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US-12624058-B2 - Promoiety strategy to enhance drug activity

US12624058B2US 12624058 B2US12624058 B2US 12624058B2US-12624058-B2

Abstract

Various nucleoside phosphate and phosphonate analogues are provided for treatment of viral infections. Methods of preparing the analogues, pharmaceutical compositions containing the analogues, and methods of using the analogues as antiviral compounds, especially against adenoviruses, coronaviruses, and varicella zoster viruses, are also provided.

Inventors

  • Charles E. McKenna

Assignees

  • UNIVERSITY OF SOUTHERN CALIFORNIA

Dates

Publication Date
20260512
Application Date
20210818

Claims (17)

  1. 1 . A nucleoside phosphonate having formula (3) or (4): B is a purine or pyrimidine base; X is CH 2 Ph, CH 2 , CH 2 CH 2 , or CHCH 3 ; R is C(O)R 2 ; R 1 is H or alkyl, alkene, ether or thioether; and R 2 is alkyl or alkene.
  2. 2 . The nucleoside phosphonate of claim 1 , wherein B is cytosine or adenine.
  3. 3 . The nucleoside phosphonate of claim 1 , wherein R 1 is C 12-18 alkyl and R 2 is alkyl.
  4. 4 . The nucleoside phosphonate of claim 1 , wherein R 1 is C 12-18 alkyl, (CH 2 ) n CH—CHC n1 , (CH 2 ) n —O—(CH 2 ) n1 or (CH 2 ) n —S—(CH 2 ) n1 wherein n and/or n1 are 4 to 9 and R 2 is C 8-18 alkyl.
  5. 5 . A pharmaceutical composition comprising at least one compound of claim 1 , and a pharmaceutically acceptable carrier.
  6. 6 . A method of treating a virus infection comprising administering to a subject an effective amount of at least one nucleoside phosphonate of claim 1 .
  7. 7 . The method of claim 6 , wherein the virus infection is caused by a virus selected from the group consisting of RNA virus, an DNA virus, a retrovirus, a herpesvirus, an adenovirus, an emerging virus of pandemic potential, VZV, CMV, HPV, and SARS-COV-2.
  8. 8 . A method of treating cancer comprising administering to a subject an effective amount of at least one compound of claim 1 .
  9. 9 . A nucleoside phosphonate having formula (3) or (4): wherein: B is a purine or pyrimidine base; X is CH 2 , CH 2 CH 2 , or CHCH 3 ; R is H or C(O)R 2 ; R 1 is H or alkyl, alkene, ether or thioether; and R 2 is alkyl or alkene.
  10. 10 . The nucleoside phosphonate of claim 9 , wherein B is cytosine or adenine.
  11. 11 . The nucleoside phosphonate of claim 9 , wherein R 1 is alkyl, alkene, ether or thioether and R 2 is alkyl.
  12. 12 . The nucleoside phosphonate of claim 9 , wherein R 1 is C 12-18 alkyl, (CH 2 ) n CH—CHC n1 , (CH 2 ) n —O—(CH 2 ) n1 or (CH 2 ) n —S—(CH 2 ) n1 wherein n and/or n1 are 4 to 9 and R 2 is C 8-18 alkyl.
  13. 13 . A nucleoside phosphonate having formula (1): wherein: Z is a cyclic or acyclic sugar-derived bivalent group; X is CH 2 , CH 2 CH 2 , or CHCH 3 ; R is C(O)R 2 ; R 1 is H or alkyl, alkene, ether or thioether; and R 2 is alkyl or alkene.
  14. 14 . A compound selected from the group consisting of:
  15. 15 . A method of preparing a nucleoside phosphate (NP), comprising conjugation of phosphorylated amino acid with pyrophosphate, as outlined in the following reaction scheme: wherein B is a purine or pyrimidine base; R is H or C(O)NHR 2 , wherein R 2 is C 8-18 alkyl; and R 1 is NHR 1a , wherein R 1a is H, alkyl, alkene, ether or thioether, and Y is O, NH, CH 2 , CHF, CHCl, CHBr, CF 2 , CCl 2 , CBr 2 , CCH 3 , C(CH 3 ) 2 , CHN 3 , or CCH 3 N 3 .
  16. 16 . The method of claim 15 , wherein B is cytosine, guanine, adenine or thymine.
  17. 17 . The method of claim 16 , wherein R 1a is C 12-18 alkyl, C n CH═CHC n1 , C n —O—C n1 or C n —S—C n1 , wherein n and/or n1=4-9 and R 2 is C 8-18 alkyl.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is the U.S. national phase of PCT Appln. No. PCT/US2021/046486 filed Aug. 18, 2021, which claims the benefit of U.S. Provisional Patent Application Ser. No. 63/067,204 filed, Aug. 18, 2020, the disclosures of which are hereby incorporated in their entirety by reference herein. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with Government support under Grant No. from NIH DMID Services HHSN272201100022I, HHSN272201000021I, HHSN27200007, HHSN272201100016I, R21A1130927, R01AI135122. The Government has certain rights in this invention. BACKGROUND Field of the Invention The invention relates to inhibition of nucleotide-binding enzymes such as nucleic acid polymerases and kinases to prevent or treat diseases. Related Art Nucleotide drugs are well-established in the prevention and treatment of diseases such as virus infections and cancer. A drawback of this approach is the poor bioavailability, low cell penetration, and toxicity of many nucleotide analogs, owing to their polarity and the charge of their ionized phosphate or phosphonate group(s). This can be exemplified by nucleoside phosphonate drugs used to treat virus infection. Viral infection remains an evolving constellation of critical unmet health challenges. An example is human adenovirus (Ad) which has a linear duplex DNA genome that encodes about 35 genes and is enclosed in a protein capsid without a lipid membrane (1). Adenovirus (Ad) is ubiquitous, infect most children, and generally cause asymptomatic or symptomatic infection of the respiratory, gastrointestinal, ocular, and other tissues that are usually self-limiting in healthy individuals with the exception of epidemic keratoconjunctivitis (1). However, Ad can cause serious infection in severely immunosuppressed individuals, especially in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), where the incidence of infection ranges from 5%-6% to 42%-47% depending on the study (2, 3). Mortality rates are up to 26% with symptomatic infection and up to 80% for disseminated disease (2, 3). In solid organ transplants, incidence ranges from 4% to 10% in pediatric liver transplants and up to 57% in small bowel recipients. Mortality can be as high as 18% in kidney transplants and 53% in liver transplants. With disseminated Ad disease, there is multi-organ involvement with Ad detected in peripheral blood, urine, bronchoalveolar fluid, and cerebrospinal fluid; death is associated with multi-organ failure and persisting or increasing levels of Ad in peripheral blood. Risk factors for Ad disease and death include young age, receipt of a mismatched and/or T cell-depleted graft, early and persistent isolation of Ad from multiple sites, high level of Ad in the blood, and increasing levels of Ad in stool beyond 106 genome copies per gram (2). Despite the seriousness of Ad disease, there are no drugs currently approved to treat Ad infections. Intravenous gamma globulins have been employed, and intravenous cidofovir (CDV, HPMPC, (S)-1-(3-hydroxy-2-phosphonomethoxypropyl)cytosine) is used in many transplant clinics (4, 5), but controlled studies on the efficacy of these treatments have not been conducted. The DNA viruses are comprised of at least six distinct families of highly diverse viruses. The DNA polymerases that direct the replication of their genomes are well conserved and it is this characteristic that transcends the biologic differences among these viruses (6). This enzyme renders them susceptible to nucleoside phosphonate (NP) analogues that represent the predominant class of inhibitors for the treatment of DNA virus infections. CDV, a nucleoside phosphonate analogue of cytosine monophosphate (FIG. 1) is converted in cells to the CDV diphosphate analogue of dCTP, which is a preferred substrate for the Ad DNA polymerases, leading to chain termination and blocking viral replication. Although CDV could in principle protect the target immunocompromised population from clinical manifestations associated with the DNA viruses, its clinical utility is limited by its modest efficacy, very low oral bioavailability (<5%) mandating i.v. or i.p. administration, and its dose limiting toxicity (7). CDV exhibits poor cellular uptake and is a substrate for organic anion transporter 1, leading to accumulation of CDV in renal tubules which causes nephrotoxicity (8). A simple C16 ether-linked propyl ester prodrug of CDV, brincidofovir (FIG. 1) (HDP-CDV, CMX001, BCV), has displayed improved efficacy against all the DNA viruses tested (9). BCV does not accumulate in renal tubules and shows little or no nephrotoxicity (10) but GI irritation has been a problematic serious side effect, suggesting premature activation of a portion of the oral dose in the GI tract (11, 12). BCV inhibits the replication of multiple Ad types in cell culture, with EC50 values near 0.02 μM (13). BCV (and CDV) was also