WO2007111993A2 - Polyamine analogs as therapeutic agents for skin diseases - Google Patents

Abstract

This disclosure relates to methods of treating atopic dermatitis, contact dermatitis, psoriasis, and certain other skin diseases using polyamine analogs. Conformationally restricted polyamine analogs are particularly useful in treating atopic dermatitis, contact dermatitis, and psoriasis.

Description

POLYAMINE ANALOGS AS THERAPEUTIC AGENTS FOR SKIN

DISEASES

CROSS REFERENCE TO RELATED APPLICATIONS

[001] This application claims priority benefit of U.S. Provisional Application

No. 60/785,051, filed March 22, 2006. The entire content of that application is hereby incorporated by reference herein.

TECHNICAL FIELD

{002] This application relates to methods of treating skin diseases, such as atopic dermatitis and psoriasis, using polyamine analogs, particularly conformationally restricted polyamine analogs and oligoamines.

BACKGROUND

[003] Skin diseases such as contact hypersensitivity, atopic dermatitis, and psoriasis are characterized by hyperproliferative and inflammatory skin reactions. A large population suffers from these diseases. For example, atopic dermatitis, a hereditary chronic disease of the skin, affects approximately 8 million adults and children in the United States. It is believed that a combination of multiple factors including genetic, environmental, and immunological factors may cause skin diseases. Although most skin diseases are not fatal, they significantly affect quality of life of those who suffer from the diseases.

[004] Commonly used steroid-containing ointment or anti-histamine agents for treating skin diseases frequently cause considerable side effects. For example, steroids of external or oral application make the skin layer thin, cause osteoporosis, and inhibit growth in children upon long-term use. It was also observed that the termination of steroid application is often followed by lesion recurrence. There is therefore a need to develop non-steroid agents for treating skin diseases. The current invention provides alternative methods of treating certain skin diseases. [005] Polyamines and analogs and their uses thereof have been described in

US 4,112,067, US 4,160,819, US 4,507,321, US 5,952,067, US 2003/0118539, US 2005/0043366, WO 96/23490, WO 99/51213, and WO 03/13245. [006] Conformationally-restricted polyamine analogs and methods of synthesizing such analogs have been disclosed in U.S Patent Nos. 5,889,061, 6,392,098, and 6,794,545, United States Patent Application Publication

Nos.2003/0072715, 2003/0195377, and International Patent Applications

WO 98/17624, WO 00/66587, WO 02/10142, and WO 03/050072. These compounds have been shown to have anti-cancer effects in vitro or in vivo.

[007] Oligoamines, defined as a non-conformationally restricted polyamine analog having 6 or more nitrogens, and methods of synthesizing oligoamines have been disclosed in US 2003/0130356, WO 03/033455, and Valasinas et al., Bioorg.

Med. Chem. 11:4121 (2003).

[008] The disclosures of all publications, patents, patent applications and published patent applications referred to herein are hereby incorporated herein by reference in their entirety.

SUMMARY OF THE INVENTION

[009] The present invention provides methods of treating skin diseases, particularly a skin disease that is any of (or, in some embodiments, selected from the group consisting of) atopic dermatitis, neurodermatitis, allergic contact dermatitis, drug-related eczematous dermatitis, seborrheic dermatitis, stasis dermatitis, perioral dermatitis, and psoriasis, comprising administering a conformational^ restricted polyamine analog or an oligoamine, or any salt, hydrate, solvate or stereoisomer thereof, to a subject in need of in an amount sufficient to have a therapeutic effect on the skin disease. In some aspects, methods of treating chronic skin diseases and/or endogenous skin diseases are provided. In some embodiments, the skin disease is atopic dermatitis. In some embodiments, the skin disease is allergic contact dermatitis. In some embodiments, the skin disease is psoriasis. In some embodiments, the skin disease is any of (and in some embodiments selected from the group consisting of) psoriasis vulgaris, guttate psoriasis, flexural psoriasis, erythrodermic psoriasis, pustular psoriasis, flaking eczema, psoriasis pustulosa, psoriasis arthropatica, and psoriatic erythroderma. In some embodiments, the skin disease is not radiation-induced dermatitis.

[010] In some embodiments, the method comprises administering a conformationally restricted polyamine having the formula: [011] R₁-NH-R₂-NH-R₃-R₄-R₃-NH-R₂-NH-Ri,

[012] wherein each Ri is independently selected from Ci-Cβ alkyl; each R₂ is independently selected from C₃-Ce alkyl; each R₃ is independently selected from Ci- Cβ alkyl; and R₄ is independently selected from C₂-C6 alkenyl, C3-C6 cycloalkyl, Cr Cβ cycloalkenyl, or C3-C6 aryl, and all salts, hydrates, solvates, and stereoisomers thereof. In some embodiments each R₂ is independently selected from C₃-C₄ alkyl. In some embodiments each R₂ is a C3 alkyl. In some embodiments each R₂ is a C₄ alkyl. In some embodiments each Ri is a C₂ alkyl.

[013] In some embodiments the method comprises administering a conformational^ restricted polyamine having the formula:

and all stereoisomers, salts, hydrates, and solvates thereof.

[014] In one embodiment, the conformational^ restricted polyamine analog is selected from among compounds of the formula: E-NH-B-A-B-NH-B-A-B-NH-B-A-B-NH-B-A-B-NH-E where A is independently selected from the group consisting of C]-Ce alkyl, C₂-C₆ alkenyl, C₂-Ce alkynyl, C3-C6 cycloalkyl, C3-C6 cycloaryl, and C3-C6 cycloalkenyl; B is independently selected from the group consisting of: a single bond, Ci -C₆ alkyl, and Cz-Ce alkenyl; and E is independently selected from the group consisting of H, Ci-Ce alkyl, C₂-Ce alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, CrCβ cycloaryl, and C₃-C₆ cycloalkenyl; with the proviso that either at least one A moiety is selected from the group consisting of C₂-C₆ alkenyl, C₂-Ce alkynyl, C3-C6 cycloalkyl, C3-C₆ cycloaryl, and C3-C6 cycloalkenyl, or at least one B moiety is selected from the group consisting OfC₂-Ce alkenyl; and all salts, hydrates, solvates, and stereoisomers thereof. In one embodiment, the only conformational restriction of the polyamine analog is due to a carbon-carbon double bond (an etheπyl group, C=C) in the molecule. In another embodiment, the only conformational restriction of the polyamine analog is due to a cycloalkyl group, such as a cyclopropyl group, in the molecule.

[015] Specific embodiments of compounds of this type include

and all salts, hydrates, solvates, and stereoisomers thereof.

[016] In another embodiment, the conformationally restricted polyamine analog is selected from among the group of compounds of the formula: E-NH-B-A-B-NH-B-A-B-NH-B-A-B-NH(-B-A-B-NH)_X-E wherein A is independently selected from the group consisting of Ci-Cβ alkyl, C₂-C₆ alkenyl, C2-C₆ alkynyl, C3-C6 cycloalkyl, C3-C6 cycloaryl, and C₃-CO cycloalkenyl; B is independently selected from the group consisting of a single bond,

alkyl, and C₂-C6 alkenyl; E is independently selected from the group consisting of H, C]-C_O alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloaryl, and C3-C₆ cycloalkenyl; and x is an integer from 2 to 16; with the proviso that either at least one A moiety is selected from the group consisting of C₂-Ce alkenyl, C2-C₆ alkynyl, C₃-Ce cycloalkyl, C3-C6 cycloaryl, and C3-Q cycloalkenyl, or at least one B moiety is selected from the group consisting of C2-Q alkenyl; and all salts, hydrates, solvates, and stereoisomers thereof. In another embodiment, x is 4, 6, 8, or 10. In another embodiment, x is 4. In another embodiment, x is 6. In another embodiment, x is 8. In another embodiment, x is 10. In one embodiment, the only conformational restriction of the polyamine analog is due to a carbon-carbon double bond (an ethenyl group, C=C) in the molecule. In another embodiment, the only conformational restriction of the polyamine analog is due to a cycJoalkyl group, such as a cyclopropyl group, in the molecule.

[017] In some embodiments, the method comprises administering a conformationally restricted polyamine analog selected from the group consisting of

and

and all salts, hydrates, and solvates thereof.

[018] In some embodiments, the method comprises administering an oligoamine having the formula: CHsCH₂NH-(R-NH)_n-CEbCHb, wherein each R is independently selected from group consisting a C₂-C₆ alkyl; and n is an integer from S to 14, and all salts, hydrates, solvates, and stereoisomers thereof. In another embodiment, n is an integer from 6 to 14. In some embodiments n is an integer from

7 to 13. In some embodiments n is any of 7, 9, 11, or 13.

[019] In some embodiments, the method comprises administering an oligoamine having the formula: CH₃CH₂NH-(CH₂CH₂CH₂CH₂NH)_n-CH₂CH₃, wherein n is an integer from 5 to 14, and all salts, hydrates, solvates, and stereoisomers thereof. In another embodiment, n is an integer from 6 to 14. In some embodiments n is an integer from 7 to 13. In some embodiments n is any of 7, 9, 11, or 13.

