MXPA01003330A - 2-substituted ketoamides - Google Patents

Abstract

The present disclosure describes novel 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 may be useful for controlling parasites and invoking immunosuppression.

Description

CHLOROAMIDES REPLACED IN POSITION 2- CAMPQ OF THE INVENTION The present invention relates to novel compounds and compositions that are particularly useful for treating hair loss in mammals, including stopping and / or reversing hair loss and stimulating hair growth. The. Present compounds and compositions may also be useful against a variety of disorders including, for example, multiple drug resistance, human immunodeficiency virus (HIV), cardiac injury and neurological disorders and may be useful for the control of parasites and induce immunosuppression.

CROSS REFERENCE This application claims priority according to the Title 35, United States Code § 119 (e), of the Provisional Application Series No. 60 / 102,448, filed on September 30, 1998.

BACKGROUND OF THE INVENTION Hair loss is a common problem that occurs, for example, through natural processes or is often chemically stimulated by the use of certain therapeutic drugs designed to alleviate conditions such as cancer. Often, this hair loss is accompanied by the lack of growth of new hair that causes partial or total baldness. From the cosmetic point of view, that baldness is unattractive and above all it is distressing for the person experiencing hair loss. As is well known in the art, hair growth is carried out through a cycle of activity that involves alternating periods of growth and rest. This cycle is often divided into three main states known as anagen, catagen, and telogen. In anagen it is the phase of growth of the cycle and can be characterized by the deep penetration of the hair follicle in the dermis, with rapid proliferation of cells that differentiate to form the hair. The next phase the catagen, which is a transition state characterized by the cessation of cell division and during which the follicle backs through the dermis and hair growth stops. The next phase is the telogen, which is often characterized as the resting state during which the follicle that regressed contains a germ with well-packed dermal papilla cells. In the telogen, the initiation of a new anagen phase is caused by the rapid cell proliferation in the germ, the expansion of the dermal papilla and the preparation of basement membrane components. The cycle is repeated in all hair growth. When hair growth ceases, most of the hair follicles reside in telogen and the anagen is not compromised, which causes the appearance of partial or total baldness. There are many attempts in the literature that seek the hair to grow back, for example, the promotion or prolongation of the anagen. Currently there are two drugs approved by the Drug Administration and United States Foods (FDA) for the treatment of male pattern baldness: topical minoxidil (marketed as Rogaine® from Pharmacia &Upjohn) and oral finasteride (marketed as Propecia® by Merck &Co., Inc.). However, there are conflicting reports regarding the ability of minoxidil for hair growth. In fact, the first clinical studies that investigated the decrease in blood pressure through the use of minoxidil did not mention hypertrichosis (hair growth) as a side effect. See Dormois et al., "Minoxidil in Severe Hypertension: Valué When Conventional Drugs Have Failed," American Heart Journal, Vol. 90, p. 360-368 (1975). In effect, minoxidil makers have reported hair growth only limited in a portion of patients using minoxidil. See, for example, Phvsician's Desk Reference®, 49th Ed. (1995), p. 2580. In addition, it is possible that minoxidil has serious side effects, including vasodilatation (which results in fluid retention around the heart and an increase in heart rate), difficulty in breathing and weight gain, Physician's Desk Reference®. 49th? D. (1995), p. 2581. In addition, while early indicators show that Propecia® may be more effective than Rogaine®, patients using Propecia® experience limited hair growth. See The New England Journal of Medicine. Vol. 338, No. 9, February 26, 1998. On the other hand, the potential side effects of Propecia® are serious. Propecia® can cause impotence, decreased sex drive, decreased volume of ejaculation, sagging and lengthening of the breast and hypersensitivity reactions, including swelling of the lips and rash. In addition, Propecia® is not indicated for women and children. In fact, women who are pregnant or who may be pregnant should not even handle crushed or broken tablets containing the drug. See, Phvsician's Desk Reference®, 49th Ed. (1995), p. 1737 and The New England Journal of Medicine, Vol. 338, No. 9, February 26, 1998. Interestingly, it is known that the immunosuppressive agent cyclosporin A and FK506 cause a remarkable hypertrotic 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, p.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, to 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, to Potent Immunosuppressant", Journal of Investigational Dermatology, Vol. 104, p. 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 bu Immunosuppression", Arch. Dermatol. Res., Vol. 288, pp. 408-410 (1996). However, the use of these compounds as activators of hair growth may not be convenient due to their remarkable potency as immunosuppressive agents. The FK506 is a complex macrocyclic molecule that has the following structure: Stocks et al., "The Contribution of 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 that closely resemble this complex macrocycle have been exhibited, which have hair-growing properties, for example, in cases of alopecia areata and / or male pattern baldness. See, for example, Kawai et al. , U.S. Patent No. 5,541,193, assigned to Abbot Laboratories, published July 30, 1996; Asakura et al. , U.S. Patent 5,496,564, assigned to Fujisawa Pharmaceutical Co., published March 5, 1996; Baumann et al. , U.S. Patent No. 5,352,671 assigned to Sandoz Ltd., published October 4, 1994; and Rupprecht et al. , U.S. Patent No. 5,550,233, assigned to Merck & Co. , Inc., published on August 27, 1996. However, the enthusiasm related to the hypertrotic activities of cyclosporin A and FK506 was somewhat calmed by the absence of reports of hypertrichosis of several smaller immunosuppressive and immunosuppressive compounds, not macrocyclic, which are less complex than the FK506 structure. See Steiner et al. , WO 96/40140, assigned to Guilford Pharmaceuticals, Inc., published December 19, 1996; Hamilton et al. , WO 96/40633, assigned to Guilford Pharmaceuticals, Inc., published December 19, 1996; Steiner et al. , U.S. Patent No. 5,696,135 assigned to GPI NIL Holdings, Inc., published December 9, 1997; Hamilton et al .. U.S. Patent No. 5,614,547, assigned to Guilford Pharmaceuticals, Inc., published March 25, 1997; Steiner et al. , WO 97/16190, assigned to Guilford Pharmaceuticals, Inc., P1250 published May 9, 1997; Zelle et al. WO 96/36630, assigned to Vertex Pharmaceuticals, Inc., published November 21, 1996; Armistead et al. , WO 97/36869, assigned to Vertex Pharmaceuticals, Inc., published October 9, 1997; Zelle et al., WO 96/15101, assigned to Vertex Pharmaceuticals, Inc., published May 23, 1996; Armistead et al. , WO 92/19593, assigned to Vertex Pharmaceuticals, Inc., published on November 12, 1992; Armistead et al. , WO 94/07858, assigned to Vertex Pharmaceuticals, Inc., published on April 14, 1994; Zelle et al. , WO 95/26337, assigned to Vertex Pharmaceuticals, Inc., published October 5, 1995; Duffy et al. , WO 92/21313, assigned to Vertex Pharmaceuticals, Inc., published on December 10, 1992; Armistead et al., U.S. Patent No. 5,192,773, assigned to Vertex Pharmaceuticals, Inc., published March 9, 1993; Armistead et al. , U.S. Patent No. 5,330,993, assigned to Vertex Pharmaceuticals, Inc., published July 19, 1994; Armistead et al. U.S. Patent No. 5,622,970, assigned to Vértex Pharmaceuticals, Inc., published on April 22, 1997; Armistead et al. U.S. Patent No. 5,654,332 assigned to Vertex Pharmaceuticals, Inc., published August 5, 1997; Armistead et al .. Patent of the United States No. 5,620,971, assigned to Vértex P1250 Pharmaceuticals, Inc., published April 15, 1997; Armistead et al. U.S. Patent No. 5,543,423, assigned to Vertex Pharmaceuticals, Inc., published August 6, 1996; Armistead et al .. U.S. Patent No. 5,516,797, assigned to Vertex Pharmaceuticals, Inc., published May 14, 1996; Armistead et al. U.S. Patent No. 5,665,774, assigned to Vertex Pharmaceuticals, Inc., published September 9, 1997; Andrés et al., "Conformationally Defined Analogs of Prolyamides, Trans-Prolyl Peptidomimetics", Journal of Organic Chemistry, Vol. 58, pp. 6609-6613 (1993); and Armistead et al., "Design Synthesis and Structure of Non-macrocyclic Inhibitors of FKBP12, the Major Binding Protein for the Immunosuppressant FK506", Acta Cristallograohica, D51, pp. 522-528 (1995). Surprisingly, the inventors of the present have discovered a novel class of compounds that stop and / or reverse hair loss or promote hair growth but do not share the complex macrocyclic structure of FK506. The present inventors have also discovered, among this novel class, compounds that induce hair growth, however, unexpectedly they are not immunosuppressive or they are only in name. The minimal and / or absent activity of these hypertrotic compounds offers diverse P1250 advantages when compared to the immunosuppressive compounds cyclosporin A and FK506.

SUMMARY OF THE INVENTION The present invention relates to compounds and compositions that are useful in particular for the treatment of hair loss in mammals, including the arrest and / or reversal of hair loss and the stimulation of hair growth. The present compounds and compositions may also be useful against a variety of disorders including, for example, multiple drug resistance, human immunodeficiency virus (HIV), cardiac injury and neurological disorders and may be useful for the control of parasites. and induce immunosuppression. The compounds of the present invention have the following structure: and pharmaceutically acceptable salts, hydrates and amides, esters and biohydrolyzable imides thereof, wherein the substituents Z, W, X, Y, V, A, G, Rlf R 2, R 3, R, P1250 R5, Rs R7 / Rs R9 and Rio are defined here.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to compounds and compositions that are useful in particular for the treatment of hair loss in mammals, including the arrest and / or reversal of hair loss and the stimulation of hair growth. In addition to discovering that the present compounds are useful for the treatment of hair loss, the inventors of the present have discovered other compounds that are useful for treating hair loss but surprisingly they are not immunosuppressants. Therefore, the preferred compounds of the present invention, as defined herein, are not immunosuppressants. The present compounds are also useful for the treatment of a variety of other conditions as will be described below. Throughout the exhibition reference will be made to publications and patents. All references cited herein are considered part of the present reference. All percentages, ratios and proportions used herein are by weight, unless otherwise specified.

