Classifications

• • 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
  • A61K31/695—Silicon compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
  • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
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  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
  • A61K47/545—Heterocyclic compounds
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  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
  • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug
  • A61K47/551—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
  • A61K47/555—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound pre-targeting systems involving an organic compound, other than a peptide, protein or antibody, for targeting specific cells
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
  • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
  • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
  • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
  • A61K9/0097—Medicinal compositions released by microdevices, e.g. microelectromechanical systems [MEMS], microdevices comprising chips or microdevices on silicon
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • 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
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  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
  • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
  • C07F15/0086—Platinum compounds
  • C07F15/0093—Platinum compounds without a metal-carbon linkage
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
  • C07F5/02—Boron compounds
  • C07F5/022—Boron compounds without C-boron linkages
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
  • C07F7/02—Silicon compounds
  • C07F7/08—Compounds having one or more C—Si linkages
  • C07F7/0834—Compounds having one or more O-Si linkage
  • C07F7/0836—Compounds with one or more Si-OH or Si-O-metal linkage
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
  • C07F7/02—Silicon compounds
  • C07F7/08—Compounds having one or more C—Si linkages
  • C07F7/0834—Compounds having one or more O-Si linkage
  • C07F7/0838—Compounds with one or more Si-O-Si sequences

Definitions

• the therapeutic efficacy of active agents is often limited by the inability to selectively deliver the drugs to the cell, e.g., most of the currently available anticancer drugs are highly cytotoxic and can kill normal cells along with cancerous cells. Thus, when high doses of drugs are used, there can be severe side effects. As a result, most of the currently used anticancer drugs have a rather limited therapeutic index. Such a limit on dosage can prevent complete eradication of cancer cells in a patient, and may lead to recurrence of the cancer in many patients. The limit in dosage can also predispose the recurring cancer to drug resistance, thus worsening the prognosis for the patient.
• the present disclosure provides, for example, a method of delivering a therapeutically effective amount of a silanol drug moiety to a patient in need thereof, comprising administering to the patient a drug conjugate represented by:
• the drug conjugate may release the silanol drug moiety in a pH dependent fashion.
• a disclosed drug conjugate may represented by:
• Lig, L 1 , A, L 22 , Y, D and n are defined herein.
• the present disclosure also provides, for example, silanol based therapeutics (e.g., a therapeutic payload) that may be used, for example, as part of a drug conjugate that can include for example, a targeting moiety, and a disclosed silanol based compound.
• silanol based therapeutics e.g., a therapeutic payload
• a drug conjugate that can include for example, a targeting moiety
• a disclosed silanol based compound e.g., provided herein are compounds that include a silanol moiety (e.g., a silanol terminus that may be used as a basis of a drug-target conjugate) and a therapeutic or drug moiety.
• a therapeutic agent that includes a) a silanol moiety bound directly or via a linker, to a drug moiety (e.g., capable of effecting a target cell or tissue) and/or b) a silanol moiety that replaces one or more carbons or heteroatoms of an existing therapeutic agent, thereby facilitiating e.g., a drug conjugate.
• a therapeutic agent that includes a silanol terminus, and optionally divalent spacer moiety, and a drug moiety, for example, a silanol based payload represented by the formula:
• the present disclosure is directed, at least in part, toward methods of delivering a therapeutically effective amount of a silanol drug moiety to a patient in need thereof, comprising administering to the patient a drug conjugate represented by:
• Lig is a targeting moiety
• L 1 is a linker moiety
• A is an adaptor moiety or a bond
• Y 2 is represented by L 22 or–BO–L 22 –SL–, wherein BO is a bond or is a fused biorthogonal linker moiety, L 22 is a second linker moiety, and SL is an optional catalytic moiety;
• n 1, 2, 3, 4, 5, 6 or 7;
• Y is a divalent spacer moiety
• D for each occurrence, is a drug moiety that effects a target cell or tissue.
• Lig may be for example, a small molecule moiety, a peptide, an antibody, an antibody fragment, a peptide and/or a carbohydrate.
• the drug conjugate may release the silanol drug moiety in a pH dependent fashion.
• the silanol drug moiety may, for example, be represented by: .
• SL may be chosen to release the silanol drug moiety from the conjugated at pH less than about 7 or greater than about 7.5 at 25 °C or 37 °C.
• A may be selected, for example, from the group
• BO may be selected, for example, from the group consisti
• BO may be:
• L 22 may be selected, for example, from the group consisting of: -(CH 2 -CH 2 -O) s -, -(OCH 2 -CH 2 ) s -, -(CH 2 -CH 2 -O) s -(CH 2 ) i -, -(CH 2 ) i -(OCH 2 -CH 2 ) s -, and C 1-6 alkylene; wherein s is 0 to 10 for each occurrence; and i is 1, 2, or 3.
• SL may be selected, for example, from the group consisting of -NR Y -C(O)-(CH 2 ) j -phenyl-(CH 2 ) q - (wherein R Y is hydrogen or C 1-3 alkyl; j is 0, 1, 2, 3 or 4; and q is 0, 1 or 2); 5-6 membered heteroaryl-S-(CH 2 ) p - (wherein p is 0, 1, 2, or 3), a bond, and -NR Y -C(O)-C 1-4 alkylene (wherein R Y is hydrogen or C 1-3 alkyl) .
• SL may be selected from the group consisting of:
• SL may be:
• Y may be selected, for example, from the group consisting of a bond, C 1-4 alkylene, C 1-4 alkylene-NR Y -, C 1-4 alkylene-C(O)-, and C 1-4 alkylene- C(O)-NR Y -, wherein R Y is hydrogen or C 1-3 alkyl.
• Y may be selected from the group consisting of:
• L 1 may be, for example C 1-30 alkylene; wherein one, two, three, four, five, six, seven or eight methylene units of L 1 are optionally and independently replaced by a substituent each selected from the group consisting of phenyl, heteroaryl, - N(R 1Y )-, C(O)N(R 1Y )-, -N(R 1Y )C(O))-, -O-, (-O-CH 2 -CH 2 ) s -, and (CH 2 -CH 2 -O) s -, wherein s is an integer from 3-10; and R 1Y is independently selected for each occurrence from the group consisting of hydrogen and C 1-3 alkyl.
• D may be selected, for example, from the group consisting of a vinca alkaloid, an auristatin, maytansine, a pyrrolobenzodiazepine dimer, a camptothecin, SN38, a PARP inhibitor, salinomycin, a kinase inhibitor, siRNA, and a nuclear hormone regulator.
• a disclosed drug conjugate may represented by: , wherein Lig, L 1 , A, L 22 , Y and D are defined herein.