[020] In some embodiments, the method comprises administering an oligoamine, wherein the oligoamine is

H_λ

H ^ ' 9

and all salts, hydrates, and solvates thereof.

[021] In some embodiments, the conformationally restricted polyamine analog or oligoamine is administered topically. In some embodiments, the conformationally restricted polyamine analog or oligoamine is administered in the form of solutions, ointments, creams, lotions, suspensions, aerosols, gels, powders, impregnated bandages, impregnated dressings, emulsions, or sotids. In some embodiments, the conformationally restricted polyamine analog or oligoamine is administered in the form of solutions. In some embodiments, the conformationally restricted polyamine analog or oligoamine is administered in the form of ointments. In some embodiments, the conformationally restricted polyamine analog or oligoamine is administered in the form of creams. In some embodiments, the conformationally restricted polyamine analog or oligoamine is administered in the form of lotions.

[022] In some embodiments, the conformationally restricted polyamine analog or oligoamine is administered with a pharmaceutically acceptable carrier comprising one or more of aqueous systems, glycerins, Ci_-4 alcohols, fatty alcohols, fatty ethers, fatty esters, polyols, glycols, vegetable oils, mineral oils, liposomes, gelatins, gums, petrolatum, laminar lipid materials, silicone oils, water or any combinations thereof. In some embodiments, the conformationally restricted polyamine analog or oligoamine is administered with a pharmaceutically acceptable carrier comprising an aqueous system. In some embodiments, the conformationally restricted polyamine analog or oligoamine is administered with a pharmaceutically acceptable carrier comprising water. BRIEF DESCRIPTION OF THE FIGURES

[023J Figure 1 shows the effect of treatment with CGC-11159 on the average ear thickness, following application of sensitizing agent, in DTH mouse models. The X-axis represents days after sensitization. The Y-axis represents average ear thickness. Dex refers to dexamethasone. On day 9, data points for ear thickness for dexamethasone (circle) and 10 μM TA (10 μM CGC-11159) (diamond) treatments are virtually coincident, while the data point for Elidel® (square box) has a higher thickness; the remaining data points at day 9, in order of increasing ear thickness, are 1 μM TA (1 μM CGC-11159), no treatment, and H₂O.

[024] Figures 2A-2B show the effect of treatment with CGC-11159 (Figure

2A) and 11093 (Figure 2B) on skin erythema following application of sensitizing agent. The X-axis represents days after sensitization. The Y-axis represents average erythema rating.

[025] Figures 3 A-3B show the effect of treatment with CGC- 11159 (Figure

3A) and 11093 (Figure 3B) on skin edema following application of sensitizing agent. The X-axis represents days after sensitization. The Y-axis represents average edema scores.

SUMMARY OF THE INVENTION

[026] In one aspect, there is provided methods of treating a skin disease selected from the group consisting of (or, in some embodiments, any one or more of) atopic dermatitis, neurodermatitis, allergic contact dermatitis, drug-related eczematous dermatitis, seborrheic dermatitis, stasis dermatitis, perioral dermatitis, and psoriasis, comprising administering a conformationally restricted polyamine analog or an oligoamine to a subject in need of in an amount sufficient to have a therapeutic effect on the skin disease. The invention contemplates treatment of any of the skin diseases described herein. In some aspects, methods of treating chronic skin diseases and/or endogenous skin diseases are provided. In some embodiments, the skin disease is not radiation-induced dermatitis.

[027] In some embodiments, the method comprises administering a conformationally restricted polyamine having the formula: [028] R₁-NH-R₂-NH-R₃-R₄-R₃-NH-R_Z-NH-RI,

[029J wherein each R₁ is independently selected from Ci-Ce alkyl; each R₂ is independently selected from C3-C6 alkyl; each R3 is independently selected from Ci-

C₆ alkyl; and R4 is independently selected from C2-C6 alkenyl, C3-C6 cycloalkyl, Cj-

Ce cycloalkenyl, or C3-C6 aryl, and all salts, hydrates, solvates, and stereoisomers thereof. In some embodiments each R2 is independently selected from C₃-C4 alkyl.

In some embodiments each R₂ is a C₃ alkyl. In some embodiments each R₂ is a C₄ alkyl. In some embodiments each Ri is C₂ alkyl.

[030] In some embodiments the method comprises administering a conformational Iy restricted polyamine having the formula:

and all stereoisomers, salts, hydrates, and solvates thereof.

[031] In one embodiment, the conformational^ restricted polyamine analog is selected from among compounds of the formula: E-NH-B-A-B-NH-B-A-B-NH-B-A-B-NH-B-A-B-NH-E where A is independently selected from the group consisting of Ci-Ce alkyl, C₂-C6 alkenyl, C₂-Ce alkynyl, C₃-C₆ cycloalkyl, C₃-C6 cycloaryl, and C₃-C6 cycloalkenyl; B is independently selected from the group consisting of: a single bond, Q-C₆ alkyl, and C₂-Ce alkenyl; and E is independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-Ce alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C3-C6 cycloaryl, and C3-C₆ cycloalkenyl; with the proviso that either at least one A moiety is selected from the group consisting OfC₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, Cj-C₆ cycloaryl, and C₃-C₆ cycloalkenyl, or at least one B moiety is selected from the group consisting OfCa-C₆ alkenyl; and all salts, hydrates, solvates, and stereoisomers thereof. In one embodiment, the only conformational restriction of the polyamine analog is due to a carbon-carbon double bond (an ethenyl group, C=C) in the molecule. In another embodiment, the only conformational restriction of the polyamine analog is due to a cycloalkyl group, such as a cyclopropyl group, in the molecule. [032] Specific embodiments of compounds of this type include

and all salts, hydrates, solvates, and stereoisomers thereof.

[033] In another embodiment, the conformationally restricted polyamine analog is selected from among the group of compounds of the formula: E-NH-B-A-B-NH-B-A-B-NH-B-A-B-NHC-B-A-B-NHK-E wherein A is independently selected from the group consisting of Ci-Ce alkyl, C₂-C₆ alkenyl, C2-C6 alkynyl, C₃-Ce cycloalkyl, C3-C6 cycloaryl, and C3-C6 cycloalkenyl; B is independently selected from the group consisting of a single bond, Ci-Cβ alkyl, and C₂-C₆ alkenyl; E is independently selected from the group consisting of H, Ci-C_δ alkyl, C₂-C6 alkenyl, C2-C6 alkynyl, C3-C0 cycloalkyl, C3-C6 cycloaryl, and C₃-C₆ cycloalkenyl; and x is an integer from 2 to 16; with the proviso that either at least one A moiety is selected from the group consisting of C2-C6 alkenyl, C₂-Cg alkynyl, C₃-C₆ cycloalkyl, C₃-C6 cycloaryl, and C3-C6 cycloalkenyl, or at least one B moiety is selected from the group consisting of C₂-C₆ alkenyl; and all salts, hydrates, solvates, and stereoisomers thereof. In another embodiment, x is 4, 6, 8, or 10. In another embodiment, x is 4. In another embodiment, x is 6. In another embodiment, x is 8. In another embodiment, x is 10. In one embodiment, the only conformational restriction of the polyamine analog is due to a carbon-carbon double bond (an ethenyl group, C=C) in the molecule. In another embodiment, the only conformational restriction of the polyamine analog is due to a cycloalkyl group, such as a cyclopropyl group, in the molecule.

[034] In some embodiments, the method comprises administering a conformationally restricted polyamine analog selected from the group consisting of

and

and all salts, hydrates, and solvates thereof.

[035] In some embodiments, the method comprises administering an oligoamine having the formula: CH₃CH₂NH-(R-NH)_n-CH₂CH₃, wherein each R is independently selected from group consisting a C₂-Ce alkyl; and n is an integer from 5 to 14, and all salts, hydrates, solvates, and stereoisomers thereof. In another embodiment, n is an integer from 6 to 14. In some embodiments n is an integer from

7 to 13. In some embodiments n is any of 7, 9, 11, or 13.

[036] In some embodiments, the method comprises administering an oligoamine having the formula: CH₃CH₂NH-(CH₂CH₂CH₂CH₂NH)_n-CH₂CH₃, wherein n is an integer from 5 to 14, and all salts, hydrates, solvates, and stereoisomers thereof. In another embodiment, n is an integer from 6 to 14. In some embodiments n is an integer from 7 to 13. In some embodiments n is any of 7, 9, 11, or 13.

[037] In some embodiments, the method comprises administering an oligoamine, wherein the oligoamine is

and all salts, hydrates, and solvates thereof.

[038] The polyamine analogs described herein can be administered via a variety of routes, including, for example, topical administration. When administered topically, the polyamine analog can be administered in various forms including, but not limited to, solutions (such as aqueous solutions), ointment, creams, lotions, suspensions, aerosols, gels, powders, impregnated bandages, impregnated dressings, emulsions, solids, and the like.

[039] The methods described herein are useful for treatment of atopic dermatitis. In some embodiments, the methods are useful for treatment of neurodermatitis. In some embodiments, the methods are useful for treatment of allergic contact dermatitis. In some embodiments, the methods are useful for treating drug-related eczematous dermatitis, seborrheic dermatitis, stasis dermatitis, and/or perioral dermatitis.

