Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
  • A61K31/52—Purines, e.g. adenine
  • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/18—Antivirals for RNA viruses for HIV
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• H ⁇ V-1 human immunodeficiency virus -1
• RT nucleoside reverse transcriptase
• AZT Retrovir ®
• didanosine or DDI or Videx ®
• stavudine or D4T or Zerit ®
• lamivudine or 3TC or Epivir ®
• zalcitabine or DDC or Hivid ®
• abacavir succinate or Ziagen ®
• tenofovir disoproxil fumarate salt or Viread ®
• emtricitabine or Emtriva ®
• Combivir ® contains 3TC and AZT
• Trizivir ® contains abacavir, 3TC and AZT
• three non-nucleoside reverse transcriptase inhibitors nevirapine (or Niramune ® ), delavirdine (or Rescriptor ® ) and e
• Compound 1 is an ⁇ IN-1 attachment inhibitor demonstrating potent antiviral activity against a variety of laboratory and clinical strains of HIN-1 (see U.S. patent application US 2003 0207910, published Nov. 6 2003).
• Compound 1 acts by selectively preventing attachment of the exterior viral envelope protein gpl20 to its cellular receptor CD4. Binding of gpl20 to CD4 is the first step in viral entry and is distinct from the subsequent interaction with a chemokine receptor (CCR5 or CXCR4) or virus-cell fusion event. By inhibiting this interaction, Compound 1 blocks viral entrance into cells. DESCRIPTION OF THE INVENTION
• the invention encompasses pharmaceutical compositions and methods for treating HIV infection and AIDS.
• One aspect of the invention is a method for treating HIV infection in a human patient comprising the administration of a therapeutically effective amount of 1- benzoyl-4-[2-[4-methoxy-7-(3-methyl-lH-l,2,4-triazol-l-yl)-lH-pyrrolo[2,3- c]pyridin-3-yl]-l,2-dioxoethyl]-piperazine (Compound 1), or a pharmaceutically acceptable salt or solvate thereof, with a therapeutically effective amount of at least one other agent used for treatment of AIDS or ⁇ IN infection selected from the group consisting of nucleoside ⁇ IN reverse transcriptase inhibitors, non-nucleoside ⁇ IN reverse transcriptase inhibitors, ⁇ IV protease inhibitors, ⁇ IV fusion inhibitors, ⁇ IN attachment inhibitors, CCR5 inhibitors, CXCR4 inhibitors, ⁇ IN budding or maturation inhibitors, and ⁇ IV integrase inhibitors.
• Another aspect of the invention is a method wherein the agent is a nucleoside ⁇ IV reverse transcriptase inhibitor.
• Another aspect of the invention is a method wherein the nucleoside ⁇ IV reverse transcriptase inhibitor is selected from the group consisting of abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, and zidovudine, or a pharmaceutically acceptable salt or solvate thereof.
• Another aspect of the invention is a method wherein the agent is a non- nucleoside ⁇ IN reverse transcriptase inhibitor.
• non-nucleoside ⁇ IN reverse transcriptase inhibitor is selected from the group consisting of delavirdine, efavirenz, and nevirapine, or a pharmaceutically acceptable salt or solvate thereof.
• Another aspect of the invention is a method wherein the agent is an ⁇ IN protease inhibitor.
• Another aspect of the invention is a method wherein the HIN protease inhibitor is selected from the group consisting of amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and fosamprenavir, or a pharmaceutically acceptable salt or solvate thereof.
• Another aspect of the invention is a method wherein the agent is an HIN fusion inhibitor.
• Another aspect of the invention is a method wherein the HIN fusion inhibitor is enfuvirtide or T-1249, or a pharmaceutically acceptable salt or solvate thereof.
• Another aspect of the invention is a method wherein the agent is an HIN attachment inhibitor.
• Another aspect of the invention is a method wherein the agent is a CCR5 inhibitor.
• Another aspect of the invention is a method wherein the CCR5 inhibitor is selected from the group consisting of Sch-C, Sch-D, TAK-220, PRO- 140, and UK-427,857, or a pharmaceutically acceptable salt or solvate thereof.
• Another aspect of the invention is a method wherein the agent is a CXCR4 inhibitor.
• Another aspect of the invention is a method wherein the CXCR4 inhibitor is
• AMD-3100 or a pharmaceutically acceptable salt or solvate thereof.
• Another aspect of the invention is a method wherein the agent is an HIN budding or maturation inhibitor.
• Another aspect of the invention is a method wherein the budding or maturation inhibitor is PA-457, or a pharmaceutically acceptable salt or solvate thereof.
