JP2002525352A - 2-substituted ketoamide - Google Patents

Abstract

  (57) [Summary] The present specification relates to novel compounds and compositions that are particularly effective in treating alopecia in mammals, including inhibiting and / or reversing alopecia and promoting hair growth. The compounds and compositions of the present invention may further be effective against a variety of disorders including, for example, multidrug resistance, human immunodeficiency virus (HIV), heart disorders, and neurological disorders, and control parasites And may also be effective in triggering immunosuppression.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD OF THE INVENTION

The present invention relates to novel compounds and compositions that are particularly effective for treating alopecia in mammals, including inhibiting and / or reversing alopecia and promoting hair growth. The compounds and compositions of the present invention may further be effective against a variety of disorders including, for example, multidrug resistance, human immunodeficiency virus (HIV), heart disorders, and neurological disorders,
It may also be effective in controlling parasites and triggering immunosuppression.

RELATED APPLICATIONS This application claims priority under 35 USC 119 (e), based on provisional application 60 / 102,448, filed September 30, 1998.

[0003]

[Prior art]

Alopecia is a common problem that occurs, for example, through the natural course or is often chemically promoted through the use of certain therapeutic agents designed to alleviate conditions such as cancer. . Such alopecia is often accompanied by a lack of hair regeneration that causes component or global baldness. Such baldness is cosmetically unattractive and particularly annoys those who are experiencing hair loss.

[0004] As is well known in the art, hair growth occurs by the hair cycle, which involves alternating repetitions of anagen and telogen. This cycle is often divided into three main phases, known as anagen, catagen, and telogen. Anagen (anagen) is the anagen phase of the hair cycle and is characterized by deep penetration of the hair follicles into the dermis with rapid proliferation of cells that are differentiated to produce hair. The next phase is the transitional phase (catagen), a transitory process characterized by cessation of cell division, during which the hair follicles regress in the dermis and hair growth stops. The next phase of telogen (telogen) is a telogen in which regressed vesicles are packed with dermal papillae cells and contain microorganisms.
Often characterized. In the telogen phase, the onset of a new anagen phase is due to rapid cell growth in microorganisms, dermal papilla swelling, and assimilation of basement membrane components.
This cycle is repeated throughout hair growth. At that time, hair growth ceases, most hair follicles are in telogen, and if anagen does not begin, it can lead to the onset of total or component baldness.

[0005] For example, there are many attempts in the literature to promote hair regeneration by promoting or 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 by Pharmacia & Upjohn as Rogaine®) And oral finasteride (sold by Merck & Co., InC. As Propecia®).

However, there are conflicting reports regarding the ability of minoxidil to grow hair. In fact, early clinical trials examining blood pressure reduction with the use of minoxidil do not even mention hirsutism (hair growth) as a side effect. Dormois
ois) et al., "Minoxidil in Severe Hypertension: Value When Conventional
Drugs Have Failed ", American Heart J
ournal), 90, 360-368 (1975). Indeed, minoxidil manufacturers report only limited hair growth of components in patients using minoxidil. See, for example, Physician Desk Reference®, 49th Edition, (1995), p. In addition, minoxidil includes vasodilation (peri-cardiac fluid retention and increased heart rate), dyspnea, and weight gain,
May have serious side effects. Physician Desk Reference (registered trademark), 49th edition (1995), p. 2581.

[0007] In addition, while early researchers have shown that Propecia® may be more effective than Rogaine®, Propecia (P
Patients using ropecia® have experienced limited hair growth. New England Journal of Medicine (The New En
gland Journal of Medicine), 338, 9 (February 26, 1998). The potential side effects of Propecia are severe. Propecia
) ® may cause hypersensitivity reactions, including impotence, decreased libido, decreased ejaculation volume, tenderness and swelling of the breast, and lip swelling and erythema of the skin.
In addition, Propecia® is not applicable to women and children. In fact, pregnant or potential pregnant women should not even touch the broken or destroyed tablets containing this drug. Physician's desk
Reference (registered trademark), 52nd edition, (1998) p. 1737, and The New England Journal of Med.
icine), 338, 9 (February 26, 1998).

Interestingly, the immunosuppressants cyclosporin A and FK506 are known to cause significant hirsutism side effects. Iwabuchi et al., "Effects of peptidylprolyl (cis-trans) isomerase (PPIase) inhibitors of immunosuppression, cyclosporin A, FK506, ascomycin, and rapamycin on hair growth initiation in mice: immunosuppression is not required for hair growth initiation (Effects of Immunosuppressive
Peptidyl-Prolyl cis-trans Isomerase (PPIase) Inhibitors, Cyclosporin
A, FK506, Ascomycin, and Rapamycin, on Hair Growth Initiation in Mouse
: Immunosuppression is not Required for New Hair Growth ”, Journal of Dermatological Scie
9), pp. 64-69 (1995); Yamamoto et al., Cyclosporin A.
And FK506, Hair Growth-Stimulating Effect of Strong Immunosuppressant
Effect Cyclosporin A and FK506, Potent Immunosuppressaant ”, Journal of Dermatological Scienc
e), Volume 7 (Supplement), S47-S54 (1994); Yamamoto et al., FK5
06, Stimulation of Hair by topical application of powerful immunosuppressant
Growth by Topical Application of FK506, a Potent Immunosuppressive Agent
) ", Journal of Investigational Dermatology (Journa
l of Investigational Dermatology), 102, 160-164 (1994).
Jiang et al., Induction of Anagen in Telogen Mou by topical application of FK506, a potent immunosuppressant, to the skin of resting mice.
se Skin by Topical Application of FK506, a Potent Immunosuppressant)
, Journal of Investigational Dermatology
Investigational Dermatology), 104, 523-525 (1995)
"Topical FK506: Powerful Immunotherapy for Alopecia Areata, Study Using a Hairy Rat Model for Dandy Experiments," by McElwee et al., British
British Journal of Dermatology, 13
77, 491-497 (1997); "Haair Gr" by Maurer et al.
owth Modulation by Topical Immunophilin Ligands ", American Journal of Pathology, 4, 150, 1
433-1441 (1997); and Paus et al., "Hair Growth Control by Immunosuppression", Arch. Dermatol.
Res., 288, 408-410 (1996). However, because these compounds have significant potency as immunosuppressants, it may not be desirable to use them as hair growth actives.

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

Embedded image

[0010] Stocks et al., "The Contribution to Binding of the Pyranosi in the Truncated Binding Region of FK506"
de Substituents in the Excised Binding Domain of FK-506), Bioorganic & Medicinal Letters
Chemistry Letters), 4, 12, 1457-1460 (1994).
Analogs very similar to this complex macrocycle have been disclosed to have hair growth properties, for example, in the form of alopecia areata and / or male pattern baldness. U.S. Pat. No. 5,541,193 (Kawai et al., Abbott Laboratories)
oratories), issued July 30, 1996); U.S. Patent No. 5,496,564 (Asakura et al., Fujisawa Pharmaceutical Company, issued March 5, 1996); U.S. Patent No. 5,352
No. 5,550,233 (Rupprecht, U.S. Pat. No. 5,550,233, issued to Baumann et al., Sandoz Ltd., Oct. 4, 1994).
), Et al., Merck, Aug. 27, 1996).

However, expectations for the hairy activity of cyclosporin A and FK506 are:
This is somewhat mitigated by the lack of reporting of hirsutism from a variety of smaller, non-macrocyclic immunosuppressive and non-immunosuppressive compounds that are less complex than FK506. PCT published patent WO96 / 40140 (Steine
r) et al., Guilford Pharmaceuticals,
Inc.), issued December 19, 1996); PCT published patent WO96 / 4063.
3 (Hamilton et al., Guilford Pharmaceuticals (Gu
Ilford Pharmaceuticals, Inc., issued December 19, 1996); U.S. Patent No. 5,696,135 (Steiner et al., GPI NIL Holdings, Inc., December 1997). U.S. Patent No. 5,614,547 (Hamilton et al., Guilford Pharmaceuticals, Inc.), March 25, 1997.
PCT published patent WO 97/16190 (Steiner et al., Guilford Pharmaceauticals, Inc.
), Issued May 9, 1997); PCT published patent WO 96/36630 (Zelle (
Zelle et al., Vertex Pharmaceautica
ls, Inc.), issued November 21, 1996); PCT published patent WO 97/368.
No. 69 (Armistead et al., Vertex Pharmaceauticals, Inc., published October 9, 1997); P
CT published patent WO96 / 15101 (Zelle et al., Vertex Pharmaceauticals, Inc.), May 23, 1996.
PCT published patent WO92 / 19593 (Armistea (Armistea)
d) et al., Vertex Pharmaceauticals,
Inc.), issued November 12, 1992); PCT published patent WO94 / 07858.
No. (Armistead et al., Vertex Pharmaceauticals, Inc., issued April 14, 1994); PCT
Published patent WO95 / 26337, Zelle et al., Vertex Pharmaceauticals, Inc., issued October 5, 1995; PCT published patent WO92 / 21313 (Duffy et al., Vertex. Pharmaceuticals (Vertex Pharmaceauticals, Inc.), 199
U.S. Pat. No. 5,192,773 (Armisted (issued Dec. 10, 2009)
Armistead et al., Vertex Pharmaceaus
ticals, Inc.), issued March 9, 1993); U.S. Patent No. 5,330,993 (
Armistead et al., Vertex Pharmaceuticals (V
ertex Pharmaceauticals, Inc.), issued July 19, 1994); U.S. Pat.
No. 5,622,970 (Armistead et al., Vertex Pharmaceauticals, Inc., issued on Apr. 22, 1997); U.S. Pat. No. 5,654,332 (Armistead et al.). ,
Vertex Pharmaceauticals, Inc.
U.S. Pat. No. 5,620,971 (Armistead et al., Vertex Pharmaceuticals, issued Aug. 5, 1997).
auticals, Inc.), issued April 15, 1997); U.S. Patent No. 5,543,423
No. (Zelle et al., Vertex Pharmaceuticals (Vertex Phar
maceauticals, Inc.), issued Aug. 6, 1996); US Pat. No. 5,516,7.
No. 97 (Armistead et al., Vertex Pharmaceauticals, Inc., issued May 14, 1996); US Pat. No. 5,665,774 (Armistead et al., Vertex).・ Pharmaceuticals (Vertex Pharmaceauticals, Inc.), 1997
September 9, 1998); and Andres et al., "Strongly defined prolylamide analogs, trans-prolyl peptide mimetics (conformationally D
efined Analogs of Prolylamides. trans-Prolyl Peptidomimetics ”, Journal of organic chemistry
58, 6609-6613 (1993); and Armisted.
ead) et al., “Design, Synthesis and Structure of Non-FKBP12, the major binding protein of the immunosuppressant FK506.
macrocyclic Inhibitors of FKBP12, the Major Binding Protein for the Immu
nosuppressant FK506), Acta crystallogra
phica), D51, pp. 522-528 (1995).

Surprisingly, the present inventors have developed a new class of compounds that inhibit and / or reverse alopecia or promote hair growth, but do not have the complex macrocyclic structure of FK506. discovered. The inventor of the present invention has further found among this new class of compounds, compounds that produce hair growth and are surprisingly non-immunosuppressants or have little immunosuppressive action. The minimal and / or absence of immunosuppressive activity of these hair-growing compounds is a distinct advantage compared to the immunosuppressants cyclosporin A and FK506.

[0013]

[Means for Solving the Problems]

The present invention relates to compounds and compositions that are particularly effective in treating alopecia in mammals, including preventing and / or reversing alopecia and promoting hair growth. The compounds and compositions of the present invention may also be effective against a variety of disorders including, for example, multidrug resistance, human immunodeficiency virus (HIV), heart disorders, and neurological disorders, It may also be effective in controlling insects and inducing immunosuppression. The compounds of the present invention have the following structure:

Embedded image And its pharmaceutically acceptable salts, hydrated compounds, and its biologically hydrolyzable amides, esters, and imides, wherein the substituents Z, W, X,
Y, V, A, G, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , and R ₁₀ are defined herein.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to compounds and compositions that are particularly effective in treating alopecia in mammals, including inhibiting and / or reversing alopecia and promoting hair growth. In addition to finding that the compounds of the present invention are effective in treating alopecia, the present inventors have surprisingly further discovered that immunosuppression is not required for stimulation of hair growth. The present inventors have further discovered compounds that are effective in treating alopecia, but are surprisingly non-immunosuppressive. Thus, preferred compounds of the present invention are non-immunosuppressive as defined herein. The compounds of the present invention are also effective for treating various other conditions described herein below. Patents and publications are cited throughout the specification. All references cited herein are hereby incorporated by reference. All percentages, ratios and parts herein are by weight unless otherwise specified.