• Lig is a targeting moiety that may include one or more ligands that selectively bind or recognize at least one of Folate Receptors, prostate specific membrane antigen (PSMA), surface antigen in leukemia SAIL, intergrin ⁇ v ⁇ 3 ,
• asialoglycoprotein receptor hydroxyapatite, delta-like protein-3 DLL3 receptor, receptor dystroglycan, cholescystokinin receptors, somatostatin receptor, onco fetal antigens, receptor tyrosine kinases, GPCRs, GPCRmAB targets, sigma-receptor, transferrin receptor, mannose receptor vitamin receptors, Trop-2, Notch receptor, CD33, CD44, and CD206.
• a targeting moiety may be selected from the group consisting of: folic acid its derivatives, DUPA its derivatives, RGD and its derivatives, GPCR mABs, transferrin, G11 and analogs thereof which target EGFR, carbohydrates, aptamers, somatostatin analogs, and extracellular ligands that induce receptor internalization upon binding.
• targeting moieties may be selected from the group consisting of: small molecules, peptides, peptidomimetics, aptamers, antibodies, and carbohydrates and derivatives thereof.
• a targeting moiety in certain embodiments is a protein (e.g., an antibody or antibody fragment), nucleic acid, lipid, oligomer, glycopeptide, polysaccharide, polymer (e.g., a dendrimer), nanoparticle, or any combination thereof.
• a viral coat protein is contemplated, as e.g., a cognate ligand of certain cell surface receptors.
• the present disclosure further provides, for example, silanol containing therapeutic payloads, such as a payload comprising a silanol terminus, an optional divalent spacer moiety, and a drug moiety capable of effecting a target cell or tissue.
• silanol containing therapeutic payloads such as a payload comprising a silanol terminus, an optional divalent spacer moiety, and a drug moiety capable of effecting a target cell or tissue.
• D is a drug moiety capable of effecting a target cell or tissue
• R 1Y is selected from the group consisting of H, C 1-6 alkyl, cycloalkyl, haloalkyl, halocycloalkyl, heteroalkyl, heterocycloalkyl, heterohaloalkyl, heterohalocycloalkyl, aryl, biaryl, heteroaryl, heterobiaryl, mono or bicyclic heterocyclic, wherein the cycloalkyl, haloalkyl, halocycloalkyl, heteroalkyl, heterocycloalkyl, heterohaloalkyl, heterohalocycloalkyl, aryl, biaryl, heteroaryl, heterobiaryl, mono or bicyclic heterocyclic are optionally substituted with one or more substituents selected from -COOH, carbonyl, oxime, hydrazide, hydrazone, urea, thiourea, amidine, guanidine, sulfonamide, acylsulfonamide,
• s is an integer from 1-15;
• R 1 and R 2 are each selected independently from the group consisting of -OH, C 1-6 alkyl, - O-C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -C 1-6 alkyl-NR a R b , phenyl, heterocyclyl, and heteroaryl; wherein C 1-6 alkyl, -O-C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -C 1- 6 alkyl-NR a R b , phenyl, heterocyclyl, and heteroaryl are optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, hydroxyl, amino, -NH(C 1- 6 alkyl), -N(C 1-6 alkyl) 2 , oxo, -COOH, -C(O)O-C 1-6 al
• R 1 , R 2 , Y, and D may, independently, together with the atoms to which they are attached, each form a 4-10 membered carbocyclic or heterocyclic or spirocyclic ring, wherein the 4-10 membered heterocyclic ring may optionally contain one or more additional heteroatoms selected from O, S, SO, SO 2 , or N; wherein the 4-10 membered carbocyclic or heterocyclic ring is optionally substituted; each ring formed may optionally be fused to another through a single shared atom or single shared bond; and
• R a and R b are independently selected, for each occurrence, from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, and phenyl; wherein C 1-6 alkyl, C 2-6 alkenyl, and phenyl may be optionally substituted; or R a and R b , together with the nitrogen to which they are attached, form a 4-8 membered heterocyclic ring, optionally containing an additional heteroatom selected from O, S, SO, SO 2 , or N; wherein the 4-8 membered heterocyclic ring is optionally substituted.
• R 1 and R 2 each may be the same or different.
• R 1 and R 2 may be each independently selected from C 1- 6 alkyl.
• R 1 and R 2 may be methyl.
• silanol based payloads disclosed herein may be a silanol based analog of a disease-modifying agent, e.g., selected from the group consisting of antigens, proteins, cytotoxic agents, metabolic modulators, anti-inflammatory agents, anti-viral agents, antibiotics, pathway modulators, siRNA, mRNA, miRNA, and endosomal escape enhancers.
• a disease-modifying agent e.g., selected from the group consisting of antigens, proteins, cytotoxic agents, metabolic modulators, anti-inflammatory agents, anti-viral agents, antibiotics, pathway modulators, siRNA, mRNA, miRNA, and endosomal escape enhancers.
• a silanol based payload disclosed herein may be a silanol based analog of a therapeutic agent selected from the group consisting of check-point inhibitors, kinase inhibitors, proteasome inhibitors, topoisomerase inhibitors, tubulin inhibitors, rapamycin analogs, auristatin F analogs, maytansinoid analogs, duocarmycin analogs, calicheamicin analogs, and DM4 analogs, for example, selected from camptothecin analogs, doxorubicin analogs, vinca alkaloid analogs, taxane analogs (docetaxel, paclitaxel), rapamycin analogs, platinum based chemotherapeutics, and tubulysin analogs.
• a therapeutic agent selected from the group consisting of check-point inhibitors, kinase inhibitors, proteasome inhibitors, topoisomerase inhibitors, tubulin inhibitors, rapamycin analogs, auristatin F analogs,
• the silanol based payload may be a molecule that is, e.g., modulating cellular pathways by binding to a biomolecule, such as, for example, a protein or a specific protein domain, a component of a biological cell such as ribosome (composed of proteins and nucleic acids), or an enzyme active site.
• a disclosed silicon based payload may be capable of binding to an intracellular biomolecular target.
• a disclosed silanol based payload may be a therapeutic moiety.
• the therapeutic moiety can be, for example, a cytotoxic moiety.
• a cytotoxic moiety may be an analog of SN-38, bendamustine, a VDA, doxorubicin, pemetrexed, vorinostat, lenalidomide, irinotecan, ganetespib, docetaxel, 17-AAG, 5-FU, abiraterone, crizotinib, KW- 2189, BUMB2, DC1, CC-1065, adozelesin, or (a) fragment(s) thereof.
• a disclosed silanol based payload may be an analog of an DNA alkylating agent or a fragment thereof (e.g., temozolomide, mitozolomide, nitrogen mustards, estramustine, or chloromethine).
• an DNA alkylating agent e.g., temozolomide, mitozolomide, nitrogen mustards, estramustine, or chloromethine.
