WO2001010838A1 - Multivalent compounds - Google Patents

Abstract

The present disclosure describes novel compounds and compositions which are particularly useful for treating hair loss in mamals, including arresting and/or reversing hair loss and promoting hair growth. The present compounds and compositions may also be useful against a variety of disorders including, for example, multi-drug resistance, human immunodeficiency virus (HIV), cardiac injury, and neurological disorders, and may be useful for controlling parasites and invoking immunosuppression. The present compounds have structure (A) wherein L is a linker through which J1, J2, J3, and J4 are attached; wherein J1 and J2 are each, independently, radicals of structure I; and J3 and J4 are each, independently, selected from nil and radicals of structure I.

Description

MULTIVALENT COMPOUNDS

FIELD OF THE INVENTION

The present invention relates to novel compounds and compositions which are particularly useful for treating hair loss m mammals, including arresting and / or reversing hair loss and promoting hair growth. The present compounds and compositions are also useful against a variety of disorders including, for example, multi-drug resistance, human immunodeficiency virus (HIV), cardiac injury, and neurological disorders, and may be useful for controlling parasites and invoking immunosuppression.

BACKGROUND OF THE INVENTION

Hair loss is a common problem which occurs, for example, through natural processes or is often chemically promoted through the use of certain therapeutic drugs designed to alleviate conditions such as cancer. Often such hair loss is accompanied by lack of hair regrowth which causes partial or full baldness.

As is well-known in the art, hair growth occurs by a cycle of activity which involves alternating periods of growth and rest. This cycle is often divided into three mam stages which are known as anagen, catagen, and telogen. Anagen is the growth phase of the cycle and may be characterized by penetration of the hair follicle deep into the dermis with rapid proliferation of cells which are differentiating to form hair. The next phase is catagen, which is a transitional stage marked by the cessation of cell division, and during which the hair follicle regresses through the dermis and hair growth is ceased. The next phase, telogen, is often characterized as the resting stage during which the regressed follicle contains a germ with tightly packed dermal papilla cells. At telogen, the initiation of a new anagen phase is caused by rapid cell proliferation in the germ, expansion of the dermal papilla, and elaboration of basement membrane components. This cycle is repeated throughout hair growth. Wherein hair growth ceases, most of the hair follicles reside in telogen and anagen is not engaged, thus causing the onset of full or partial baldness.

There have been many attempts in the literature to invoke the regrowth of hair by, for example, the promotion or prolongation of anagen Currently, there are two drugs approved by the United States Food and Drug Administration for the treatment of male pattern baldness: topical minoxidil (marketed as Rogame^® by Pharmacia & Upjohn), and oral fϊnasteπde (marketed as Propecia^® by Merck & Co., Inc.). There are conflicting reports, however, regarding the ability of minoxidil to grow hair to any significant extent. In fact, early clinical studies investigating decreased blood pressure via the use of minoxidil did not even mention hypertrichosis (hair growth) as a side effect. See Dormois et al., "Minoxidil in Severe Hypertension: Value When Conventional Drugs Have Failed", American Heart Journal, Vol. 90, pp. 360 - 368 (1975). Indeed, the manufacturers of minoxidil have reported only limited hair growth in a portion of patients using minoxidil. See, e.g.. Physician's Desk Reference^®, 49^th Ed. (1995), p. 2580. Furthermore, serious side effects of minoxidil are possible, including vasodilation (which leads to retention of fluid around the heart and increased heart rate), difficulty in breathing, and weight gain. Physician's Desk Reference^®, 49^th Ed. (1995), p. 2581.

Furthermore, while early indicators show that Propecia^® may be more effective than Rogaine^®, patients using Propecia^® are also experiencing limited hair growth. See The New England Journal of Medicine, Vol. 338, No. 9, February 26, 1998. Furthermore, potential side effects of Propecia^® are serious. Propecia^® may cause impotence, decreased sexual drive, decreased volume of ejaculate, breast tenderness and enlargement, and hypersensitivity reactions, including lip swelling and skin rash. Furthermore, Propecia^® is not indicated for women and children. In fact, women who are pregnant or potentially pregnant should not even handle crushed or broken tablets containing the drug. See Physician's Desk Reference^®. 52^th Ed. (1998), p. 1737 and The New England Journal of Medicine. Vol. 338, No. 9, February 26, 1998.

Interestingly, the immunosuppressive agents cyclosporin A and FK506 are known to invoke a prominent hypertrichotic side effect. See Iwabuchi et al., "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 Science, Vol. 9, pp. 64 - 69 (1995); Yamamoto et al., "Hair Growth-Stimulating Effects of Cyclosporin A and FK506, Potent Immunosuppressants", Journal of Dermatological Science. Vol. 7 (suppl.), pp. S47 - S54 (1994); Yamamoto et al., "Stimulation of Hair Growth by Topical Application of FK506, a Potent Immunosuppressive Agent", Journal of Investigational Dermatology. Vol. 102, pp. 160 - 164 (1994); Jiang et al., "Induction of Anagen in Telogen Mouse Skin by Topical Application of FK506, a Potent Immunosuppressant", Journal of Investigational Dermatology. Vol. 104, pp. 523 - 525 (1995); McElwee et al, "Topical FK506: A Potent Immunotherapy for Alopecia Areata? Studies Using the Dundee Experimental Bald Rat Model", British Journal of Dermatology, Vol. 137, pp. 491 - 497 (1997); Maurer et al., "Hair Growth Modulation by Topical Immunophilin Ligands", American Journal of Pathology, Vol. 150, No. 4, pp. 1433 - 1441 (1997); and Paus et al., "Hair Growth Control by Immunosuppression", Arch. Dermatol. Res.. Vol. 288, pp. 408 - 410 (1996). However, use of these compounds as hair growth actives may not be desirable due to their striking potency as immunosuppressive agents.

FK506 is a complex, macrocyclic molecule having the following structure:

Stocks et al., "The Contribution to Binding of the Pyranoside Substituents in the Excised Binding Domain of FK-506", Bioorganic & Medicinal Chemistry Letters, Vol.. 4, No. 12, pp. 1457 - 1460 (1994). Analogs closely resembling this complex macrocycle have been disclosed as having hair growth properties in the form of, for example, alopecia areata and / or male pattern baldness. See, e.g., Kawai et al., U.S. Patent No. 5,541,193, assigned to Abbott Laboratories, issued July 30,1996; Asakura et al.. U.S. Patent No. 5,496,564, assigned to Fujisawa Pharmaceutical Co., issued March 5, 1996; Baumann et al.. U.S. Patent No. 5,352,671 assigned to Sandoz Ltd., issued October 4, 1994; and Rupprecht et al., U.S. Patent No. 5,550,233, assigned to Merck & Co., Inc., issued August 27, 1996.

However, excitement related to the hypertrichotic activities of cyclosporin A and FK506 was historically somewhat quelled by the lack of reports of hypertrichosis by various non- macrocyclic immunosuppressive and non-immunosuppressive compounds which are less complex in structure than FK506. Only recently has it been reported that certain non- immunosuppressive analogs of FK506 have hypertrichotic potential. See Hamilton et al., WO 98/55090, assigned to Guilford Pharmaceuticals Inc., published December 10, 1998.

Divalent ketoamide analogs of such FK506 analogs have been reported in, for example, Keenan et al., "Synthesis and Activity of Bivalent FKBP12 Ligands for the Regulated Dimerization of Proteins", Bioorganic & Medicinal Chemistry, Vol. 6, pp. 1309 - 1335 (1998); Holt et al, WO 97/31898, assigned to Ariad Gene Therapeutics, Inc., published September 4, 1997; and Holt et al.. WO 97/31899, assigned to Ariad Gene Therapeutics, Inc., published September 4, 1997. However, there are no reports of utility of these types of compounds for treatment of hair loss.

Surprisingly, the present inventors have discovered a novel class of multivalent compounds, which are combination sulfonamides and ketoamides and / or amides, which arrest and / or reverse hair loss or promote hair growth but do not share the macrocyclic structure of FK506. The present inventors have further discovered compounds among this novel class which invoke hair growth yet are surprisingly non-immunosuppressive or are nominally immunosuppressive. The minimized and / or absent immunosuppressive activity of these hypertrichotic compounds are distinct advantages as compared to the immunosuppressive compounds cyclosporin A and FK506.

SUMMARY OF THE INVENTION

The present invention relates to compounds and compositions which are particularly useful for treating hair loss in mammals, including arresting and / or reversing hair loss and promoting hair growth. The present compounds and compositions may also be useful against a variety of disorders including, for example, multi-drug resistance, human immunodeficiency virus (HIV), cardiac injury, and neurological disorders, and are useful for controlling parasites and invoking immunosuppression. The compounds of the present invention have the structure:

^τ3

Ji— L— J₂ I J₄

and pharmaceutically acceptable salts, hydrates, and biohydrolyzable amides, esters, and imides thereof, wherein L is a linker through which J J₂, J₃, and J are attached; wherein Ji and J₂ are each, independently, radicals of structure I; and J₃ and J₄ are each, independently, selected from nil and radicals of structure I; wherein structure I is:

wherein the substituents R,, R₂, R₃, R₄, R₅, Re, R₇, R₈, R₉, R₁₀, W, V, Q, Z, A, X, Y, and U are defined herein.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds and compositions which are particularly useful for treating hair loss in mammals, including arresting and / or reversing hair loss and promoting hair growth.

In addition to discovering that the present compounds are useful for treating hair loss, the present inventors have also surprisingly discovered that immunosuppression is not required for hair growth stimulation. The present inventors have further discovered compounds that are useful for treating hair loss but are surprisingly non-immunosuppressive. Preferred compounds of the present invention are therefore, as defined herein, non-immunosuppressive. The present compounds are also useful for treating a variety of other conditions as described herein below.

Relative to compounds previously described, the present inventors have surprisingly discovered that the multivalent compounds of the present invention promote hair growth at equivalent and / or surprisingly enhanced levels. See copending provisional patent application serial numbers: 60/102,449 CMcIver et al.): 60/102,448 (Mclver et al.): 60/102,539 (Mclver et al); 60/102,458 (Tiesman et al.): and 60/102,437 (Tiesman et al.). Without intending to be limited by theory, it is believed that the present multivalent compounds are often more active than their "single ligand" counterparts because they provide a higher concentration of pharmacophore at the receptor binding site.

Publications and patents are referred to throughout this disclosure. All references cited herein are hereby incorporated by reference.

All percentages, ratios, and proportions used herein are by weight unless otherwise specified. In the description of the invention various embodiments and/or individual features are disclosed. As will be apparent to the ordinarily skilled practitioner all combinations of such embodiments and features are possible and can result in preferred executions of the invention.

As used herein, wherein any variable, moiety, group, or the like occurs more than one time m any variable or structure, its definition at each occurrence is independent of its definition at every other occurrence. For example, each A of structure I is independently selected from ml and alkyl. Because the definition at each occurrence of A is independent of its definition at every other occurrence, the A of Jj may be nil even though the A of J₂ is alkyl.

Definition and Usage of Terms

The following is a list of definitions for terms used herein:

As used herein "salt" is a catiomc salt formed at any acidic (e.g. , carboxyl) group, or an amonic salt formed at any basic (e g., ammo) group Many such salts are known m the art. Preferred catiomc salts include the alkali metal salts (such as, for example, sodium and potassium), alkaline earth metal salts (such as, for example, magnesium and calcium), and organic salts. Preferred amonic salts include the hahdes (such as, for example, chloride salts). Such acceptable salts must, when administered, be appropriate for mammalian use.

As used herein, "alkenyl" is an unsubstituted or substituted hydrocarbon chain radical having from 2 to about 15 carbon atoms; preferably from 2 to about 10 carbon atoms; more preferably from 2 to about 8 carbon atoms, and most preferably from about 2 to about 6 carbon atoms. Alkenyls have at least one olefimc double bond. Non-hmitmg examples of alkenyls include vinyl, allyl, and butenyl.

As used herein, "alkoxy" is an oxygen radical having an alkyl, alkenyl, or alkynyl, preferably an alkyl or alkenyl, and most preferably an alkyl substituent. Examples of alkoxy radicals include -O-alkyl and -O-alkenyl. An alkoxy radical may be substituted or unsubstiruted.

As used herein, "aryloxy" is an oxygen radical having an aryl substituent. An aryloxy radical may be substituted or unsubstiruted.

As used herein, "alkyl" is an unsubstituted or substituted saturated hydrocarbon chain radical having from 1 to about 15 carbon atoms; preferably from 1 to about 10 carbon atoms; more preferably from 1 to about 6 carbon atoms; and most preferably from 1 to about 4 carbon atoms. Preferred alkyls include, for example, methyl, ethyl, propyl, zsopropyl, and butyl.