Definitions and Usage of Terms The following is a list of definitions of terms used in this specification. A "salt" used in the present invention is a cationic salt formed on any acid group (for example, carboxyl group) or a negative salt formed on any base (for example, amino group). It is an ionic salt. Many such salts are known in the art. Preferred cationic salts include the alkali metal salts (such as, for example, sodium and potassium), the alkaline earth metal salts (such as, for example, magnesium and calcium), and organic salts. Preferred anionic salts include halides (eg, chloride). Such acceptable salts, if applicable, must also be suitable for use in mammals.

Unless otherwise indicated, “alkenyl” as used herein refers to unsubstituted or substituted 2 to about 15 carbon atoms, preferably 2 to about 10 carbon atoms, more preferably A straight or branched chain hydrocarbon group having 2 to about 8 carbon atoms, and most preferably about 2 to about 6 carbon atoms. Alkenyl has at least one
It has two olefinic double bonds. Examples of alkenyl include, but are not limited to, vinyl, allyl, and butenyl.

Unless otherwise indicated, “alkoxy” as used herein is an oxygen radical having an alkyl, alkenyl, or alkynyl, preferably an alkyl or alkenyl, and most preferably an alkyl substituent. Examples of alkoxy groups include-
O-alkyl and -O-alkenyl are included. An alkoxy group can be substituted or unsubstituted.

Unless otherwise indicated, “aryloxy” as used herein is an oxygen radical having an aryl substituent. An aryloxy group may be substituted or unsubstituted.

Unless otherwise indicated, “alkyl” as used herein refers to unsubstituted or substituted, 1 to about 15 carbon atoms, preferably 1 to about 10 carbon atoms, more preferably A straight or branched chain hydrocarbon group having 1 to about 6 carbon atoms, and most preferably about 1 to about 4 carbon atoms. Preferred alkyls include, for example, methyl, ethyl, propyl, isopropyl, and butyl.

“Alkylene” as used herein refers to a two-terminal radical, alkyl, alkenyl, or alkynyl. For example, "methylene" is -CH ₂
-. Alkylene can be substituted or unsubstituted. Unless otherwise indicated, "aryl" as used herein is either a carbocyclic or a heterocyclic aromatic ring group. Preferred aryl groups include, for example, phenyl, benzyl, tolyl, xylyl, cumenyl, naptyl, biphenyl, thienyl, furyl, pyrrolyl, pyridinyl, pyrazinyl, thiazolyl, pyrimidinyl, quinolinyl, triazoyl, tetrazolyl, benzothiazolyl, benzofuryl, indolyl, indenyl, azulenyl, Fluorenyl, anthracenyl, oxazolyl, isoxazolyl, isotriazoyl, imidazolyl, pyrazoyl,
Oxadiazolyl, indolizinyl, indolyl, isoindolyl, purinyl,
Quinolidinyl, quinolinyl, isoquinolinyl, cinnolinyl and the like.
Aryl may be substituted or unsubstituted.

Unless otherwise indicated, “arylalkenyl” as used herein is an alkenyl group substituted with an aryl group or an aryl group substituted with an alkenyl group. Arylalkenyl can be substituted or unsubstituted.

Unless otherwise indicated, “arylalkyl” as used herein refers to
An alkyl group substituted with an aryl group, or an aryl group substituted with an alkyl group. Preferred arylalkyl groups include benzyl, phenylethyl, and phenylpropyl. An arylalkyl can be substituted or unsubstituted.

As used herein, a “biohydrolyzable amide” is a compound that does not interfere with the activity of the compound of the invention, or that is immediately converted in vivo in a mammalian subject to form an effective compound Is an amide of the above compound.

As used herein, a “biologically hydrolyzable ester” is a compound that does not interfere with the activity of the compounds of the present invention or that is immediately converted in vivo in a mammalian subject to provide an effective compound Which is an ester of the compound.

As used herein, a “biologically hydrolyzable imide” does not interfere with the activity of the compounds of the present invention or is immediately converted in vivo to an effective subject in a mammalian subject animal. An imide of said compound, which results in a compound.

As used herein, unless otherwise indicated, “cyclic carbon”, “carbocycle”
And the like are hydrocarbon cyclic groups. The cyclic carbon is a single ring or a fused ring,
It is a bridged ring or a spiro polycycle. Unless otherwise indicated, a monocycle contains 3 to about 9 atoms, preferably about 4 to about 7 atoms, and most preferably 5 or 6 atoms. Polycycles contain about 7 to about 17 atoms, preferably about 7 to about 14 atoms, and most preferably 9 or 10 atoms. Cyclic carbon (Carbocycle)
May be substituted or unsubstituted.

Unless otherwise indicated, “cycloalkyl” as used herein is a saturated cyclic carbon or heterocyclic group. Preferred cycloalkyl groups include, for example,
Cyclobutyl, cyclopentyl, and cyclohexyl are included. Cycloalkyls can be substituted or unsubstituted.

As used herein, unless otherwise indicated, “halo”, “halogen”,
“Halide” and the like mean a chlorine, bromine, fluorine or iodine atom group, preferably bromine, chlorine or fluorine, more preferably chlorine or fluorine.

Unless otherwise indicated, “heteroalkenyl” as used herein refers to an alkenyl group containing carbon atoms and one or more heteroatoms in the alkenyl chain (eg, C ( Rather than hanging up like O)),
For example, a -CHOCH2 _2), the hetero atom is oxygen, sulfur, nitrogen, and phosphorus, more preferably, oxygen, selected from sulfur, and nitrogen. Heteroalkenyl can be substituted or unsubstituted.

Unless otherwise indicated, “heteroalkyl,” as used herein, refers to
An alkyl group containing a carbon atom and one or more heteroatoms in the alkyl chain (eg, rather than being pendant as in C (O), for example,
—CH ₂ OCH ₂ ), the heteroatoms of which are selected from the group consisting of oxygen, sulfur, nitrogen and phosphorus, more preferably oxygen, sulfur and nitrogen. It may be heteroalkyl-substituted or unsubstituted.

Unless otherwise indicated, “heteroaryl” as used herein refers to an aryl group that contains carbon atoms and one or more heteroatoms in the aryl ring (eg, Rather than being suspended like C (O), for example, -CHOCH-) wherein the heteroatoms consist of oxygen, sulfur, nitrogen and phosphorus, more preferably oxygen, sulfur and nitrogen Selected from the group. Heteroaryl may be substituted or unsubstituted.

Unless otherwise indicated, “heteroarylalkenyl” as used herein is an arylalkenyl group, wherein said aryl group is heteroaryl and / or alkenyl group is heteroalkenyl. Heteroarylalkenyl can be substituted or unsubstituted.

Unless otherwise indicated, “heteroarylalkyl” as used herein is an arylalkyl group, wherein the aryl group is heteroaryl and the alkyl group is heteroalkyl. Or one of them. Heteroarylalkyl-substituted or unsubstituted.

Unless otherwise indicated, “heterocyclic compound”, “heterocycle”, and the like, as used herein, refer to a cyclic compound containing carbon atom (s) and one or more heteroatoms. A heteroatom wherein the heteroatoms are oxygen, sulfur, nitrogen, and phosphorus;
More preferably, it is selected from the group consisting of oxygen, sulfur, and nitrogen. Heterocycles are monocyclic or fused, bridged, or spiro polycyclic. Unless otherwise indicated, a monocycle contains 3 to about 9 atoms, preferably about 4 to about 7 atoms, and most preferably 5 or 6 atoms. Polycycles contain about 7 to about 17 atoms, preferably about 7 to about 14 atoms, and most preferably 9 or 10 atoms. Heterocyclic compounds (heterocycles) may be substituted or unsubstituted.

“Heterocycloalkyl,” as used herein, unless otherwise indicated.
Is a saturated heterocycle. Heterocycloalkyl can be substituted or unsubstituted.

Unless otherwise indicated, the “lower” components used herein (eg, “
"Lower" alkyl) is a moiety having 1 to about 6, preferably 1 to about 4 carbon atoms.

“Pharmacologically acceptable” as used herein means suitable for use in humans or other mammals.

As used herein, “safe and effective amount of a compound (or composition, etc.)” means an amount effective to exhibit biological activity, and when used in the methods of the present invention. Preferably, at that time, (toxicity, irritation,
Or that the biological activity inhibits and / or ameliorates alopecia or promotes hair growth, without showing undue adverse side effects (such as or allergic reactions) and at a reasonable profit / loss ratio.

As used herein, a “spiro moiety” is a cyclic moiety that shares one carbon with another ring, and is preferably a Z ring. Such spiro moieties can be carbocyclic or heterocyclic. Spiro components may be substituted or unsubstituted.

Unless otherwise indicated, as used herein, “groups, components, etc.”
The term "substituted" refers to each independently hydrogen, alkoxy, hydroxy, nitro, amino, alkylamino, cyano, halo, carboxy, thiol, imino, and aryloxy (further oxo, amide,- O-alkyl-
A substituent selected from C (O) OR ₃₂ , and —O-alkyl-C (O) NHR _32, wherein R ₃₂ is a substituent selected from hydrogen and alkyl),
Preferably hydrogen, alkoxy, aryloxy, hydroxy, nitro, amino,
Halo, and thiol, more preferably hydrogen, alkoxy, hydroxy, nitro,
It is meant having one or more substituents selected from amino, alkylamino, and halo, even more preferably hydrogen, halo, hydroxy, and alkoxy, and most preferably hydrogen.

Unless otherwise indicated, the term “unsubstituted” as used herein refers to replacement with a hydrogen component. However, when it is replaced with a hydrogen moiety then it may be described as being "substituted" with respect to one group or consistently.

As used herein, for any variable, component, group, etc., the definition at each occurrence is independent of the definition at every other occurrence, and any variable or structure is 1 Appear more than once.

Compounds of the Invention The compounds of the invention have the following structure:

Embedded image

And its pharmacologically acceptable salts, hydrated compounds, and
With possible amides, esters and imides, wherein: (a) Z is a saturated or unsaturated 4-, 5-, 6-, 7-, 8- or 9-membered carbon
A ring or a heterocycle, wherein the heterocycle is O, N, S, S (O), S (O_Two)
, And one or more heteroatoms selected from P ((O) OK).
(B) V is -CU-, wherein U is hydrogen, alkyl, alkenyl, hetero
Alkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl
, Arylalkyl, heteroarylalkyl, arylalkenyl, and
(C) G is nil (absent), O, S, and NR₁₇(D) K is hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl
, Cycloalkyl, heterocycloalkyl, aryl, arylalkyl, hete
From loarylalkyl, arylalkenyl, and heteroarylalkenyl
Selected; (e) R₁Is alkyl, alkenyl, heteroalkyl, heteroalkenyl, cyclo
Loalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl
Selected from arylalkyl, arylalkenyl, and heteroarylalkenyl
(F) W is selected from nil (absent), hydrogen, and lower alkyl; (g) A is selected from nil (absent) and alkyl; (h) X and Y are each independently C From (O), P (O), N, O, and S
(I) If X is C (O), then R_ThreeIs nil (absent) and Y is N, O,
And (ii) if X is P (O), then R_ThreeIs nil (absent) and Y is N, and
And (iii) if X is N, then R_ThreeIs hydrogen, alkyl, and arylalkyl
And Y is selected from C (O) and P (O), and R_TwoIs ni
l (absence); (iv) if X is O, then R_ThreeIs nil (absent), Y is C (O) and
Selected from P (O) and R_TwoIs nil (absent); and (v) if X is S, then R_ThreeIs nil (absence), Y is C (O)
And R_TwoIs nil (absent); (i) R_TwoAnd R_ThreeAre each independently nil (absent), hydrogen, alkyl, and
Selected from arylalkyl; (j) R_FourIs alkyl; (k) R_FiveAnd R₆Are each independently nil (absent), hydrogen, at least two
Alkyl, alkenyl, heteroalkyl, heteroalkenyl having the carbon atoms of
, Cycloalkyl, heterocycloalkyl, aryl, arylalkyl, hete
From loarylalkyl, arylalkenyl, and heteroarylalkenyl
Selected; or R_FiveAnd R₆Are linked together to form a carbocyclic or heterocyclic ring
(L) R₇, R₈, R₉, And R_TenAre independently nil (absent), hydrogen,
Alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, f
Telocycloalkyl, aryl, arylalkyl, heteroarylalkyl,
Arylalkenyl, heteroarylalkenyl, halo, cyano, hydroxy,
Oxo, imino, -R₁₄SR_Fifteen, -R₁₄S (O_Two) R_Fifteen, -R₁₄S (O) R_Fifteen,
-R₁₄C (O) R_Fifteen, -R₁₄C (O) NR_FifteenR₁₆, -R₁₄C (O) OR_Fifteen, -R ₁₄ OR_Fifteen, -R₁₄NR_FifteenR₁₆, -R₁₄P (O)) NR_FifteenR₁₆, -R₁₄P (O))
OR_FifteenR₁₆And a spiro component, wherein R₇And R₈Arbitrarily
Can combine with each other to form an aromatic or saturated, carbocyclic or heterocyclic ring
The ring then fuses with Z; (m) R₁₄, And R_FifteenAre each independently nil (absent), hydrogen, alkyl,
Alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocyclyl
Loalkyl, aryl, arylalkyl, heteroarylalkyl, aryl
Alkenyl and heteroarylalkenyl; and (n) R₁₆And R₁₇Are each independently selected from hydrogen and alkyl.

