WO2008045945A1 - Benzindole derivatives and method of treating hiv/aids - Google Patents

Abstract

Disclosed are compounds of formula (I): wherein R1-7 and n are as described herein, which comprises a DNA alkylator. Also disclosed is a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier. Also disclosed is a method of prophylactically or therapeutically inhibiting a retroviral infection in a mammal.

Description

BENZiNDOLE DERIVATIVES AND METHOD OF TREATING HIV/AIDS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This patent application claims the benefit of U.S. Provisional Patent Application No. 60/850,437, filed October 10, 2006, which is incorporated by reference.

BACKGROUND OF THE INVENTION

[0002] The Centers for Disease Control and Prevention (CDC) estimate that in the United States, 850,000 to 950,000 people are living with HIV infection and approximately 25% are unaware of their infection (CDC, Morb. Mortal. WkIy. Rep., 52(47), 1145-8 (2003)). Worldwide, the rate of new HIV infections continues to increase at an unacceptably high level. Although new AIDS diagnoses and deaths have fallen significantly in developed countries since the advent of highly active antiretro viral therapy (HAART), in the developing world the HIV/AIDS epidemic continues to accelerate. The global impact of the epidemic is considerable. According to the Joint United Nations Programme on HIV/AIDS and the World Health Organization, as of the end of 2002, 40-42 million people were estimated to be living with HIV/AIDS, with 95% of the global total residing in the developing world (WHO, Treating 3 Million by 2005: The WHO Strategy, Geneva, Switzerland, p. 1-53 (2003), and UNAIDS, AIDS Epidemic Update December 2003). Worldwide there were an estimated 2.5- 3.5 million deaths due to HIV/AIDS in 2003 (UNAIDS, AIDS Epidemic Update December 2003) and there have been as many as 30 million deaths as a result of HIV infection since the beginning of the epidemic (WHO, Treating 3 Million by 2005: The WHO Strategy, Geneva, Switzerland, p. 1-53 (2003)). Beyond the human tragedy of HIV/AIDS, the costs of the epidemic pose a significant impediment to the economic growth and political stability of many countries.

[0003] Nucleoside derivatives, such as AZT, which inhibit the viral reverse transcriptase, were among the first clinically active agents available commercially for anti-HIV therapy. Although very useful in some patients, the utility of AZT and related compounds is limited by toxicity and insufficient therapeutic indices for fully adequate therapy. The foregoing shows that new anti-viral agents, to be used alone or in combination with existing anti- viral agents, are needed for effective anti- viral therapy. New agents are also important for the prophylactic inhibition of viral infection. [0004] The invention provides such an anti-viral agent. This and other objects and advantages, as well as additional inventive features, will be apparent from the description of the invention provided herein.

BRIEF SUMMARY OF THE INVENTION

[0005] The invention provides novel compounds which are benzindole derivatives comprising a benzindole moiety, a linker, and a fatty acid residue or dendrimer residue comprising at least one fatty acid residue, for example compounds of formula I described below. The benzindole moiety is a DNA alkylator. It is contemplated that the compounds of formula (I) are virus-specific (i.e., attack a molecular target specific to the virus but not the host) and render the intact virus noninfectious. An advantage of the compounds of the present invention is that the compounds are torsionally-activated and can be used to scavenge cytoplasmic DNA. Because of the fatty acid(s) linked to the benzindole moiety, the compounds become immobilized on the cytoplasmic side of the plasma membrane and are stable until activated by binding to DNA. The anchored compounds are designed to intercept newly retrotranscribed retroviral DNA before it translocates to the host nucleus and becomes integrated into the host genome. By being immobilized on the cytoplasmic side of the plasma membrane, the compound does not affect nuclear or mitochondrial DNA. [0006] In addition, it is contemplated that the compounds of the invention are designed such that cells containing viral DNA (e.g., retroviral DNA) are less resistant to the administered compounds. Specifically, it is believed that in order for viral DNA in the cytoplasm to become resistant, the virus has to develop a shield for the DNA and/or find a way to replicate somewhere other than cytoplasm. Since neither of these processes is facile, embodiments of the compounds of formula (I)₃ which are immobilized on the cytoplasm, could render the DNA less resistant to treatment.