As used herein, "alkylene" refers to an alkyl, alkenyl, or alkynyl which is a diradical. For example, "methylene" is -CH2-. Alkylenes may be substituted or unsubstituted. As used herein, "aryl" is an aromatic ring radical which is either carbocyclic or heterocychc. Preferred aryl groups include, for example, phenyl, benzyl, tolyl, xylyl, cumenyl, napthyl, biphenyl, thienyl, furyl, pyrrolyl, pyridmyl, pyrazinyl, thiazolyl, pyπmidmyl, qumolmyl, triazolyl, tetrazolyl, benzothiazolyl, benzofuryl, indolyl, indenyl, azulenyl, fluorenyl, anthracenyl, oxazolyl, isoxazolyl, isotriazolyl, imidazolyl, pyraxolyl, oxadiazolyl, mdohzmyl, indolyl, isoindolyl, puπnyl, quinohzmyl, qumolmyl, lsoquinohnyl, cmnolinyl, and the like. Aryls may be substituted or unsubstituted.

As used herein, "arylalkenyl" is an alkenyl radical substituted with an aryl group or an aryl radical substituted with an alkenyl group. Arylalkenyls may be substituted or unsubstituted.

As used herein, "arylalkyl" is an alkyl radical substituted with an aryl group or an aryl radical substituted with an alkyl group. Preferred arylalkyl groups include benzyl, phenylethyl, and phenylpropyl. Arylalkyls may be substituted or unsubstituted.

As used herein, "biohydrolyzable amides" are amides of the compounds of the present invention which do not interfere with the activity of the compound, or that are readily converted in vivo by a mammalian subject to yield an active compound.

As used herein, "biohydrolyzable esters" are esters of the compounds of the present invention which do not interfere with the activity of the compound, or that are readily converted in vivo by a mammalian subject to yield an active compound.

As used herein, "biohydrolyzable lmides" are lmides of the compounds of the present invention which do not interfere with the activity of the compound, or that are readily converted in vivo by a mammalian subject to yield an active compound.

As used herein, "carbocyclic ring", "carbocycle", or the like is a hydrocarbon ring radical. Carbocyclic rings are monocyclic or are fused, bridged, or spiro polycyclic rings. Unless otherwise specified, monocyclic rings contain from 3 to about 9 atoms, preferably from about 4 to about 7 atoms, and most preferably 5 or 6 atoms. Polycyclic rings contain from about 7 to about 17 atoms, preferably from about 7 to about 14 atoms, and most preferably 9 or 10 atoms. Carbocyclic rings (carbocycles) may be substituted or unsubstituted.

As used herein, "cycloalkyl" is a saturated carbocyclic or heterocychc πng radical Preferred cycloalkyl groups include, for example, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyls may be substituted or unsubstituted

As used herein, "heteroalkenyl" is an alkenyl radical comprised of carbon atoms and one or more heteroatoms wherein the heteroatoms are selected from the group consisting of oxygen, sulfur, nitrogen, and phosphorous, more preferably, oxygen, sulfur, and nitrogen. Heteroalkenyls may be substituted or unsubstituted.

As used herein, "heteroalkyl" is an alkyl radical comprised of carbon atoms and one or more heteroatoms wherein the heteroatoms are selected from the group consisting of oxygen, sulfur, nitrogen, and phosphorous, more preferably, oxygen, sulfur, and nitrogen. Heteroalkyls may be substituted or unsubstituted.

As used herein, "heteroaryl" is an aryl radical comprised of carbon atoms and one or more heteroatoms wherein the heteroatoms are selected from the group consisting of oxygen, sulfur, nitrogen, and phosphorous, more preferably, oxygen, sulfur, and nitrogen. Heteroaryls may be substituted or unsubstituted.

As used herein, "heteroarylalkenyl" is an arylalkenyl radical wherein the aryl group and / or the alkenyl group is comprised of carbon atoms and one or more heteroatoms wherein the heteroatoms are selected from the group consisting of oxygen, sulfur, nitrogen, and phosphorous, more preferably, oxygen, sulfur, and nitrogen. Heteroarylalkenyls may be substituted or unsubstituted.

As used herein, "heteroarylalkyl" is an arylalkyl radical wherein the aryl group and / or the alkyl group is comprised of carbon atoms and one or more heteroatoms wherein the heteroatoms are selected from the group consisting of oxygen, sulfur, nitrogen, and phosphorous, more preferably, oxygen, sulfur, and nitrogen. Heteroarylalkyls may be substituted or unsubstituted.

As used herein, "heterocychc ring", "heterocycle", or the like is a ring radical comprised of carbon atoms and one or more heteroatoms in the ring wherein the heteroatoms are selected from the group consisting of oxygen, sulfur, nitrogen, and phosphorous, more preferably, oxygen, sulfur, and nitrogen. Heterocycles are monocyclic or are fused, bridged, or spiro polycyclic rings. Unless otherwise specified, monocycles contain from 3 to about 9 atoms, preferably from about 4 to about 7 atoms, and most preferably 5 or 6 atoms. Polycycles contain from about 7 to about 17 atoms, preferably from about 7 to about 14 atoms, and most preferably 9 or 10 atoms. Heterocychc rings (heterocycles) may be substituted or unsubstituted.

As used herein, "heterocycloalkyl" is a saturated heterocycle. Heterocycloalkyls may be substituted or unsubstituted.

As used herein, a "lower" moiety (e.g., "lower" alkyl) is moiety having 1 to about 6, preferably 1 to about 4, carbon atoms. Wherein the term "ml" is used herein with reference to a group, substituent, moiety, or the like, it is meant that that group, substituent, or moiety is not present. Wherein a group, substituent, or moiety is ordinarily bonded to two or more other groups, substituents, or moieties, the others are bonded together m lieu of the group, substituent, or moiety which is nil. For example, with a compound having the structure A-B-C; wherein B is nil, then A is directly bonded to C and the compound is A-C. As another example, with a compound having the structure A-B-C; wherein C is nil, then the compound is A-B.

As used herein, "pharmaceutically acceptable" means suitable for use in a human or other mammal, preferably human.

As used herein, "safe and effective amount of a compound" (or composition, or the like) means an amount that is effective to exhibit biological activity, preferably wherein the biological activity is arresting and / or reversing hair loss or promoting hair growth, at the sιte(s) of activity in a mammalian subject, without undue adverse side effects (such as toxicity, irritation, or allergic response), commensurate with a reasonable benefit / risk ratio when used m the manner of this invention.

As used herein unless otherwise specified, the term "substituted" in reference to a group, moiety, or the like, means having one or more substituent groups each independently selected from alkyl, alkenyl, alkoxy, hydroxy, oxo, nitro, ammo, amido, alkylammo, cyano, halo, carboxy, alkoxyacyl (e.g , carboethyoxy), thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl (e g , pipeπdmyl, morpholmyl, pyrrolidmyl), lmmo, thioxo, hydroxyalkyl, aryloxy, and arylalkyl, preferably alkyl, alkenyl, alkoxy, hydroxy, oxo, nitro, ammo, alkylammo, halo, thiol, and aryloxy, more preferably alkyl, alkenyl, alkoxy, hydroxy, nitro, ammo, alkylammo, and halo, even more preferably alkyl, and alkoxy, and most preferably alkoxy.

Compounds of the Present Invention

The compounds of the present invention have the structure:

J₃

Ji— L— J₂

I

and pharmaceutically acceptable salts, hydrates, and biohydrolyzable amides, esters, and lmides thereof, wherein L is a linker through which J J₂, J₃, and J₄ are attached; wherein Jj and J₂ are each, independently, radicals of structure I; and J₃ and J are each, independently, selected from ml and radicals of structure I; wherein structure I is-

wherein:

(a) each V is independently a heteroatom wherein the heteroatom is nitrogen;

(b) each Q is selected from the group consisting of -S(0)₂-, -C(O)-, -C(0)C(0)-; wherein at least one Q of the compound is -S(0)₂- and at least one Q of the compound is selected from the group consisting of -C(O)- and -C(0)C(0)-;

(c) each Rj is independently selected from the group consisting of nil, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl;

(d) each Z is independently a saturated or unsaturated A-, 5-, 6-, 7-, 8-, or 9-membered heterocycle optionally containing one or more additional heteroatoms selected from O, N, S, S(O), S(0)₂, and P((0)OK);

(e) each K is independently selected from the group consisting of hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl;

(f) each W is independently selected from the group consisting of nil, hydrogen, and lower alkyl;

(g) each A is independently selected from the group consisting of nil and alkyl;

(h) each X and Y is independently selected from the group consisting of C(O), P(O), S(0)₂, N, O, and S, wherein:

(i) when X is selected from the group consisting of C(O), P(O), and S(0)₂, then the R₃ attached thereto is nil and the Y attached thereto is selected from the group consisting of N, O, and S; (ii) when X is N then the R₃ attached thereto is selected from the group consisting of hydrogen, alkyl, and arylalkyl, the Y attached thereto is selected from the group consisting of C(O), P(O), and S(0)₂, and the R₂ attached thereto through Y is nil; (iii) when X is O then the R₃ attached thereto is nil, the Y attached thereto is selected from the group consisting of C(O) and P(O), and the R₂ attached thereto through Y is nil; and (iv) when X is S then the R₃ attached thereto is nil, the Y attached thereto is C(O), and the R₂ attached thereto through Y is nil;

(i) each R₂ and R₃ is independently selected from the group consisting of nil, hydrogen, alkyl, and arylalkyl;

(j) each U is independently selected from the group consisting of nil, NH, N(R_I7), and O; wherein when Y is selected from the group consisting of P(O), S(0)₂, N, O, and S, then U is nil;

(k) each P is independently alkyl;

(1) each R₅ and Re is independently selected from the group consisting of nil, hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl; or wherein each R₅ and R₆ bonded to the same R₄ may optionally be bonded together to form a carbocyclic or heterocychc ring;

(m) each R₇, R₈, R9, and Rio is independently selected from the group consisting of nil, hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, halo, cyano, hydroxy, oxo, imino, -R₁₄SR₁₅, -R]₄S(0₂)Rι₅,

-R₁₄S(0)R,5, -R₁₄C(0)R,5, -R,₄C(0)NR₁₅R₁₆, -R,₄C(0)OR₁₅, -R₁₄OR₁₅, -Rι₄NR₁₅Rι₆, -R₁₄P(0)NR₁₅R₁₆, -R_I4P(0)OR₁₅R₁₆, and a spiro moiety; and wherein each R₇ and R₈ bonded to the same Z ring may be optionally bonded together to form an aromatic or saturated, carbocyclic or heterocychc ring which is fused to said same Z ring;

(n) each R₁₄ and R₁₅ is independently selected from the group consisting of nil, hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl;

(o) each R_]6 is independently selected from the group consisting of hydrogen and alkyl; and

(p) each R_]7 is independently selected from the group consisting of alkyl and arylalkyl. The Linker L The present compounds are "multivalent" meaning they have two or more groups selected from J J₂, J₃, and J₄ (collectively described as J radicals) which can potentially bind with a receptor binding site. The linker, L, may be any mechanism through which two or more of J], J₂, J₃, and J may be covalently bonded together. The linker may itself, but need not, participate in binding which a receptor binding site. However, a preferred linker will optimize, e.g., physiochemical and / or pharmacokinetic properties of the compound of the present invention.

Because the linker is a mechanism for covalent bonding, the ordinarily skilled artisan will recognize that the linker may be selected from a broad range of structures. A simple, and preferred, linker is merely a covalent bond which links one J radical to one or more others, herein referred to as "bond". Another preferred linker is a heteroatom diradical e.g., -O- or -N(OH)-, or triradical, e.g. :

I

Preferred heteroatom diradicals and triradicals are selected from oxygen, nitrogen, and sulfur; more preferably oxygen and nitrogen; and most preferably oxygen. Wherein nitrogen is the linker and J₃ and J₄ are nil, the nitrogen preferably bears a hydrogen, but may be substituted wherein the preferred substituent is alkyl.

Other non-limiting examples of linkers include radicals such as, for example, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, and heteroarylalkynyl. These radicals may be substituted or unsubstituted. Preferred among these examples are alkyl, alkenyl, heteroalkyl, heteroalkenyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, and heteroarylalkenyl. More preferred among these examples are alkyl, heteroalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, most preferably aryl. Most preferred among these examples are phenyl, naphthyl, and biphenyl.

Other preferred linkers include ethers, thioethers, amines, amides, ureas, carbamates, sulfonamides, thiocarbamates, esters, thioesters, and ketones.

Other preferred linkers are those in which two or more heteroatoms are bonded through a radical (referred to as L_H) selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, and heteroarylalkynyl, preferably alkyl, alkenyl, heteroalkyl, heteroalkenyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, and heteroarylalkenyl, more preferably alkyl, heteroalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, most preferably aryl, and most preferably phenyl, naphthyl, and biphenyl. Non-limiting examples of these types of linkers include -0-L_H-0- and -NH-L_H-NH-.

In a preferred embodiment of the invention, the linker is a bis-amide linker, a retro bis- amide linker, a polyether urea linker, or a polyether linker. These linkers are described below. The "attachment locations" are the points at which a J radical is linked to L.

