rats in the test compound group, this is kg of rat
This corresponds to a dose of 250 μg of test compound per unit.

Day 2 is the first treatment day with dose solution for both groups. Weight is 3, 5,
Measurements are made on days 8, 10, 12, 15, 17, 17, 19, 22, 24, 26, and 29, respectively, prior to that day; the dose solution is recalculated for each rat and dosed according to the change in body weight.

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

On the morning of day 30, rats in each group are euthanized with CO ₂ from dry ice. Immediately after each rat, the total body weight is measured.

The heart of each rat is then excised as follows. The excision leaves the abdominal cavity exposed. The rib cage is carefully resected in the sternum with small scissors, leaving the heart and lungs exposed. Using small scissors and forceps, the tube that connects to the heart is excised from the heart. These vessels include the caudal vena cava, the left cranial vena cava (main lung), the right cranial vena cava, the thoracic aorta, the right clavicular artery, the internal thoracic arteries and veins, and any other small appendages. The heart is completely removed immediately after and includes the left and right atrial appendages and the left and right ventricles. Immediately thereafter, any excess tissue is excised, the heart is gently blotted onto the paper towel until no more blood is visibly falling on the paper towel, and the heart is weighed.

The heart / body weight ratio is given by dividing the weight of the heart by the post-euthanasia weight of each rat. The RV (ratio of vehicle control group) is given by adding the heart / body weight ratio of each rat in the vehicle control group and dividing by 6 (ie the total number of rats in the group). Similarly, RT (ratio of test compound group) is given by adding the heart / body weight days of each rat in the test compound group and dividing by 6.

The index C is then calculated by dividing RT by RV. As defined above, test compounds are cardiotolerant when C is less than 1.3. Preferably C is below 1.2, more preferably below 1.15 and most preferably below 1.1. According to this method, T3 and T4 are not cardiotolerant.

Rest period inversion assay: The rest period inversion assay is a test compound in which the test compound is in the rest phase of the hair growth cycle (rest period).
Mice are tested for their ability to convert to the growth stage (growth phase) of the hair growth cycle.

Without intending to be bound by theory, there are three major stages in the hair growth cycle: anagen, interphase, and telogen. C3H mice from about 40 days to about 75 days (Harlan Sprague Dawley, Inc.
． , Indianapolis, IN) is believed to have a longer telogen when hair growth is synchronized. It is believed that over 75 days of age, hair growth is no longer synchronized. When 40-day-old mice with dark fur are used in a hair growth experiment, melanogenesis occurs with hair (fur) growth, where topical application of hair growth inducers is evaluated. Melanin formation is measured to screen compounds for potential hair growth by using the resting phase inversion assay herein below.

Three groups of 44 day old C3H mice are utilized: vehicle control group and test compound group, where test compound group is administered compound according to the present invention. The length of the assay is at least 19 days, with 15 treatment days (treatment days are Monday to Friday). Day 1 is the first treatment day. Most of the research ends on day 19, but
If the melanogenic response is positive and occurs slowly, it may be done up to 24 days. Typical dose concentrations are listed in Table 4, but one of ordinary skill in the art will readily recognize that such concentrations may be modified.

[0095]                                 Table 4

[0096]

[Table 14]

** Vehicle is 60% ethanol, 20% propylene glycol, and 20% dimethyl isosorbide (commercially available from Sigma Chemical Co., St. Louis, MO). Topical treatment is performed Monday to Friday on the mouse's lower back (base of tail to bottom ribs). Use a pipettor and tip to deliver 400 μL to the back of each mouse. The 400 μL application is applied slowly while moving the mouse hair to allow the application to reach the skin.

Each treatment is applied topically to mice, but a visual grade of 0 to 4 is given to the skin color within the application area of each animal. As the mouse transitions from telogen to anagen, its skin color becomes more bluish-black. As shown in Table 5, grades 0 to 4 represent the following visible observations in which the skin progresses from white to bluish black.

[0099]                                 Table 5

[0100]

[Table 15]

Methods of Making The compounds of this invention are prepared by methods well known to those of ordinary skill in the art. The starting materials used to prepare the compounds of the invention are known, made by known methods, or are commercially available as starting materials.

It will be appreciated that one skilled in the art of organic chemistry can readily perform standard procedures for organic compounds without further instruction. Examples of such operations are standard text,
For example, J. March, Advanced Organic Chemistr
Y, John Wiley & Sons, 1992.

Those skilled in the art will be able to perform certain reactions well when masking or protecting other functional groups in the compound, ie to increase the yield of the reaction, and / or for any undesired side reactions. Easily recognize that you can avoid. Often, one of ordinary skill in the art will utilize protecting groups to achieve such increased yields or avoid unwanted reactions. These reactions have been found in the literature and are also within the skill of those in the art. Many examples of such operations are described, for example, in T.W. Greene, Protecting Grou
ps in Organic Synthesis, John Wiley &
Can be found in Sons, 1981.

The compounds of this invention may possess one or more chiral centers. As a result, one or more optical isomers containing diastereomers and enantiomers over others may be selectively produced, for example, by chiral starting materials, catalysts or solvents, or compatibilities containing diastereomers and enantiomers at once. The isomers or both optical isomers may be prepared (racemic mixture). Since the compounds of the present invention may exist as racemic mixtures, optical isomers or stereoisomers, including diastereomers and enantiomers, are prepared using known methods, for example, through the use of chiral salts and chiral chromatography. Good.

Furthermore, it is recognized that one optical isomer or stereoisomer, including diastereomers and enantiomers, may have favorable properties over the other. That is, when disclosing and claiming the present invention, when one racemic mixture is disclosed, both one optical isomer or stereoisomer containing substantially no other diastereomers and enantiomers are disclosed. Clearly intended to be made and claimed.