[0007] The invention further provides pharmaceutical compositions comprising at least one compound of the invention and a pharmaceutically acceptable carrier. [0008] The invention also provides a method of prophylactically or therapeutically inhibiting a retroviral infection in a mammal, a method of removing a virus from a sample, and a method of disinfecting an object suspected to contain a virus.

DETAILED DESCRIPTION OF THE INVENTION [0009] The present invention provides, in an embodiment, a compound of the formula (I):

(D wherein

R¹ is NR⁸, O, or S;

R² is a linker;

R³ is a fatty acid residue or a dendrimer residue comprising at least one fatty acid residue;

R⁴ and R⁵ are the same or different and each is selected from the group consisting of hydrogen, optionally substituted C_1-12 alkyl, optionally substituted C_2-12 alkenyl, optionally substituted C_3-30 cycloalkyl, optionally substituted C_6-30 aryl, optionally substituted C_1-12 alkylcarbonyl, and optionally substituted C_6-30 aroyl;

R⁶ and R⁷ are the same or different and each is selected from the group consisting of hydrogen, optionally substituted C_1-12 alkyl, optionally substituted C_2-12 alkenyl, optionally substituted C_3-30 cycloalkyl, optionally substituted C_6-30 aryl, optionally substituted C_1-12 haloalkyl, optionally substituted C_1-12 alkylcarbonyl, and optionally substituted C_6-30 aroyl;

R is hydrogen, optionally substituted C_1-12 alkyl, optionally substituted C_2-12 alkenyl, optionally substituted C_3-30 cycloalkyl, or optionally substituted C_6-30 aryl; and n is 1, 2, or 3; or a salt thereof.

[0010] The linker, R², comprises any moiety that can form a chemical bond between the fatty acid residue or a dendrimer residue comprising at least one fatty acid residue (e.g., R³) and the DNA alkylator. The linker can be a bi-, tri-, or tetrafunctional linker, depending on how many R groups are attached. IfR is bifunctional, then n is 1; if R is trifunctional, then n is 2; whereas if R² is tetrafunctional, then n is 3. Preferably, R² is bifunctional and n is 1. The linker can optionally bind to DNA, but can have little to no ability for sequence-specific interaction. The linker can be of any suitable charge, length and/or rigidity, but preferably the linker is linker derived from a compound comprising one or more amino groups, one or more caxboxyl groups, and/or one or more aryl, heteroaryl, or heterocyclyl groups. Examples of a suitable heteroaryl include

[0011] In an embodiment, R² is derived from a polyamine, such as amino-Cμ^ alkylamino, bisamino-Cμπ alkylpiperazinyl, or bisamino-Ci-π alkyl-C_1-12 alkylamino (e.g., spermidine). In another embodiment, R is derived from an amino acid (e.g., β-alanine) or selected from the group consisting of

wherein X' is hydrogen, C_1-12 alkyl, C_3-30 cycloalkyl, or C_6-30 aryl, and n and m are independently 0 to 3. Specific examples of suitable linkers include, but are not limited to, 3- aminopropylamine, benzofuranyl, indolyl, N,iV-bis(aminopropyl)piperazme, NJSF- bis(aminopropyl)methylamine, 8-amino-3,6-dioxaoctanoic acid, spermidine (N-(3- aminopropyl)-l,4-butanediamine), and β-alanine.

[0012] The fatty acid residue, R³, is any suitable fatty acid that immobilizes the compound of formula (I) on the cytoplasmic side of the plasma membrane. As commonly understood in the art, a fatty acid is a carboxylic acid with a long aliphatic tail, and can be saturated, unsaturated, or a combination thereof. Typically, fatty acids are understood to have at least 8 carbon atoms, e.g., caprylic acid (octanoic acid) and up to about 30 carbons (e.g., 8-30 carbon atoms, 12-24 carbon atoms). The fatty acid can be natural or synthetic, and can have an odd or even number of carbon atoms. Most of the natural fatty acids have an even number of carbon atoms. Examples of saturated fatty acids include lauric acid (dodecanoic acid), myristic acid (tetradecanoic acid), palmitic acid (hexadecanoic acid), stearic acid (octadecanoic acid), and arachidic acid (eicosanoic acid). Examples of unsaturated fatty acids include alpha-linolenic acid, docosahexaenoic acid, eicosapentaenoic acid, linoleic acid, arachidonic acid, oleic acid, and erucic acid. A "fatty acid residue" means a fatty acid with a hydrogen or hydroxy removed to leave an open valency for bonding to the bifunctional linker (i.e., R²) in a compound of formula (I). In an embodiment, the fatty acid residue is selected from the group consisting of myristoyl, palmitoyl, and stearoyl. [0013] The dendrimer residue comprises at least one fatty acid residue, typically 2, 3, or more of a residue, for example, the fatty acid residue as described herein. Dendrimers are typically well-defined globular or rod-like macromolecules constructed around a core unit. During synthesis, each successive reaction step leads to an additional "generation" of branching. Typically, dendrimers exhibit monodispersity, which means that all the molecules are exactly the same in terms of their structure, composition, and molecular weight. However, because the syntheses of higher generations require numerous steps, the final products often contain defects. The core unit is any suitable unit that is polyfunctional. A dendrimer with multiple fatty acid residues can provide the advantage of a firmer anchor to the plasma membrane.

