Classifications

• • 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
  • A61K47/68—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
  • A61K47/6835—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
  • A61K47/6851—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
  • A61K47/6855—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from breast cancer cell
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/07—Tetrapeptides
• • 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
  • A61K47/68—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
  • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
  • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
• • 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
  • A61K47/68—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
  • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
  • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
  • A61K47/68031—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being an auristatin
• • 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
  • A61K47/68—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
  • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
  • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
  • A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
• • 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
  • A61K47/68—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
  • A61K47/6835—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
  • A61K47/6849—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• • 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
  • A61K47/68—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
  • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
• • 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
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • 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
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/04—Immunostimulants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
  • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D277/587—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with aliphatic hydrocarbon radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms, said aliphatic radicals being substituted in the alpha-position to the ring by a hetero atom, e.g. with m >= 0, Z being a singly or a doubly bound hetero atom
  • C07D277/593—Z being doubly bound oxygen or doubly bound nitrogen, which nitrogen is part of a possibly substituted oximino radical
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • 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
  • C07F5/025—Boronic and borinic acid compounds
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06008—Dipeptides with the first amino acid being neutral
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06008—Dipeptides with the first amino acid being neutral
  • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
  • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06008—Dipeptides with the first amino acid being neutral
  • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
  • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
  • C07K5/06052—Val-amino acid
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/10—Tetrapeptides
  • C07K5/1002—Tetrapeptides with the first amino acid being neutral
  • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
  • C07K5/1008—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
  • C07K7/04—Linear peptides containing only normal peptide links
  • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids

Definitions

• Cytotoxic agents can provide therapeutic benefits in the treatment of various conditions, including various cancers. Accordingly, it is desirable to provide cytotoxic agents with therapeutically useful properties, for example, as chemotherapies in cancer treatments.
• cytotoxic agents as chemotherapies usually develop drug resistances, and thus, drop their therapeutic efficacies. Accordingly, it is desirable to provide cytotoxic agents with improved drug resistance profiles.
• One possibility is to design cytotoxic compounds with efflux pump resistances.
• Another possibility is to design cytotoxic compounds potentially act on more than one targets.
• Tubulins are a class of targets for anti-mitotic agents as chemotherapies alone or in combination with other chemotherapies or as active agent-conjugates.
• Examples of Tubulin-B hidin Agents include, but are not limited to, the following compounds:
• Proteasome inhibitors include, but are not limited to, the following compounds:
• MMP Inhibitors examples include, not limited to:
• Some embodiments provide compounds, methods of preparing compounds, and uses thereof.
• Some embodiments provide compound-conjugates, methods of preparing compound-conjugates, and uses thereof.
• Some embodiments provide a compound having the structure of Formula
• Some embodiments provide a compound having the structure of Formula la:
• B is a moiety might have contribution to enzyme inhibition or efflux pump resistance
• R 1 -R.8 are each independently selected from the group consisting of H (hydrogen), Ci-Cg alkyl, and substituted or cyclic Ci-Cg alkyl, or optionally Ri and R 2 together with the nitrogen to which they are attached are a cyclic 5- to 7-membered ring, or optionally Ri and R3 together with the atoms to which they are attached are a cyclic 5- to 7- membered ring, or optionally R 7 and Rs together with the atoms to which they are attached are a cyclic 5- to 7-membered ring;
• the compound having the structure of Formula I has the structure of F
• B is a moiety might have contribution to enzyme inhibition or efflux pump resistance
• Ri-Rs are each independently selected from the group consisting of H (hydrogen), Ci-Cg alkyl, and substituted or cyclic Ci-Cg alkyl, or optionally Ri and R 2 together with the nitrogen to which they are attached are a cyclic 5- to 7-membered ring, or optionally Ri and R 3 together with the atoms to which they are attached are a cyclic 5- to 7- membered ring, or optionally R 7 and Rs together with the atoms to which they are attached are a cyclic 5- to 7-membered ring;
• Z is -F, -SR, -N 3 , -NRR, -ONHR, -OAc, or -OR, where each R is independently H, Ci-C 8 alkyl or substituted Ci-C 8 alkyl.
• Some embodiments provide a compound having the structure of Formula
• X is OR 10 , selected from, but not limited to, a group consisting of at least one hetero atom:
• X is S0 2 R 10 , selected from, but not limited to, a group consisting of at least one hetero atom:
• R 1 -R 10 are each independently selected from the group consisting of H (hydrogen), Ci-Cg alkyl, and substituted or cyclic Ci-Cg alkyl, or optionally Ri and R3 together with the atoms to which they are attached are a cyclic 5- to 7-membered ring, or optionally and respectively R 7 , Rs and R9 together with the atoms to which they are attached are a cyclic 5- to 7-membered ring;
• X is a group consisting of at least one heteroatom
• the dual active compound having the structure of Formula I has the structure of Formula lib:
• n 0 or 1;
• X is OR 10 , selected from, but not limited to, a group consisting of at least one hetero atom:
• n 0 or 1;
• X is S0 2 R 10 , selected from, but not limited to, a group consisting of at least one hetero atom:
• R 1 -R 10 are each independently selected from the group consisting of H (hydrogen), Ci-Cg alkyl, and substituted or cyclic Ci-Cg alkyl, or optionally Ri and R 2 together with the nitrogen to which they are attached are a cyclic 5- to 7-membered ring, or optionally Ri and R3 together with the atoms to which they are attached are a cyclic 5- to 7- membered ring, or optionally and respectively R 7 , Rs and R9 together with the atoms to which they are attached are a cyclic 5- to 7-membered ring;
• X is a group of at least one heteroatom
• Z is -F, -SR, -N 3 , -NRR, -ONHR, -OAc, or -OR, where each R is independently H, Ci-Cg alkyl or substituted Ci-Cg alkyl.
• R 1 and R 2 together with the nitrogen to which they are attached are an optionally substituted cyclic 5- to 7-membered ring, or optionally R 1 and R 3 together with the atoms to which they are attached are an optionally substituted cyclic 5- to 7-membered ring, or optionally R 7 and R 8 together with the atoms to which they are attached are an optionally substituted cyclic 5- to 7- membered ring, or optionally R 1 is R 1A or R 1B ;
• R 1A comprises a targeting moiety
• R 1B is -L 1 (CH 2 ) n R c , -L 1 0(CH 2 ) n R c or -(CH 2 ) n R c ;
• R is Ci-Cg alkyl, C 3 -Cg cycloalkyl, aryl, heteroaryl, and heterocyclyl, each optionally substituted with one or more R , or optionally R comprises a targeting moiety;
• each NR E R F is independently selected, wherein R E and R F are each independently selected from hydrogen, -[(L 1 ) s (C(R 2A ) 2 ) r (NR 2A ) s (C(R 2A ) 2 ) r ]- [L 1 (C(R 2A ) 2 ) r (NR 2A ) s (C(R 2A ) 2 ) r ] s -(L 1 ) s -R J , -[(i MQR ⁇ NR ⁇ MQR 2 ⁇ ),.]- (L 1 ) s [(C(R 2A ) 2 ) r O(C(R 2A ) 2 ) r (L 2 ) s ] s -(L 1 ) s -R J , optionally substituted C 1-8 alkyl, optionally substituted C 3 _ 8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and
• each R H is independently hydrogen, optionally substituted Ci-Cg alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or -NR E R F ;
• each NR R is independently selected, wherein each R is independently selected from the group consisting of hydrogen, -OH, optionally substituted Ci-Cg alkyl, optionally substituted C 3 -Cg cycloalkyl, optionally substituted -0-(Ci-Cg alkyl), optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl, or optionally both R together with the nitrogen to which they are attached are an optionally substituted heterocyclyl;
• each R 2F is independently selected from the group consisting hydrogen, optionally substituted Ci-C 8 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl;
• each L 2 is independently selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl;
• each m independently is 1 or 2;
• each n independently is 0, 1, 2, 3, 4, 5, or 6;
• each r independently is 0, 1, 2, 3, 4, 5, or 6;
• each s independently is 0 or 1 ;
• each z independently is 1 or 2
• R 7 is selected from the group consisting of H (hydrogen), optionally substituted Ci-Cg alkyl, optionally substituted C 3 -Cg cycloalkyl, optionally substituted aryl, and optionally substituted heterocyclyl;
• R 8 is selected from the group consisting of H (hydrogen), -(CH 2 ) utilizatR C , optionally substituted Ci-C 8 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, and optionally substituted heterocyclyl;
• E is selected from the roup consisting of:
• H hydrogen
• Ci-Cg alkyl optionally substituted Ci-Cg alkoxy
• C 3 -C 8 cycloalkyl optionally substituted aryl, and optionally substituted heteroaryl
• Figures 1-10 shows the cytotoxic effects of compounds or antibody drug conjugates (ADCs) on various cell types.
• the antibody used in the antibody drug conjugates is Trastuzumab.
• Some embodiments provide a compound.
• the compound includes a linker.
• the compound includes a cytotoxic agent.
• the compound includes a functional group that has tubulin-binding properties or tubulin inhibitory properties.
• the compound includes a functional group that has protease inhibitory or efflux pump resistant properties.
• the functional group may have proteasome inhibitory properties.
• pharmaceutically acceptable salt refers to salts that retain the biological effectiveness and properties of a compound and, which are not biologically or otherwise undesirable for use in a pharmaceutical.
• the compounds disclosed herein are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
• Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
• Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
• Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
• Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts.
• Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art, as described in WO 87/05297, Johnston et al, published September 11 , 1987 (incorporated by reference herein in its entirety).
• C a to C b “ or “C a _ b “ in which "a” and “b” are integers refer to the number of carbon atoms in the specified group. That is, the group can contain from “a” to “b", inclusive, carbon atoms.
• a “Ci to C 4 alkyl” or “Ci_ 4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH 3 -, CH 3 CH 2 -, CH 3 CH 2 CH 2 -, (CH 3 ) 2 CH-, CH 3 CH 2 CH 2 CH 2 -, CH 3 CH 2 CH(CH 3 )- and (CH 3 ) 3 C-.
• halogen or "halo,” as used herein, means any one of the radio- stable atoms of column 7 of the Periodic Table of the Elements, e.g., fluorine, chlorine, bromine, or iodine, with fluorine and chlorine being preferred.
• alkyl refers to a straight or branched hydrocarbon chain that is fully saturated (i.e., contains no double or triple bonds).
• the alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20" refers to each integer in the given range; e.g., "1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term "alkyl” where no numerical range is designated).
• the alkyl group may also be a medium size alkyl having 1 to 9 carbon atoms.
• the alkyl group could also be a lower alkyl having 1 to 4 carbon atoms.
• the alkyl group may be designated as "Ci_ 4 alkyl” or similar designations.
• “Ci_ 4 alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.
• Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like.
• alkoxy refers to the formula -OR wherein R is an alkyl as is defined above, such as “Ci_9 alkoxy”, including but not limited to methoxy, ethoxy, n- propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy, and the like.
• alkylthio refers to the formula -SR wherein R is an alkyl as is defined above, such as "Ci_9 alkylthio” and the like, including but not limited to methylmercapto, ethylmercapto, n-propylmercapto, 1-methylethylmercapto (isopropylmercapto), n-butylmercapto, iso-butylmercapto, sec-butylmercapto, tert- butylmercapto, and the like.
• alkenyl refers to a straight or branched hydrocarbon chain containing one or more double bonds.
• the alkenyl group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term "alkenyl” where no numerical range is designated.
• the alkenyl group may also be a medium size alkenyl having 2 to 9 carbon atoms.
• the alkenyl group could also be a lower alkenyl having 2 to 4 carbon atoms.
• the alkenyl group may be designated as "C2-4 alkenyl" or similar designations.
• C2-4 alkenyl indicates that there are two to four carbon atoms in the alkenyl chain, i.e., the alkenyl chain is selected from the group consisting of ethenyl, propen-l-yl, propen-2-yl, propen-3-yl, buten-l-yl, buten-2-yl, buten-3-yl, buten- 4-yl, 1-methyl-propen-l-yl, 2-methyl-propen-l-yl, 1-ethyl-ethen-l-yl, 2-methyl-propen-3-yl, buta-l,3-dienyl, buta-l,2,-dienyl, and buta-l,2-dien-4-yl.
• Typical alkenyl groups include, but are in no way limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl, and the like.
• alkynyl refers to a straight or branched hydrocarbon chain containing one or more triple bonds.
• the alkynyl group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term "alkynyl” where no numerical range is designated.
• the alkynyl group may also be a medium size alkynyl having 2 to 9 carbon atoms.
• the alkynyl group could also be a lower alkynyl having 2 to 4 carbon atoms.
• the alkynyl group may be designated as "C 2 - 4 alkynyl" or similar designations.
• C 2 - 4 alkynyl indicates that there are two to four carbon atoms in the alkynyl chain, i.e., the alkynyl chain is selected from the group consisting of ethynyl, propyn-l-yl, propyn-2-yl, butyn-l-yl, butyn-3-yl, butyn-4-yl, and 2- butynyl.
• Typical alkynyl groups include, but are in no way limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl, and the like.
• aromatic refers to a ring or ring system having a conjugated pi electron system and includes both carbocyclic aromatic (e.g., phenyl) and heterocyclic aromatic groups (e.g., pyridine).
• carbocyclic aromatic e.g., phenyl
• heterocyclic aromatic groups e.g., pyridine
• the term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of atoms) groups provided that the entire ring system is aromatic.
• aryloxy and arylthio refers to RO- and RS-, in which R is an aryl as is defined above, such as “C 6 -io aryloxy” or “C 6 -io arylthio” and the like, including but not limited to phenyloxy.
• an "aralkyl” or “arylalkyl” is an aryl group connected, as a substituent, via an alkylene group, such as "C7_i 4 aralkyl” and the like, including but not limited to benzyl, 2- phenylethyl, 3-phenylpropyl, and naphthylalkyl.
• the alkylene group is a lower alkylene group (i.e., a Ci_ 4 alkylene group).
• heteroaryl refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent atoms) that contain(s) one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur, in the ring backbone.
• heteroaryl is a ring system, every ring in the system is aromatic.
• the heteroaryl group may have 5-18 ring members (i.e., the number of atoms making up the ring backbone, including carbon atoms and heteroatoms), although the present definition also covers the occurrence of the term "heteroaryl" where no numerical range is designated.
• the heteroaryl group has 5 to 10 ring members or 5 to 7 ring members.
• the heteroaryl group may be designated as "5-7 membered heteroaryl,” "5-10 membered heteroaryl,” or similar designations.