Ring Structure Z The compound of the present invention may be a saturated or unsaturated four-, five-, six-, seven-, eight-, or nine-membered
It includes a ring structure Z containing a membered carbocycle or heterocycle. Preferably, the Z ring structure has 5 members,
It contains a 6 or 7 membered carbocyclic or heterocyclic ring, more preferably a 5 or 6 membered carbocyclic or heterocyclic ring. Preferably, the Z ring is a carbocycle.

Position 1 of the ring structure is a V substituent that is —CU—, where U is hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, Heteroarylalkyl, arylalkenyl, and heteroarylalkenyl, preferably selected from hydrogen, alkyl, and arylalkyl, most preferably hydrogen.

The Z ring optionally contains one or more heteroatoms or hetero moieties (collectively referred to herein as heteroatoms for simplicity), wherein the heteroatoms are It is selected from oxygen (O), nitrogen (N), sulfur (S), sulfoxide (S (O)), sulfone (S (O) ₂ ), and phosphonate (P ((O) OK)). Preferably, the optional heteroatoms are O, N, S, S (O), and S (O) ₂
Selected from the group consisting of: Of course, since the V substituent must be in the 1 position, the heteroatom cannot be in the 1 position.

When N is a heteroatom heteroatom, the additional N heteroatoms should most preferably be replaced by hydrogen or alkyl. S (O) for clarity
, S (O) 2, and P (O)) OK are shown in Table 1 below:

Table 1

[Table 1]

G Component Directly attached to the V substituent is the G component. G is selected from nil, O, S, and NR ₁₇ , wherein NR ₁₇ is selected from hydrogen and alkyl. Preferably, G is selected from O, S, and NR ₁₇ , preferably O and NR ₁₇ , and most preferably, G is NR ₁₇ .

[0051]R ₁ component Directly bonded to the G component is a ketoamide component as shown in the above structure.
is there. R₁Side chains are also directly attached to the ketoamide component. R₁The ingredient is alk
Alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, hetero
Cycloalkyl, aryl, arylalkyl, heteroarylalkyl, ant
Alkenyl, and heteroarylalkenyl. R₁The ingredients are
It is preferably substituted with at least one substituent other than hydrogen. In this specification
In addition to the substituents that can be substituted for all components,
SO, amide, -O-alkyl-C (O) OR₃₂And -O-alkyl-C (O)
NHR₃₂And then R₃₂Is a substituent selected from hydrogen and alkyl. ₁ Components can also be replaced.

The R ₁ component is preferably alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, and heteroarylalkyl,
Even more preferably selected from aryl, arylalkyl and heteroarylalkyl, most preferably aryl. The most preferred aryl for the R ₁ component is a substituted aryl (most preferably a substituted phenyl), especially an aryl having at least one alkoxy substituent. Particularly preferred R ₁ components are shown in Table 2.

Table 2-Preferred R ₁ components

[Table 2]

Substituted AXYR ₄ Component Position 2 of the Z ring is an AXYR ₄ component, and as described herein, R ₂ , R ₃ , R ₅ , And R ₆ . The A component of the side chain is selected from nil and alkyl. Most preferably, the A component is nil. Of course, if A is not present, X is directly bonded to the Z ring. The X component of the side chain depends on the structure of the Y component, and vice versa. X and Y are each independently selected from C (O) (ie, carbonyl), P (O), N, O, S, with the following restrictions: (i) X is C (O) R ₃ is nil and Y is selected from the group consisting of N, O and S. (ii) If X is P (O), then R ₃ is nil and Y is (Iii) if X is N, then R ₃ is selected from hydrogen, alkyl, and arylalkyl; and Y is selected from the group consisting of C (O) and P (O). And R ₂ is ni
(iv) if X is O, then R ₃ is nil, Y is selected from the group consisting of C (O) and P (O), and R ₂ is nil; and (v) ) If X is S, then R ₃ is nil, Y is C (O), and R ₂ is n
Preferably, X and Y are each independently selected from C (O), N, and O. More preferably, X and Y are each independently selected from C (O) and N.

X and Y are substituted by R ₃ and R ₂ respectively. R ₃ and R ₂ are each independently selected from nil, hydrogen, alkyl, and arylalkyl.
If X is N, R ₃ is hydrogen, alkyl, and arylalkyl, preferably hydrogen and alkyl, most preferably selected from hydrogen. If Y is N, R ₂ is hydrogen, alkyl, and arylalkyl, more preferably hydrogen and alkyl,
Most preferably it is selected from hydrogen.

The R ₄ component is an alkyl component. Preferred alkyl moieties in accordance with the preferred limits set above, the most preferred R ₄ component is methylene or methine group (i.e., C ₁ component has only one hydrogen substituent).

The R ₅ and R ₆ components are each directly bonded to R ₄ . R ₅ and R ₆ are each independently nil, hydrogen, alkyl having at least 2 carbon atoms, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, aryl alkenyl, and is selected from heteroaryl alkenyl; or R ₅ and R ₆ join to form a carbocyclic or heterocyclic ring; at least one of or R ₅ and R ₆ are not nil or hydrogen.

Preferably, R ₅ and R ₆ are each independently nil, hydrogen, alkyl having at least 2 carbon atoms, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl , Heteroarylalkyl, arylalkenyl, and heteroarylalkenyl. More preferably, independently R ₅ and R ₆ each is selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, and heteroarylalkyl having at least 2 carbon atoms. Most preferably, R ₅ and R ₆ are each independently arylalkyl. It is often preferred that R ₅ and R ₆ are equivalent components. Naturally, R ₅
And R ₆ can be each independently substituted. Specific examples of the R ₅ and R ₆ components are shown in Table 3 below.

[0059] Specific examples of Table 3-R ₅ and R ₆ component

[Table 3]

The 2 position of the W component Z ring can be substituted with an additional component, W. The W component is selected from nil, hydrogen, and lower alkyl, preferably hydrogen and lower alkyl, most preferably hydrogen. Here, W is lower alkyl, most preferably methyl.

[0061]Z ring substituents, R ₇ , R ₈ , R ₉ , and R ₁₀  In addition to the aforementioned substituents at the 1- and 2-positions of the Z ring, the Z ring may also have other possible
Additional substituents at positions can be provided, and such additional substituents
R₇, R₈, R₉, And R_TenIs defined as These substituents R₇, R₈, And R₉ , And R_TenIs independently nil, hydrogen, alkyl, alkenyl, hetero
Alkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl
, Arylalkyl, heteroarylalkyl, arylalkenyl, hetero
Arylalkenyl, halo, cyano, hydroxy, oxo, imino, -R₁₄SR _Fifteen , -R₁₄S (O_Two) R_Fifteen, -R₁₄S (O) R_Fifteen, -R₁₄C (O) R_Fifteen, -R₁₄
C (O) NR_FifteenR₁₆, -R₁₄C (O) OR_Fifteen, -R₁₄OR_Fifteen, -R₁₄NR_FifteenR₁₆ , -R₁₄P (O)) NR_FifteenR₁₆, -R₁₄P (O)) OR_FifteenR₁₆And spiro components
And then R₇And R₈Are optionally bonded to each other to be aromatic or saturated
It is possible to form a unified, carbocyclic or heterocyclic ring, wherein the ring is fused with Z
I do. R₁₄, And R_FifteenIs independently nil, hydrogen, alkyl, alkenyl
, Heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl
, Aryl, arylalkyl, heteroarylalkyl, arylalkenyl
And heteroarylalkenyl. R₁₆Is hydrogen and alkyl
Is selected from

Preferably, R₇, R₈, And R₉, And R_TenAre each independently nil, water
Alkyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocy
Chloroalkyl, aryl, arylalkyl, heteroarylalkyl, halo,
Hydroxy, oxo, -R₁₄SR_Fifteen, -R₁₄S (O_Two) R_Fifteen, -R₁₄S (O) R_{1 Five} , -R₁₄C (O) R_Fifteen, -R₁₄C (O) NR_FifteenR₁₆, -R₁₄Or_Fifteen, -R₁₄N
R_FifteenR₁₆And a spiro component, wherein R₇And R₈Are arbitrarily
To form a second aromatic or saturated, carbocyclic or heterocyclic ring.
The second ring then fuses with Z. More preferably, R₇, R₈,
And R₉, And R_TenIs independently nil, hydrogen, alkyl, heteroalkyl
, Heteroalkenyl, aryl, arylalkyl, heteroarylalkyl
, Halo, hydroxy, oxo, -R₁₄SR_Fifteen, -R₁₄S (O_Two) R_Fifteen, -R₁₄S
(O) R_Fifteen, -R₁₄C (O) R_Fifteen, -R₁₄C (O) NR_FifteenR₁₆, -R₁₄OR_Fifteen,
-R₁₄NR_FifteenR₁₆And a spiro component, wherein R₇And R₈Is
Optionally linked together to form a second aromatic or saturated, carbocyclic or heterocyclic ring
It is possible for the second ring to fuse with Z. Also more preferably
, R₇, R₈, And R₉, And R_TenIs independently nil, hydrogen, alkyl
, Heteroalkyl, heteroalkenyl, aryl, arylalkyl, heteroa
Reel alkyl, halo, hydroxy, -R₁₄C (O) R_Fifteen, -R₁₄C (O) NR _Fifteen R₁₆, -R₁₄OR_Fifteen, -R₁₄NR_FifteenR₁₆, And spiro components, and
At that time R₇And R₈Are optionally linked together to form an aromatic or saturated, carbocyclic or heterocyclic
It is possible to form a second ring of the ring, wherein the second ring is fused with Z
. Most preferably, R₇And R₈Are aromatic or saturated (preferably aromatic)
A second ring of a carbocyclic or heterocyclic ring (preferably a carbocyclic ring)
The second ring is fused to Z.

When R ₇ and R ₈ combine with each other to form an aromatic or saturated, carbocyclic or heterocyclic second ring, wherein the second ring is fused to Z, Of course may be substituted or unsubstituted. A preferred second ring is phenyl. Specific examples of the compounds of the present invention are shown in the following table.

Table 4-Compounds as specific examples of the present invention

[Table 4A]

[0065]

[Table 4B]

Table 5-Compounds as specific examples of the present invention

[Table 5A]

[0067]

[Table 5B]

R ₁₈ , R ₁₉ and R ₂₀ in Table 5 are each independently hydrogen, alkoxy,
Selected from aryloxy, hydroxy, nitro, amino, halo, and thiol.

Table 6-Compounds as specific examples of the present invention

[Table 6]

R ₃₀ in Table 6 is selected from the group consisting of —OR ₃₂ and —OCH ₂ C (O) OR ₃₂ , wherein R ₃₂ is selected from the group consisting of hydrogen and alkyl.

Table 7-Exemplary compounds of the present invention

[Table 7]

R ₃₅ in Table 7 is selected from hydrogen and —OR ₃₆ , wherein R ₃₆ is selected from hydrogen and alkyl.

Table 8-Compounds as specific examples of the present invention

[Table 8A]

[0074]

[Table 8B]

[0075]

[Table 8C]

[0076]

[Table 8D]

In Table 8, R ₃₀ and R ₃₅ are each independently —OR ₃₂ and —OCH ₂ C (
O) is selected from OR _32, that case R ₃₂ is selected from hydrogen and alkyl.

Analytical Methods The compounds of the present invention are hair-growth active substances, and among them, more preferred are non-immunosuppressive compounds. The compounds of the present invention (test compounds) can be tested for their ability to induce a anagen phase and their immunosuppressive activity (or their non-immunosuppressive) using the following methods. Alternatively, other methods known in the art may be used (but the term "non-immunosuppressive" is defined according to the methods disclosed herein).