[0014] In any of the embodiments, R⁴ and R⁵ are the same or different and each is hydrogen or optionally substituted C_1-12 alkyl and/or R and R⁷ are the same or different and each is hydrogen, optionally substituted C_1-12 alkyl, or optionally substituted C_1-12 haloalkyl. [0015] In an embodiment, the compound of formula (I) is

[0016] As regards the term "substituted" referring to the various groups in formula (I), any one of the groups that can be substituted, wherever possible, generally can have 1 to 10 substituents (e.g., 1 to 8, 1 to 6, 1 to 4, 1 to 3 substituents) that are independently selected from the group consisting of C_1-12 alkyl, C_3-30 cycloalkyl, C_6-30 aryl, C_1-12 alkoxy, C_6-30 aryloxy, acyloxy, formyl, carboxyl, C_1-12 alkylcarbonyl, nitrile, phenylcarbonyl, benzylcarbonyl, halo, cyano, hydroxy, mercapto, amino, C_1-12 alkylamino, C_1-12 diallcylamino, C_6-30 arylamino, and C_6-30 diarylamino.

[0017] For example, a substituted alkyl can be cyanoalkyl, hydroalkyl, mercaptoalkyl, aminoalkyl, arylalkyl, alkoxyalkyl, aryloxyalkyl, formylalkyl, carboxylalkyl, etc. A substituted alkenyl can be, for example, cyanoalkenyl, hydroalkenyl, mercaptoalkenyl, aminoalkenyl, arylalkenyl, alkoxyalkenyl, aryloxyalkenyl, formylalkenyl, carboxylalkenyl, etc. A substituted cycloalkyl can be, for example, cyanocycloalkyl, hydrocycloalkyl, mercaptocycloalkyl, aminocycloalkyl, arylcycloalkyl, alkoxycycloalkyl, aryloxycycloalkyl, formylcycloalkyl, carboxylcycloalkyl, etc. A substituted aryl can be, for example, cyanoaryl, hydroaryl, mercaptoaryl, aminoaryl, alkoxyaryl, aryloxyaryl, formylaryl, carboxylaryl, etc. A substituted alkylcarbonyl can be, for example, cyanoalkylcarbonyl, hydroalkylcarbonyl, mercaptoalkylcarbonyl, aminoalkylcarbonyl, arylalkylcarbonyl, alkoxyalkylcarbonyl, aryloxyalkylcarbonyl, formylalkylcarbonyl, carboxylalkylcarbonyl, etc. A substituted aroyl can be, for example, cyanoaroyl, hydroaroyl, mercaptoaroyl, aminoaroyl, alkoxyaroyl, aryloxyaroyl, formylaroyl, carboxylaroyl, etc.

[0018] Referring now to terminology used generically herein, the term "alkyl" implies a straight or branched alkyl substituent containing from, for example, 1 to 12 carbon atoms, preferably from 1 to 8 carbon atoms, more preferably from 1 to 6 carbon atoms. Examples of such substituents include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert- butyl, pentyl, isoamyl, hexyl, octyl, dodecanyl, and the like.

