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WO2025054460A1 - Analogues de 2'3'-gampc substitués par endo-phosphorothioate et stables à la photodiestérase en tant qu'agonistes du stimulateur des gènes de l'interféron - Google Patents

Analogues de 2'3'-gampc substitués par endo-phosphorothioate et stables à la photodiestérase en tant qu'agonistes du stimulateur des gènes de l'interféron Download PDF

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WO2025054460A1
WO2025054460A1 PCT/US2024/045601 US2024045601W WO2025054460A1 WO 2025054460 A1 WO2025054460 A1 WO 2025054460A1 US 2024045601 W US2024045601 W US 2024045601W WO 2025054460 A1 WO2025054460 A1 WO 2025054460A1
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compound
cancer
hydrogen
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adenine
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Herman O. Sintim
Kofi Simpa YEBOAH
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Purdue Research Foundation
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    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A61K31/708—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid

Definitions

  • TECHNICAL FIELD [0002] The present disclosure relates to endo-phosphorothioate-substituted 2'3'-cGAMP analogues that are agonists of Stimulator of Interferon Genes (STING), pharmaceutical compositions comprising the same, and their use for inducing an immune response and treating and/or inhibiting cancer and infectious diseases.
  • STING Stimulator of Interferon Genes
  • cGAMP synthase catalyzes the synthesis of 2’3’cGAMP (an asymmetric dipurine cyclic dinucleotides (CDN)) from guanosine triphosphate (GTP) and adenosine triphosphate (ATP) upon recognition of cytosolic double-stranded DNA (dsDNA).
  • 2’3’cGAMP tightly binds to STING and triggers downstream inflammation signaling.
  • ENPP1 promotes cancer cell metastases by selectively metabolizing 2’3’cGAMP.
  • the enzyme uses two Zn 2+ ions, which initially form a complex with Asp358/His362/His517 and Asp200/Asp405/His406 residues, to interact with the 2’-5’ phosphodiester oxygen of 2’3’cGAMP.
  • This phosphodiesterase hydrolyzes the 2’3’cGAMP to form pA[3’-5’]pG (phosphoadenylyl phosphoguanosine), followed by a second hydrolysis after the linear dinucleotide is flipped over to produce 5’adenosine monophosphate (AMP) and 5’guanosine monophosphate (GTP).
  • the rate-limiting step is the first step of the mechanism.
  • vaccinia virus encodes poxin (poxvirus immune nuclease), which specifically cleaves the 3’5’-linkage of 2’3’cGAMP (Eaglesham et al., Nature, 2019, 566 (7743), 259-263).
  • Poxin catalysis doesn’t involve a metal ion.
  • Poxin’s 2’3’cGAMP hydrolysis mechanism follows a self-cleavage step in which the enzyme induces the free or labile 2’OH functionality of 2’3’cGAMP with a lysine (Lys142) residue in its active site, leading to an attack to form adenosine-2’3’-cyclophosphate with a 3’-5’ phosphodiester linkage as illustrated in Fig.1B.
  • ADU-S100 is, however, not desirable in clinical practice, especially for “hard-to-reach” tumors.
  • Another 2’3’cGAMP analog, MK-1454 (3) (Fig.1A) was reported to completely regress tumor growth and boost the efficacy of anti-programmed cell death protein 1(PD1)therapy in mouse syngeneic models (Chang et al., Journal of Medicinal Chemistry, 2022, 65 (7), 5675–5689).
  • MK-1454 is currently in clinical studies in combination with pembrolizumab for the treatment of advanced metastatic solid tumors, lymphomas, and unresectable or metastatic, reoccurring head and neck squamous cell carcinoma (HNSCC) (McIntosh et al., Nature, 2022, 603 (7901), 439-444).
  • HNSCC head and neck squamous cell carcinoma
  • 2’3’cGAMP is susceptible to enzymatic degradation by both ectophosphodiesterases and cytosolic phosphodiesterases of human and viral 70418-02 origin. Therefore, a synthetic CDN analogue that overcomes the aforementioned challenge is desirable.
  • 2’3’cGAMP-based analogues in particular, endo-phosphorothioate-substituted 2'3'-cGAMP analogues that are STING agonists, stable to phosphodiesterases, such as ENPP1, and can be used to treat or inhibit cancer and infectious diseases.