The telogen conversion test : The telogen conversion test is a test compound capable of converting a mouse in the telogen phase of the hair growth cycle ("telogen") to the anagen phase of the hair growth cycle ("anagen"). Measure gender. While not intending to be limited by theory, the hair growth cycle has three major phases: anagen, catagen, and telogen. C3H mice (Harlan Sprague Dawley, Inc., Indianapolis, Ind.) Have a relatively long telogen and hair growth occurs simultaneously from about 40 days to about 75 days of age. Is believed to be. After 75 days of age, hair growth no longer proceeds simultaneously. When approximately 40-day-old mice with dark fur (brown or black) are used in the hair growth test, melanogenesis occurs with hair growth (fur) where the application of the hair restorer is evaluated. The telogen conversion test described below was used to screen for potential hair growth potential of the compounds by measuring melanogenesis.

The 44-day-old C3H mice are divided into three groups, that is, a solvent control group, a positive control group, and a test compound group, and the compound of the present invention is applied to the test compound group.
The test period is at least 19 days, of which the test compound is applied for 15 days (application date is Monday to Friday). "Day 1" is the date of first application. Most studies end on "day 19", but if melanogenesis appears to be responding positively but is slow, a few will run the study until "day 24". A typical test design is shown in Table 9 below:

Table 9

[Table 9]

^** Solvents were 60% ethanol, 20% propylene glycol, and 20% dimethyl isosorbide (Sigma Chemical Company, St. Louis, Mo.)
Chemical Co.).

The mice were applied topically on the lower back (from the base of the tail to the lower ribs) from Monday to Friday. Use a pipettor and tip to place 400 on the back of each mouse.
Each μL was applied. The application of 400 μL was performed slowly, moving the hair of the mouse to reach the skin.

During each topical application to the mice, the color of the skin at the application site of each animal was rated from 0 to 4 by visual assessment. When the skin of a mouse changes from a telogen to a anagen, its color becomes more bluish black. As shown in Table 10,
As the skin changes from white to bluish black, a rating of 0 to 4 represents the following visual evaluation results:

Table 10

[Table 10]

Immunosuppressive assay : The immunosuppressive assay herein predicts the immunosuppressive activity of the compounds of the invention.
This assay is carried out as follows: male adult range were euthanized (asphyxiation with CO ₂₎ 7-week-old to 16-week-old CH3
The spleen is excised from a mouse (a living mouse commercially available from Harlan Sprague Dawley, Inc., Indianapolis, IN). The excised spleen is immediately cold Hanks solution (Hanks Balanced SaltSolution)
(HBSS commercially available from Gibco-BRL, Gaithersburg, MD). The spleen is then ground between frosted glass slides and filtered through a sterile filter to remove tissue debris. An equal volume of Ficoll-Paque Plus (commercially available from Pharmacia Biotech, Piscataway, NJ) is spread beneath the resulting cell suspension and splenocytes are collected. At 20 ° C, 400x
Centrifuge at G for about 40 minutes. Splenocytes are collected from the interface using a disposable pipette, washed twice with HBSS, and then centrifuged at 20 ° C, 100 x G for 10 minutes. Splenocytes were 10% heat-inactivated fetal bovine serum (Gibco-BRL), penicillin (50 U / ml), streptomycin (100 μG / ml), L-glutamine (2 mm), 2-mercaptoethanol (10 ⁵ M), And phenol red-free RPMI 1640 (Gibco-BRL) containing N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES) (10 mm).
RL) in 5-10 ml of cell culture medium. The cell number is counted and its viability checked using, for example, trypan blue. The spleen cells are resuspended at 10 ⁶ cells / ml in the medium and transferred to a 96-well round bottom plate with a pet at 10 ⁵ cells / well. 50 μL for splenocytes
/ Well of Concanavalin A (final assay concentration = 5 μl)
(G / ml) Activate in the presence or absence of test compound. Test compounds are prepared in methyl sulfoxide (DMSO) as a stock solution, then diluted in culture medium and added at 50 μL / well so that the final concentration of DMSO under analysis is less than 0.05%. Plates are incubated at 37 ° C. with 5% CO _{2 for} 48 hours.
After 48 hours, cells are pulsed with 1 μCi / well of methyl- ³ H-thymidine (commercially available from Amersham, Buckinghamshire, UK) and cultured for an additional 24 hours.

Twenty-four hours later, cells were harvested on GF / C filter plates (commercially available from Packard, Downers Grove, Illinois) and packed with
Solubilize in Microscint 20 (Packard) and count on a Topcount microplate scintillation and luminescence plate counter (Packard). Activity is measured as a percentage of control activity in the absence of test compound and plotted against test compound concentration. The data were compared to a 4-parameter curve (Sigmaplot) and the IC50
Calculate the value. The test compounds used herein can be prepared using this method.
The ratio of × 100 (IC ₅₀ of IC ₅₀ / test compound cyclosporin A) 0.02
If it is below, that is, the non-immunosuppressive test compound is ≦ 2% of the immunosuppressive activity of cyclosporin A, and is considered to be nonimmunosuppressive.

The cell viability discrimination is described by (Nelson) et al., Journal of Immunology ((Jo
urnal of Immunology), Vol. 150, No. 6, pp. 2139-2147 (1993)), and Nelson MTT (3- [4,5-dimethyl-thiazoyl-2-yl] -2,5-diphenyl-bromide). Tetrazolium) staining test.
At this time, the test was performed in RPMI1640 containing no serum and no phenol red, and the dye was dissolved in 100 μL / well DMSO.
lecular Devices, Menlo Park, CA) Spectramax
SpectraMax Plus microplate reader
Was measured at an OD of 540 nm and background correction was performed at 650 nm.

[0089] As disclosed in multidrug resistance herein, the compounds of the present invention are further useful, for example, increase the antiproliferative activity of the drug, and / or prevent multidrug resistance, and / or treatment It is also useful for This property of the compounds of the present invention is described in US Pat.
No. (Zelle et al., Vertex Pharmaceuticals (Vertex Phar
maceauticals, Inc.), issued April 28, 1998), U.S. Pat.
No. 184 (Zelle et al., Vertex Pharmaceuticals (Verte
x Pharmaceauticals, Inc.), issued March 10, 1998), U.S. Pat.
20,971 (Armistead et al., Vertex Pharmaceauticals, Inc., issued April 15, 1997); and US Pat. No. 5,543,423 (Zelle). Et al., Vertex Pharmaceauticals, Inc., issued Aug. 6, 1996.

Preparation Methods The compounds of the present invention are prepared according to methods well known to those skilled in the art. Starting materials used in the preparation of the compounds of the present invention are known, made by known methods, or are commercially available as starting materials.

It is clear that a person skilled in the art of organic chemistry can easily carry out standard procedures dealing with organic compounds without further explanation. Examples of such operating methods are described in March (
J. March) Advanced Organic Chemistry
Chemistry), John Wiley & Sons (1992).

One skilled in the art will readily recognize that for certain reactions, the other reactions in a compound will be most efficient when masked or protected, thus reducing the yield of the reaction. Raise and / or avoid unwanted side reactions,
Or do both. Often, those skilled in the art will perform functional group protection to achieve such yield enhancements or to avoid undesired reactions. These reactions are also found in the literature and are well within the knowledge of the skilled technician. Examples of many such procedures are described, for example, in "Protecting Groups in Organic Synthesis" by T. Greene (John Wiley & Sons), 1981).

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

Moreover, one optical isomer, including diastereomers and enantiomers,
Or, it has been recognized that a stereoisomer may have advantageous properties over the other. Thus, when disclosing and claiming the present invention, when disclosing a racemic mixture,
It is clear that both optical isomers, including diastereomers and enantiomers, or stereoisomers substantially free of the other are disclosed and are intended to be claimed as well. The following examples illustrate, but are not limited to, methods for synthesizing various compounds of the present invention.

The following abbreviations are used herein:

[Table 11]

[0096]

Embodiment 1

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1a. 2- (1,7-diphenyl-4-heptyl) -4,4-dimethyl-2-
Oxazoline: 2,4,4-trimethyl-2-oxazoline (5.64 ml, 4
4.2 mmol) is dissolved in anhydrous THF (40 ml) at room temperature under an inert atmosphere. The solution was cooled to -78 ° C and n-butyllithium (31 in hexane).
. 3 ml / 1.6 M, 50 mmol) are added dropwise. A solution of 1-bromo-3-phenylpropane (7.42 ml, 48.8 mmol) is added dropwise to THF (20 ml) over 10 minutes. Remove the cooling bath and allow the reaction solution to reach room temperature. After 30 minutes, the solution is cooled again to -78 ° C. n-Butyllithium (31.3 ml / 1.6 M in hexane, 50 mmol) is added dropwise. After 30 minutes, 1-bromo-3-phenylpropane (7.42 ml, 48.8 mm
ol) in THF (20 ml) dropwise over 10 minutes. Stir for 12 hours then allow the reaction to slowly reach room temperature. The reaction product was washed with water (200 m
1), acidify with 1N HCl and extract with ethyl ether (150 ml). The aqueous layer was cooled, neutralized with 50% NaOH solution and treated with ethyl ether (3.
× 100 ml). Ethyl ether extracts mixed and are was dried over MgSO _4, filtered and concentrated in vacuo. The crude product is purified by preparative chromatography on silica gel to give the desired bis-alkylated oxazoline. 1a.

1b. (1,7-diphenyl-4-heptyl) carboxylic acid: oxazoline 1a
(9.36 g, 26.8 mmol) is dissolved in dioxane (100 ml) at room temperature. 3N HCL (200 ml) is added and the resulting solution is heated at reflux for 18 hours. The solution is cooled to room temperature, poured into water (200 ml) and extracted with ethyl ether (3 × 150 ml). The combined ethyl ether extracts were washed with water (75 ml) and then with brine (75 ml) before
Dried SO _4, filtered to give the desired product were concentrated in vacuo.

1c. Trans-1,2-diaminocyclohexane, (1,7-diphenyl-
4-heptyl) carboxylic acid amide: carboxylic acid 1b (1.0 g, 3.37 mmol)
l) is dissolved in dichloromethane (50 ml) at room temperature under an inert atmosphere. Trans-1,2-diaminocyclohexane (0.77 g, 6.75 mmol) was added, followed by iPr ₂ NEt (0.6 ml, 3.4 mmol) and PyBOP (1.
9 g, 3.7 mmol) are added. The reaction mixture is stirred at room temperature for 18 hours, poured into ethyl acetate (300 ml), and subsequently washed with 0.1 N HCl (150 ml), saturated sodium bicarbonate solution (75 ml), and brine (50 ml). The organic solution was dried over MgSO _4, filtered, and concentrated in vacuo. The crude product is purified by preparative chromatography on silica gel to give the desired product.

1d. Trans-1,2-diaminocyclohexane, 1-N- (1,7-diphenyl-4-heptyl) carboxylic acid amide, 2-N- (3′4′5′-trimethoxyphenylglyoxyl) amide: amide 1c (0 0.73 g, 1.83 mmol
Is dissolved in anhydrous dichloromethane (30 ml) at room temperature. 3 ', 4', 5'-
Trimethoxyphenylglyoxylic acid (0.67 g, 2.8 mmol) was added in one lump followed by triethylamine (0.6 ml, 4.3 mmol) and E
DAC (0.53 g, 2.8 mmol) is added. The reaction mixture is heated at room temperature for 1 hour.
Stir for 8 hours, then pour into water (50 ml) and add dichloromethane (3 × 40 ml)
) To extract. The combined organic extracts are washed with 0.1 N HCL (40 ml), followed by saturated sodium bicarbonate solution (40 ml), then dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product is purified by preparative chromatography on silica gel to give the desired product 1d.

Embodiment 2

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2a. Cis-2- (N-tert-butoxycarbonylamino) 1-cyclopentanecarboxylic acid, 4-phenylbutylamide: cis-2- (N-tert-butoxycarbonylamino) -1-cyclopentanecarboxylic acid (4.1 g, 17.7 mmol
) Is dissolved in 160 ml of DMF. 4-phenylbutylamine (2.4 g,
16.1 mmol) and _{i-Pr 2 NEt (5.6ml,} 32.2mmol) was added, followed by addition of PyBOP (8.8g, 16.9mmol). The reaction is stirred at room temperature for 19 hours, then poured into ice-cold 0.1 N HCl (600 ml) and extracted with ethyl acetate (600 ml). The organic layer was continuously added to a saline solution (10
0 ml), saturated NaHCO ₃ solution (300 ml), and saline (2 × 200 ml)
). The organic solution was dried over MgSO _4, filtered and concentrated in vacuo. Purify the product by chromatography to obtain the desired amide 2a.

