阅读说明：本技术 比卡格韦的代谢物 (Metabolites of bicalutavir ) 是由 金浩崙 边衡正 B·J·史密斯 R·萨布拉玛尼安 王建红 于 2019-01-18 设计创作，主要内容包括：本发明提供了抗病毒药物比卡格韦(bictegravir)的代谢物,包括其组合物和盐,可用于预防和/或治疗HIV以及与比卡格韦的施用有关的分析方法。(The present invention provides metabolites of the antiviral drug bicalutavir (bictegravir), including compositions and salts thereof, useful in the prevention and/or treatment of HIV and in analytical methods related to the administration of bicalutavir.)

1. A compound selected from M15, M20, and M23:

or a pharmaceutically acceptable salt thereof, which is substantially isolated.

2. A compound comprising a compound selected from M15, M20, and M23:

or a pharmaceutically acceptable salt thereof, wherein the compound or pharmaceutically acceptable salt thereof is present in the composition in an amount greater than about 25% by weight.

3. The composition of claim 2, wherein the compound or pharmaceutically acceptable salt thereof is present in the composition in an amount greater than about 50% by weight.

4. The composition of claim 2, wherein the compound or pharmaceutically acceptable salt thereof is present in the composition in an amount greater than about 75% by weight.

5. A compound selected from M15, M20, and M23:

or a pharmaceutically acceptable salt thereof, said preparation having a purity of greater than about 95%.

6. A pharmaceutical composition comprising a compound selected from M15, M20, and M23:

or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

7. The pharmaceutical composition of claim 6, further comprising one to three additional therapeutic agents.

8. The pharmaceutical composition of claim 7, wherein the one to three additional therapeutic agents are anti-HIV agents.

9. The pharmaceutical composition of claim 8, wherein each of the one to three additional therapeutic agents is selected from the group consisting of: HIV protease inhibitors, HIV reverse transcriptase non-nucleoside inhibitors, HIV reverse transcriptase nucleotide inhibitors, and combinations thereof.

10. A method of preventing or treating HIV infection in a human comprising administering to the human a therapeutically effective amount of a compound selected from the group consisting of M15, M20, and M23:

or a pharmaceutically acceptable salt thereof.

11. The method of claim 10, further comprising administering to the human a therapeutically effective amount of one to three additional therapeutic agents.

12. The method of claim 11, wherein the one to three additional therapeutic agents are anti-HIV agents.

13. The method of claim 12, wherein the one to three additional therapeutic agents are selected from the group consisting of: HIV protease inhibitors, HIV reverse transcriptase non-nucleoside inhibitors, HIV reverse transcriptase nucleotide inhibitors, and other drugs for the treatment of HIV, and combinations thereof.

14. A method of detecting or confirming administration of bicalutavir to a patient comprising identifying in a biological sample obtained from said patient a compound selected from the group consisting of M15, M20 and M23:

or a salt thereof.

15. The method of claim 14, wherein the biological sample is derived from plasma, urine, or feces.

16. A method of measuring the metabolic rate of bicalutavir in a patient comprising measuring at one or more time points after administration of bicalutavir a compound selected from the group consisting of M15, M20 and M23:

or the amount of a salt thereof.

17. The method of claim 16, wherein the amount of the compound is measured from a blood sample.

18. The method of claim 16, wherein the amount of the compound is measured from plasma.

19. The method of claim 16, wherein the amount of the compound is measured from a urine sample.

20. The method of claim 16, wherein the amount of the compound is measured from a fecal sample.

21. A method of determining a patient's prophylactic or therapeutic response to bicalutavir in treating HIV infection comprising measuring in said patient at one or more time points after administration of bicalutavir a compound selected from the group consisting of M15, M20 and M23:

or the amount of a salt thereof.

22. A method of optimizing bicalutavir dosage for a patient in need of treatment with bicalutavir comprising measuring in said patient at one or more time points after administration of bicalutavir a compound selected from the group consisting of M15, M20 and M23:

or the amount of a salt thereof.

Technical Field

The present invention provides metabolites of the antiviral drug bicalutavir (bictegravir), including compositions and salts thereof, useful in the prevention and/or treatment of HIV, and analytical methods associated with the administration of bicalutavir.