• heteroaryl rings include, but are not limited to, furyl, thienyl, phthalazinyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinlinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoindolyl, and benzothienyl.
• a “heteroaralkyl” or “heteroarylalkyl” is heteroaryl group connected, as a substituent, via an alkylene group. Examples include but are not limited to 2-thienylmethyl, 3-thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazollylalkyl, and imidazolylalkyl.
• the alkylene group is a lower alkylene group (i.e., a Ci_ 4 alkylene group).
• carbocyclyl means a non-aromatic cyclic ring or ring system containing only carbon atoms in the ring system backbone.
• carbocyclyl is a ring system, two or more rings may be joined together in a fused, bridged or spiro-connected fashion.
• Carbocyclyls may have any degree of saturation provided that at least one ring in a ring system is not aromatic.
• carbocyclyls include cycloalkyls, cycloalkenyls, and cycloalkynyls.
• the carbocyclyl group may have 3 to 20 carbon atoms, although the present definition also covers the occurrence of the term "carbocyclyl” where no numerical range is designated.
• the carbocyclyl group may also be a medium size carbocyclyl having 3 to 10 carbon atoms.
• the carbocyclyl group could also be a carbocyclyl having 3 to 6 carbon atoms.
• the carbocyclyl group may be designated as "C3-6 carbocyclyl" or similar designations.
• carbocyclyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydro-indene, bicycle[2.2.2]octanyl, adamantyl, and spiro[4.4]nonanyl.
• a "(carbocyclyl)alkyl” is a carbocyclyl group connected, as a substituent, via an alkylene group, such as "C 4 _io (carbocyclyl)alkyl” and the like, including but not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, and the like.
• the alkylene group is a lower alkylene group.
• cycloalkyl means a fully saturated carbocyclyl ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
• cycloalkenyl means a carbocyclyl ring or ring system having at least one double bond, wherein no ring in the ring system is aromatic.
• An example is cyclohexenyl.
• heterocyclyl means a non-aromatic cyclic ring or ring system containing at least one heteroatom in the ring backbone. Heterocyclyls may be joined together in a fused, bridged or spiro-connected fashion. Heterocyclyls may have any degree of saturation provided that at least one ring in the ring system is not aromatic. The heteroatom(s) may be present in either a non-aromatic or aromatic ring in the ring system.
• the heterocyclyl group may have 3 to 20 ring members (i.e., the number of atoms making up the ring backbone, including carbon atoms and heteroatoms), although the present definition also covers the occurrence of the term "heterocyclyl” where no numerical range is designated.
• the heterocyclyl group may also be a medium size heterocyclyl having 3 to 10 ring members.
• the heterocyclyl group could also be a heterocyclyl having 3 to 6 ring members.
• the heterocyclyl group may be designated as "3-6 membered heterocyclyl" or similar designations.
• the heteroatom(s) are selected from one up to three of O, N or S, and in preferred five membered monocyclic heterocyclyls, the heteroatom(s) are selected from one or two heteroatoms selected from O, N, or S.
• heterocyclyl rings include, but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4- dioxinyl, 1 ,4-dioxanyl, 1,3-oxathianyl, 1 ,4-oxathianyl, 2H-l,2-oxazinyl, trioxanyl
• a "(heterocyclyl)alkyl” is a heterocyclyl group connected, as a substituent, via an alkylene group. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.
• Non- limiting examples include formyl, acetyl, propanoyl, benzoyl, and acryl.
• R is selected from hydrogen, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 3 -7 carbocyclyl, C 6 -io aryl, 5- 10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
• a "cyano" group refers to a "-CN” group.
• a "cyanato” group refers to an "-OCN” group.
• An "isocyanato” group refers to a "-NCO” group.
• a "thiocyanato" group refers to a "-SCN” group.
• An “isothiocyanato” group refers to an "-NCS” group.
• a “sulfonyl” group refers to an "-S0 2 R” group in which R is selected from hydrogen, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 3 _ 7 carbocyclyl, C 6 _io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
• S-sulfonamido refers to a "-S0 2 NR A RB” group in which R A and R B are each independently selected from hydrogen, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C3-7 carbocyclyl, C 6 -io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
• N-sulfonamido refers to a "-N(R A )S0 2 R B " group in which R A and R b are each independently selected from hydrogen, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 3 _7 carbocyclyl, C 6 _io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
• An “amino” group refers to a "-NR A R B " group in which R A and R B are each independently selected from hydrogen, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 3 _ 7 carbocyclyl, C 6 -io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
• a non- limiting example includes free amino (i.e., -NH 2 ).
• An “aminoalkyl” group refers to an amino group connected via an alkylene group.
• alkoxyalkyl refers to an alkoxy group connected via an alkylene group, such as a “C 2 -8 alkoxyalkyl” and the like.
• a substituted group is derived from the unsubstituted parent group in which there has been an exchange of one or more hydrogen atoms for another atom or group.
• substituted it is meant that the group is substituted with one or more subsitutents independently selected from Ci-C 6 alkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, C3-C7 carbocyclyl (optionally substituted with halo, Ci-C 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, and Ci-C 6 haloalkoxy), C 3 -C 7 -carbocyclyl- Ci-C 6 -alkyl (optionally substituted with halo, Ci-C 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, and Ci-C 6 haloalkoxy),
• radical naming conventions can include either a mono-radical or a di-radical, depending on the context.
• a substituent requires two points of attachment to the rest of the molecule, it is understood that the substituent is a di-radical.
• a substituent identified as alkyl that requires two points of attachment includes di-radicals such as -CH 2 -, -CH 2 CH 2 -, -CH 2 CH(CFi3)CFi 2 -, and the like.
• Other radical naming conventions clearly indicate that the radical is a di-radical such as "alkylene” or "alkenylene.”
• R groups are said to form a ring (e.g., a carbocyclyl, heterocyclyl, aryl, or heteroaryl ring) "together with the atom to which they are attached," it is meant that the collective unit of the atom and the two R groups are the recited ring.
• the ring is not otherwise limited by the definition of each R group when taken individually. For example, when the following substructure is present:
• R 1 and R 2 are defined as selected from the group consisting of hydrogen and alkyl, or R 1 and R 2 together with the nitrogen to which they are attached form a heterocyclyl, it is meant that R 1 and R 2 can be selected from hydrogen or alkyl, or alternatively, the substructure has structure:
• ring E is a heteroaryl ring containing the depicted nitrogen.
• R 1 and R 2 are defined as selected from the group consisting of hydrogen and alkyl, or R 1 and R 2 together with the atoms to which they are attached form an aryl or carbocylyl, it is meant that R 1 and R 2 can be selected from hydrogen or alkyl, or alternatively, the substructure has structure:
• E is an aryl ring or a carbocylyl containing the depicted double bond.
• a substituent is depicted as a di-radical (i.e., has two points of attachment to the rest of the molecule), it is to be understood that the substituent can be attached in any directional configuration unless otherwise indicated.
• a substituent depicted as -AE- or v 3 ⁇ 4 A ⁇ E A includes the substituent being oriented such that the A is attached at the leftmost attachment point of the molecule as well as the case in which A is attached at the rightmost attachment point of the molecule.
• Subject as used herein, means a human or a non-human mammal, e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-human primate or a bird, e.g., a chicken, as well as any other vertebrate or invertebrate.
• Isotopes may be present in the compounds described. Each chemical element present in a compound either specifically or generically described hereinmay include any isotope of said element.
• a hydrogen atom may be explicitly disclosed or understood to be present in the compound and each such hydrogen atom is any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium).
• reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.
• Some embodiments provide a method of treating a patient in need thereof comprising administering a compound as disclosed and described herein to said patient.
• the patient may have cancer, an infection, or an immune system disease.
• the compound may have anti-tumor, antibiotic, or anti-inflammatory activity.
• Some embodiments provide a compound having the structure
• A is a tubulin binding moiety
• B is a group might have protease inhibitory or efflux pump resistant properties
• Ri-Rs are each independently selected from the group consisting of H (hydrogen), Ci-Cg alkyl, substituted or cyclic Ci-Cg alkyl, aryl, and substituted aryl, or optionally Ri and R 2 together with the nitrogen to which they are attached are a cyclic 5- to 7-membered ring, or optionally Ri and R3 together with the atoms to which they are attached are a cyclic 5- to 7-membered ring, or optionally R 7 and Rs together with the atoms to which they are attached are a cyclic 5- to 7-membered ring.
• the compound may be used alone as API (active pharmaceutical ingredient) or in a prodrug form.
• the compound may be included in a conjugate including a linker and another component.
• the compound may be included in a conjugate including a linker and a targeting moiety, such as antibody, Fab, peptide, protein ligand, and the like.
• the compound may be included in a conjugate including a linker and a carrier molecule, such as HSA, lipid, polymers, nanoparticles, and the like.
• the compound may be included in a conjugate including a linker and a small molecule drug/ligand, such as folic acid.
• tubulin binding moiety refers to a structural component of a compound that inhibits tubulin polymerization under a certain set of conditions.
• the compound may inhibit tubulin polymerization under in vivo or in vitro conditions.
• the compound may inhibit tubulin polymerization in PBS. Examples of compounds that inhibit tubulin polymerization are described in Peltier, et al, "The Total Synthesis of Tubulysin D," J. Am. Chem. Soc, 2006, 128 (50): 16018-16019, and U.S. Publication No.: 2005/0239713 the disclosures of which are incorporated herein by reference in their entirety.
• the term "functional moiety” refers to a structural component of a compound that interacts with a biological moiety or fragment of the biological moiety under a certain set of conditions.
• the functional moiety may interact with a biological moiety or fragment of the biological moiety under in vivo or in vitro conditions.
• the functional moiety may interact with a biological moiety or fragment of the biological moiety in PBS.
• the functional moiety may afford a desirable effect in a compound comparison to a compound that does not include the functional moiety.
• the functional moiety may contribute to enzyme inhibition or efflux pump resistance in a compound.
• the cytotoxic compound having the structure of Formula la having the structure of Formula la:
• B is a moiety might have contribution to enzyme inhibition or efflux pump resistance
• Ri-R.8 are each independently selected from the group consisting of H (hydrogen), Ci-Cg alkyl, and substituted or cyclic Ci-Cg alkyl, or optionally Ri and R 2 together with the nitrogen to which they are attached are a cyclic 5- to 7-membered ring, or optionally Ri and R3 together with the atoms to which they are attached are a cyclic 5- to 7- membered ring, or optionally R 7 and Rs together with the atoms to which they are attached are a cyclic 5- to 7-membered ring;
• the dual active compound having the structure of Formula I has the structure of Formula lb:
• B is a moiety might have contribution to enzyme inhibition or efflux pump resistance
• Ri-Rs are each independently selected from the group consisting of H (hydrogen), Ci-Cg alkyl, and substituted or cyclic Ci-Cg alkyl, or optionally Ri and R 2 together with the nitrogen to which they are attached are a cyclic 5- to 7-membered ring, or optionally Ri and R3 together with the atoms to which they are attached are a cyclic 5- to 7- membered ring, or optionally R 7 and Rs together with the atoms to which they are attached are a cyclic 5- to 7-membered ring;
• Z is -F, -SR, -N 3 , -NRR, -ONHR, -OAc, or -OR, where each R is independently H, Ci-Cg alkyl or substituted Ci-Cg alkyl
• X is OR 10 , selected from, but not limited to, a group consisting of at least one hetero atom:
• Ri-Rio are each independently selected from the group consisting of H (hydrogen), Ci-Cg alkyl, and substituted or cyclic Ci-Cg alkyl, , or optionally Ri and R3 together with the atoms to which they are attached are a cyclic 5- to 7-membered ring, or optionally and respectively R 7 , Rs and R9 together with the atoms to which they are attached are a cyclic 5- to 7-membered ring;
• X is a group consisting of at least one heteroatom
• the dual active compound having the structure of Formula I has the structure of Formula lib:
• n 0 or 1 ;
• X is OR 10 , selected from, but not limited to, a group consisting of at least one hetero atom:
• n is 0 or 1 ;
• XX i is S0 2 R , selected from, but not limited to, a group consistin of at least one hetero atom:
• Ri-Rio are each independently selected from the group consisting of H (hydrogen), Ci-Cg alkyl, and substituted or cyclic Ci-Cg alkyl, or optionally Ri and R 2 together with the nitrogen to which they are attached are a cyclic 5- to 7-membered ring, or optionally Ri and R3 together with the atoms to which they are attached are a cyclic 5- to 7- membered ring, or optionally and respectively R 7 , Rs and R9 together with the atoms to which they are attached are a cyclic 5- to 7-membered ring;
• X is a group of at least one heteroatom
• Z is -F, -SR, -N 3 , -NRR, -ONHR, -OAc, or -OR, where each R is independently H, Ci-C 8 alkyl or substituted Ci-C 8 alkyl
• Examples of compounds having the structure of Formula la include but not limited to the following:
• Examples of compounds having the structure of Formula la include the following:
• Examples of general compounds having the structure of Formula la include the following:
• Examples of compounds having the structure of Formula la include the following:
• Examples of general compounds having the structure of Formula la include the following:
• Examples of compounds having the structure of Formula la include the following:
• Examples of general compounds having the structure of Formula la include the following:
• Examples of compounds having the structure of Formula la include the following:
• Examples of general compounds having the structure of Formula la include the following: H
• Examples of compounds having the structure of Formula la include the following:
• Examples of general compounds having the structure of Formula la include the following:
• Examples of compounds having the structure of Formula lb include the following:
• Examples of compounds having the structure of Formula lb include the following:
• the compound is conjugated to a targeting moiety.
• the targeting moiety includes a monoclonal antibody (mAB).
• the compound includes a spacer or a multifunctional linker.
• the spacer connects to the mAB by a group including a N (nitrogen) atom.
• the multifunctional linker connects to the mAB by a group including a N (nitrogen) atom.
• the spacer or multifunctional linker may be optionally connected to an auxiliary moiety.
• the auxiliary moiety may be a second targeting moiety such as mAB and peptide.
• the auxiliary moiety may be a hydrophilic polymer such as polyethylene glycol (PEG), and the like.
• the spacer or multifunctional linker may include a group including a N (nitrogen) atom.
• the spacer or multifunctional linker may include a cyclic group including a N (nitrogen) atom.
• the spacer connects to the mAB by a sulfide bond.
• the multifunctional linker connects to the mAB by a sulfide bond.
• the spacer or multifunctional linker may be optionally connected to an auxiliary moiety.
• the auxiliary moiety may be a second targeting moiety such as mAB and peptide.
• the auxiliary moiety may be a hydrophilic polymer such as polyethylene glycol (PEG), and the like.
• the spacer or multifunctional linker may include a 2- to 5- atom bridge.
• the spacer or multifunctional linker may include a 4C bridge.
• Some embodiments provide a method of conjugating of a targeting moiety through a spacer or a multifunctional linker.
• the spacer or multifunctional linker may include a 2- to 5- atom bridge.
• the method includes a single-step or sequential conjugation approach.
• the compound includes a spacer or a multifunctional linker.
• the spacer or multifunctional linker may include a noncleavable or cleavable unit such as peptides.
• the spacer or multifunctional linker may include a group including a N (nitrogen) atom.
• the method includes a single- step or sequential conjugation approach.
• the spacer or multifunctional linker may include a noncleavable or cleavable unit such as a peptide.
• Some embodiments provide a compound-conjugate having the structure of Formula Ila:
• R ⁇ R 9 are each independently selected from the group consisting of H (hydrogen), optionally substituted Ci-Cg alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, or optionally R 1 and R 2 together with the nitrogen to which they are attached are an optionally substituted cyclic 5- to 7-membered ring, or optionally R 1 and R 3 together with the atoms to which they are attached are an optionally substituted cyclic 5- to 7- membered ring, or optionally R 7 , R 8 and R 9 together with the atoms to which they are attached are an optionally substituted cyclic 5- to 7-membered ring, or optionally R 1 is R 1A or R 1B ;
• R 1A comprises a targeting moiety
• R 1B is -L 1 (CH 2 ) n R c , -L 1 0(CH 2 ) n R c or -(CH 2 ) n R c ;
• R is Ci-Cg alkyl, C 3 -C 8 cycloalkyl, aryl, heteroaryl, and heterocyclyl, each optionally substituted with one or more R , or optionally R comprises a targeting moiety;
• each NR E R F is independently selected, wherein R E and R F are each independently selected from hydrogen, -[(L 1 ) s (C(R 2A ) 2 ) r (NR 2A ) s (C(R 2A ) 2 ) r ]- [L 1 (C(R 2A ) 2 ) r (NR 2A ) s (C(R 2A ) 2 ) R ] S -(L 1 ) s -R J , -[(LW ⁇ NR 24 ), ⁇ ),]- (L 1 ) s [(C(R 2A ) 2 ) r O(C(R 2A ) 2 ) r (L 2 ) s ] s -(L 1 ) s -R J , optionally substituted d_ 8 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycly
• each R is independently hydrogen, optionally substituted Ci-Cg alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;
• each R H is independently hydrogen, optionally substituted Ci-Cg alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or -NR E R F ;
• each NR R is independently selected, wherein each R is independently selected from the group consisting of hydrogen, -OH, optionally substituted Ci-Cg alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted -0-(Ci-C 8 alkyl), optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl, or optionally both R together with the nitrogen to which they are attached are an optionally substituted heterocyclyl; each R is independently selected from the group consisting of hydrogen, optionally substituted Ci-Cg alkyl, optionally substituted C 3 -C8 cycloalkyl, optionally substituted -0-(Ci-C 8 alkyl), optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl;
• each R 2F is independently selected from the group consisting hydrogen, optionally substituted Ci-Cg alkyl, optionally substituted C 3 -C8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl;
• each L 2 is independently selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl;
• each m independently is 1 or 2;
• each n independently is 0, 1, 2, 3, 4, 5, or 6;
• each r independently is 0, 1, 2, 3, 4, 5, or 6;
• each s independently is 0 or 1 ;
• each z independently is 1 or 2
• R 7 is selected from the group consisting of H (hydrogen), optionally substituted Ci-Cg alkyl, optionally substituted C 3 -Cg cycloalkyl, optionally substituted aryl, and optionally substituted heterocyclyl;
• R 8 is selected from the group consisting of H (hydrogen), -(CH 2 ) utilizatR C , optionally substituted Ci-Cg alkyl, optionally substituted C 3 -Cg cycloalkyl, optionally substituted aryl, and optionally substituted heterocyclyl;
• X is a group consisting of at least one heteroatom, or selected from groups consisting of -OR 10 , -S02-R 10 , where R 10 is R c
• the active compound having the structure of Formula I has the structure of Formula lib:
• R 9 is selected from the group consisting of H (hydrogen), optionally substituted Ci-Cg alkyl, optionally substituted C 3 -C 8 cycloalkyl, substituted Ci-Cg alkyl, substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally R 7 , R 8 and R 9 together with the atoms to which they are attached are an optionally substituted cyclic 5- to 7-membered ring,
• X is selected from groups consisting of -OR 10 , -S02-R 10 , where R 10 is R c ; and n is 0 or 1.
• At least one of R 1 , R 10 and X comprises a targeting moiety. In some embodiments, at least one of R 1 , R 10 and X further comprises a linker. In some embodiments, at least one of R 1 , R 10 and X comprises -(CH 2 ) n - where n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, at least one of R 1 , R 10 and X comprises - (CH 2 CH 2 0)n- where n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
• At least one of R 1 , R 10 and X comprises Val-Cit-PAB, Val-Ala-PAB, Phe-Lys-PAB, D-Val-Leu-Lys, Gly- Gly-Arg, or Ala-Ala-Asn-PAB.
• At least one of R 1 , R 10 and X comprises a peptide, oligosaccharide, -(CH 2 ) lake-, -(CH 2 CH 2 0) n -, Val-Cit-PAB, Val-Ala-PAB, Phe-Lys-PAB, D-Val-Leu-Lys, Gly-Gly-Arg, Ala-Ala-Asn-PAB, or combinations thereof.
• the targeting moiety is a monoclonal antibody (mAB).
• the targeting moiety is an antibody fragment, surrogate, or variant.
• the targeting moiety is a protein ligand.
• the targeting moiety is a protein scaffold. In some embodiments, the targeting moiety is a peptide. In some embodiments, the targeting moiety is a small molecule ligand. In some embodiments, the linker includes a 4-carbon bridge and at least two sulfur atoms. In some embodiments, the linker includes a fragment selected from the group consisting of:
• At least one of R 1 , R 10 and X comprises
• the A-component is the targeting moiety;
• the E-component is an optionally substituted heteroaryl or an optionally substituted heterocyclyl;
• L 3 is an optionally substituted Ci-C 6 alkyl, or L 3 is null, when L 3 is null the sulfur is directly connected to the E-component;
• L 4 is an optionally substituted Ci-C 6 alkyl, or L 4 is null, when L 4 is null the sulfur is directly connected to the E-component.
• the E-component includes a fragment selected from the group consisting of:
• L is -(CH 2 )-; and L is -(CH 2 )-. In some embodiments, L is null; and L 4 i iss nnuullll..
• At least one ofR 1 , R 10 and X comprises:
• A is the targeting moiety; X is N (nitrogen) or CH; Y is N (nitrogen), or CH; m is 0, 1, or 2; L is a linker, or null; and L 1A is a linker, or null.
• L is null.
• At least one of R 1 , R 10 and X comprises, consists of, ists essentially of:
• L may be optionally substituted Ci-C 8 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted Ci-Cg alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or combination thereof.
• L 5 is an optionally substituted Ci-Cg alkyl. In some embodiments, L 5 is Ci-Cg alkyl.
• At least one of R 1 , R 10 and X comprises, consists of, or consist essentially of:
• L may be optionally substituted Ci-Cg alkyl, optionally substituted C 3 -Cg cycloalkyl, optionally substituted Ci-Cg alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or combination thereof.
• L 5 is an optionally substituted Ci-Cg alkyl. In some embodiments, L 5 is Ci-Cg alkyl.
• At least one of R 1 , R 10 and X comprises, consists of, or consist essentially of: , wherein A is the targeting moiety, L 5 may be optionally substituted Ci-Cg alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted Ci-C 8 alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or combination thereof. In some embodiments, L 5 is an optionally substituted Ci-Cg alkyl. In some embodiments, L 5 is Ci-Cg alkyl.
• L 6 may be H, optionally substituted Ci-C 8 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or combination thereof.
• At least one of R 1 , R 10 and X comprises, consists of, or consist essentially of:
• L 5 may be optionally substituted Ci-C 8 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C3-C8 cylcoalkyl annulated to cyclooctyl ring, optionally substituted Ci-C 8 alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or combination thereof.
• L 5 is an optionally substituted Ci-C 8 alkyl.
• L 5 is Ci-C 8 alkyl.
• Some embodiments provide a compound-conjugate having the structure of Formula V:
• a 1 may be a targeting moiety
• B 1 is an auxiliary moiety that optionally includes a second targeting moiety, or B 1 is null
• L 1 includes a group including a N (nitrogen) atom or a group including a 2- to
• a 1 may be a monoclonal antibody (mAB). In some embodiments, A 1 may be an antibody fragment, surrogate, or variant. In some embodiments, A 1 may be a protein ligand. In some embodiments, A 1 may be a protein scaffold. In some embodiments, A 1 may be a peptide. In some embodiments, A 1 may be RNA or DNA. In some embodiments, A 1 may be a RNA or DNA fragment.
• mAB monoclonal antibody
• a 1 may be an antibody fragment, surrogate, or variant.
• a 1 may be a protein ligand. In some embodiments, A 1 may be a protein scaffold. In some embodiments, A 1 may be a peptide. In some embodiments, A 1 may be RNA or DNA. In some embodiments, A 1 may be a RNA or DNA fragment.
• a 1 may be a small molecule ligand.
• B 1 may be a hydrophilic polymer.
• the hydrophilic polymer may polyethylene glycol (PEG), and the like.
• B 1 may be a biodegradable polymer.
• the biodegradable polymer may be unstructured proteins polyamino acids, polypeptides polysaccharides and combinations thereof.
• B 1 may be a monoclonal antibody (mAB).
• mAB monoclonal antibody
• B 1 may be an antibody fragment, surrogate, or variant.
• B 1 may be a protein ligand.
• B 1 may be a protein scaffold.
• B 1 may be a peptide.
• B 1 may be RNA or DNA.
• B 1 may be a RNA or
• B 1 may be a small molecule ligand.
• D may includes a biologically active compound.
• D may includes a core from tubulin-binder or tubulin-binder derivative.
• D include a core from epothilone A, epothilone B, paclitaxel, or derivatives thereof.
• D includes
• A is a tubulin binding moiety
• B is a protease inhibition moiety
• Ri-Rs are each independently selected from the group consisting of H (hydrogen), Ci-Cg alkyl, substituted or cyclic Ci-Cg alkyl, aryl, and substituted aryl, or optionally Ri and R 2 together with the nitrogen to which they are attached are a cyclic 5- to 7-membered ring, or optionally Ri and R3 together with the atoms to which they are attached are a cyclic 5- to 7-membered ring, or optionally R 7 and Rs together with the atoms to which they are attached are a cyclic 5- to 7-membered ring.
• A may be