2b. Dissolve cis-2-amino-1-cyclopentanecarboxylic acid, 4-phenylbutylamide: amide 2a (5.5 g, 15.3 mmol) in 150 ml of anhydrous dichloromethane. TFA (120 ml) is added dropwise over 5 minutes.
After 2 hours, the mixture was cooled in an ice bath and saturated K ₂ CO ₃ solution was added to approximately pH 8
To Transfer the mixture to a separatory funnel containing dichloromethane (200 ml) and water (200 ml) and shake. Water before the organic layer is dried with MgSO ₄ (
200 ml). The mixture is filtered and concentrated in vacuo to give the desired amine 2b.

2c. Cis-2- (3 ', 4', 5'-trimethoxyphenylglyoxylamino) -1-cyclopentanecarboxylic acid, 4-phenylbutylamide: amine 2
b (3.4 g, 13.1 mmol) is dissolved in 150 ml of anhydrous DMF. 3
', 4', 5'-Trimethoxyphenylglyoxylic acid (3.9 g, 16.4 m
mol) and _{i-Pr 2 NEt (5.7ml,} 32.7mmol) was added, followed by addition of PyBOP (8.85g, 17.0mmol). The reaction is stirred at room temperature for 18 hours, then poured into 0.1 N HCl (600 ml) in an ice bath and extracted with ethyl acetate (600 ml). The organic layer was continuously washed with saline (100 ml),
Wash with saturated NaHCO ₃ solution (300 ml) and brine (2 × 100 ml). The organic solution was dried over MgSO _4, filtered, and concentrated in vacuo. Purify the product by chromatography to obtain the desired amide 2c.

Embodiment 3

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3a. Cis-1,2-diaminocyclohexane, (1,7-diphenyl-4-
Heptyl) carboxylic amide: carboxylic acid 1b (2.0 g, 6.74 mmol)
Is dissolved in DMF (100 ml) at room temperature under an inert atmosphere. Cis-1,2-
Diaminocyclohexane (1.43 g, 12.5 mmol) was added followed by iP
r ₂ NEt (1.18 ml, 6.8 mmol) and PyBOP (3.9 g, 7.
45 mmol) are added. The reaction mixture was stirred at room temperature for 18 hours, poured into ethyl acetate (600 ml), followed by 0.1N HCl (300 ml), brine (10 ml).
0 mL) and saturated sodium bicarbonate solution (150 ml) and saline (100 mL)
). The organic solution was dried over MgSO _4, filtered, and concentrated in vacuo. The crude product is purified by preparative chromatography on silica gel to give the desired amide 3a.

3b. Cis-1,2-diaminocyclohexane, 1-N- (1,7-diphenyl-4-heptyl) carboxylic acid amide, 2-N- (phenylglyoxyl) amide: amine 3a (1.46 g, 3.68 mmol) At room temperature, anhydrous DMF (50m
Dissolve in 1). Phenylglyoxylic acid (0.8 g, 5.48 mmol) was added to the bunch, followed by _{i-Pr 2 NEt (1.5ml,} 8.6mmol) and PyBOP (2.9 g, 5.54 mmol) is added. The reaction mixture was stirred at room temperature for 18 hours, poured into ethyl acetate (300 ml) followed by 0.1N HCl
(150 ml), saline (50 ml), saturated sodium bicarbonate solution (150 ml)
) And saline (50 ml). The organic solution is dried over MgSO ₄ ,
Filter and concentrate in vacuo. The crude product is purified by preparative chromatography on silica gel to give the desired amide 3b.

Embodiment 4

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4a. Cis-2- (N-tert-butoxycarbonylamino) 1-cyclohexanecarboxylic acid. Cis-2-amino-1-cyclohexane-carboxylic acid (5.0 g
, 35 mmol) are dissolved in 40 ml of a 1: 1 solution of dioxane: water. Triethylamine (7.3 ml, 52.4 mmol) was added followed by Boc-ON (
9.5 g, 38.4 mmol) are added. The mixture is then stirred for 4 hours, poured into water (75 ml) and extracted with ethyl acetate (3 times, 75 ml each). The aqueous solution is cooled in an ice bath and the pH is adjusted to approximately 2.5 with ice-cold 1N HCl solution. The resulting mixture is extracted with dichloromethane (3 times, 75 ml each). Combine the organic extracts, dry over MgSO ₄ , filter and concentrate in vacuo to give 4a.

4b. Cis 2- (N-tert-butoxycarbonylamino) -1-cyclohexanecarboxylic acid, 1,7-diphenyl-4-heptylamide: carboxylic acid 4a (4
. (3 g, 17.7 mmol) are dissolved in 160 ml of DMF. 1,7-diphenyl-4-amino-heptane (4.3 g, 16.1 mmol) and i-Pr ₂ N
Et (5.6 ml, 32.2 mmol) was added, followed by PyBOP (8.8 g,
16.9 mmol). The reaction is stirred at room temperature for 19 hours, then poured into ice-cold 0.1 N HCl (600 ml) and extracted with ethyl acetate (600 ml). The layers were separated and the organic layer was washed successively with brine (100 ml), saturated NaHC
Wash with O ₃ solution (300 ml) and brine (2 × 200 ml). The organic solution was dried over MgSO _4, filtered, and concentrated in vacuo. The product is purified by chromatography on silica gel to give the desired amide 4b.

4c. Cis-2-amino-1-cyclohexanecarboxylic acid, 1,7-diphenyl-4-heptylamide: amide 4b (7.54 g, 15.3 mmol) was added to 15
Dissolve in 0 ml of anhydrous dichloromethane. TFA (120 ml) is added dropwise over 5 minutes. After 2 hours, the mixture is cooled in an ice bath and saturated K ₂ CO ₃ solution is added to approximately pH 8. Transfer the mixture to a separatory funnel containing dichloromethane (200 ml) and water (200 ml) and shake. The organic layer is separated and water (
(200 ml) and dried over MgSO ₄ . The mixture is filtered and concentrated in vacuo to give the desired amine 4c.

4d. Cis-2- (3 ', 4', 5'-trimethoxyphenylglyoxylamino) -1-cyclohexanecarboxylic acid, 1,7-diphenyl-4-heptylamide: amine 4c (5.14 g, 13.1 mmol) 150 ml of anhydrous DMF
To dissolve. 3 ′, 4 ′, 5′-Trimethoxyphenylglyoxylic acid (3.
93 g, 16.4 mmol) and _{i-Pr 2 NEt (5.7ml,} 32.7mm
ol), followed by PyBOP (8.9 g, 17.0 mmol). The reaction was stirred for 18 hours at room temperature, and then ice-cooled 0.1N HCl (600 m
1) and extract with ethyl acetate (600 ml). The layers are separated and the organic layer is washed successively with brine (100 ml), saturated NaHCO ₃ solution (300 ml), and brine (2 × 100 ml). The organic solution was dried over MgSO _4, filtered, and concentrated in vacuo. The product is purified by chromatography on silica gel to give the desired amide 4d.

Embodiment 5

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5a. N- (diphenylmethylene) -2-amino-5-phenylpentanoic acid benzyl ester: N- (diphenylmethylene) -glycine benzyl ester (2
(0.0 g, 60.8 mmol) are dissolved in 130 ml of acetonitrile. 1
- bromo-3-phenylpropane _{(14.5g, 72.8mmol), K 2} CO 3 (25.2g, 182.2mmol) and tetrabutyl ammonium bromide (1.9
6 g, 6.0 mmol) are added and the mixture is refluxed. After 3 hours, the mixture is cooled to room temperature, filtered, and concentrated in vacuo. Water (400 ml) is added and the mixture is extracted with ether (1.2 L). The organic extract was washed with water (400 ml)
And washed with brine (200 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The product is purified by chromatography on silica gel to give the desired ester 5a.

5b. 2-amino-5-phenylpentanoic acid benzyl ester: ester 5a
(24.62 g, 55.0 mmol) is dissolved in IN aqueous HCl (600 ml) and ether (200 ml) and the mixture is stirred at room temperature. 20 hours later,
Separate the layers and extract the aqueous layer with ether (200 ml). Cool the aqueous layer with an ice bath and adjust the pH to approximately 10 with saturated aqueous K ₂ CO ₃ . The mixture was extracted with dichloromethane (3 × 300 ml) and brine (100 ml), then MgS
Dry over O ₄ , filter and concentrate in vacuo to give the amino ester 5b.

5c. Cis-2- (N-tert-butoxycarbonylamino) -1-cyclopentanecarboxylic acid, benzyl-5-phenyl-2-pentanoateamide: cis-
Dissolve 2- (N-tert-butoxycarbonylamino) -1-cyclopentanecarboxylic acid (4.8 g, 20.9 mmol) in 230 ml of dichloromethane.
Amino ester 5b (5.4g, 19.0mmol) and i-Pr ₂ NEt (7
. 0B, 39.9 mmol) was added, followed by PyBOP (10.9 g, 20.
9 mmol) are added. The reaction was stirred for 18 hours at room temperature and then cooled on ice.
. Pour into 1N HCl (250 ml) and extract with ethyl acetate (300 ml).
The layers were separated and the organic layer was combined with a saturated NaHCO ₃ solution (150 ml) and brine (
50 ml). The organic solution was dried over MgSO _4, filtered, and concentrated in vacuo. The product is purified by chromatography on silica gel to give the desired amide 5c.

5d. Cis-2-amino-1-cyclopentanecarboxylic acid, benzyl-5-phenyl-2-pentanoate amide: amide 5c (9.6 g, 19.4 mmol)
Is dissolved in 185 ml of anhydrous dichloromethane. 5 TFA (150 ml)
Add dropwise over minutes. After 2 hours, the mixture is cooled in an ice bath and saturated K ₂ CO ₃ solution is added to approximately pH 8. The mixture was added to dichloromethane (250 ml).
) And water (250 ml) into a separatory funnel and shake. Separate the organic layer and wash with water (200 ml). The aqueous layer is back-extracted with dichloromethane (100 ml). Combine the organic extracts, dry over MgSO ₄ , filter and concentrate in vacuo to give the desired amine 5d.

5e. Cis-2- (3 ', 4', 5'-trimethoxyphenylglyoxylamino) -1-cyclopentanecarboxylic acid, benzyl-5-phenyl-2-pentanoateamide: amine 5d (7.14 g, 18. 1 mmol) is dissolved in 220 ml of anhydrous dichloromethane. 3 ′, 4 ′, 5′-Trimethoxyphenylglyoxylic acid (5.2 g, 21.7 mmol) and i-Pr ₂ NEt (5.14 g,
39.8 mmol), followed by PyBOP (11.3 g, 21.7 mmol).
). The reaction was stirred for 13 hours at room temperature and then ice-cooled 0.1N H
Pour into CL (250 ml) and extract with ethyl acetate (300 ml). The layers were separated and the organic layer was successively washed with saturated NaHCO ₃ solution (200 ml) and brine (50 ml).
ml). The organic solution was dried over MgSO _4, filtered and concentrated in vacuo. The product is purified by chromatography on silica gel and the desired amide 5
e.

Embodiment 6

Embedded image

6a. N, N'-dimethyl-trans-1,2-diaminocyclohexane, 5
-Phenylpentanoic acid amide: 5-phenylpentanoic acid (6.0 g, 33.7 m
mol) is dissolved in dichloromethane (500 ml) at room temperature under an inert atmosphere. N, N'-dimethyl-trans-1,2-diaminocyclohexane (9.6 g
, 67.5 mmol) was added, followed by _{i-Pr 2 NEt (5.9ml,} 33.9
mmol) and PyBOP (19.3 g, 37.1 mmol). The reaction mixture was stirred at room temperature for 18 hours, poured into ethyl acetate (300 ml),
. Wash with 1N HCL (150 ml), saturated sodium bicarbonate solution (75 ml), and brine (50 mL). The organic solution was dried over MgSO ₄ , filtered,
And concentrate in vacuo. The crude product is purified by preparative chromatography on silica gel to give the desired amide 6a.

6b. N, N'-dimethyl-trans-1,2-diaminocyclohexane, 1
-N-5-phenylpentanoic acid amide, 2-N- (phenylglyoxyl) amide: The amide 6a (0.55 g, 1.83 mmol) is dissolved in anhydrous dichloromethane (30 ml) at room temperature. Phenylglyoxylic acid (0.42 g, 2.8 mm
ol) added in one portion, followed by _{i-Pr 2 NEt (0.75ml,} 4.3mmol)
And PyBOP (1.44 g, 2.77 mmol). The reaction is stirred at room temperature for 18 hours, then poured into ice-cold 0.1 N HCl (30 ml) and extracted with dichloromethane (40 ml). The layers are separated and the organic layer is continuously saturated with N 2
Wash with aHCO ₃ solution (30 ml) and brine (15 ml). The crude product is purified by preparative chromatography on silica gel to give the desired product 6b.