Examples of bis-amide linkers are:

Examples of retro bis-amide linkers are:

An example of a polyether urea linker is:

attachment location

Examples of polyether linkers are:

OH

attachment attachment location location

O. ,O attachment X ^"O' attachment location location attachment attachment location location

attachment attachment location bcation

A preferred sulfonamide linker is shown below:

Overall, the most preferred linkers are selected from bond, aryl, alkyl, biaryl ether (i e , aryl-O- aryl), biaryl methyl (i e , aryl-CH₂-aryl), -0-, -S-, and -NH-, more preferably bond, lower alkyl, aryl, biaryl ether, -0-, and-NH-, even more preferably bond, aryl, biaryl ether, and -0-, with the most preferable among these being phenyl, naphthyl, biphenyl, biphenyl ether, biphenyl methyl, methyl, and -0-. Wherein G is not nil, L is most preferably selected from bond, alkyl, aryl, -0-, - S-, and -NH-. Wherein G is nil, L is most preferably selected from phenyl, naphthyl, and biphenyl. The Radicals J^ J₇. J₃. and J₄

The compounds of the present invention have two or more radicals selected from J J₂, J₃, and J . Ji and J₂ are each, independently, a radical of structure I. J₃ and J₄ are each, independently, selected from nil and a radical of structure I Preferably, Ji, J₂, J₃, and J₄ are each, independently, a radical of structure I More preferably, J J₂, and J₃ are each, independently, a radical of structure I, and J is ml. Most preferably, Jj and J₂ are each, independently, a radical of structure I, and J₃ and J₄ are each nil The Ring System Z

Each Z πng system is, independently, saturated or unsaturated 4-, 5-, 6-, 7-, 8-, or 9- membered heterocycles. Preferably, each Z ring system is, independently, a 5-, 6-, or 7- membered heterocycle, more preferably, independently, a 5- or 6-membered heterocycle Preferably, Z is saturated.

At the 1 -position of each ring system is the V heteroatom which is a nitrogen atom Each Z ring independently and optionally contains one or more heteroatoms or heteromoieties (herein collectively descπbed as heteroatoms for simplicity) in addition to the V nitrogen atoms wherein the additional heteroatoms are independently selected from oxygen (O), nitrogen (N), sulfur (S), sulfoxide (S(O)), sulfone (S(0)₂), and phosphonate (P((0)OK)). Preferably the additional heteroatoms are selected from the group consisting of O, N, S, S(O), and S(0)₂, but more preferably each of the Z rings do not contain any heteroatoms other than the V nitrogen atoms at the 1 -position of each ring.

Of course, wherein N is an additional heteroatom, the additional N heteroatom will be substituted, most preferably with hydrogen, alkyl, or oxo; and / or the linker L is covalently bonded to this heteroatom or the substituent thereon. The S(O), S(0)₂, and P(0)OK heteroatoms are depicted below m Table 1 to exemplify:

Table 1

The R_L Moiety

As shown m structure I, each Rj moiety is attached to the Q moiety. Each R moiety is independently selected from nil, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl. Wherein a R] moiety is nil, the linker (L) is bonded directly to the respective Q moiety. For example, wherein the R, moiety of J] is nil, then L is bonded to J_! through the Q moiety of Jj. Preferably, wherein any or each (more preferably each) Ri moiety is nil, then L is selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, and heteroarylalkynyl.

Each Ri moiety may be independently substituted with at least one substituent other than hydrogen. In addition to the substituents defined herein which can substitute all moieties, the substituents -0-alkyl-C(0)OR₃₂, and -0-alkyl-C(0)NHR₃₂, wherein R₃₂ is selected from hydrogen and alkyl, may also substitute on any of the G moieties.

Each i moiety is preferably independently selected from nil, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, and heteroarylalkyl, even more preferably nil, aryl, arylalkyl, and heteroarylalkyl, most preferably aryl Preferred aryls are substituted or unsubstituted phenyl and biphenyl. The most preferred aryl for each Rj moiety is substituted aryl (most preferably substituted phenyl), particularly aryl having at least one alkoxy substituent. Particularly preferred Ri moieties are shown below in Table 2.

Table 2 - Preferred Ri Moieties

The A-X-Y-U-R Side Chains

Substituting on each Z ring is, independently, the A-X-Y-U-R₄ side chain which is substituted, as described herein, by R₂, R₃, R₅, and R*.

Each A moiety of the side chains is, independently, selected from nil and alkyl. Most preferably, each A moiety is nil. Of course, wherein A is nil, the respective X moiety is directly attached to the respective Z ring. For example, wherein the A moiety of J] is nil, then the X moiety of Ji is directly attached to the Z ring of Ji .

The X moiety of each side chain is dependent upon the structure of the Y moiety of the same side chain and vice versa. Each X and Y moiety is, independently, selected from C(O) (i.e., carbonyl), P(O) (i.e., P=0), S(0)₂ (i.e., S(=0)₂), N, O, and S, with the following limitations:

(i) when X is selected from C(O), P(O), and S(0)₂, then the R₃ attached thereto is nil and the Y attached thereto is selected from N, O, and S; (ii) when X is N then the R₃ attached thereto is selected from hydrogen, alkyl, and arylalkyl, the Y attached thereto is selected from C(O), P(O), and S(0)₂, and the R₂ attached thereto through Y is nil; (iii) when X is O then the R₃ attached thereto is nil, the Y attached thereto is selected from C(O) and P(O), and the R₂ attached thereto through Y is nil; and (iv) when X is S then the R₃ attached thereto is nil, the Y attached thereto is C(O), and the R₂ attached thereto through Y is nil.

Preferably, each X and Y is, independently, selected from C(O), N, and O. More preferably, each X and Y is, independently, selected from C(O) and N.

Each X and Y is, independently, substituted by R₃ and R₂, respectively. Each R₃ and R₂ is, independently, selected from nil, hydrogen, alkyl, and arylalkyl. Wherein X is O or S, then the R₃ attached thereto is nil. Wherein Y is O or S, then the R₂ attached thereto is nil. Wherein X is P(O), then the R₃ attached thereto is nil, and wherein Y is P(O) then the R₂ attached thereto is nil. Wherein X is N, then the R₃ attached thereto is selected from hydrogen, alkyl, and arylalkyl, preferably hydrogen and alkyl, most preferably hydrogen. Wlierein Y is N, then the R₂ attached thereto is selected from hydrogen, alkyl, and arylalkyl, preferably hydrogen and alkyl, most preferably hydrogen.

Each U moiety is selected from nil, N, N(Rπ), and O, preferably nil, N, and O; with the proviso that wherein when Y is selected from the group consisting of N, O, and S, then U is nil. The substituent R₁₇ is selected from alkyl and arylalkyl, preferably alkyl. Wlierein a U moiety is nil, the respective Y and moieties are directly covalently attached to each other. Regardless of the identity of Y, U is most preferably nil.

Each R, moiety is, independently, alkyl. The preferred alkyls for each R follow the preferred limitations set forth above, with the most preferred R₄ being a methylene or methyne group (i.e., a d moiety bearing only one hydrogen substituent).

Each of the R₅ and R₆ moieties are directly attached to the respective R,. Each R₅ and Re is, independently, selected from nil, hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl; or wherein each R₅ and R₆ bonded to the same R₄ may be optionally bonded together to form a carbocyclic or heterocychc ring.

Preferably, each R₅ and Re is, independently, selected from nil, hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl. More preferably, each R₅ and R₆ is, independently, selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, and heteroarylalkyl. Most preferably, each R₅ and ^ is, independently, arylalkyl. It is often preferred that the R₅ and R₆ moieties which are bonded to the same R_» are equivalent moieties. Of course, each R₅ and Re may be, independently, substituted. Exemplary R₅ and Re moieties are shown in Table 3 below.

Table 3 - Exemplary Rs and Re Moieties

The W Moieties

Each of the Z rings may be substituted at the 2-position by an additional moiety, W. Each W moiety is, independently, selected from nil, hydrogen, and lower alkyl, preferably hydrogen and lower alkyl, most preferably hydrogen. The most preferable lower alkyl for W is methyl. The Ring Substituents R , R«, Rg, and R_jn

The R₇, R₈, R9, and R₁₀ substituents are each, independently, selected from nil, hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, halo, cyano, hydroxy, oxo, imino, -R₎₄SR₁₅, - R₁₄S(0₂)R₁₅, -R₁₄S(0)R₁₅, -R₁₄C(0)R₁₅, -R₁₄C(0)NR₁₅R₁₆, -R₁₄C(0)OR₁₅,

-R_]4ORi₅, -R]₄NR₁₅R₁₆, -R₁₄P(0)NR₁₅R₁₆, -Rι₄P(0)OR₁₅R₁₆, and a spiro moiety, and wherein each R₇ and R₈ bonded to the same Z ring may be optionally bonded together to form an aromatic or saturated, carbocyclic or heterocychc ring which is fused to said same Z ring. Preferably, at least one R₇, R₈, R₉, and Rι₀ is not nil or hydrogen. Each R₁ and R₁₅ is, independently, selected from nil, hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl. R₎₆ is selected from hydrogen and alkyl.

Preferably, each R₇, R₈, R₉, and R_I0 is, independently, selected from nil, hydrogen, alkyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, halo, hydroxy, oxo, -R,₄SR₁₅, -R₁₄S(0₂)R₁₅, -R_I4S(0)R₁₅, -R₁₄C(0)R₁₅,

-R]₄C(0)NRi₅Ri₆, -Rι₄OR₁₅, -Rι₄NR₁₅R₁₆, and a spiro moiety, and wherein each R₇ and R₈ bonded to the same Z ring may be optionally bonded together to form an aromatic or saturated, carbocyclic or heterocychc ring which is fused to said same Z ring. More preferably, each R₇, R₈, R₉, and R_]0, is, independently, selected from nil, hydrogen, alkyl, heteroalkyl, heteroalkenyl, aryl, arylalkyl, heteroarylalkyl, halo, hydroxy, oxo, -R₁ SR_]5, -R₁₄S(0₂)R_I5, -R,₄S(0)R₁₅, -R₁₄C(0)R₁₅, -R,₄C(0)NR₁₅R₁₆, -R,₄OR₁₅, -R_I4NR₁₅R₁₆, and a spiro moiety, and wherein each R₇ and R₈ bonded to the same Z ring may be optionally bonded together to form an aromatic or saturated, carbocyclic or heterocychc ring which is fused to said same Z ring. Even more preferably, each R₇, R₈, R₉, and R_]0 is, independently, selected from nil, hydrogen, alkyl, heteroalkyl, heteroalkenyl, aryl, arylalkyl, heteroarylalkyl, halo, hydroxy, - R₁₄C(0)R₎₅, -R_MC(0)NR₁₅R₁₆, -R_]4OR,₅ -Rι₄OR₁₅ (particularly -0-CH₂-phenyl; wherein R,₄ is nil and R₁₅ is arylalkyl (in this case, benzyl),

-Rι₄NRι₅Ri₆, and a spiro moiety, and wherein each R₇ and R_g bonded to the same Z ring may be optionally bonded together to form an aromatic or saturated, carbocyclic or heterocychc ring which is fused to said same Z ring. Most preferably, each R₇ and R₈ bonded to the same Z ring is bonded together to form an aromatic or saturated, carbocyclic or heterocychc ring which is fused to said same Z ring.

Wherein R₇ and R₈ are bonded together to form an aromatic or saturated, carbocyclic or heterocychc second ring wherein the second ring is fused to Z, the second ring may, of course, be substituted or unsubstituted. A preferred second ring is phenyl, optionally substituted. A more preferred second ring is unsubstituted phenyl.

Preferred Compounds of the Present Invention

Ji, J₂, J₃, and J may be equivalent or different radicals. Preferably, the J radicals of the compound are equivalent, particularly due to efficiency of synthesis and / or optimization of the binding moiety.

The J radicals may be attached through L at any atom ("attachment locations") on each of the radicals. Preferred attachment locations include Ri of each of J_{1 (} J₂, J₃, and J₄. By way of example, therefore, wherein Ri is the attachment location with respect to Ji, the R] of Jj is directly covalently bonded to L. Other preferred attachment locations include any of R₅, R , R₇, R₈, R₉, and Rι₀, preferably R₅ and Re. The more preferred attachment locations for each of J₎₅ J₂, J₃, and J₄ are R_l5 R₅, and R^, most preferably R, (or wherein R_! is nil, the respective Q moiety).

To exemplify, the attachment locations of the following compound are Rj with respect to Jj and J₂ (here, J₃ and J are each nil):

The attachment locations of the following compound are R₅ with respect to Ji, and R₅ with respect to J₂ (here, J₃ and J₄ are each nil):

The attachment locations of the following compound are R₅ with respect to Ji, and G with respect to J₂ (here, J₃ and J₄ are each nil):

To exemplify, the attachment locations of the following compound are R₇ with respect to Ji and J₂ (here, J₃ and J₄ are each nil):

or, directly through each of the Z rings:

Non-limiting examples of compounds linked through each R₇ or through each Z ring in the above manners include:

wherein L is -0-L_H-0-, and L_H is preferably selected from alkyl, aryl, heteroalkyl, and heteroaryl;

A non-limitmg example wherein each R and R₈ are bonded together to form an aromatic or saturated, carbocyclic or heterocychc second ring wherein the second ring is fused to Z, wherein the second ring is optionally substituted, and the linker L is attached through the second ring or any optional substituents thereon is as follows:

Preferred compounds of the present invention are disclosed below m Tables 4 - 16: Table 4 - Preferred Compounds of the Present Invention

wherein each Rj is independently selected from nil, phenyl, 4-methylphenyl, and 3,4- dimethoxyphenyl; each R₅ is independently selected from hydrogen and 3-phenylpropyl; and each Re is independently selected from phenyl and 3-phenylpropyl. Most preferably, wherein each R] is ml, L is aryl (preferably phenyl or biphenyl). Most preferably, wherein each R] is not nil, L is -0-.