• Another aspect of the invention is a method wherein the agent is an HIN integrase inhibitor.
• HIN integrase inhibitor is 3-[(4-fluorobenzyl)methoxycarbamoyl]-2-hydroxyacrylic acid or 2-(2,2)- dimethyl-5-oxo-[l,3]-dioxolan-4-ylidene)- ⁇ -(4-fluorobenzyl)- ⁇ -methoxyacetamide, or a salt or solvate thereof.
• Another aspect of the invention is a pharmaceutical composition
• a pharmaceutical composition comprising a therapeutically effective amount of l-benzoyl-4-[2-[4-methoxy-7-(3-methyl-lH- l,2,4-triazol-l-yl)-lH-pyrrolo[2,3-c]pyridin-3-yl]-l 5 2-dioxoethyi]-piperazine, or a pharmaceutically acceptable salt or solvate thereof, with at least one other agent used for treatment of AIDS or ⁇ IN infection selected from the group consisting of nucleoside ⁇ IN reverse transcriptase inhibitors, non-nucleoside ⁇ IN reverse transcriptase inhibitors, ⁇ IN protease inhibitors, ⁇ IN fusion inhibitors, ⁇ IN attachment inhibitors, CCR5 inhibitors, CXCR4 inhibitors, ⁇ IN budding or maturation inhibitors, and ⁇ IN integrase inhibitors, and a pharmaceutically acceptable carrier.
• the agent is a pharmaceutical
• nucleoside ⁇ IN transcriptase inhibitor is selected from the group consisting of abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, and zidovudine, or a pharmaceutically acceptable salt or solvate thereof.
• composition wherein the agent is a non- nucleoside ⁇ IN reverse transcriptase inhibitor.
• composition wherein the non- nucleoside ⁇ IV reverse transcriptase inhibitor is selected from the group consisting of delavirdine, efavirenz, and nevirapine, or a pharmaceutically acceptable salt or solvate thereof.
• composition wherein the agent is an HIN protease inhibitor.
• composition wherein the HIV protease inhibitor is selected from the group consisting of amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and fosamprenavir, or a pharmaceutically acceptable salt or solvate thereof.
• compositions wherein the agent is an HIV fusion inhibitor.
• composition method wherein the HIV fusion inhibitor is enfuvirtide or T-1249, or a pharmaceutically acceptable salt or solvate thereof.
• composition wherein the agent is an HIN attachment inhibitor.
• compositions wherein the agent is a CCR5 inhibitor.
• CCR5 inhibitor is selected from the group consisting of Sch-C, Sch-D, TAK-220, PRO- 140, and UK-427,857, or a pharmaceutically acceptable salt or solvate thereof.
• Another aspect of the invention is a method wherein the agent is a CXCR4 inhibitor.
• Another aspect of the invention is a method wherein the CXCR4 inhibitor is AMD-3100, or a pharmaceutically acceptable salt or solvate thereof.
• Another aspect of the invention is the composition wherein the agent is an HIN budding or maturation inhibitor.
• composition wherein the budding or maturation inhibitor is PA-457, or a pharmaceutically acceptable salt or solvate thereof.
• composition wherein the agent is an HIV integrase inhibitor.
• composition wherein the HIV integrase inhibitor is 3-[(4-fluorobenzyl)methoxycarbamoyl]-2-hydroxyacrylic acid or 2-(2,2) ⁇ dimethyl-5-oxo-[l,3]-dioxolan-4-ylidene)- ⁇ -(4-fluorobenzyl)- ⁇ -methoxyacetamide, or a pharmaceutically acceptable salt or solvate thereof.
• the HIV integrase inhibitor is 3-[(4-fluorobenzyl)methoxycarbamoyl]-2-hydroxyacrylic acid or 2-(2,2) ⁇ dimethyl-5-oxo-[l,3]-dioxolan-4-ylidene)- ⁇ -(4-fluorobenzyl)- ⁇ -methoxyacetamide, or a pharmaceutically acceptable salt or solvate thereof.
• Compound 1 “Combination,” “coadministration,” “concurrent,” and similar terms referring to the administration of Compound 1 with at least one anti-HIV agent mean that the components are part of a combination antiretroviral therapy or highly active antiretro iral therapy (HAART) as understood by practitioners in the field of AIDS and HIV infection.
• HAART highly active antiretro iral therapy
• “Therapeutically effective” means the amount of agent required to provide a meaningful patient benefit as understood by practitioners in the field of AIDS and HIV infection. In general, the goals of treatment are suppression of viral load, restoration and preservation of immunologic function, improved quality of life, and reduction of HIV-related morbidity and mortality.