• A may be ; may be N (nitrogen), CH, C-OH, C-OR,
• L 2 may include a spacer or a multifunctional linker. In some embodiments, L 2 may include a spacer and a multifunctional linker. In some embodiments, L 2 may include a multifunctional linker.
• each L 2 may be a linker, wherein the linker may be cleavable or non-cleavable under biological conditions. In some embodiments, the linker may be cleavable by an enzyme. In some embodiments, L 2 may include Linker. In some embodiments, L 1 includes a cyclic group including at least one N (nitrogen) atom. In some embodiments, L 1 includes a cyclic group including at least two N (nitrogen) atoms. In some embodiments, L 1 includes a cyclic group including at least one N (nitrogen) atom and a spacer. In some embodiments, L 1 includes a cyclic group including at least two N (nitrogen) atoms and a spacer.
• the spacer connects to the mAB by an amide bond. In some embodiments, the spacer connects to the mAB through an amine bond.
• L 1 includes a 2- to 5- carbon bridge and at least one sulfur atom. In some embodiments, L 1 includes a 2- to 5- carbon bridge and at least two sulfur atoms. In some embodiments, L 1 includes a 2- to 5- carbon bridge and a spacer. In some embodiments, L 1 includes a 2- to 5 -carbon bridge, at least two sulfur atoms and a spacer. In some embodiments, L 1 may include one or more sulfurs. In some embodiments, the L 1 may include two or more sulfurs. In some embodiments, the L 1 may include exactly two sulfurs.
• L 1 may include a 4-carbon bridge and/or a spacer.
• L 1 include a 4-carbon bridge or a spacer.
• L 1 may include a 4-carbon bridge and a spacer.
• L 1 includes a 4-carbon bridge and at least two sulfur atoms.
• the spacer connects to the mAB by a sulfide bond.
• the spacer connects to the mAB through a thioether.
• a 1 comprises at least one modified n-butyl L-a-amino acid.
• at least one modified L-Lysine residue is from an L-Lysine residue of a peptide before conjugation.
• At least one nitrogen of L 1 is from an at least one modified n-butyl L-a-amino acid of a peptide before conjugation.
• a 1 and L 1 together comprise at least one modified L-Lysine residue.
• the terminal nitrogen of the side chain of an L- Lysine residue of a peptide before conjugation is the at least one N (nitrogen) atom of L 1 .
• a 1 comprises the -(CH 2 )4- of the side chain of an L-Lysine residue of a peptide before conjugation that provides the at least one N (nitrogen) atom of L 1 .
• a 1 comprises a modified n-butyl a-amino acid residue.
• Linker may be a peptide.
• Linker may include an oligosaccharide.
• Linker may include chitosan.
• L 2 may include Linker and - (CH 2 ) reckon- where n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
• L 2 may include Linker and -(CH 2 CH 2 0) n - where n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
• Linker may include -(CH 2 ) opinion- where n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
• Linker may include -(CH 2 CH 2 0) n - where n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
• Linker may include Val-Cit-PAB, Val-Ala-PAB, Phe-Lys-PAB, D-Val-Leu- Lay, Gly-Gly-Arg, Ala-Ala-Asn-PAB, or the like.
• Linker may include any combination of peptide, oligosaccharide, -(CH 2 ) briefly-, -(CH 2 CH 2 0) n -, Val-Cit-PAB, Val-Ala-PAB, Phe-Lys-PAB, D-Val-Leu-Lay, Gly-Gly-Arg, Ala-Ala-Asn-PAB, and the like.
• the spacer may include a peptide.
• the spacer may include an oligosaccharide.
• the spacer may include chitosan.
• the spacer may include -(CH 2 ) compassion- where n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
• L 1 may include a component including a 4-carbon bridge and -(CH 2 ) admir- where n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
• the spacer may include - (CH 2 CH 2 0) n - where n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
• L 1 may include a component including a 4-carbon bridge and -(CH 2 CH 2 0) n - where n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
• the spacer may include Val-Cit-PAB, Val-Ala-PAB, Phe- Lys-PAB, Ala-Ala-Asn-PAB, or the like.
• the spacer may be any combination of peptide, oligosaccharide, -(CH 2 ) seldom-, -(CH 2 CH 2 0) n -, Val-Cit-PAB, Val-Ala- PAB, Phe-Lys-PAB, Ala-Ala-Asn-PAB, and the like.
• L 1 may include,
• the compound-conjugates may include one or more components selected from the group consisting of an amino acid, an amino acid residue, an amino acid analog, and a modified amino acid.
• peptide refers to a structure including one or more components each individually selected from the group consisting of an amino acid, an amino acid residue, an amino acid analog, and a modified amino acid. The components are typically joined to each other through an amide bond.
• amino acid includes naturally occurring amino acids, a molecule having a nitrogen available for forming an amide bond and a carboxylic acid, a molecule of the general formula NH 2 -CHR-COOH or the residue within a peptide bearing the parent amino acid, where "R” is one of a number of different side chains.
• R can be a substituent found in naturally occurring amino acids.
• R can also be a substituent referring to one that is not of the naturally occurring amino acids.
• amino acid residue refers to the portion of the amino acid which remains after losing a water molecule when it is joined to another amino acid.
• amino acid analog refers to a structural derivative of an amino acid parent compound that often differs from it by a single element.
• modified amino acid refers to an amino acid bearing an "R" substituent that does not correspond to one of the twenty genetically coded amino acids.
• the abbreviations for the genetically encoded L- enantiomeric amino acids are conventional and are as follows:
• amino acid residues in the compound-conjugate can be replaced with other amino acid residues without significantly deleteriously affecting, and in many cases even enhancing, the activity of the peptides.
• altered or mutated forms of the active agent-conjugate wherein at least one defined amino acid residue in the structure is substituted with another amino acid residue or derivative and/or analog thereof. It will be recognized that in preferred embodiments, the amino acid substitutions are conservative, i.e., the replacing amino acid residue has physical and chemical properties that are similar to the amino acid residue being replaced.
• the amino acids can be conveniently classified into two main categories—hydrophilic and hydrophobic—depending primarily on the physical-chemical characteristics of the amino acid side chain. These two main categories can be further classified into subcategories that more distinctly define the characteristics of the amino acid side chains.
• hydrophilic amino acids can be further subdivided into acidic, basic and polar amino acids.
• hydrophobic amino acids can be further subdivided into nonpolar and aromatic amino acids.
• the definitions of the various categories of amino acids are as follows:
• hydrophilic amino acid refers to an amino acid exhibiting a hydrophobicity of less than zero according to the normalized consensus hydrophobicity scale of Eisenberg et al., 1984, J. Mol. Biol. 179: 125-142. Genetically encoded hydrophilic amino acids include Thr (T), Ser (S), His (H), Glu (E), Asn (N), Gin (Q), Asp (D), Lys (K) and Arg (R).
• hydrophobic amino acid refers to an amino acid exhibiting a hydrophobicity of greater than zero according to the normalized consensus hydrophobicity scale of Eisenberg, 1984, J. Mol. Biol. 179:1.25-142. Genetically encoded hydrophobic amino acids include Pro (P), He (I), Phe (F), Val (V), Leu (L), Trp (W), Met (M), Ala (A), Gly (G) and Tyr (Y).
• acidic amino acid refers to a hydrophilic amino acid having a side chain pK value of less than 7. Acidic amino acids typically have negatively charged side chains at physiological pH due to loss of a hydrogen ion. Genetically encoded acidic amino acids include Glu (E) and Asp (D).
• basic amino acid refers to a hydrophilic amino acid having a side chain pK value of greater than 7.
• Basic amino acids typically have positively charged side chains at physiological pH due to association with hydronium ion.
• Genetically encoded basic amino acids include His (H), Arg (R) and Lys (K).
• polar amino acid refers to a hydrophilic amino acid having a side chain that is uncharged at physiological pH, but which has at least one bond in which the pair of electrons shared in common by two atoms is held more closely by one of the atoms.
• Genetically encoded polar amino acids include Asn (N), Gin (Q) Ser (S) and Thr (T).
• nonpolar amino acid refers to a hydrophobic amino acid having a side chain that is uncharged at physiological pH and which has bonds in which the pair of electrons shared in common by two atoms is generally held equally by each of the two atoms (i.e., the side chain is not polar). Genetically encoded nonpolar amino acids include Leu (L), Val (V), He (I), Met (M), Gly (G) and Ala (A).
• aromatic amino acid refers to a hydrophobic amino acid with a side chain having at least one aromatic or heteroaromatic ring.
• the aromatic or heteroaromatic ring may contain one or more substituents such as— OH,— SH, — CN,— F,—CI,—Br,—I,— N0 2 ,—NO,— NH 2 ,— NHR,— NRR,— C(0)R,— C(0)OH, — C(0)OR, — C(0)NH 2 , — C(0)NHR, — C(0)NRR and the like where each R is independently (Ci - C 6 ) alkyl, substituted (Ci - C 6 ) alkyl, (Ci - C 6 ) alkenyl, substituted (Ci - C 6 ) alkenyl, (Ci - C 6 ) alkynyl, substituted (Ci - C 6 ) alkynyl, (C 5 - C 20 ) aryl, substituted (C 5 - C 2 o) aryl, (C 6 - C 26 ) alkaryl, substituted (C 6 - C 6
• aliphatic amino acid refers to a hydrophobic amino acid having an aliphatic hydrocarbon side chain. Genetically encoded aliphatic amino acids include Ala (A), Val (V), Leu (L) and He (I).
• Cys (C) is unusual in that it can form disulfide bridges with other Cys (C) residues or other sulfanyl-containing amino acids.
• the ability of Cys (C) residues (and other amino acids with— SH containing side chains) to exist in a peptide in either the reduced free— SH or oxidized disulfide -bridged form affects whether Cys (C) residues contribute net hydrophobic or hydrophilic character to a peptide.
• Cys (C) exhibits a hydrophobicity of 0.29 according to the normalized consensus scale of Eisenberg (Eisenberg, 1984, supra), it is to be understood that for purposes of the preferred embodiments Cys (C) is categorized as a polar hydrophilic amino acid, notwithstanding the general classifications defined above.
• targeting moiety refers to a structure that binds or associates with a biological moiety or fragment thereof.
• the targeting moiety may be a monoclonal antibody (mAB). In some embodiments, the targeting moiety may be an antibody fragment, surrogate, or variant. In some embodiments, the targeting moiety may be a protein ligand. In some embodiments, the targeting moiety may be a protein scaffold. In some embodiments, the targeting moiety may be a peptide. In some embodiments, the targeting moiety may be RNA or DNA. In some embodiments, the targeting moiety may be a RNA or DNA fragment. In some embodiments, the targeting moiety may be a small molecule ligand.
• mAB monoclonal antibody
• the targeting moiety may be an antibody fragment, surrogate, or variant.
• the targeting moiety may be a protein ligand. In some embodiments, the targeting moiety may be a protein scaffold. In some embodiments, the targeting moiety may be a peptide. In some embodiments, the targeting moiety may be RNA or DNA. In some embodiments, the targeting moiety may be a RNA or
• the targeting moiety may be an antibody fragment described in Janthur et al., "Drug Conjugates Such as Antibody Drug Conjugates (ADCs), Immunotoxins and Immunoliposomes Challenge Daily Clinical Practice," Int. J. Mol. Sci. 2012, 13, 16020-16045, the disclosure of which is incorporated herein by reference in its entirety.
• the targeting moiety may be an antibody fragment described in Trail, PA, "Antibody Drug Conjugates as Cancer Therapeutics," Antibodies 2013, 2, 113- 129, the disclosure of which is incorporated herein by reference in its entirety.
• the targeting moiety may be HuM195-Ac-225, HuM195-Bi-213, Anyara (naptumomab estafenatox; ABR-217620), AS1409, Zevalin (ibritumomab tiuxetan), BIIB015, BT-062, Neuradiab, CDX-1307, CR011-vcMMAE, Trastuzumab-DMl (R3502), Bexxar (tositumomab), IMGN242, IMGN388, IMGN901, 131 I- labetuzumab, IMMU-102 ( 90 Y-epratuzumab), IMMU-107 ( 90 Y-clivatuzumab tetraxetan), MDX-1203, CAT-8015, EMD 273063 (hul4.18-IL2), Tucotuzumab celmoleukin (EMD 273066; h
• the targeting moiety may comprise, consist of, or consist essentially of the antibody portion of HuM195-Ac-225, HuM195-Bi-213, Anyara (naptumomab estafenatox; ABR-217620), AS 1409, Zevalin (ibritumomab tiuxetan), BUBO 15, BT-062, Neuradiab, CDX-1307, CR011-vcMMAE, Trastuzumab-DMl (R3502), Bexxar (tositumomab), IMGN242, IMGN388, IMGN901, 131 I-labetuzumab, IMMU-102 ( 90 Y- epratuzumab), IMMU-107 ( 90 Y-clivatuzumab tetraxetan), MDX-1203, CAT-8015, EMD 273063 (hul4.18-IL2), Tucotuzumab celmoleukin (
• the targeting moiety may be Brentuximab vedotin, Trastuzumab emtansine, Inotuzumab ozogamicin, Lorvotuzumab mertansine, Glembatumumab vedotin, SAR3419, Moxetumomab pasudotox, Moxetumomab pasudotox, AGS-16M8F, AGS-16M8F, BIIB-015, BT-062, IMGN-388, or IMGN-388.
• the targeting moiety may comprise, consist of, or consist essentially of the antibody portion of Brentuximab vedotin, Trastuzumab emtansine, Inotuzumab ozogamicin, Lorvotuzumab mertansine, Glembatumumab vedotin, SAR3419, Moxetumomab pasudotox, Moxetumomab pasudotox, AGS-16M8F, AGS-16M8F, BIIB-015, BT-062, IMGN-388, or IMGN-388.
• the targeting moiety may comprise, consist of, or consist essentially of Brentuximab, Inotuzumab, Gemtuzumab, Milatuzumab, Trastuzumab, Glembatumomab, Lorvotuzumab, or Labestuzumab.