Table 5 - Preferred Compounds of the Present Invention

dimethoxyphenyl; each R₅ is independently selected from hydrogen and 3-phenylpropyl; and each R₆ is independently selected from the group consisting of phenyl and 3-phenylpropyl. Most preferably, wherein each Rj is nil, L is aryl (preferably phenyl or biphenyl). Most preferably, wherein each Ri is not nil, L is -O-.

Table 6 - Preferred Compounds of the Present Invention

wherein each R_t is independently selected from the group consisting of nil, 4-methylphenyl, 2- thienyl, 2,4,6-trnsopropylphenyl, 4-fluorophenyl, phenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,5-dιmethoxyphenyl, 3,4,5-trιmethoxyphenyl, methyl, 8-qumolyl, l-(5-N,N- dιmethylammo)naphthyl, 4-methoxyphenyl, 5-methylphenyl, 4-ιodophenyl, 2,4,6- trimethylphenyl, benzyl, 2-naphthyl, 4-fluorophenyl, 4-nιtrophenyl, 3-nιtrophenyl, 4- chlorophenyl, E-styrenyl, 2-ethylphenyl, 2-ethyl(3,4,5-trιmethoxy)phenyl, and 3,4- dimethoxyphenyl; each R₅ is independently selected from the group consisting of hydrogen, 3- phenylpropyl, benzyl, 2-phenylethyl, 3-phenylpropyl; and each Re is independently selected from the group consisting of phenyl, 3-phenylpropyl, 4-phenoxyphenyl, 3-phenoxyphenyl. Most preferably, wherein each R] is nil, L is aryl (preferably phenyl or biphenyl). Most preferably, wherein each R] is not nil, L is -O-.

Table 7 - Preferred Compounds of the Present Invention

wherem each Rj is independently selected from the group consisting of nil, 4-methylphenyl, 2- thienyl, 2,4,6-trnsopropylphenyl, 4-fluorophenyl, phenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,5-dιmethoxyphenyl, 3,4,5-trιmethoxyphenyl, methyl, 8-qumolyl, l-(5-N,N- dιmethylamιno)naphthyl, 4-methoxyphenyl, 5-methylphenyl, 4-ιodophenyl, 2,4,6- tπmethylphenyl, benzyl, 2-naphthyl, 4-fluorophenyl, 4-nιtrophenyl, 3-nιtrophenyl, 4- chlorophenyl, E-styrenyl, 2-ethylphenyl, 2-ethyl(3,4,5-tπmethoxy)phenyl, and 3,4- dimethoxyphenyl; each R₅ is independently selected from the group consisting of hydrogen, 3- phenylpropyl, benzyl, 2-phenylethyl, 3-phenylpropyl; and each R is independently selected from the group consisting of phenyl, 3-phenylproρyl, 4-phenoxyphenyl, 3-phenoxyphenyl. Most preferably, wherein each R] is nil, L is aryl (preferably phenyl or biphenyl). Most preferably, wherein each R_! is not nil, L is -0-.

Table 8 - Preferred Compounds of the Present Invention

wherein each R] is independently selected from the group consisting of phenyl, 4-methylphenyl, and 3,4-dimethoxyphenyl; each R is independently selected from the group consisting of hydrogen and 3-phenylpropyl; and each R₅ is independently selected from the group consisting of phenyl and 3-phenylpropyl.

Table 9 - Preferred Compounds of the Present Invention

wherein each Ri is independently selected from the group consisting of phenyl, 4-methylphenyl, and 3,4-dimethoxyphenyl; each Re is independently selected from the group consisting of hydrogen and 3-phenylpropyl; and each R₅ is independently selected from the group consisting of phenyl and 3-phenylpropyl.

Table 10 - Preferred Compounds of the Present Invention

wherein each R] is independently selected from the group consisting of 4-methylphenyl, 2- thienyl, 2,4,6-triisopropylphenyl, 4-fluorophenyl, phenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, methyl, 8-quinolyl, l-(5-N,N- dimethylamino)naphthyl, 4-methoxyphenyl, 5-methylphenyl, 4-iodophenyl, 2,4,6- trimethylphenyl, benzyl, 2-naphthyl, 4-fluorophenyl, 4-nitrophenyl, 3-nitrophenyl, 4- chlorophenyl, E-styrenyl, 2-ethylphenyl, 2-ethyl(3,4,5-trimethoxy)phenyl, and 3,4- dimethoxyphenyl; each R is independently selected from the group consisting of hydrogen, 3- phenylpropyl, benzyl, 2-phenylethyl, 3-phenylpropyl; and each R₅ is independently selected from the group consisting of phenyl, 3-phenylpropyl, 4-phenoxyphenyl, 3-phenoxyphenyl. Table 11 - Preferred Compounds of the Present Invention

wherein each Ri is independently selected from the group consisting of 4-methylphenyl, 2- thienyl, 2,4,6-triisopropylphenyl, 4-fluorophenyl, phenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, methyl, 8-quinolyl, l-(5-N,N- dimethylamino)naphthyl, 4-methoxyphenyl, 5-methylphenyl, 4-iodophenyl, 2,4,6- trimethylphenyl, benzyl, 2-naphthyl, 4-fluorophenyl, 4-nitrophenyl, 3-nitrophenyl, 4- chlorophenyl, E-styrenyl, 2-ethylphenyl, 2-ethyl(3,4,5-trimethoxy)phenyl, and 3,4- dimethoxyphenyl; each R is independently selected from the group consisting of hydrogen, 3- phenylpropyl, benzyl, 2-phenylethyl, 3-phenylpropyl; and each R₅ is independently selected from the group consisting of phenyl, 3-phenylpropyl, 4-phenoxyphenyl, 3-phenoxyphenyl.

Particularly preferred compounds of the present invention are set forth below. Table 12 - Preferred Compounds of the Present Invention

In the following preferred compounds, J₃ and J₄ are each nil, L is biphenyl, R, of Jj is nil, and R_! of J₂ is nil:

Table 13 - Preferred Compounds of the Present Invention In the following preferred compounds, J₃ and J₄ are each nil, L is phenyl, Ri of Ji is nil,

Table 14 - Preferred Compounds of the Present Invention In the following preferred compounds, J₃ and J₄ are each nil, L is phenyl, R_λ of Ji is biphenyl, Rj of J₂ is biphenyl, Re of Ji is heteroarylalkyl, R₅ of Jj is heteroalkyl substituted with oxo, Re of J₂ is heteroarylalkyl, and R₅ of J₂ is heteroalkyl substituted with oxo:

Table 15 - Preferred Compounds of the Present Invention In the following preferred compounds, J₃ and J₄ are each nil, Ri of Ji is phenyl, R, of J₂ is phenyl, and L is bond:

Table 16 - Preferred Compounds of the Present Invention In the following preferred compounds, J₃ and J₄ are each nil, Rj of J] is phenyl, Ri of J₂ is phenyl, and L is oxygen:

Table 17 - Preferred Compounds of the Present Invention In the following preferred compound, L is phenyl, R] of Ji is nil, R] of J₂ is nil, Rj of J₃ is nil, and J₄ is nil:

Table 18 - Preferred Compounds of the Present Invention In the following preferred compounds, L is -0-phenyl-O-, Ri of Jj is biphenyl, Ri of J₂ is biphenyl, J₃ is nil, and J₄ is nil:

Table 19 - Preferred Compounds of the Present Invention In the following preferred compounds, L is -0-C(0)-phenyl-C(0)-0-, Ri of J] is biphenyl, Rj of J₂ is biphenyl, J₃ is nil, and J₄ is nil:

Table 20 - Preferred Compounds of the Present Invention

Analytical Methods

The present compounds are useful for treating hair loss, the more preferred among these being non-immunosuppressive The compounds (test compounds) of the present invention may be tested for their ability to induce anagen and their immunosuppressive activity (or lack thereof) using the following methods. Alternatively, other methods well-known in the art may be used (but with the term "non-immunosuppressive" being defined according to the method disclosed herein).

Telogen Conversion Assay:

The Telogen Conversion Assay measures the potential of a test compound to convert mice m the resting stage of the hair growth cycle ("telogen"), to the growth stage of the hair growth cycle ("anagen").

Without intending to be limited by theory, there are three principal phases of the hair growth cycle: anagen, catagen, and telogen. It is believed that there is a longer telogen penod m C3H mice (Harlan Sprague Dawley, Inc., Indianapolis, IN) from approximately 40 days of age until about 75 days of age, when hair growth is synchronized. It is believed that after 75 days of age, hair growth is no longer synchronized. Wherein about 40 day-old mice with dark fur (brown or black) are used in hair growth experiments, melanogenesis occurs along with hair (fur) growth wherein a hair growth promoter is applied. The Telogen Conversion Assay herein below is used to screen compounds for potential hair growth by measuπng melanogenesis.

Three groups of 44 day-old C3H mice are utilized: a vehicle control group, a positive control group, and a test compound group, wherein the test compound group is administered a compound of the present invention. The length of the assay is at least 19 days with 15 treatment days (wherein the treatment days occur Mondays through Fridays). Day 1 is the first day of treatment. Most studies will end on Day 19, but a few may be carried out to Day 24 if the melanogenesis response looks positive, but occurs slowly. A typical study design is shown in Table 19 below:

Table 19

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

The mice are treated topically Monday through Friday on their lower back (base of tail to the lower πb). A pipettor and tip are used to deliver 400 μL to each mouse's back. The 400 μL application is applied slowly while moving hair on the mouse to allow the application to reach the skin.

While each treatment is being applied to the mouse topically, a visual grade of from 0 to 4 will be given to the skm color m the application area of each animal. As the mice convert from telogen to anagen their skm color will become more bluish-black. As indicated m Table 20, the grades 0 to 4 represent the following visual observations as the skm progresses from white to bluish-black:

Table 20

Immunosuppression Assay:

The immunosuppression assay herein predicts the immunosuppressive activity of a compound of the present invention. The assay is performed as follows:

Spleens are excised from euthanized (C0₂ asphyxiation) adult male C3H mice ranging in age from seven to sixteen weeks old (live mice commercially available from Harlan Sprague Dawley, Inc., Indianapolis, IN). The spleens are placed immediately in cold Hanks Balanced Salt Solution (HBSS, commercially available from Gibco-BRL, Gaithersburg, MD). The spleens are then ground up between frosted glass slides and filtered through a sterile screen to remove tissue debris. The resulting cell suspension is underlayed with an equal volume of Ficoll-Paque Plus (commercially available from Pharmacia Biotech, Piscataway, NJ) and centrifuged at 400 x g for approximately forty minutes at 20 °C in order to collect the splenocytes. The splenocytes are collected from the interface using a disposable pipet and are washed twice with HBSS, followed by centrifugation at 100 x g for ten mm at 20 °C. Splenocytes are resuspended in five to ten mL of cell culture media consisting of phenol red-free RPMI 1640 (culture media commercially available from Gibco-BRL) containing 10% heat-mactivated fetal bovine serum (Gibco-BRL), penicillin (50 U/mL), streptomycin (100 μg/mL), L-glutamme (2 mM), 2-mercaptoethanol (10^"5 M), and N-2-hydroxyethylpιperazιne-N'-2-ethanesulfonιc acid (HEPES) (10 mM). The cells are counted and checked for viability using, for example, trypan blue. Splenocytes are resuspended in medium at 10⁶ cells/mL and pipetted into 96 well round bottom plates at 10⁵ cells/well. Splenocytes are activated by addition of 50 μL/well of conconavahn A (final assay concentration = 5 μg/ml) in the presence or absence of a test compound. Test compounds are made up as stock solutions in methyl sulfoxide (DMSO), then diluted in medium and 50 μL/well added, such that the final concentration of DMSO in the assay is below 0.05%. The plates are incubated at 37 °C with 5% C0₂ for 48 hours. After 48 hours, the cells are pulsed with 1 μCi/well of methyl-³H- thymidme (commercially available from Amersham, Buckinghamshire, England) and incubated an additional 24 hours.

After 24 hours, the cells are harvested onto GF/C filter plates (commercially available from Packard, Downers Grove, IL), solubihzed in Microscint 20 (Packard), and counted on a TopCount microplate scintillation and luminescence plate counter (Packard). Activity is measured as a percentage of control activity m the absence of test compound and plotted versus test compound concentration. The data are fit to a 4-parameter curve fit (Sigmaplot) and IC50 values are calculated. As used herein, test compounds are considered non-immunosuppressive if, by using this method, the ratio of (cyclospoπn A IC₅₀/test compound IC₅₀) x 100 is less than or equal to 0.02, i.e., a non-immunosuppressive test compound has < 2% of the immunosuppressive activity of cyclospoπn A.