• Patient means a person infected with the HIV virus and suitable for therapy as understood by practitioners in the field of AIDS and HIV infection.
• the invention includes all pharmaceutically acceptable salt forms of Compound 1.
• Pharmaceutically acceptable salts are those in which the counter ions do not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents. In many instances, salts have physical properties that make them desirable for formulation, such as solubility or crystallinity.
• the salts can be made according to common organic techniques employing commercially available reagents.
• Suitable anionic salt forms include acetate, acistrate, besylate, bromide, chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate.
• the invention also includes all solvated forms of Compound 1, particularly hydrates.
• Solvates do not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents. Solvates may form in stoichiomefric amounts or may form from adventitious solvent or a combination of both.
• One type of solvate is hydrate. Some hydrated forms include monohydrate, hemihydrate, and dihydrate.
• Compound 1 demonstrated synergistic or additive-synergistic HIV antiviral activity when used in conjunction with a variety of other antiviral agents, as described below.
• Virus and cell lines The T-cell lines, MT-2 and PM-1 were obtained through the AIDS Research and Reference Reagent Program, NIAID, and were contributed by Dr. D. Richman and Dr. R. Gallo, respectively. Both cell lines were cultured in RPMI 1640 medium supplemented with 10 % fetal bovine serum, 2 mM L-glutamine and sub-cultured twice a week.
• the LAI strain of HIV- 1 was obtained from the Fred Hutchinson Cancer Research Center, and the Bal strain was from NIH.
• Both virus stocks were amplified and titered in MT-2 cells (LAI) and PM-1 cells (Bal) using a virus infectivity assay.
• Chemicals. Compound 1 , atazanavir, didanosine, stavudine, efavirenz, enfuvirtide (T-20), T-1249, AMD-3100, Sch-C, Sch-D and UK-427,857 were synthesized using published or known reactions.
• Amprenavir, indinavir, nelfinavir, nevirapine, lopinavir, lamivudine, ritonavir, tenofovir, saquinavir, delavirdine and abacavir were extracted from commercial formulations of the prescribed drugs and purified using published or common techniques. Tenofovir was tested as tenovir disopoxil fiimerate. Zalcitabine was obtained from the National Institutes of Health. Zidovudine was purchased from Sigma and emtricitabine from Moravek Biochemicals .
• MT-2 cells were infected with HIV-1 LAI (or PM-1 cells with HIV-1 Bal) at an MOI of 0.005, and seeded into 96-well microtiter plates (0.1 x 10 cells/ml) containing serial dilutions of test compounds.
• the drug combinations were set up using ratios of the two drugs of 1 : 1 , 1 :2.5 and 2.5:1 times the EC 50 value determined for each drug in prior multiple experiments. Each drug ratio consisted of an array of 3 -fold serial dilutions, and was performed in quadruplicate. The plates were incubated at 37°C/5% CO 2 .
• the MT-2 cells infected with HIV-1 LAI were incubated for 5 days.
• the CC 50 values were calculated by using the exponential form of the median effect equation as mentioned below for calculation of EC 50 .
• Analysis of Drug Combination Effects drugs were diluted in a fixed ratio and multiple ratios were analyzed. The drug serial dilutions spanned a range of concentrations near the EC 50 value of each compound, so that equivalent antiviral activities could be compared. Concentration-response curves were estimated for each individual drug and every combination using the median-effect equation. The equation was fit using a nonlinear regression routine (Proc Nlin) in PC SAS version 8.01 (SAS Institute Inc., SAS Version 8.01, Cary, NC: SAS Institute Inc., 1990).
• Fa 1/[1+ (ED 50 /drug concentration) 111 ].
• Fa stands for "fraction affected,” and represents the fraction of the viral load that has been inactivated. For example, Fa of 0.75 indicates that viral replication had been inhibited by 75%, relative to the no-drug controls.
• ED 50 is drug concentration that is expected to reduce the amount of virus by 50%
• m is a parameter that reflects the slope of the concentration-response curve.
• combination indices were calculated according to Chou and Rideout.
• the combination index was computed as
• [Dm] 1 and [Dm]2 are the concentrations of drugs that would individually produce a specific level of effect, while [D] 1 and [D]2 are the concentrations of drugs in combination that would produce the same level of effect.
• Nucleoside RT inhibitors Two-Drug Combinations of Compound 1 with Nucleoside Reverse Transcriptase Inhibitors.