Background

The HIV/AIDS epidemic lives millions of people, and millions of people are currently infected. Antiretroviral therapy has turned HIV infection into a chronic, controlled disease; however, there is no cure for HIV. Patients must adhere to treatment for life, which makes drug resistance a persistent problem. In addition, concomitant treatment of other diseases and conditions becomes more prevalent as patients age, thereby increasing the likelihood of drug-drug interactions with HIV antiviral therapy. Therefore, the continued development of new antiviral drugs and combination therapies is a priority in the field of HIV therapeutics.

Integrase chain transfer inhibitors (INSTI) are a class of antiretroviral drugs that act by inhibiting the essential HIV protein integrase to allow insertion of the viral DNA genome into the chromatin of host cells. An example of an INSTI is Bicavir (BIC), currently being tested in combination with emtricitabine (FTC) and Tenofovir Alafenamide (TAF) in human clinical trials. Bicalutavir has the molecular structure shown below and is described in WO 2014/100212.

In view of the widespread HIV infection and the challenge to overcome drug resistance and drug-drug interactions, there is a continuing need for new and improved antiviral agents. The metabolites of bicalutavir and the compositions and methods of use thereof described herein are intended to meet this need.

Disclosure of Invention

The present invention provides a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof, which is substantially isolated.

The present invention also provides compositions comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

The invention also provides a preparation comprising a compound of the invention or a pharmaceutically acceptable salt thereof.

The present invention also provides a method of preventing or treating HIV infection in a human by administering to the human a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.

The present invention also provides a method of detecting or confirming administration of bicalutavir to a patient comprising identifying a compound of the present invention or a salt thereof in a biological sample obtained from said patient.

The present invention also provides a method of measuring the metabolic rate of bicalutavir in a patient comprising measuring the amount of a compound of the present invention or a salt thereof in said patient at one or more time points after administration of bicalutavir.

The present invention also provides a method of determining the prophylactic or therapeutic response of a patient to pegavir in the treatment of HIV infection comprising measuring the amount of a compound of the invention or a salt thereof in said patient at one or more time points after administration of pegavir.

The present invention also provides a method of optimizing the dosage of bicalutavir for a patient in need of treatment with bicalutavir comprising measuring the amount of a compound of the present invention or a salt thereof in said patient at one or more time points after administration of bicalutavir.

Drawings

FIG. 1 shows a single oral dose of 100 μ Ci/100mg of the human healthy adult male subject¹⁴C]After bicalutavir, proposed metabolite structures and biotransformation pathways of bicalutavir in human plasma, urine and feces.

Fig. 2 shows an extracted ion chromatogram of M15 obtained by analyzing an M15 standard solution.

FIG. 3 shows a single oral dose (100mg, 100. mu. Ci) of [ alpha ], [¹⁴C]The radiochromatogram and extracted ion chromatogram of metabolite M15 obtained by combining plasma samples for 8 hours after bicalutavir.

FIG. 4 shows a single oral dose of the standard solution of M15 (100mg, 100. mu. Ci) in a human male subject by single injection or co-injection of the solution¹⁴C]And combining the plasma samples for 8 hours to obtain an extracted ion chromatogram of the Bicagvir.

FIG. 5A shows the MS precursor and MS/MS product ion mass spectra (M/z626) obtained by analyzing a standard solution of M15.

FIG. 5B shows the proposed structure and proposed fragmentation pattern of M15.

FIG. 6 shows a single oral dose (100mg, 100. mu. Ci) of [ alpha ], [¹⁴C]MS precursor and MS/MS product ion Mass Spectrometry (M/z626) of metabolite M15 from 8 hour pooled plasma samples obtained after bicalutavir.

Figure 7 shows an extracted ion chromatogram obtained by analysis of a standard solution of M20.

FIG. 8 shows a single oral dose (100mg, 100. mu. Ci) of [ alpha ], [¹⁴C]Combining the extracted ion chromatogram and the radioactive chromatogram obtained after the Bikagevir for 8 hours to obtain the Bikagevir.

FIG. 9 shows a pass sheetA standard solution of M20 is injected separately or together with a single oral dose (100mg, 100. mu. Ci) of the drug in a human male subject¹⁴C]And combining the plasma samples for 8 hours to obtain an extracted ion chromatogram of the Bicagvir.

FIG. 10A shows the product ion (M/z 546) mass spectrum of M20 obtained by analysis of a standard solution of M20.