• a disclosed silanol based payload may be an analog of a therapeutic agent selected from the group consisting of peptidyl-prolyl isomerase ligands, e.g., FK506 (tacrolimus), rapamycin and cyclosporin A; steroid hormone receptor ligands, e.g., naturally occurring steroid hormones such as estrogen, progestin, testosterone, as well as synthetic derivatives and mimetics thereof; small molecules that bind to cytoskeletal proteins, e.g., antimitotic agents, such as taxanes, colchicine, colcemid, nocadozole, vinblastine, and vincristine, actin binding agents, such as cytochalasin, latrunculin, halloidin; lenalidomide, pomalidomide, camptothecins including SN-38 , topotecan, combretastatins, capecitabine, gemcitabine, vinca al
• a disclosed silanol based payload may an analog of a therapeutic agent selected from the group consisting of central nervous system depressants, e.g., general anesthetics (barbiturates, benzodiazepines, steroids, cyclohexanone derivatives, and miscellaneous agents), sedative-hypnotics (benzodiazepines, barbiturates, piperidinediones and triones, quinazoline derivatives, carbamates, aldehydes and derivatives, amides, acyclic ureides, benzazepines and related drugs, phenothiazines), central voluntary muscle tone modifying drugs (anticonvulsants, such as hydantoins, barbiturates, oxazolidinediones, succinimides, acylureides, glutarimides, benzodiazepines, secondary and tertiary alcohols, dibenzazepine derivatives, valproic acid and
• central nervous system depressants
• psychopharmacological/psychotropics e.g., anxiolytic sedatives (benzodiazepines, propanediol carbamates) antipsychotics (phenothiazine derivatives, thioxanthine derivatives, other tricyclic compounds, butyrophenone derivatives and isosteres, diphenylbutylamine derivatives, substituted benzamides, arylpiperazine derivatives, indole derivatives), antidepressants (tricyclic compounds, MAO inhibitors).
• anxiolytic sedatives benzodiazepines, propanediol carbamates
• antipsychotics phenothiazine derivatives, thioxanthine derivatives, other tricyclic compounds, butyrophenone derivatives and isosteres, diphenylbutylamine derivatives, substituted benzamides, arylpiperazine derivatives, indole derivatives
• antidepressants tricyclic compounds, MAO inhibitors
• a disclosed silanol based payload may be an analog of a therapeutic agent selected from the group consisting of respiratory tract drugs, e.g., central antitussives (opium alkaloids and their derivatives); immunosuppressive agents;
• respiratory tract drugs e.g., central antitussives (opium alkaloids and their derivatives); immunosuppressive agents;
• peripheral nervous system drugs e.g., local anesthetics (ester derivatives, amide derivatives); drugs acting at synaptic or neuroeffector junctional sites, e.g., cholinergic agents, cholinergic blocking agents, neuromuscular blocking agents, adrenergic agents, antiadrenergic agents; smooth muscle active drugs, e.g., spasmolytics (anticholinergics, musculotropic spasmolytics), vasodilators, smooth muscle stimulants; histamines and antihistamines, e.g., histamine and derivative thereof (betazole), antihistamines (H1- antagonists, H2-antagonists), histamine metabolism drugs; cardiovascular drugs, e.g., cardiotonics (plant extracts, butenolides, pentadienolids, alkaloids from erythrophleum species, ionophores,-adrenoceptor stimulants), antiar
• alkylating agents e.g., mechlorethamine hydrochloride (nitro
• a disclosed silanol based payload may be an analog of a therapeutic agent selected from the group consisting of anti-inflammatory agents; antibiotics, such as: aminoglycosides, e.g., amikacin, apramycin, arbekacin, bambermycins, butirosin, dibekacin, dihydrostreptomycin, fortimicin, gentamicin, isepamicin, kanamycin, micronomcin, neomycin, netilmicin, paromycin, ribostamycin, sisomicin, spectinomycin, streptomycin, tobramycin, trospectomycin; amphenicols, e.g., azidamfenicol, chloramphenicol, florfenicol, and theimaphenicol; ansamycins, e.g., rifamide, rifampin, rifamycin, rifapentine, rif
• antibiotics such as: amino
• a disclosed silanol based payload may be an analog of a therapeutic agent selected from the group consisting of antifungal agents, such as: polyenes, e.g., amphotericin B, candicidin, dermostatin, filipin, fungichromin, hachimycin, hamycin, lucensomycin, mepartricin, natamycin, nystatin, pecilocin, perimycin; synthetic antifungals, such as allylamines, e.g., butenafine, naftifine, terbinafine; imidazoles, e.g., bifonazole, butoconazole, chlordantoin, chlormidazole, thiocarbamates, e.g., tolciclate, triazoles, e.g., fluconazole, itraconazole, or terconazole.
• antifungal agents such as: polyenes, e.g., amphoter
• a disclosed silanol based payload may be an analog of a therapeutic agent selected from the group consisting of anthelmintics, such as: arecoline, aspidin, aspidinol, dichlorophene, embelin, kosin, napthalene, niclosamide, pelletierine, quinacrine, alantolactone, amocarzine, amoscanate, ascaridole, bephenium, bitoscanate, carbon tetrachloride, carvacrol, cyclobendazole, or diethylcarbamazine.
• anthelmintics such as: arecoline, aspidin, aspidinol, dichlorophene, embelin, kosin, napthalene, niclosamide, pelletierine, quinacrine, alantolactone, amocarzine, amoscanate, ascaridole, bephenium, bitoscanate, carbon tetrachloride, carvacrol, cycl
• a disclosed silanol based payload may be an analog of a therapeutic agent selected from the group consisting of antimalarials, such as: acedapsone, amodiaquin, arteether, artemether, artemisinin, artesunate, atovaquone, bebeerine, berberine, chirata, chlorguanide, chloroquine, chlorprogaunil, cinchona, cinchonidine, cinchonine, cycloguanil, gentiopicrin, halofantrine, hydroxychloroquine, mefloquine hydrochloride, 3- methylarsacetin, pamaquine, plasmocid, primaquine, pyrimethamine, quinacrine, quinidine, quinine, quinocide, quinoline, or dibasic sodium arsenate.
• antimalarials such as: acedapsone, amodiaquin, arteether, artemether, art
• a disclosed silanol based payload may be an analog of a therapeutic agent selected from the group consisting of antiprotozoan agents, such as: acranil, tinidazole, ipronidazole, ethylstibamine, pentamidine, acetarsone, aminitrozole, anisomycin, nifuratel, tinidazole, benzidazole, or suramin.
• antiprotozoan agents such as: acranil, tinidazole, ipronidazole, ethylstibamine, pentamidine, acetarsone, aminitrozole, anisomycin, nifuratel, tinidazole, benzidazole, or suramin.
• a disclosed silanol based payload may be an analog of a therapeutic agent selected from the group consisting of docetaxel or paclitaxel; BEZ235; temsirolimus; PLX4032; cisplatin; AZD8055; and crizotinib.
• a disclosed silanol based payload may be an analog of topotecan or irinotecan.
• a disclosed silanol based payload may be an analog of siRNA, mRNA or miRNA optionally in combination with endosomal escape enhancers.
• a disclosed silanol based payload may be an analog of an antigen.