[040] In some embodiments, the method is useful for the treatment of psoriasis, including, but not limited to, psoriasis vulgaris, guttate psoriasis, flexural psoriasis, erythrodermic psoriasis, pustular psoriasis, flaking eczema, psoriasis pustulosa, psoriasis arthropatica, and psoriatic erythroderma. DETAILED DESCRIPTION OF THE INVENTION

[041] The present invention provides methods of treating a skin disease (such as atopic dermatitis or psoriasis) by administering (such as administering topically) conformationally restricted polyamine analogs or oligoamines (collectively referred to herein as "polyamine analogs") to a subject in need of in an amount sufficient to have a therapeutic effect on the skin diseases.

[042] "Treating" or "to treat" a skin disease using methods of the invention is defined as administering one or more polyamine analogs, with or without additional therapeutic agents, in order to palliate, ameliorate, stabilize, reverse, slow, delay, reduce, or eliminate either the skin disease or one or more symptoms of the skin disease, such as symptom(s) associated with inflammation or allergic reactions of the skin. "Treating" or "to treat" a skin diseases also encompasses reducing frequency of occurrence and/or preventing, delaying, or reducing frequency of recurrence of the skin disease or one or more symptoms of the skin disease, such as symptoms associated with inflammation or allergic reactions of the skin. A "therapeutically effective amount" or "an amount sufficient to have a therapeutic effect" is an amount sufficient to treat a skin disease, as defined above. An effective amount can be administered in one or more administrations.

[043] To "prevent" a skin disease using methods of the invention is defined as administering one or more polyamine analogs, with or without additional therapeutic agents, in order to suppress the skin disease or one or more symptoms of the skin disease, such as symptom(s) associated with inflammation or allergic reactions of the skin, prior to onset of the disease. Prevention can be partial or total. [044] As used herein, the singular form "a", "an", and "the" includes plural references unless indicated otherwise. For example, "an" antibody includes one or more antibodies.

[045] The term "subject," used interchangeably with "individual," includes any of vertebrates, mammals, and humans. In some embodiments, the subject is a mammal, including, but not limited to, human, bovine, horse, feline, canine, rodent, or primate. In some embodiments, the subject is human. [046] It is understood that aspect and embodiments of the invention described herein include "consisting" and/or "consisting essentially of aspects and embodiments. [047] The invention includes the use of all of the compounds described herein or incorporated by reference herein, including any and all stereoisomers, salts, hydrates and solvates of the compounds described herein or incorporated by reference herein. The invention also includes the use of all compounds described herein or incorporated by reference herein in their non-salt (free base) form. The invention also includes the use of all compounds described herein or incorporated by reference herein in their non-salt, non-hydrate/non-solvate form. Particularly preferred are pharmaceutically acceptable salts. Pharmaceutically acceptable salts are those salts which retain the biological activity of the free bases and which are not biologically or otherwise undesirable. The desired salt may be prepared by methods known to those of skill in the art by treating the compound with an acid. Examples of inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of organic acids include, but are not limited to, formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, sulfonic acids, and salicylic acid. Salts of the compounds with amino acids, such as aspartate salts and glutamate salts, can also be prepared.

[048] The invention also includes all stereoisomers of the compounds, including diastereomers and enantiomers, as well as mixtures of stereoisomers, including, but not limited to, racemic mixtures. Unless stereochemistry is explicitly indicated in a structure, the structure is intended to embrace all possible stereoisomers of the compound depicted.

[049] The invention also includes all crystalline and non-crystalline forms of the compounds, including all polymorphs of the compounds.

[050] When the language "any salt, hydrate, solvate, or stereoisomer thereof or "all salts, hydrates, solvates, or stereoisomers thereof is used, the language is intended to apply to all items previously enumerated. For example, in the phrase "polyamine analogs, oligoamines, or any salt, hydrate, solvate, or stereoisomer thereof," salts, hydrates, solvates and stereoisomers of both polyamine analogs and oligoamines are intended. Conformationally restricted poly amine analogs and oligoamines [051] The methods described herein comprise administration of one or more polyamine analogs, specifically, conformationally restricted polyamine analogs and oligoamines.

[052] By a "polyamine", a term well-understood in the art, is meant any of a group of naturally occurring, aliphatic, straight-chain amines. Examples of polyamines are spermine, spermidine, and putrescine. Natural polyamines are typically derived biosynthetically from amino acids; polyamines are reviewed in Marton et al. (1995) Ann. Rev. Pharm. Toxicol. 35:55-91. By "polyamine analog" is meant an organic cation structurally similar but non-identical to naturally occurring polyamines, that is, a polyamine analog is a non-naturally-occurring aliphatic amine having at least two amino groups. Polyamine analogs can also incorporate alicyclic or aromatic groups; certain polyamine analogs may form macrocyclic rings. Polyamine analogs can be branched or un-branched. Polyamine analogs include, but are not limited to, BE-4444 [\,\9-bis (ethylamino)-5,10,15-triazanonadecane]; BE-333 [NIjNl 1-diethylnorspermine; DENSPM; 1,1 l-bis (ethylamino)-4,8-diazaundecane; thermine; Warner-Parke-Davis]; BE-33 [Nl,N7-Z>Hr(ethyl) norspermidine]; BE-34 [Nl,N8-έw(ethyl) spermidine]; BE-44 [N l,N9-i/-f (ethyl) homospermidine]; BE-343 [Nl,N12-όw(ethyl) spermine; diethylspermine-Nl-N12; DESPM]; BE-373 [N,N'-δw (3-ethylamino) propyl)- 1,7-heptane diamine, Merrell-Dow]; BE-444 [N1,N14- Ms(ethyl) homospermine; diethylhomospermine-Nl-N14]; BE-3443 [1,17- 6w(ethylamino)-4,9,14-triazaheptadecane]; and BE-4334 [ l,\7-b w(ethy lam ino)- 5,9,13-triazaheptadecane]; I,12-Me₂-SPM [1,12-dimethylspermine]. See also Feuerstein et al. (1991); Gosule et al. (1978) J. MoI. Biol. 121:311-326; Behe et al. (1981) Proc. Natl. Acad. ScL USA 78:1619-23; Jain et al. (1989) Biochem. 28:2360- 2364; Basu et al. (1990) Biochem. J. 269:329-334; Porter et al. (1988), Advances in Enzyme Regulation, Pergamon Press, pp. 57-79; Frydman et al. (1992) Proc. Natl. Acad. ScL USA 89:9186-9191 ; and Fernandez et al. (1994) Cell MoI Biol. 40: 933- 944.

[053] By "conformationally restricted polyamine analog" is meant that, in a polyamine analog, at least two amino groups in the molecule are locked or limited in spatial configuration relative to each other. The amino groups within the molecule may be primary, secondary, tertiary, or quaternary, and are preferably primary or secondary amino groups, more preferably secondary amino groups. The relative movement of two amino groups can be restricted, for example, by incorporation of a cyclic or unsaturated moiety between them (exemplified, but not limited to, a ring, such as a three-carbon ring, four-carbon ring, five-carbon-ring, six-carbon ring, or a double or triple bond, such as a double or triple carbon bond). Polyamines can also be constrained by incorporation of two or more amino groups into a macrocyclic structure. Groups restricting conformational flexibility by means of steric hindrance, yet favorable to the therapeutic effects of the compound, can also be used. A conformationally restricted polyamine analog can comprise at least two amino groups which are conformationally restricted relative to each other; a conformationally restricted polyamine analog can also further comprise amino groups which are not conformationally restricted relative to other amino groups. Flexible molecules such as spermine and BE-444 can have a myriad of conformations and are therefore not conformationally restricted. Conformationally restricted polyamine analogs include, but are not limited to, the compounds disclosed in International Patent Application WO 98/17624, U.S. Patent No. 5,889,061, and U.S. Patent No. 6,392,098; the compounds disclosed in WO 00/66587 and U.S. Patent No. 6,794,545; and the compounds disclosed in United States Patent Application Publication Nos. 2003/0072715, 2003/0195377, and International Patent Applications WO 02/10142, and WO 03/050072. Several of these compounds are depicted below in Table 1. All of the polyamine analog compounds (both conformationally restricted polyamine analog compounds and non-conformatkmally restricted polyamine analog compounds) disclosed in those patents or patent applications, including but not limited to the specification, claims, tables, examples, figures, and schemes of those patents or patent applications, are expressly incorporated by reference herein as compounds useful in the invention. The conformationally restricted polyamine analog compounds disclosed in those patents or patent applications, including but not limited to the specification, claims, tables, examples, figures, and schemes of those patents or patent applications, are expressly incorporated by reference herein as preferred compounds useful in the invention.

[054] In certain embodiments, the saturated oligoamines disclosed in U.S.

Patent Application Publication No.2003/0130356, WO 03/033455, and Valasinas et ai., Bioorg. Med. Chem. 11:4121 (2003) can be used for treatment of skin diseases, and all oligoamine compounds disclosed therein, including but not limited to the specification, claims, tables, examples, figures, and schemes of those patent applications, and the text, figures, examples and schemes of the published article, are expressly incorporated by reference herein as compounds useful in the invention. [055] In certain additional embodiments, the polyamine analog-peptide conjugates disclosed in United States Patent No. 6,649,587 can be used for treatment of skin diseases, and all polyamine analog-peptide conjugates disclosed therein, including but not limited to the specification, claims, tables, examples, figures, and schemes of that patent, are expressly incorporated by reference herein as compounds useful in the invention.