Cell viability is assessed using the MTT (3-[4,5-dιmethyl-thιazoyl-2-yl]2,5-dιphenyl- tetrazohum bromide) dye assay as described by Nelson et al., Journal of Immunology, Vol. 150, No 6, pp. 2139 - 2147 (1993), with the exception that the assay is earned out m serum-free, phenol red-free RPMI 1640 and the dye is solubihzed in 100 μL/well DMSO and read at an OD of 540 nm with a background correction at 650 nm on a SpectraMax Plus microplate reader (Molecular Devices, Menlo Park, CA).

Multi-Drug Resistance

As disclosed herein, the present compounds are also useful, for example, to increase the antiprohferative activity of a drug and / or prevent and / or treat multi-drug resistance. The present compounds may be assayed for this property as described in U.S. Patent No. 5,744,485, Zelle et al., assigned to Vertex Pharmaceuticals Inc., issued April 28, 1998, U.S. Patent No 5,726,184, Zelle et al., assigned to Vertex Pharmaceuticals Inc., issued March 10, 1998, U.S Patent No. 5,620,971, Armistead et al , assigned to Vertex Pharmaceuticals Inc., issued April 15, 1997, and U.S. Patent No. 5,543,423, Zelle et al.. assigned to Vertex Pharmaceuticals Inc., issued August 6, 1996.

Methods of Making

The compounds of the present invention are prepared according to methods which are well-known to those skilled in the art. The starting materials used in preparing the compounds of the invention are known, made by known methods, or are commercially available as a starting material.

It is recognized that the skilled artisan in the art of organic chemistry can readily carry out standard manipulations of organic compounds without further direction. Examples of such manipulations are discussed m standard texts such as J. March, Advanced Organic Chemistry. John Wiley & Sons, 1992.

The skilled artisan will readily appreciate that certain reactions are best carried out when other functionalities are masked or protected in the compound, thus increasing the yield of the reaction and / or avoiding any undesirable side reactions Often, the skilled artisan utilizes protecting groups to accomplish such increased yields or to avoid the undesired reactions. These reactions are found m the literature and are also well withm the scope of the skilled artisan. Examples of many such manipulations can be found in, for example, T. Greene, Protecting Groups m Organic Synthesis. John Wiley & Sons, 1981.

The compounds of the present invention may have one or more chiral center. As a result, one may selectively prepare one optical isomer, including diastereomers and enantiomers, over another, for example by chiral starting materials, catalysts or solvents, or may prepare both stereoisomers or both optical isomers, including diastereomers and enantiomers at once (a racemic mixture). Since the compounds of the invention may exist as racemic mixtures, mixtures of optical isomers, including diastereomers and enantiomers, or stereoisomers may be separated using known methods, such as through the use of, for example, chiral salts and chiral chromatography.

In addition, it is recognized that one optical isomer, including a diastereomer and enantiomer, or a stereoisomer, may have favorable properties over the other. Thus, when disclosing and claiming the invention, when one racemic mixture is disclosed, it is clearly contemplated that both optical isomers, including diastereomers and enantiomers, or stereoisomers substantially free of the other are disclosed and claimed as well.

The following provides non-limitmg examples illustrating more specifically the methods of making various compounds of the present invention. As used herein, the following abbreviations are used:

Example 1

la. ^-(N-tert-Butoxycarbonytypipecolinic acid l,7-diphenyl-4-heptylamide: (S)-(N-tert- Butoxycarbonyl)pipecolinic acid (4.66 g, 20.3 mmol) is dissolved in 200 mL of DMF. 1,7- Diphenyl-4-aminoheptane (5.44 g, 20.3 mmol) and i-Pr₂EtN (5.25 g, 40.7 mmol) are added followed by PyBOP (10.6 g, 20.3 mmol). The reaction is stirred for 18 hours at room temperature, then poured onto ice-cold 0.1N HCl (800 mL) and extracted with ethyl acetate (800 mL). The layers are separated and the organic layer washed successively with brine (200 mL), saturated NaHC0₃ solution (400 mL) and brine (200 mL). The organic solution is dried over MgS0₄, filtered, and concentrated under reduced pressure. Purification of the product by chromatography on silica gel affords the desired amide la.

lb. (S)-Pipecolinic acid l,7-diphenyl-4-heptylamide: The amide la (8.74 g, 18.3 mmol) is dissolved in 150 mL of anhydrous dichloromethane. TFA (100 mL) is added dropwise over a 5 minute period. After about 1 - 2 hours the mixture is cooled in an ice-bath and saturated K₂C0₃ solution is added until the pH is approximately 8. The mixture is transferred to a separatory funnel containing dichloromethane (200 mL) and water (200 mL) and shaken. The organic layer is separated and washed with water (200 mL) before drying over MgS0₄. The mixture is filtered and concentrated under reduced pressure to afford the desired amine lb.

Example 2

2a. 3,5-Disulfobenzoic acid: 3,5-Disulfobenzoic acid, disodium salt (3 g, 9.2 mmol; Aldrich Chemical Co., Milwaukee, WI) is slurried in deionized water (30 mL) at ambient temperature, then heated until a solution is achieved. Acidic ion-exchange resin (Dowex^® 50x8-400 (H⁺), 3 g, Aldrich Chemical Co., Milwaukee, WI) is added and the slurry is stirred for one minute. The warm solution is filtered and washed with warm water. The filtrate is lyophilized to afford the desired 3,5-disulfobenzoic acid 2a.

2b

2b. 3,5-DichlorosulfonylbenzoyI chloride: 3,5-Disulfobenzoic acid (2.6 g, 9.2 mmol) is slurried in thionyl chloride (10 mL, 137 mmol) and DMF (10 μL, 0.13 mmol) at ambient temperature. The mixture is heated at reflux for 18 hours, then cooled to ambient temperature. Dichloromethane (100 mL) is added and the mixture is filtered and washed with dichloromethane. The filtrate is concentrated under vacuum to afford 3,5- dichlorosulfonylbenzoyl chloride 2b.

2c. l-Benzoyl-3,5-Disulfonyl-((S)-N-pipecolic acid l,7-diphenyl-4-heptylamide): 3,5- dichlorosulfonylbenzoyl chloride 2b (3.1 g, 9.2 mmol) is dissolved in dichloromethane (100 mL). A solution of amine lb (10.45 g, 27.6 mmol) and dichloromethane (50 mL) and i-Pr EtN (6.4 mL, 36.8 mmol) is added at ambient temperature. The reaction mixture is stirred for 36 hours then concentrated under reduced pressure. The residue is purified by preparative chromatography (silica gel) to afford the desired combination amide-sulfonamide 2c.

3a. (S)-(N-tert-Butoxycarbonyl)-l,2,3,4-tetrahydro-3-isoquinoline carboxylic acid 1,7- diphenyl-4-heptylamide: (S)-(N-tert-Butoxycarbonyl)-l,2,3,4-tetrahydro-3-ιsoqumohne carboxylic acid (4.9 g, 17.7 mmol) is dissolved in 160 mL of DMF. l,7-Dιphenyl-4- am oheptane (4.3 g, 16.1 mmol) and ι-Pr₂EtN (5.6 mL, 32.2 mmol) are added followed by PyBOP (8.8 g, 16.9 mmol). The reaction is stirred for about 19 hours at room temperature, then poured onto ice-cold 0.1N HCl (600 mL) and extracted with ethyl acetate (600 mL). The layers are separated and the organic layer washed successively with brme (100 mL), saturated NaHC0₃ solution (300 mL) and brine (2 x 200 mL). The organic solution is dried over MgS0 , filtered, and concentrated under reduced pressure. Purification of the product by chromatography on silica gel affords the desired amide 3a. 3b. (S)-l,2,3,4-tetrahydro-3-isoquinoline carboxylic acid l,7-diphenyl-4-heptylamide: The amide 3a (8.1 g, 15.3 mmol) is dissolved in 150 mL of anhydrous dichloromethane. TFA (120 mL) is added dropwise over a 5 minute period. After 2 hours the mixture is cooled in an ice-bath and saturated K₂C0₃ solution is added until the pH is approximately 8. The mixture is transferred to a separatory funnel containing dichloromethane (200 mL) and water (200 mL) and shaken. The organic layer is separated and washed with water (200 mL) before drying over MgS0 . The mixture is filtered and concentrated under reduced pressure to afford the desired amine 3b.

3c. (S)-N-(4-Carboxyphenylsulfonyl)-l,2,3,4-tetrahydro-3-isoquinoline carboxylic acid 1,7- diphenyl-4-heptylamide: The amine 3b (6.0 g, 14.1 mmol) is dissolved in anhydrous dichloromethane (150 mL) at room temperature. N,N-Diisopropylethylamine (4.9 mL, 35.2 mmol) and 4-DMAP (0.17 g, 1.4 mmol) are added and the solution is cooled in an ice-bath. 4- Chlorosulfonylbenzoic acid (3.1 g, 14.1 mmol; Aldrich Chemical Co., Milwaukee, WI) is added in one portion. The reaction mixture is stirred for 18 hours at room temperature then poured onto ice-cold 0.1N HCl (200 mL) and extracted with dichloromethane (1 x 200 mL, 2 x 100 mL). The combined dichloromethane extracts are washed with water, dried over MgS0₄, filtered, and concentrated in vacuo to afford the desired sulfonamide 3c.

3d. 4-Carboxyphenylsulfonyl-bis-[(S)-N-l,2,3,4-tetrahydro-3-isoquinoline carboxylic acid 1,7- diphenyl-4-heptylamide]: Sulfonamide 3c (5.92 g, 9.7 mmol) is dissolved in 100 mL of DMF. Amine 3b (4.96 g, 11.6 mmol) and i-Pr₂EtN (3.7 mL, 21.3 mmol) are added followed by PyBOP (6.04 g, 11.6 mmol). The reaction is stirred for 18 hours at room temperature, then poured onto ice-cold 0.1N HCl (400 mL) and extracted with ethyl acetate (400 mL). The layers are separated and the organic layer washed successively with brine (100 mL), saturated NaHC0₃ solution (300 mL) and brine (2 x 200 mL). The organic solution is dried over MgS0 , filtered, and concentrated under reduced pressure. Purification of the product by chromatography on silica gel affords the desired combination sulfonamide-amide 3d. Example 4

4a. (S)-N-(3-Carboxyphenylsulfonyl)-l,2,3,4-tetrahydro-3-ιsoquιnolme carboxylic acid 1,7- dιphenyl-4-heptylamιde: The amme 3b (3 g, 7.1 mmol) is dissolved in anhydrous dichloromethane (75 mL) at room temperature. ι-Pr₂EtN (2.5 mL, 17.6 mmol) and 4-DMAP (0.1 g, 0.7 mmol) are added and the solution is cooled in an ice-bath 3-Chlorosulfonylbenzoιc acid (1.55 g, 7.1 mmol; Aldrich Chemical Co., Milwaukee, WI) is added in one portion. The reaction mixture is stirred for 18 hours at room temperature then poured onto ice-cold 0.1N HCl (100 mL) and extracted with dichloromethane (1 x 100 mL, 2 x 50 mL). The combined dichloromethane extracts are washed with water, dried over MgS0₄, filtered, and concentrated in vacuo to afford the desired sulfonamide 4a.

4b. 3-Carboxyphenylsulfonyl-bιs-((S)-N-l,2,3,4-tetrahydro-3-ιsoqumohne carboxylic acid 1,7- dιphenyl-4-heptylamιde): Sulfonamide 4a (2.8 g, 4.9 mmol) is dissolved in 50 mL of DMF. Amme 3b (2.48 g., 5.8 mmol) and ι-Pr₂EtN (1.85 mL, 10.7 mmol) are added followed by PyBOP (3.02 g, 5.8 mmol). The reaction is stirred for 18 hours at room temperature, then poured onto ice-cold 0.1N HCl (200 mL) and extracted with ethyl acetate (200 mL). The layers are separated and the organic layer washed successively with brine (50 mL), saturated NaHC0₃ solution (150 mL) and brine (2 x 100 mL). The organic solution is dried over MgS0₄, filtered, and concentrated under reduced pressure. Purification of the product by chromatography on silica gel affords the desired amide 4b.

5. (S)-N-(Carboxymethylsulfonyl)-l,2,3,4-tetrahydro-3-isoquinoline carboxylic acid 1,7- diphenyl-4-heptylamide: The amine 3b (3 g, 7.1 mmol) is dissolved in anhydrous dichloromethane (75 mL) at room temperature. i-Pr₂EtN (2.5 mL, 17.6 mmol) and 4-DMAP (0.1 g, 0.7 mmol) are added and the solution is cooled in an ice-bath. Chlorosulfonylacetyl chloride (0.7 g, 3.2 mmol; Aldrich Chemical Co., Milwaukee, WI) is added in one portion. The reaction mixture is stirred for 18 hours at room temperature then poured onto ice-cold 0.1N HCl (100 mL) and extracted with dichloromethane (1 x 100 mL, 2 x 50 mL). The combined dichloromethane extracts are washed with water, dried over MgS0₄, filtered, and concentrated in vacuo to afford the desired combination sulfonamide-amide 3a.