FIG. 10B shows the proposed structure and proposed fragmentation pattern of M20.

FIG. 11 shows a single oral dose of (100mg, 100. mu. Ci) of [ alpha ]¹⁴C]Product ion (M/z 546) mass spectra of M20 from pooled plasma samples obtained 8 hours after bicalutavir.

FIG. 12 shows proposed structures of the in vitro identified BIC metabolites M465a, M465b, M465c, M305, M625, M641 and M611.

Detailed Description

The present invention relates to metabolites of bicalutavir and uses thereof. In some embodiments, the metabolite is bicalutar that has undergone (1) glucuronidation, (2) dehydrogenation, (3) hydroxylation, (4) hydroxylation with loss of fluorine, (5) sulfation or glucuronic acid conjugation of hydroxy-bicalutar, (6) sulfation or glucuronic acid or cysteine conjugation of defluoro-hydroxy-bicalutar, or (7) combinations thereof. In some embodiments, the metabolite is selected from M15, M58, M51, M52, M21, M23, M54, M55, M22, M53, M20, M35, M12, M59, M45, M56, M16, M57, M9, and M37 (see fig. 1). In some embodiments, the metabolite is selected from M465a, M465b, M465c, M305, M625, M641, and M611 (see fig. 12).

In some embodiments, the metabolite is a compound selected from M15, M20, and M23:

in some embodiments, the metabolite is a compound selected from M15 and M20. In some embodiments, the metabolite is M15. In some embodiments, the metabolite is M20. In some embodiments, the metabolite is M23.

The invention also includes salts, such as pharmaceutically acceptable salts, of the metabolites of the invention. Salts generally refer to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety into its salt form. Pharmaceutically acceptable salts are those that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; alkali metal or organic salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. In general, these salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid. A list of suitable salts can be found in Remington's Pharmaceutical sciences (Remington's Pharmaceutical sciences), 17 th edition, Mack Publishing Company, Iston, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66,2(1977), which are incorporated herein by reference in their entirety. In a particular embodiment, the pharmaceutically acceptable salt is a sodium salt.

In some embodiments, the metabolite compound or salt thereof is substantially isolated. By "substantially isolated" is meant that the metabolite compound or salt thereof is at least partially or substantially separated from the environment in which it is formed or detected. Partial separation may include, for example, enrichment of a composition with a compound of the invention. Substantial separation may include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the metabolite or salt thereof. In some embodiments, M15, M20, and M23 are substantially separated.

The metabolite of the invention or a salt thereof may be present in a composition, wherein the composition comprises at least one compound other than the metabolite. In some embodiments, the composition comprises more than one metabolite of the invention. In some embodiments, the composition comprises one or more metabolites of the invention or salts thereof, and bicalutavir or salts thereof. The composition may be a mixture comprising the metabolite of the invention or a salt thereof, and one or more solvents, substrates, carriers, and the like. In some embodiments, the composition comprises the metabolite of the invention or a salt thereof in an amount of greater than about 25% by weight. In some embodiments, the composition comprises the metabolite of the invention or a salt thereof in an amount of greater than about 50% by weight. In some embodiments, the composition comprises the metabolite of the invention or a salt thereof in an amount of greater than about 75% by weight. In some embodiments, the composition comprises the metabolite of the invention or a salt thereof in an amount of greater than about 80% by weight. In some embodiments, the composition comprises the metabolite of the invention or a salt thereof in an amount of greater than about 85% by weight. In some embodiments, the composition comprises the metabolite of the invention or a salt thereof in an amount of greater than about 90% by weight. In some embodiments, the composition comprises the metabolite of the invention or a salt thereof in an amount of greater than about 95% by weight.

The preparation of the metabolite of the present invention or a salt thereof may be prepared by chemical synthesis or by isolating the metabolite from a biological sample. The purity of the article may be greater than about 50%, greater than about 60%, greater than about 70%, greater than about 80%, greater than about 90%, or greater than about 95%. Purity can be determined by any conventional method, such as by chromatography or spectroscopy, such as NMR, MS, LC-MS, and the like.

The metabolites of the invention are asymmetric (e.g., have one or more stereogenic centers). Unless otherwise indicated, all stereoisomers, such as enantiomers and diastereomers, are meant. Methods of how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis.