[056] In certain additional embodiments, the polyamine analog-amino acid conjugates disclosed in International Patent Application WO 02/38105 can be used for treatment of skin diseases, and all polyamine analog-amino acid conjugates disclosed therein, including but not limited to the specification, claims, tables, examples, figures, and schemes of that patent application, are expressly incorporated by reference herein as compounds useful in the invention. [057] In certain additional embodiments, the polyamines and analogs described in US 4,112,067, US 4,160,819, US 4,507,321, US 5,952,067, US 2003/0118539, US 2005/0043366, WO 96/23490, WO 99/51213, and WO 03/13245 can be used for treatment of skin diseases, and all polyamines and polyamine analogs disclosed therein, including but not limited to the specification, claims, tables, examples, figures, and schemes of the patent applications, are expressly incorporated by reference herein as compounds useful in the invention. [058] The invention includes the use of all of the compounds described herein or incorporated by reference herein, including any and all stereoisomers, salts, hydrates and solvates of the compounds described herein or incorporated by reference herein. The invention also includes the use of all compounds described herein or incorporated by reference herein in their non-salt, non-hydrate/non-solvate form. Particularly preferred are pharmaceutically acceptable salts. Pharmaceutically acceptable salts are those salts which retain the biological activity of the free bases and which are not biologically or otherwise undesirable. The desired salt may be prepared by methods known to those of skill in the art by treating the compound with an acid. Examples of inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of organic acids include, but are not limited to, formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fiimaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, sulfonic acids, and salicylic acid. Salts of the compounds with amino acids, such as aspartate salts and glutamate salts, can also be prepared. [059] The invention also includes all stereoisomers of the compounds, including diastereomers and enantiomers, as well as mixtures of stereoisomers, including, but not limited to, racemic mixtures. Unless stereochemistry is explicitly indicated in a structure, the structure is intended to embrace all possible stereoisomers of the compound depicted.

[060] The term "alkyl" refers to saturated aliphatic and alicyclic groups including straight-chain, branched-chain, cyclic groups, and combinations thereof, having the number of carbon atoms specified, or if no number is specified, having up to 12 carbon atoms, with preferred subsets of alkyl groups including Ci-Ci₂, Ci-Cio, Ci-Cg, Ci-Ce, and Ci-C₄ alkyl groups. "Straight-chain alkyl" or "linear alkyl" groups refer to alkyl groups that are neither cyclic nor branched, commonly designated as "n- alkyl" groups. Examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, butyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, n-pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl. Cyclic groups can consist of one ring, including, but not limited to, groups such as cycloheptyl, or multiple fused rings, including, but not limited to, groups such as adamantyl or norbornyl.

[061] "Substituted alkyl" refers to alkyl groups substituted with one or more substituents including, but not limited to, groups such as halogen (fluoro, chloro, bromo, and iodo), alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group. Examples of substituted alkyl groups include, but are not limited to, -CF3, -CF₂-CFs, and other perfluoro and perhalo groups.

[062] "Hydroxyalkyl" specifically refers to alkyl groups having the number of carbon atoms specified substituted with one -OH group. Thus, "C3 linear hydroxyalkyl" refers to -CH₂CH₂CHOH-, -CH₂CHOHCH₂-, and -CHOHCH₂CH₂-. [063] The term "alkenyl" refers to unsaturated aliphatic and alicyclic groups including straight-chain (linear), branched-chain, cyclic groups, and combinations thereof, having the number of carbon atoms specified, or if no number is specified, having up to 12 carbon atoms, which contain at least one double bond (-C=C-). Examples of alkenyl groups include, but are not limited to,

and -CH₂-CH₂-cyclohexenyl, where the ethyl group can be attached to the cyclohexenyl moiety at any available carbon valence. The term "alkynyl" refers to unsaturated aliphatic and alicyclic groups including straight-chain (linear), branched-chain, cyclic groups, and combinations thereof, having the number of carbon atoms specified, or if no number is specified, having up to 12 carbon atoms, which contain at least one triple bond (-CsC-). "Hydrocarbon chain" or "hydrocarbyl" refers to any combination of straight-chain, branched-chain, or cyclic alkyl, alkenyl, or alkynyl groups, and any combination thereof. "Substituted alkenyl," "substituted alkynyl," and "substituted hydrocarbon chain" or "substituted hydrocarbyl" refer to the respective group substituted with one or more substituents, including, but not limited to, groups such as halogen, alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group.

[064] "Aryl" or "Ar" refers to an aromatic carbocyclic group having a single ring (including, but not limited to, groups such as phenyl) or multiple condensed rings (including, but not limited to, groups such as naphthyl or anthryl), and includes both unsubstituted and substituted aryl groups. "Substituted aryls" refers to aryls substituted with one or more substituents, including, but not limited to, groups such as alkyl, alkenyl, alkynyl, hydrocarbon chains, halogen, alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group. [065] "Heteroalkyl," "heteroalkenyl," and "heteroalkynyl" refer to alkyl, alkenyl, and alkynyl groups, respectively, that contain the number of carbon atoms specified (or if no number is specified, having up to 12 carbon atoms) which contain one or more heteroatoms as part of the main, branched, or cyclic chains in the group. Heteroatoms include, but are not limited to, N, S, O, and P; N and O are preferred. Heteroalkyl, heteroalkenyl, and heteroalkynyl groups may be attached to the remainder of the molecule either at a heteroatom (if a valence is available) or at a

IS carbon atom. Examples of heteroalkyl groups include, but are not limited to, groups such as -OCH₃, -CH₂-O-CH₃, -CH₂-CH₂-O-CH₃, -S-CH₂-CH₂-CH₃, -CH₂-CH(CH₃)-S-CH₃, -CH₂-CH₂-NH-CH₂-CH₂-, 1 -ethyl-6-propylpiperidino, 2- ethylthiophenyl, and morpholino. Examples of heteroalkenyl groups include, but are not limited to, groups such as -CH=CH-NH-CH(CH₃)-CH₂-. "Heteroaryl" or "HetAr" refers to an aromatic carbocyclic group having a single ring (including, but not limited to, examples such as pyridyl, thiophene, or fiiryl) or multiple condensed rings (including, but not limited to, examples such as imidazolyl, indolizinyl or benzothienyl) and having at least one hetero atom, including, but not limited to, heteroatoms such as N, O₅ P, or S, within the ring. Unless otherwise specified, heteroalkyl, heteroalkenyl, heteroalkynyl,, and heteroaryl groups have between one and five heteroatoms and between one and twelve carbon atoms. "Substituted heteroalkyl," "substituted heteroalkenyl," "substituted heteroalkynyl," and "substituted heteroaryl" groups refer to heteroalkyl, heteroalkenyl, heteroalkynyl, and heteroaryl groups substituted with one or more substituents, including, but not limited to, groups such as alkyl, alkenyl, alkynyl, benzyl, hydrocarbon chains, halogen, alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group. Examples of such substituted heteroalkyl groups include, but are not limited to, piperazine, substituted at a nitrogen or carbon by a phenyl or benzyl group, and attached to the remainder of the molecule by any available valence on a carbon or nitrogen, -NH-SO₂-phenyl, -NH-(C=O) O-alkyl, -NH-(C=O)O-alkyl-aryI, and -NH-(C=O)-alkyl. If chemically possible, the heteroatom(s) as well as the carbon atoms of the group can be substituted. The heteroatom(s) can also be in oxidized form, if chemically possible.

[066] The term "alkylaryl" refers to an alkyl group having the number of carbon atoms designated, appended to one, two, or three aryl groups. [067] The term "alkoxy" as used herein refers to an alkyl, alkenyl, alkynyl, or hydrocarbon chain linked to an oxygen atom and having the number of carbon atoms specified, or if no number is specified, having up to 12 carbon atoms. Examples of alkoxy groups include, but are not limited to, groups such as methoxy, ethoxy, and t-butoxy. [068] The term "alkaπoate" as used herein refers to an ionized carboxylic acid group, such as acetate (CH₃C(=O)-O^("1 ^, propionate (CH₃CH₂C(=O)-O^("1)), and the like. "Alkyl alkanoate" refers to a carboxylic acid esterified with an alkoxy group, such as ethyl acetate (CH₃CX=O)-O-CH₂CH₃). "ω-haloalkyl alkanoate" refers to an alkyl alkanoate bearing a halogen atom on the alkanoate carbon atom furthest from the carboxyl group; thus, ethyl ω-bromo propionate refers to ethyl 3- bromopropionate, methyl ω-chloro n-butanoate refers to methyl 4-chloro n-butanoate, etc.

[069] The terms "halo" and "halogen" as used herein refer to Cl, Br, F or I substituents.