  • STING Stimulator of Interferon Genes
  • endo-phosphorothioate-substituted 2'3'-cGAMP analogues are compounds of formula (I) or formula (II): wherein: Z is adenine, uracil, guanine, cytosine, inosine, purine, or a purine derivative; B is adenine, guanine, cytosine, uracil, inosine, purine, or a purine derivative; Q is a heteroatom selected from O, N, and S; W is hydrogen, halogen, hydroxy, or OCH 3 ; X is hydrogen, halogen, or hydroxy; Y is hydrogen or halogen; and M + is a cation selected from a group consisting of sodium + (Na + ), potassium + (K + ), lithium + (Li + ), and R 1 R 2 R 3 NH + ; wherein each R 1 , R 2 , and R 3 is independently hydrogen, alkyl,
  • the compound of formula (I) is a compound of formula (IA): 70418-02 wherein: B is adenine, guanine, cytosine, uracil, inosine, purine, or a purine derivative; X is hydrogen, halogen, or hydroxy; Y is hydrogen or halogen; and M + is a cation selected from Na + , K + , Li + , and R 1 R 2 R 3 NH + ; wherein each R 1 , R 2 , and R 3 is independently hydrogen, alkyl or aryl; and a sulfur atom in a phosphorothioate moiety is endocyclic; or a prodrug or an analogue thereof.
  • X is hydroxy; B is adenine or guanine; and Y is hydrogen.
  • X is halogen; B is adenine, cytosine, uracil, or inosine; and Y is hydrogen.
  • X is hydrogen; B is adenine; and Y is hydrogen or halogen.
  • the compound of formula (I) is a compound of formula (IB): wherein: 70418-02 B is adenine, guanine, cytosine, uracil, purine or a purine derivative; X is hydrogen, halogen, or hydroxy; Y is hydrogen or halogen; and M + is a cation selected from Na + , K + , Li + , and R 1 R 2 R 3 NH + ; wherein each R 1 , R 2 , and R 3 is independently hydrogen, alkyl or aryl; and a sulfur atom in a phosphorothioate moiety is endocyclic; or a prodrug or an analogue thereof.
  • X is hydroxy; B is adenine or guanine; and Y is hydrogen.
  • X is halogen; B is adenine; and Y is hydrogen.
  • the compound of formula (I) is: 70418-02 Compound 39' or a prodrug or an analogue thereof.
  • the compound of formula (II) is a compound of formula (IIA): wherein: M + is a cation selected from Na + , K + , Li + , and R 1 R 2 R 3 NH + ; wherein each R 1 , R 2 , and R 3 is independently hydrogen, alkyl or aryl; and a sulfur atom in a phosphorothioate moiety is endocyclic; or a prodrug or an analogue thereof.
  • the compound of formula (II) is a compound of formula (IIB): wherein: M + is a cation selected from Na + , K + , Li + , and R 1 R 2 R 3 NH + ; wherein each R 1 , R 2 , and R 3 is independently hydrogen, alkyl or aryl; and a sulfur atom in a phosphorothioate moiety is endocyclic; or a prodrug or an analog thereof. [0019] In some embodiments, the compound of formula (II) is: 70418-02 Compound 19 or a prodrug or an analog thereof.
  • a compound of formula (IV) wherein: Z is adenine, uracil, guanine, cytosine, inosine, purine, or a purine derivative; B is adenine, guanine, cytosine, uracil, inosine, purine, or a purine derivative; M + is a cation selected from a group consisting of sodium + (Na + ), potassium + (K + ), lithium + (Li + ), and R 1 R 2 R 3 NH + ; wherein each R 1 , R 2 , and R 3 is independently hydrogen, alkyl, or aryl; or a prodrug or an analogue thereof.
  • the compound of formula (IV) is: 70418-02 or a prodrug or an analogue thereof.
  • a pharmaceutical composition comprising an above-described compound (or a prodrug or an analogue thereof) and a pharmaceutically acceptable carrier, excipient, or diluent.
  • the compound can induce an immune response by activating STING.
  • a method of inducing an immune response in a patient in need thereof by administering to the patient a therapeutically effective amount of an above-described compound (or a prodrug or an analogue thereof) or a pharmaceutical composition comprising the same and a pharmaceutically acceptable carrier, excipient or diluent.