Embodiment 7

Embedded image

7a. N, N'-dimethyl-trans-1,2-diaminocyclohexane, 1
-N-5-phenylpentanoic acid amide, 2-N- (2-furyl) glyoxylic acid amide: N, N'-dimethyl-trans-1,2-diaminocyclohexane,
-Phenylpentanoic amide 6a (10.0 g, 33.1 mmol) is dissolved in anhydrous dichloromethane (600 ml) at room temperature. Phenylglyoxylic acid (5.
5 g, 49.7 mmol) added in one portion, followed by i-Pr ₂ NEt (13.5ml
, 77.8 mmol) and PyBOP (25.8 g, 49.6 mmol). Stir at room temperature for 18 hours to react, then ice-cooled 0.1 N HCl
(600 ml) and extracted with dichloromethane (800 ml). The layers were separated and the organic layer was successively combined with a saturated NaHCO ₃ solution (600 ml) and brine (30 ml).
0 ml). The crude product is purified by preparative chromatography on silica gel to give the desired product 7a.

Embodiment 8

Embedded image

8b. Cis-2- (2-butylglyoxylamino) -1-cyclohexanecarboxylic acid, 1,7-diphenyl-4-heptylamide: amine 4c (3.14 g)
, 8.0 mmol) are dissolved in 100 ml of anhydrous dichloromethane. 2-butyl glyoxylic acid (1.56 g, 12.0 mmol) and iPr ₂ NEt (4.2
ml, 24.0 mmol), followed by PyBOP (7.3 g, 14.0 mm).
ol). Stir at room temperature for 18 hours to react, then pour into ice-cold 0.1 N HCL (100 ml) and extract with ethyl acetate (150 ml). The layers were separated and the organic layer was successively combined with a saturated NaHCO ₃ solution (1500 ml) and brine (1500 ml).
100 ml). The organic solution was dried over MgSO _4, filtered and concentrated in vacuo. The product is purified by chromatography on silica gel to give the desired amide 8b.

Embodiment 9

Embedded image

9a. Magnesium (40.2 g, 1.6 mol) and anhydrous ether (3.2
L) is mixed in the reaction vessel with stirring. A 1.6 L solution of 1-bromo-3-phenylpropane in anhydrous ether is added to the addition funnel. The bromide solution is added dropwise to the stirred reaction vessel over 1 hour. When the addition is complete, add the mixture to 1
Stir for ~ 2 hours. A solution of 4-phenylbutyronitrile (160 g, 1.1 mol) in anhydrous ether (2.4 L) is placed in a dropping funnel. This solution is added to the reaction vessel over 1 hour. The solution after completion of the dropwise addition is heated at reflux for 10 hours,
Stir for hours to obtain a solution of 9a.

9b. The reaction mixture of 1,7-diphenyl-4-aminoheptane: 9a is diluted with methanol (3.2 L) using a dropping funnel. Sodium borohydride (8
3.4 g, 2.2 mol) are added to the ingredients. When the addition is completed, the mixture is stirred at room temperature for 6 hours to react. The reaction is stopped by slowly adding water (3.2 L) to the reaction mixture. The mixture is diluted with ether (3.2L) and water (1.6L). Separate the ether layer and extract the aqueous layer twice with ether (3.2 L × 2).
Combine the ether extracts, wash once with sodium chloride solution, dry, filter and
Concentrate in vacuo to obtain the composition. This product was diluted with ether (1.2 L),
Acidify by slowly adding 1 M HCl (1.2 L). The mixture is stirred for 1 hour and concentrated in vacuo. Dilute the resulting precipitate with acetonitrile,
Stir for 16 hours. The desired 1,7-diphenyl-4-aminoheptane 9b is collected by filtration.

Uses of the Compounds of the Invention The compounds of the present invention may be used in the treatment of conditions involving the prevention and / or reversal of alopecia and promotion of hair growth, such as the treatment of alopecia in mammals. obtain. Such conditions are manifest themselves in, for example, alopecia, including male pattern baldness and female pattern baldness.

While certain compounds of the invention may exhibit immunosuppressive activity, preferred compounds of the invention are non-immunosuppressive, as described herein. Furthermore, in addition to treating alopecia, the compounds of the present invention may also be useful in treating multidrug resistance (particularly for use in cancer chemotherapy), neurological and neurodegenerative diseases, ischemia / reperfusion (reperf
various clinical conditions, including, but not limited to, treatment of fungal, microbial, viral (particularly HIV), malarial, or other parasitic diseases or conditions. Can be used to treat The compounds of the present invention may further be effective as blocking multidrug transporter protein, eg, enhancing pharmacokinetics and bioavailability. Certain compounds of the present invention may exhibit immunomodulatory properties. These compounds include organ transplant rejection and Behcet's disease, Crohn's disease, systemic lupus erythematosus, psoriasis, rheumatoid arthritis, eczema, multiple sclerosis, myasthenia gravis, insulin-dependent diabetes, and Graves' disease Will prove effective in treating a variety of autoimmune diseases including, but not limited to. In addition, the compounds of the present invention may be useful in certain inflammatory and allergic disease states, including urticaria, allergic contact dermatitis, atopic dermatitis, atopic keratoconjunctivitis, inflammatory bowel disease, and asthma. May be useful in the treatment of The compounds of the present invention may further be effective in treating cardiac hypertrophy in congestive heart failure.

The compounds of the present invention may further be combined with a matrix metalloproteinase inhibitor, for example, to reduce excess matrix metalloproteinase activity, cancer, and multidrug resistance, as well as all conditions described herein above. It may be effective in treating various conditions, including mediated tissue destructive diseases. Particularly preferred matrix metalloproteinase inhibitors effective in such combinations include US Provisional Patent Application No. 60 / 024,765 (Pikul et al., The Procter & Gamble co. U.S. Provisional Patent Application No. 60 / 024,842 (Natchus et al., The Procter & Gamble co.), Aug. 28, 1996. U.S. Provisional Application No. 60 / 024,846 (Pikul et al.
Procter & Gamble co., Filed August 28, 1996, U.S. Provisional Patent Application No. 60 / 024,746 (Almstead et al., Procter & Gamble) (The Procter & Gamb
le co.), filed August 28, 1996), U.S. Provisional Patent Application No. 60/024.
No. 830, (Pikul et al., Procter & Gamble, Inc.
cter & Gamble co.), filed August 28, 1996), US Provisional Application No. 6
No. 0 / 024,764 (De et al., Procter & Gamble, Inc.)
Procter & Gamble co.), Filed August 28, 1996), U.S. Provisional Patent Application No. 60 / 024,764 (De et al., Procter & Gamble, Th.
e Procter & Gamble co.), filed August 28, 1996, and US Provisional Patent Application No. 60 / 024,766 (Wang et al., The Procter & Gamble co.). ), Filed Aug. 28, 1996).

Preferably, the compounds of the present invention are formulated into a pharmaceutical composition for use in treating or preventing a condition as described above. Standard pharmaceutical prescribing techniques include Remington's Pharmaceutical Sciences, Mac Publishing Company, Easton, PA, 199.
0)).

Typically, about 5 mg to about 3000 mg, more preferably about 5 mg to about 1000 mg, even more preferably about 10 mg to about 100 mg of a compound of the present invention will be administered systemically per day. It is understood that these dose ranges are limited to the examples only, and the daily dose can be adjusted by various factors. The particular dose of the compound to be administered will depend on the duration of the treatment and whether the treatment is local or systemic, as well as on one another. Dosage and treatment will also depend on the particular compound used, the therapeutic indication, the efficacy of the compound, the patient's personal characteristics (eg, patient weight, age,
(Such as gender and health), adaptability to treatment, and the likelihood and extent of side effects of treatment.

In addition to the compound of interest, the compositions of the subject invention contain a pharmacologically acceptable carrier (“carrier”). As used herein, the term pharmacologically acceptable carrier refers to one or more compatible solid or liquid bulking agent diluents or encapsulating materials suitable for administration to mammals. Means As used herein, the term "compatible" refers to the ability of the components of the composition to be admixed with the compounds of the present invention, and substantially enhances the effectiveness of the composition with each other under normal conditions of use. It does not cause any degrading interaction. Of course, the carrier is suitable for administration to the animal, preferably a mammal, to be treated,
It must be sufficiently pure and have sufficiently low toxicity. The carrier itself may be inert, or it may itself have a pharmaceutical effect.

The compositions of the present invention can be in any of a variety of forms suitable for (for example) oral, rectal, topical, nasal, ocular, or parenteral administration. Of these, topical application or oral administration is particularly preferred. Depending on the particular desired route of administration, a variety of pharmacologically acceptable carriers well known to those skilled in the art can be used. These include solid or liquid bulking agents, diluents, hydrotropes, surfactants, and encapsulating materials. It can include any pharmaceutically active substance that does not substantially interfere with the activity of the compound of the present invention. The amount of carrier used with the compound is sufficient to provide the practical amount of substance to be administered per unit dose of the compound. Techniques and compositions that allow for effective dosage forms for the methods of the invention are described in the following references: Modern Pharmaceuticals (Modern Pharmaceuticals)
Pharmaceutics), Chapters 9 and 10, Banker & Rhodes
(Eds.), (1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction.
Two Pharmaceutical Dosage Forms (Introduction to Ph
armaceutical Dosage Forms), 2nd edition (1976)

Some examples of pharmacologically acceptable carriers or substances that can be components thereof include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; sodium carboxymethylcellulose Cellulose and its derivatives, such as ethyl cellulose, methyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; peanut oil, cottonseed oil, sesame oil, olive oil, corn. Vegetable oils such as oil and cocoa oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers such as TWEENS Wetting agents such as sodium lauryl sulphate; coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; Can be

The choice of a pharmaceutically acceptable carrier to use with the compound of interest is basically determined by the method of administration of the compound. In particular, pharmacologically acceptable carriers for systemic administration include sugars, starches,
Cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate, phosphate buffers, emulsifiers, isotonic saline, and pyrogen-free water are included. Preferred carriers for certain administrations include propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil. Preferably, the pharmaceutically acceptable carrier in the parenterally administered composition comprises at least about 90% by weight of the total composition.

A variety of oral administration forms may be used, including solid forms such as tablets, capsules, granules, and powders. These oral forms generally contain a safe and effective amount of at least about 5%, preferably about 25% to about 50%, of a compound of the present invention. Tablets contain suitable binders, lubricants, diluents, disintegrants, coloring agents, flavoring agents, glidants, and dissolving agents, compressed tablets, mouldable tablets, enteric coatings, dragees, film-coated tablets, Or it may be a multiple compressed tablet. Liquid oral dosage forms include:
Reduced from aqueous solutions, emulsions, suspensions, non-effervescent granules containing suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, solubilizers, colorants, and flavors It includes solutions and / or suspensions and effervescent preparations reduced from effervescent granules.

Pharmaceutically acceptable carriers suitable for adjusting the dosage unit form for oral administration are well known in the art. Tablets typically contain the usual, pharmacologically compatible, adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose, and cellulose; starch, gelatin, and sucrose. Such binders; starch, alginic acid, and cross carmelose (Crosca
disintegrants such as rmelose); lubricants such as magnesium stearate, stearic acid and talc. Slip agents such as silicon dioxide can be used to improve the flow properties of the powder mixture. Colorants such as FD & C dyes may be added to enhance appearance. Sweetening and flavoring agents such as aspartame, saccharin, menthol, peppermint, and fruit flavors are effective as chewable tablet adjuvants. Capsules (including sustained release and sustained release formulations) typically include one or more solid diluents disclosed above. The choice of carrier component is not critical to the purpose of the subject invention and depends on secondary requirements such as taste, cost, and storability, and can be readily made by one skilled in the art.

Compositions for oral administration further include solutions, emulsions, suspensions, powders, granules,
Elixir, tincture, syrup and the like are included. Pharmaceutically acceptable carriers suitable for the preparation of such compositions are well-known in the art. Typical components for syrups, elixirs, emulsions, and suspension carriers include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid, liquid sucrose, sorbitol and water. Suspensions, typical suspending agents include methylcellulose, sodium carboxymethylcellulose, AviCel RC-591, tragacanth, and sodium alginate; typical wetting agents include lecithin and polysorbate 80 Included; typical preservatives include methyl paraben and sodium benzoate. Internal solution compositions may further contain one or more components such as sweetening agents, flavoring agents, and coloring agents as disclosed above.