[070] "Protecting group" refers to a chemical group that exhibits the following characteristics: 1) reacts selectively with the desired functionality in good yield to give a protected substrate that is stable to the projected reactions for which protection is desired; 2) is selectively removable from the protected substrate to yield the desired functionality; and 3) is removable in good yield by reagents compatible with the other functional group(s) present or generated in such projected reactions. Examples of suitable protecting groups can be found in Greene et al. (1991) Protective Groups in Organic Synthesis, 2nd Ed. (John Wiley & Sons, Inc., New York). Amino protecting groups include, but are not limited to, mesitylenesulfonyl (Mes), benzyloxycarbonyl (CBz or Z), t-butyloxycarbonyl (Boc)_s t-butyldimethylsilyl (TBDIMS or TBDMS), 9-fluorenylmethyloxycarbonyl (Fmoc), tosyl, benzenesulfonyl, 2-pyridyl sulfonyl, or suitable photolabile protecting groups such as 6-nitroveratryloxy carbonyl (Nvoc), nitropiperonyl, pyrenylmethoxycarbonyl, nitrobenzyl, dimethyl dimethoxybenzil, 5-bromo-7-nitroindolinyL, and the like. Hydroxyl protecting groups include, but are not limited to, Fmoc, TBDIMS₅ photolabile protecting groups (such as nitroveratryl oxymethyl ether (Nvom)), Mom (methoxy methyl ether), and Mem (methoxy ethoxy methyl ether), NPEOC (4- nitrophenethyloxycarbonyl) and NPEOM (4-nitrophenethyloxymethyloxycarbonyl). [071] Examples of compounds useful in the invention are depicted in Table

1. While some of the compounds are depicted as salts, such as the hydrochloride salt, it is to be understood that the disclosure in the table embraces all stereoisomers, salts, hydrates, and solvates of the compounds depicted therein, as well as the non-salt, non- hydrate/non-solvate form of the compound, as is well understood by the skilled artisan. Table 1 includes both non-conformationally restricted polyamine analogs (oligoamines) and conformationally restricted polyamine analogs.

Table 1

Skin diseases

[072] The invention embraces methods of treating a variety of skin diseases, particularly inflammatory skin diseases, as evidenced by symptoms such as itching, redness, irritation, and various skin lesions.

[073] In some embodiments, the skin disease is a chronic skin disease (such as a chronic inflammatory dermatoses) including, but not limited to, psoriasis and acne vulgaris. In some embodiments, the skin disease is an acute skin disease (such as an acute eczematous dermatitis), including, but not limited to, allergic contact dermatitis, atopic dermatitis, drug-related eczematous dermatitis, photoeczematous dermatitis, and primary irritant dermatitis. The skin disease can be endogenous (or constitutional), i.e., occurring without any obvious external cause. Examples of endogenous skin diseases (and of endogenous eczema in particular) include, but are not limited to, atopic, discoid, pompholyx (dishydrotic), seborrheic, and varicose. In some embodiments, the skin disease is induced by external causes, such as poison ivy, corrosives, acids, or other irritants. In some embodiments, the skin disease is selected from the group consisting of (or may be any one or more of) atopic dermatitis, neurodermatitis, allergic contact dermatitis, drug-related eczematous dermatitis, seborrheic dermatitis, stasis dermatitis, perioral dermatitis, and psoriasis. In some embodiments, the skin disease is not radiation-induced dermatitis. [074] The methods described herein are particularly useful for treatment of atopic dermatitis. Atopic dermatitis is dermatitis of unknown etiology marked by itching and scratching in an individual with inherently irritable skin. There appears to be a genetic predisposition to atopic dermatitis that can be exacerbated by numerous factors including food allergy, skin infections, irritating clothes or chemical and emotions. Patients with atopic dermatitis usually have a history of allergy. The allergic responses give rise to an inflammatory response that manifests the nasal, lung, or other dermal tissue. There are six general symptoms or signs associated with atopic dermatitis: erythema, exudation, excoriation, dryness, cracking and lichenification. Briefly, exudation and cutaneous eruption are early symptoms of the disease. In chronic cases, the skin exhibits key features such as scaling, excoriation, dryness and cracking. Eventually, the skin acquires a leathery appearance with hyperkeratosis (lichenification) usually exacerbated by concomitant symptoms such as itching. Lichenification is usually considered as the clinical hallmark of atopic dermatitis.

[075] Another skin disease that can be treated be methods described herein is contact dermatitis. Contact dermatitis is an acute or chronic skin inflammation caused by exposure to a chemical, physical, or biological agent. In mild cases the symptoms include itching, burning, or reddening of the skin. In more severe cases vesiculation and edema (i.e., excessive accumulation of fluid) may be present and may be followed by weeping and crusting. In most severe cases the symptoms described above may also be accompanied by bleeding vesicles and gross edema. Contact dermatitis can be classified as primary irritant dermatitis (the causative agent acting as an irritant) and allergic contact dermatitis (the causative agent acting as a specific allergic sensitizer). In some instances, the causative agent acts both as an irritant and as a sensitizer, producing both disease forms. Primary irritant dermatitis can occur in any individual after one or more exposure to an irritant. The period between contact with the primary irritant and the onset of symptoms is short or absent. Allergic contact dermatitis represents a delayed hypersensitivity reaction in the skin. The reaction usually does not occur with the initial contact, but only upon subsequent exposure. Moreover, the reaction occurs only in these now "sensitized" subjects and there is a time interval between contact and development of symptoms. The methods described herein are particularly suitable for treating allergic contact dermatitis. [076] Contact dermatitis can be caused by a variety of irritants. The most widely known natural allergens which are capable of sensitizing and causing contact dermatitis in many people are antigenic plants of the genus Rhus, such as poison ivy, poison oak and poison sumac. Other widely known allergens are commercial products such as insecticides containing Pyrethrum or Rotenone, dye intermediates such as aniline, nitro compounds, anthracene, and derivatives thereof, dyes such as paraphenylenediamine and aniline black, photo developers such as hydroquinone and para-aminophenol, antioxidants such as hexamethylenetetramiπe, and synthetic and natural resins such as wood rosin and phenol formaldehyde, and detergents and constituents of rubber and latex gloves.

[077] Other dermatitis suitable for treatment by methods described herein include seborrheic dermatitis and neurodermatitis. Seborrheic dermatitis is a chronic cutaneous inflammatory condition, marked by frequent exacerbations, and affecting areas of skin in which sebaceous glands have a dense distribution and are highly active. Neurodermatitis, also known as lichen simplex chronicus, occurs because of repeated scratching. Chronic scratching can cause patches of thickened, brownish skin. These patches have definite margins that are thick and leather-like (lichenϊfied). [078] The methods described herein are also useful for treating psoriasis.

Psoriasis is a chronic skin disease characterized by circumscribed red patches covered with white scales. The major pathophysiological events involved in the diseases process are accelerated epidermal proliferation and metabolic activity, proliferation of capillaries in the dermal region, and invasion of the dermis and epidermis by inflammatory cells. At the cellular level, psoriasis is a benign proliferative disease of keratinocytes of unknown etiology. The diseases can be triggered or exacerbated by external factors such as trauma, infection, and drugs. Histologically, the skin pathology of psoriasis is characterized by acanthosis (i.e., thickening of the epidermis), angiogenesis of superficial blood vessels and an inflammatory response. Diagnosis of psoriasis is usually determined through examination of the skin by a physician or other health care provider. Less commonly, a skin biopsy is examined under the microscope for biological evidence of psoriasis. The presence of small pits in the fingernails is also an indicator of psoriasis.

[079] There are several types of psoriasis with different symptoms and degrees of severity. Exemplary types of psoriasis that can be treated by methods of the present invention include, but are not limited to, plaque psoriasis (or psoriasis vulgaris), guttate psoriasis, inverse psoriasis (or flexural psoriasis), erythrodermic psoriasis, pustular psoriasis, flaking eczema, psoriasis pustulosa, psoriasis arthropatica, and psoriatic erythroderma.

[080] Other examples of skin diseases that can be treated by methods of the present invention include, but are not limited to, acne, primary irritant dermatitis, infective dermatitis, autosensitization dermatitis, nummular eczematous dermatitis, exfoliative dermatitis, asteatosis eczema dermatitis, parapsoriasis, folliculitis, exudative discoid and lichenoid dermatitis, chronic scaly superficial dermatitis, poison ivy, acne inflammation, and irritation induced by extrinsic factors such as chemicals, trauma, and pollutants (such as cigarette smoke). Methods of diagnosing these skin diseases are known in the art.

Modes of administration

[081] Compounds useful in the methods of the invention can be administered to a patient or subject (such as human) via any route(s) known in the art, including, but not limited to, topical, systemic, transpleural, intravenous, oral, intraarterial, intramuscular, topical, via inhalation (e.g., as mists or sprays), via nasal mucosa, subcutaneous, transdermal, intraperitoneal, and gastrointestinal. [082] The optimal effective concentration of the compounds used in methods described herein can be determined empirically and will depend on the type and severity of the disease, route of administration, disease progression, and health, mass and body area of the patient. Such determinations are within the skills of one of ordinary skill in the art. Examples of dosages include, but are not limited to, an effective amount within the dosage range of about 0.1 μg/kg to about 300 mg/kg, or within about 1.0 μg/kg to about 40 mg/kg body weight, or within about 10 μg/kg to about 20 mg/kg body weight, or within about 0.1 mg/kg to about 20 mg/kg body weight, or within about 1 mg/kg to about 20 mg/kg body weight, or within about 0.1 μg/kg to about 10 mg/kg body weight. The dosages may be administered in a single daily dose, or the total daily dosage may be administered in divided dosage of two, three, four, or more times daily. Dosages may also be administered less frequently than daily, for example, six times a week, five times a week, four times a week, three times a week, twice a week, or once a week.