The compounds of this invention may be made using a variety of techniques known to those of ordinary skill in the art. Non-limiting examples include: The compounds of the invention have the structure:

[0107]

[Chemical 4]

Compounds of formula (I) can be prepared after removal of temporary protecting groups by concentration (eg acylation or alkylation) with the proviso that R ₁ , R ₂ , R ₃ , R _{4 , R 5, R 6, R} 6 ', R 7, R 8, R 9, R 10, Y, and X are as defined above herein, a suitable protected form if necessary (Eg, T. Greene, Protecting Groups in O.
organic Synthesis, John Wiley & Sons, 1
981), structure:

[0109]

[Chemical 5]

A reactive derivative of is used, provided that R ₁₂ is as defined herein above and is a suitable protected form if necessary, and Q is halogen, preferably bromine or Iodine, and most preferably iodine. Reactive derivatives of structure II include activated esters, such as 1-hydroxybenzotriazole esters and similar active esters known to those skilled in the art, and organic or inorganic acids such as hydrochloric acid, other halogen acids and Includes anhydrides mixed with sulfuric acid as well as similar acids known to those skilled in the art. Further, structure II
Reactive derivatives of include the symmetric anhydrides of acids of structure II. Activated derivatives of structure III include trifluoromethanesulfonyl ester and other activated derivatives known to those skilled in the art. Compounds of structure IV are generally reasonably reactive without further modification; however, it may be necessary for one skilled in the art to convert less reactive halogens to more reactive halogens such as bromine or iodine. Is known to. Many suitable activated derivatives of formula II, III or IV are commercially available, others can be prepared by methods known to those skilled in the art. A non-limiting example of this type of enrichment is described in Example 4 below.

In addition, further modification of the appropriately protected compound resulting from the concentration of the compound of structure I with the compound of structure II, III or IV may result in removal of the invention after removal of the temporarily protected group. Additional compounds may be provided. These modifications are
Including, but not limited to, reduction of the amide to an amine as described in Example 5 provides alkylation of secondary or tertiary amines and amines as described in Example 9. .

Furthermore, by reducing a compound of the invention wherein R ₆ and R ₆ ′ are oxo,
Reducing the ketone functionality to a functionality that provides benzhydrol such that R ₆ is hydroxy and R ₆ 'is hydrogen to provide additional compounds of the invention after removal of any temporary protecting groups. You can do it. A non-limiting example of this reaction is described in Example 5. Additional reduction of such compounds, if appropriate in appropriately protected form, then makes it possible to provide compounds of the invention in which R ₆ and R ₆ 'are both hydrogen. Non-limiting examples of this reaction are provided in Examples 2, 6 and 8. Using a compound in which R ₆ is hydroxy and R ₆ 'is hydrogen, an oxidant such as pyridinium dichromate in an inert solvent (eg, dichloromethane) at a reduced temperature, eg, 0 ° C., both R ₆ and R ₆ ′ are It may be oxidized to an oxo compound of the invention.

Compounds of structure I may be prepared from compounds of structure V (see below) where P is for example nitro or cyano. Compounds of structure V were prepared by alkylation of anisole of structure VII using Friedel-Crafts conditions known to those skilled in the art.
Manufactured by activation of the aromatic acids of Compounds of structures V and IV are either commercially available or may be prepared by means well known to those of ordinary skill in the art. A non-limiting example of this alkylation is shown in Example 3.

[0114]

[Chemical 6]

Compounds of structure V may be converted to compounds of structure I by further component substitution. For example, when P is nitro, the resulting compound of structure V is converted to a compound of structure I by reduction to an amine using standard chemical reaction conditions such as hydrogen on carbon and palladium as in Example 3. You can do it. When P is cyano, the compound of structure V is converted to a compound of structure I by reduction to an alkylated amine using conditions known to those skilled in the art.
May be converted to a compound of

[0116]

[Chemical 7]

The compounds of this invention may also be prepared using an aromatic halide of structure VIII and a benzaldehyde derivative of structure IX. Compounds of structures VIII and IX are either commercially available or may be prepared using means well known to those skilled in the art. Structure VI
A non-limiting example of the preparation of compounds of II is provided in Example 1. Derivatives of structure IX may be prepared from aromatic halides as described in Examples 1, 7, and 10.
The aromatic halide of structure VIII was converted to aryl lithium using the lithium-halogen exchange reaction as described in Examples 1, 7 and 10 to give structure I
Reaction with a derivative of X provides compounds of the invention where R ₆ is hydroxy and R ₆ 'is hydrogen.

For still further guidance, the following provide non-limiting examples that more specifically illustrate how to make various compounds of the invention. As used herein, the following abbreviations are used:

[0119]

[Table 16]

[0120]                               Example 1

[0121]

[Chemical 8]

1a. 4-Bromo-3,5-dimethyl-nitrobenzene: 2 ', 6'-Dimethyl-4-nitrophenol (3 g) is added to 50 mL dichloromethane and 3.6 mL pyridine. The above solution was cooled to 0 ° C. and 3.6 mL
Of trifluoromethanesulfonic acid anhydride is added dropwise over 20 minutes. The reactants are mixed for about 2.5 hours at 0 ° C. Quench the reaction by adding water (25 mL). 25 mL of 1N hydrochloric acid, 25 mL of water twice, 25 mL of organic layer twice
1N sodium hydroxide, twice with 25 mL water, dried over magnesium sulfate and concentrated under reduced pressure. The remaining residue is dissolved in 40 mL DMF and then lithium bromide (4.7 g) is added. The mixture is refluxed at 150 ° C. for 17 hours. The mixture is concentrated under high vacuum. 6 for this remnant
Add 0 mL water and 60 mL ethyl acetate and stir. The organic layer was concentrated under high vacuum and the remaining residue was adsorbed onto silica gel using dichloromethane (pres).
orb) The adsorbed residue is then purified by chromatography on silica gel and crystallization from hexane to provide 1a.