Definition and Use of Terms The following is a list of definitions for the terms used herein. As used herein, the term "salt" refers to a cationic salt formed by any acid group (eg, carboxyl) or an anoic salt formed by any basic group (eg, amino). Many of these salts are known in the art. Preferred cationic salts include the alkali metal salts (eg, sodium and potassium), the alkaline earth metal salts (eg, magnesium and calcium) and the organic salts. Preferred anionic salts include the halides (e.g., chloride salts). Acceptable salts, when administered, should be appropriate for use in mammals. As used herein, unless otherwise indicated, the term "alkenyl" is a straight or branched hydrocarbon chain radical, substituted or unsubstituted, having from 2 to about 15 carbon atoms. carbon; preferably between 2 and about 10 carbon atoms; more preferably between 2 and about 8 carbon atoms and preferably superlative between 2 and about 6 carbon atoms. Alkenyl- have at least one olefinic double bond. Non-exclusive examples of Pl250 alkenyls include vinyl, allyl and butenyl. As used herein, unless otherwise indicated, the term "alkoxy" is an oxygenated radical having an alkyl, alkenyl or alkynyl substituent, preferably an alkyl or an alkenyl substituent and preferably superlative an alkyl substituent. Examples of alkoxy radicals include -O-alkyl and -O-alkenyl. An alkoxy radical can be substituted or unsubstituted. In the sense in which it is used herein, unless otherwise indicated, the term "aryloxy" is an oxygenated radical having an aryl substituent. An aryloxy radical can be substituted or unsubstituted. As used herein, unless otherwise indicated, the term "alkyl" is a straight or branched hydrocarbon chain radical, substituted or unsubstituted, having from 1 to about 15 carbon atoms. carbon; preferably between 1 and about 10 carbon atoms; more preferably between 1 and about 6 carbon atoms and preferably superlative between 1 and about 4 carbon atoms. Preferred alkyls include, for example, methyl, ethyl, propyl, iso-propyl and butyl. As used herein, the term "alkylene" refers to an alkyl, alkenyl or alkynyl that is a biradical. For example, methylene is -CH2-. Alkylene can be substituted or unsubstituted. As used herein, unless otherwise indicated, the term "aryl" is an aromatic ring radical whether carbocyclic or heterocyclic. Preferred aryl groups include, for example, phenyl, benzyl, tolyl, xylyl, cumenyl, naphthyl, biphenyl, thienyl, furyl, pyrrolyl, pyridinyl, pyrazinyl, thiazolyl, pyrimidinyl, quinilonyl, triazolyl, tetrazolyl, benzothiazolyl, benzofuryl, indolyl, indenyl, azulenyl, fluorenyl, anthracenyl, oxazolyl, isoxazolyl, isotriazolyl, imidazolyl, pyrazolyl, oxadiazolyl, indolizinyl, indolyl, isoindolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinolinyl and the like. The aryls may be substituted or unsubstituted. As used herein, unless otherwise indicated, the term "arylakenyl" is an alkenyl radical substituted with an aryl group or an aryl radical substituted with an alkenyl group. The arylalkenyls may be substituted or unsubstituted. In the sense in which it is used in the P1250 present, unless otherwise indicated, the term "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. Arylalkyl groups may be substituted or unsubstituted. As used herein, the term "biohydrolysable amides" refers to amides of the compounds of the present invention that do not interfere with the activity of the compound or that are easily converted in vivo by a mammalian subject to give an active compound. As used herein, the term "biohydrolyzable esters" refers to esters of the compounds of the present invention that do not interfere with the activity of the compound or that are easily converted in vivo by a mammalian subject to give an active compound. As used herein, the term "biohydrolyzable imides" refers to imides of the compounds of the present invention that do not interfere with the activity of the compound or that are readily converted in vivo by a mammalian subject to give an active compound. In the sense in which it is used in the P1250 present, unless otherwise indicated, the terms "carbocyclic ring", carbocycle or the like, refer to a radical of a hydrocarbon ring. The carbocyclic rings are monocyclic or are fused, bridged or polycyclic spiro rings. Unless otherwise specified, the monocyclic rings contain between 3 and about 9 carbon atoms, preferably between 4 and about 7 carbon atoms and preferably superlative between 5 and 6 carbon atoms. The polycyclic rings contain between about 7 and 17 carbon atoms, preferably between about 7 and 14 carbon atoms and preferably superlative between 9 and 10 carbon atoms. The carbocyclic rings (carbocycles) can be substituted or unsubstituted. In the sense in which it is used herein, unless otherwise indicated, the term "cycloalkyl" is a saturated carbocyclic or heterocyclic ring radical. Preferred cycloalkyl groups include, for example, cyclobutyl, cyclopentyl and cyclohexyl. Cycloalkyls may be substituted or unsubstituted. In the sense in which it is used herein, unless otherwise indicated, the terms "halo", "halogen", "halide" or the like, refer to P1250 is a radical of chlorine, bromine, fluorine or iodine atoms, preferably bromine, chlorine or fluorine, more preferably chlorine or fluorine. As used herein, unless otherwise indicated, the term "heteroalkenyl" is an alkenyl radical containing carbon atoms and one or more heteroatoms in the alkenyl chain (e.g., -CHOCH2 rather than one that hangs as for example, C (0)) where the heteroatoms are selected from oxygen, sulfur, nitrogen and phosphorus, more preferably oxygen, sulfur and nitrogen. The heteroalkenyls may be substituted and unsubstituted. As used herein, unless otherwise indicated, the term the term "heteroalkyl" is an alkyl radical containing carbon atoms and one or more heteroatoms in the alkyl chain (e.g. -CH0CH2 rather than one that hangs from it such as, for example, C (0)) wherein the heteroatoms are selected from the group consisting of oxygen, sulfur, nitrogen and phosphorus, more preferably oxygen, sulfur and nitrogen. Heteroalkyls may be substituted and unsubstituted. In the sense in which it is used herein, unless otherwise indicated, the term "heteroaryl" is an aryl radical containing carbon atoms.

P1250 carbon and one or more heteroatoms in the aryl ring (eg, -CHOCH- rather than one that hangs from it as for example, C (O)) wherein the heteroatoms are selected from the group consisting of oxygen, sulfur, nitrogen and phosphorus, more preferably oxygen, sulfur and nitrogen. The heteroaryls may be substituted and unsubstituted. As used herein, unless otherwise indicated, the term "heteroarylalkenyl" is an arylalkenyl radical wherein the aryl group is a heteroaryl and / or the alkenyl group is a heteroalkenyl. Heteroarylalkenyls may be substituted or unsubstituted. As used herein, unless otherwise indicated, the term "heteroarylalkyl" is an arylalkyl radical wherein the aryl group is a heteroaryl and / or the alkyl group is a heteroalkyl. The heteroarylalkys may be substituted or unsubstituted. In the sense in which it is used herein, unless otherwise indicated, the terms "heterocyclic ring", "heterocycle" or the like refer to a ring radical consisting of carbon atoms and one or more heteroatoms in the ring, where the heteroatoms are selected from the group consisting of Pl250 oxygen, sulfur, nitrogen and phosphorus, more preferably oxygen, sulfur and nitrogen. The heterocycles are monocyclic rings or are fused, bridged or polycyclic spiro. Unless otherwise specified, the monocycles contain between 3 and about 9 carbon atoms, preferably between about 4 and 7 carbon atoms and more preferably between 5 and 6 carbon atoms. The polyclysters contain between about 7 and 17 carbon atoms, preferably between about 7 and 14 carbon atoms and more preferably between 9 and 10 carbon atoms. The heterocyclic rings (heterocycles) may be substituted or unsubstituted. As used herein, unless otherwise indicated, the term "heterocycloalkyl" is a saturated heterocycle. The heterocycloalkyls may be substituted or unsubstituted. As used herein, unless otherwise indicated, a "lower" unit (eg, "lower" alkyl) is a unit having from 1 to about 6 carbon atoms, preference between 1 and about 4 carbon atoms. In the sense in which it is used herein, the term "pharmaceutically acceptable" means that it is suitable for use in a human or in a P1250 another mammal. In the sense in which it is used herein, "safe and effective amount of a compound" (or composition or the like) refers to an amount that is effective to present biological activity, preferably, wherein the biological activity is stopping and / or reversing hair loss or promoting or stimulating hair growth, at the site (s) of activity, in a mammalian subject, without presenting excessive adverse side effects (eg, toxicity, irritation or allergic response) ), proportional to a reasonable ratio of benefit to risk when used according to the present invention. In the sense in which it is used herein, a "spiro unit" is a cyclic unit that shares a carbon in another ring, preferably the Z-ring. This spiro unit can be carbocyclic or heterocyclic. Spiro units may be substituted or unsubstituted. In the sense in which it is used herein, unless otherwise indicated, the term "substituted" with respect to a group, unit or the like, refers to one or more substituent groups each independently selected from hydrogen, alkoxy, hydroxyl, nitro, amino, alkylamino, cyano, halo, P1250 carboxyl, thiol, imino and aryloxy (with additional substituents allowed in unit G, which are selected from oxo, amido, -O-alkyl-C (0) OR32 and -O-alkyl-C (0) NHR32, wherein R32 is selected from hydrogen and alkyl), preferably hydrogen, alkoxy, hydroxyl, nitro, amino, alkylamino and halo, even more preferably hydrogen, halo, hydroxyl and alkoxy and preferably superlative hydrogen. In the sense in which it is used herein, unless otherwise indicated, the term "unsubstituted" refers to a substitution by a unit of hydrogen. However, alternatively a group can be consistently described as "substituted" when the substitution is with a unit of hydrogen. According to the present, when any variable, unit, group or the like occurs more than once in any variable or structure, its definition in each case is independent of its definition in any other case.

Compounds of the present invention The compounds of the present invention have the structure: Pl250 and salts, hydrates and amides, esters and biohydrolyzable, pharmaceutically acceptable imides thereof, wherein: (a) Z is a carbocycle or heterocycle of 4, 5, 6, 7, 8 or 9 members, saturated or unsaturated, wherein the heterocycle contains one or more heteroatoms selected from O, N, S, S (0), S (02) and P ((0) OK); (b) V is -CU-, wherein U is selected from hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl and heteroarylalkenyl; (c) G is selected from nothing, O, S and NR17; (d) K is selected from hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl and heteroarylalkenyl; (e) Ri is selected from alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, P1250 heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl and heteroarylalkenyl; (f) W is selected from none, hydrogen and lower alkyl; (g) A is selected from nothing and alkyl; (h) X and Y independently are each selected from C (0), P (O), N, O and S where: (i) when X is C (0) then R3 is nothing and Y is selected from N , O and S; (ii) when X is P (O) then R3 is nothing and Y is selected from N and O; (iii) when X is N then R3 is selected from hydrogen, alkyl and arylalkyl, Y is selected from C (0) and P (O) and R2 is nothing; (iv) when X is O then R3 is nothing, and is selected from C (O) and P (O) and R2 is nothing; and (v) when X is S then R3 is nothing, Y is C (0) and R2 is nothing; (i) R2 and R3 each, independently, are selected from none, hydrogen, alkyl and arylalkyl; (j) R4 is alkyl; (k) R5 and R6 independently are each selected from none, hydrogen, alkyl having at least two carbon atoms, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, P1250 arylalkyl, heteroarylalkyl, arylalkenyl and heteroarylalkenyl; or wherein R5 and R6 are joined to form a carbocyclic or heterocyclic ring; (1) R7, R8, R9 and Rio independently are each selected from none, hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, halo, cyano, hydroxyl, oxo, imino, -R? 4SR? 5, -R? S (02) R? 5, -R? 4S (0) R15, -R? 4C (0) R? 5, -R? 4C (0) NR15R? 6, -Ri4C (0) 0R? 5, -R ? 4OR15, -R? 4NR15R? 6, Ri P (O) NR15R? 6, -Ri P (0) OR15R16 and a spiro unit and wherein R7 and Re can optionally be linked to form a carbocyclic or heterocyclic, aromatic or saturated, where the rings fuse to form Z; (m) R 14 and R 5 are each independently selected from none, hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl and heteroarylalkenyl; and (n) R16 and R17 are each independently selected from hydrogen and alkyl.