Example 6

6a. 4-(4-Sulfophenoxy)benzoic acid: 4-(4-Sulfophenoxy)benzoic acid, magnesium salt (6.1 g, 10 mmol; Aldrich Chemical Co., Milwaukee, WI) is slurried in deionized water (100 mL) at ambient temperature, then heated until solution is achieved. Strongly acidic ion-exchange resin (Dowex 50x8-400 (H⁺), 6.1 g, Aldrich Chemical Co., Milwaukee, WI) is added and the slurry is stirred for one minute. The warm solution is filtered and washed with warm water. The filtrate is lyophilized to afford the desired 4-(4-Sulfophenoxy)benzoic acid 6a.

6b 6b. 4-(4-Chlorosulfonylphenoxy)benzoyl chloride: 4-(4-Sulfophenoxy)benzoic acid (2.94 g, 10 mmol) is slurried in thionyl chloride (10 mL, 137 mmol) and DMF (10 μL, 0.13 mmol) at ambient temperature. The mixture is heated at reflux for 18 hours, then cooled to ambient temperature. Dichloromethane (100 mL) is added and the mixture is filtered and washed with dichloromethane. The filtrate is concentrated under vacuum to afford 4-(4-

Chlorosulfonylphenoxy)benzoyl chloride 6b.

6c. 4-Benzoyl-4'-sulfonyldiphenyl ether[(S)-N-pipecolic acid l,7-diphenyl-4-heptylamide]:

4-(4-Chlorosulfonylphenoxy)benzoyl chloride 6b (3.31 g, 10 mmol) is dissolved in dichloromethane (50 mL). A solution of amine lb (8.33 g, 22 mmol) and dichloromethane (50 mL) and i-Pr₂EtN (5.23 mL, 30 mmol) is added at ambient temperature. The reaction mixture is stirred for 18 hours then concentrated under reduced pressure. The residue is purified by preparative chromatography over silica gel to afford the desired mixed amide-sulfonamide 6c.

Example 7

COOH COC1

HOOC CDC S0₃H so₂α

7a

7a. Chlorosulfonylsuccinoyl chloride: Sulfosuccinic acid (3 mL of 70 wt% solution in water, 10.6 mmol; Aldrich Chemical Co., Milwaukee, WI) is combined with toluene (100 mL) and heated to remove the water by azeotropic distillation. To the resulting toluene solution of sulfosuccinic acid is added thionyl chloride (20 mL, 274 mmol) and DMF (20 μL, 0.26 mmol) at ambient temperature. The mixture is heated at reflux for 18 hours, then cooled to ambient temperature. The solution is concentrated under vacuum to afford chlorosulfonylsuccmoyl chloride 7a.

7b. Sulfonylsuccinoyl-[(S)-N-pipecolic acid l,7-diphenyl-4-heptylamide]:

Chlorosulfonylsuccmoyl chloride 7a (2.53 g, 10 mmol) is dissolved in dichloromethane (50 mL). A solution of amme lb (12.5 g, 33 mmol) and dichloromethane (50 mL) and ι-Pr₂EtN (6.98 mL, 40 mmol) is added at ambient temperature. The reaction mixture is stirred for 18 hours then concentrated under reduced pressure. The residue is purified by preparative chromatography over silica gel to afford the desired mixed amide-sulfonamide 7b.

Example 8

8a a. 3,6-Dichlorosulfonylnapthalene-l,8-dicarboxylic acid chloride: 3,6-Dιsulfonaphthalene- 1,8-dιcarboxyhc acid (3.76 g, 10 mmol, Aldπch Chemical Co., Milwaukee, WI) is slurried m thionyl chloride (20 mL, 274 mmol) and DMF (20 μL, 0.26 mmol) at ambient temperature. The mixture is heated at reflux for 18 hours, then cooled to ambient temperature. Dichloromethane (100 mL) is added and the mixture is filtered and washed with dichloromethane. The filtrate is concentrated under vacuum to afford the desired 3,6-Dichlorosulfonylnapthalene-l,8- dicarboxylic acid chloride 8a.

8b. 3,6-Disulfonylnapthalene-l,8-dicarboxyl-((S)-N-pipecolic acid l,7-diphenyl-4- heptylamide): 3,6-Dichlorosulfonylnapthalene-l,8-dicarboxylic acid chloride 8a (4.46, 10 mmol) is dissolved in dichloromethane (50 mL). A solution of amine lb (16.66 g, 44 mmol) and dichloromethane (50 mL) and i-Pr₂EtN (8.72 mL, 50 mmol) is added at ambient temperature. The reaction mixture is stirred for 18 hours then concentrated under reduced pressure. The residue is purified by preparative chromatography [silica gel; gradient elution with 9: 1 to 1 : 1 (hexane:ethyl acetate)] to afford the desired mixed amide-sulfonamide 8b.

Example 9

9a

9a. 4-Chlorosulfonylphthaloyl chloride: 4-Sulfophthahc acid (2.46 g, 10 mmol, Aldrich Chemical Co., Milwaukee, WI) is slurried m thionyl chloride (20 mL, 274 mmol) and DMF (20 μL, 0.26 mmol) at ambient temperature. The mixture is heated at reflux for 18 hours, then cooled to ambient temperature. Dichloromethane (100 mL) is added and the mixture is filtered and washed with dichloromethane. The filtrate is concentrated under vacuum to afford the desired 4- chlorosulfonylphthaloyl chloride 9a.

9b. 4-Sulfonylphthaloyl-((S)-N-pipecolic acid l,7-diphenyl-4-heptylamide): 4- chlorosulfonylphthaloyl chloride 9a (3 g, 10 mmol) is dissolved m dichloromethane (50 mL). A solution of amme lb (12.5 g, 33 mmol) and dichloromethane (50 mL) and ι-Pr₂EtN (7 mL, 40 mmol) is added at ambient temperature. The reaction mixture is stirred for 18 hours then concentrated under reduced pressure. The residue is purified by preparative chromatography (sihca gel; gradient elution with 9: 1 to 1.1 (hexane:ethyl acetate)) to afford the desired mixed amide-sulfonamide 9b. Example 10

4-Acetylbenzenesulfonic acid: 4-Acetylbenzenesulfonιc acid, sodium salt (2.22 g, 10 mmol; Acros Orgamcs, Pittsburgh, PA) is slurπed in deiomzed water (50 mL) at ambient temperature, then heated until solution is achieved. Strongly acidic ion-exchange resm [Dowex 50x8-400 (H⁺), 2.2 g, Aldrich Chemical Company, Milwaukee, WI] is added and the slurry is stirred for one mmute. The warm solution is filtered and washed with warm water. The filtrate is lyophilized to afford the desired 4-acetylbenzenesulfomc acid.

4-Glyoxylbenzenesulfonic acid: 4-Acetylbenzenesulfonιc acid (2 g, 10 mmol) is dissolved m anhydrous pyπdme (50 mL) at ambient temperature. Selenium dioxide (2.22 g, 20 mmol) is added in one portion and the resulting mixture is carefully heated to reflux. After 24 hours at reflux the reaction mixture is cooled to ambient temperature then filtered through a pad of diatomaceous earth, washed with pyπdme, and concentrated under reduced pressure. The residue is dissolved in ethyl acetate (250 mL) and extracted successively with 1 N HCl (100 mL), then saturated aqueous sodium bicarbonate (2x 50 mL). The combined aqueous bicarbonate extracts are acidified with concentrated HCl then extracted with dichloromethane (3x 50 mL). The combined dichloromethane extracts are dried over MgS0_4> then filtered and concentrated under vacuum to afford the desired α-ketoacid.

10a

10a. 4-Chloroglyoxylbenzenesulfonyl chloride. 4-Glyoxylbenzenesulfonιc acid (2.3 g, 10 mmol) is slurried m thionyl chloride (10 mL, 137 mmol) plus DMF (10 μL, 0.13 mmol) at ambient temperature. The mixture is heated at reflux for 18 hours, then cooled to ambient temperature. Dichloromethane (100 mL) is added and the mixture is filtered and washed with dichloromethane. The filtrate is concentrated under vacuum to afford 4- chloroglyoxylbenzenesulfonyl chloride 10a.

10b. 4-Glyoxylbenzenesulfonyl((S)-N-pipecolic acid l,7-diphenyl-4-heptylamide): 4-

Chloroglyoxybenzenesulfonyl chloride 10a (2.67 g, 10 mmol) is dissolved in dichloromethane (50 mL). A solution of amine lb (8.33 g, 22 mmol) and dichloromethane (50 mL) and ι-Pr₂EtN (5.23 mL, 30 mmol) is added at ambient temperature. The reaction mixture is stirred for 18 hours then concentrated under reduced pressure The residue is purified by preparative chromatography (silica gel, gradient elution with 9' 1 to I T (hexane:ethyl acetate)) to afford the desired mixed α-ketoamide-sulfonamide 10b. Example 11

11a. 2-Chloroglyoxylbenzoyl chloride: 2-Carboxy-α-oxobenzeneacetιc acid (1.94 g, 10 mmol; Aldrich Chemical Co., Milwaukee, WI) is slurried in thionyl chloride (10 mL, 137 mmol) and DMF (10 μL, 0.13 mmol) at ambient temperature. The mixture is heated at reflux for 18 hours, then cooled to ambient temperature. Dichloromethane (100 mL) is added and the mixture is filtered and washed with dichloromethane. The filtrate is concentrated under vacuum to afford 2- chloroglyoxylbenzoyl chloride 11a.

lib. 2-Chloroglyoxylbenzoyl((S)-N-pipecolic acid l,7-diphenyl-4-heptylamide): 2-

Chloroglyoxylbenzoyl chloride 11a (2.31 g, 10 mmol) is dissolved in dichloromethane (50 mL). A solution of amme lb (8.33 g, 22 mmol) and dichloromethane (50 mL) and ι-Pr₂EtN (5.23 mL, 30 mmol) is added at ambient temperature. The reaction mixture is stirred for 18 hours then concentrated under reduced pressure. The residue is purified by preparative chromatography (silica gel; gradient elution with 9: 1 to 1 :1 (hexane:ethyl acetate)) to afford the desired mixed α- ketoamide-amide lib.

Use of the Present Compounds The compounds herein may be used for the treatment of such conditions as, for example, treating hair loss in mammals, including arresting and / or reversing hair loss and promoting hair growth. Such conditions may manifest themselves in, for example, alopecia, including male pattern baldness and female pattern baldness.

While certain of the present compounds may exhibit immunosuppressive activity, the preferred compounds of the present invention are, as defined herein, non-immunosuppressive.

Furthermore, in addition to treating hair loss, the compounds of the present invention may be used to treat a vaπety of clinical conditions which include, but are not limited to, multi- drug resistance (particularly for use in cancer chemotherapy), neurological disorders and neurodegenerative diseases, cardiac injury associated with ischemia/reperfusion injury, and treatment of fungal, microbial, viral (especially HIV), malarial or other parasitic diseases or conditions. The present compounds may also be useful as inhibitors of multi-drug transporter proteins to enhance, for example, pharmacokmetics and bioavailability. Certain compounds of the present invention may exhibit lmmunomodulatory properties. These compounds would prove useful m the treatment of organ transplant rejection and various autoimmune diseases which include, but are not limited to, Behcet's disease, Crohn's disease, systemic lupus erythematosus, psoriasis, rheumatoid arthritis, eczema, multiple sclerosis, myasthema gravis, msulm-dependent diabetes melhtus, and Graves' disease. In addition, the present compounds may have utility for the treatment of certain inflammatory and allergic disease states, including urticaria, allergic contact dermatitis, atopic dermatitis, atopic keratoconjunctivitis, inflammatory bowel disease, and asthma. The present compounds may also be useful m the treatment of cardiac hypertrophy in congestive heart failure.

The present compounds may also be useful in combination with a matrix metalloproteinase inhibitor for treatment of various conditions including, for example, tissue destructive diseases mediated by excessive metalloproteinase activity, cancer, and multi-drug resistance, as well as all of the conditions previously mentioned herein above. Particularly preferred matrix metalloproteinase inhibitors useful in such combination include those described in U.S. Patent No. 5,830,915, Pikul et al.. assigned to The Procter & Gamble Co., filed August 26, 1997; U.S. Patent Application Serial No. 08/918,317, Natchus et al., assigned to The Procter & Gamble Co., filed August 26, 1997; U.S. Patent Application Serial No. 08/918,957, Pikul et al_, assigned to The Procter & Gamble Co., filed August 26, 1997; U.S. Patent Application Serial No. 08/918,419, Pikul et al., assigned to The Procter & Gamble Co., filed August 26, 1997; U.S. Patent Application Serial No. 08/921,953, De et al , assigned to The Procter & Gamble Co., filed August 28, 1996; and U.S Patent Application Serial No. 08/918,328, Wang et al.. assigned to The Procter & Gamble Co., filed August 26, 1997. Preferably, the compounds of the present invention are formulated into pharmaceutical compositions for use in treatment or prophylaxis of conditions such as the foregoing. Standard pharmaceutical formulation techniques are used, such as those disclosed m Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. (1990).

Typically, from about 5 mg to about 3000 mg, more preferably from about 5 mg to about 1000 mg, more preferably from about 10 mg to about 100 mg, of a compound of the present invention is administered per day for systemic administration. It is understood that these dosage ranges are by way of example only, and that daily administration can be adjusted depending on various factors. The specific dosage of the compound to be administered, as well as the duration of treatment, and whether the treatment is topical or systemic are interdependent. The dosage and treatment regimen will also depend upon such factors as the specific compound used, the treatment indication, the efficacy of the compound, the personal attributes of the subject (such as, for example, weight, age, sex, and medical condition of the subject), compliance with the treatment regimen, and the presence and severity of any side effects of the treatment.