  • the patient has cancer.
  • the patient has an infectious disease.
  • the compound (or a prodrug or an analogue thereof) can be administered subcutaneously or intratumorally.
  • a method of treating or inhibiting cancer in a patient by administering to the patient a therapeutically effective amount of an above-described compound (or a prodrug or an analogue thereof) or a pharmaceutical composition comprising the compound (or a prodrug or an analogue thereof) and a pharmaceutically acceptable carrier, excipient, or diluent, whereupon the cancer in the patient is treated or inhibited.
  • the cancer is colon cancer.
  • the compound can be administered subcutaneously or intratumorally.
  • a method of treating or inhibiting a disease in a patient by administering to the patient a therapeutically effective amount of a compound of formula (I’) or (II’), agonists of Stimulator of Interferon Genes (STING): 70418-02 wherein: Z is adenine, uracil, guanine, cytosine, inosine, purine, or a purine derivative; B is adenine, guanine, cytosine, uracil, inosine, purine, or a purine derivative; Q is a heteroatom selected from O, N, and S; W is hydrogen, halogen, hydroxy, or OCH 3 ; X is hydrogen, halogen, or hydroxy; Y is hydrogen or halogen; and M + is a cation selected from a group consisting of Na + , K + , Li + , and R 1 R 2 R 3 NH + ; wherein each R 1 , R 1 , R 1 R 2
  • the disease is cancer. In some embodiments, the disease is an infectious disease. [0027] In some embodiments, the compound of formula (I’) or (II’) is: 70418-02 Compound 24 Compound 25 Compound 26 C ompound 28 or a prodrug or an analogue thereof.
  • the prodrug is: 70418-02 wherein: Z is adenine, uracil, guanine, cytosine, inosine, purine, or a purine derivative; B is adenine, guanine, cytosine, uracil, purine or a purine derivative; Y is hydrogen or halogen; W is hydrogen, halogen, hydroxy, or OCH 3 ; each R 4 , and R 5 is independently selected from 70418-02 or [0030] Still further provided is a compound selected from: Compound 21 Compound 22 Compound 23 or a prodrug or an analogue thereof.
  • Fig. 1A shows structures of 2’3’cGAMP and two other previously reported cyclic dinucleotides (CDNs)-based Stimulator of Interferon Genes (STING) agonists in clinical trials.
  • CDNs cyclic dinucleotides
  • STING Interferon Genes
  • Fig.1B shows ribose-based strategies used to garner enzymatic stability.
  • A) represents 2’OH substitution strategies that offer stability to various CDN phosphodiesterases (PDEs), and B) represents a chair conformation view of locked nucleic acid (LNA) endo-S-CDNs.
  • Fig.2A shows a differential scanning fluorimetry (DSF) assay that characterizes STING bonding with ⁇ T m values.
  • Fig. 2B shows the fraction of fluorescent probe bound to hSTING when treated with 20 ⁇ M CDNs.
  • Fig.3A shows the fraction bound of listed 2’3’CDNs upon incubation with STING.
  • FIG. 3B shows the dose-dependent curves depicting anisotropy values vs ligand concentrations with IC 50 values.
  • Fig.4A shows a single dose interferon regulatory factor (IRF) induction (QuantiLuc assay) after treating of THP1 dual WT cells with 10 ⁇ M CDNs.
  • Fig.4B shows the dose-response (EC 50 ) curves of CDNs in THP1 dual WT cells.
  • Fig.4C shows a single dose IRF induction (QuantiLuc assay) after treating THP1 STING KI H232 cells with 10 ⁇ M of representative CDNs.
  • Fig.4D shows the dose-response (EC 50 ) curves of CDNs in THP1 STING KI H232.
  • Fig.5A shows the fraction bound of listed 2’3’CDNs upon incubation with STING.
  • Fig. 5B shows dose-dependent curves depicting anisotropy values vs ligand concentrations.
  • Fig.5C shows IC 50 values as calculated by the dose-response curves in Fig.5B.
  • Fig.6A shows the chemical stability of the known drug ADU-S100 compared to untreated after incubating for 90 minutes.
  • Fig.6A shows the chemical stability of the known drug ADU-S100 compared to untreated after incubating for 90 minutes.