The Z-Ring System The present compounds are constituted by a Z-ring system, which is a 4, 5, 6, 7, 8 or 9 membered carbocycle or heterocycle, saturated or unsaturated. Preferably the ring system Z is a carbocycle or 5-, 6- or 7-membered heterocycle, more preferably a 5- or 6-membered carbocycle or heterocycle. Preferably, the Z ring is a carbocycle. In the 1-position of the ring system is the substituent V which is -CU-, wherein U is selected from hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl and heteroarylalkenyl, preferably hydrogen, alkyl and arylalkyl, preferably hydrogen superlative. Optionally, the Z ring contains one or more heteroatoms or heterounits (generally described herein as heteroatoms by simplification), wherein the heteroatoms are selected from oxygen (O), nitrogen (N), sulfur (S), sulfoxide (S (0)) ), sulfone (S (0) 2) and phosphonate (P ((0) OK)). Preferably, the optional heteroatoms are selected from the group consisting of 0, N, S, S (0) and S (0) 2. Of course, the heteroatom can not be in position 1 because substituent V is required to be in position 1. When N is a heteroatom in the heterocycle, the additional N heteroatom must be replaced, more preferably with hydrogen or alkyl. The heteroatoms S (0) P1250 and S (0) 2 and P (0) OK are shown below in Table 1 for clarity.

Table 1 Unit G Directly attached to substituent V is unit G. G is selected from nothing, O, S and NR? 7, where NR17 is selected from hydrogen and alkyl. Preferably, G is selected from O, S and NR17, preferably O and NRi7 and preferably superlative G is NR17.

The R Unit? Directly attached to unit G is a ketoamide unit as shown in the above structure. The side chain Ri is also directly attached to the ketoamide unit. Unit Ri is selected from alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl and heteroarylalkenyl. The unit Ri is preferably substituted by at least one substituent other than hydrogen. In addition to the substituents defined here which can be substituted in all units, substituents R, substituents, oxo, amido, -O-alkyl-C (0) OR32 and -O-alkyl-C (O) NHR32 can also be substituted in the unit. wherein R32 is selected from hydrogen and alkyl. The Rx unit is preferably selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl and heteroarylalkyl, still more preferably aryl, arylalkyl and heteroarylalkyl, preferably aryl superlative. The most preferred aryl for the Ri unit is substituted aryl (preferably superlative substituted phenyl), in particular an aryl having at least one alkoxy substituent. The Ri units that are particularly preferred are shown below in Table 2.

Pl250 Table 2 - Preferred Ri units The Substituted Unit A-X-Y-R In the 2- position of the ring Z is the unit A-X-Y-R4 which is substituted as described herein, by R2, R3, R5 and R6. Unit A of the side chain is selected from nothing and alkyl. With superlative preference, unit A is nothing. Of course, when A is nothing, X is directly attached to the Z ring. Unit X of the side chain is dependent on the structure of unit Y and vice versa. X and Y independently are each selected from C (O) (ie, carbonyl), P (O), N, O and S with the following limitations: (i) when X is C (O) then R3 is nothing and And it is selected from the group consisting of N, 0 and S; (ii) when X is P (O) then R3 is nothing and Y is selected from the group consisting of N and O; (iii) when X is N then R3 is selected from hydrogen, alkyl and arylalkyl, and is selected from the group Pl250 consisting of C (0) and P (O) and R2 is nothing; (iv) when X is O then R3 is nothing, and is selected from the group consisting of C (0) and P (0) and R2 is nothing; and (v) when X is S then R3 is nothing, Y is C (0) and R2 is nothing; Preferably, X and Y independently are each selected from C (O), N and O. More preferably, X and Y independently are each selected from C (0) and N. X and Y are replaced by R3 and R2 , respectively.

R3 and R2 are each independently selected from hydrogen, alkyl and arylalkyl. When X is N then R3 is selected from hydrogen, alkyl and arylalkyl, preferably hydrogen and alkyl, preferably hydrogen superlative. When Y is N then R 2 is selected from hydrogen, alkyl and arylalkyl, preferably hydrogen and alkyl, preferably superlative hydrogen. The unit R4 is an alkyl unit. Preferred alkyl units conform to the limitations set forth above, the most preferred unit R4 is a methylene or methine group (i.e., a Ci unit with only one available hydrogen substituent). Each of the units R5 and R6 is directly linked to R4, R5 and R6 independently are selected each P1250 an enter nothing, hydrogen, alkyl having at least two carbon, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl and heteroarylalkenyl; or R5 and R6 join to form a carbocyclic or heterocyclic ring; wherein at least one of R5 and R6 is nothing or hydrogen. Preferably, R5 and R6 independently are each selected from none, hydrogen, alkyl having at least two carbon atoms, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl and heteroarylalkenyl. More preferably, R5 and R6 independently are each selected from alkyl having at least two carbon, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl and heteroarylalkyl atoms. With superlative preference, R5 and R6 independently are each arylalkyl. It is often preferred that R5 and Re be equivalent units. Of course, R5 and R6 each may be independently substituted. Exemplary R5 units and Rs are presented below in Table 3.

P1250 Table 3 - Rq and Rs units and the emplificativas The Unit W The Z ring can be substituted in the 2- position by an additional unit, W. The unit W is selected from none, hydrogen and lower alkyl, preferably hydrogen and lower alkyl, preferably superlative hydrogen. When W is lower alkyl, preferably superlative is methyl.

Substituents R7, RR. RQ and Rt_n of the Z Ring In addition to the aforementioned substituents in positions 1 and 2 of the Z ring, the ring Z may also have additional substituents in other available positions, these additional substituents are defined as R7, R8, R9 and R10. These substituents R7, R8, Rg and Rio independently are each selected from none, hydrogen, alkyl, alkenyl, heteroalkyl, Heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, P1250 arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, halo, cyano, hydroxy, oxo, imino, R14SR15, -R? 4S (02) R? 5, -R14S (0) R15, -R? 4C (0) R? 5, -R? 4C (0) NR? 5R? S, -R? 4C (0) ORi5, -R14OR15, -? 4NR? 5Ri6, Ri4P (0) NR? 5R? 6, -R14P (0) OR? 5R? 6 and a spiro unit and wherein R7 and R8 can optionally be linked to form a carbocyclic or heterocyclic, aromatic or saturated ring, wherein the ring is fused with Z. Ri4 and R5 independently are each selected from nothing, hydrogen , alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl and heteroarylalkenyl. Ri6 is selected from hydrogen and alkyl. Preferably, R7, R8, Rg and Rio independently are each selected from none, hydrogen, alkyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, halo, hydroxy, oxo, -R? SR? 5, - RiS (02) R15, -R? 4S (0) R? 5, R? 4C (0) R? 5, -Ri4C (0) NR? 5Ri6, -R? 40R? 5, -R? 4NR? 5R? 6 and a spiro unit and wherein R7 and R8 can optionally be joined to form a second carbocyclic or heterocyclic, aromatic or saturated ring, wherein the second ring is fused with Z. More preferably, R7, R8, Rg and Rio independently are they select each one from nothing, hydrogen, alkyl, heteroalkyl, heteroalkenyl, aryl, P1250 arylalkyl, heteroarylalkyl, halo, hydroxy, oxo, R? 4SRi5, -R? 4S (02) R? 5, -R? 4S (0) R? 5, -R14C (0) R? 5, -R14C (0 ) NR? 5R? 6, -R? ORi5, -R? 4NR? 5R? 6 and a spiro unit and wherein R7 and R8 can optionally be joined to form a second carbocyclic or heterocyclic, aromatic or saturated ring, wherein the second ring is fused with Z. Even more preferably, R7, R8, R9 and Rio independently are each selected from none, hydrogen, alkyl, heteroalkyl, heteroalkenyl, aryl, arylalkyl, heteroarylalkyl, halo, hydroxy, -R? 4C ( ) R? 5, R? 4C (0) NR? 5R? 6, -R? ORi5, -R? NR? 5R? 6 and a spiro unit and wherein R7 and R8 may optionally be joined to form a second carbocyclic or heterocyclic, aromatic or saturated ring , wherein the second ring is fused with Z. Preferably superlative, R7 and R8 are joined to form a carbocyclic or heterocyclic (preferably carbocyclic), aromatic or saturated (preferably aromatic) second ring, wherein the second ring is fused with Z. Where R7 and R8 are joined to form second carbocyclic or heterocyclic, aromatic or saturated ring, wherein the second ring is fused with Z, the second ring, of course, may be substituted or unsubstituted. A second preferred ring is phenyl. Exemplary compounds of this P1250 invention, are shown in the following tables.

Table 4 - Emplifying Compounds of the Present Invention P1250 Table 5 - Emphycifying Compounds Ei of the Present Invention wherein, in Table 5, R? 8, Ri9 and R2o independently are each selected from hydrogen, alkoxy, aryloxy, hydroxy, nitro, amino, halo and thiol.

Table 6 - Emplifying Compounds of the Present Invention P1250 wherein, in Table 6, R30 is selected from the group consisting of -OR32 and -OCH2C (0) OR32, wherein R32 is selected from the group consisting of hydrogen and alkyl.

Table 7 - Emplifying Compounds of the Present Invention wherein, in Table 7, R35 is selected from hydrogen and -OR36, wherein R36 is selected from hydrogen and alkyl.

P1250 Table 8 - Emplifying Compounds of the Present Invention 0 P1250 wherein, in Table 8, R30 and R35 independently are each selected from -OR32 and -OCH2C (0) OR32, wherein R32 is selected from hydrogen and alkyl. 5 Analytical Methods The present compounds are active ingredients for hair growth, among which those that are most preferred are those that are not immunosuppressants (no immunosuppressants). The compounds (test compounds) of the present invention can be analyzed in order to test their ability to induce anagen and their immunosuppressive activity (or lack of it) by the following methods. Alternatively, you can use other methods well known in the art (but the term "non-immunosuppressant" is defined according to the method set forth herein).

Telogen Conversion Test: 20 The telogen conversion test measures the Pl 50 potential of a test compound to convert the resting state of the hair growth cycle ("telogen") to the growth state of the hair growth cycle ("anagen") in mice. Without pretending to be limited to theory, there are three main phases in the hair growth cycle: anagen, catagen and telogen. It is believed that a longer telogen period occurs in C3H mice (Harlan Sprague Dawley, Inc., Indianapolis, IN) between about 40 days of age to 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. When in the hair growth experiments, mice approximately 40 days old with dark hair were used (brown or black) melanogenesis was presented along with hair growth and the topical application of hair growth promoters was evaluated. The telogen conversion test described below is used to select compounds based on their potential to induce hair growth, through the measurement of melanogenesis. Three groups of 44-day-old C3H mice were used: a control group with vehicle, a positive control group and a group of the test compound, in P1250 where the compound of the test compound is administered a compound of the present invention. The duration of the test is at least 19 days with 15 days of treatment (the days of treatment are from Monday to Friday). Day 1 is the first day of treatment. Most studies end on day 19, but a few can be done until day 24 if the response of melanogenesis is positive, but develops slowly. In Table 9 below, a typical study design is shown.

Table 9 ** The vehicle is 60% ethanol, 20% propylene glycol and 20% dimethyl isosorbide (commercially available from Sigma Chemical Co., St. Louis, MO).