[083] One preferred route of administration is topical administration. The term "topical administration" is used in its conventional sense to mean application of an active agent to the skin or mucosa to achieve a local effect. The polyamine compounds for use in the present methods are contained in a topical formulation in a concentration effective to cause therapeutic effect, such as preventing or reducing the skin irritation and/or inflammation (such as inflammation) symptoms that are sought to be eliminated. The formulation can contain the selected compound in a suitable topical vehicle at any suitable total concentration, such as any of about IμM to about 100 mM₅ about 1 μM to about 10 mM, about IuM to about ImM, about IuM to about 100 uM, about lOμM to about SOuM, or about 10 μM. The appropriate concentration can be achieved using a single polyamine analog, or multiple different such compounds may be combined to yield the total desired concentration. If other therapeutic agents are included in the formulation, then lower concentrations of the compounds of the invention may be utilized.

[084] Suitable concentrations of the polyamine analogs can also be expressed in weight/volume or weight/weight percentage terms which may vary depending on the density of the vehicle and other components in the formulation. For example, the polyamine analogs may be present in the formulation at a concentration (w/v) of at least about any of 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10%. In some embodiments, the concentration of the polyamine analog is such that a topical dosage of approximately 0.5 grams of formulation over a 5 cm x 5 cm area of skin (25 cm²) can be applied. In typical topical vehicles, the compositions are readily formulated and do not leave any significant visible residue when applied to the skin. Higher concentration formulations, such as saturated pastes or other forms, may also be successfully used, particularly where visible appearance is not a limiting consideration (as in therapeutic applications).

[085] Furthermore, routine clinical assessments such as those described below can readily be employed to optimize the concentration of the polyamine anti- irritant compound(s) of the invention and to ascertain if lower, or higher, concentrations are appropriate for a given formulation or skin disorder indication. For example, the concentration may be adjusted to account for the amount of formulation that is typically applied to a given skin area by the user, which will depend to an extent on the physical nature of the topical vehicle (e.g., lotion as compared to liquid spray vehicles). Likewise, the amount of the compound required may be reduced in such cases where the formulation contains a skin penetration-enhancing ingredient or other agent which increases the ability of the compounds to permeate the stratum corneum to their site of skin disorder indication.

[086] The polyamine analogs are typically incorporated into the present formulations by mixing an appropriate amount of a sufficiently soluble form of the selected compound into the chosen formulation vehicle at an appropriate pH such that the polyamine is multiply protonated (e.g., where the side chains of the amine compounds are positively charged). The pH of the formulation can be about pH 4 to about pH 8, or about pH 5 to about pH 7, or about pH 6 to about pH 7. Typically, the selected compound is sufficiently soluble in the formulation vehicle as to allow a consistent formulation having the desired physical and topical application characteristics. Generally, for topical application, the compound (or compounds) chosen is sufficiently soluble in aqueous formulation such that, upon application to the skin, the component compounds are taken up into the water-containing milieu of the skin. Preferably, the polyamine analogs are not themselves irritating, toxic or otherwise deleterious to the user.

[087] Suitable topical vehicles for use with the formulations of the invention are well known in the cosmetic and pharmaceutical arts, and include such vehicles (or vehicle components) as water; organic solvents such as alcohols (particularly lower alcohols readily capable of evaporating from the skin such as ethanol), glycols (such as glycerin), aliphatic alcohols (such as lanolin); alicyclic alcohols; mixtures of water and organic solvents (such as water and alcohol); mixtures of organic solvents such as alcohol and glycerin (optionally also with water); lipid-based materials such as fatty acids, acylglycerols (including oils, such as mineral oil, and fats of natural or synthetic origin), phosphoglycerides, sphingolipids and waxes; protein-based materials -such as collagen and gelatin; silicone- based materials (both non-volatile and volatile) such as cyclomethicone, demethiconol and dimethicone copolyol (Dow Coming); hydrocarbon-based materials such as petrolatum and squalene; anionic, cationic and amphoteric surfactants and soaps; sustained-release vehicles such as microsponges and polymer matrices; stabilizing and suspending agents; and other vehicles and vehicle components that are suitable for administration to the skin, as well as mixtures of topical vehicle components as identified above or otherwise known to the art. The vehicle may further include components adapted to improve the stability or effectiveness of the applied formulation, such as preservatives, antioxidants, skin penetration enhancers, sustained release materials, and the like. Examples of such vehicles and vehicle components are well known in the art and are described in such reference works as Martin (ed.), Remington's Pharmaceutical Sciences and Remington: The Science and Practice of Pharmacy, 20th Edition, Lippincott, Williams & Wilkins (2000). [088] The formulations described herein may also include other excipients such as preservatives, coloring, flavoring, sweetening, thickening, suspending, disbursing, emulsifying, swelling, stabilizing, and buffering agents. [089] The choice of a suitable vehicle will depend on the particular physical form and mode of delivery that the formulation is to achieve. Examples of suitable forms include ointments, creams, lotions, solutions (such as solution in the form of a liquid spray), suspensions, aerosols, gels, impregnated bandages, impregnated dressings, emulsions, solids, liquids, dispersions, foams, mousses, powders, patches, pomades, solutions, pump sprays, sticks, and towelettes.

[090] Solutions are the most traditional types of formulations for topical dermal drugs, where the agent is solubilized in a solvent. Solvent-based systems are effective for topical administration of polyamine analogs. For example, the polyamine analogs can simply be dissolved in water or water-based solutions. The water or water based solution may contain a buffer to control the pH. Physiologically compatible buffers included, but are not limited to, phosphates, bicarbonates, citrates, acetates, Tris-buffer, borates, sulfates, sulfites, nitrates, and the like. [091] Alcohols are also suitable solvents for topical solutions. Typically, the drug is combined into a water and alcohol mixture. The alcohol content varies between 10-100% of the liquid component. Alcohols used include ethanol, propylene glycol, polyethylene glycols, methanol, or butanediol. Each of these types of alcohols is suitable for use in the present invention; others not listed are also suitable, as would be understood by one of skill in the art.

[092] Emulsions form the basis of cream and lotion type formulations.

Typically, these formulations are colloidal dispersions composed of two immiscible phases; an oil phase and an aqueous phase with an emulsifier. Typical oils used in emulsions include stearyl alcohol, isopropyl lanolate, isopropyl myristate, cetyl alcohol, and vitamin E. Emulsifϊers are essentially surfactants that lower the surface tension of the immiscible phases. Most emulsifiers tend to be fatty acid esters or stearates of glycerol, sorbitan, or polyoxyethylene (POE). Depending on the location of the oil and water, emulsions are oil-in-water, water-in-oil or combinations thereof. The preparation of an emulsion commonly requires some mechanical shear force with heat to mix the internal and external phases. Most topical emulsions contain viscosity builders such as natural gums (alginates, carrageenan, tragacanth, pectin, xanthan or collagen) at 1-5% to thicken the preparation. Higher percentages of viscosity builders produce creams, a lower percentage form lotions. Exemplary formulations for emulsions (creams and lotions) generally include water, alcohol, propylene glycol, sodium lauryl sulfate and white wax. In alternative formulations, they include water, alcohol, glycerol, phosphatidyl choline, lysophosphatidyl choline and triglycerides. In other embodiments of the invention, particularly for administration of polyamine analogs to the epidermis, emulsions are particularly well suited. Ease of administration, good local retention and slow release of drug are some of the attractive characteristics of emulsions for a topical delivery system. [093] Ointments are composed of fluid hydrocarbons meshed in a matrix of higher melting solid hydrocarbons, such as the hydrocarbon ointment base petrolatum and white ointment. Ointments are prepared by melting the base, followed by the addition of excipients, such as antioxidants to the fluid. The drug is then suspended into the ointment by milling. Additional components, such as microcrystalline cellulose, which gives the ointment a dry feel on the skin, can be included to reduce greasiness.

[094] Gels are semisolids consisting of a gelling agent that is penetrated with liquid solvent. The concentration and the molecular weight of the gelling agent affect the consistency of vehicle formulation. The gelling agent is a suspension of either large organic or small inorganic molecules. The large organic molecules consisting of either natural or synthetic polymers exist as randomly coiled chains that entangle and form the gel structure. Some common polymers of this kind are natural gums, cellulose derivatives and acrylic acid polymers. Another class of these gels, called thermally sensitive gels, is prepared from poloxamers. In contrast, the small inorganic molecules form the gel structure by forming a somewhat organized three- dimensional network. Common small inorganic polymers include colloidal solids found in silica and clays. The nature of the solvent determines whether the gel is a hydrogel (water-based) or an organogel (non-aqueous solvent based). The viscosity of gels decreases upon application of shear forces (mixing or squeezing from a tube) or increases in temperature. One embodiment includes various formulations of a polyamine analog compound within a gel. The property of gels overall are attractive for a topical delivery vehicle because they are relatively easy to prepare and tend to have a long residence time at the site of application allowing the slow release of compound at the desired site. All ingredients listed above for preparation of gels are suitable for use in the present invention, as well as unlisted ingredients typically employed by one skilled in the art for such purpose.