1b. 4-Bromo-3,5-dimethylaniline: 4-Bromo-3,5-dimethyl-nitrobenzene (1a; 0.6 g) is dissolved in 10 mL ethyl acetate and 80 mg 10% palladium on carbon is added. The reaction is hydrogenated, then filtered through light and concentrated under reduced pressure to provide 1b.

1c. N- [4-Bromo-3,5-dimethylphenyl] pyrrolidone: 4-Bromo-3,5-dimethylanaline (1b; 0.88 g) was dissolved in 2 mL of ethanol and 0.75 mL of 1,4- Add diiodobutane. Reflux the sample overnight. At this time, it is concentrated under reduced pressure. The sample is taken on ethyl acetate and extracted with 0.1 N sodium hydroxide, water, and brine. Dry over sodium sulfate, filter and concentrate under reduced pressure before chromatography on silica gel (
Purify with hexane: ethyl acetate) to provide 1c.

1d. N- [4-carboxaldehyde-3,5-dimethylphenyl [pyrrolidone: N- [4-bromo-3,5-dimethylphenyl] pyrrolidone (1c;
44 g) is dissolved in 10 mL THF and cooled to -78 ° C under nitrogen atmosphere. To this solution is added 2.0 mL of tert-butyllithium (1.7 M in pentane) and the reaction is stirred for 10 minutes. At this time, remove it from the cooling bath and
Allow to stir for 0 minutes. Then cool to −78 ° C. and add 0.27 mL DMF. After 10 minutes, the cooling bath is removed and the reaction is stirred for a further 2 hours. The reaction is acidified with 1N HCl. The organic layer is isolated, extracted 5 times with brine, and the organic layer is dried over sodium sulfate and concentrated under reduced pressure. Purification by chromatography on silica gel (hexane: ethyl acetate) provides 1d.

1e. 2-iso-propylanisole: potassium hydroxide (5.6 g) 13.
In addition to 4 mL acetone, then 2-iso-propylphenyl (13.6 g) is added. After addition of potassium hydroxide, iodomethyl (14.2 g) is added. The reaction is refluxed overnight. 15. Add mL of water. 100 times this reaction
Extract with mL of diethyl ether. The organic layer is extracted twice with 100 mL of 10% aqueous sodium hydroxide, once with 100 mL of water, and once with 100 mL of saturated ammonium chloride. After drying over magnesium sulfate, the organic solution is added over magnesium sulfate, filtered and concentrated under reduced pressure. Fractional distillation of the above material under reduced pressure provides 1e.

1f. 4-Bromo-2-iso-propylanisole: potassium bromide (6.3 g
) Is dissolved in 80 mL of dichloromethane and the reaction is cooled to 0 ° C. under nitrogen.
To this mixture was added 18-crown-6 (0.7
g) is added. At this time, 3-chloroperoxybenzoic acid (9.2 g) in 100 mL dichloromethane is added. Next, 2-iso-propylanisole (1e
4 g) are added dropwise and the reaction is stirred for a further 3 hours under nitrogen at 0 ° C. At this time, the reaction is poured into 300 mL ice water and stirred for 30 minutes.
The organic layer is isolated, washed with saturated sodium hydrogen carbonate solution, then with water, and the organic layer is dried over magnesium sulphate and concentrated under reduced pressure. Purification by chromatography on silica gel (hexane: ethyl acetate) provides If.

1 g. N- [3,5-dimethyl-4- (3'-iso-propyl-4'-methoxybenzylhydroxy) phenyl] pyrrolidone: 4-bromo-2-iso-propylanisole (1f; 0.6g) in 15 mL. Dissolve in THF and cool to -78 ° C under a nitrogen atmosphere. To this solution, 3.4 mL of tert-butyllithium (1.7 M in pentane) is added and the reaction is stirred for 10 minutes. At this time, the mixture is taken out of the cooling bath and stirred for 10 minutes. Then cool to −78 ° C. and add N- [4 [carboxaldehyde-3,5-dimethylphenyl] pyrrolidone (1d; 0.53 g). The reaction is stirred for 1 hour, then the cooling bath is removed and stirred for an additional 2 hours. The title reaction was treated with 15 mL of ether and 15 m
Transfer to a separatory funnel with L water and acidify the aqueous layer with 1N HCl. The organic layer is isolated, washed 5 times with brine, then dried over sodium sulfate and concentrated under reduced pressure. Purification by chromatography on silica gel (hexane: ethyl acetate) provides 1 g.

[0129]                               Example 2

[0130]

[Chemical 9]

2. N- [3,5-dimethyl-4- (3'-iso-4'-methoxybenzyl)
Phenyl] pyrrolidone: N- [3,5-dimethyl-4- (3′-iso-propyl-4′-methoxybenzylhydroxy) phenyl] pyrrolidone (1 g; 0.4 g
) Was added to 10 mL of 9% acetic acid in ethanol and 50 mg of 1 on carbon was added.
Add 0% palladium. The reaction is hydrogenated, then filtered through Celite and concentrated under reduced pressure to provide 2.

[0132]                               Example 3

[0133]

[Chemical 10]

3a. 2,6-Dichloro-4-nitrobenzoic acid: 2,6-Dichloro-4-nitrotoluene (3 g) is dissolved in 12.5 mL pyridine and then 12.8 mL water is added. The mixture was warmed to 90 ° C and potassium permanganate (14
． 1 g) is added over 1 hour. The mixture is then refluxed for 1 hour and the hot is filtered. The filtrate is extracted once with 50 mL chloroform. The aqueous layer is acidified with 6N hydrochloric acid and extracted twice with 50 mL chloroform. After drying over magnesium sulfate, the organic layer is filtered and concentrated under reduced pressure to provide 3a.