  • FIG. 6B shows the chemical stability of compound endo-S-cGALMP (compound 15) compared to untreated after incubating for 90 mins.
  • Fig. 7 shows ectonucleotide phosphodiesterase (ENPP1) stability of potent endo-S- 2’3’CDNs analogues with reference to 2’3’cGAMP in time intervals and poxin degradation result of endo-S-2’3’CDNs over time with reference to 2’3’cGAMP.
  • the reactions were monitored via 70418-02 HPLC, and the relative abundance values were determined by normalization with samples of the different 2’3’CDNs that didn’t have any enzyme.
  • the term 'endo-phosphorothioate-substituted 2'3'-cGAMP analogues' refers to 2'3'- cGAMP analogues whereby the sulfur atom forms part of the phosphodiester linkage (hereafter called “endo-s-CDNs”).
  • endo-s-CDNs 2'3'-cGAMP analogues' and 2'3'-cGAMP compounds are used interchangeably.
  • the present disclosure is predicated, at least in part, on the discovery that evasion of immune surveillance happens when cyclic dinucleotides (CDNs) are degraded by respective phosphodiesterases (PDEs), leading to the progression of cancer and viral and bacterial infections.
  • the native 2'3'-cGAMP can be degraded by ectonucleotide phosphodiesterase 1(ENPP1) and poxin, which greatly limits the host’s ability to counter cancer or infections. Therefore, most CDN-based STING agonists in clinical trials contain a phosphorothioate modification. Notwithstanding their efficacy, phosphorothioates contain a P-chiral center, which can be extremely challenging to control asymmetrically. [0053] In view of the above, 5’endo-phosphorothioate-substituted 2'3'-cGAMP analogues are provided.
  • These compounds can be stable to phosphodiesterases, such as ENPP1, a mammalian phosphodiesterase, and poxin, a phosphodiesterase in poxvirus, but can potently activate STING in macrophages to produce inflammatory cytokines, which have been shown to activate immune response to clear tumors.
  • the canonical oxygen bridge of the 2’-5’phosphodiester linkage can be replaced with a sulfur atom to form 5’endo-phosphodiester-substituted 2'3'-cGAMP, and the replacement of 2’OH on the ribose group with non-hydrogen bond donor groups can enable access to ENPP1 and poxin-stable 2’3’CDN analogues which can retain STING agonism.
  • endo- 70418-02 phosphorothioate-substituted 2'3'-cGAMP analogues can disrupt the first step of ENNP1 cleavage mechanism where Thr238 in the catalytic center of ENPP1 can attack the phosphorus in the 2’- 5’phosphodiester linkage and, with modification of the 2’OH group of 2’3’cGAMP, they can provide a promising template to generate powerful STING agonist that can potentially be resistant to both cancer and viral escape pathways.
  • Z is adenine, uracil, guanine, cytosine, inosine, purine, or a purine derivative
  • B is adenine, guanine, cytosine, uracil, inosine, purine, or a purine derivative
  • Q is a heteroatom selected from O, N, and S
  • W is hydrogen, halogen, hydroxy, or OCH 3
  • X is hydrogen, halogen, or hydroxy
  • Y is hydrogen or halogen
  • M + is a cation selected from a group consisting of sodium + (Na + ), potassium + (K + ), lithium (Li + ), and R 1 R 2 R 3 NH + ; wherein each R 1 , R 2 , and R 3 is independently hydrogen, alkyl, or aryl; and a sulfur atom in a phosphorothioate moiety is endocyclic; or
  • the compound of formula (I) is a compound of formula (IA): 70418-02 wherein: B is adenine, guanine, cytosine, uracil, inosine, purine, or a purine derivative; X is hydrogen, halogen, or hydroxy; Y is hydrogen or halogen; and M + is a cation selected from Na + , K + , Li + , and R 1 R 2 R 3 NH + ; wherein each R 1 , R 2 , and R 3 is independently hydrogen, alkyl or aryl; and a sulfur atom in a phosphorothioate moiety is endocyclic; or a prodrug or an analogue thereof.
  • X is hydroxy; B is adenine or guanine; and Y is hydrogen.
  • X is halogen; B is adenine, cytosine, uracil, or inosine; and Y is hydrogen.