In addition to the subject compound, the compositions of the subject invention contain a pharmaceutically-acceptable earner ("carrier"). The term pharmaceutically-acceptable carrier, as used herein, means one or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for administration to a mammal. The term "compatible", as used herein, means that the components of the composition are capable of being commingled with a compound of the present invention, and with each other, in a manner such that there is no interaction which would substantially reduce the efficacy of the composition under ordinary use situations. Carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the animal, preferably mammal, being treated. The earner can itself be inert or it can possess pharmaceutical benefits of its own.

The compositions of this invention may be in any of a variety of forms, suitable (for example) for oral, rectal, topical, nasal, ocular or parenteral administration. Of these, topical or oral administration is especially prefened. Depending upon the particular route of administration desired, a variety of pharmaceutically-acceptable earners well-known in the art may be used. These include solid or liquid fillers, diluents, hydrotropes, surface-active agents, and encapsulating substances. Optional pharmaceutically-active materials may be included, which do not substantially interfere with the activity of the compound of the present invention. The amount of earner employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods of this invention are described in the following references: Modern Pharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2^nd Ed., (1976).

Some examples of substances which can serve as pharmaceutically-acceptable carriers or components thereof are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as the TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

The choice of a pharmaceutically-acceptable canier to be used in conjunction with the subject compound is basically determined by the way the compound is to be administered.

In particular, pharmaceutically-acceptable earners for systemic administration include sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffer solutions, emulsifiers, isotonic saline, and pyrogen-free water. Prefened caniers for parenteral administration include propylene glycol, ethyl oleate, pynolidone, ethanol, and sesame oil. Preferably, the pharmaceutically-acceptable canier, in compositions for parenteral administration, comprises at least about 90% by weight of the total composition.

Various oral dosage forms can be used, including such solid forms as tablets, capsules, granules and bulk powders. These oral forms comprise a safe and effective amount, usually at least about 5%, and preferably from about 25% to about 50%, of a compound of the present invention. Tablets can be compressed, tablet triturates, enteric- coated, sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.

The pharmaceutically-acceptable carrier suitable for the preparation of unit dosage forms for oral administration are well-known in the art. Tablets typically comprise conventional pharmaceutically-compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, manmtol, lactose and cellulose; binders such as starch, gelatin and sucrose; dismtegrants such as starch, alginic acid and croscarmelose; lubncants such as magnesium stearate, steanc acid and talc. Ghdants such as silicon dioxide can be used to improve flow characteristics of the powder mixture. Coloring agents, such as the FD&C dyes, can be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets. Capsules (including time release and sustained release formulations) typically comprise one or more solid diluents disclosed above. The selection of carrier components depends on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of the subject invention, and can be readily made by a person skilled in the art.

Orally administered compositions also include liquid solutions, emulsions, suspensions, powders, granules, elixirs, tinctures, syrups, and the like. The pharmaceutically-acceptable carriers suitable for preparation of such compositions are well known m the art. Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For a suspension, typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, AVICEL RC-591, tragacanth and sodium algmate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate. Peroral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and colorants disclosed above.

Such compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that the subject compound is released in the gastrointestinal tract in the vicinity of the desired topical application, or at various times to extend the desired action Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvmylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac

Other compositions useful for attaining systemic delivery of the subject compounds include sublmgual, buccal and nasal dosage forms Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.

The compounds of the present invention may also be topically administered. The carrier of the topical composition preferably aids penetration of the present compounds into the skin to reach the environment of the hair follicle. Topical compositions of the present invention may be in any form including, for example, solutions, creams, ointments, gels, lotions, shampoos, leave- on and rinse-out hair conditioners, milks, cleansers, moisturizers, sprays, skin patches, and the like.

Topical compositions containing the active compound can be admixed with a variety of carrier materials well known in the art, such as, for example, water, alcohols, aloe vera gel, allantoin, glycerine, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, and the like.

Other materials suitable for use in topical caniers include, for example, emollients, solvents, humectants, thickeners and powders. Examples of each of these types of materials, which can be used singly or as mixtures of one or more materials, are as follows:

Emollients, such as stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane- 1,2-diol, butane- 1,3-diol, mink oil, cetyl alcohol, z^'so-propyl isostearate, stearic acid, iso- butyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, dimethylpolysiloxane, di-/z-butyl sebacate, isopropyl myristate, wo-propyl palmitate, zjo-propyl stearate, butyl stearate, polythylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolin alcohols, petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, and myristyl myristate; propellants, such as propane, butane, wo-butane, dimethyl ether, carbon dioxide, and nitrous oxide; solvents, such as ethyl alcohol, methylene chloride, wopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulphoxide, dimethyl formamide, tetrahydrofuran; humectants, such as glycerin, sorbitol, sodium 2- pynolidone-5-carboxylate, soluble collagen, dibutyl phthalate, and gelatin; and powders, such as chalk, talc, fullers earth, kaolin, starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetra alkyl ammonium smectites, trialkyl aryl ammonium smectites, chemically modified magnesium aluminium silicate, organically modified montmorillonite clay, hydrated aluminium silicate, fumed silica, carboxyvmyl polymer, sodium carboxymethyl cellulose, and ethylene glycol monostearate.

The compounds of the present invention may also be administered in the form of hposome delivery systems, such as small umlamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phosphohpids, such as cholesterol, stearylamme or phosphatidylchol es. A prefened formulation for topical delivery of the present compounds utilizes liposomes such as descπbed in Dowton et al., "Influence of Liposomal Composition on Topical Delivery of Encapsulated Cyclospoπn A: I. An in vitro Study Using Hairless Mouse Skm", S.T.P. Pharma Sciences. Vol. 3, pp. 404 - 407 (1993), Wallach and Phihppot, "New Type of Lipid Vesicle: Novasome^®", Liposome Technology, Vol. 1, pp. 141 - 156 (1993), and Wallach, U.S. Patent No. 4,911,928, assigned to Micro-Pak, Inc., issued March 27, 1990.

The compounds of the present invention may also be administered by iontophoresis. See, e.g.. www.umpr.it/arpa/dipfarm/erasmus/erasml4.html, Banga et al., "Hydrogel-based Iontotherapeutic Delivery Devices for Transdermal Delivery of Peptide/Protem Drugs", Pharm. Res.. Vol. 10 (5), pp. 697-702 (1993), Ferry L.L., "Theoretical Model of Iontophoresis Utilized in Transdermal Drug Delivery", Pharmaceutical Acta Helvetiae, Vol 70, pp. 279-287 (1995), Gangarosa et al., "Modern Iontophoresis for Local Drug Delivery", Int. J. Pharm, Vol. 123, pp. 159-171 (1995), Green et al., "Iontophoretic Delivery of a Series of Tπpeptides Across the Skm in vitro", Pharm. Res., Vol 8, pp. 1121-1127 (1991), Jadoul et al., "Quantification and Localization of Fentanyl and TRH Delivered by Iontophoresis in the Skm", Int. J. Pharm., Vol. 120, pp. 221-8 (1995), O'Brien et al., "An Updated Review of its Antiviral Activity, Pharmacokmetic Properties and Therapeutic Efficacy", Drugs, Vol. 37, pp. 233-309 (1989), Parry et al., "Acyclovir Biovailabihty m Human Skm", J. Invest. Dermatol., Vol. 98 (6), pp. 856-63 (1992), Santi et al., "Drug Reservoir Composition and Transport of Salmon Calcitonin in Transdermal Iontophoresis", Pharm. Res., Vol 14 (1), pp. 63-66 (1997), Santi et al., "Reverse Iontophoresis - Parameters Determining Electroosmotic Flow. I. pH and Ionic Strength", J. Control. Release. Vol. 38, pp. 159-165 (1996), Santi et al., "Reverse Iontophoresis - Parameters Determining Electroosmotic Flow: II. Electrode Chamber Formulation", J. Control. Release. Vol 42, pp. 29-36 (1996), Rao et al., "Reverse Iontophoresis: Nonmvasive Glucose Monitoring in vivo in Humans", Pharm Res , Vol. 12 (12), pp. 1869-1873 (1995), Thysman et al., "Human Calcitonm Delivery in Rats by Iontophoresis", J. Pharm Pharmacol , Vol. 46, pp. 725-730 (1994), Volpato et al., "Iontophoresis Enhances the Transport of Acyclovir through Nude Mouse Skm by Electrorepulsion and Electroosmosis", Pharm Res . Vol. 12 (1 1), pp 1623-1627 (1995).

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

Additional hair growth stimulants can be chosen from a wide variety of molecules which can function in different ways to enhance the hair growth effects of a compound of the present invention These optional other hair growth stimulants, when present, are typically employed the compositions herein at a level ranging from about 0.01% to about 15%, preferably from about 0.1% to about 10%, most preferably from about 0.5% to about 5% by weight of the composition.

Vasodilators such as potassium channel agonists including, for example, minoxidil and minoxidil derivatives such as ammexil and such as those described m U.S. Patent 3,382,247, U.S. Patent 5,756,092, issued May 26, 1998, U.S. Patent 5,772,990, issued June 30, 1998, U.S. Patent 5,760,043, issued June 2, 1998, U.S. Patent 328,914, issued July 12, 1994, U.S. Patent 5,466,694, issued November 14, 1995, 5,438,058, issued August 1, 1995, and U.S. Patent 4,973,474, issued November 27, 1990, (all of which are herein incorporated by reference), and cromakalm and diazoxide can be used as an additional hair growth stimulant m the compositions herein.

One suitable class of additional hair growth stimulant for use herein are antiandrogens. Examples of suitable antiandrogens may include, but are not limited 5-α-reductase inhibitors such as finesteπde and those described in U.S Patent 5,516,779, issued May 14, 1996 (herein incorporated by reference) and in Nane et al , Cancer Research 58. "Effects of Some Novel Inhibitors of C17,20-Lyase and 5α-Reductase in vitro and in vivo and Their Potential Role in the Treatment of Prostate Cancer," as well as cyproterone acetate, azelaic acid and its derivatives and those compounds descnbed in U.S. Patent 5,480,913, issued January 2, 1996, flutamide, and those described m U.S Patents 5,411,981, issued May 2, 1995, U.S. Patent5,565,467, issued October 15, 1996 and U.S. Patent 4,910,226, issued March 20, 1990, all of which are herein incorporated by reference.

Another suitable class of optional hair growth stimulants are lmmunosuppressants or non-immunosuppressants such as 1) cyclosporin and cyclosporin analogs including those described m U.S. Provisional Patent Application No 60/122,925, Fulmer et al., "Method of Treating Hair Loss Using Non-immunosuppressive Compounds", filed March 5, 1999, herein incorporated by reference, and 2) FK506 analogs such as those described in U.S. Provisional Patent Application No. 60/102,449, Mclver et al., "Heterocychc 2-Substιtuted Ketoamides", filed September 30, 1998, U.S. Provisional Patent Application No. 60/102,448, Mclver et al., "2- Substituted Ketoamides", filed September 30, 1998, U.S. Provisional Patent Application No. 60/102,539, Mclver et al., "2-Substιtuted Heterocychc Sulfonamides", filed September 30, 1998, U.S. Provisional Patent Application No. 60/102,458. Tiesman et al., "Method of Treating Hair Loss Using Ketoamides", filed September 30, 1998, and U.S. Provisional Patent Application No. 60/102,437, Mclver et al., "Method of Treating Hair Loss Using Sulfonamides", filed September 30, 1998, all of which are herein incorporated by reference.

Another suitable class of optional hair growth stimulants are antimicrobials such as selenium sulfide, ketoconazole, tπclocarbon, tπclosan, zmc pynthione, ltraconazole, asiatic acid, hmokitiol, mipirocm and those described in EPA 0,680,745 (herein incorporated by reference), chnacycm hydrochloπde, benzoyl peroxide, benzyl peroxide and mmocyclm.

Anti-inflammatoπes can also be incorporated into the compositions herein as an optional hair growth stimulant. Examples of suitable anti-mflammatoπes may include glucocorticoids such as hydrocortisone, mometasone furoate and predmsolone, nonsteroidal anti-inflammatones including cyclooxygenase or hpoxygenase inhibitors such as those descnbed in U.S. Patent 5,756,092, and benzydamme, salicylic acid, and those compounds descnbed in EPA 0,770,399, published May 2, 1997, WO 94/06434, published March 31, 1994, and FR 2,268,523, published November 21, 1975, all of which are herein incorporated by reference.