The metabolites of the present invention also include all isotopes of atoms occurring in the metabolites. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. In some embodiments, the metabolite includes at least one deuterium.

As used herein, the term "compound" or "metabolite" is meant to include all stereoisomers, geometric isomers, tautomers and isotopes of the described structures.

As used herein, the term "metabolite" is meant to include any and all metabolic derivatives of bicalutavir, including derivatives that have undergone one or more transformation processes selected from the group consisting of: (1) glucuronidation, (2) dehydrogenation, (3) hydroxylation, (4) hydroxylation with loss of fluorine, (5) sulfation of hydroxy-bicagvir or glucuronic acid conjugation; (6) sulphated or glucuronic or cysteine conjugation of defluoro-hydroxy-bikavir. In some embodiments, the metabolites of the present invention undergo more than one transformation process, including the metabolic transformation of a bicalutavir derivative that has undergone one or more metabolic transformations.

The compound bicalutavir may also be considered a prodrug of the metabolites of the present invention (e.g., prodrugs of metabolites M15, M20, M23, etc.) because bicalutavir is metabolically converted upon administration to provide the metabolites of the present invention. Thus, bicalutavir may be administered to a human as a means of providing the metabolite of the invention to the human, e.g. for the prevention or treatment of HIV infection in a human.

The invention also includes a pharmaceutical composition comprising a metabolite of the invention, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" refers to any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been approved by the U.S. food and drug administration for use in humans or livestock.

Method of producing a composite material

The invention also relates to methods of preventing or treating HIV infection (e.g., HIV-1 and/or HIV-2) in a human by administering to the human a therapeutically effective amount of a metabolite of the invention, or a pharmaceutically acceptable salt thereof. The human may have or be at risk of having an infection.

As used herein, the term "treatment" or "treating" means administering a metabolite, composition thereof, or preparation thereof according to the present invention to reduce or eliminate symptoms of HIV infection and/or reduce the viral load of a patient.

The term "preventing" or "prevention" refers to the administration of a metabolite, composition thereof or product thereof according to the invention after exposure of a human to a virus but before symptoms of the disease appear and/or before the virus is detected in the blood. The term also refers to preventing the appearance of disease symptoms and/or preventing the virus from reaching detectable levels in the blood. The term includes both pre-exposure prophylaxis and post-exposure prophylaxis. The term also refers to the prevention of perinatal transmission of HIV from mother to infant by administration to the mother prior to delivery and to the infant during the first few days of life.

The term "effective amount" or "therapeutically effective amount" refers to an amount of a metabolite according to the invention that, when administered to a patient in need thereof, is sufficient to effect treatment of a disease state, condition or disorder for which the compound has utility. Such an amount will be sufficient to elicit the biological or medical response of the tissue system or patient sought by the researcher or clinician. The amount of metabolite according to the invention that constitutes a therapeutically effective amount will vary depending on factors such as: the compounds and their biological activity, the composition for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of the treatment, the type of disease state or condition being treated and its severity, the drugs used in combination or concomitantly with the compounds of the invention, and the age, body weight, general health, sex and diet of the patient. Such therapeutically effective amounts can be routinely determined by those of ordinary skill in the art, given their own knowledge, current technology, and this disclosure.

Administration of the metabolites of the present invention, or pharmaceutically acceptable salts thereof, may be by any acceptable mode of administration of the agents for similar utility. The pharmaceutical composition of the present invention may be prepared by mixing the metabolite of the present invention or a pharmaceutically acceptable salt thereof with an appropriate pharmaceutically acceptable carrier, and in particular embodiments, formulated into preparations in solid, semi-solid, liquid or gaseous form, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols. Exemplary routes of administration of such pharmaceutical compositions include, but are not limited to, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal, and intranasal. In a particular embodiment, the pharmaceutical composition of the invention is a tablet. In another embodiment, the pharmaceutical composition of the invention is an injection (intramuscular (IM) or Intraperitoneal (IP)). The pharmaceutical compositions of the present invention are formulated such that the active ingredients contained therein are bioavailable at the time the composition is administered to a patient. The composition to be administered to a subject or patient takes the form of one or more dosage units, where for example a tablet may be a single dosage unit and a container of a compound of the invention in aerosol form may contain a plurality of dosage units. The actual methods of preparing such dosage forms are known or will be apparent to those skilled in the art; see, for example, Remington's Pharmaceutical Sciences (Remington's Pharmaceutical Sciences), 20 th edition (Philadelphia College of Pharmacy and Science, 2000). In any event, the composition to be administered will comprise a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, for the treatment of a disease or disorder of interest in accordance with the teachings described herein.