[0019] The term "alkenyl," as used herein, means a linear alkenyl substituent containing from, for example, 2 to 12 carbon atoms (branched alkenyls are 3 to 12 carbons atoms), preferably from 2 to 8 carbon atoms (branched alkenyls are preferably from 3 to 8 carbon atoms), more preferably from 3 to 6 carbon atoms. Examples of such substituents include propenyl, isopropenyl, n-butenyl, sec-butenyl, isobutenyl, tert-butenyl, pentenyl, isopentenyl, hexenyl, octenyl, dodecenyl, and the like.

[0020] The term "cycloalkyl," as used herein, means a cyclic alkyl substituent containing from, for example, 3 to 30 carbon atoms, preferably 3 to 8 carbon atoms, preferably from 5 to 8 carbon atoms, more preferably from 5 to 6 carbon atoms. Examples of such substituents include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. [0021] The term "aryl" refers to an unsubstituted or substituted aromatic carbocyclic substituent, as commonly understood in the art, and includes monocyclic and polycyclic aromatics such as, for example, phenyl, biphenyl, tolyl, naphthyl, xylyl, anthracenyl and the like. An aryl substituent generally contains from, for example, 6 to 30 carbon atoms, preferably from 6 to 18 carbon atoms, more preferably from 6 to 14 carbon atoms and most preferably from 6 to 10 carbon atoms. It is understood that the term aryl applies to cyclic substituents that are planar and comprise 4n+2 π electrons, according to Hϋckel's Rule. [0022] The term "heterocyclyl" means a stable, saturated, or partially unsaturated monocyclic, bridged monocyclic, bicyclic, and spiro ring system containing 5 to 7 ring members of carbon atoms and other atoms selected from nitrogen, sulfur and/or oxygen. Preferably, a heterocyclyl is a 5 or 6-membered monocyclic ring and contains one, two, or three heteroatoms selected from nitrogen, oxygen, and/or sulfur. The heterocyclyl may be attached to the parent structure through a carbon atom or through any heteroatom of the heterocyclyl that results in a stable structure. Examples of such heterocyclic rings are isoxazolyl, imidazolinyl, thiazolinyl, imidazolidinyl, pyrrolyl, pyrrolinyl, pyranyl, pyrazinyl, piperidyl, morpholinyl, and triazolyl.

[0023] The term "heteroaryl" refers to aromatic 5 or 6 membered monocyclic groups, 9 or 10 membered bicyclic groups, and 11 to 14 membered tricyclic groups which have at least one heteroatom (O, S or N) in at least one of the rings. Each ring of the heteroaryl group containing a heteroatom can contain one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen atoms may optionally be quaternized. Heteroaryl groups which are bicyclic or tricyclic must include at least one folly aromatic ring but the other fused ring or rings may be aromatic or non-aromatic. The heteroaryl group may be attached at any available nitrogen or carbon atom of any ring. Illustrative examples of heteroaryl groups are pyridinyl, pyridazinyl, pyrimidyl, pyrazinyl, benzimidazolyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3,)- and

(l,2,4)-triazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, furyl, thienyl, isothiazolyl, thiazolyl, furyl, phienyl, isoxazolyl, oxadiazolyl, and oxazolyl.

[0024] The term "alkoxy" embraces linear or branched alkyl groups that are attached to an ether oxygen. The alkyl group is the same as described herein. Examples of such substituents include methoxy, ethoxy, t-butoxy, and the like. The term "aryloxy" refers to substituents that have an aryl group attached to an ether oxygen. The aryl group is the same as described herein. An example of such substituents is phenoxy.

[0025] The terms "alkylamino," "cycloalkylamino," and "arylamino" refer to a group with one hydrogen and one alkyl, cycloalkyl, or aryl group, respectively, directly attached to a trivalent nitrogen atom. The terms "dialkylamino" and "diarylamino" refer to a group with two of the same or different alkyl or aryl groups, respectively, directly attached to a trivalent nitrogen atom.

[0026] The terms "C_1-12 alkylamino-C_1-12 alkyl," "C_3-S0 cycloalkylamino-C_1-12 alkyl," and

"C_6-30 arylamino-Ci-π alkyl" refer to the group "R' -NH-R," in which R is an alkyl group, and

R' is alkyl, cycloalkyl, or aryl group, respectively.

[0027] The term "amino-C_1-12 alkylamino" refers to the group "NH₂-R-NH₂," in which R is alkyl as described herein. The term "bisamino-C_1-12 alkyl-C_1-12 alkylamino" refers to the group "NH2-R-N(R")-R'-NH₂," in which R and R' are the same or different and each is an alkyl group as described herein. R" is hydrogen or an alkyl group as described herein.