P1250 Mice are treated Monday through Friday by topical application on the lower part of the spine (from the base of the tail to the lower rib). A pipettor and dropper is used to deliver 400 μl to the spine of each mouse. The application of the 400 μl is carried out slowly while moving the mouse hair to allow the application to reach the skin. While each treatment is applied to the mouse by topical route, a visual grade of 0 to 4 will be assigned to the skin color in the area of application of each animal. As mice move from telogen to anagen, the color of their skin will change to a more intense bluish black. As indicated in Table 10, grades 0 to 4 represent the following visual observations as the skin changes from white to bluish black.

Table 10 P1250 Immunosuppression Test The immunosuppression test predicts the immunosuppressive activity of a compound of the present invention. The test is performed as follows: The spleens of sacrificed male adult C3H mice (asphyxia by C02) are excised, with ages ranging from seven to sixteen weeks (commercially available live mice from Harlan Sprague Dawley, Inc., Indianapolis, IN. ). The spleens are immediately placed in Hanks balanced salt solution (HBSS, which is commercially available from Gibco-BRL, Gaithersburg, MD). The spleens are then milled between cold coverslips and filtered through a sterile mesh to remove tissue debris. The resulting cell suspension is covered 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. Splenocytes are harvested at the interface with a disposable pipette and washed twice with HBSS and then P1250 are centrifuged at 100 x g for ten minutes at 20 ° C. Splenocytes are resuspended in a volume of five to ten mL of cell culture medium consisting of RPMI 1640 without phenol red (culture medium commercially available from Gibco-BRL) containing 10% heat inactivated bovine fetal serum (Gibco -BRL), penicillin (50 U / mL), streptomycin (100 μg / mL), L-glutamine (2 mM), 2-mercaptoethanol (10 ~ 5 M) and N-2-hydroxyethylpiperazine-N '-2 - acid Ethanesulfonic acid (HEPES) (10 mM). Cells are counted and their viability evaluated using, for example, trypan blue. Splenocytes are resuspended in medium at 10 6 cells / mL and pipetted in 96-well round bottom plates at 10 5 cells / well. Splenocytes are activated by the addition of 50 μl / well of conconavalin A (final test concentration = 5 μg / ml) in the presence or absence of the test compound. The test compounds are prepared as buffer solutions in dimethyl sulfoxide (DMSO), then diluted in medium and 50 μl / well added, so that the final concentration of DMSO in the test is less than 0.05%. 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-thymidine (commercially available from Amersham, Buckinghamshire, England) and incubated for a further 24 hours. After 24 hours, the cells are harvested in P1250 GF / C filter plates (commercially available from Packard, Downers Grove, IL), are solubilized in Microscint 20 (Packard) and counted in a TopCount microplate scintillation and luminescence plate counter (Packard). The activity is measured as a percentage of the control activity in the absence of the test compound and plotted against the concentration of the test compound. The data is adjusted to a curve of 4 parameters (Sigmaplot) and IC50 values are calculated. According to the present invention, the test compounds are considered non-immunosuppressive if, when using this method, the ratio of (IC50 of cyclosporin A / IC50 of the test compound) x 100 is less than or equal to 0.02, that is, a test compound is not immunosuppressant has < . 2% of the immunosuppressive activity of cyclosporin A. Cell viability is evaluated by the color test with MTT (3- [4,5-dimethyl-thiazol-2-yl] -2,5-diphenyl-tetrazolium bromide) as described by Nelson et al., Journal of Immunology, Vol. 150, No. 6, pp. 2139-2147 (1993), with the exception that the test is performed in RMPI 1640 free of serum and free of phenol red and the dye is solubilized in 100 μl / well of DMSO and read in a OD (optical densitometer) of 540 nm with a 650 nm background correction on a SpectraMax Plus microplate reader (Molecular Devices, Menlo Park, CA).

P1250 Multiple Resistance to Drugs As discussed here, the compounds present are also useful, for example, to increase the antiproliferative activity of a drug and / or prevent and / or treat multiple drug resistance. The present compounds can be analyzed with respect to this property as described in the following patents, U.S. Patent No. 5,744,485, Zelle et al. , issued to Vértex Pharmaceuticals, Inc., published on April 28, 1998, U.S. Patent No. 5,726,184, Zelle et al. , issued to Vértex Pharmaceuticals, Inc., published March 10, 1998, U.S. Patent No. 5,620,971, Armistead et al. , issued to Vértex Pharmaceuticals, Inc., published on April 15, 1997 and U.S. Patent 5,543,423, Zelle et al. , awarded to Vértex Pharmaceuticals, Inc., published on August 6, 1996.

Methods of Preparation The compounds of the present invention are prepared according to methods well known to those skilled in the art. The raw materials used in the preparation of the compounds of the invention are known, prepared by known methods or commercially available as raw material. It is considered that the technician with experience in the technique of organic chemistry, can easily carry out the common manipulations of organic compounds without additional direction. Examples of such manipulations are studied in standard texts such as J. March, Advanced Organic Chemistry, John Wiley & Sons, 1992. The experienced technician will easily realize that certain reactions are best performed when other functional groups in the compound are masked or protected, thereby increasing the reaction yield and / or avoiding any undesirable side reactions. . Frequently, experienced technicians use protective groups to achieve that increase in performance or to avoid undesirable reactions. These reactions are found in the literature and are also within the capacity of experienced technicians. Examples of many manipulations of this type can be found, for example, in T. Greene, Protecting Groups in Organic Synthesis, John Wiley & Sons, 1981. The compounds of the present invention may have one or more chiral centers. Accordingly, an optical isomer, including diastereomers and enantiomers, for example, by raw materials, catalysts or chiral solvents can be prepared selectively with respect to each other, or both stereoisomers and the two optical isomers can be prepared at the same time, P1250 including diastereomers and enantiomers (a racemic mixture). Since the compounds of the invention can exist as racemic mixtures, mixtures of optical isomers, including diastereomers and enantiomers or stereoisomers, can be separated using known methods, for example, through the use of chiral salts and chiral chromatography. Furthermore, it is recognized that an optical isomer, including a diastereomer and enantiomer or a stereoisomer, may have favorable properties with respect to other. Thus, when exposing and claiming the invention, when a racemic mixture is exposed, it is evident that those two optical isomers, including diastereomers and enantiomers or stereoisomers, practically isolated from the others, are exposed and claimed as well. The following are non-exclusive examples that illustrate more specifically the methods for preparing various compounds of the present invention. The following abbreviations are used here: P1250 Example 1 the. 2- (1, 7-diphenyl-4-heptyl) -4,4-dimethyl-2-oxazoline: 2,4,4-trimethyl-2-oxazoline (5.64 mL, 44.2 mmol) are dissolved in anhydrous THF (40 mL) ) at room temperature in an inert atmosphere. The solution is cooled to -78 ° C and n-butyl lithium (31.3 mL / 1.6 M in hexanes, 50 mmol) is added dropwise. A solution of l-bromo-3-phenylpropane (7.42 mL, P1250 48.8 mmoles) in THF (20 mL) is added dropwise in 10 minutes. The cooling bath is removed and the reaction solution is allowed to come to room temperature. After 30 minutes the solution is cooled again to -78 ° C. Dropwise, n-butyl lithium (31.3 mL / 1.6 M in hexanes, 50 mmol) was added. After 30 minutes a solution of l-bromo-3-phenylpropane (7.42 mL, 48.8 mmol) in THF (20 mL) is added dropwise over 10 minutes. The reaction is allowed to come slowly at room temperature for the next 12 hours while stirring. The reaction is poured into water (200 mL) and acidified with HCl and extracted with ethyl ether (150 mL). The aqueous phase is cooled, neutralized with 50% NaOH solution and extracted with ethyl ether (3 x 100 mL). The combined ethyl ether extracts are dried over MgSO 4, filtered and concentrated in vacuo. Purification of the crude product by preparative silica gel chromatography gives the expected product, bis-alkylated oxazoline. Ib. (1, 7-Diphenyl-4-heptyl) carboxylic acid: Oxazoline (9.36 g, 26.8 mmol) is dissolved in dioxane. (100 mL) at room temperature. 3N HCl (200 mL) is added and the resultant is heated to reflux for 18 hours. The solution is cooled to room temperature and then poured into water (200 mL) and extracted with ethyl ether (3 x 150 mL). The combined ethyl ether extracts are washed P1250 successively with water (75 mL) and brine (75 mL) then dried over MgSO4, filtered and concentrated in vacuo to give the desired product. you. trans -1, 2-Diaminocyclohexane, (1,7-diphenyl-4-heptyl) carboxylic acid amide: The carboxylic acid Ib (1.0 g, 3.37 mmol) is dissolved in dichloromethane (50 mL) at room temperature under an inert atmosphere. Trans-1,2-diaminocyclohexane (0.77 g, 6.75 mmol) and then i-Pr2NEt (0.6 mL, 3.4 mmol) and PyBOP (1.9 g, 3.7 mmol) are added. The reaction mixture is stirred at room temperature for 18 hours and then poured into ethyl acetate (300 mL) and washed with 0.1 N HCl (150 mL), saturated sodium bicarbonate solution (75 mL) and brine (50 mL). mL). The organic solution is dried over MgSO 4, filtered and concentrated in vacuo. Purification of the crude product by preparative chromatography on silica gel gives the desired product. Id. Trans-1, 2-Diaminocyclohexane, 1-N- (1, 7-diphenyl-4-heptyl) carboxylic acid amide, 2-N- (3 ', 4', 5'-trimethoxyphenylglyoxyl) amide: Amide le (0.73 g, 1.83 mmol) is dissolved in anhydrous dichloromethane (30 mL) at room temperature. 3 ', 4', 5'-trimethoxyphenylglyoxylic acid (0.67 g, 2.8 mmol) is added in one portion and then triethylamine (0.6 mL, 4.3 mmol) and EDAC (0.53 g, 2.8 mmol). the reaction mixture is stirred P1250 for 18 hours at room temperature, then poured into water (50 mL) and extracted with dichloromethane (3 x 40 mL). The combined organic extracts are washed successively with 0.1 N HCl (40 mL) and saturated sodium bicarbonate solution (40 mL), then dried over MgSO4, filtered and concentrated in vacuo. Purification of the crude product by preparative chromatography on silica gel gives the desired product Id.

Example 2 2a. Cis-2 - (N-tert-butoxycarbonylamino) -1-cyclopentanecarboxylic acid, 4-phenylbutylamide: cis-2- (N-tert-butoxycarbonylamino) -1-cyclopentanecarboxylic acid (4.1 g, 17.7 mmol) is dissolved in 160 mL of DMF. 4-Phenylbutylamine (2.4 g, 16.1 mmol) and i-Pr2NEt (5.6 mL, 32.2 mmol) and then PyBOP (8.8) are added.