The invention also relates to a method for detecting or confirming administration of bifovir to a patient, comprising identifying a metabolite of the invention or a salt thereof in a biological sample obtained from the patient. In some embodiments, the biological sample is derived from plasma, urine, or feces.

The present invention also relates to a method of measuring the metabolic rate of bicalutavir in a patient, comprising measuring the amount of a metabolite of bicalutavir or a salt thereof in the patient's body at one or more time points after administration of bicalutavir.

The invention also relates to a method for determining the prophylactic or therapeutic response of a patient to pegavir in the treatment of HIV infection, which method comprises measuring the amount of a metabolite of the invention or a salt thereof of the invention in the patient at one or more time points after administration of pegavir.

The invention also relates to a method for optimizing the dose of bicalutavir for a patient in need of treatment with bicalutavir, which comprises measuring the amount of the metabolite or salt of the invention in the patient at one or more time points after administration of bicalutavir. The amount of metabolite may be indicative of the rate at which the patient metabolizes than canavir. Patients who metabolize more rapidly or more efficiently than canavir than other patients may develop higher amounts of metabolites and may require higher doses of the same or additional doses than canavir. A patient who metabolizes less rapidly or less efficiently than canavir than another patient may develop lower amounts of metabolites and may require lower doses of canavir or less than the dose required for canavir as compared to a patient that metabolizes more rapidly than the canavir. Thus, the method of optimizing the dosage of bicalutavir may further comprise determining if the measured amount of metabolite is above or below the average value and adjusting the dosage of bicalutavir accordingly.

The measurement of the amount of the metabolite or salt thereof in the patient may be performed by obtaining a biological sample from the patient and measuring the amount of the metabolite or salt thereof in the sample. In some embodiments, the sample is blood. In other embodiments, the sample is plasma. In other embodiments, the sample is urine. In other embodiments, the sample is stool.

The term "patient" refers to a human or other mammal in need of therapeutic or prophylactic treatment of viral infections, such as HIV infections, such as laboratory animals and domestic pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits), as well as non-domestic animals such as non-human primates, wild mammals, and the like.

Combination therapy

One or more additional pharmaceutical agents may be used in combination with the compounds, salts, and compositions of the present invention to prevent or treat HIV infection (e.g., in a human patient). In some embodiments, the compositions of the present invention further comprise one or more additional therapeutic agents. In some embodiments, the compositions of the present invention further comprise 1 to 3 additional therapeutic agents (a)E.g. 1 to 3 anti-HIV agent). In some embodiments, the one or more additional therapeutic agents are anti-HIV agents.

In the above embodiments, the additional therapeutic agent may be an anti-HIV agent. For example, in some embodiments, the additional therapeutic agent is selected from: HIV protease inhibitors, HIV reverse transcriptase non-nucleoside inhibitors, HIV reverse transcriptase nucleotide inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, entry inhibitors (e.g., CCR5 inhibitors, gp41 inhibitors (i.e., fusion inhibitors) and CD4 attachment inhibitors), CXCR4 inhibitors, gp120 inhibitors, G6PD and NADH oxidase inhibitors, HIV capsid targeting compounds ("capsid inhibitors"; e.g., capsid polymerization inhibitors or capsid disrupting compounds such as those disclosed in WO 2013/006738(Gilead Sciences), US 2013/0165489(University of Pennsylvania) and WO 2013/006792(Pharma Resources)), pharmacokinetic enhancers and other drugs for the treatment of HIV, and combinations thereof. In some embodiments, the anti-HIV agent is an HIV protease inhibitor, an HIV reverse transcriptase non-nucleoside inhibitor, an HIV reverse transcriptase nucleotide inhibitor, a pharmacokinetic enhancer, or a combination thereof. In some embodiments, the anti-HIV agent is an HIV reverse transcriptase nucleoside inhibitor, an HIV reverse transcriptase nucleotide inhibitor, or a combination thereof.