[0028] The term "halo" as used herein, means a substituent selected from Group VIIA, such as, for example, fluorine, bromine, chlorine, and iodine. Preferably, the halo is bromine or chlorine.

[0029] The term "haloalkyl" as utilized herein means alkyl as defined herein, wherein at least one hydrogen atom is replaced with a halo substituent as defined herein. Haloalkyls include, for example, chloromethyl, bromomethyl, and chloroethyl.

[0030] The term "alkylcarbonyl" refers to the group -C(O)R, in which R is an alkyl group as described herein. The term "aroyl" refers to the group -C(O)Ar, in which Ar is an aryl group as described herein. [0031] In accordance with an embodiment, the compounds of the invention induce a torsional twist in the DNA of the host virus following binding to the minor groove. [0032] The compounds of formula (I) can be prepared by any suitable method. For example, the benzindole group can be prepared first, and the linker added. Next, the fatty acid residue or dendrimer residue comprising at least one fatty acid residue can be attached to the terminal end of the linker on the benzindole moiety. Alternatively, the linker can be attached to the fatty acid residue or dendrimer residue comprising at least one fatty acid residue, and then the benzindole moiety can be attached to the terminal end of the linker to form the compounds of formula (I).

[0033] Preferably, inert organic solvents, which are solvents that are passive or non- reactive under the conditions of the reaction being described in conjunction therewith are used in the synthesis of compounds of formula (I). Such solvents include, for example, benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), dimethylformamide ("DMF"), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, pyridine, and the like.

[0034] The reaction temperature can vary widely depending on the reactivity of the reactants. However, the temperature should not be so high as to decompose the reactants or so low as to cause inhibition of the condensation or freezing of the solvent. Unless specified to the contrary, the reactions described herein take place at atmospheric pressure over a temperature range from the temperature of dry ice to about 100 °C, more preferably from about 10 ⁰C to about 50 °C, and most preferably at "room" or "ambient" temperature ("RT"), e.g. about 20 ⁰C.

[0035] The time required for the reactions described herein will depend to a large extent on the temperature being used and the relative reactivities of the starting materials. Therefore, the reaction time can vary greatly, for example from about five minutes to about two days. Various known techniques such as different types of chromatography, especially thin layer chromatography ("TLC"), gas chromatography ("GC"), or spectroscopy can be used to follow the progress of the reaction by the disappearance of the starting compound(s). [0036] Unless otherwise specified, the reaction times and conditions are intended to be approximate.

[0037] Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography, thick-layer chromatography, centrifugal chromatography, or preparatory HPLC, or a combination of these procedures.

[0038] Suitable reactions and reaction parameters are well known to those skilled in the art. See, e.g., WO 2005/032594 and WO 2003/072058, which are incorporated herein by reference.

[0039] The present invention also provides a pharmaceutical composition comprising at least one compound or salt of formula (I) and a pharmaceutically acceptable carrier. The composition can further comprise other active agents, such as adjuvants and other HIV and AIDS therapies and vaccines.

[0040] Any suitable pharmaceutically acceptable carrier can be used within the context of the invention, and such carriers are well known in the art. For example, the carrier comprises aqueous and non-aqueous solutions, a liquid that contains a buffer and a salt, sterile powders, granules, and tablets, a semipermeable matrix, a parenteral vehicle, or an intravenous vehicle. The choice of carrier will be determined, in part, by the particular site to which the pharmaceutical composition is to be admim^'stered and the particular method used to administer the pharmaceutical composition.