P1250 g, 16.9 mmol). The reaction is stirred for nineteen hours at room temperature, then poured into ice cold 0.1N HCl (600 mL) and extracted with ethyl acetate (600 mL). The organic phase is washed successively with brine (100 mL), saturated NaHCO 3 solution (300 mL) and brine (2 x 200 mL). The organic solution is dried over MgSO 4, filtered and concentrated in vacuo. Purification of the product by chromatography gives the desired amide 2a. 2b. Cis-2-amino-1-cyclopentanecarboxylic acid, 4-phenylbutylamide: Amide 2a (5.5 g, 15.3 mmol) is dissolved in 150 mL of anhydrous dichloromethane. TFA (120 mL) is added dropwise over a period of 5 minutes. 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). mL) and stirred. The organic phase is washed with water (200 mL) before drying in MgSO4. The mixture is filtered and concentrated in vacuo to give the desired amine 2b. 2 C. Cis-2- (3 ', 4', 5'-trimethoxyphenylglyoxylamino) -1-cyclopentanecarboxylic acid, 4-phenylbutylamide: Amine 2b (3.4 g, 13.1 mmol) is dissolved in 150 L of anhydrous DMF. 3 ', 4', 5 '-trimethoxyphenylglyoxylic acid (3.9 g, 16.4 mmol) and i-Pr2NEt (5.7 mL, 32.7 mmol) and then PyBOP (8.85) were added.

P1250 g, 17.0 mmol). The reaction is stirred for 18 hours at room temperature, then it is poured into ice cold 0.1 N HCl (600 mL) and extracted with ethyl acetate (600 mL). The organic phase is washed successively with brine (100 mL), saturated NaHCO 3 solution (300 mL) and brine (2 x 100 mL). The organic solution is dried over MgSO 4, filtered and concentrated in vacuo. Purification of the product by chromatography gives the desired amide 2c.

Example 3 3a. Cis-1, 2-diaminocyclohexane, (1,7-diphenyl-4-heptyl) carboxylic acid amide: The carboxylic acid Ib (2.0 g, 6.74 mmol) is dissolved in DMF (100 mL) at room temperature under an inert atmosphere. Cis-1, 2- is added P1250 diaminocyclohexane (1.43 g, 12.5 mmol) and then i-Pr2NEt (1.18 mL, 6.8 mmol) and PyBOP (3.9 g, 7.45 mmol) successively. The reaction mixture is stirred at room temperature for 18 hours, then poured into ethyl acetate (600 mL) and washed successively with 0.1 N HCl (300 mL), brine (100 mL), saturated sodium bicarbonate solution ( 150 mL) and brine (100 mL). The organic solution is dried over MgSO 4, filtered and concentrated in vacuo. Purification of the crude product by preparative chromatography on silica gel gives the desired amide 3a. 3b. cis-1, 2-diaminocyclohexane, 1-N- (1, 7-diphenyl-4-heptyl) carboxylic acid amide, 2-N- (phenylglyxyl) amide: Amine 3a (1.46 g, 3.68 mmol) is dissolved in DMF anhydrous (50 mL) at room temperature. Phenylglyoxylic acid (0.8 g, 5.48 mmol) is added in one portion and then i-Pr2NEt (1.5 mL, 8.6 mmol) and PyBOP (2.9 g, 5.54 mmol). The reaction mixture is stirred for 18 hours at room temperature, then poured into ethyl acetate (300 mL) and washed successively with 0.1 N HCl (150 mL), brine (50 mL), saturated sodium bicarbonate solution ( 150 mL) and brine (50 mL). The organic solution is dried over MgSO 4, filtered and concentrated in vacuo. Purification of the crude product by preparative chromatography on silica gel gives the desired amide 3b.

Pl250 Example 4 4a. Cis-2- (N-tert-butoxycarbonylamino) -1-cyclohexanecarboxylic acid. Cis-2-amino-1-cyclohexanecarboxylic acid (5.0 g, 35 mmol) is dissolved in 40 mL of a 1: 1 dioxane: water mixture. Triethylamine (7.3 mL, 52.4 mmol) and then Boc-ON (9.5 g, 38.4 mmol) are added. The mixture is stirred for 4 hours and then poured into water (75 mL) and extracted with ethyl acetate (3 times, 75 mL each time). The aqueous solution is cooled in a Pl250 ice bath and the pH is adjusted to approximately 2.5 with ice cold HCl solution. The resulting mixture is extracted with dichloromethane (3 times, 75 mL each time). The combined organic extracts are dried over MgSO4, filtered and concentrated in vacuo to give 4a. 4b. Cis-2- (N-tert-butoxycarbonylamino) -1-cyclohexanecarboxylic acid, 1,7-diphenyl-4-heptylamide: The carboxylic acid 4a (4.3 g, 17.7 mmol) is dissolved in 160 mL of DMF. 1,7-Diphenyl-4-aminoheptane (4.3 g, 16.1 mmol) and i-Pr2NEt (5.6 mL, 32.2 mmol) and then PyBOP (8.8 g, 16.9 mmol) are added. The reaction is stirred for 19 hours at room temperature, then poured into ice cold 0.1 N HCl (600 mL) and extracted with ethyl acetate (600 mL). The phases are separated and the organic phase is washed successively with brine (100 mL), saturated NaHCO 3 solution (300 mL) and brine (2 x 200 mL). The organic solution is dried over MgSO 4, filtered and concentrated in vacuo. Purification of the product by chromatography on silica gel gives the desired amide 4b. 4c. Cis-2-amino-1-cyclohexanecarboxylic acid, 1,7-diphenyl-4-heptylamide: Amide 4b (7.54 g, 15.3 mmol) is dissolved in 150 mL of anhydrous dichloromethane. TFA (120 mL) is added dropwise in for 5 minutes. After 2 hours, the mixture is cooled in an ice bath and saturated K2C03 solution is added until the pH is P1250 approximately 8. The mixture is transferred to a separatory funnel containing dichloromethane (200 mL) and water (200 mL) and stirred. The organic phase is separated and washed with water (200 L) before being dried in MgSO4. The mixture is filtered and concentrated in vacuo to give the desired amine 4c. 4d. Cis-2 - (3 ', 4', 5'-trimethoxyphenylglyoxylamino) -1-cyclohexanecarboxylic acid, 1,7-diphenyl-4-heptylamide: Amine 4c (5.14 g, 13.1 mmol) is dissolved in 150 mL of anhydrous DMF . 3 ', 4', 5'-trimethoxyphenylglyoxylic acid (3.93 g), 16.4 mmoles) and i-Pr2NEt (5.7 mL, 32.7 mmoles) are added and then PyBOP (8.9 g, 17.0 mmoles). The reaction is stirred for 18 hours at room temperature, then poured into ice cold 0.1 N HCl (600 mL) and extracted with ethyl acetate (600 mL). The phases are separated and the organic phase is washed successively with brine (100 mL), saturated NaHCO 3 solution (300 mL) and brine (2 x 100 mL). The organic solution is dried in MgSO, filtered and concentrated in vacuo. Purification of the product by chromatography on silica gel gives the desired amide 4d.

Pl250 E emplo 5 Ph Ph 5b 5a. N- (diphenylmethylene) -2-amino-5-phenylpentanoic acid benzyl ester: The N- (diphenylmethylene) glycine benzyl ester (20.0 g, 60.8 mmol) is dissolved in 130 mL of acetonitrile. L-bromo-3-phenylpropane is added (14.5 g, 72.8 mmol), K2CO3 (25.2 g, 182.2 mmol) and tetrabutylammonium bromide (1.96 g, 6.0 mmol) and the mixture is refluxed. After three hours, the mixture is cooled to room temperature, filtered and P1250 concentrated in vacuo. Water (400 mL) is added and the mixture is extracted with ether (1.2 L). The organic extract is washed with water (400 mL) and brine (200 mL), dried over MgSO, filtered and concentrated in vacuo. The product is purified by chromatography on silica gel to give the desired ester 5a. 5b. Benzyl Ester of 2-amino-5-phenylpentanoic acid: The ester 5a (24.62 g, 55.0 mmol) is dissolved in IN aqueous HCl (600 mL) and ether (200 mL) and the mixture is stirred at room temperature. After 20 hours the phases are separated and the aqueous phase is extracted with ether (200 mL). The aqueous phase is cooled in an ice bath and the pH is adjusted to approximately 10 with saturated aqueous K2C03 solution. The mixture is extracted with dichloromethane (3 x 300 mL) and brine (100 mL) then dried over MgSO4, filtered and concentrated in vacuo to give the amino ester 5b. 5c. Cis-2- (N-tert-butoxycarbonylamino) -1-cyclopentanecarboxylic acid, benzyl 5-phenyl-2-pentanoate amide: cis-2- (N-tert-butoxycarbonylamino) -1-cyclopentanecarboxylic acid is dissolved (4.8 g, 20.9 mmoles) in 230 mL of dichloromethane. The amino ester 5b (5.4 g, 19.0 mmol) and i-Pr2NEt (7.0 mL, 39.9 mmol) and then PyBOP (10.9 g, 20.9 mmol) are added. The reaction is stirred for 18 hours at room temperature, then poured into ice cold 0.1 N HCl (250 mL) and extracted with ethyl acetate.

P1250 ethyl (300 mL). The phases are separated and the organic phase is washed with saturated NaHCO 3 solution (150 mL) and brine (50 mL). The organic solution is dried over MgSO 4, filtered and concentrated in vacuo. Purification of the product by chromatography on silica gel gives the desired amide 5c. 5 d. Cis-2-amino-1-cyclopentanecarboxylic acid, benzyl 5-phenyl-2-pentanoate amide: Amide 5c (9.6 g, 19.4 mmol) is dissolved in 185 mL of anhydrous dichloromethane. TFA (150 mL) is added dropwise over 5 minutes. After two hours the mixture is cooled in an ice bath and saturated K2C03 solution is added until the pH is about 8. The mixture is transferred to a separatory funnel containing dichloromethane (250 mL) and water (250 mL) and it is agitated. The organic phase is separated and washed with water (200 mL). The aqueous phase is back extracted with dichloromethane (100 mL). The combined organic extracts are dried in MgSO, filtered and concentrated in vacuo to give the desired amine 5d. 5e. Cis-2- (3 ', 4', 5'-trimethoxyphenylglyoxylamino) -1-cyclopentanecarboxylic acid, benzyl 5-phenyl-2-pentanoate amide: Amine 5d (7.14 g, 18.1 mmol) is dissolved in 220 mL of anhydrous dichloromethane . 3 ', 4', 5'-trimethoxyphenylglyoxylic acid (5.2 g, 21.7 mmol) and i-Pr2NEt (5.14 g, 39.8 mmol) and then PyBOP (11.3 g, 21.7 g) are added.

P1250 mmoles). The reaction is stirred for 13 hours at room temperature, then poured into ice-cold 0.1 N HCl (250 mL) and extracted with ethyl acetate (300 mL). The phases are separated and the organic phase is washed with saturated NaHCO 3 solution (200 mL) and brine (50 mL). The organic solution is dried over MgSO 4, filtered and concentrated in vacuo. Purification of the product by chromatography on silica gel gives the desired amide 5e.

