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EA-053292-B1 - VERRUCARINE A DERIVATIVES AND THEIR ANTIBODY-DRUG CONJUGATES

EA053292B1EA 053292 B1EA053292 B1EA 053292B1EA-053292-B1

Abstract

Derivatives of verrucarin A of Formula I, wherein the values of X, Y, and Z are defined in the claims, are provided, along with the linker-verrucarin A derivatives and antibody-drug conjugates thereof, suitable for the treatment of viral diseases. A pharmaceutical composition based on the claimed compounds and the use of the claimed compounds for the treatment of influenza, SARS-CoV-2, and Ebola virus infections are also provided.

Inventors

  • Ниттоли Томас

Assignees

  • РИДЖЕНЕРОН ФАРМАСЬЮТИКАЛЗ, ИНК.

Dates

Publication Date
20260504
Application Date
20230113
Priority Date
20220114

Claims (15)

  1. 1. Compound of formula I: or a pharmaceutically acceptable salt thereof, where: X represents NR'R 2 or OR 3 ; each of R 1 and R 2 independently represents N, 0μ24 alkyl, C(O)-C]_24 alkylene-CO-W, C(O)CH(V)-CH3, OR 5 or COR 6 , or together with the nitrogen atom to which they are attached form 0μ24 heterocycloalkyl comprising 1-8 heteroatoms selected from O, N, P, Si and S, or C] _24 heterocycloalkyl comprising 1-8 heteroatoms selected from O, N, P, Si and S, substituted 1-24 times with a substituent independently selected from the group consisting of deuterium, -OR', =O, =NR', =N-OR', -NR'R, -SR', halogen, -SiR'RR', -OC(O)R', -C(O)R', -CO 2 R', -CONR'R, -OC(O)NR'R, -NRC(O)R', -NR'- C(O)NRR', -NRC(O) 2 R', -NR-C(NR'RR')=NR, -NR-C(NR'R)=NR', -S(O)R', -S(O) 2 R', -S(O) 2 NR'R, -NRSO 2 R', -CN and -NO 2 ; R 3 is C] 2 4 alkyl; R 5 is H or C]_ 2 4 alkyl; R 6 is R 9 , -Ci. 24 alkylene-COOH, CH 2 CH 2 CH 2 COOMe, CH 2 CH 2 CH 2 CONHOH, CH 2 CH 2 CH 2 CONHOMe, OR 10 or NR n R 12 ; each of R 8 and R 9 independently represents C]_ 2 4 alkyl or C 7 . 3 o aralkyl; each of R 10 -R 12 independently represents H, Oμ 24 alkyl or C 7 .zoaralkyl ; each of R', R, R' and R independently represents H, Oμ 24 alkyl, Oμ 24 alkoxy, Oμ 24 thioalkoxy, C7 . 3 aralkyl , C3 . 24 cycloalkyl, C6 . 24 aryl, Oμ 24 heteroalkyl comprising 1-8 heteroatoms selected from O, N, P, Si and S, or Oμ 24 heterocycloalkyl comprising 1-8 heteroatoms selected from O, N, P, Si and S; W represents OR 13 or NR 14 R 15 ; V represents OR 16 or NR 17 R 18 ; each of R 13 and R 16 independently represents H or C]_ 2 4 alkyl; each of R 14 , R 15 , R 17 and R 18 independently represents H, C]_ 2 4 alkyl, hydroxy or C]_ 2 4 alkoxy; Y is H or OH; and (i) Z is O and is a single bond; or (ii) Z is absent and is a double bond. -93 053292
  2. 2. A compound according to claim 1, wherein R 1 and R 2 are each independently H, Qg alkyl, or CO R 6 , or together with the nitrogen atom to which they are attached form a heterocycloalkyl; or wherein R 1 and R 2 are each independently H, methyl, ethyl, C(O)-C]_24 alkylene-CO-W, where W is OR 13 or NR 14 R 15 , or C(O)-CH(V)-CH 3 , where V is OR 16 or nr 17 r 18 , or together with the nitrogen atom to which they are attached form piperazinyl, piperidinyl, pyrrolidinyl, imidazolidinyl, or azepinyl; R 13 and R 16 are each independently H or Q24 alkyl; and each of R 14 , R 15 , R 17 and R 18 independently represents H, C]_24 alkyl, hydroxy or C]_24 alkoxy; or where each of R 1 and R 2 independently represents H, methyl, ethyl, C(O)-(C2.4 alkylene)-CO2, where W represents OR 13 or NR 14 R 15 , or C(O)-CH(V)-CH3 where V