In other embodiments, the additional therapeutic agent is selected from one or more of the following:

(1) an HIV protease inhibitor selected from: amprenavir (amprenavir), atazanavir (atazanavir), fosamprenavir (fosamprenavir), indinavir (indinavir), lopinavir (lopinavir), ritonavir (ritonavir), nelfinavir (nelfinavir), saquinavir (saquinavir), tipranavir (tipranavir), brecanavir, darunavir (daronavir), TMC-126, TMC-114, mozenavir (DMP-450), JE-2147(AG1776), L-756423, RO0334649, KNI-272, DPC-681, DPC-684, GW640385X, DG17, PPL-100, DG35 and AG 1859;

(2) a non-nucleoside or non-nucleotide inhibitor of HIV reverse transcriptase selected from the group consisting of: capravirine (capravirine), emivirine (emivirine), delavirdine (delaviridine), efavirenz (efavirenz), nevirapine (nevirapine), (+) calanolide a, etravirine (etravirine), GW5634, DPC-083, DPC-961, DPC-963, MIV-150, TMC-120, rilpivirine, BILR 355BS, VRX 840773, lersivirine (UK-453061), RDEA806, KM023 and MK-1439;

(3) an HIV reverse transcriptase nucleoside inhibitor selected from the group consisting of: zidovudine (zidovudine), emtricitabine (emtricitabine), didanosine (didanosine), stavudine (stavudine), zalcitabine (zalcitabine), lamivudine (lamivudine), abacavir (abacavir), amdoxovir (amdoxovir), elvucitabine (elvucitabine), alovudine (alovudine), MIV-210, ± -FTC, D-D4FC, emtricitabine (emtricitabine), phohazazine, fozivudine tikitazine (fozivudine), aricitabine (apricitibine, AVX754), KP-1461, GS-9131 (gileac scixenes) and fosalvudine tikitazine (formerly HDP 99.99);

(4) an HIV reverse transcriptase nucleotide inhibitor selected from the group consisting of:

tenofovir (tenofovir), tenofovir disoproxil fumarate (tenofovir disoproxil fumarate), tenofovir alafenamide (tenofovir alafenamide, Gilead Sciences), GS-7340(GileadSciences), GS-9148(Gilead Sciences), adefovir (adefovir), adefovir dipivoxil (adefovir), CMX-001(Chimerix) or CMX-157 (Chimerix);

(5) an HIV integrase inhibitor selected from: raltegravir (raltegravir), etilog (elvitegravir), dolutegravir (dolutegravir), caboteravivir, curcumin derivatives, chicoric acid derivatives, 3, 5-dicaffeoylquinic acid derivatives, aurintricarboxylic acid derivatives, caffeic acid phenethyl ester derivatives, tyrphostin (tyrphostin), tyrphostin derivatives, quercetin derivatives, S-1360, AR-177, L-870812 and L-870810, BMS-538158, GSK364735C, BMS-70707035, MK-2048, BA 011 and GSK-744;

(6) HIV non-catalytic site or allosteric integrase inhibitors (NCINI), including but not limited to: compounds disclosed in BI-224436, CX0516, CX05045, CX14442, WO 2009/062285(Boehringer Ingelheim), WO 2010/130034(Boehringer Ingelheim), WO 2013/159064(Gilead Sciences), WO 2012/145728(GileadSciences), WO 2012/003497(Gilead Sciences), WO 2012/003498(Gilead Sciences), each of which is incorporated herein by reference in its entirety;

(7) a gp41 inhibitor selected from: enfuvirtide (enfuvirtide), ceffuvirtide (sifuvirtide), aibuvir tai (albrevitide), FB006M and TRI-1144;

(8) CXCR4 inhibitor AMD-070;

(9) entry inhibitor SP 01A;

(10) the gp120 inhibitor BMS-488043;

(11) g6PD and NADH-oxidase inhibitor Immunitin;

(12) a CCR5 inhibitor selected from: aplaviroc, vicriviroc, maraviroc, cenicriviroc, PRO-140, INCB15050, PF-232798(Pfizer), and CCR5mAb 004;

(13) a CD4 attachment inhibitor selected from: ibalizumab (TMB-355) and BMS-068 (BMS-663068);

(14) a pharmacokinetic enhancer selected from the group consisting of: ritonavir (ritonavi), cobicistat (cobicistat) and SPI-452; and

(15) other agents for treating HIV selected from: BAS-100, SPI-452, REP 9, SP-01A, TNX-355, DES6, ODN-93, ODN-112, VGV-1, PA-457 (bevirimat), HRG214, VGX-410, KD-247, AMZ0026, CYT 99007A-221 HIV, DEBIO-025, BAY 50-4798, MDX010 (Yipimema), PBS 119, ALG 889 and PA-1050040(PA-040),

and combinations thereof.