Example 6 6a. N, N'-dimethyl-trans-1,2-diaminocyclohexane, 5-phenylpentanoic acid amide: 5-phenyl pentanoic acid (6.0 g, 33.7 mmol) is dissolved in dichloromethane (500 mL) at room temperature under inert atmosphere. N, N'-dimethyl-trans-1,2-diaminocyclohexane (9.6 g, 67.5 mmol) is added and P1250 below i-Pr2NEt (5.9 mL, 33.9 mmoles) and PyBOP (19.3 g, 37.1 mmoles). The reaction mixture is stirred at room temperature for 18 hours, then poured into ethyl acetate (300 mL) and washed successively with ice cold 0.1 N HCl (150 mL), saturated sodium bicarbonate solution (75 mL) and brine (50 mL). The organic solution is dried over MgSO 4, filtered and concentrated in vacuo. Purification of the crude product by preparative chromatography on silica gel gives the desired amide 6a. 6b. N, N'-dimethyl-trans-1,2-diaminocyclohexane, lN-5-phenylpentanoic acid amide, 2-N- (phenylglyxyl) amide: Amide 6a (0.55 g, 1.83 mmol) is dissolved in anhydrous dichloromethane (30mg). mL) at room temperature. Phenylglyoxylic acid (0.42 g, 2.8 mmol) is added in one portion and then i-Pr2NEt (0.75 mL, 4.3 mmol) and PyBOP (1.44 g, 2.77 mmol) successively. The reaction is stirred for 18 hours at room temperature, then poured into 0.1 N HCl cooled on ice (30 mL) and extracted with dichloromethane (40 mL). The phases are separated and the organic phase is washed with saturated NaHCO3 solution (30 mL) and brine (15 mL). Purification of the crude product by preparative chromatography on silica gel gives the desired product 6b.

P1250 Example 7 7a. N, N 'Dimethyl-trans-1,2-diaminocyclohexane, lN-5-phenylpentanoic acid amide, 2-N- (2-furyl) glyoxylic acid amide: N, N' Dimethyl-traps-1, 2 are dissolved -diaminocyclohexane, 5-phenyl pentanoic acid amide 6a (10.0 g, 33.1 mmol) in anhydrous dichloromethane (600 mL) at room temperature. Phenylglyoxylic acid (5.5 g, 49.7 mmoles) is added in one portion and then i-Pr2NEt (13.5 mL, 77.8 mmol) and PyBOP (25.8 g, 49.6 mmol) successively. The reaction is stirred for 18 hours at room temperature, then poured into ice-cold 0.1N HCl (600 mL) and extracted with dichloromethane (800 mL). The phases are separated and the organic phase is washed with saturated NaHCO3 solution (600 mL) and brine (300 mL). Purification of the crude product by preparative chromatography on silica gel gives the desired product 7a.

P1250 Example 8 8b. Cis-2- (2-Butylglyoxylamino) -1-cyclohexanecarboxylic acid, 1,7-diphenyl-4-heptylamide: Amine 4c (3.14 g, 8.0 mmol) is dissolved in 100 mL of anhydrous dichloromethane. 2-Butylglyoxylic acid (1.56 g, 12.0 mmol) and i-Pr2NEt (4.2 mL, 24.0 mmol) and then PyBOP (7.3 g, 14.0 mmol) are added. The reaction is stirred for 18 hours at room temperature, then poured into ice cold 0.1 N HCl (100 mL) and extracted with ethyl acetate (150 mL). The phases are separated and the organic phase is washed successively with saturated NaHCO 3 solution (1500 mL) and brine (100 mL). The organic solution is dried over MgSO 4, filtered and concentrated in vacuo. Purification of the product by chromatography on silica gel gives the desired amide 8b.

P1250 Example 9 9a. Magnesium (40.2 g, 1.65 moles) and anhydrous ether (3.2 L) are combined with stirring in a reaction vessel. A solution of l-bromo-3-phenylpropane in 1.6 L of anhydrous ether is added in an addition funnel. The bromide solution is added dropwise to the stirred reaction vessel for 1 hour. At the end of the addition, the mixture is stirred for 1 to 2 hours. A solution of 4-phenylbutyronitrile (160 g, 1.1 mol) in anhydrous ether (2.4 L) is placed in the addition funnel. The solution is added to the reaction vessel for 1 hour. At the end of the addition, the solution is refluxed for 10 hours and then stirred at room temperature for six hours to give a solution of 9a. 9b. 1, 7-diphenyl-4-aminoheptane: Reaction mixture 9a is diluted with methanol (3.2 L) using an addition funnel. Sodium borohydride (83.4 g, 2.2 moles) is added in portions. At the end of the addition, the reaction is stirred at room temperature for six hours. The reaction mixture is stopped by the slow addition of water P1250 (3.2 L). The mixture is diluted with ether (3.2 L) and water (1.6 L). The ether phase is separated and the aqueous phase is extracted twice with ether (3.2 L x 2). The combined ether extracts are washed once with sodium chloride solution, dried, filtered and concentrated in vacuo to give the crude product. The product is diluted with ether (1.2 L) and acidified by the slow addition of 1M HCl (1.2 L). The mixture is stirred for one hour and concentrated in vacuo. The resulting precipitate is diluted with acetonitrile and stirred for 16 hours. The desired 1, 7-diphenyl-4-aminoheptane 9b is collected by filtration.

Use of the Present Compounds The compounds of the present invention can be used for the treatment of conditions such as, for example, treatment of hair loss in mammals, including the arrest and / or reversal of hair loss and the stimulation of hair growth. These conditions are manifested, for example, in alopecia, including male pattern baldness and female pattern baldness. While some of the present compounds may exhibit immunosuppressive activity, the preferred compounds of the present invention are, as defined herein, non-immunosuppressants.

P1250 Moreover, in addition to treating hair loss, the compounds of the present invention can be used to treat a variety of clinical conditions including, but not limited to, multiple drug resistance (in particular, to be used in cancer chemotherapy), neurological and neurodegenerative diseases, cardiac injury associated with ischemia / reperfusion and treatment of diseases or conditions of fungal, microbial, viral (especially HIV), malarial or other diseases or parasitic conditions. The present compounds may also be useful as inhibitors of multi-drug transport proteins to enhance, for example, pharmacokinetics and bioavailability. Certain compounds of the present invention may exhibit immunomodulatory properties. These compounds could prove useful in the treatment of rejection by organ transplantation and various autoimmune diseases including, but not limited to, Behcet's disease, Crohn's disease, systemic lupus erythematosus, psoriasis, rheumatoid arthritis, eczema, multiple sclerosis, myasthenia severe, insulin dependent diabetes mellitus and Graves disease. In addition, the present compounds may be useful for the treatment of certain allergic or inflammatory disease states, among which are included P1250 urticaria, allergic contact dermatitis, atopic dermatitis, atopic keratoconjunctivitis, inflammatory bowel disease and asthma. The present compounds may also be useful in the treatment of cardiac hypertrophy in congestive heart failure. The present compounds can also be used in combination with a matrix metalloproteinase inhibitor, for the treatment of various conditions, including, for example, tissue destructive diseases mediated by excessive metalloproteinase activity, cancer and multiple drug resistance. , as well as all the conditions mentioned above. In particular, preferred matrix metalloproteinase inhibitors, useful in such combinations, include those described in U.S. Patent Application Serial No. 60 / 024,765, Pikul et al. , awarded to The Procter & Gamble Co., filed August 28, 1996, United States Patent Application Series No. 60 / 024,842, Natchus et al. , awarded to The Procter & Gamble Co. , filed August 28, 1996, U.S. Patent Application Series No. 60 / 024,846, Pikul et al. , awarded to The Procter & Gamble Co. , filed August 28, 1996, U.S. Patent Application Serial No. 60 / 024,746, Almstead et al. , awarded to The Procter & P1250 Gamble Co., filed August 28, 1996, U.S. Patent Application Serial No. 60 / 024,830, Pikul et al. , awarded to The Procter & Gamble Co., filed August 28, 1996, United States Patent Application Series No. 60 / 024,764, De et al. , awarded to The Procter & Gamble Co., filed August 28, 1996, United States Patent Application Series No. 60 / 024,764, De et al. , awarded to The Procter & Gamble Co., filed August 28, 1996 and United States Patent Application Series No. 60 / 024,766, Wang et al. , awarded to The Procter & Gamble Co. , filed August 28, 1996. Preferably, the compounds of the present invention are formulated into pharmaceutical compositions for use in the treatment or prophylaxis of conditions such as those mentioned above. Standard pharmaceutical formulation techniques are used, such as those set forth in Remington's Pharmaceutical Sciences. Mack Publishing Company, Easton, PA (1990). Generally, for systemic administration approximately 5 mg to 3000 mg, more preferably approximately 5 mg to 1000 mg, and even more preferably approximately 10 mg to 100 mg of a compound of the present invention are administered per day. It is understood that these dosing intervals are only P1250 exemplars and that the administration can be adjusted depending on several 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 on factors such as the specific compound being used, indication of treatment, efficacy of the compound, personal attributes of the subject (eg, weight, age, sex and medical condition), compliance with the treatment regimen and the presence and severity of any side effect of the treatment. In addition to the specific compound, the compositions of the present invention contain a pharmaceutically acceptable carrier ("vehicle"). The term "pharmaceutically acceptable carrier", in the sense in which it is used herein, refers to one or more solid or liquid fillers, diluent substances, compatible encapsulating substances, which are suitable for administration to a mammal. The term "compatible", in the sense in which it is used herein, refers to the components of the composition that are capable of mixing with a compound of the present invention and with each other, such that there is no interaction that reduce in essence the effectiveness of the composition in situations of P1250 common use. The vehicles must of course have sufficiently high purity and sufficiently low toxicity for their administration to be adequate in animals, preferably mammals, to be treated. The vehicle itself can be inert or have pharmaceutical advantages per se. The compositions of this invention may be presented in a variety of forms, suitable (for example) for oral, topical rectal, nasal, ocular or parenteral administration. Among these, topical or oral administration is especially preferred. Depending on the particular route of administration desired, a variety of pharmaceutically acceptable carriers well known in the art may be used. These include solid or liquid fillers, diluents, hydrotropes, surfactants, and encapsulating substances. Optional pharmaceutically active materials can be included, which almost do not interfere with the activity of the compound of the present invention. The amount of vehicle used together with the compound will be sufficient to provide a practical amount of material for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods of this invention are described in the following references: Modern Pharmaceutics, Chapters 9 and 10, Banker & Rhodes, P1250 eds. (1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms. 2nd Ed., (1976). Some examples of substances that may be useful as pharmaceutically acceptable carriers or components thereof, are sugars such as lactose, glucose and sucrose; starches, for example, 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 theobroma oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol and polyethylene glycol; alginic acid, emulsifiers such as TWEENS, wetting agents such as sodium lauryl sulfate, coloring agents, flavoring agents, tableting agents, stabilizers, antioxidants, preservatives, pyrogen-free water, isotonic saline and buffered phosphate solutions. The choice of a pharmaceutically acceptable carrier to be used in conjunction with the present compound is basically determined by the manner in which the compound is to be administered.