[095] Liposomes are vesicles consisting of amphipathic lipids arranged in one or more concentric bilayers. When lipids are placed in aqueous medium, the hydrophilic interaction of the lipid head groups with water results in the formation of multilamellar and unilamellar systems or vesicles which resemble biological membranes in the form of a spherical shell. Liposomes may be small (0.025-0.05 urn) to large multilamellar vesicles (0.05-10 um). Lipids used to prepare the liposomes include phospholipids, sphingolipids, glycosphingolipids, saturated glycerides, steroids (e.g., cholesterol) and synthetic phospholipids. Liposomes are typically prepared by melting the lipid together in aqueous solvent with an emulsifier like POE. The drug is then added and the liposomes are generated through mixing or sonication. The drug is usually entrapped in the vesicle structure. These basic liposomes are sometimes referred to as "conventional liposomes." Several other types of liposomal preparations exist, including (1) sterically stabilized liposomes, which are surface coated with an inert hydrophilic polymer, such as polyethylene glycol; (2) targeted liposomes, to which are attached targeting ligands, such as antibodies or fragments thereof, lectins, oligosaccharides or peptides; and (3) reactive or "polymorphic" liposomes, which change their phase and structure in response to a particular interaction (this group includes liposomes sensitive to ions (pH, cations), heat and light, among other stimuli.

[096] Liposomes are good vehicles for dermatological applications.

Liposomal delivery offers several advantages over more conventional formulations. The major advantages are: (1) reduced serious side effects and incompatibility from undesirably high systemic absorption; (2) significantly enhanced accumulation of the delivered substance at the site of administration due to high compatibility of liposomes with stratum corneum; (3) ready incorporation of a wide variety of hydrophilic and hydrophobic molecules into the skin; (4) protection of the entrapped compound from metabolic degradation; and (5) close resemblance to the natural membrane structure and their associated biocompatibility and biodegradability. All ingredients listed above and for preparation of various types of liposomes are suitable for use in the present invention, as well as any other such ingredients typically employed by one skilled in the art for such purpose. [097] The polyamine analogs for use in the invention can be administered as the sole active ingredient, or can be administered in combination with other active ingredients. These other ingredients can be administered simultaneously with the polyamine analogs described herein (such as in the same composition), or separately (such as in different compositions). Compounds and formulations that have been used to treat skin diseases include, for example, steroid or non-steroidal antiinflammatory agents (such as corticosteroids), anti-infective agents, symptom relieving agents (such as chamomile, eucalyptus, camphor, menthol, zinc oxide, talc, glycerin, and calamine), antihistamines, calcium-channel blocking or regulatory agents, or immunosuppressive agents such as cyclosporine and FK506. When used in combination with other active ingredients, the optimum concentration of a polyamine compound and the other active ingredients may be reduced below (or within) their preferred ranges when used alone.

Kits

[098] The invention also provides articles of manufacture and kits containing materials useful for treating skin diseases. The article of manufacture comprises a container with a label. Suitable containers include, for example, bottles, vials, and test tubes. The containers may be formed from a variety of materials such as glass or plastic. The container holds a composition having an active agent which is effective for treating the skin disease. The active agent in. the composition is one or more conformationally restricted polyamine analogs or oligoamines described herein. The label on the container indicates that the composition is used for treating skin diseases such as atopic dermatitis and psoriasis, and may also indicate directions for use. [099] The invention also provides kits comprising any one or more of a conformationally restricted polyamine analogs or oligoamines described herein. In some embodiments, the kit of the invention comprises the container described above. In other embodiments, the kit of the invention comprises the container described above and a second container comprising a buffer. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, and package inserts with instructions for performing any methods described herein (methods for treating skin diseases, such as atopic dermatitis and psoriasis). [0100] In other aspects, the kits may be used for any of the methods described herein, including, for example, treating a patient or subject suffering from a skin disease.

[0101] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is apparent to those skilled in the art that certain minor changes and modifications will be practiced. Therefore, the description and examples should not be construed as limiting the scope of the invention.

[0102] The following Examples are provided to illustrate, but not limit, the invention.

EXAMPLE l

[0103] This example shows effect of a polyamine analog on chronic skin sensitivity in a mouse model with oxalazone-induced delayed type hypersensitivity (DTH).

[0104] Fifty-four adult (6-8 weeks old) female BALB/c mice were divided into six groups (9 animals in each group) and each were sensitized by a single painting with 25 μl of sensitizing reagent (3% oxazolone in acetone: olive oil 4:1) on the shaved abdomen and 5 μl on each footpad on Day 0. On Day 5, ear thickness was measured and to each animal 10 μl of challenge reagent (1% Oxazolone in acetone:olive oil 4:1) was applied to each side of both ears. On Days 7 and 9, ear thickness was measured again and to each animal 10 μl Re-Challenge reagent (0.25% Oxazolone in acetonerolive oil 4:1) was applied to each side of both ears. [0105] From Day 5 to Day 8, CGC-1 1159, controls, and vehicle (water) were applied to both ears of the groups twice daily according to the following treatment schedules:

[0106] Group 1 : no treatment

[0107] Group 2: water

[0108] Group 3: CGC-11159 1 μM, topical, 5 μ Low Dose BID

[0109] Group 4: CGC-11159 10 μM, topical, 5 μ High Dose BID

[0110] Group 5: Dexamethasone, SID (1.5 mg/kg i.p.)

[0111] Group 6: Elidel® topical (1% cream) twice a day; 2.5 mm paste squeezed from tube) (Elidel® is a registered trademark of Novartis AG Corporation, Basel, Switzerland for a dermatological preparation of the active ingredient pimecroHmus);

[0112] Ear thickness was measured once a day on Day 0 and from Day 5 to

Day 9 with sacrifice on Day 9. The measurements were made in the morning prior to any treatment, using an engineering micrometer (for example, Mitutoyo). Body weights were also measured at the time of ear thickness measurement. [0113] The result of the experiment is shown in Figure 1. As shown in the figure, DTH ear sensitivity was successfully established through sensitization with 3% Oxazolone, followed by challenge with 1% Oxazolone on day 5 and re-challenge with 0.25% Oxazolone on day 7. Positive controls topical Elidel® (twice daily) and dexamethasone (SID, IP) have demonstrated significant efficacy in reducing ear thickness starting on Day 6 through Day 9 (P<0.05), as compared to water treatment. CGC-11159, when applied at 10 μM, also demonstrated significant efficacy in reducing ear thickness on Day 8 and Day 9 (P<0.05), as compared to water treatment. In addition, the therapeutic efficacy of 10 μM of CGC-11159 was comparable with that of Elidel® and dexamethasone on Day 9. There were no CGC-11159 related changes in body weights over the course of the study.

EXAMPLE 2

[0114] This example demonstrates the effect of polyamine analogs in Guinea

Pig models on skin inflammation and edema following multiple topical applications. [0115] Forty-eight adult (8-12 weeks old) female guinea pigs (Duncan-Hatley) w.ere divided into eight groups (6 animals in each group) and each were sensitized by a single painting with 0.5 ml sensitizing agent (5% DNCB in acetone:olive oil 4:1, Sigma-Aldrich, MO) on the shaved back skin area on day 0 (1 hour). On Day 5, skin erythema and edema were measured and to each animal 0.5 ml challenge reagent (1% DNCB in acetone-olive oil 4:1) was applied to the same shaved back skin area (1 hour). On Days 7, 9, 11, 13, and 15, skin erythema and edema were measured and to each animal 0.5 ml re-challenge reagent (0.5% DNCB in acetone-olive oil 4:1) was applied to the same shaved back skin area (1 hour).

[0116] From Day 7 to Day 21, CGCl 1159 and CGCl 1093, positive controls

(dexamethasone and Elidel^®), and vehicle (water) were applied to the groups twice daily according to the following treatment schedules: [0117] Group 1: no treatment [0118] Group 2: water, BID

[0119] Group 3: CGC-11159 10 μM, 0.1 ml topically, BID.

[0120] Group 4: CGC-11159 10 mM, 0.1 ml topically, BID.

[0121] Group 5: CGC-11093 10 μM. 0.1 ml topically, BID.

[0122] Group 6: CGC-11093 10 mM, 0.1 ml topically, BID.

[0123] Group 7: Elidel® topical (1% cream), 5 mm paste squeezed from tube), BID.

[0124] Group 8: Dexamethasone, SQ, SID (1.5 mg/kg)

[0125] S Skkiinn wwaass scored using a modified Draize's test daily starting on day 5 through day 22. Representative photographs were taken at 3-4 occasions over the course of the treatment period. At the end of the treatment phase, animals were sacrificed. The blood and kidneys were collected and frozen. A skin biopsy was collected and fixed in 10% formalin or frozen in OCT blocks for possible histopathologic examination.