In certain embodiments, the metabolites disclosed herein, or pharmaceutically acceptable salts thereof, are combined with two, three, four, or more additional therapeutic agents. The two, three, four or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents, or they may be selected from different classes of therapeutic agents. In a specific embodiment, the metabolites disclosed herein or pharmaceutically acceptable salts thereof are combined with a nucleotide or nucleoside inhibitor of HIV reverse transcriptase and a non-nucleoside inhibitor of HIV reverse transcriptase. In another specific embodiment, the metabolites disclosed herein or pharmaceutically acceptable salts thereof are combined with an HIV reverse transcriptase nucleotide or nucleoside inhibitor and an HIV protease inhibiting compound. In another embodiment, the metabolites disclosed herein or pharmaceutically acceptable salts thereof are combined with HIV reverse transcriptase nucleotide or nucleoside inhibitors, HIV reverse transcriptase non-nucleoside inhibitors, and HIV protease inhibiting compounds. In another embodiment, the metabolites disclosed herein or pharmaceutically acceptable salts thereof are combined with an HIV reverse transcriptase nucleotide or nucleoside inhibitor, an HIV reverse transcriptase non-nucleoside inhibitor, and a pharmacokinetic enhancer.

In certain embodiments, when the metabolites disclosed herein are combined with one or more other therapeutic agents as described above, the components of the composition are administered on a simultaneous or sequential schedule. When administered consecutively, the combination may be administered in two or more administrations.

In certain embodiments, the metabolites disclosed herein are administered to a patient in combination with one or more other therapeutic agents simultaneously in a single dosage form, e.g., as a solid dosage form for oral administration (e.g., a fixed dose combination tablet).

In certain embodiments, the metabolites disclosed herein are administered with one or more other therapeutic agents. Co-administration of a metabolite disclosed herein or a pharmaceutically acceptable salt thereof with one or more additional therapeutic agents generally refers to the simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents such that a therapeutically effective amount of both the metabolite and the one or more additional therapeutic agents are present in the patient.

Co-administration includes administering a unit dose of a metabolite disclosed herein before or after administering a unit dose of one or more other therapeutic agents, e.g., within seconds, minutes, or hours of administering one or more other therapeutic agents. For example, in some embodiments, a unit dose of a metabolite disclosed herein is administered first, followed by a unit dose of one or more other therapeutic agents within seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more other therapeutic agents is administered first, followed by a unit dose of a metabolite disclosed herein within seconds or minutes. In some embodiments, a unit dose of a metabolite disclosed herein is administered first, followed by administration of a unit dose of one or more other therapeutic agents after a few hours (e.g., 1 to 12 hours). In other embodiments, a unit dose of one or more other therapeutic agents is administered first, followed by a unit dose of a metabolite disclosed herein after a few hours (e.g., 1 to 12 hours).

Pharmaceutical formulations and dosage forms

The pharmaceutical compositions disclosed herein can be prepared by methods well known in the pharmaceutical arts. For example, in certain embodiments, a pharmaceutical composition intended for administration by injection may be prepared by combining a metabolite of the invention with sterile distilled water to form a solution. In some embodiments, a surfactant is added to facilitate the formation of a homogeneous solution or suspension. Surfactants are compounds that non-covalently interact with the compounds of the present invention to facilitate dissolution or uniform suspension of the compounds in an aqueous delivery system.

The metabolites of the present invention, or pharmaceutically acceptable salts thereof, may be administered in therapeutically effective amounts which will vary depending on a variety of factors including: the activity of the particular compound employed; the metabolic stability and duration of action of the compound; the age, weight, general health, sex, and diet of the patient; mode and time of administration; the rate of excretion; a pharmaceutical composition; the severity of a particular disease or condition; and the treatment the subject is receiving.

The present invention will be described in more detail by way of specific examples. The following examples are provided for illustrative purposes and are not intended to limit the invention in any way. Those skilled in the art will readily recognize a variety of non-critical parameters that may be altered or modified to produce substantially the same result.