• a disclosed silanol based payload may be an analog of a therapeutic agent selected from the group consisting of mechanistic target of rapamycin (mTOR) inhibitors, e.g., apitolisib and everolimus; BCR-ABL fusion gene agents, e.g., dasatinib, potanibib and gleevec; pan-cyclin-dependent kinase (pan-CDK) inhibitors, e.g., (R)- roscovitine and (S)-CR8; selective cyclin-dependent kinase (CDK) inhibitors, e.g., palbociclib, abemaciclib, ribociclib and SNS-032; Bruton tyrosine kinase (BTK) inhibitors, e.g., ibrutinib, Janus kinase (JAK) inhibitors; Aurora kinase inhibitors, e.g.
• mTOR mechanistic
• bisphosphonate analogs e.g., zoledronate, triazole zoledronate, ibandronate and risedronate.
• a disclosed silanol based payload may be represented by:
• a disclosed silanol based payload may be combined with a second disclosed silanol based payload, and the resulting silanol based payload combination may act as a synthetic lethal combination or as a synergistic combination.
• a disclosed silanol based payload may be a
• conditionally activated payload CAP: this conditionally activated payload will be charged at pH7.4 resulting in poor cellular effects; however, targeted delivery, and endosomal or microenvironmental release will activate the payload and result in potent cell kill.
• the targeted delivery of these conditionally activated payloads will result of a cellular EC50 of ⁇ 80 nM, in some embodiments the targeted delivery of these conditionally activated payloads will result of a cellular EC50 of ⁇ 20 nM, the targeted delivery of these conditionally activated payloads will result of a cellular EC50 of ⁇ 10 nM, the targeted delivery of these conditionally activated payloads will result of a cellular EC50 of ⁇ 1 nM, the targeted delivery of these conditionally activated payloads will result of a cellular EC50 of ⁇ 0.1nM.
• targeted delivery of a disclosed silanol based payload may result in improved intracellular concentrations and, for example, may overcome exposure challenges.
• the presence of the silanol moiety i.e., HO- Si(R 1 )(R 2 )-, may not negate the potency of the drug moiety, D.
• a disclosed silanol based payload may have improved cell permeability and, for example, may permeate to neighboring cells.
• Lig is a targeting moiety
• L 1 is a linker moiety
• A is an adaptor moiety or a bond
• Y 2 is represented by L 22 or–BO–L 22 –SL–, wherein BO is a bond or is a fused biorthogonal linker moiety, L 22 is a second linker moiety, and SL is an optional catalytic moiety;
• R 1 , R 2 , R 3 and R 4 are each independently selected from C 1-6 alkyl;
• n 1, 2, 3, 4, 5, 6 or 7;
• Y is the divalent spacer moiety
• D for each occurrence, is a drug moiety.
• Lig may be, e.g., a small molecule moiety, a peptide, an antibody, an antibody fragment, a peptide and/or a carbohydrate.
• a therapeutically effective amount of a contemplated silanol based payload may be administered (e.g., by administering a contemplated drug conjugate) to a patient in need thereof.
• a disclosed silanol based payload may have a molecular weight between 50 Da and 2000 Da, in some embodiments between 50 Da and 1500 Da, in some embodiments, between 50 Da and 1000 Da, and in some embodiments, between 50 Da and 500 Da.
• a targeting moiety may have a molecular weight of less than 2000 Da, in some embodiments, less than 1000 Da, and in some embodiments less than 500 Da.
• Disclosed silanol based payloads may be administered (e.g., by administering a contemplated drug conjugate) to patients (animals and humans) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. It will be appreciated that the dose required for use in any particular application will vary from patient to patient, not only with the particular compound or composition selected, but also with the route of administration, the nature of the condition being treated, the age and condition of the patient, concurrent medication or special diets then being followed by the patient, and other factors which those skilled in the art will recognize, with the appropriate dosage ultimately being at the discretion of the attendant physician.
• a compound e.g., a contemplated silicon based payload and/or drug conjugate
• a compound may be administered orally, subcutaneously, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles.
• Parenteral administration may include subcutaneous injections, intravenous or intramuscular injections, or infusion techniques.
• Treatment can be continued for as long or as short a period as desired.
• the compositions may be administered on a regimen of, for example, one to four or more times per day.
• a suitable treatment period can be, for example, at least about one week, at least about two weeks, at least about one month, at least about six months, at least about 1 year, or indefinitely.
• a treatment period can terminate when a desired result, for example a partial or total alleviation of symptoms, is achieved.
• silanol based payloads and/or drug conjugated disclosed herein may be formulated together with a pharmaceutically acceptable carrier provided.
• the present disclosure provides silanol based payloads and/or drug conjugates disclosed herein formulated together with one or more pharmaceutically acceptable carriers.
• These formulations include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used.
• disclosed compositions may be formulated as a unit dose, and/or may be formulated for oral, i.v., or subcutaneous administration.
• Exemplary pharmaceutical compositions may be used in the form of a pharmaceutical preparation, for example, in solid, semisolid, spray-dried, dispersion, or liquid form, which contains one or more of the compounds, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral, or parenteral applications.
• the active ingredient may be compounded, for example, with the usual non- toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use.
• the active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.
• the principal active ingredient may be mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid
• a pharmaceutical carrier e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water
• preformulation composition containing a homogeneous mixture of a compound, or a non-toxic pharmaceutically acceptable salt thereof.
• preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
• solid dosage forms for oral administration capsules, tablets, pills, dragees, powders, granules and the like
• the subject composition is mixed with one or more
• pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4)
• disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents.
• solution retarding agents such as paraffin
• absorption accelerators such as quaternary ammonium compounds
• wetting agents such as, for example, acetyl alcohol and glycerol monostearate
• absorbents such as kaolin and bentonite clay
• lubricants such a talc,
• compositions may also comprise buffering agents.
• Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
• compositions suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
• aqueous and non-aqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins.
• polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
• vegetable oils such as olive oil
• injectable organic esters such as ethyl oleate and cyclodextrins.
• Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
• enteral pharmaceutical formulations including a disclosed silanol based payload, an enteric material, and a pharmaceutically acceptable carrier or excipient thereof are provided.
• Enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach, and that are predominantly soluble in intestinal fluids at specific pHs.
• the small intestine is the part of the gastrointestinal tract (gut) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum.
• the pH of the duodenum is about 5.5
• the pH of the jejunum is about 6.5
• the pH of the distal ileum is about 7.5.
• enteric materials are not soluble, for example, until a pH of about 5.0, of about 5.2, of about 5.4, of about 5.6, of about 5.8, of about 6.0, of about 6.2, of about 6.4, of about 6.6, of about 6.8, of about 7.0, of about 7.2, of about 7.4, of about 7.6, of about 7.8, of about 8.0, of about 8.2, of about 8.4, of about 8.6, of about 8.8, of about 9.0, of about 9.2, of about 9.4, of about 9.6, of about 9.8, or of about 10.0.
• Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymer of methylmethacrylic acid and methyl methacrylate, copolymer of methyl acrylate, methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series), ethyl methacrylate-methylmethacrylate- chlorotrimethylammonium ethyl acrylate copolymer, natural resins such as
• a silanol based payload may be substituted with any number of substituents or functional moieties.
• substituted whether preceded by the term“optionally” or not, and substituents contained in formulas, refer to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent.
• the substituent when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
• the term“substituted” is contemplated to include all permissible substituents of organic compounds.
• the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non- aromatic substituents of organic compounds.
• heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms.
• Non-limiting examples of substituents include acyl; aliphatic; heteroaliphatic; aryl; heteroaryl; arylalkyl; heteroarylalkyl; alkoxy; cycloalkoxy; heterocyclylalkoxy; heterocyclyloxy;
• heterocyclyloxyalkyl alkenyloxy; alkynyloxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; oxo; -F; -Cl; -Br; -I; -OH; -NO 2 ; -CN; -SCN; -SR x ; - CF 3 ; -CH 2 CF 3 ; -CHCl 2 ; -CH 2 OH; -CH 2 CH 2 OH; -CH 2 NH 2 ; -CH 2 SO 2 CH 3 ; -OR x , -C(O)R x ; - CO 2 (R x ); -C(O)N(R x ) 2 ; -OC(O)R x ; -OCO 2 R x ; -OC(O)N(R x ) 2 ; -N(
• the compounds described herein are not intended to be limited in any manner by the permissible substituents of organic compounds. In some embodiments, combinations of substituents and variables described herein may be preferably those that result in the formation of stable compounds.
• stable refers to compounds which possess stability sufficient to allow manufacture and which maintain the integrity of the compound for a sufficient period of time to be detected and preferably for a sufficient period of time to be useful for the purposes detailed herein.
• acyl refers to a moiety that includes a carbonyl group.
• an acyl group may have a general formula selected from - C(O)R x ; -CO 2 (R x ); -C(O)N(R x ) 2 ; -OC(O)R x ; -OCO 2 R x ; and -OC(O)N(R x ) 2 ; wherein each occurrence of R x independently includes, but is not limited to, hydrogen, aliphatic,
• heteroaliphatic, aryl, heteroaryl, arylalkyl, or heteroarylalkyl wherein any of the aliphatic, heteroaliphatic, arylalkyl, or heteroarylalkyl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl or heteroaryl substituents described above and herein may be substituted or unsubstituted.
• the term“aliphatic,” as used herein, includes both saturated and unsaturated, straight chain (i.e., unbranched), branched, acyclic, cyclic, or polycyclic aliphatic
• hydrocarbons which are optionally substituted with one or more functional groups.
• “aliphatic” is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties.
• the term“heteroaliphatic,” as used herein, refers to aliphatic moieties that contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms, e.g., in place of carbon atoms.
• Heteroaliphatic moieties may be branched, unbranched, cyclic or acyclic and include saturated and unsaturated heterocycles such as morpholino, pyrrolidinyl, etc.
• heteroaliphatic moieties are substituted by independent replacement of one or more of the hydrogen atoms thereon with one or more moieties including, but not limited to acyl; aliphatic; heteroaliphatic; aryl; heteroaryl; arylalkyl; heteroarylalkyl; alkoxy; cycloalkoxy;
• aryl and“heteroaryl,” as used herein, refer to stable mono- or polycyclic, heterocyclic, polycyclic, and polyheterocyclic unsaturated moieties having preferably 3-14 carbon atoms, each of which may be substituted or unsubstituted.
• Substituents include, but are not limited to, any of the previously mentioned substituents, i.e., the substituents recited for aliphatic moieties, or for other moieties as disclosed herein, resulting in the formation of a stable compound.
• aryl refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, and the like.
• heteroaryl refers to a cyclic aromatic radical having from five to ten ring atoms of which one ring atom is selected from the group consisting of S, O, and N; zero, one, or two ring atoms are additional heteroatoms independently selected from the group consisting of S, O, and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and the like.
• any of the above aryl or heteroaryl rings may be fused to a heteroaryl or heteroaryl rings.
• aryl and heteroaryl groups can be unsubstituted or substituted, wherein substitution includes replacement of one, two, three, or more of the hydrogen atoms thereon independently with any one or more of the following moieties including, but not limited to: aliphatic; heteroaliphatic; aryl; heteroaryl; arylalkyl;
• heteroarylalkyl alkoxy; cycloalkoxy; heterocyclylalkoxy; heterocyclyloxy;
• heterocyclyloxyalkyl alkenyloxy; alkynyloxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; oxo; -F; -Cl; -Br; -I; -OH; -NO 2 ; -CN; -CF 3 ; -CH 2 CF 3 ; -CHCl 2 ; -CH 2 OH; -CH 2 CH 2 OH; -CH 2 NH 2 ; -CH 2 SO 2 CH 3 ; -C(O)R x ; -CO 2 (R x ); -CON(R x ) 2 ; - OC(O)R x ; -OCO 2 R x ; -OCON(R x ) 2 ; -N(R x ) 2 ; - S(O) 2 R x ; -NR x
• heterocyclic refers to an aromatic or non-aromatic, partially unsaturated or fully saturated, 3- to 10-membered ring system, which includes single rings of 3 to 8 atoms in size and bi- and tri-cyclic ring systems which may include aromatic five- or six-membered aryl or aromatic heterocyclic groups fused to a non-aromatic ring.
• heterocyclic rings include those having from one to three heteroatoms independently selected from the group consisting of oxygen, sulfur, and nitrogen, in which the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
• the term heterocyclic refers to a non-aromatic 5-, 6-, or 7-membered ring or a polycyclic group wherein at least one ring atom is a heteroatom selected from the group consisting of O, S, and N (wherein the nitrogen and sulfur heteroatoms may be optionally oxidized), including, but not limited to, a bi- or tri-cyclic group, comprising fused six-membered rings having between one and three heteroatoms independently selected from the group consisting of the oxygen, sulfur, and nitrogen, wherein (i) each 5-membered ring has 0 to 2 double bonds, each 6-membered ring has 0 to 2 double bonds, and each 7-membered ring has 0 to 3 double bonds, (ii) the nitrogen and
• alkenyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group of 2-6 or 3-4 carbon atoms, referred to herein for example as C 2-6 alkenyl, and C 3- 4 alkenyl, respectively.
• alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, etc.
• alkenyloxy refers to a straight or branched alkenyl group attached to an oxygen (alkenyl-O).
• exemplary alkenoxy groups include, but are not limited to, groups with an alkenyl group of 3-6 carbon atoms referred to herein as C 3-6 alkenyloxy.
• Exemplary“alkenyloxy” groups include, but are not limited to allyloxy, butenyloxy, etc.
• alkoxy refers to a straight or branched alkyl group attached to an oxygen (alkyl-O-).
• exemplary alkoxy groups include, but are not limited to, groups with an alkyl group of 1-6 or 2-6 carbon atoms, referred to herein as C 1-6 alkoxy, and C 2 - C 6 alkoxy, respectively.