P1250 In particular, pharmaceutically acceptable vehicles for systemic administration include sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, buffered phosphate solutions, emulsifiers, solution Isotonic saline and pyrogen-free water. Preferred vehicles for parenteral administration include propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil. Preferably, the pharmaceutically acceptable carrier, in the compositions for parenteral administration, comprises at least about 90% by weight of the total composition. Various forms of oral dosage can be used, including solid forms such as tablets, capsules, granules and bulk powders. These oral forms comprise a safe and effective amount, generally at least about 5% and preferably between about 25% and 50% of a compound of the present invention. Tablets can be compressed, crushed into tablets, enteric-coated, sugar-coated, film-coated or multicomprimed, containing binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents and melting agents P1250 suitable. 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 solvents, preservatives, emulsifying agents, suspending agents, diluents , sweeteners, fusion agents, coloring agents and suitable flavoring agents. Suitable pharmaceutically acceptable carriers for the preparation of unit dosage forms for oral administration are well known in the art. The tablets generally comprise pharmaceutically compatible adjuvants as inert diluents, for example, calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmellose; lubricants such as magnesium stearate, stearic acid and talc. Sliding agents such as silicon dioxide can be used to improve the flow characteristics of the powder mixture. To modify the appearance, coloring agents such as approved food coloring, pharmaceuticals and cosmetics (FD &C) can be added. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint P1250 and fruit flavors are useful adjuvants for chewable tablets. Capsules (including sustained-release and sustained-release formulations) generally comprise one or more of the solid diluents set forth above. The selection of vehicle components depends on secondary considerations such as taste, costs and shelf stability, which are not critical for the purposes of the present invention and can be easily made by a person skilled in the art. The compositions that are orally administered also include liquid solutions, emulsions, suspensions, powders, granules, elixirs, dyes, syrups and the like. Suitable pharmaceutically acceptable carriers for the preparation of such compositions are well known in the art. Typical vehicle components 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 alginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate. Oral liquid compositions can P1250 also contains one or more components such as sweeteners, flavoring agents and colorants discussed above. Said compositions may also be coated by conventional methods, generally with time or pH dependent coatings, so that the compound of the invention is released in the gastrointestinal tract in the vicinity of the desired topical application or at various times to prolong said action. These dosage forms generally include, but are not limited to, one or more of the following substances: cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragit coating, waxes and shellac. Other compositions useful for achieving systemic delivery of the present compounds include sublingual, buccal and nasal dosage forms. Said compositions generally comprise one or more soluble fillers, such as sucrose, sorbitol and mannitol; and binders such as acacia gum, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. You can also include the. glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents discussed above. The compounds of the present invention also P1250 can be administered topically. The vehicle of the topical composition, preferably helps the penetration of the compounds present in the skin, so that they reach the environment of the hair follicle. The topical compositions of the present invention can be presented in any form, including for example, solutions, creams, ointments, gels, lotions, shampoos, conditioners that remain and conditioners that are rinsed, milks, cleansers, humectants, dews, skin patches and so on. similar. Topical compositions containing the active compound can be mixed with a variety of materials well known in the art, such as, for example, water, alcohols, aloe vera gel (aloe vera), allantoin, glycerin, vitamin A and E oils, mineral oil , propylene glycol, PPG-2 myristyl propionate and the like. Other materials suitable for use in topical vehicles include, for example, emollients, solvents, humectants, thickeners and powders. Examples of each of these types of materials that can be used alone or as mixtures of one or more materials are the following: Emollients, such as stearyl alcohol, glyceryl monothricinoleate, glyceryl monostearate, propane-1,2-diol, butane- 1,3-diol, ermine oil, P1250 cetyl alcohol, iso-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-n-butyl sebacate, iso-propyl myristate, iso-propyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, arachidic oil, castor oil, alcohols of acetylated lanolin, petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate and myristyl myristate; propellants, for example, propane, butane, isobutane, dimethyl ether, carbon dioxide and nitrous oxide; solvents such as ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran; humectants such as glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate and gelatin; and powders such as chalk, talc, Fuller's earth, kaolin, starch, gums, colloidal silicon dioxide, sodium polyacrylate, smectites modified with tetraalkyl ammonium, modified smectites P1250 with trialkyl ammonium, chemically modified magnesium aluminosilicate silicate, organically modified montmorillonite clay, hydrated aluminum silicate, calcined silica, carboxyvinyl polymer, sodium carboxymethyl cellulose and ethylene glycol monostearate. The compounds of the present invention can also be administered in the form of liposome delivery systems, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, for example, cholesterol, stearylamine or phosphatidylcholines. A preferred formulation for topical delivery of the present compounds utilizes liposomes such as those described in Dowton et al., "Influence of Liposomal Composition on Topical Delivery of Encapsulated Cyclosporin A: I. An in vi tro Study Using Hairless Mouse Skin", S.T.P. Pharma Sciences, Vol. 3, pp. 404-407 (1993), Wallach and Philippot, "New Type of Lipid Vesicle: Novasome®", Liposome Technology, Vol. 1, pp. 141-156 (1993) and Wallach. U.S. Patent No. 4,911,928, issued to Micro-Pak, Inc., published March 27, 1990. The compounds of the present invention can also be administered by iontophoresis. See, for example, www.unipr.it/arpa/dipfarm/erasmus/erasml4.html, Banga et P1250 al., "Hydrogel based Iontotherapeutic Delivery Devices for Transdermal Delivery of Peptide / Protein Drugs", Pharm. Res .. Vol 10 (5), pp. 697-702 (1993), Ferry L.L., "Theoretical Model of Ionthophoresis Used in Transdermal Drug Delivery", Pharmaceutical Acta Helvetiae, Vol. 70, pp. 279-287 (1995), Gangarosa et al., "Modern Ionthophoresis for Local Drug Delivery", Int. J. Pharm. , Vol. 123, pp. 159-171 (1995), Green et al., "Ionthophoretic Delivery of a Series of Tripeptides Across the Skin in vitro", Pharm. Res., Vol. 8, pp. 1121-1127 (1991), Jadoul et al., "Quantification and Localization of Fentanyl and TRH Delivered by Ionthophoresis in the Skin", Int. J. Pharm. Vol. 120, p. 221-8 (1995), O'Brien et al., "An Updated Review of its Antiviral Ativity, Pharmacokinetic Properties and Therapeutic Efficacy", Drugs, Vol. 37, pp. 233-309 (1989), Parry et al., "Acyclovir Bioavailability in Human Skin ", J. Invest. Dermatol., Vol. 98 (6), pp. 856-63 (1992), Santi et al., Drug Reservoir Composition and Transport of Salmon Calcitonin in Transdermal Ionthophoresis ", Pharm. Res., Vol. 14 (1), pp. 63-66 (1997), Santi et al., "Reverse Ionthophoresis-Parameters Determining Electroosmotic Flow: I. pH and Ionic Strength ", J. Control. Reread, Vol. 38, pp. 159-165 (1996), Santi et al., "Reverse Ionthophoresis-Parameters Determining Electroosmotic Flow: II Electrode Chamber Formulation", J.

P1250 Control. Reread. Vol. 42, pp. 29-36 (1996), Rao et al., "Reverse Ionthophoresis: Noninvasive Glucose Monitoring in | vivo in Humans ", Pharm. Res., Vol. 12 (12), pp. 1869-1873 (1995), Thysman et al.," Human Calcitonin Delivery in Rats 5 by Ionthophoresis ", J. Pharm. Pharmacol .. Vol 46, pp. 725-730 (1994), Volpato et al., "Ionthophoresis Enhances the Transport of Acyclovir through Nude Mouse Skin by Electrorepulsion and Electroosmosis", Pharm. Res., Vol. 12 (11), pp. 1623- 1627 (1995) The compositions of the present invention optionally can also comprise an activity enhancer.The activity enhancer can be chosen from a wide variety of molecules that can function in different ways to enhance the effects of a compound of the present invention in hair growth. Particular groups of activity enhancers include other hair growth stimulants and penetration enhancers. Stimulants for hair growth Further, one can choose from a wide variety of molecules, which can function in different ways to enhance the effects of a compound of the present invention on hair growth. These other optional hair growth stimulants, when are present, they are usually used in the P1250 compositions here at a level ranging between about 0.01% and 15%, preferably between about 0.1% and 10%, with superlative preference between about 0.5% and 5% by weight of the composition. Vasodilators such as potassium channel agonists, including for example, minoxidil and minoxidil derivatives such as aminexyl and those described in U.S. Patent No. 3,382,247, U.S. Patent No. 5,756,092, issued on May 26, 1998, U.S. Patent No. 5,772,990, issued June 30, 1998, U.S. Patent No. 5,760,043, issued June 2, 1998, U.S. Patent No. 328,914, granted on July 12, 1994, U.S. Patent No. 5,466,694, issued November 14, 1995, U.S. Patent No. 5,438,058, issued August 1, 1995 and U.S. Pat.

United No. 4,973,474, granted on November 27, 1990 (which is considered part of the present reference) and cromakalin and diazoxide can be used as additional hair growth stimulants in the compositions herein. A suitable class of additional hair growth stimulants that are used in the present, are antiandrogens. Examples of Suitable P1250 antiandrogens may include, but are not limited to, 5-a-reductase inhibitors, e.g., finasteride and those described in U.S. Patent No. 5,516,779, ed May 14, 1996 (which is incorporated herein by reference). considered part of this, as a reference) and in Nane et al., Cancer Research 58. "Effects of Some Novel Inhibitors of C17.20-Lyase and 5-a-Reductase in vi tro and in vivo and Their Potential Role in the Treatment of Prostate Cancer ", as well as cyproterone acetate, azelaic acid and its derivatives and the compounds described in U.S. Patent No. 5,480,913, ed January 2, 1996, flutamide and those described in Patent of the United States No. 5,411,981, ed May 2, 1995, United States Patent No. 5,565,467 ed October 15, 1996 and United States Patent No. 4,910,226 ed March 20, 1990, which is considered part of the present, as a ferencia. Another suitable class of additional hair growth stimulants, are immunosuppressants or non-immunosuppressants, for example, 1) cyclosporin and cyclosporin analogs, including those described in United States Provisional Patent Application No. 60 / 122,925, Fulmer et al. , filed on March 5, 1999, which is considered part of the P1250 present, as reference and 2) analogs of FK506 such as those described in United States Provisional Patent Application No. 60 / 147,279, Degenhardt et al. , filed on August 5, 1999; U.S. Provisional Patent Application No. 90 / 147,313, Degenhardt et al. , filed on August 5, 1999; U.S. Provisional Patent Application No. 60 / 147,280, Degenhardt et al. , filed on August 5, 1999; U.S. Provisional Patent Application No. 60 / 147,278, Degenhardt et al. , filed August 5, 1999 and United States Provisional Patent Application No. 60 / 147,276, Eickhoff et al. , filed on August 5, 1999; which is considered part of this, as a reference. Another suitable class of additional hair growth stimulants are antimicrobials such as selenium sulfide, ketoconazole, triclocarbon, triclosan, zinc pyrithione, itraconazole, Asian acid, hinokitiol, mipirocin and those described in EPA 0,680,745 (which is considered to be part of the present, as a reference), clinacicin hydrochloride, benzoyl peroxide, benzyl peroxide and minocycline. Also anti-inflammatories can be incorporated into the compositions here, as stimulants P1250 of optional hair growth. Examples of suitable anti-inflammatories may include glucocorticoids such as hydrocortisone, mometasone furoate and prednisolone, non-steroidal anti-inflammatories including cyclooxygenase and lipoxygenase inhibitors, such as those described in U.S. Patent 5,756,092 and benzydamine, salicylic acid and compounds described 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, which are considered part of this, as reference. Another suitable class of optional hair growth stimulants are thyroid hormones and derivatives and analogs thereof. Examples of suitable thyroid hormones that are used herein may include triiodothyronine. Examples of thyroid hormone analogues that may be suitable for use herein include those described in U.S. Provisional Patent Application No. 60 / 136,996, Zhang et al., Filed June 1. of 1999, United States Provisional Patent Application No. 60 / 137,024, Zhang et al., filed June 1, 1999, United States Provisional Patent Application No. 60 / 137,022, Zhang et al., filed on June 1, 1999, Provisional Patent Application of P1250 United States No. 60 / 137,023, Zhang et al., Filed June 1, 1999, 60 / 137,052, Youngquist et al., Filed June 1, 1999, United States Provisional Patent Application No. 60 / 137,063, Youngquist et al., Filed June 1, 1999, United States Provisional Patent Application No. 60 / 136,958, Youngquist et al., Filed June 1, 1999. Prostaglandin agonists or antagonists. they can also be used as optional hair growth stimulants in the compositions herein. Examples of suitable prostaglandin 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 that are used here are retinoids. Suitable retinoids may include isotretinoin, acitretin and tazarotene. Another class of optional hair growth stimulants that are used herein are triterpenes, for example, those described in Bradbury et al., United States Patent Application.