  • Y is hydrogen or halogen.
  • the compound of formula (I) is a compound of formula (IB): wherein: 70418-02 B is adenine, guanine, cytosine, uracil, purine or a purine derivative; X is hydrogen, halogen, or hydroxy; Y is hydrogen or halogen; and M + is a cation selected from Na + , K + , Li + , and R 1 R 2 R 3 NH + ; wherein each R 1 , R 2 , and R 3 is independently hydrogen, alkyl or aryl; and a sulfur atom in a phosphorothioate moiety is endocyclic; or a prodrug or an analogue thereof.
  • X is hydroxy; B is adenine or guanine; and Y is hydrogen.
  • X is halogen; B is adenine; and Y is hydrogen.
  • the compound of formula (I) is : 70418-02 70418-02 or a prodrug or an analogue thereof.
  • the compound of formula (II) is a compound of formula (IIA): wherein: M + is a cation selected from Na + , K + , Li + , and R 1 R 2 R 3 NH + ; wherein each R 1 , R 2 , and R 3 is independently hydrogen, alkyl or aryl; and a sulfur atom in a phosphorothioate moiety is endocyclic; or a prodrug or an analogue thereof.
  • the compound of formula (II) is a compound of formula (IIB): 70418-02 wherein: M + is a cation selected from Na + , K + , Li + , and R 1 R 2 R 3 NH + ; wherein each R 1 , R 2 , and R 3 is independently hydrogen, alkyl or aryl; and a sulfur atom in a phosphorothioate moiety is endocyclic; or a prodrug or an analogue thereof. [0065] In some embodiments, the compound of formula (II) is: Compound 19 or a prodrug or an analogue thereof.
  • Scheme 2 highlights the synthesis using 3’OTBS protected adenosine phosphoramidite as the starting material to access compounds 12-14 using the same chemistry as Scheme 1.
  • Abbreviations used are: A- Adenine, G- guanine, C- cytosine, U- uracil, I- inosine, DMTrO- Dimethoxytrityl ether 70418-02 Ibu- isobutyryl, OTBS- tert-butyldimethylsilyl ether, N-Bz- N-benzoyl, Bz- benzoyl, CN- cyano, OH- hydroxy, ACN- acetonitrile, DCM- dichloromethane, tBuOOH- tertbutyl hydroperoxide, DMF- dimethylformamide, RT- room temperature.
  • Scheme 2 depicts the synthesis of 5’endophosphorothioate 2’3’CDNs compounds 12-14.
  • the reagents and conditions used are: a) 3-hydroxypropionitrile (5 eq), dicyanoimidazole (4 eq), 18 hours, then 3H-1,2-benzodithiol-3-one 1,1-dioxide or beacauge reagent (2.5 eq), 1 hour, ACN, RT; b) Dichloroacetic acid (12 eq), 10 minutes DCM; c) 3’O phosphoramidite (1.5 eq), dicyanoimidazole (2 eq), 18 h, then ammonium hydroxide, RT, 24 hours; f) triethylamine trifluoride (10-20 eq), 6 hours, 55 °C.
  • alkynyl refers to an unsaturated monovalent chain of carbon atoms, including at least one triple bond, which may be optionally branched. In various embodiments that include alkynyl, illustrative examples include lower alkynyl, such as C 2 -C 6, C 2 -C 4 alkynyl, and the like.
  • hydroxyalkyl refers to alkyl groups substituted with at least one hydroxyl (- OH) group.
  • 1X reaction buffer 50 mM HEPES– KOH pH 7.5, 35 mM KCl, and 1 mM DTT
  • Example 3 O-((2R,3R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-2-(2,4-dioxo-3,4-dihydropyrimidin- 1(2H)-yl)-5-(hydroxymethyl)tetrahydrofuran-3-yl) O,O-bis(2-cyanoethyl) phosphorothioate (X): Used the same method as described for the synthesis of II.