• linker refers to a moiety that connects two or more components to each other.
• the linker may be a linker disclosed in Janthur et al., "Drug Conjugates Such as Antibody Drug Conjugates (ADCs), Immunotoxins and Immunoliposomes Challenge Daily Clinical Practice," Int. J. Mol. Sci. 2012, 13, 16020- 16045.
• the linker may be a linker disclosed in Trail, PA, "Antibody Drug Conjugates as Cancer Therapeutics," Antibodies 2013, 2, 113-129.
• the linker may be a linker disclosed in US Patent No.: 7,829, 531.
• the linker may comprise, consist of, or consist essentially of the linker portion of HuM195-Ac-225, HuM195-Bi-213, Anyara (naptumomab estafenatox; ABR-217620), AS 1409, Zevalin (ibritumomab tiuxetan), BUBO 15, BT-062, Neuradiab, CDX-1307, CR011-vcMMAE, Trastuzumab-DMl (R3502), Bexxar (tositumomab), IMGN242, IMGN388, IMGN901, 131 I-labetuzumab, IMMU-102 ( 90 Y- epratuzumab), IMMU-107 ( 90 Y-clivatuzumab tetraxetan), MDX-1203, CAT-8015, EMD 273063 (hul4.18-IL2), Tucotuzumab celmol
• the linker may comprise, consist of, or consist essentially of the linker portion of Brentuximab vedotin, Trastuzumab emtansine, Inotuzumab ozogamicin, Lorvotuzumab mertansine, Glembatumumab vedotin, SAR3419, Moxetumomab pasudotox, Moxetumomab pasudotox, AGS-16M8F, AGS-16M8F, BIIB-015, BT-062, IMGN-388, or IMGN-388.
• the linker may comprise, consist of, or consist essentially of Valine-citrulline residue, hydrazine, 4-mercaptobutanoyl, 4-(N- succinimidomethyl)cyclohexanecarbonyl (SMCC), Maleimidocaproyl, Phenylalaninelysine, 6-(3-(thio)propanamido)hexanoyl, 3-mercaptopropanoyl, 4-mercaptopentanoyl, or lysine residue.
• SMCC succinimidomethylcyclohexanecarbonyl
• the linker may comprise, consist of, or consist essentially of:
• L 5 may be optionally substituted Ci-C 8 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted Ci-Cg alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or combination thereof.
• L 5 is an optionally substituted Ci-Cg alkyl.
• L 5 is Ci-Cg alkyl.
• the linker may comprise, consist of, or consist essentially of:
• L may be optionally substituted Ci-Cg alkyl, optionally substituted C 3 -Cg cycloalkyl, optionally substituted Ci-Cg alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or combination thereof.
• L 5 is an optionally substituted Ci-Cg alkyl. In some embodiments, L 5 is Ci-Cg alkyl.
• the linker may comprise, consist of, or consist essentially of:
• L 5 is an optionally substituted
• L 5 is Ci-Cg alkyl.
• L 6 may be H, optionally substituted Ci-
• Cg alkyl optionally substituted C 3 -Cg cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or combination thereof.
• the linker may comprise, consist of, or consist essentially of:
• L 5 may be optionally substituted Ci-Cg alkyl, optionally substituted C 3 -Cg cycloalkyl, optionally substituted C3-C8 cylcoalkyl annulated to cyclooctyl ring, optionally substituted Ci-Cg alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or combination thereof.
• L 5 is an optionally substituted Ci-Cg alkyl.
• L 5 is Ci-Cg alkyl.
• the linker may comprise, consist of, or consist essentially of:
• amino acids having side chains exhibiting two or more physical-chemical properties can be included in multiple categories.
• amino acid side chains having aromatic moieties that are further substituted with polar substituents, such as Tyr (Y) may exhibit both aromatic hydrophobic properties and polar or hydrophilic properties, and can therefore be included in both the aromatic and polar categories.
• polar substituents such as Tyr (Y)
• the amino acid substitutions need not be, and in certain embodiments preferably are not, restricted to the genetically encoded amino acids.
• the active agent-conjugate may contain genetically non-encoded amino acids.
• amino acid residues in the active agent-conjugate may be substituted with naturally occurring non- encoded amino acids and synthetic amino acids.
• Certain commonly encountered amino acids which provide useful substitutions for the active agent-conjugates include, but are not limited to, ⁇ -alanine ( ⁇ -Ala) and other omega-amino acids such as 3-aminopropionic acid, 2,3-diaminopropionic acid (Dpr), 4-aminobutyric acid and so forth; a-aminoisobutyric acid (Aib); ⁇ -aminohexanoic acid (Aha); ⁇ -aminovaleric acid (Ava); N-methylglycine or sarcosine (MeGly); ornithine (Orn); citrulline (Cit); t-butylalanine (t-BuA); t-butylglycine (t-BuG); N-methylisoleucine (Melle); phenylglycine (Phg); cyclohexylalanine (Cha); norleucine (Nle); naphthylalanine (Nal); 4-
• Aromatic F Y, W Phg, Nal, Thi, Tic, Phe (4-Cl), Phe (2-F),
• the amino acids of the compound-conjugate will be substituted with L-enantiomeric amino acids, the substitutions are not limited to L- enantiomeric amino acids.
• the peptides may advantageously be composed of at least one D-enantiomeric amino acid. Peptides containing such D-amino acids are thought to be more stable to degradation in the oral cavity, gut or serum than are peptides composed exclusively of L-amino acids.
• Examples of compound-conjugates include, but are not limited to, the following general compounds:
• R may be H (hydrogen), Ci-Cg alkyl, substituted or cyclic Ci-Cg alkyl
• Examples of compounds include, but are not limited to, the following general compounds:
• compound-conjugates include, but are not limited to, the following general compounds:
• R may be H (hydrogen), Ci-C 8 alkyl, substituted or cyclic Ci-C 8 alkyl, and the like
• Examples of compounds include, but are not limited to, the following compound and general compounds:
• the compounds disclosed herein are used in pharmaceutical compositions.
• the compounds can be used, for example, in pharmaceutical compositions comprising a pharmaceutically acceptable carrier prepared for storage and subsequent administration.
• embodiments relate to a pharmaceutically effective amount of the products and compounds disclosed above in a pharmaceutically acceptable carrier or diluent.
• Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A.R. Gennaro edit. 1985), which is incorporated herein by reference in its entirety.
• Preservatives, stabilizers, dyes and even flavoring agents can be provided in the pharmaceutical composition.
• sodium benzoate, ascorbic acid and esters of p- hydroxybenzoic acid can be added as preservatives.
• antioxidants and suspending agents can be used.
• compositions can be formulated and used as tablets, capsules, or elixirs for oral administration; suppositories for rectal administration; sterile solutions, suspensions for injectable administration; patches for transdermal administration, and sub- dermal deposits and the like.
• injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride, and the like.
• the injectable pharmaceutical compositions may contain minor amounts of nontoxic auxiliary substances, such as wetting agents, pH buffering agents, and the like. If desired, absorption enhancing preparations (for example, liposomes), can be utilized.
• compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds can be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or other organic oils such as soybean, grapefruit or almond oils, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
• Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
• the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
• compositions for oral use can be obtained by combining the active compounds with solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
• suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
• PVP polyvinylpyrrolidone
• disintegrating agents can be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
• Dragee cores are provided with suitable coatings.
• suitable coatings for this purpose, concentrated sugar solutions can be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
• Dyestuffs or pigments can be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
• concentrated sugar solutions can be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
• Dyestuffs or pigments can be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
• ком ⁇ онентs to formulate the compounds of Formulae I and II as an anti-cancer agent, known surface active agents, excipients, smoothing agents, suspension agents and pharmaceutically acceptable film-forming substances and coating assistants, and the like can be used.
• alcohols, esters, sulfated aliphatic alcohols, and the like can be used as surface active agents; sucrose, glucose, lactose, starch, crystallized cellulose, mannitol, light anhydrous silicate, magnesium aluminate, magnesium methasilicate aluminate, synthetic aluminum silicate, calcium carbonate, sodium acid carbonate, calcium hydrogen phosphate, calcium carboxymethyl cellulose, and the like can be used as excipients; magnesium stearate, talc, hardened oil and the like can be used as smoothing agents; coconut oil, olive oil, sesame oil, peanut oil, soya can be used as suspension agents or lubricants; cellulose acetate phthalate as a derivative of a carbohydrate such
• the compounds of Formulae I and II or compositions including compounds of Formulae I and II can be administered by either oral or non-oral pathways.
• it can be administered in capsule, tablet, granule, spray, syrup, or other such form.
• it can be administered as an aqueous suspension, an oily preparation or the like or as a drip, suppository, salve, ointment or the like, when administered via injection, subcutaneously, intraperitoneally, intravenously, intramuscularly, or the like.
• the anti-cancer agent can be mixed with additional substances to enhance their effectiveness.
• the disclosed compounds and the disclosed pharmaceutical compositions are administered by a particular method as an anti-cancer, or anti-inflammatory.
• Such methods include, among others, (a) administration though oral pathways, which administration includes administration in capsule, tablet, granule, spray, syrup, or other such forms; (b) administration through non-oral pathways, which administration includes administration as an aqueous suspension, an oily preparation or the like or as a drip, suppository, salve, ointment or the like; administration via injection, subcutaneously, intraperitoneally, intravenously, intramuscularly, intradermally, or the like; as well as (c) administration topically, (d) administration rectally, or (e) administration vaginally, as deemed appropriate by those of skill in the art for bringing the compound of the present embodiment into contact with living tissue; and (f) administration via controlled released formulations, depot formulations, and infusion pump delivery.
• compositions that include the described compounds required as a dose will depend on the route of administration, the type of animal, including human, being treated, and the physical characteristics of the specific animal under consideration.
• the dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.
• a compound represented by Formulae I and II can be administered to a patient in need of an anti-cancer agent, until the need is effectively reduced or preferably removed.
• the products or compositions can be used alone or in combination with one another, or in combination with other therapeutic or diagnostic agents. These products can be utilized in vivo, ordinarily in a mammal, preferably in a human, or in vitro. In employing them in vivo, the products or compositions can be administered to the mammal in a variety of ways, including parenterally, intravenously, subcutaneously, intramuscularly, colonically, rectally, vaginally, nasally or intraperitoneally, employing a variety of dosage forms. Such methods may also be applied to testing chemical activity in vivo.
• the useful in vivo dosage to be administered and the particular mode of administration will vary depending upon the age, weight and mammalian species treated, the particular compounds employed, and the specific use for which these compounds are employed.
• the determination of effective dosage levels can be accomplished by one skilled in the art using routine pharmacological methods. Typically, human clinical applications of products are commenced at lower dosage levels, with dosage level being increased until the desired effect is achieved. Alternatively, acceptable in vitro studies can be used to establish useful doses and routes of administration of the compositions identified by the present methods using established pharmacological methods.
• dosages In non-human animal studies, applications of potential products are commenced at higher dosage levels, with dosage being decreased until the desired effect is no longer achieved or adverse side effects disappear.
• the dosage may range broadly, depending upon the desired affects and the therapeutic indication. Typically, dosages can be between about 10 mg/kg and 100 mg/kg body weight, preferably between about 100 mg/kg and 10 mg/kg body weight. Alternatively dosages can be based and calculated upon the surface area of the patient, as understood by those of skill in the art. Administration is preferably oral on a daily or twice daily basis.
• the exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. See for example, Fingl et al. , in The Pharmacological Basis of Therapeutics, 1975, which is incorporated herein by reference in its entirety. It should be noted that the attending physician would know how to and when to terminate, interrupt, or adjust administration due to toxicity, or to organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity).
• the magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the condition to be treated and to the route of administration. The severity of the condition may, for example, be evaluated, in part, by standard prognostic evaluation methods. Further, the dose and perhaps dose frequency, will also vary according to the age, body weight, and response of the individual patient. A program comparable to that discussed above can be used in veterinary medicine.