• Nucleoside ,RT inhibitors were combined with Compound 1 at a range of concentrations near the EC o value of each compound, so that equivalent antiviral activities could be compared. All estimates were computed using SAS Proc NLIN, and a two-parameter logistic. Data is presented in Table 2 as the combination indices and the asymptotic confidence intervals for RT inhibitors at different molar ratios (see Materials and Methods). Nucleoside RT inhibitors show synergistic to additive-synergistic antiviral effects combination with Compound 1. No significant antagonism of anti-HIN activity is observed.
• Ratio of Compound 1 to comparator compound b
• a lower bound of the asymptotic confidence interval greater than 1 indicates antagonisms, an upper bound of less than 1 indicates synergism, and a value of 1 being contained in the interval indicates additivity.
• the 95% confidence intervals are shown in parenthesis, and represent a measure of variability in the data.
• BMS-538203 1:80 (1:1) 0.48 (0.39, 0.58) 0.51 (0.37, 0.65) 0.54 (0.31, 0.76) Moderate- 1:200 (1:2.5) 0.44 (0.36, 0.53) 0.51 (0.37, 0.65) 0.59 (0.34, 0.85) Synergistic 1:32 (2.5:1) 0.50 (0.36, 0.63) 0J0 (0.44, 0.97) 1.00 (0.41, 1.59) a Ratio of Compound 1 to comparator compound? b A lower bound of the asymptotic confidence interval greater than 1 indicates antagonisms, an upper bound of less than 1 indicates synergism, and a value of 1 being contained in the interval indicates additivity. The 95% confidence intervals are shown in parenthesis, and represent a measure of variability in the data.
• Compound 1 inhibits HIN attachment, an essential step in HIN replication, and can be useful for the treatment of HIN infection and the consequent pathological conditions such as AIDS or ARC. As shown above, Compound 1 is active in conjunction with a wide variety of other agents and may be particularly beneficial in HAART and other new combination compositions and therapies.
• Compound 1 will generally be given as a pharmaceutical composition, and the active ingredient of the composition may be comprised of Compound 1 alone or Compound 1 and at least one other agent used for treating AIDS or HIN infection.
• the compositions will generally be made with a pharmaceutically accepted carrier or vehicle, and may contain conventional exipients.
• the compositions are made using common formulation techniques.
• the invention encompasses all conventional forms. Solid and liquid compositions are preferred. Some solid forms include powders, tablets, capsules, and lozenges. Tablets include chewable, buffered, and extended release. Capsules include enteric coated and extended release capsules. Powders are for both oral use and reconstitution into solution. Powders include lyophilized and flash-melt powders.
• Compound 1 and any antiretroviral agent are present in dosage unit ranges.
• Compound 1 will be in a unit dosage range of 1-1000 mg/unit. Some examples of dosages are 1 mg, 10 mg, 100 mg, 250 mg, 500 mg, and 1000 mg.
• other antiretroviral agents will be present in a unit range similar to agents of that class used clinically. Typically, this is 0.25-1000 mg/unit.
• Liquids include aqueous solutions, syrups, elixers, emusions, and suspensions.
• Compound 1 and any antiretroviral agent are present in dosage unit ranges. Generally, Compound 1 will be in a unit dosage range of 1-100 mg/mL.
• dosages are 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100 mg/mL.
• other antiretroviral agents will be present in a unit range similar to agents of that class used clinically. Typically, this is 1-100 mg/mL.
• the invention encompasses all conventional modes of administration; oral and parenteral (injected intramuscular, intravenous, subcutanaeous) methods are preferred.
• the dosing regimen will be similar to other antiretroviral agents used clinically.
• the daily dose will be 1-100 mg/kg body weight daily for Compound 1.
• more compound is required orally and less parenterally.
• the specific dosing regime will be determined by a physician using sound medical judgement.
• the invention also encompasses methods where Compound 1 is given in combination therapy. That is, Compound 1 can be used in conjunction with, but separately from, other agents useful in treating AIDS and HIN infection.
• HIN attachment inhibitors CCR5 inhibitors, CXCR4 inhibitors, HIN cell fusion inhibitors, HIN integrase inhibitors, HIN nucleoside reverse transcriptase inhibitors, HIN non-nucleoside reverse transcriptase inhibitors, HIN protease inhibitors, budding and maturation inhibitors, immunomodulators, and anti- infectives.
• Compound 1 will generally be given in a daily dose of 1-100 mg/kg body weight daily in conjunction with other agents.
• the other agents generally will be given in the amounts used therapeutically.
• the specific dosing regime will be determined by a physician using sound medical judgement.
• Table 7 lists some agents useful in treating AIDS and HIN infection, which are suitable for this invention. The invention, however, is not limited to these agents.

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