  • Example 4 (2S,3R,4R,5R)-5-(6-benzamido-9H-purin-9-yl)-4-((tert-butyldimethylsilyl)oxy)-2- (iodomethyl)tetrahydrofuran-3-yl(((2R,3R,4R,5R)-4-((bis(2 cyanoethoxy)phosphorothioyl)oxy)-3-((tert-butyldimethylsilyl)oxy)-5-(2-isobutyramido-6- oxo-1,6-dihydro-9H-purin-9-yl)tetrahydrofuran-2-yl)methyl) (2-cyanoethyl) phosphate (IVa): 70418-02 A mixture of phosphorothioate II (0.27 g, 0.42 mmol) and adenosine (n-bz) 2’-tBDSilyl CED phosphorothio
  • Example 5 ((2R,3R,4R,5R)-4-((bis(2-cyanoethoxy)phosphorothioyl)oxy)-3-((tert- butyldimethylsilyl)oxy)-5-(2-isobutyramido-6-oxo-1,6-dihydro-9H-purin-9- yl)tetrahydrofuran-2-yl)methyl ((2S,3R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-2- (iodomethyl)-5-(2-isobutyramido-6-oxo-1,6-dihydro-9H-purin-9-yl)tetrahydrofuran-3-yl) (2-cyanoethyl) phosphate (IVb): A mixture of phosphorothioate II (0.27 g, 0.42 mmol) and guanosine (n-ibu) 2’
  • Example 6 (2S,3R,4R,5R)-5-(4-benzamido-2-oxopyrimidin-1(2H)-yl)-4-fluoro-2- (iodomethyl)tetrahydrofuran-3-yl (((2R,3R,4R,5R)-4-((bis(2- cyanoethoxy)phosphorothioyl)oxy)-3-((tert-butyldimethylsilyl)oxy)-5-(2-isobutyramido-6- oxo-1,6-dihydro-9H-purin-9-yl)tetrahydrofuran-2-yl)methyl) (2-cyanoethyl) phosphate (IVc): A mixture of phosphorothioate II (0.27 g, 0.42 mmol) and 5'-Dimethoxytrityl-N-acetyl- deoxyCytidine,2'-fluoro-3'-[
  • Example 7 ((2R,3R,4R,5R)-4-((bis(2-cyanoethoxy)phosphorothioyl)oxy)-3-((tert- butyldimethylsilyl)oxy)-5-(2-isobutyramido-6-oxo-1,6-dihydro-9H-purin-9- yl)tetrahydrofuran-2-yl)methyl ((2S,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)- yl)-4-fluoro-2-(iodomethyl)tetrahydrofuran-3-yl) (2-cyanoethyl) phosphate (IVd): A mixture of phosphorothioate II (0.27 g, 0.42 mmol) and 5'-Dimethoxytrityl-deoxyUridine, 2'- fluoro-3'-[
  • Example 8 (2S,3R,4R,5R)-5-(6-benzamido-4,5-dihydro-9H-purin-9-yl)-4-fluoro-2- (iodomethyl)tetrahydrofuran-3-yl (((2R,3R,4R,5R)-4-((bis(2- cyanoethoxy)phosphorothioyl)oxy)-3-((tert-butyldimethylsilyl)oxy)-5-(2-isobutyramido-6- oxo-1,6-dihydro-9H-purin-9-yl)tetrahydrofuran-2-yl)methyl) (2-cyanoethyl) phosphate (IVe): A mixture of phosphorothioate II (0.27 g, 0.42 mmol) and 5'-Dimethoxytrityl-N-benzoyl- deoxyAdenosine, 2'-fluoro-3'-
  • Example 10 ((2R,3R,4R,5R)-4-((bis(2-cyanoethoxy)phosphorothioyl)oxy)-3-((tert- butyldimethylsilyl)oxy)-5-(2-isobutyramido-6-oxo-1,6-dihydro-9H-purin-9- yl)tetrahydrofuran-2-yl)methyl ((2S,3R,4R,5R)-4-fluoro-2-(iodomethyl)-5-(6-oxo-1,6- dihydro-9H-purin-9-yl)tetrahydrofuran-3-yl) (2-cyanoethyl) phosphate (IVh): A mixture of phosphorothioate II (0.27 g, 0.42 mmol) and 5'-Dimethoxytrityl-deoxyInosine, 2'- fluoro-3'-[(2-cyanoethyl)
  • Example 11 ((2R,3R,4R,5R)-5-(6-benzamido-9H-purin-9-yl)-4-((bis(2- cyanoethoxy)phosphorothioyl)oxy)-3-((tert-butyldimethylsilyl)oxy)tetrahydrofuran-2- yl)methyl ((2S,3S,5R)-2-(iodomethyl)-5-(2-isobutyramido-6-oxo-1,6-dihydro-9H-purin-9- yl)tetrahydrofuran-3-yl) (2-cyanoethyl) phosphate (VIIIb): A mixture of phosphorothioate VI (0.289 g, 0.42 mmol) and guanosine (n-ibu) 3’-tBDSilyl CED phosphoramidite (I, 0.611 g, 0.63 mmol) was dissolved in an