• Suitable administration routes may include oral, rectal, transdermal, vaginal, transmucosal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections.
• the agents of the embodiment can be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer.
• physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer.
• penetrants appropriate to the barrier to be permeated are used in the formulation.
• penetrants are generally known in the art.
• Use of pharmaceutically acceptable carriers to formulate the compounds herein disclosed for the practice of the embodiment into dosages suitable for systemic administration is within the scope of the embodiment. With proper choice of carrier and suitable manufacturing practice, the compositions disclosed herein, in particular, those formulated as solutions, can be administered parenterally, such as by intravenous injection.
• the compounds can be formulated readily using pharmaceutically acceptable carriers well known in the art into dosages suitable for oral administration.
• Such carriers enable the compounds of the embodiment to be formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
• Agents intended to be administered intracellularly can be administered using techniques well known to those of ordinary skill in the art. For example, such agents can be encapsulated into liposomes, then administered as described above. All molecules present in an aqueous solution at the time of liposome formation are incorporated into the aqueous interior. The liposomal contents are both protected from the external micro- environment and, because liposomes fuse with cell membranes, are efficiently delivered into the cell cytoplasm. Additionally, due to their hydrophobicity, small organic molecules can be directly administered intracellularly.
• these pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
• suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
• the preparations formulated for oral administration can be in the form of tablets, dragees, capsules, or solutions.
• the pharmaceutical compositions can be manufactured in a manner that is itself known, for example, by means of conventional mixing, dissolving, granulating, dragee-making, levitating, emulsifying, encapsulating, entrapping, or lyophilizing processes.
• Compounds disclosed herein can be evaluated for efficacy and toxicity using known methods.
• the toxicology of a particular compound, or of a subset of the compounds, sharing certain chemical moieties can be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans.
• the toxicity of particular compounds in an animal model such as mice, rats, rabbits, dogs or monkeys, can be determined using known methods.
• the efficacy of a particular compound can be established using several art recognized methods, such as in vitro methods, animal models, or human clinical trials.
• needle is not an absolute term and merely implies that the patient can benefit from the treatment of the anti-cancer agent in use.
• patient what is meant is an organism that can benefit by the use of an anticancer agent.
• “Therapeutically effective amount,” “pharmaceutically effective amount,” or similar term means that amount of drug or pharmaceutical agent that will result in a biological or medical response of a cell, tissue, system, animal, or human that is being sought. In a preferred embodiment, the medical response is one sought by a researcher, veterinarian, medical doctor, or other clinician.
• a described compound preferably a compound having any one of Formulas I and II, including those as described herein, is considered an effective anti-cancer agent if the compound can influence 10% of the cancer cells, for example.
• the compound is effective if it can influence 10 to 50% of the cancer cells.
• the compound is effective if it can influence 50-80% of the cancer cells.
• the compound is effective if it can influence 80-95% of the cancer cells.
• the compound is effective if it can influence 95-99% of the cancer cells.
• "Influence" is defined by the mechanism of action for each compound.
• Conjugation method B Conjugation on Lys residues via reductive alkylation with an dialdehyde
• Conjugation method D Conjugation on two Cys side chains by forming a cyclic structure
• Method 1-1 Linker and Drug connected via a carbamate bond. The following general procedures were employed:
• Method 1-3 Active molecule containing a carboxylic acid moiety connected to an alkoxyamino linker via formation of hydoxamate (General procedure A or B), followed by removal of protective groups.
• Step 3 Introducing the final functional groups prior to conjugation
• the carboxylic acid can be activated using a variety of methods to afford an activated form.
• the carboxylic acid can be activated using the following methods: A) Tetrahedron 61 (2005) 10827-10852; B) Beckwith, A. L. J. In The Chemistry of
• amino acid sulfonamide derivatives 11, 15, 17, 19 were synthesized according to previously reported procedure (ARKIVOC 2004 (xii) 14-22) using Boc protected amino acid and cyclopropyl/methyl sulfonamide, followed by removal of Boc
• Compound 27 was synthesized using the general procedures described above as following: HATU mediated amide bond formation (General procedure A) between compound 21 and amine 25, followed by removal of Boc (General procedure C). The final compound was purified by reverse phase HPLC to give compound 27 as a white powder after lyophilization. MS m/z Calcd. for C 3 6H 5 9N 5 0 8 S 721.4, Found 722.5 ([M+H] + ).
• Compound 30 was synthesized using the general procedures described above as following: HATU mediated amide bond formation (General procedure A) between ⁇ -Cl-N-Boc-Ala-OH (compound 28) and amine 27, followed by removal of Boc (General procedure C). The final compound was purified by reverse phase HPLC to give compound 30 as a white powder after lyophilization. MS m/z Calcd for C 3 H 63 CIN 6 O 9 S 826.4, Found 827.5 ([M+H] + ).
• amino acid sulfonamide derivatives 33 and 36 were synthesized according to previously reported procedure (WO 2007146695) using Boc protected amino acid and cyclopropyl/methyl sulfonamide, followed by removal of Boc (General procedure C)
• Compound 35 was synthesized using the general procedures described above as following: DIC/HOAt mediated amide bond formation (General procedure B) between Boc-N-Me-Val-Val-Dil-Dap-OH (compound 10) and amine 33, followed by removal of Boc (General procedure C). The final compound was purified by reverse phase HPLC to give compound 35 as a white powder after lyophilization. MS m/z Calcd for
• the compound 45 was synthesized according to the same procedures as described for the synthesis of compound 44. The final compound was purified by reverse phase HPLC to give compound 45 as a white powder after lyophilization. MS m/z Calcd for
• Example III -4 Other compounds synthesized using the same procedures as described for the synthesis of compound 49
• the intermediate 136 was synthesized using the general procedures described above as following (0.1 mmol scale): HATU mediated amide bond formation
• the compound 138 was synthesized employing the same sequence as described for the preparation of compound 137. (compound 139 as a starting material). It was obtained as a white powder after RP-HPLC purification and lyophilization. MS m/z Calcd for
• Compound 56 was synthesized using the general procedures described above as following: DIC/HOAt mediated amide bond formation (General procedure B) between Me 2 -Val-Val-Dil-Dap-LeuOH (compound 49) and THP-0-NH 2 , followed by removal of THP (General procedure C, using 4N aq. HCl). The final compound was purified by reverse phase HPLC to give compound 56 as a white powder after lyophilization. MS m/z
• Dimethyl Auristatin F was synthesized from compound 10 and NH 2 -Phe-
• Compound 60 was synthesized using the general procedures described above as following: DIC/HOAt mediated amide bond formation (General procedure B) between compound 50 and THP-0-NH 2 , followed by removal of THP (General procedure C, using 4N aq. HCl). The final compound was purified by reverse phase HPLC to give compound 47 as a white powder after lyophilization. MS m/z Calcd for C 3 9H 72 N 6 0 8 752.5,
• Compound 61 was synthesized using the general procedures described above as following: DIC/HOAt mediated amide bond formation (General procedure B) between compound 52 and THP-0-NH 2 , followed by removal of THP (General procedure C, using 4N aq. HCl). The final compound was purified by reverse phase HPLC to give compound 61 as a white powder after lyophilization. MS m/z Calcd for C 4 iH 78 N 6 0 9 798.5,
• Compound 84 was synthesized using the general procedures described above as following: DIC/HOAt mediated amide bond formation (General procedure B) between Auristatin F and compound 66, followed by removal of Fmoc (General procedure
• Compound 98 was synthesized using the general procedures described above as following: Carbamate formation (General procedure I) between compound 4 and Fmoc-A-PAB-PNP, followed by removal of Fmoc (General procedure D), and amide formation with acid 87 using HATU (General procedure A, 3eq of acid 87 and 1 eq of HATU were used). The final compound was purified by reverse phase HPLC to give compound 98 as a white powder after lyophilization. MS m/z Calcd for C 61 H 94 N 8 O 17 S 1242.7, Found 1243.8 ([M+H] + ).
• Compound 102 was synthesized using the general procedures described above as following: Carbamate formation (General procedure I) between compound 16 and Fmoc-A-PAB-PNP, followed by removal of Fmoc (General procedure D), and reaction with glutaric anhydride (General procedure H). The final compound was purified by reverse phase HPLC to give compound 102 as a white powder after lyophilization. MS m/z Calcd for C 55 H 9 oN 8 Oi 5 S 1134.6, Found 1135.6 ([M+H] + ).
• Compound 103 was synthesized using the general procedures described above as following: Carbamate formation (General procedure I) between compound 16 and Fmoc-A-PAB-PNP, followed by removal of Fmoc (General procedure D), and amide formation with acid 87 using HATU (General procedure A, 3 eq of acid 87 and 1 eq of HATU were used). The final compound was purified by reverse phase HPLC to give compound 103 as a white powder after lyophilization. MS m/z Calcd for CssHgeNgOnS 1208.7, Found 1209.8 ([M+H] + ).
• Compound 104 was synthesized using the general procedures described above as following: DIC/HOAt mediated amide bond formation (General procedure B) between compound 42 and compound 66, followed by removal of Fmoc (General procedure D), and reaction with glutaric anhydride (General procedure H). The final compound was purified by reverse phase HPLC to give compound 104 as a white powder after lyophilization. MS m/z Calcd for C71H115N13O19S 1485.8, Found 1486.9 ([M+H] + ).
• Compound 114 was synthesized using the general procedures described above as following: HATU mediated amide bond formation (General procedure A) between compound 113 and methyl isonipecotate, followed by saponification to remove methyl group from ester (General procedure F). The final compound was purified by reverse phase HPLC to give compound 114 as a white powder after lyophilization. MS m/z Calcd for CsiHssNyOisS 1033.6, Found 1034.7 ([M+H] + ).
• Compound 115 was synthesized using the general procedures described above as following: DIC/HOAt mediated amide bond formation (General procedure B) between compound 113 and compound 67, followed by removal of Fmoc (General procedure D), HATU mediated amidation reaction with acid 116 (General procedure A), and saponification to remove methyl group from ester (General procedure F). The final compound was purified by reverse phase HPLC to give compound 115 as a white powder after lyophilization. MS m/z Calcd for CesHioo ioOnS 1324.7, Found 1325.9 ([M+H] + ).
• Compound 101 was synthesized using the general procedures described above as following: Carbamate formation (General procedure I) between compound 13 and FmocVC-PAB-PNP, followed by removal of Fmoc (General procedure D), and amidation reaction with 6-maleimidohexanoic acid (General procedure A). The final compound was purified by reverse phase HPLC to give compound 101 as a white powder after lyophilization. MS m/z Calcd for C71H108N12O17S 1432.8, Found 1433.9 ([M+H] + ).
• Example X-2 Converting an existing amino group to maleimide directly using N-methoxycarbonylmaleimide
• HPLC Hydrophilic Interaction Chromatography-HPLC
• the average DAR drug antibody ratio was calculated by UV absorption and/or MS spectroscopy.
• the cell lines used were SK-BR-3 human breast adenocarcinoma (HER2 triple positive), HCC1954 human Ductal Carcinoma (HER2 triple positive), MCF7 human breast adenocarcinoma (HER2 normal), and MDA-MB-468 human breast adenocarcinoma
• SK-BR-3 cells were grown in McCoy's 5 A medium (Caisson Labs, North Logan, UT) supplemented with 10% fetal bovine serum.
• HCC1954 cells were grown in RPMI-1640 medium (Caisson Labs, North Logan, UT) supplemented with 10% fetal bovine serum.
• MCF7 and MDA-MB-468 cells were grown in DMEM/F12 medium (Caisson Labs, North Logan, UT) supplemented with 10% fetal bovine serum.
• SK-BR-3, MCF7, and MDA-MB-468 cells were plated in 96-well plates at approximately 7,500 cells/well, and HCC1954 cells were plated in 96-well plates at approximately 20,000 cells/well. Compounds or the antibody-drug conjugates were added in duplicates in the same day. After 72 hour incubation at 37°C, CellTiter-Glo (Promega, Madison, WI) were added and cell viability was determined as describe by the manufacture's protocol. The percent viability was determined as following:
• % Viability Average Luminescence Value of the duplicates (treated wells) /