• exemplary alkoxy groups include, but are not limited to methoxy, ethoxy, isopropoxy, etc.
• alkoxycarbonyl refers to a straight or branched alkyl group attached to oxygen, attached to a carbonyl group (alkyl-O-C(O)-).
• exemplary alkoxycarbonyl groups include, but are not limited to, alkoxycarbonyl groups of 1-6 carbon atoms, referred to herein as C 1-6 alkoxycarbonyl.
• Exemplary alkoxycarbonyl groups include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc.
• alkynyloxy refers to a straight or branched alkynyl group attached to an oxygen (alkynyl-O)).
• exemplary alkynyloxy groups include, but are not limited to, propynyloxy.
• alkyl refers to a saturated straight or branched hydrocarbon, for example, such as a straight or branched group of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as C 1-6 alkyl, C 1-4 alkyl, and C 1-3 alkyl, respectively.
• Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2- methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 3-methyl-2-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2- pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.
• alkylcarbonyl refers to a straight or branched alkyl group attached to a carbonyl group (alkyl-C(O)-).
• exemplary alkylcarbonyl groups include, but are not limited to, alkylcarbonyl groups of 1-6 atoms, referred to herein as C 1- 6 alkylcarbonyl groups.
• Exemplary alkylcarbonyl groups include, but are not limited to, acetyl, propanoyl, isopropanoyl, butanoyl, etc.
• alkynyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond, such as a straight or branched group of 2-6, or 3-6 carbon atoms, referred to herein as C 2-6 alkynyl, and C 3-6 alkynyl, respectively.
• exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, etc.
• carbonyl refers to the radical -C(O)-.
• cycloalkoxy refers to a cycloalkyl group attached to an oxygen (cycloalkyl-O-).
• cycloalkyl refers to a monocyclic saturated or partially unsaturated hydrocarbon group of for example 3-6, or 4-6 carbons, referred to herein, e.g., as C 3-6 cycloalkyl or C 4-6 cycloalkyl and derived from a cycloalkane.
• exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclohexenyl, cyclopentyl, cyclobutyl or, cyclopropyl.
• halo or“halogen” as used herein refer to F, Cl, Br, or I.
• heterocyclylalkoxy refers to a heterocyclyl- alkyl-O- group.
• heterocyclyloxyalkyl refers to a heterocyclyl-O-alkyl- group.
• heterocyclyloxy refers to a heterocyclyl-O- group.
• heteroaryloxy refers to a heteroaryl-O- group.
• connector refers to an atom or a collection of atoms optionally used to link interconnecting moieties, such as a disclosed linker and a
• Contemplated connectors are generally hydrolytically stable.
• Treating includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder and the like.
• “Pharmaceutically or pharmacologically acceptable” include molecular entities and compositions that do not produce an adverse, allergic, or other untoward reaction when administered to an animal, or a human, as appropriate.
• preparations should meet sterility, pyrogenicity, general safety and purity standards as required by FDA Office of Biologics standards.
• pharmaceutically acceptable carrier or“pharmaceutically acceptable excipient” as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical
• compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.
• composition refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.
• “Individual,”“patient,” or“subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
• the compounds can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).
• veterinary treatment e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).
• “Modulation” includes antagonism (e.g., inhibition), agonism, partial antagonism and/or partial agonism.
• the term“therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by the researcher, veterinarian, medical doctor, or other clinician.
• the compounds are administered in therapeutically effective amounts to treat a disease.
• a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and/or prophylactic effect.
• salts of acidic or basic groups that may be present in compounds used in the present compositions.
• Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
• the acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1'-methylene-bis-
• Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
• Examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.
• Compounds included in the present compositions that include a basic or acidic moiety may also form pharmaceutically acceptable salts with various amino acids.
• the compounds of the disclosure may contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt.
• the silanol based payloads of the disclosure may contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as geometric isomers, enantiomers, atropisomers, or diastereomers.
• stereoisomers when used herein consist of all geometric isomers, enantiomers or diastereomers. These compounds may be designated by the symbols“R” or“S,” depending on the configuration of substituents around the stereogenic carbon atom. Various stereoisomers of these compounds and mixtures thereof are encompassed by this disclosure.
• Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be designated“( ⁇ )” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.
• the compounds of the disclosure may contain one or more chiral centers and/or double bonds and, therefore, exist as geometric isomers, enantiomers, atropisomers, or diastereomers.
• the enantiomers and diastereomers may be designated by the symbols“(+),” “(-).”“R” or“S,” depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.
• Geometric isomers resulting from the arrangement of substituents around a carbon- carbon double bond or arrangement of substituents around a cycloalkyl or heterocyclic ring, can also exist in the compounds.
• the arrangement of substituents around a carbocyclic ring can also be designated as“cis” or“trans.”
• the term“cis” represents substituents on the same side of the plane of the ring and the term“trans” represents substituents on opposite sides of the plane of the ring.
• Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated“cis/trans.”
• Individual enantiomers and diastereomers of the compounds can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, (3) direct separation of the mixture of optical enantiomers on chiral liquid chromatographic columns or (4) kinetic resolution using stereoselective chemical or enzymatic reagents.
• Racemic mixtures can also be resolved into their component enantiomers by well-known methods, such as chiral-phase gas chromatography or crystallizing the compound in a chiral solvent.
• Stereoselective syntheses a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre-existing one, are well known in the art.
• Stereoselective syntheses encompass both enantio- and diastereoselective transformations. For examples, see Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.
• the compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
• the compound is amorphous.
• the compound is a polymorph.
• the compound is in a crystalline form.
• isotopically labeled compounds which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
• isotopes that can be incorporated into the compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 10 B, and 36 Cl, respectively.
• a compound may have one or more H atom replaced with deuterium.
• isotopically-labeled disclosed compounds are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
• prodrug refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable salt, hydrate or solvate of the compound.
• the transformation may occur by various mechanisms (such as by esterase, amidase, phosphatase, oxidative and or reductive metabolism) in various locations (such as in the intestinal lumen or upon transit of the intestine, blood, or liver).
• Prodrugs are well known in the art (for example, see Rautio, Kumpulainen, et al, Nature Reviews Drug Discovery 2008, 7, 255).
• a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as (C 1-8 )alkyl, (C 2-12 )alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,
• di-N,N-(C 1 -C 2 )alkylamino(C 2 -C 3 )alkyl such as ⁇ -dimethylaminoethyl
• carbamoyl-(C 1 -C 2 )alkyl N,N-di(C 1 -C 2 )alkylcarbamoy
• a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (C 1- 6 )alkanoyloxymethyl, 1-((C 1-6 )alkanoyloxy)ethyl, 1-methyl-1-((C 1-6 )alkanoyloxy)ethyl (C 1- 6 )alkoxycarbonyloxymethyl, N-(C 1-6 )alkoxycarbonylaminomethyl, succinoyl, (C 1-6 )alkanoyl, ⁇ - amino(C 1-4 )alkanoyl, arylacyl and ⁇ -aminoacyl, or ⁇ -aminoacyl- ⁇ -aminoacyl, where each ⁇ - aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH) 2 , -P(O)(O( C1 -C 6 )alkyl) 2 or
• a prodrug can be formed, for example, by creation of an amide or carbamate, an N-acyloxyalkyl derivative, an
• oxodioxolenyl (oxodioxolenyl)methyl derivative, an N-Mannich base, imine, or enamine.