[0126] Body weights were collected on day 0, weekly thereafter and on day

21. Skin erythema and edema was measured on day 0 and days 5-22 in the morning before any applications. Skin erythema and edema was scored daily from day 5 through day 22, using a modified Draize's test system indicated below.

[0127] Erythema Edema

[0128] Grade 0 no erythema no edema

[0129] Grade 1 slightly erythema slightly edema

[0130] Grade 2 erythema clearly visible moderate edema

[0131] Grade 3 moderate erythema intense edema with bulging

[0132] Grade 4 intense erythema N/A

[0133] Figures 2 A, 2B, 3 A, and 3B were generated, based on the data fi the skin scoring, to visualize the effects of CGC-11159 and CGC-11093 on skin erythema (Figures 2A and 2B) and edema (Figures 3A and 3B). For statistical analysis, one-way ANOVA test was used to perform a non-parametric multiple group comparisons, followed by Bonferroni-Dunn's post-hoc test to compare every 2 groups. [0134] As shown in the figures, positive controls dexamethasone demonstrated significant efficacy in reducing both skin erythema and edema when treatment started on day 5 and through day 21 (P<0.001 vs H₂O treatment re erythema; P<0.05 vs EbO treatment re edema). However, Elidel® did not have any significant effect in reducing either skin erythema or edema when daily topical treatment started on day 5 through day 21 (P>0.05 vs H₂O treatment re erythema; P>0.05 vjf H2O treatment re edema).

10135] CGC-11159, when dosed at either 10 μM or 10 mM concentrations, did not demonstrate any significant efficacy in reducing either skin erythema or skin edema when entire curves were compared with EbO-treated animals (P>0.05 re erythema; P>0.05 re edema). Similarly, CGC-11093, when dosed at either 10 μM or 10 mM concentrations, did not demonstrate any significant efficacy in reducing either skin erythema or skin edema when entire curves were compared with H^O-treated animals.

[0136] Although no significant difference could be demonstrated when the entire curves were compared statistically, there is a trend of reduced skin erythema and edema in both CGC-11159 and CGC-11093 treated animals in the last 5 treatment days (from day 16 to day 21). Therefore, we analyzed the difference between H₂O- treated group and CGC-1 1 159 and CGC-11093 groups on days 16 to 22. The results are summarized in Table 2 (erythema endpoint) and Table 3 (edema endpoint) (see below).

[0137] A comparison of the difference on the individual date basis revealed the effect of CGC-11159 and CGC-11093 during the later phase of the treatment. As shown in tables 2 and 3, 10 μM CGC-11159 showed significant reduction of erythema on Day 21, and of edema on Day 19. 10 μM CGC-11093 showed significant reduction of erythema on Days 19 and 21, and of edema on Day 19. 10 mM CGC-11093 showed significant reduction of erythema on Day 21 and 22, and of edema on Day 19. Both dexamethasone and Elidel® showed significant effect on erythema and edema when analyzed on individual date basis. These data suggested that the effect of CGC-11159 and CGC-11093 is latent.

[0138] As shown in Table 4, there were no significant CGC-11159 or CGC-

11093 related changes in body weights over the course of the study. Table 2: ANOVA one-way analysis test based on individual date (from D 16 to D22) regarding erythema

Table 3: ANOVA one-way analysis test based on individual date (from DI6 to D22) Re Edema

Table 4: Group average body weights (g) (mean + SD)

[0139] The disclosures of all publications, patents, patent applications and published patent applications referred to herein by an identifying citation are hereby incorporated herein by reference in their entirety.

[0140] Although the foregoing invention has been described in some detail for purposes of clarity of understanding, it is apparent to those skilled in the art that certain minor changes and modifications will be practiced. Therefore, any description or examples should not be construed as limiting the scope of the invention.

Claims

CLAIMSWhat is claimed is:

1. A method of treating a skin disease selected from the group consisting of atopic dermatitis, neurodermatitis, allergic contact dermatitis, drug-related eczematous dermatitis, seborrheic dermatitis, stasis dermatitis, perioral dermatitis, and psoriasis, comprising: administering one or more conformationally restricted polyamine analogs, oligoamines, or any salt, hydrate, solvate, or stereoisomer thereof, to a subject in need of an amount sufficient to have a therapeutic effect on the skin disease.

2. The method of claim 1, wherein the conformationally restricted polyamine analog, oligoamine or salt, hydrate, solvate, or stereoisomer thereof is administered topically.

3. The method of claim 2, wherein the conformationally restricted polyamine analog, oligoamine or salt, hydrate, solvate, or stereoisomer thereof is administered in the form of solutions, ointments, creams, lotions, suspensions, aerosols, gels, powders, impregnated bandages, impregnated dressings, emulsions, or solids.

4. The method of claim 2, wherein the conformationally restricted polyamine analog, oligoamine or salt, hydrate, solvate, or stereoisomer thereof is administered with a pharmaceutically acceptable carrier comprising one or more of aqueous systems, glycerins, Ci_-4 alcohols, fatty alcohols, fatty ethers, fatty esters, polyols, glycols, vegetable oils, mineral oils, liposomes, gelatins, gums, petrolatum, laminar lipid materials, silicone oils, water or any combinations thereof.

5. The method of claim 2, wherein the conformationally restricted polyamine analog, oligoamine or salt, hydrate, solvate, or stereoisomer thereof is administered in an aqueous formulation.

6. The method of claim 1, wherein the skin disease is atopic dermatitis.

7. The method of claim 1, wherein the skin disease is psoriasis.

8. The method of claim 7, wherein the psoriasis is selected from the group consisting of psoriasis vulgaris, guttate psoriasis, flexural psoriasis, erythrodermic psoriasis, pustular psoriasis, flaking eczema, psoriasis pustulosa, psoriasis arthropatica, and psoriatic erythroderma.

9. The method of claim 1, wherein the method comprises administering a conformationally restricted analog, and wherein said conformationally restricted polyamine analog is selected from a compound of the formula: R_I-NH-R₂-NH-R₃-R₄-R₃-NH-R₂-NH-R_I, wherein each Ri is independently selected from Ci-Cβ alkyl; each R₂ is independently selected from C3-C6 alkyl; each R₃ is independently selected from Ci-Ce alkyl; and

R₄ is independently selected from C₂-C₆ alkenyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkenyl, or C3-C6 aryl, and any salt, hydrate, solvate, or stereoisomer thereof.

10. The method of claim 9, wherein each R2 is independently selected from C3-C4 alkyl.

11. The method of claim 10, wherein each Ri is a C₂ alkyl.

12. The method of claim 9 wherein in the conformationally restricted polyamine analog is

and all stereoisomers, salts, hydrates, and solvates thereof.

13. The method of claim 1 wherein the method comprises administering a conformationally restricted analog, and wherein the conformationally restricted polyamine analog is selected from among the group of compounds of the formula: E-NH-B-A-B-NH-B-A-B-NH-B-A-B-NHC-B-A-B-NH)_x-E wherein A is independently selected from the group consisting of Ci -C_O alkyl, C₂-C_O alkenyl, C₂-C_O alkynyl, C3-C6 cycloalkyl, C₃-C₆ cycloaryl, and C₃-Ce cycloalkenyl;

B is independently selected from the group consisting of a single bond, Ci-Cβ alkyl, and C₂-C6 alkenyl;

E is independently selected from the group consisting of H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C₆ cycloaryl, and C₃-C_O cycloalkenyl; and x is an integer from 2 to 16; with the proviso that either at least one A moiety is selected from the group consisting of C₂-C6 alkenyl, Cr-C₆ alkynyl, C3-C6 cycloalkyl, C₃-Ce cycloaryl, and C3-C6 cycloalkenyl, or at least one B moiety is selected from the group consisting of C₂-Cg alkenyl; and all salts, hydrates, solvates, and stereoisomers thereof.

14. The method of claim 13, wherein the conformationally restricted polyamine analog is selected from the group consisting of

and

and all salts, hydrates, and solvates thereof.

15. The method of claim 1, wherein the method comprises administering an oligoamine, and wherein the oligoamine is selected from a compound of the formula: CH₃CH₂NH-(R-NH)_n-CH₂CH₃, wherein each R is independently selected from group consisting a C₂-C_O alkyl; and n is an integer from 6 — 14. and all salts, hydrates, solvates, and stereoisomers thereof.

16. The method of claim 15 wherein n is an integer from 7-13.

17. The method of claim 16 wherein n is any of 7, 9, 11, or 13

18. The method of claim 17 wherein n is 7.

19. The method of claim 17 wherein n is 9.

20. The method of claim 17 wherein n is 11.

21. The method of claim 17 wherein n is 13.

22. The method of claim 1, wherein the method comprises administering an oligoamine, and wherein the oligoamine is selected from a compound of the formula: CH₃CH₂NH-(CH₂CH₂CH₂CH₂NH)_n-CH₂CH₃, wherein n is an integer from 6-14, and all salts, hydrates, solvates, and stereoisomers thereof.

23. The method of claim 22 wherein n is an integer from 7-13.

24. The method of claim 23 wherein n is any of 7, 9, 11, or 13

25. The method of claim 24 wherein n is 7.

26. The method of claim 24 wherein n is 9.

27. The method of claim 24 wherein n is 11.

28. The method of claim 24 wherein n is 13.