[0041] Suitable formulations include aqueous and non-aqueous solutions, isotonic sterile solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood or other bodily fluid of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. In one embodiment, the pharmaceutically acceptable carrier is a liquid that contains a buffer and a salt. The formulation can be presented in unit-dose or multi-dose sealed containers, such as ampules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water, immediately prior to use. Extemporaneous solutions and suspensions can be prepared from sterile powders, granules, and tablets. [0042] Further carriers include sustained-release preparations, such as semipermeable matrices of solid hydrophobic polymers containing the active agent, which matrices are in the form of shaped articles (e.g., films, liposomes, or microparticles). [0043] The pharmaceutical composition can include thickeners, diluents, buffers, preservatives, surface active agents, and the like. The pharmaceutical compositions can also include one or more additional active ingredients, such as antimicrobial agents, antiinflammatory agents, anesthetics, and the like. [0044] The pharmaceutical composition comprising the compound of formula (I) can be formulated for any suitable route of administration, depending on whether local or systemic treatment is desired, and on the area to be treated. Desirably, the pharmaceutical composition is formulated for parenteral administration, such as intravenous, intraperitoneal, intraarterial, intrabuccal, subcutaneous, or intramuscular injection. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for suspension in liquid prior to injection, or as emulsions. Additionally, parental administration can involve the preparation of a slow-release or sustained-release system, such that a constant dosage is maintained. Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives also can be present such as, for example, antimicrobials, anti-oxidants, chelating agents, and inert gases and the like.

[0045] The pharmaceutical composition also can be administered orally. Oral compositions can be in the form of powders or granules, suspensions or solutions in water or non-aqueous media, capsules, sachets, or tablets. Thickeners, flavorings, diluents, emulsifiers, dispersing aids, or binders may be desirable.

[0046] Formulations for rectal administration can be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate. Formulations suitable for vaginal administration can be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulas. Similarly, the active ingredient can be combined with a lubricant as a coating on a condom. Indeed, preferably, the active ingredient is applied to any contraceptive device, including, but not limited to, a condom, a diaphragm, a cervical cap, a vaginal ring, and a sponge.

[0047] Suitable carriers and their formulations are further described in A.R. Gennaro, ed., Remington: The Science and Practice of Pharmacy (19th ed.), Mack Publishing Company, Easton, PA (1995). [0048] The compound of the invention or a composition thereof can potentially be administered as a pharmaceutically acceptable acid-addition, base neutralized or addition salt, formed by reaction with inorganic acids, such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, benzene sulfonate, methane sulfonate, tartaric acid, citric acid, gluconic acid, salicylic acid, and fumaric acid, or by reaction with an inorganic base, such as sodium hydroxide, ammonium hydroxide, potassium hydroxide, and organic bases, such as mono-, di-, trialkyl, and aryl amines and substituted ethanolamines. [0049] The compound or a pharmaceutical composition comprising at least one compound of formula (I) can be administered in or on a device that allows controlled or sustained release of the compound of formula (I), such as a sponge, biocompatible meshwork, mechanical reservoir, or mechanical implant. Implants (see, e.g., U.S. Patent 5,443,505), devices (see, e.g., U.S. Patent 4,863,457), such as an implantable device, e.g., a mechanical reservoir or an implant or a device comprised of a polymeric composition, are particularly useful for administration of the active agents. The pharmaceutical compositions of the inventive method also can be administered in the form of sustained-release formulations (see, e.g., U.S. Patent 5,378,475) comprising, for example, gel foam, hyaluronic acid, gelatin, chondroitin sulfate, a polyphosphoester, such as bis-2-hydroxyethyl-terephthalate (BHET), and/or a polylactic-glycolic acid. Of course, administration of the compound or pharmaceutical composition can be accomplished via any route that efficiently delivers the active agents to the target tissue.

[0050] In an embodiment, the present invention provides a method of prophylactically or therapeutically inhibiting a retroviral infection in a mammal comprising administering an effective amount of at least one compound of formula (I). The mammal is any suitable subject infected by, or at risk of infection by, a retroviral infection. A suitable mammal includes a human, feline, or simian. By "prophylactically" is meant any degree in inhibition of the onset of a retroviral infection, including complete inhibition. By "therapeutic" is meant any degree in inhibition of a retroviral infection in the mammal (e.g., human), including inhibiting the growth or replication of a virus, inhibiting entry of a virus into a host cell, and limiting the spread of viral infection by inhibiting cell to cell fusion. Preferably, the compound of formula (I) is administered before viral infection or immediately upon determination of viral infection and is continuously administered until the virus is undetectable.

[0051] The retroviral infection can be HIV (Human Immunodeficiency Virus), FIV (Feline Immunodeficiency Virus), SIV (Simian Immunodeficiency Virus), or HTLV (Human T cell lymphotropic virus). The inventive method can inhibit infection by any type of HIV, but preferably inhibits HIV-I and/or HIV-2 infection. The inventive method can be used to inhibit infection by any HIV group (e.g., groups M and/or O), and subtype (e.g., clades A, B, C, D, E, EA, F, and/or G).