represents OR 16 or NR 17 R 1!8 , or together with the nitrogen atom to which they are attached form piperazinyl; each of R 13 and R 16 independently represents H or methyl; and each of R 14 , R 15 , R 17 and R 18 independently represents H, methyl, hydroxy or methoxy; or where R 1 is H, methyl, ethyl, C(O)CH 2 CH 2 COOH, C(O)CH 2 CH 2 CH 2 COOH, C(O)CH2CH 2 CH2CH 2 COOH, C(O)CH 2 CH 2 CH 2 COOMe, C(O)CH 2 CH 2 CH 2 CONHOH, C(O)CH 2 CH 2 CH 2 CONHOMe, C(O)-CH(OH)-CH 3 , C(O)-CH(NH 2 )-CH 3 or C(O)-CH(NMe 2 )-CH 3 ; or where R 2 is H or methyl; or where R 1 and R 2 together with the nitrogen atom to which they are attached form 4-methyl-1-piperazinyl.
  3. 3. The compound according to claim 1 or 2, wherein R 3 is methyl.
  4. 4. The compound according to claim 1, wherein R 6 is CH2CH2COOH, CH2CH2CH2COOH, CH2CH2CH2CH2COOH, CH 2 CH 2 CH 2 COOMe, CH 2 CH 2 CH 2 CONHOH or CH 2 CH 2 CH 2 CONHOMe.
  5. 5. The compound according to claim 1, wherein R 8 is methyl.
  6. 6. The compound of claim 1, wherein each R 10 -R 12 is independently H or methyl.
  7. 7. A compound according to claim 1, having formula II: or a pharmaceutically acceptable salt thereof, wherein: R 1 is H or -COR 6 ; and R 6 is -C1.24 alkylene-COOH. -94053292
  8. 8. The connection selected from. -95053292 -96053292 54 /Υ Η \ /Ό -γ V H 0 n 3 s Τ \ь/ οΎ Υ /- 1 ο \ Υο ο ζ 55 ΗθΥγΗ \ Υο Υ Η / \ 0 / ηο\ Υ /..... 0 \ )=° 0' 56 ζ 9^0 Υ ; ΧΥο ο 57 ο -97053292 -98053292 -99053292 or a pharmaceutically acceptable salt thereof.
  9. 9. Compound of formula III: o III or its pharmaceutically acceptable salt, where X 1 is NH; D is absent or is -C(O)-(CH 2 ) 2 . 5 -C(O)- or -O-NH-C(O)-(CH 2 ) 2 . 5 -C(O)-; L is a linking group comprising (a) 6-maleimidocaproyl (MC), maleimidopropanoyl (MP), 6-aminocaproyl, paminobenzyloxy, p-aminobenzyl (PAB), p-aminobenzyloxycarbonyl (PABC), or p-amino-amethylbenzyl (MePAB) groups; or (b) one or more amino acids selected from alanine, valine, glycine, leucine, isoleucine, methionine, tryptophan, phenylalanine, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, and citrulline; or (c) a peptide, a carbohydrate, a glucuronide, one or more polyethyleneglycol units, or a hydrazone; or (d) a combination of two or more of the above; Y is H or OH; and (i) Z is O and is a single bond; or (ii) Z is absent and is a double bond.
  10. 10. A compound according to claim 9, having formula IV: or a pharmaceutically acceptable salt thereof, where η is an integer from 1 to 4. - 100053292 - 101 053292
  11. 12. The compound selected from. Compound 10a (n=1) 10b (n=2) - 102053292 10c(n=3) \ /° l \>* H ο γ ο γγ^ο-^ΥΥζ ......... \ ] ” HN^ 12a (n=l) U--. J 1 V-/ °v H γ..++/+Λ τ ^ HN^ 12b (n=2) \_/^Y H y'·........ HN^ Η Ϊ Ν'^% 12c(n=3) Y^XJ 4 (γ y φ....... HN^ - 103 053292 - 104053292 - 105053292 - 106053292 - 107053292 - 108053292
  12. 13. A pharmaceutical composition comprising a compound according to any one of paragraphs 1-12 and a pharmaceutically acceptable carrier.
  13. 14. The use of a compound according to any one of paragraphs 1-12 or a composition according to paragraph 13 for the treatment of influenza infection.
  14. 15. Use of a compound according to any one of paragraphs 1-12 or a composition according to paragraph 13 for the treatment of SARS-CoV-2 infection.
  15. 16. The use of a compound according to any one of paragraphs 1-12 or a composition according to paragraph 13 for the treatment of Ebola virus infection.