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Life Sciences & Earth Sciences (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Immunology (AREA)
• Epidemiology (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Molecular Biology (AREA)
• Biochemistry (AREA)
• Genetics & Genomics (AREA)
• Biophysics (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Cell Biology (AREA)
• Diabetes (AREA)
• Oncology (AREA)
• Gastroenterology & Hepatology (AREA)
• Obesity (AREA)
• Hematology (AREA)
• Emergency Medicine (AREA)
• Communicable Diseases (AREA)
• Endocrinology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Peptides Or Proteins (AREA)
• Medicinal Preparation (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Priority Applications (6)

Applications Claiming Priority (8)

Related Child Applications (2)

Publications (1)

Family

ID=49584226

Family Applications (3)

Family Applications After (2)

Country Status (7)

Cited By (53)

Families Citing this family (89)

Citations (12)

Family Cites Families (42)

• 2013
  • 2013-05-14 US US14/401,115 patent/US9981046B2/en active Active
  • 2013-05-14 US US14/401,318 patent/US9801951B2/en not_active Expired - Fee Related
  • 2013-05-14 ES ES19167808T patent/ES2887208T3/es active Active
  • 2013-05-14 CN CN201380025775.8A patent/CN104662000B/zh active Active
  • 2013-05-14 EP EP13790334.0A patent/EP2849797B1/en active Active
  • 2013-05-14 EP EP18199921.0A patent/EP3520817A1/en active Pending
  • 2013-05-14 HK HK15108783.7A patent/HK1208216A1/xx unknown
  • 2013-05-14 CN CN201710584374.6A patent/CN107982545B/zh active Active
  • 2013-05-14 EP EP13790777.0A patent/EP2850059A4/en not_active Ceased
  • 2013-05-14 ES ES13790623T patent/ES2734259T3/es active Active
  • 2013-05-14 JP JP2015512771A patent/JP6280103B2/ja not_active Expired - Fee Related
  • 2013-05-14 JP JP2015512770A patent/JP6239598B2/ja active Active
  • 2013-05-14 US US14/401,114 patent/US9884127B2/en active Active
  • 2013-05-14 EP EP21189993.5A patent/EP3925627A1/en active Pending
  • 2013-05-14 JP JP2015512769A patent/JP6239597B2/ja active Active
  • 2013-05-14 WO PCT/US2013/041028 patent/WO2013173393A1/en not_active Ceased
  • 2013-05-14 CN CN201380025785.1A patent/CN104640572B/zh active Active
  • 2013-05-14 EP EP19167808.5A patent/EP3590541B1/en active Active
  • 2013-05-14 WO PCT/US2013/041027 patent/WO2013173392A1/en not_active Ceased
  • 2013-05-14 CN CN201380025774.3A patent/CN104379168B/zh active Active
  • 2013-05-14 WO PCT/US2013/041026 patent/WO2013173391A1/en not_active Ceased
  • 2013-05-14 EP EP13790623.6A patent/EP2849790B1/en active Active
• 2017
  • 2017-08-17 US US15/679,599 patent/US20180085471A1/en not_active Abandoned
  • 2017-11-01 JP JP2017212167A patent/JP2018052951A/ja active Pending
  • 2017-11-01 JP JP2017212053A patent/JP2018058851A/ja active Pending
  • 2017-12-26 US US15/854,742 patent/US10967071B2/en active Active
• 2021
  • 2021-03-01 US US17/189,135 patent/US12115228B2/en active Active
• 2024
  • 2024-09-04 US US18/824,613 patent/US20250135024A1/en active Pending

Patent Citations (12)

Non-Patent Citations (23)

Also Published As

Similar Documents

Legal Events