  • Example 12 ((2R,3R,4R,5R)-5-(6-benzamido-9H-purin-9-yl)-4-((bis(2- cyanoethoxy)phosphorothioyl)oxy)-3-((tert-butyldimethylsilyl)oxy)tetrahydrofuran-2- yl)methyl ((2S,3R,4R,5R)-5-(6-benzamido-9H-purin-9-yl)-4-fluoro-2- (iodomethyl)tetrahydrofuran-3-yl) (2-cyanoethyl) phosphate (VIIIc): A mixture of phosphorothioate VI (0.289 g, 0.42 mmol) and 5'-Dimethoxytrityl-N-benzoyl- deoxyAdenosine, 2'-fluoro-3'-[(2-cyanoethyl)-(N,N-diisopropyl)-
  • Endo-S-3’3’CDNs 5ml of Ammonium hydroxide (30 % NH 3 in water) was added to 5’iododinucleotidephosphorothioate (0.038 mmol) and stirred for 24 hrs at RT. After drying at reduced pressure, 5 ml of water was added to the products and subsequently purified via HPLC with the same conditions as used for the purification of endo-S-2’3’CDNs.
  • Example 15 Compound 4 70418-02 O O
  • Compound 4 Ammonium hydroxide (5 ml, 30 % NH 4 OH in water) was added to 5’-Iodo adenosine guanosine phosphorothioate IVa (52 mg, 0.038 mmol) and stirred for 24 h at RT. The solution was concentrated at reduced pressure to complete dryness under a high vacuum. The crude product was redissolved in dry pyridine (2 ml) and then Et 3 N.3HF (0.25 ⁇ l, 1.6 mmol) at 50 °C for 6 h.
  • Example 16 Compound 5 O O Compound 5 70418-02 Ammonium hydroxide (5 ml, 30 % NH 4 OH in water) was added to 5’-Iodo diguanosine phosphorothioate IVb (50 mg, 0.038 mmol) and stirred for 24 h at RT. The subsequent steps follow that described for compound 4.
  • Example 17 Compound 6 O O Compound 6 Ammonium hydroxide (5 ml, 30 % NH 4 OH in water) was added to 5’-Iodo 2’Fluoro cytidine guanosine phosphorothioate IVc (45 mg, 0.038 mmol) and stirred for 24 h at RT. The subsequent steps follow that described for compound 4.
  • Example 18 Compound 7 70418-02 O O
  • Compound 7 Ammonium hydroxide (5ml, 30 % NH 4 OH in water) was added to 5’-Iodo 2’Fluoro uridine guanosine phosphorothioate IVd (45 mg, 0.038 mmol) and stirred for 24 h at RT. The subsequent steps follow that described for compound 4.
  • Example 19 Compound 8 O O Compound 8 Ammonium hydroxide (5ml, 30 % NH 4 OH in water) was added to 5’-Iodo 2’Fluoro adenosine guanosine phosphorothioate IVe (48 mg, 0.038 mmol) and stirred for 24 h at RT. The subsequent steps follow that described for compound 4.
  • Example 20 Compound 9 Ammonium hydroxide (5ml, 30 % NH 4 OH in water) was added to 5’-Iodo 2’Fluoro adenosine guanosine phosphorothioate IVf (48 mg, 0.038 mmol) and stirred for 24 h at RT. The subsequent steps follow that described for compound 4.
  • Example 21 Compound 10 70418-02 Ammonium hydroxide (5ml, 30 % NH 4 OH in water) was added to 5’-Iodo 2’deoxyadenosine guanosine phosphorothioate IVg (47 mg, 0.038 mmol) and stirred for 24 h at RT. The subsequent steps follow that described for compound 4.