Description

Related applications This application claims priority to U.S. Provisional Patent Application Nos. 63/299,824, filed January 14, 2022, and 63/367,108, filed June 27, 2022. The contents of each of the aforementioned applications are incorporated herein by reference in their entirety. Statement of funding for research by the US Federal Government. This invention was supported by the U.S. Government under contract OTA No. HHSO100201700020C to the Biomedical Advanced Research and Development Authority (BARDA). The U.S. Government has certain rights in this invention. List of sequences This application contains a Sequence Listing, which is provided as an XML file named 10968W001_SL.xml, generated on January 9, 2023, of size 457,018 bytes, which is incorporated herein by reference in its entirety. Field of invention This document describes verrucarin A derivatives and their antibody-drug conjugates (ADCs). The verrucarin A derivatives and ADCs described herein can be used, among other things, in the treatment of viral diseases. State of the art Verrucarin A is a trichothecene toxin that has been studied in the treatment of various cancers. However, the toxicity of verrucarin A is too high to provide a therapeutic window for its use as a therapy. Therefore, verrucarin ADCs have been proposed to address this issue (U.S. Patents 4,744,981, 10,232,051, and 10,985,112; U.S. Patent Application Publication No. US 2015/0250896). Verrucarin A has also been shown to have significant antiviral activity against, for example, vaccinia virus strain DII and Newcastle disease virus (NDV) strain Miyadera (Tamura et al. J. Anitbiot. (Tokyo) 1968, 21(2):160-161), as well as Junin arenavirus (JUNV) (Garcia et al. Planta Med. 2002, 68(3):209-212). ADCs combine the specificity of antibodies with the ability to site-specifically target a specific cell type or tissue containing a payload. This site-specificity allows for the use of toxic payloads that would otherwise lack a sufficient therapeutic window. Research in this area has generated significant interest and led to the introduction of pharmaceutical products, including ADCETRIS® (brentuximab vedotin) and KADCYLA™ (ado-trastuzumab emtansine). With some exceptions, current antiviral therapies simply treat symptoms or inhibit viral replication. These treatments can slow disease progression until the natural immune response becomes effective or viral stasis is achieved. Furthermore, few, if any, broad-spectrum antiviral therapies exist. Thus, there is a significant unmet need in the treatment and prevention of viral infections. Furthermore, the development of antiviral agents that utilize an alternative mechanism of action is critical to reducing the risk of viral resistance to existing therapeutics. The use of ADCs containing a broad-spectrum payload can facilitate the use of a wide range of antiviral antibodies, which often lack sufficient neutralizing activity to be effective on their own. Thus, there is a continuing need for effective site-specific treatments for viral infections. The essence of the invention Provided herein are derivatives of verrucarin A and their ADCs. In one embodiment, the derivatives of verrucarin A for use in the compositions and methods provided herein have formula I: or a pharmaceutically acceptable derivative thereof, wherein X, Y and Z have the meanings as defined herein. In another embodiment, the verrucarin A derivatives for use in the compositions and methods provided herein have formula II: or a pharmaceutically acceptable derivative thereof, wherein R 1 has the meaning as defined herein. In another embodiment, verrucarin A linker derivatives of formula III are provided for use in the compositions and methods provided herein: or a pharmaceutically acceptable derivative thereof, wherein X 1 , D, L, Y and Z have the meanings as defined herein. In another embodiment, verrucarin A linker derivatives of formula IV are provided for use in the compositions and methods provided herein: or a pharmaceutically acceptable derivative thereof, wherein L and η have the meanings as defined herein. In another embodiment, ADCs of Formula V are provided for use in the compositions and methods provided herein: Z-(LX) V V or a pharmaceutically acceptable derivative thereof, where: Z represents the antiviral antigen-binding domain; L represents a linking group as defined herein; X is a derivative of verrucarine A; and v is an integer from 1 to 12. In another embodiment, the verrucarin A derivatives and their ADCs provided herein can be used in methods for treating viral diseases. In one embodiment, the viral disease is influenza, COVID-19, or Ebola. Detailed description of the invention I. Definitions. To facilitate understanding of the present invention as described in this specification, a number of terms are defined below. -2 053292 Unless otherwise specified, all technical and scientific terms used in this document have the same meaning as commonly understood by one o