3b. 2,6-Dichloro-4-nitro-3'-iso-propyl-4'-methoxy-benzophenone: 2,6-dichloro-4-nitrobenzoic acid (3a; 0.4g
) Is dissolved in 5 mL of thionyl chloride and refluxed for 1 hour. Then thionyl chloride is evaporated under reduced pressure and the remaining residue is dissolved in 300 μL of dichloromethane. To this solution, 150 μL of trifluoromethane sulfonic acid and 2-iso-propylanisole (1e; 0.17 g) are added and allowed to react for 5 hours. Dichloromethane was then removed under reduced pressure and the remaining residue was 20 m
Dissolve in L ethyl acetate. The organic layer is extracted twice with 20 mL of brine solution. The organic layer is concentrated under reduced pressure and purified by chromatography on silica gel (hexane: ethyl acetate) to provide 3b.

3c. 2,6-Dichloro-4-amino-3'-iso-4'-methoxy-benzophenone: 2,6-dichloro-4-3'-iso-propyl-methoxy-benzophenone (3b; 144 mg) in 10 mL ethanol and 10 mL Dissolve in a mixture containing ethyl acetate. To this mixture is added 19.2 mg of 10% palladium on carbon. The reaction is hydrogenated, then filtered through Celite and concentrated under reduced pressure to provide 3c.

[0137]                               Example 4

[0138]

[Chemical 11]

4. 2,6-dichloro-4-butyrylamide-3'-iso-propyl-4'-
Methoxy-benzophenone: pyridine (91 μL) and butyric anhydride (184 μL)
Is added to 2,6-dichloro-4-amino-3′-iso-propyl-4′-methoxy-benzophenone (3c; 130 mg) and the reaction is stirred overnight.
The reaction is concentrated under reduced pressure and the residue is taken up in 20 mL ethyl acetate. The organic layer was extracted once with 20 mL saturated sodium hydrogen carbonate, once with 20 mL 0.1N hydrochloric acid, concentrated under reduced pressure and chromatographed on silica gel (9: 1 hexane: ethyl acetate). Purify to provide 4.

[0140]                               Example 5

[0141]

[Chemical 12]

5. N- [3,5-dichloro-4- (3'-iso-propyl-4'-methoxybenzylhydroxy) phenyl] butylamine: 2,6-dichloro-4-butyrylamide-3'-iso-propyl-4'- Methoxy-benzophenone (4; 0.
53 g) is dissolved in THF (10 mL) and added dropwise to a mixture of lithium aluminum hydride (0.33 g) in THF (20 mL) under nitrogen and reacted overnight. The reaction is cooled in an ice bath and water (2 mL) is added dropwise, then 2 mL of 15% sodium hydroxide and then 15 mL of water are added. The precipitate that forms is filtered off and the precipitate is washed with THF and ethyl acetate. The filtrate is concentrated under reduced pressure and the product is purified by chromatography on silica gel (hexane: methyl chloride) to provide 5.

[0143]                               Example 6

[0144]

[Chemical 13]

6. N- [3,5-Dimethyl-4- (3'-iso-propyl-4'-methoxybenzyl) phenyl] butylamine: N- [3,5-dichloro-4- (3'-iso-propyl-4 ' -Methoxybenzylhydroxy) phenyl] butylamine (
5; 0.6 g) is dissolved in 12 mL of 9% ethanolic acetic acid solution and 75 mg of 10% palladium on carbon is added. The above reactant is hydrogenated. The reaction is filtered through Celite and concentrated under reduced pressure, and the product is purified by chromatography on silica gel (hexane: dichloromethane) to provide 6.

[0146]                               Example 7

[0147]

[Chemical 14]

7a. N- [4-Bromo-3,5-dimethylphenyl] morpholine: 4-Bromo-3,5-dimethylanaline (1b; 0.72 g) was dissolved in 2 mL ethanol to give 0.95 mL di (2 -Iodoethyl) ether is added. Reflux the sample overnight. At this time, it is concentrated under reduced pressure. The sample is taken on ethyl acetate and extracted with 0.1N sodium hydroxide, water, and brine.
After drying over sodium sulfate, filter paper, and concentration under reduced pressure, the mixture is purified by chromatography on silica gel (hexane: ethyl acetate),
7a is provided.

7b. N- [3,5-Dimethyl-4- (3'-isopropyl-4'-methoxybenzylhydroxy) phenyl] morpholine: N- [3,5-Dimethyl-4-
(3'-iso-propyl-4'-methoxybenzylhydroxy) phenyl] morpholine (7b) was added to the above N- [3,5-dimethyl-4- (3'-isopropyl-4'-methoxybenzylhydroxy)]. Prepared in analogy to the process for phenyl] pyrrolidone (1 g).

[0150]                               Example 8

[0151]

[Chemical 15]

8. N- [3,5-Dimethyl-4- (3'-iso-propyl-4'-methoxybenzyl) phenyl] morpholine: N- [3,5-Dimethyl-4- (3'-isopropyl-4'- Methoxybenzylhydroxy) phenyl] morpholine (7
b; 03 g) was dissolved in 10 mL of a 9% solution of acetic ether and 45 on carbon.
Add 10 mg of 10% palladium. The reaction was hydrogenated (about 16 hours), then filtered through Celite and concentrated under reduced pressure to provide 8.