Such compositions may be further coated in a conventional manner so that the compound of interest is released in the peripheral gastrointestinal tract where topical application is desired or exhibits the desired activity at various times. , Typically with a pH-dependent or time-dependent coating. Such dosage forms typically include one or more cellulose acetate phthalates, polyvinyl acetate phthalate, cellulose hydroxypropyl methyl phthalate, ethyl cellulose, Eudragit coatings, waxes, and shellac. Including, but not limited to.

Other compositions effective for systemic delivery of a compound of interest include sublingual, buccal and nasal dosage forms. Such compositions typically comprise one or more soluble bulking substances, such as sucrose, sorbitol, and mannitol; and gum arabic, microcrystalline cellulose, carboxymethylcellulose, and hydroxypropylmethylcellulose. Contains various binders. The glidants, lubricants, sweeteners, colorings, antioxidants, and flavoring agents disclosed above may also be included.

The compounds of the present invention may be further administered topically. The carrier of the topical composition preferably helps the compound of the present invention to penetrate the skin and reach around the hair follicles. The topical composition of the present invention can be in any dosage form including, for example, solutions, creams, ointments, gels, lotions, shampoos, leave-on and rinse-out hair conditioners, emulsions, cleansers, humidifiers, sprays, patches and the like. possible.

Topical compositions containing the active compound include, for example, water, alcohol, aloe vera gel, allantoin, glycerin, vitamin A and vitamin E oils, mineral oil, propylene glycol, PPG-2 myristyl vinyl propio It can be mixed with various carrier materials known to those skilled in the art, such as nates and the like.

[0145] Other materials suitable for use in topical carriers include, for example, emollients, solvents, humectants, thickeners, and powders. Examples of each of these types of substances, which can be used alone or as one or more mixtures, are:

Stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane-1,2-diol, butane-1,3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate , Isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecane-2-
Ol, isocetyl alcohol, cetyl palmitate, dimethylpolysiloxane,
Di-n-butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, peanut oil, castor oil, acetylated lanolin alcohol, petroleum, mineral oil Emollients such as butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, and myristyl myristate; propane, butane, isobutane, dimethyl ether, carbon dioxide,
And propellants such as 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 chalk, talc, fuller's earth, kaolin, starch, rubber, colloidal silicon dioxide, sodium poly Acrylate, tetraalkylammonium smectite, trialkylarylammonium smectite, chemically modified aluminum magnesium silicate, systematically modified montmorillonite clay, hydrous aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethylcellulose, And powders such as ethyl glycol monostearate.

The compounds of the present invention can further be administered in the form of liposome delivery systems such as small unilamellar liposomes, large unilamellar liposomes, and multilamellar liposomes. Liposomes that can be formed from various phospholipids such as cholesterol, stearylamine, or phosphatidylcholine. Preferred formulations for topical delivery of the compounds of the present invention include those described by Dowton et al., Influenc.
e of Liposomal Composition on Topical Delivery of Encapsulated Cyclosporin A: I. In vitro test using hairless mouse skin (Influence of Liposom
al Composition on Topical Delivery of Encapsulated Cyclosporin A: I. An
in vitro Study Using Hairless Mouse Skin) ", S.M. T. P. Pharma Sciences (STP Pharma Sciences), 3, 404-407 (1993),
Wallach and Philippot, "New Type of Lipid Vesicle: Novasome®", Liposome Technology, Volume 1, 1
41-156 (1993) and U.S. Pat. No. 4,911,928 (Wallach, Micro-Pak, Inc.), March 2, 1990.
Liposomes as described in US Pat.

The compounds of the present invention may also be administered by iontophoresis. For example, www.unipr.it
/arpa/dipfarm/erasmus/erasm14.html, Banga et al., "Hydrogel-Based Ion Therapy Delivery Device for Transdermal Application of Peptide / Protein Drugs (Hydr
ogel-based Iontotherapeutic Delivery Devices for Transdermal Delivery o
f Peptide / Protein Drugs), Pharm. Res., 10 (5), 697-702 (1993), Ferry LL, "Theoretical model of iontophoresis in transdermal drug delivery ( Theoretical Model of Iontophoresis Utilized in Tra
nsdermal Drug Delivery ", Pharmaceutical Acta Helvetiae, 70, 279-287 (1995), Gangarosa et al.," Modern iontophoresis in topical drug delivery (M).
Odern Iontophoresis for Local Drug Delivery, "Int. J. Pharm, 123, 159-171 (1995), Green et al.," Iontophoretic delivery of a series of tripeptides through in vitro skin ( Iontophoretic Delivery o
fa Series of Tripeptides Across the Skin in vitro), Pharm. Res., 8
Vol. 1121-1127 (1991), Jadoul et al., "Quantification and localization of fentanyl and TRH delivered by iontophoresis into the skin (Quan
tification and Localization of Fentanyl and TRH Delivered by Iontophores
is in the Skin) ", Int. J. Pharm., 120, 221-8 (1995).
O'Brien et al., "An Updated Review of its Antiviral Activity, Pharmacok."
inetic Properties and Therapeuticc Efficacy ”, Drugs, 3
7, pp. 233-309 (1989), Parry et al., "Acyclovir Biovailability in Human Sk.
in ", J. Invest. Dermatol., 98 (6), 856-63 (1992),
Santi et al., "Drug Reservoir Composition and Transport of Drug Reservoir Composition and Salmon Calcitonin in Transdermal Iontophoresis.
Salmon Calcitonin in Transdermal Iontophoresis), Pharm. Res., 14 (
1) Vol. 63-66 (1997), Santi et al., "Reverse iontophoresis-parameters determining electroosmotic flow: I. pH and ionic strength (Reverse Io).
ntophoresis-Parameters Determining Electroosmotic Flow: I. pH and Ioni
c Strength) ", J. Control. Release, 38, 159-165 (1996)
Santi et al., "Parameters for determining reverse iontophoresis-electroosmotic flow: II. Electrode chamber formulation (Revers).
e Iontophoresis-Parameters Determining Electroosmotic Flow: II. Elect
Rode Chamber Formulation, "J. Control. Release, 42, 29-36 (1996), Rao et al.," Reverse iontophoresis: non-invasive glucose monitoring reverse iontophoresis in humans in vivo. Reverse Iontophoresis: Noninvasive Glucose
Monitoring in vivo in Humans) ", Pharm. Res., 12 (12), 1869.
１８1873 (1995), Thysman et al., “Human Calcitonin Delivery in Rats by Rats by Iontophoresis.
Iontophoresis) ", J. Pharm. Pharmacol., 46, 725-730 (19
1994), Volpato et al., "Iontophoresis by electron repulsion and electroosmosis enhances the transport of acyclovir through the skin of nude mice.
Enhances the Transport of Acyclovir through Nude Mouse Skin by Electrore
pulsion and Electroosmosis), Pharm. Res., 12 (11), 1623-
See page 1627 (1995).

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

Other hair growth stimulating agents may be selected from a wide variety of molecules that can function in a variety of ways to enhance the hair growth effect of the compounds of the present invention. These optional other hair growth stimulating agents, when present, typically comprise from about 0.01 to about 1 in the compositions of the present invention.
5% by weight, preferably about 0.1 to about 10% by weight, most preferably about 0.5 to about 5% by weight.
Used at concentrations in the range of weight percent.

For example, minoxidil derivatives such as minoxidil and aminexil and US Pat. No. 3,382,247, US Pat. No. 5,756,092 (May 1998
U.S. Pat. No. 5,772,990 (issued on June 30, 1998), U.S. Pat. No. 5,760,043 (issued on June 2, 1998), and U.S. Pat. No. 328,914. No. 5,466,694 (November 14, 1995), US Pat. No. 5,438,058, issued on Aug. 1, 1995, and US Pat. No. 973,474 (issued November 27, 1990), (
Vasodilators such as potassium channel agonists, including those described in all of which are incorporated by reference herein, and cromakaline and diazoxide are other sources in the compositions of the present invention. It can be used as a hair stimulant.

One preferred type of other hair growth stimulants for use in the present invention are antiandrogens. Examples of suitable antiandrogens include finasteride and U.S. Patent No. 5,516,779 (issued May 14, 1996), which is incorporated by reference in the incorporated capital specification, and cancers described by Nane et al. Research 58 (Cancer Research 5)
8), "In vitro and in vivo effects of novel inhibitors of C17,20-relase and 5α-reductase, and their possible role in prostate cancer (Eff.
ects of Some Novel Inhibitors of C17, 20-Lyase and 5 -Reductase in v
itro and in vivo and Their Potential Role in the Treatment of Prostate C
ancer), as well as cyproterone acetate, azelaic acid and its derivatives and US Pat. No. 5,480,91.
No. 3, phthalimide and U.S. Pat. No. 5,411,981 (issued on May 2, 1995), which are described in US Pat. No. 5,411,981 (issued on Jan. 2, 1995). U.S. Pat. No. 5,565,467 (October 1996
And US Patent No. 4,910,226, issued March 20, 1990, all of which are incorporated by reference and incorporated herein. It is not limited to these.

Suitable types of optional hair growth stimulants are: 1) US Provisional Application No. 60 / 122,925 (Fulmer et al., 1999), which is incorporated herein by reference.
Immunosuppressive or non-immunosuppressive agents, such as cyclosporine and cyclosporin analogs, including the substances described on March 5, 2013) and 2) all of which are incorporated herein by reference. US Provisional Application No. 60 / 147,279
No. 60 / 147,313 (Degenhardt et al., Filed Aug. 5, 1999); US Provisional Application No. 60 / 147,313; Application No. 60 / 147,280 (Dejanhard (
Degenhardt et al., Filed August 5, 1999); US Provisional Application No. 60/147,
No. 278 (Degenhardt et al., Filed August 5, 1999); and US Provisional Application No. 60 / 147,276 (Eickhoff et al., 1999).
FK506 analogs, such as those described in US Pat.

Other suitable optional hair growth stimulants include selenium sulfide, ketoconazole, triclocarbon, triclosan, zinc pyrithione, itraconazole, asiatic acid (
asiatic acid), hinokitiol, mipirocin, and European published patent EPA
No. 0,680,745 (incorporated herein by reference), antibacterial substances such as clinasaicin hydrochloride, benzoyl peroxide, benzyl peroxide, and minocycline.

Anti-inflammatory substances may also be incorporated into the compositions of the present invention as optional hair growth stimulating agents.
Examples of suitable anti-inflammatory agents include hydrocortisone, mometasone furoate (mometa
sone furoate) and glucocorticoids such as prednisolone, US Pat.
Non-steroidal anti-inflammatory agents, including cyclooxygenase or lipoxygenase inhibitors as described in U.S. Pat.
PA No. 0,770,399 (issued on May 2, 1997), PCT published patent WO
94/06434 (issued March 31, 1994) and French Patent FR 2,
No. 268,523 (issued on November 21, 1975),
Salicylic acids and their compounds are mentioned, all of which are incorporated herein by reference.

Another suitable class of hair growth stimulants are thyroid hormones and derivatives and analogs thereof. Examples of thyroid hormones suitable for use in the present invention may include triiodothyrionine. Examples of thyroid hormone analogs suitable for use in the present invention include U.S. Provisional Application No. 60 / 136,996 (Zhang et al., Filed June 1, 1999); U.S. Provisional Application No. 60/136. 137,
No. 024 (Zhang et al., Filed on June 1, 1999), US Provisional Application No. 60 / 137,022 (Zhang et al., Filed on June 1, 1999), US Provisional Application No. No. 60 / 137,023 (Zhang et al., Filed on June 1, 1999); U.S. Provisional Application No. 60 / 137,052 (Young Quist)
gquist) et al., filed June 1, 1999), US Provisional Application No. 60 / 137,06.
No. 3 (Youngquist et al., Filed June 1, 1999) and US Provisional Application No. 60 / 136,958 (Youngquist et al., 19).
(Filed on June 1, 1999).

Prostaglandin agonists or prostaglandin antagonists can further be used as the hair growth stimulating agents in the compositions herein. Examples of suitable prostaglandin agonists or prostaglandin antagonists include latanoprost and PC
T Patent Publication WO98 / 33497 (Johnstone, issued August 6, 1998); PCT Patent Publication WO95 / 11003 (Stje Shantz)
rnschantz), issued on April 27, 1995), Japanese Patent JP 97-10009.
No. 1 (Ueno), and substances described in Japanese Patent JP 96-134242 (Nakamura).