Another suitable class of optional hair growth stimulants are thyroid hormones and derivatives and analogs thereof. Examples of suitable thyroid hormones for use herein may include tπiodothynonine. Examples of thyroid hormone analogs which may be suitable for use herein include those described in U.S. Provisional Patent Application No. 60/136,996, Zhang et al., "Method of Treating Hair Loss", filed June 1, 1999, U.S. Provisional Patent Application No. 60/137,024, Zhang et al., "Method of Treating Hair Loss Using Biphenyl Compounds", filed June 1, 1999, U.S. Provisional Patent Application No 60/137,022, Zhang et al., "Method of Treating Hair Loss Using Carboxyl Derivatives", filed June 1, 1999, U.S. Provisional Patent Application No. 60/137,023, Zhang et al., "Method of Treating Hair Loss Using Sulfonyl Thyromimetic Compounds", filed June 1, 1999, U.S. Provisional Patent Application No. 60/137,052, Youngquist et al., "Biaryl Compounds", filed June 1, 1999, U.S. Provisional Patent Application No. 60/137,063, Youngquist et al., "Sulfur-Bridged Compounds", filed June 1, 1999, and U.S. Provisional Patent Application No. 60/136,958, Youngquist et al., "Substituted Biaryl Ether Compounds", filed June 1, 1999.

Prostaglandin agonists or antagonists can also be used as optional hair growth stimulants in the compositions herein. Examples of suitable prostaglandins agonists or antagonists include latanoprost and those described in WO 98/33497, Johnstone, published August 6, 1998, WO 95/11003, Stjernschantz, published April 27, 1995, JP 97-100091, Ueno and JP 96-134242, Nakamura.

Another class of optional hair growth stimulants for use herein are retinoids. Suitable retinoids may include isotretinoin, acitretin, and tazarotene.

Another class of optional hair growth stimulants for use herein are triterpenes such as, for example, those disclosed in Bradbury et al., U.S. Patent Application Serial No. 09/353,408, "Method for Regulating Hair Growth", filed July 15, 1999 and Bradbury et al., U.S. Patent Application Serial No. 09/353,409, "Compositions Which Contain Triterpenes for Regulating Hair Growth", filed July 15, 1999, each incorporated by reference in their entirety.

Other classes of optional hair growth stimulants for use herein include flavinoids, ascomycin derivatives and analogs, histamine antagonists such as diphenhydramine hydrochloride, other triterpenes such as oleanolic acid and ursolic acid and those described in U.S. Patent 5,529,769, JP 10017431, WO 95/35103, U.S. Patent 5,468,888, JP 09067253, WO 92/09262, JP 62093215, U.S. Patent 5,631,282, U.S. Patent 5,679,705, JP 08193094, saponins such as those described in EP 0,558,509 to Bonte et al., published September 8, 1993 and WO 97/01346 to Bonte et al, published January 16, 1997 (both of which are herein incorporated by reference in their entirety), proteoglycanase or glycosaminoglycanase inhibitors such as those described in U.S. Patents 5,015,470, issued May 14, 1991, U.S. Patent 5,300,284, issued April 5, 1994 and U.S. Patent 5,185,325, issued February 9, 1993 (all of which are herein incorporated in their entirety by reference) estrogen agonists and antagonists, pseudoterins, cytokine and growth factor promotors, analogs or inhibitors such as interleukinl inhibitors, interleukin-6 inhibitors, interleukin-10 promotors, and tumor necrosis factor inhibitors, vitamins such as vitamin D analogs and parathyroid hormone antagonists, Vitamin B12 analogs and panthenol, interfuron agonists and antagonists, hydroxyacids such as those described in U.S. Patent 5,550,158, benzophenones, and hydantoin anticonvulsants such as phenytoin.

Other additional hair growth stimulants are described in detail in, for example, JP 09- 157,139 to Tsuji et al., published June 17, 1997; EP 0277455 Al to Mirabeau, published August 10, 1988; WO 97/05887 to Cabo Soler et al., published February 20, 1997; WO 92/16186 to Bonte et al., published March 13, 1992; JP 62-93215 to Okazaki et al., published April 28, 1987; U.S. Patent 4,987,150 to Kurono et al., issued January 22, 1991; JP 290811 to Ohba et al., published October 15, 1992; JP 05-286,835 to Tanaka et al., published November 2, 1993, FR 2,723,313 to Greff, published August 2, 1994, U. S. Patent 5,015,470 to Gibson, issued May 14, 1991, U.S. Patent 5,559,092, issued September 24, 1996, U.S. Patent 5,536,751, issued July 16, 1996, U.S. Patent 5,714,515, issued February 3, 1998, EPA 0,319,991, published June 14, 1989, EPA 0,357,630, published October 6, 1988, EPA 0,573,253, published December 8, 1993, JP 61- 260010, published November 18, 1986, U.S. Patent 5,772,990, issued June 30, 1998, U.S. Patent 5,053, 410, issued October 1, 1991, and U.S. Patent 4,761,401, issued August 2, 1988, all of which are herein incorporated by reference.

Non-limiting examples of penetration enhancers which may be used in the compositions herein include, for example, 2-methyl propan-2-ol, propan-2-ol, ethyl-2-hydroxypropanoate, hexan-2,5-dιol, POE(2) ethyl ether, dι(2-hydroxypropyl) ether, pentan-2,4-dιol, acetone, POE(2) methyl ether, 2-hydroxypropιonιc acid, 2-hydroxyoctanoιc acid, propan-1-ol, 1,4-dιoxane, tetrahydrofuran, butan-l,4-dιol, propylene glycol dipelargonate, polyoxypropylene 15 stearyl ether, octyl alcohol, POE ester of oleyl alcohol, oleyl alcohol, lauryl alcohol, dioctyl adipate, dicapryl adipate, di-isopropyl adipate, di-isopropyl sebacate, dibutyl sebacate, diethyl sebacate, dimethyl sebacate, dioctyl sebacate, dibutyl suberate, dioctyl azelate, dibenzyl sebacate, dibutyl phthalate, dibutyl azelate, ethyl myristate, dimethyl azelate, butyl myristate, dibutyl succmate, didecyl phthalate, decyl oleate, ethyl caproate, ethyl sahcylate, zsσ-propyl palmitate, ethyl laurate, 2-ethyl-hexyl pelargonate, z^o-propyl isostearate, butyl laurate, benzyl benzoate, butyl benzoate, hexyl laurate, ethyl caprate, ethyl caprylate, butyl stearate, benzyl sahcylate, 2-hydroxypropanoιc acid, 2-hyroxyoctanoιc acid, dimethyl sulphoxide, N,N-dιmethyl acetamide, N,N-dιmethyl formamide, 2-pynohdone, l-methyl-2-pynohdone, 5-methyl-2-pyrrohdone, l,5-dιmethyl-2- pyrrohdone, 1 -ethyl -2 -pyrroh done, phosphme oxides, sugar esters, tetrahydrofurfural alcohol, urea, diethyl -zw-toluamide, and, l-dodecylazacyloheptan-2-one.

In all of the foregoing, of course, the compounds of the invention can be administered alone or as mixtures, and the compositions may further include additional drugs or excipients as appropriate for the indication.

The present invention further relates to kits comprising a compound and / or composition of the present invention and information and / or instructions by words, pictures, and / or the like, that use of the kit will provide treatment for hair loss m mammals (particularly humans) including, for example, arresting and / or reversing hair loss and / or promoting hair growth. In addition or m the alternative, the kit may comprise a compound and / or composition of the present invention and information and / or instructions regarding methods of application of the compound and / or composition, preferably with the benefit of treating hair loss m mammals.

Composition Examples

The following composition and method examples do not limit the invention, but provide guidance to the skilled artisan to prepare and use the compounds, compositions, and methods of the invention. In each example, a compound of the present invention other than the one mentioned may be substituted in the example with similar results.

Example A

A tablet for oral administration according to the present invention is made, compnsmg:

A human female subject weighing 60 kg (132 lbs), suffering from rheumatoid arthntis, is treated by a method of this invention. Specifically, for two years, a regimen of three tablets per day of the above composition is administered orally to the subject.

Example B

A composition for topical administration according to the present invention is made, comprising:

A human male subject suffering from male pattern baldness is treated by a method of this invention. Specifically, for 6 weeks, the above composition is daily administered topically to the subject.

Example C A composition for topical administration according to the present invention is made according to the method of Dowton et al., "Influence of Liposomal Composition on Topical Delivery of Encapsulated Cyclosporin A: I. An in vitro Study Using Hairless Mouse Skin", S.T.P. Pharma Sciences, Vol. 3, pp. 404 - 407 (1993), using the compound of Example 2c in lieu of cyclosporin A and using the Novasome 1 for the non-ionic liposomal formulation.

A human male subject suffering from male pattern baldness is treated each day with the above composition. Specifically, for 6 weeks, the above composition is administered topically to the subject.

Example D

A shampoo according to the present invention is made, comprising:

Claims

What is claimed is:

1. A compound characterized by the structure:

— L— ^τ2

I J₄ and pharmaceutically acceptable salts, hydrates, and biohydrolyzable amides, esters, and imides thereof, wherein L is a linker through which Ji, J₂, J₃, and J₄ are attached; wherein Ji and J₂ are each, independently, radicals of structure I; and J₃ and J₄ are each, independently, selected from the group consisting of nil and radicals of structure I; wherein structure I is:

wherein:

(a) each N is independently a heteroatom wherein the heteroatom is nitrogen;

(b) each Q is selected from the group consisting of -S(O)₂-, -C(O)-, -C(O)C(O)-; wherein at least one Q of the compound is -S(O) - and at least one Q of the compound is selected from the group consisting of -C(O)- and -C(O)C(O)-;

(c) each Ri is independently selected from the group consisting of nil, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl;

(d) each Z is independently a saturated or unsaturated 4-, 5-, 6-, 7-, 8-, or 9- membered heterocycle optionally containing one or more additional heteroatoms selected from O, Ν, S, S(O), S(O)₂, and P((O)OK);

(e) each K is independently selected from the group consisting of hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl; (f) each W is independently selected from the group consisting of nil, hydrogen, and lower alkyl;

(g) each A is independently selected from the group consisting of nil and alkyl; (h) each X and Y is independently selected from the group consisting of C(O),

P(O), S(O)₂, N, O, and S, wherein:

(i) when X is selected from the group consisting of C(O), P(O), and S(O) , then the R₃ attached thereto is nil and the Y attached thereto is selected from the group consisting of N, O, and S; (ii) when X is N then the R₃ attached thereto is selected from the group consisting of hydrogen, alkyl, and arylalkyl, the Y attached thereto is selected from the group consisting of C(O), P(O), and S(O)₂, and the R attached thereto through Y is nil; (iii) when X is O then the R₃ attached thereto is nil, the Y attached thereto is selected from the group consisting of C(O) and P(O), and the R₂ attached thereto through Y is nil; and (iv) when X is S then the R attached thereto is nil, the Y attached thereto is C(O), and the R attached thereto through Y is nil; each R₂ and R₃ is independently selected from the group consisting of nil, hydrogen, alkyl, and arylalkyl;

(j) each U is independently selected from the group consisting of nil, NH, N(R_]7), and O; wherein when Y is selected from the group consisting of N, O, and S, then U is nil; (k) each R₄ is independently alkyl;

(1) each R₅ and R₆ is independently selected from the group consisting of nil, hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl; or wherein each R₅ and R₆ bonded to the same Rzi may optionally be bonded together to form a carbocyclic or heterocychc ring; (m) each R₇, R₈, R₉, and Rio is independently selected from the group consisting of nil, hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, halo, cyano, hydroxy, oxo, imino, -R₁₄SRι₅, -R_]4S(O₂)Rι₅, - R,₄S(O)Ri5, -Ri₄C(O)Ri₅, -Rι₄C(O)NR₁₅R₁₆, -R_]4C(O)OR₁₅, -R₁₄ORι₅, - Rι₄NR₁₅R₁₆, -R_]4P(O)NRι₅Rι₆, -Rι₄P(O)ORι₅Rι₆, and a spiro moiety; and wherein each R₇ and R₈ bonded to the same Z ring may be optionally bonded together to form an aromatic or saturated, carbocyclic or heterocychc ring which is fused to said same Z ring;

(n) each Rι₄ and R1₅ is independently selected from the group consisting of nil, hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl;

(o) each Rι₆ is independently selected from the group consisting of hydrogen and alkyl; and

(p) each Rπ is independently selected from the group consisting of alkyl and arylalkyl.

2. The compound according to claim 1 wherein J₃ and J₄ are each nil.

3. The compound according to claim 2 wherein each Z is, independently, a 5-, 6-, or 7- membered heterocycle; wherein each W is hydrogen; and wherein each U is nil.

4. The compound according to claim 3 wherein each Z is, independently, a 5-membered heterocycle, each A is nil, each X is C(O), each Y is O, and each R is nil.

5. The compound according to claim 3 wherein each Z is, independently, a 5-membered heterocycle, each A is nil, each X is C(O), each Y is N, and each R₂ is hydrogen.

6. The compound according to claim 3 wherein each Z is, independently, a 6-membered heterocycle, each A is nil, each X is C(O), each Y is O, and each R₂ is nil.

7. The compound according to claim 3 characterized by the structure:

8. The compound according to claim 3 characterized by the structure:

9. A composition characterized by comprising a compound according to claim 1 and a pharmaceutically-acceptable carrier.

10. The composition according to claim 9 additionally comprising an additional hair growth stimulant selected from the group consisting of vasodilators, antiandrogens, non- immunosuppressants, antiinflammatories, antimicrobials, thyroid hormone analogs, prostaglandins, retinoids, vitamin D analogs, and parathyroid hormone analogs.