• a secondary amine can be metabolically cleaved to generate a bioactive primary amine, or a tertiary amine can be metabolically cleaved to generate a bioactive primary or secondary amine.
• LCMS Liquid Chromatography Mass Spectrometry
• Solvent B (100% acetonitrile) Neutral mobile phase B
• Solvent B (100% acetonitrile) Slightly acidic mobile phase
• Table 2 shows the parent compounds of the silanol based payloads of Table 1,
• d ⁇ is the value difference of silanol from the parent compound.
• Example 1 Scheme for the preparation of Example 1
• reaction mixture was charged with 1 drop of of 6N HCl and heated to 40 oC for 16 h with stirring. (Note upon addition of HCl the solution went homogeneous again)
• the reaction was purified by reverse phase preperative HPLC [Prep_AmmBicarb-pH7.4_Method1B] resulting in 18 mg, 20.3% yield of the title compound as a white solid after lyophilization.
• the reaction mixture was charged with a solution of 2-(4-(3-(3-aminopropyl)-1,1,3,3-tetramethyldisiloxanyl)phenyl)-N- (17-azido-3,6,9,12,15-pentaoxaheptadecyl)acetamide (230 mg, 0.375 mmol) in DMF (2.00 ml) then allowed to warm to rt and stirred at rt for an additional 16 h. The reaction mixture was partitioned between DCM (30 mL) and H 2 O (20 mL) and separated.
• the reaction mixture was concentrated in vacuo resulting in the crude intermediate 3 and 4.
• the intermediate 3 and 4 was dissolved in acetonitrile (200 mL) and followed by addition of water (0.11 mL, 6.097 mmol) and DIPEA (3.09 mL, 18.29 mmol) and stirred at room temperature for another 1 h.
• the reaction mixture was concentrated in vacuo resulting in the crude compound which was purified by CombiFlash column chromatography eluting with 10-30% ethyl acetate in n-hexane to afford 1.2 g (50% yield) of the title compound as colourless oil.
• Iron (II) sulfate heptahydrate (24.0 mg, 0.055 mmol) was dissolved in 30% aqueous sulfuric acid (148 ⁇ l, 0.086 mmol) at rt. After stirring for 20 minutes at room temperature, a solution of 3,3'-(1,1,3,3-tetramethyldisiloxane-1,3-diyl)bis(propan-1-ol) (53.9 mg, 0.215 mmol; prepared according to Frampton, Mark B., Izabela Subczynska, and Paul M. Zelisko.
• Example 12 Scheme for the preparation of Example 12
• Example 17 (14S,16S,32S,33S,2R,4S,10E,12E,14R)-86-Chloro-14-hydroxy-85,14- dimethoxy-33,2,7,10-tetramethyl-12,6-dioxo-7-aza-1(6,4)-oxazinana-3(2,3)-oxirana-8(1,3)- benzenacyclotetradecaphane-10,12-dien-4-yl N-(4-(hydroxydimethylsilyl)butanoyl)-N- methyl-L-alaninate
• Example 19 (1S,2R)-2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-2-((S)-2-(dimethylamino)-3- methylbutanamido)-N,3-dimethylbutanamido)-3-methoxy-5-methylheptanoyl)pyrrolidin- 2-yl)-3-methoxy-2-methylpropanamido)-1-phenylpropyl (3- (hydroxydimethylsilyl)propyl)carbamate [00138]
• the title compound can be prepared according to the scheme shown below.
• Example 20 (S)-N-((3R,4S,5S)-1-((S)-2-((7S,10R,11R)-7-benzyl-2-hydroxy-2,10-dimethyl- 6,9-dioxo-12-oxa-5,8-diaza-2-silatridecan-11-yl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1- oxoheptan-4-yl)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N,3-dimethylbutanamide [00139]
• the title compound can be prepared according to the scheme shown below.
• siRNA Silanols siRNA Silanols:
• reaction mixture was charged with sodium ascorbate (7.14 mg, 0.036 mmol) in water (36.1 ⁇ l) followed by the addition of copper sulfate pentahydrate (8.47 mg, 0.027 mmol) in water (36.1 ⁇ l). After 15 min the reaction mixture was checked by LCMS and found to have a mass consistent with desired product. The reaction mixture was partitioned between DCM and water and separated.
• the crude was further purified by chromatography on silica gel [ISCO CombiFlash, 12g Gold cartridge, eluting with 0% of (10% 7N NH3 in MeOH) to 8% (10% 7N NH3 in MeOH) in DCM resulting in 127mg, 44% yield of the title compound as a pale yellow foam solid.
• reaction mixture was heated to 60 oC for 16h then stirred at rt for an additional 6 hrs.
• the reaction mixture was poured into 90 mL of HPLC grade water and the aqueous was extracted with 5X90mL of DCM and the combined organic fractions were washed with water 1X90mL and brine 1X120mL and dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo resulting in crude product that was further purified by column chromatography on silica gel [ISCO Combiflash, 12 g gold catridge] eluting with a gradient of 100% DCM to 8% 7N NH3 in MeOH in DCM] resulting in 1.42 g, 67.1% yield of the title compound as an off-white solid.
• the reaction mixture was concentrated in vacuo resulting in the crude intermediate 5 and 6.
• the intermediate 5 and 6 was dissolved in acetonitrile (250 mL) and followed by addition of water (250 mL) and DIPEA (4.90 mL, 28.79 mmol) and stirred at room temperature for another 1 h.
• the reaction mixture was concentrated in vacuo resulting in the crude compound which was purified by combiflash chromatography on silica gel eluting with 50-80% ethyl acetate in n-hexane to afford 3.56 g, 55% yield, of the title compound as a colorless oil.
• reaction mixture was concentrated in vacuo resulting in a light tan solid which was purified by chromatography on silica gel [ISCO CombiFlash, 12g Gold cartridge, eluting with 0% of (10% 7N NH3 in MeOH) to 8% (10% 7N NH3 in MeOH) in DCM resulting in 65.5 mg, 41% yield of the title compound as a light yellow solid.
• the reaction mixture was concentrated in vacuo resulting in the crude compound.
• the crude compound was stirred in diethyl ether (40 mL) for 10 min and the solid was filtered and washed with diethyl ether (20 mL) and dried to afford 2.2 g, 83% yield of the title compound as a yellow solid.