[0158] Another type of any hair growth stimulant used herein is a retinoid. Suitable retinoids may include isotretinoin, acitretin, and tazarotene. Any other type of hair growth stimulating agent used herein is described, for example, in US Patent Application No. 09 / 353,408 (“Method for Regulating Hair Growth”).
Hair Growth, "Bradbury et al., Filed July 15, 1999, U.S. Patent Application Serial No. 09 / 353,409 (" Compositions Which contain triterpenes for regulating hair growth. Contain Triterpenes for Regul
ating Hair Growth) ", Bradbury et al., July 15, 1999.
, Such as the materials disclosed in US patent application Ser.

Other types of any hair growth stimulant used herein include flavinoids, derivatives and analogs of ascomycin, histamine antagonists such as diphenhydramine hydrochloride, and other triterpenes such as oleanolic acid. And US Pat. No. 5,529,769, Japanese Patent JP 10017431, PCT Publication WO95 / 35103, US Pat. No. 5,468,888, Japanese Patent JP 0
No. 9067253, PCT published patent WO92 / 09262, Japanese patent JP6
No. 2093215, U.S. Pat. No. 5,631,282, U.S. Pat.
No. 705, substances as described in Japanese Patent JP 08193,094, European Patent EP 0,558,509 (Bonte et al., September 8, 1993).
And WO 97/01346 (Bonte et al., 1).
Saponins, such as those described in U.S. Pat. No. 5,015, issued Jan. 16, 997, both of which are incorporated by reference and which are all incorporated herein by reference.
, 470 (issued May 14, 1991); U.S. Patent No. 5,300,284 (
(Issued April 5, 1994) and U.S. Patent No. 5,185,325 (issued February 9, 1993), all of which are incorporated by reference and all of which are incorporated herein. Proteoglycanase inhibitor or glycosaminoglycanase inhibitor, estrogen agonist and antagonist, pseudotelin, cytokine, and growth factor promoter, interleukin 1 inhibitor, interleukin 6 inhibitor, interleukin 10 inhibitors and analogues or inhibitors such as tumor necrosis factor inhibitors, vitamins and parathyroid hormone antagonists such as vitamin D analogues, vitamin B12 analogues and agonists and antagonism of panthenol, interferon Substances, hydroxy acids, such as the substances described in U.S. Pat. Phenone, and a hydantoin anticonvulsants such as phenytoin.

Further, other hair growth stimulating agents are described in, for example, Japanese Patent JP 09-157,
No. 139 (Tsuji et al., Issued June 17, 1997); European Patent EP0277
455A1 (Mirabeau, issued August 10, 1988); PCT published patent WO 97/05878 (Cabo Soler et al., Issued February 20, 1997); P
CT published patent WO92 / 16186 (Bonte et al., March 13, 1992
Japan Patent No. 62-93215 (Okazaki et al., Apr. 2, 1987)
U.S. Pat. No. 4,987,150 (Kurono et al., 1991).
Published on January 22, 2000); Japanese Patent JP2909081 (Oba et al., 1992/1)
Published on January 15, 2001); Japanese Patent No. 05-286,835 (Tanaka et al., 199).
Published November 2, 3rd), French Patent FR 2,723,313 (Greff
eff), issued August 2, 1994), U.S. Patent No. 5,015,470 (Gibson, issued May 14, 1991), and U.S. Patent No. 5,559,092 (September 1996). U.S. Pat. No. 5,536,751 (issued on Jul. 16, 1996), U.S. Pat. No. 5,714,515 (issued on Feb. 3, 1998), European Published Patent EPA No. 0, No. 319,991 (issued on June 14, 1989), European Published Patent Application EPA 0,357,630 (issued on October 6, 1988), and European Published Patent EPA 0,573,253 (issued on January 1, 1993).
Issued on February 8), Japanese Patent No. 61-260010 (November 18, 1986)
U.S. Pat. No. 5,772,990 (issued on June 30, 1998), U.S. Pat. No. 5,053,410 (issued on October 1, 1991), and U.S. Pat. No. 4,761, No. 401 (issued August 2, 1988), all of which are incorporated by reference and incorporated herein.

Non-limiting examples of penetration enhancers that can be used in the compositions of the present invention include, for example, 2-
Methylpropan-2-ol, propan-2-ol, ethyl-2-hydroxypropanoate, hexane-2,5-diol, POE (2) ethyl ether, di (
2-hydroxypropyl) ether, pentane-2,4-diol, acetone,
POE (2) methyl ether, 2-hydroxypropionic acid, 2-hydroxyoctanoic acid, propan-1-ol, 1,4-dioxane, tetrahydrofuran,
Butane-1,4-diol, propylene glycol diperargonate, polyoxypropylene 15 stearyl ether, octyl alcohol, POE ester of oleyl alcohol, oleyl alcohol, lauryl alcohol, dioctyl adipate, dicapryl adipate, diisopropyl adipate, diisopropyl seba Kate, 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, 2-ethyl-hexyl pelargonate, isopropyl isostear Rate, butyl laurate, benzyl benzoate, butyl benzoate, hexyl laurate, ethyl caprate, ethyl caprylate, butyl stearate, benzyl salicylate, 2-hydroxypropanoic acid, 2-hydroxyoctanoic acid, dimethyl sulfoxide, N, N-dimethylacetamide, N, N-dimethylformamide, 2-pyrrolidone, 1-methyl-2-
Pyrrolidone, 5-methyl-2-pyrrolidone, 1,5-dimethyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone, phosphine oxide, sugar ester, tetrahydrofurfural alcohol, urea, diethyl-m-toluamide, and 1 -Dodecylazacycloheptan-2-one.

In all of the foregoing, it will be appreciated that the compounds of the present invention may be administered alone or as a mixture, and the composition may further comprise other drugs or excipients appropriate for the indication.

Composition Examples The following composition and method examples do not limit the invention but provide guidance to those skilled in the art in preparing and using the compounds, compositions and methods of the invention. In each of the examples, compounds of the present invention other than those already described are substitutions of the examples and show similar results.

Example A A tablet for oral administration according to the present invention is made in the following configuration:

[Table 12] A 60 kg (132 lbs) female subject with rheumatoid arthritis is treated with the method of the present invention. Specifically, the above composition is orally administered 3 tablets a day for 2 years.

Example B A topical composition according to the present invention is made in the following configuration:

[Table 13] A male subject with male pattern baldness is treated with the method of the present invention. Specifically, the composition is applied topically to the subject daily for 6 weeks.

Example C A composition for topical application according to the present invention was prepared by Dowton et al., "Effect of liposome composition on local delivery of encapsulated cyclosporin A: I. Using hairless mouse skin. In vitro test (Influence of Liposomal Composi)
tion on Topical Delivery of Encapsulated Cyclosporin A: I. An in vitr
o Study Using Hairless Mouse Skin), S.M. T. P-Pharma Science (ST
P. Pharma Sciences), vol. 3, pp. 404-407 (1993), using the compound of Example 4 in place of cyclosporin A and Novasome 1 for nonionic liposome formulations. did. A male subject with male pattern baldness is treated with the composition. Specifically, the composition is applied topically to the subject for 6 weeks.

Example D A shampoo according to the invention is made in the following configuration:

[Table 14]

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61P 17/14 A61P 17/14 C07C 237/24 C07C 237/24 C07D 307/40 C07D 307/40 (71) Applicant ONE PROCTER & GANBLE PLAZA, CINCINNATI, OHIO, UNITED STATES OF AMERICA (72) Inventor Degenhart, Charles Raymond Cincinnati, Wellingwood, Ohio, U.S.A. State, Edgewood, Garden, Way 505 F-term (reference) 4C037 HA19 4C083 AB332 AC072 AC122 AC172 AC392 AC562 AC642 AC782 AC852 AD132 AD152 AD212 AD222 BB41 CC37 CC38 DD23 EE22 4C086 AA01 AA02 BA03 MA01 MA17 MA22 MA23 MA28 MA32 MA35 MA37 MA41 MA43 MA52 MA63 NA14 ZA92 4C206 AA01 AA02 FA09 MA01 MA33 MA37 MA42 MA48 MA52 MA55 MA57 MA61 A63 MA72 A83 NA006 BJ50 BP30 BR30 BT12

Claims (10)

[Claims] 1. The following structure:And its pharmacologically acceptable salts and hydrates, and its biological hydrolysis potential
(A) Z is a saturated or unsaturated four-, five-, six-, seven-, eight-, or nine-membered carbon;
A ring or heterocycle, wherein the heterocycle is O, N, S, S (O), S (O_Two) And P
One or more heteroatoms selected from the group consisting of ((O) OK)
(B) V is -CU-, wherein U is hydrogen, alkyl, alkenyl,
Loalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, ant
, Arylalkyl, heteroarylalkyl, arylalkenyl, and
Selected from the group consisting of heteroarylalkenyl; (c) G is nil, O, S, and NR₁₇(D) K is hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl
, Cycloalkyl, heterocycloalkyl, aryl, arylalkyl, hete
From loarylalkyl, arylalkenyl, and heteroarylalkenyl
(E) R₁Is alkyl, alkenyl, heteroalkyl, heteroalkenyl, cyclo
Loalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl
The group consisting of arylalkyl, arylalkenyl, and heteroarylalkenyl
(F) W is selected from the group consisting of nil, hydrogen, and lower alkyl; (g) A is selected from the group consisting of nil and alkyl; (h) X and Y are each independently And C (O), P (O), N, O, and S
Selected from the group consisting of: (i) if X is C (O), then R_ThreeIs nil and Y is N, O, and
Selected from the group consisting of S; (ii) if X is P (O), then R_ThreeIs nil and Y is N and O
(Iii) if X is N, then R_ThreeIs hydrogen, alkyl, and arylalkyl
And Y is selected from the group consisting of C (O) and P (O), and R_TwoIs
(iv) if X is O, then R_ThreeIs nil and Y is C (O) and P (O)
And R is selected from the group consisting of_TwoIs nil; and (v) if X is S, then R_ThreeIs nil, Y is C (O), and R_Two Is nil; (f) R_TwoAnd R_ThreeIs independently nil, hydrogen, alkyl, and aryl
Selected from the group consisting of alkyl; (g) R_FourIs alkyl; (h) R_FiveAnd R₆Are each independently nil, hydrogen, at least two carbon sources
Alkyl, alkenyl, heteroalkyl, heteroalkenyl, cyclo
Alkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl
A group consisting of alkyl, arylalkenyl, and heteroarylalkenyl
Or R_FiveAnd R₆Are linked together to form a carbocyclic or heterocyclic ring
Or R_FiveAnd R₆At least one is not nil or hydrogen; (i) R₇, R₈, R₉, And R_TenIs independently nil, hydrogen, alkyl
, Alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocy
Chloroalkyl, aryl, arylalkyl, heteroarylalkyl, aryl
Alkenyl, heteroarylalkenyl, halo, cyano, hydroxy, oxo
, Imino, -R₁₄SR_Fifteen, -R₁₄S (O_Two) R_Fifteen, -R₁₄S (O) R_Fifteen, -R₁₄
C (O) R_Fifteen, -R₁₄C (O) NR_FifteenR₁₆, -R₁₄C (O) OR_Fifteen, -R₁₄OR _Fifteen , -R₁₄NR_FifteenR₁₆, -R₁₄P (O) NR_FifteenR₁₆, -R₁₄P (O) OR_FifteenR₁₆ , And a spiro component, wherein R₇And R₈Are arbitrarily
To form an aromatic or saturated carbocyclic or heterocyclic ring,
The ring fuses with Z, (j) R₁₄, And R_FifteenIs independently nil, hydrogen, alkyl, alkenyl
, Heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl
, Aryl, arylalkyl, heteroarylalkyl, arylalkenyl
And (k) R is selected from the group consisting of₁₆And R₁₇Is independently selected from the group consisting of hydrogen and alkyl
Is done. 2. The compound according to claim 1, wherein Z is a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring. 3. The compound according to claim 1, wherein Z is a 5-membered carbocyclic or heterocyclic ring. 4. The compound according to claim 1, wherein Z is a 6-membered carbocyclic or heterocyclic ring. 5. The compound according to claim 1, wherein G is —NH—, A is nil, X is C (O), Y is N, and R ₂ is hydrogen. 6. The compound according to claim 1, wherein R ₈ , R ₉ , and R ₁₀ are each independently selected from the group consisting of nil and hydrogen. 7. The method according to claim 1, wherein R ₇ and R ₈ are bonded together to form a 5-, 6-, or 7-membered carbocyclic or heterocyclic aromatic ring, and are fused with Z. A compound as described. 8. A composition characterized by the compound according to claim 1 and a pharmaceutically acceptable carrier. 9. A method for treating alopecia, comprising applying the composition according to any one of claims 1 to 8 to a mammal. 10. A method for treating or preventing multidrug resistance, which comprises applying the composition according to any one of claims 1 to 9 to a mammal.