[0153]                               Example 9

[0154]

[Chemical 16]

9. N-methyl-N- [3,5-dimethyl-4- (3'-iso-4'-methoxybenzyl) phenyl] butylamine: N- [3,5-dimethyl-4- (3'-
Iso-propyl-4′-methoxybenzyl) phenyl] butylamine (6), 0
． Dissolve 1 g in 1 mL THF. To this solution is added 50 mg sodium borohydride. The resulting slurry was treated with 0.24 mM 3.0 M sulfuric acid, 0.08
Add to 6 mL of 37% aqueous formaldehyde and 1 mL of a 0 ° C. solution of THF. The reaction is stirred for 2 hours and then poured into 3 mL 1N sodium hydroxide. The aqueous layer is extracted twice with diethyl ether, and the organic layers are combined and washed twice with brine.
The organic layer is filtered, and the filtrate is concentrated under reduced pressure and the product is purified by chromatography on silica gel (hexane: dichloromethane) to provide 9.

[0156]                               Example 10

[0157]

[Chemical 17]

10c. N- [3,5-Dimethyl-4- (3'-benzyl-4'-methoxybenzylhydroxy) phenyl] pyrrolidone: N- [3,5-Dimethyl-4- (3
'-Benzyl-4'-methoxybenzylhydroxy) phenyl] pyrrolidone (1
0c) is prepared in analogy to N- [3,5-dimethyl-4- (3′-iso-propyl-4′-methoxybenzylhydroxy) phenyl] pyrrolidone (1 g), but with 2-iso-propylphenol. Is replaced with 2-benzylphenol.

Uses of the Invention In accordance with the methods of the invention, a compound having the structure described herein is administered, but most preferably with a pharmaceutically or cosmetically acceptable carrier.

The compounds of the present invention may be used to treat such conditions in animals as treating hair loss, stopping hair loss and / or reversing hair loss, and promoting hair growth. including. Such symptoms may manifest themselves in alopecia, including, for example, male pattern baldness and female pattern baldness.

Additionally, the compounds of the present invention may be useful in controlling body weight, including the treatment and / or prevention of obesity. Other uses of the compounds of the invention include stimulation of nail growth, treatment of skin conditions, prevention of hair bleaching, cholesterol reduction, treatment of thyroid failure, and treatment of osteoporosis.

Preferably, the compounds of the invention are cardiotolerant as defined herein. Preferably, the compound is formulated into a pharmaceutical or cosmetic composition for use in treating or preventing the above conditions. Using standard pharmaceutical formulation techniques, eg, Remington's Pharmaceutical Sciences
S., Mack Publishing Company, Easton, PA.
This is the technique disclosed in (1990).

Typically, a compound having the structure described herein, from about 5 mg to about 30
0 mg, more preferably about 5 mg to about 1000 mg, more preferably about 10 m
From g to about 100 mg is administered by systemic administration per day. It is understood that these dosage ranges are exemplary and that daily administration can be adjusted depending on various factors. The particular dose of compound administered, and the duration of treatment, and whether treatment is local or systemic, are interdependent. Dosage and treatment regimen will depend on the particular compound used, the indication of treatment, the effect of the compound, the individual characteristics of the subject (eg, weight, age, sex, and medical condition of the subject), compliance with the treatment regimen, and treatment. It will also depend on factors such as the presence and severity of any side effects of.

According to the present invention, the subject compounds are co-administered with a pharmaceutically or cosmetically acceptable carrier (collectively herein "carrier"). As used herein, the term "carrier" means one or more compatible solid or liquid fill diluents or encapsulating substances which are suitable for administration to mammals. As used herein, the term "compatibility" means that the components of the composition are such that the components of the composition are in accordance with the compound of the invention in a manner such that there is no interaction that would substantially diminish the effectiveness of the composition under normal conditions of use. And that they can be mixed with each other. The carrier is, of course, of sufficiently high degree of purification and of sufficiently low toxicity that it is suitable for administration to the animal to be treated, preferably a mammal (most preferably a human). The carrier can be inert per se, or it can possess its own pharmaceutical and / or cosmetic benefits.

The compositions of this invention may be in any of a variety of forms suitable for (eg) oral, rectal, topical, intranasal, intraocular or parenteral administration. Of these, intranasal and / or oral administration is particularly preferred, and topical is most preferred. Various carriers known in the art may be used, depending on the particular route of administration desired. These include solid or liquid fillers, diluents, hydrotropic agents, surfactants, and encapsulating materials.
Any pharmaceutically or cosmetically active substance which does not substantially interfere with the activity of the compounds of the present invention may be included. The amount of carrier used with the compound is sufficient to provide a practical amount of material for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods of this invention are described in the following literature: Modern Pharmaceuticals, Chapters 9 and 10, Banker & Rhodes, eds. (1979); Lieberma.
n et al. , Pharmaceutical Dosage Forms
: Tablets (1981); and Ansel, Induction.
to Pharamaceutical Dosage Forms, 2 ^nd Ed
． , (1976).

Some examples of substances that may function as carriers or components thereof are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starches; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and Methyl cellulose; powdered tragacanth gum; 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 theobrom oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol, And polyethylene glycol; alginic acid; emulsifiers such as TWEENS; wetting agents such as sodium lauryl sulfate; coloring agents; flavoring agents; molding agents; stabilizers, antioxidants; preservatives; pyrogen-free water; isotonic salt solutions; And a phosphate buffer solution.

The choice of carrier for use with the subject compounds is typically determined by the method by which the compound is administered. In particular, carriers for systemic administration include sugar, starch, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oil, synthetic oil, polyol, alginic acid, phosphate buffer solution, emulsifier, isotonic salt solution, and Includes pyrogen-free water.
Preferred carriers for parenteral administration are propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil. Preferably, the carrier in a composition for parenteral administration comprises at least about 90% by weight of the total composition.