[0052] hi an embodiment of the invention, the present invention provides a method of prophylactically or therapeutically inhibiting a viral infection in a mammal, wherein the viral genome is replicated in the cytoplasm of the mammal's cell, said method comprising administering an effective amount of at least one compound of formula (I). The viral infection can be any infection in which the viral genome (DNA or RNA) is replicated in the cytoplasm.

[0053] In each of the above-described methods, the administering may be in vivo, or may be ex vivo. Preferably, the compounds are administered in vivo. In vivo treatment is useful for treating diseases in a mammal, preferably the mammal is a human; and ex vivo treatment is useful for purging body fluids, such as blood, plasma, bone marrow, and the like, for return to the body. Thus, the present invention also provides a method of removing a virus from a sample (e.g., transcribed retrovirus).

[0054] An "effective amount" means an amount sufficient to show a meaningful benefit in an individual, e.g., promoting at least one aspect of inhibition of a retrovirus, or treatment, healing, prevention, delay of onset, or amelioration of other relevant medical condition(s) associated with a particular retrovirus. Effective amounts may vary depending upon the biological effect desired in the individual, condition to be treated, and/or the specific characteristics of the compound of formula (I), and the individual, ha this respect, any suitable dose of the compound of formula (I) can be administered to the mammal, according to the type of retrovirus to be treated. Various general considerations taken into account in determining the "effective amount" are known to those of skill in the art and are described, e.g., in Gilman et al., eds., Goodman And Gilman's: The Pharmacological Bases of Therapeutics, 8th ed., Pergamon Press, 1990; and Remington's Pharmaceutical Sciences, 17th Ed., Mack Publishing Co., Easton, Pa., 1990, each of which is herein incorporated by reference. The dose of the compound of formula (I) desirably comprises about 0.1 mg per kilogram (kg) of the body weight of the mammal (mg/kg) to about 400 mg/kg (e.g., about 0.75 mg/kg, about 5 mg/kg, about 30 mg/kg, about 75 mg/kg, about 100 mg/kg, about 200 mg/kg, or about 300 mg/kg). In another embodiment, the dose of the compound of formula (I) comprises about 0.5 mg/kg to about 300 mg/kg (e.g., about 0.75 mg/kg, about 5 mg/kg, about 50 mg/kg, about 100 mg/kg, or about 200 mg/kg), about 10 mg/kg to about 200 mg/kg (e.g., about 25 mg/kg, about 75 mg/kg, or about 150 mg/kg), or about 50 mg/kg to about 100 mg/kg (e.g., about 60 mg/kg, about 70 mg/kg, or about 90 mg/kg). For ex vivo uses, such as virucidal treatments of inanimate objects or materials, blood or blood products, or tissues, the amount of the compound of formula (I) to be employed should be sufficient that any virus or virus-producing cells present will be rendered noninfectious or will be destroyed. [0055] The compound of formula (I) can be combined with other well-known HIV therapies and prophylactic vaccines already in use. The combination of the compound of formula (I) can generate an additive or a synergistic effect with current treatments. The compound of formula (I) can be combined with other HFV and AIDS therapies and vaccines, such as highly active antiretroviral therapy (HAART), which comprises a combination of protease inhibitors and reverse transcriptase inhibitors, azidothymidine (AZT), structured treatment interruptions of HAART, cytokine immune enhancement therapy (e.g., interleukin (IL)-2, IL-12, CD40L + IL-12, IL-7, HIV protease inhibitors (e.g., ritonavir, indinavir, and nelfinavir, etc.), and interferons (IFNs), cell replacement therapy, recombinant viral vector vaccines, DNA vaccines, inactivated virus preparations, immunosuppressive agents, such as Cyclosporin A, and cyanovirin therapy (see, e.g., U.S. Patent No. 6,015,876 and International Patent Application Publication No. WO 03/072594). Such therapies can be administered in the manner already in use for the known treatment providing a therapeutic or prophylactic effect (see, e.g., Silvestri et al. Immune Intervention in AIDS, hi: Immunology of Infectious Disease, H.E. Kauffman, A. Sher, and R. Ahmed eds., ASM Press, Washington DC (2002)).