  • Example 22 Compound 11 O O Compound 11 Ammonium hydroxide (5ml, 30 % NH 4 OH in water) was added to 5’-Iodo 2’Fluoro inosine guanosine phosphorothioate IVh (47 mg, 0.038 mmol) and stirred for 24 h at RT. The subsequent steps follow that described for compound 4.
  • Example 23 Compound 12 Ammonium hydroxide (5ml, 30 % NH 4 OH in water) was added to 5’-Iodo diadenosine phosphorothioate VIIa (52 mg, 0.038 mmol) and stirred for 24 h at RT. The subsequent steps follow that described for compound 4.
  • Example 24 Compound 13 70418-02 Ammonium hydroxide (5ml, 30 % NH 4 OH in water) was added to 5’-Iodo guanosine adenosine phosphorothioate VIIb (52 mg, 0.038 mmol) and stirred for 24 h at RT. The subsequent steps follow that described for compound 4.
  • Example 25 Compound 14 Ammonium hydroxide (5ml, 30 % NH 4 OH in water) was added to 5’-Iodo 2’Fluoro diadenosine phosphorothioate VIIc (49 mg, 0.038 mmol) and stirred for 24 h at RT. The subsequent steps follow that described for compound 4.
  • Example 26 Compound 15 70418-02 Ammonium hydroxide (5ml, 30 % NH 4 OH in water) was added to 5’-Iodo adenosine phosphorothioate IX (48 mg, 0.038 mmol) and stirred for 24 h at RT. The subsequent steps follow that described for compound 4.
  • Example 27 Compound 16 O
  • Ammonium hydroxide (5ml, 30 % NH 4 OH in water) was added to 5’-Iodo adenosine uridine phosphorothioate XI (46 mg, 0.038 mmol) and stirred for 24 h at RT. The subsequent steps follow that described for compound 4.
  • Example 33 Compound 22 70418-02 Off-white solid.19% yield.
  • 1 H NMR 800 MHz, D 2 O
  • Example 34 Compound 23 Off-white solid.21% yield.
  • Endo-S-CDNs (20 ⁇ mol, trietylammonium salt of endo-S-CDNs) is dissolved in dry MeOH, after which tetrabutylammonium hydroxide (40 ⁇ mol, 1 M solution in MeOH) was added. After bubbling in argon, the solution was left to stir for 30 mins. The solution was concentrated under reduced pressure and co-evaporated firstly with toluene (1 ml) and subsequently co-evaporated twice with dry acetonitrile (1 ml).

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Abstract

L'invention concerne des analogues de 2'3'-GAMPC substitués par endo-phosphorothioate qui sont des agonistes du stimulateur des gènes de l'interféron (STING) ; des compositions pharmaceutiques les comprenant, et leur utilisation pour traiter ou inhiber des cancers et des maladies infectieuses.
PCT/US2024/045601 2023-09-07 2024-09-06 Analogues de 2'3'-gampc substitués par endo-phosphorothioate et stables à la photodiestérase en tant qu'agonistes du stimulateur des gènes de l'interféron Pending WO2025054460A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019161171A1 (fr) * 2018-02-16 2019-08-22 Sperovie Biosciences, Inc. Formulations de nanoparticules d'agonistes de sting

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019161171A1 (fr) * 2018-02-16 2019-08-22 Sperovie Biosciences, Inc. Formulations de nanoparticules d'agonistes de sting

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ABLASSER ET AL.: "cGAS produces a 2'-5'-linked cyclic dinucleotide second messenger that activates STING", NATURE, vol. 498, no. 7454, 2013, pages 380 - 384, XP055376054, DOI: 10.1038/nature12306 *
DUBENSKY ET AL.: "Rationale, progress and development of vaccines utilizing STING- activating cyclic dinucleotide adjuvants", THER ADV VACCINES, vol. 1, no. 4, 2013, pages 131 - 143, XP055177403, DOI: 10.1177/2051013613501988 *
GARLAND ET AL.: "Chemical and Biomolecular Strategies for STING Pathway Activation in Cancer Immunotherapy", CHEM REV., vol. 122, no. 6, 2022, pages 5977 - 6039, XP093105097, DOI: 10.1021/acs.chemrev.1c00750 *

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