A variety of oral dosage forms can be used, including solid forms such as tablets, capsules, granules and powders of masses. These oral forms contain a safe and effective amount of the compound used in the present invention, usually at least about 5%, and preferably about 25% to about 50%. Tablets may be compressed, tablet milled, enteric coated, sugar coated, film coated or double compressed and may contain suitable binders, lubricants, diluents, Includes disintegrants, colorants, flavoring agents, glidants, and melting agents. Liquid oral forms are suitable solvents, including aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules. , Preservatives, emulsifying agents, suspending agents, diluents, sweetening agents, melting agents, coloring agents and flavoring agents.

Suitable carriers for the manufacture of unit doses for oral administration are well known in the art. Tablets typically contain conventional pharmaceutically compatible adjuvants, inert diluents such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch. , Alginic acid and croscarmellose; as lubricants such as magnesium stearate, stearic acid and talc. Glidant
Can improve the flowability of the powder mixture, for example by using silicon dioxide. Color formers 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 secretory and sustained release formulations) typically include one or more solid diluents disclosed above. The choice of carrier component depends on secondary considerations such as taste, cost, and shelf stability, is not critical for the purposes of the subject invention, and can be readily made by one of ordinary skill in the art.

Orally administered compositions also include liquid solutions, emulsions, suspensions, powders, granules, elixirs, colorants, syrups and the like. Suitable carriers for the manufacture of such compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. With regard to suspensions, typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, AVICEL RC-591, gum tragacanth and sodium alginate; typical humectants include rayin and polysorbate 80; and typical preservatives. Includes methylparaben and sodium benzoate. Oral liquid compositions may also include one or more components such as sweeteners, flavoring agents and colorants disclosed above.

Such compositions may be coated by conventional methods, typically pH or time dependent coatings, whereby the subject compounds are in the vicinity of the desired topical application or at the desired level. It is released into the gastrointestinal tract at various times for its effect. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate, ethylcellulose, Eudragit coatings, waxes and shellac.

Other compositions useful for achieving systemic delivery of the subject compounds include sublingual, buccal, and intranasal 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. . The glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may be included.

The compounds of this invention may be administered topically. The carrier of the topical composition preferably assists in permeating the compound of the present invention into the skin and reaching the environment of the hair follicles. The topical compositions of the present invention may be in any form such as a solution, oil,
Includes creams, ointments, gels, lotions, shampoos, leave-on and rinse-out hair conditioners, milks, cleansers, moisturizers, sprays, skin patches and the like.

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

Other substances suitable for use in topical carriers are, for example, softeners, solvents, wetting agents,
Includes concentrates and powders. Examples of each of this type of substance can be used as a single or as a mixture of one or more substances, as follows: Softeners, such as stearyl alcohol, glyceryl monoricinolate, gueryl monostearate. Rate, propane-1,2-diol, butane-1,3-diol, mink oil, cetyl alcohol, iso-propyl isostearylate, stearic acid, iso-butyl palnate, isocetyl alcohol, oleyl alcohol, iso-propyl. Laurate, hexyl laurate, decyl oleate,
Octadecan-2-ol, isocetyl alcohol, cetyl palmitate, dimethyl polysiloxane, di-n-butyl laurate, iso-propyl myristate, iso-propyl palmitate, iso-propyl stearate, butyl stearate, polyethylene glycol , Triethyl glycol, lanolin, sesame oil, coconut oil, peanut oil, castor oil, acetylated lanolin alcohol, petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid,
Iso-propyl linoleate, lauryl lactate, myristyl lactate, decyl orriate, and myristyl myristate; radiopharmaceuticals such as propane, butane, iso-butane, dimethyl ether, carbon dioxide, and dinitrogen monoxide; solvents such as ethyl alcohol, methylene chloride. , Iso-propanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, methyl sulfoxide, dimethylformamide, tetrahydrofuran; wetting agents such as glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate , Soluble collagen, dibutyl phthalate, and gelatin; and powders such as chalk, talc, earth for filling, starch, gums, Loid silicon dioxide, sodium polyacrylate, tetraalkylammonium smectite, trialkylarylammonium smectite, chemically modified magnesium aluminum silicate, organically modified montmorillonite viscosity, hydrated aluminum silicate, fumigated silicon dioxide , Carboxyvinyl polymer, sodium carboxymethyl cellulose, and ethylene glycol monostearic acid.

The compounds used in the present invention may be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. Preferred formulations for topical delivery of the compounds of the invention are described by Dowton et al. , "Influence
of Liposomal Composition on Topical
Delivery of Encapsulated Cyclospori
n A: I. An in vitro Study Using Haire
ss Mouse Skin ", S.T.P.Pharma Sciences
, Vol. 3, pp. 404-407 (1993); Wallach and.
Philippot, "New Type of Lipid Vicele"
: Novasome (registered trademark) ", Kiposome Technology
, Vol. 1, pp. 141-156 (1993); Wallach, US Pat. No. 4,911,928, assigned to Micro-Pak, issued March 27, 1990;
And Weiner et al. , US Pat. No. 5,834,014, assigned to University of Michigan and Micro-Pak, issued November 10, 1998 (Weiner
For et al, instead of or in addition to minoxidil, the compounds described herein are administered).

