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EP-4281083-B1 - COMBINATION THERAPY FOR HIV WITH ADENOSINE DERIVATIVE AND CAPSID INHIBITORS

EP4281083B1EP 4281083 B1EP4281083 B1EP 4281083B1EP-4281083-B1

Inventors

  • XU, LIANHONG
  • HONG, ZHI

Dates

Publication Date
20260513
Application Date
20220125

Claims (9)

  1. A compound of formula (4-A), (4-C), or (6-A) having the structure: or pharmaceutically acceptable salt or solvate thereof, for use in a method of treating or preventing an HIV infection in a subject in need thereof, wherein the method further comprises administering to the subject a capsid inhibitor having the structure: or a pharmaceutically acceptable salt thereof.
  2. The compound for use of claim 1, wherein the compound has the structure of formula (4-A): or a pharmaceutically acceptable salt or solvate thereof.
  3. The compound for use of claim 1 or 2, wherein the capsid inhibitor and the compound or pharmaceutically acceptable salt or solvate thereof are administered to the subject simultaneously or sequentially, optionally wherein the capsid inhibitor and the compound or pharmaceutically acceptable salt or solvate thereof are administered to the subject sequentially within a time period in a range of from 0.1 minute to 72 hours.
  4. The compound for use of any one of claims 1-3, wherein the capsid inhibitor and the compound or pharmaceutically acceptable salt or solvate thereof are administered to the subject: (a) once every day to once every 12 months; (b) once every 6 months; (c) once every 1 to 8 weeks; or (d) once every month.
  5. The compound for use of claim 1, wherein: (a) the effective dosage of the capsid inhibitor is a single dosage in a range of from 100 mg to 2000 mg administered every 6 months; (b) the effective dosage of the capsid inhibitor is in a range of from 200 mg to 1200 mg administered every 1 to 7 days; (c) the effective dosage of the capsid inhibitor is in a range of from 300 mg to 1200 mg administered once every week (QW) and the effective dosage of the compound or pharmaceutically acceptable salt or solvate thereof is a range of from 100 mg to 2000 mg administered once every week (QW) to once every 8 weeks (Q8W); or (d) the effective dosage of the capsid inhibitor is in a range of from 900 mg to 2000 mg administered once every month (QM) and the effective dosage of the compound or pharmaceutically acceptable salt or solvate thereof is in a range of from 100 mg to 2000 mg administered once every week (QW) to once every 8 weeks (Q8W).
  6. The compound for use of any one of claims 1-5, wherein the capsid inhibitor is administered: (a) orally; or (b) parentally, optionally wherein the parental administration is by intramuscular and/or subcutaneous injection.
  7. The compound for use of any one of claims 1-6, wherein the compound or pharmaceutically acceptable salt or solvate thereof is administered: (a) orally; or (b) parentally, optionally wherein the parental administration is by intramuscular and/or subcutaneous injection.
  8. A pharmaceutical composition, comprising: (a) a capsid inhibitor having the structure: or a pharmaceutically acceptable salt thereof; and (b) a compound of formula (4-A), (4-C), or (6-A) having the structure: or a pharmaceutically acceptable salt or solvate thereof.
  9. The pharmaceutical composition of claim 8, wherein the compound is a compound of formula (4-A) having the structure: or a pharmaceutically acceptable salt or solvate thereof.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Application Serial No. 63/141,445, filed January 25, 2021. FIELD This disclosure is directed to adenosine derivative prodrugs that can inhibit reverse transcriptase. This disclosure is also directed to pharmaceutical compositions comprising an adenosine derivative prodrug and a capsid inhibitor that can be used for the treatment or prevention of acquired immunodeficiency syndrome (AIDS), HIV-1, HIV-2, multidrug resistant HIV or a combination thereof. BACKGROUND Retroviruses such as human immunodeficiency virus (HIV) have been linked to the immunosuppressive disease known as acquired immunodeficiency syndrome (AIDS). Multiple strains of retrovirus, such as HIV type-1 (HIV-1) and type-2 (HIV-2) are known to be related to the diseases. The HIV retrovirus infected individuals can be initially asymptomatic, but then develop AIDS related complex (ARC) followed by AIDS. Replication of HIV by a host cell requires integration of the viral genome into the DNA of host cells. A key step in the process involves transcription of the viral RNA genome into DNA via an enzyme known as reverse transcriptase (RT). A reverse transcriptase typically can have multiple enzymatic functions that can act (1) as an RNA-dependent DNA polymerase transcribing a single-stranded DNA copy of the viral RNA (first DNA), (2) as a ribonuclease destroying the original viral RNA and frees the DNA just produced from the original RNA, and (3) as a DNA-dependent DNA polymerase producing a second, complementary DNA strand using the first DNA strand as a template. The two DNA strands then form double-stranded DNA, which is integrated into the genome of the host cells by an integrase enzyme. A number of compounds can inhibit reverse transcriptase (RT) activity. These compounds can be useful for the treatment of HIV infection in humans by inhibiting HIV replication in infected cells or individuals. Examples of the compounds approved for use in treating HIV infection and AIDS include nucleoside RT inhibitors (NRTI) such as 3'-azido-3'-deoxythymidine (AZT, also known as Zidovudine (ZDV), azidothymidine (AZT)), 2',3'-dideoxyinosine (ddl), 2',3'-dideoxycytidine (ddC), d4T, 3TC, abacavir, emtricitabine, and tenofovir disoproxil fumarate, as well as non-nucleoside RT inhibitors (NNRTI) such as nevirapine, delavirdine, efavirenz, rilpivirine and doravirine (DHHS guidelines: https://aidsinfo.nih.gov/understanding-hiv-aids, Iyidogan & Anderson, Viruses, 6, 4095-4139, 2014, doi:10.3390/v6104095; Hayakawa et al., Antiviral Chem & Chemotherapy, 15:169-187, 2004; Ohrul et al., J. Med. Chem. 43, 4516-4525, 2000; Pauwels, Antiviral Research, 71, 77-89, 2006.). An adenosine derivative EFdA (4'-ethynyl-2-fluoro-2'-deoxyadenosine, also known as MK-8591, islatravir) is a long-acting (LA) NRTI that has been demonstrated to have anti-HIV activity via inhibiting reverse transcriptase by preventing translocation (U.S. Patent Nos.: 7,339,053, 7,625,877, 8,039,614. Singh et al., Pharmaceuticals, 12, 62, 2019, DOI: 10.3390/ph120062). This compound has broad inhibitory activity and potency for different subtypes and mutations including HIV-1, HIV-2, and multidrug resistant (MDR) and wildtype (WT) strains, and reverse transcriptase inhibitor (RTI) resistant viruses. Some modified EFdA analogs and prodrugs have been described in U.S. Patent Publication No.: 2018/0002366. Further prodrugs of EFdA useful in HIV therapy are disclosed in WO2020/178767. A common issue that arises from the treatment of HIV infection with anti-retroviral inhibitory compounds is resistance of the viruses to the inhibitors. Such resistance is typically the result of mutations that occur in the reverse transcriptase segment of the pol gene. The continued use of antiviral compounds, such as the inhibitory compounds, to prevent HIV infection will inevitably result in the emergence of new resistant strains of HIV. Therefore, there is a continuing need for new RT inhibitors that are effective against HIV strains including mutant HIV and multidrug-resistant HIV strains. Another common issue is the medication adherence. Medication adherence is essential for individuals with HIV to have successful therapy over a lifetime. Adherence to a daily regimen can be challenging, which also has negative impact on the patient's quality of life with daily reminders of their HIV status. Increasing patient adherence to a drug regimen can potentially be achieved through reducing the dosing frequency. Therefore, there is a need to identify long-acting compounds or regimens (for example, once a week, once a month or once every two-month therapy) for patients to overcome these challenges tied to taking daily, oral medication. SUMMARY The present disclosure, which addresses these and other problems, is related to adenosine derivatives and compositions thereof that can be used to treat retroviral diseases such as HIV and AID