P1250 Series No. 09 / 353,408"Method for Regulating Hair Growth", filed July 15, 1999 and Bradbury et al., United States Patent Application Series No. 09 / 353,409. "Compositions which Contain Triterpenes for Regulating Hair Growth" presented on July 15, 1999, which in its entirety is considered part of this, as a reference. Another class of optional hair growth stimulants used herein includes flavinoids, ascomycin derivatives and analogues, histamine antagonists such as phenhydramine hydrochloride, other triterpenes such as oleanolic acid and usrsolic acid and those described in U.S. Patent No. 5,529,769, JP 10017431, WO 95/35103, U.S. Patent No. 5,468,888, JP 09067253, WO 92/09262, JP 62093215, U.S. Patent No. 5,631,282, U.S. Patent No. 5,679,705, JP 08193094, saponins such as those described in EP 0,558,509 of Bonte et al., Published September 8, 1993 and WO 97/01346 of Bonte et al., Published January 16, 1997 (the which in its entirety is considered part of the present, as reference), proteoglycanase or glycosaminoglycanase inhibitors such as those described in U.S. Patent No. 5,015,470, issued May 14, 1991, Patent of the P1250 United States No. 5,300,284, issued April 5, 1994 and United States Patent No. 5,185,325, issued February 9, 1993 (all of which are considered hereby, by reference), estrogen agonists and antagonists, pseudoterines, promoters, analogs or inhibitors of cytokine and growth factors, for example, interleukin-1 inhibitors, interleukin-6 inhibitors, interleukin-10 promoters and tumor necrosis factor inhibitors, vitamins such as vitamin D and parathyroid hormone antagonists, analogs of vitamin B12 and panthenol, interferon agonists and antagonists, hydroxy acids such as those described in U.S. Patent No. 5,550,158, benzophenones and hydantoin anticonvulsants such as phenytoin. Other additional hair growth stimulants are described in detail, for example, in JP 09-157,139 of Tsuji et al., Published June 17, 1997; EP 0277455 Al de Mirabeau, published on August 10, 1988; WO 97/05887 of 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 No. 4,987,150 to Kurono et al., Issued on 22 P1250 January 1991; JP 290811 to Ohba et al., Published October 15, 1992; JP 05-286,835 of Tanaka et al., Published on November 2, 1993, FR 2,723,313 of Greff, published on August 2, 1994, United States Patent No. 5,015,470 of Gibson, issued May 14, 1991, Patent of the United States NO. 5,559,092, issued September 24, 1996, U.S. Patent No. 5,536,751 issued July 16, 1996, U.S. Patent No. 5,714,515 issued February 3, 1998, EPA 0,319,991, published June 14. of 1989, EPA 0,357,630 published October 6, 1998, EPA 0,573,253 published December 8, 1993, JP 61-260010, published November 18, 1986, United States Patent No. 5,772,990, issued June 30 of 1998, U.S. Patent No. 5,053,410, issued October 1, 1991 and U.S. Patent No. 4,761,401, issued August 2, 1988, which are considered part of this, as a reference. Non-limiting examples of penetration enhancers that can be used in the compositions herein include, for example, 2-methyl propan-2-ol, propan-2-ol, ethyl 2-hydroxypropanoate, hexan-2, 5-diol , ethyl ether POE (2), di (2-hydroxypropyl) ether, pentane-2,4-diol, acetone, methyl ether POE (2), 2-hydroxypropionic acid, 2-hydroxyoctanoic acid, propan-1-ol, P1250 1,4-dioxane, tetrahydrofuran, butan-1,4-diol, propylene glycol dipelargonate, polyoxypropylene 15 stearyl ether, octyl alcohol, POE ester of oleyl alcohol, oleyl alcohol, lauryl alcohol, dioctyl adipate, dicapryl adipate, diisopropyl adipate, diisopropyl sebacate, dibutyl sebacate, diethyl sebacate, dimethyl sebacate, dioctyl sebacate, dibutyl suberate, dioctyl azelate, dibenzyl sebacate, dibutyl phthalate, dibutyl azelate, ethyl myristate, azelate dimethyl, butyl myristate, dibutyl succinate, didecyl phthalate, decyl oleate, ethyl caproate, ethyl salicylate, isopropyl palmitate, ethyl laurate, 2-ethylhexyl pelargonate, isopropyl isostearate, butyl laurate, benzoate of benzyl, butyl benzoate, hexyl laurate, ethyl caprate, ethyl caprylate, butyl stearate, benzyl salicylate, 2-hydroxypropanoic acid, 2-hydroxyoctanoic acid, sulphoxy of dimethyl, N, N-dimethyl acetamide, N, N-dimethylformamide, 2-pyrrolidone, 1-methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone, 1,5-dimethyl-2-pyrrolidone, l-ethyl -2-pyrrolidone, phosphine oxides, sugar esters, tetrahydrofurfuryl alcohol, urea, diethyl-m-toluamide and l-dodecylazacycloheptan-2-one. In all of the above mentioned, of course the compounds of the invention can be administered alone or P1250 as mixtures and compositions may further include additional drugs or excipients, as appropriate for the indication.

Examples of Compositions The following examples of compositions and methods do not limit the invention, but provide a guide for experienced technicians to prepare and use the compounds, compositions and methods of the invention. In each example, a compound of the present invention can be substituted with another compound than that mentioned in the example and similar results are obtained.

Example A A tablet is prepared for oral administration according to the present invention, comprising: A human subject with a weight of 60 kg (132 lbs), who suffers from rheumatoid arthritis, P1250 deals with the method of this invention. Specifically, for two years, the subject is administered orally a regimen of three tablets per day, of the previous composition.

Example B A male human subject, suffering from male pattern baldness, is treated with the method of this invention. Specifically, for 6 weeks, every day, the subject is administered topically to the above composition.

Example C A composition for topical administration according to the present invention is prepared according to the method of Dowton et al., "Influence of Liposomal Compositions 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 P1250 composed of Example 4 in place of cyclosporin A and using Novasome 1 for the nonionic liposomal formulation. A male human subject, suffering from baldness with male pattern, is treated every day with the previous composition. Specifically, for 6 weeks, the above composition is administered to the subject topically.

Example D According to the present invention, a shampoo is prepared, comprising: P1250 P1250

Claims (10)

1. CLAIMS: A compound characterized by the structure: and salts, hydrates and amides, esters and biohydrolyzable imides thereof, pharmaceutically acceptable, wherein: a) Z is a carbocycle or heterocycle of 4, 5, 6, 7, 8 or 9 members, saturated or unsaturated, wherein the heterocycle contains one or more heteroatoms selected from O, N, S, S (O), S (02) and P ((0) 0K); (b) V is -CU-, wherein U is selected from hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl and heteroarylalkenyl; (c) G is selected from the group consisting of nothing, O, S and NR17; (d) K is selected from the group consisting of P1250 hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl and heteroarylalkenyl; (e) Ri is selected from the group consisting of alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl and heteroarylalkenyl; (f) W is selected from the group consisting of nothing, hydrogen and alkyl groups of 1 to 6 carbon atoms; (g) A is selected from the group consisting of nothing and alkyl; (h) X and Y independently are each selected from the group consisting of C (O), P (O), N, O and S where: (i) when X is C (O) then R3 is nothing and Y it is selected from the group consisting of N, O and S; (ii) when X is P (O) then R3 is nothing and Y is selected from the group consisting of N and O; (iii) when X is N then R3 is selected from hydrogen, alkyl and arylalkyl, and Y is selected from the group consisting of C (0) and P (O) and R2 is nil; (iv) when X is O then R3 is nothing, and is selected from the group consisting of C (O) and P (0) and R2 is P1250 nothing; and (v) when X is S then R3 is nothing, Y is C (O) and R2 is nothing; (f) R2 and R3 independently are each selected from the group consisting of hydrogen, alkyl, and arylalkyl; (g) R4 is alkyl; (h) R5 and R6 independently are each selected from the group consisting of nothing, hydrogen, alkyl having at least two carbon atoms, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl and heteroarylalkenyl; or wherein R5 and R6 are joined to form a carbocyclic or heterocyclic ring; wherein at least one of R5 and R6 is nothing or hydrogen; (i) R7, R8, R9 and Rio independently are each selected from the group consisting of hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, halo, cyano, hydroxyl, oxo, imino, -R? 4SR15, -R? 4S (02) R? 5, -R14S (0) Ri5, -R? 4C (0) R? 5, -R14C (0) NR? 5R? 6, - R14C (O) 0R? 5, -R14OR15, -R? 4NR? 5Ri6, Ri4P (0) NR? 5R? 6, -Ri4P (O) OR? 5R? 6 and a spiro unit and wherein R7 and R8 can optionally be joined to form a carbocyclic or heterocyclic, aromatic or P1250 saturated, where the rings fuse to form Z; (j) Ri4 is selected from the group consisting of nothing, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl and heteroarylalkenyl; (k) R15 is selected from the group consisting of hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl and heteroarylalkenyl; and (n) Ri6 and R? independently, each is selected from the group consisting of hydrogen and alkyl.
2. 2. A compound according to claim 1, wherein Z is a carbocycle or a 5-, 6- or 7-membered heterocycle.
3. 3. A compound according to any of the preceding claims, wherein Z is a carbocycle or a 5-membered heterocycle.
4. 4. A compound according to any of claims 1 or 2, wherein Z is a 6-membered carbocycle or heterocycle.
5. A compound according to any of the preceding claims, wherein G is -NH-, A is nothing, X is C (O), Y is N and R2 is hydrogen.
6. 6. A compound according to any of the P1250 preceding claims, wherein R8, R9 and Rio independently each is selected from the group consisting of nothing and hydrogen.
7. 7. A compound according to any one of claims 1, 2, 3, 4 or 5, wherein R7 and R8 are joined to form a carbocyclic or heterocyclic ring of 5, 6 or 7 members which is fused with Z.
8. 8. A composition which is characterized by a compound according to any of the preceding claims and a pharmaceutically acceptable carrier.
9. 9. The use of a compound according to any of claims 1, 2, 3, 4, 5, 6 or 7, in the manufacture of a composition for treating hair loss. The use of a compound according to any of claims 1, 2, 3, 4, 5, 6 or 7, in the manufacture of a composition for treating or preventing multiple drug resistance. P1250