The compounds of the present invention may be administered by iontophoresis. For example, the Internet site www. unipr. it / arpa / dipfarm / e
rasmus / erasm14. html; Banga et al. , "Hy
dragel-based Iontotherapeutic Delive
ry Devices for Transdermal Delivery
of Peptide / Protein Drugs ", Pharm. Res.
, Vol. 10 (5), pp. 697-702 (1993); Ferry, "T.
theoretical Model of Iontophoresis Ut
illized in random Drug Delivery ”,
Pharmaceutical Acta Helvetiae, Vol 70
, Pp. 279-287 (1995); Gangarosa et al. 、 ”
Modern Iontophoresis for Local Drug
Delivery ”, Int. J. Pharm, Vol. 123, pp. 159.
-171 (1995); Green et al. , "Iontopholet
ic Delivery of a Series of Tripeptid
es Across the Skie in vitro ", Pharm. R
es. , Vol 8, pp. 1121-1127; Jadoul et al.
, "Quantification and Localization of
Fentanyl and TRH Delivered by Ionto
phoresis in the Skin ", Int. J. Pharm., V.
ol. 120, pp. 221-8 (1995); O'Brien et al.
, "An Updated Review of it's Antivirual
Activity, Pharmacokinetic Properties
and Therapeutic Efficacy ", Drugs, Vol
． 37, pp. 233-309 (1989); Parry et al. , "A
cyclovir Bioavailability in Human Ski
n ", J. Invest. Dermatol., Vol.98 (6), pp.8.
56-63 (1992); Santi et al. , "Drug Reser
Vor Composition and Transport of Sa
lmon Calcitonin in Transdermal Ionto
Phoresis ", Pharm. Res., Vol 14 (1), pp.63.
-66 (1997); Santi et al. , "Reverse Iont
opphoresis-Parameters Determinating E
electrophoretic Flow: I. pH and Ionic S
strength ”, J. Control. Release, Vol. 38, pp.
． 159-165 (1996); Santi et al. , "Reverse
Iontophoresis-Parameters Determin
ing Electrophoretic Flow: II. Electrod
e Chamber Formation ", J. Control.Rel
ease, Vol. 42, pp. 29-36 (1996); Rao et al.
． , "Reverse Iontophoresis: Noninvasive
Glucose Monitoring in vivo in Human
s ", Pharm. Res., Vol. 12 (12), pp. 1869-187.
3 (1995); Thysman et al. , "Human Calcit
onin Delivery in Rats by Iontophores
is ", J. Pharm. Pharmacol., Vol. 46, pp. 725.
-730 (1994); and Volpato et al. , "Iontoph
oresis Enhances the Transport of Acy
clovir through Nude Mouse Skin by Ek
Electrorepulsion and Electroosmosis ”, P
harm. Res. , Vol. 12 (11), pp. 1623-1627 (19
95).

The compositions used in the present invention may optionally use an activity enhancer. The activity enhancer can be selected from a variety of molecules that can function in different ways to enhance the hair growth effects of the compounds of the invention. A particular class of activity enhancers includes other hair growth stimulants and penetration enhancers.

Non-limiting examples of other hair stimulants may be used in the compositions herein, including both systemic and topical, eg, benzalkonium chloride, benzezonium chloride, phenol. , Estradiol, diphenhydramine hydrochloride, chloropheniramine maleate, chlorophyllin derivative, cholesterol, salicylic acid, cysteine, methionine, red pepper colorant, benzylnicotinate, 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. Including harmful agents, glycosaminoglycanase inhibitors, esters of pyroglutamic acid, hexosaccharinic acid or acylated hexosaccharinic acid, aryl-substituted ethylene, N-acylated amino acids, and of course minoxidil or finasteride .

Non-limiting examples of penetration enhancers that may be used in the compositions herein are, for example, 2-methylpropan-2-ol, propan-2-ol, ethyl-2-hydroxypropanoate, hexane. -2,5-diol, POE (2) ethyl ether, di (
2-hydroxypropyl) ether, pentane-2,4-diol, acetone,
POE (2) methyl ether, 2-hydroxypropionic acid, 2-hydroxyoctanoic acid, propan-1-ol, 1,4-dioxane, tetrahydrofuran,
Butane-1,4-diol, propylene glycol dipelargonate, polyoxypropylene 15 stearyl ether, octyl alcohol, POE ester of 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 salicinate,
Iso-propyl palmitate, ethyl laurate, 2-ethyl-hexyl pelargonate, iso-propyl isostearate, butyl laurate, benzyl benzoate, butyl benzoate, hexyl laurate, ethyl caprate, ethyl caprylate, butyl stearate. , Benzyl salicylate, 2-hydroxypropionic acid, 2-hydroxyoctanoic acid, methylsulfoxide, N, N-dimethylacetamide, N, N-dimethylformamide, 2-pyrrolidone, 1-methyl-2-pyrrolidone, 5-methyl -2-pyrrolidone, 1,5-dimethyl-2-
Includes pyrrolidone, 1-ethyl-2-pyrrolidone, phosphine oxide, sugar esters, tetrahydrofurfural alcohol, urea, diethyl-m-toluamide, and 1-dodecylazacyclopheptan-2-one.

In all of the above, of course, the compounds used in the method may be administered alone or in admixture, and the composition may further comprise an additional drug or excipient suitable for indication. May be included.

The present invention further comprises compounds and / or compositions and languages of the invention, paintings, and / or
A kit comprising information and / or instructions such as or the like, the use of said kit providing a method of treating hair loss in mammals (especially humans), eg stopping and / or reversing hair loss, and / or Including promoting hair growth. Additionally or alternatively, the kit comprises a compound and / or composition of the invention and the compound and / or
Alternatively, it may include information and / or instructions regarding how to apply the composition, particularly regarding the benefits of treating hair loss in mammals.

Examples of Composition Administration The following examples do not limit the invention but provide guidance to those of skill in the art to practice the methods of the invention. In each example, compounds other than those mentioned may be replaced with another having the structure described herein with similar results in the examples.

Example A A composition for topical administration was made up and consisted of: Ingredient Amount Compound of Example 3 5% Ethanol 57% Propylene glycol 19% Dimethylisosorbide 19% Human suffering from male pattern baldness Men are treated by the method of this invention.
In particular, the composition is topically administered daily to a subject for 6 weeks.