[0056] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

[0057] The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms "comprising," "having," "including," and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to,") unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. AU methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0058] Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

CLAIM(S): 1. A compound of the formula (I):

(D wherein

RMs NR⁸, O, or S;

R² is a linker;

R³ is a fatty acid residue or a dendrimer residue comprising at least one fatty acid residue;

R⁴ and R⁵ are the same or different and each is selected from the group consisting of hydrogen, optionally substituted C_1-12 alkyl, optionally substituted C_2-12 alkenyl, optionally substituted Cs_-30 cycloalkyl, optionally substituted C_6-30 aryl, optionally substituted Cj_-12 alkylcarbonyl, and optionally substituted C_6-30 aroyl;

R⁶ and R⁷ are the same or different and each is selected from the group consisting of hydrogen, optionally substituted C_1-12 alkyl, optionally substituted C_2-12 alkenyl, optionally substituted C_3-30 cycloalkyl, optionally substituted C_6-30 aryl, optionally substituted C_1-12 haloalkyl, optionally substituted C_1-I2 alkylcarbonyl, and optionally substituted C_6-30 aroyl;

R⁸ is hydrogen, optionally substituted C_1-12 alkyl, optionally substituted C_2-I2 alkenyl, optionally substituted C_3-30 cycloalkyl, or optionally substituted C_6-30 aryl and n is 1, 2, or 3; or a salt thereof.

2. The compound or salt of claim 1, wherein the fatty acid residue comprises 8 to 30 carbon atoms.

3. The compound or salt of claim 1 or 2, wherein the fatty acid residue is selected from the group consisting of lauroyl, myristoyl, palmitoyl, stearoyl, arachidoyl, alpha- linolenoyl, docosahexaenoyl, eicosapentaenoyl, linoloyl, arachidonoyl, oloyl, and erucoyl.

4. The compound or salt of any of claims 1-3, wherein the fatty acid residue is selected from the group consisting of myristoyl, palmitoyl, and stearoyl.

5. The compound or salt of any of claims 1-4, wherein R² is a bifunctional linker and n is 1.

6. The compound or salt of any of claims 1-5, wherein R² is a bifunctional linker derived from a compound comprising one or more amino groups, one or more carboxyl groups, and/or one or more aryl, heteroaryl, or heterocyclyl groups.

7. The compound or salt of any of claims 1-5, wherein R² is derived from a polyamine.

8. The compound or salt of claim 7, wherein the polyamine is amino-C_1-12 alkylamino, bisamino-C_1-12 alkylpiperazinyl, or MSaIiUnO-C_1-12 alkyl-C_1-12 alkylamino.

9. The compound or salt of claim 7, wherein the polyamine is spermidine.

10. The compound or salt of claim 6, wherein R² is derived from an amino acid.

11. The compound or salt of claim 10, wherein the amino acid is β-alanine.

12. The compound or salt of any of claims 1 -6, wherein R² is selected from the group consisting of

wherein

X' is hydrogen, C_1-12 alkyl, C_3-30 cycloalkyl, or C_6-30 aryl; and n and m are independently 0 to 3.

13. The compound or salt of any of claims 1-12, wherein R⁴ and R⁵ are the same or different and each is hydrogen or optionally substituted C_1-12 alkyl.

14. The compound or salt of any of claims 1-13, wherein R⁶ and R⁷ are the same or different and each is hydrogen, optionally substituted C_1-12 alkyl, or optionally substituted Ci_-12 haloalkyl.

15. The compound or salt of claim 1 , wherein the compound is

16. A pharmaceutical composition comprising the compound or salt of any of claims 1-15 and a pharmaceutically acceptable carrier.

17. A method of prophylactically or therapeutically inhibiting a retroviral infection in a mammal comprising administering an effective amount of at least one compound or salt of any of claims 1-14.

18. The method of claim 17, wherein the retroviral infection is HIV, FIV, SIV, or HTLV.

19. The method of claim 18, wherein the HIV is HIV- 1 or HTV-2.

20. Use of the compound or salt of any of claims 1 - 15 in medicine.

21. Use of the compound of any of claims 1 - 15 in the manufacture of a medicament for the prophylactic or therapeutic inhibition of a retroviral infection.

23. Compound or salt of any one of claims 1 - 15 for use in the prophylactic or therapeutic treatment of a retroviral infection.