• reaction mixture was concentrated in vacuo resulting in the crude compound which was purified by flash column chromatography eluting with 0-15% methanol saturated with ammonia in DCM to afford 2.2 g, 75% yield, of the title compound as a colorless oil.
• the reaction mixture was concentrated under reduced pressure resulting in the crude Int-13 and Int-14.
• To Int-13 and Int-14 in acetonitrile (30 mL) was added water (0.073 mL, 4.084 mmol) and DIPEA (1.06 mL, 6.126 mmol) at room temperature and stirred for 30 min.
• the reaction mixture was concentrated under reduced pressure resulting in the crude compound which was purified by CombiFlash column chromatography eluting with 0-10 % methanol in DCM to afford 700 mg, 53% yield of the title compound 2 as a colorless oil.
• Example 36 was synthesized according to the procedure described for Example 35 employing the intermediates shown in the Scheme below:
• the reaction mixture was concentrated in vacuo resulting in the crude intermediates Int-5 and Int-6.
• the mixture of intermediate Int-5 and Int-6 was dissolved in acetonitrile (50 mL) and followed by addition of water (0.12 mL, 6.459 mmol) and DIPEA (1.7 mL, 9.689 mmol) and stirred at room temperature for 1 h.
• the reaction mixture was concentrated in vacuo resulting in the crude compound which was purified by Combiflash chromatography eluting with 0-5% methanol in DCM to afford 57 mg (30% yield) of 1 as colorless oil.
• Example 37 was synthesized according to the procedure described for Example 35 employing the intermediates shown in the Scheme below:
• Example 38 was synthesized according to the procedure described for Example 35 employing the intermediates shown in the Scheme below:
• Example 39 was synthesized according to the procedure described for Example 35 employing the intermediates shown in the Scheme below:
• Example 40 was synthesized according to the procedure described for Example 35 employing the intermediates shown in the Scheme below:
• Scheme 1 depicts a route where first a targeting moiety, folic acid, is activated by reaction with DCC and N-hydroxysuccinimide and then reacted with a protected siloxane or silylether core to form a targeting moiety-core conjugate.
• Scheme 1 depicts a route where first a targeting moiety, folic acid, is activated by reaction with DCC and N-hydroxysuccinimide and then reacted with a protected siloxane or silylether core to form a targeting moiety-core conjugate.
• Scheme 2 shows an alternate route where a protected targeting moiety- core conjugate is reacted with an activated payload to form a targeting moiety-core-payload conjugate.
• Siloxane conjugates with a vinblastine payload and a folic acid targeting moiety are synthesized following a route as described in Example 41.
• Example 43 Vinblastine-Arginylglycylaspartic acid (Vinblastine-RGD) conjugate: [00188] Siloxane conjugates with vinblastine payload and a RGD targeting moiety are synthesized following a route as described in Example 41.
• (Vinblastine-DUPA) conjugates [00189] Siloxane conjugates with vinblastine payload and DUPA targeting moiety are synthesized following a route as described in Example 41.
• Siloxane conjugates with camptothecin/SN38 payload and folic acid-targeting moiety are synthesized following a route as described in Example 41.
• Example 46 Platinum(II)-Folic acid and Platinum(IV)-DUPA acid conjugates:
• Siloxane conjugates with platinum (II) and platinum (IV) payload and DUPA targeting moieties are synthesized following a route as described in Example 41.
• Example 47 Fluorophore/Quencher-Folic acid conjugates: [00192] Siloxane conjugates with a fluorophor/quencher payload and folic acid-targeting moieties are synthesized following a route as described in Example 41.
• Example 48 Fluorescein-Folic acid conjugates: [00193] Siloxane conjugates with a fluorescein payload and folic acid targeting moieties are synthesized following a route as described in Example 41.
• Silyldiether and silylmonoether conjugates with a payload and a targeting moiety are synthesized following a route as described in Example 41.
• Siloxane conjugates with a paclitaxel payload and folic acid targeting moiety are synthesized following a route as described in Example 41.
• Example 51 contains a folate receptor targeting ligand, a spacer moiety, a siloxane core and two different fluorescent dyes (BODIPY and rhodamine) positioned on either side of the siloxane core.
• Folate receptor alpha expressing KB cells were grown in folic acid free media. The cells were incubated for 30 minutes on ice with 50nM of Example 51, washed with fresh culture medium and then incubated in media at 37° C for the desired length of time.
• Example 51 was bound to the folate receptor on the cell surface as visualized by colocalization of red and green signals and overlap of fluorescent dyes on the cell surface, thereby showing Folate Receptors-specific binding of the silicon based conjugate.
• t 30 min, cleavage of the siloxane core was observed as visualized by color separation of the two fluorescent dyes.
• Example 53 Cellular data:
• Washout protocol KB cells in culture were seeded in white clear bottom 96- well tissue culture plate at a density of 5,000 cells per well in a folate free RPMI media with 10% FBS a day prior to compound addition. Cells were counted visually with a hemocytometer and diluted accordingly to obtain the desired density. Cells were allowed to incubate for 24 hours in a humidified CO2 atmosphere in an incubator at 37° C. The spent media was aspirated and replenished with 100 ⁇ L of fresh media containing a 3-fold serial dilution of compound with concentrations ranging from 0.3 to 2000 nM and with a final DMSO concentration of 0.1%. Blank wells without compound were also treated with media containing 0.1% DMSO.
• the CellTiter-Glo (CTG) assay (Promega) was used to measure cell viability in various different cell lines included KB cells obtained from American Type Culture Collection (ATCC). Only cells that showed greater than 95% viability were used.
• CTG CellTiter-Glo
• ATCC American Type Culture Collection
• 5,000 cells per well were plated in a 96-well tissue culture treated plate in RPMI 1640 medium (ThermoFisher Scientific) containing 5% FBS. Cells were allowed to settle at 37°C in a humidified CO2 incubator for 24 hours. Cells were dosed with compound or vehicle control in duplicate for 72 hours at 37°C in a humidified CO2 incubator. After the 72 hour dosing period, the CTG assay was performed according to the manufacturer’s
• Luminescence was read using a Victor X5 (PerkinElmer) plate reader. Data was analyzed using Prism software and was normalized to the vehicle control.
• Table 3 shows EC50 values (72 h incubation protocol) for silanol based payloads. Table 3.
• Table 4 shows EC50 values (washout protocol) of siloxane based conjugates. Table 4.
• Table 5 shows percent cell kill (washout protocol) with silicon based conjugates at 48 h. Table 5.
• Example 54 Synthetic lethal payload combinations: [00207] Silicon based conjugates for treating VHL clear cell renal carcinoma via delivery of synthetic lethal payload combinations include:
• Silicon based conjugates for treating triple negative breast cancer via delivery of synthetic lethal payload combinations using folic acid as a targeting ligand include:
• Silicon based conjugates for treating mutant KRAS cancers via an EGFR- targeting approach include (where it can be appreciated that L 1 defined above can include INCORPORATION BY REFERENCE

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