Example B A composition for topical administration is prepared according to Dowton et al. , "Influence
of Liposomal Composition on Topical
Delivery of Encapsulated Cyclosporin
A: I. An in vitro Study Using Hairs
s Mouse Skin ", S.T.P. Pharma Sciences,
Vol. 3, pp. 404-407 (1993), substituting the compound of Example 2 for cyclosporin A, and N for nonionic liposomal formulations.
Created using ovasome1.

A human male with a male pattern of baldness is treated with the above composition. In particular, the composition is topically administered daily to a subject for 6 weeks.

[0187]                               Example C   I created a shampoo, which consists of:

[0188]

[Table 17]

Human males with a male pattern of baldness are treated by the methods of this invention.
In particular, the shampoo is used on the subject daily for 12 weeks.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 31/167 A61K 31/167 31/40 31/40 31/5375 31/5375 A61P 3/04 A61P 3 / 04 3/06 3/06 5/14 5/14 17/14 17/14 19/10 19/10 C07C 225/22 C07C 225/22 233/33 233/33 C07D 295/08 C07D 295/08 Z (72 ) Inventor Mackiver, John Macmillan 45241, Ohio, United States, Cincinnati, Indian Springs Driven 9999 F-term (reference) 4C083 AC072 AC102 AC122 AC132 AC172 AC352 AC442 AC561 AC562 AC712 AC782 AC851 AC852 AD152 CC37 CC38 DD23 EE22 4C086 AA01 AA03 BC07 BC73 MA01 MA04 NA14 ZA92 4C206 AA01 AA03 FA31 MA01 MA04 NA14 ZA92 4H006 AA01 AA03 AB20 BJ50 BM30 BN10 BN30 BP30 BR60

Claims (10)

[Claims] 1. Structure: Wherein R ₁ , R ₂ , R ₅ , R ₇ and R ₁₀ are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl and heteroalkynyl; R ₄ Is from halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarylalkyl, and heteroarylalkenyl. R ₂ is H, Y is —CH ₂ CHK ₁ , and X is —N.
Selected Z- and from the group consisting of -NH-, and R ₁₂ is C ₁ -C ₄ alkyl, provided that K ₁ is selected from hydrogen and C ₁ -C ₄ alkyl, and Z is C ₁ -C ₄ When alkyl, R ₄ is not arylalkyl; R ₈ and R ₉ are each independently hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroalkyl, heteroalkenyl, Selected from the group consisting of heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarylalkyl, and heteroarylalkenyl; provided that at least one of R ₈ and R ₉ is not hydrogen; R ₃ is hydrogen , Alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, Selected from the group consisting of arylalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarylalkyl, and heteroarylalkenyl; R ₆ and R ₆ 'are each independently Selected from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, thio, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroarikinyl; with the proviso that R ₆ and R ₆ ′ are both oxo and thioxo. Y is selected from the group consisting of a bond, alkyl, alkenylalkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl; X is selected from the group consisting of -NZ-, -NH- and -O-. R ₁₁ is a bond or -C (O) - is selected from the group consisting of; however, Y is a bond, and when X is -O-, R ₁₁ is -C (O) -; R ₁₂ is alkyl, alkenyl, Selected from the group consisting of alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, and heteroarylalkenyl; When R ₁₁ is a bond, R ₁₂ and Z are optionally joined together to form a ring selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl. ;
R ₁₂ is heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarylalkyl,
Or when heteroarylalkenyl, the heteroatom of R ₁₂ is not directly covalently bonded to R ₁₁ ; and Y is a bond, X is —O—, and R ₁₁ is —C (O) —, R ₁₂ is not alkyl; and Z is selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl; provided that R ₁₁ is a bond,
R ₁₂ and Z optionally combine together to form a ring selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl) And pharmaceutically acceptable salts, hydrates, and biohydrolyzable amides, esters and imides thereof. 2. The compound of claim 1, wherein Y is a bond; and each of R ₈ and R ₉ is not hydrogen. 3. The compound according to claim 1 or 2, wherein X is selected from the group consisting of -NH- and -NZ-. 4. R ₄ , R ₈ and R ₉ are each independently selected from the group consisting of halogen, alkyl, alkenyl and heteroalkyl; R ₃ is selected from the group consisting of hydrogen and lower alkyl. The compound according to any one of claims 1 to 3. 5. R ₆ and R ₆ 'each independently represent hydrogen, halogen, hydroxy,
And it is selected from the group consisting of lower alkyl; provided that R ₆ and R ₆ optionally 'are both oxo, claims 1 to any one compound according to 4. 6. R₁₂Is alkyl, heteroalkyl, arylalkyl, and
Selected from the group consisting of heteroarylalkyl; wherein R₁₁When is a bond, R ₁₂ And Z are optionally linked together to form cycloalkyl, cycloalkenyl
, Heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl
6. Forming a ring selected from the group consisting of
Compound of. 7. The compound according to claim 1, wherein R ₁ , R ₂ , R ₅ , R ₇ , and R ₁₀ are each hydrogen. 8. X is -NZ- and Z is C ₁ -C ₃ alkyl, provided that when R ₁₁ is a bond, R ₁₂ and Z are optionally bonded together to form a cycloalkyl. , Cycloalkenyl, heterocycloalkyl, heterocycloalkenyl,
2. A ring selected from the group consisting of aryl and heteroaryl.
8. The compound according to any one of 1 to 7. 9. A composition characterized by a compound according to any one of claims 1 to 8 and a carrier. 10. A method for treating hair loss, which comprises administering the composition according to claim 9 to a mammal.