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US 2006/0223785 A1Published application
Andrographolide derivatives to treat viral infections
AssigneeCornell Research Foundation, Inc.
InventorsRui Liu, James Jacob, Bud Tennant
Life of this patent
Estimating the term…
Abstract
The present invention provides a methods and compositions for treating a host afflicted with a viral infection, particularly a Flaviviridae infection, including hepatitis C infection, comprising administering an effective antiviral amount of a derivative of andrographolide alone or in combination or alternation with another antiviral compound.
Claims32
A method for treating a host infected with a Flaviviridae virus comprising administering to the host an effective amount of an andrographolide derivative of the formula:
- or its cis isomer, or its pharmaceutically acceptable salt, ester, salt of an ester or prodrug, wherein:
- B1, B2 and B3 are independently CR1R2, C(Y1), O, NR4, PR5, P(═Y2)R6, P(═Y3)2, S(═Y4)k, a spacer group or a covalent bond;
- and k can be 0, 1 or 2;
- and
- W1, W2 and W3 are independently CR7R8, CR9, C, C(Y5), O, NR10, PR11, P(═Y6)R12, P(═Y7)2, S(═Y8)f or a covalent bond;
- and f can be 0, 1 or 2;
- or
- B1—W1, B2—W2, and/or B3—W3 are independently CR3═CR9 or C≡C;
- and
- X1, X2 and X3 are independently hydrogen, CR18R19R20, C═R21R22, C≡R23, C≡N, C(═Y9)R24, OR25, NR26R27, N═NR28, P(═Y10)d(R29)V, S(═Y11)d(R30)i or NO2;
- and d can be 0, 1 or 2;
- and v can be 0, 1 or 2;
- and i can be independently 0 or 1;
- and
- Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10 and Y11 are independently O, S or NZ;
- and Z can be independently hydrogen, R13, OR14, SR15 or NR16R17;
- and
- R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31 and R32 are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, alkaryl, arylalkyl, heterocyclic, heteroaromatic, acyl, aldehyde, carbamide, alkoxy, amino, halogen, silyl, thiol, sulfoxy, sulfinyl, sulfamoyl, hydroxyl, ester, carboxylic acid, amide, nitro, cyano, phosphonyl, phosphinyl, phosphoryl, imide, thioester, ether, acid halide, oxime, carbamate, thioether, residue of a natural or synthetic amino acid or a carbohydrate, any of which can be optionally attached to the targeting moiety or oxygen radical through a spacer group;
- or alternatively,
- R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31 and R32 can individually come together to form a bridged compound comprising of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, alkaryl, aryl alkyl, heterocyclic, heteroaromatic, acyl, carbamide, alkoxy, amino, halogen, silyl, thiol, sulfinyl, sulfamoyl, ester, amide, phosphonyl, phosphinyl, phosphoryl, imide, thioester, ether, oxime, carbamate, thioether, residue of a natural or synthetic amino acid or a carbohydrate, any of which can be optionally attached to the targeting moiety or oxygen radical through a spacer group;
- and
- each carbon atom cannot be covalently bound to more than two heteroatoms;
- and wherein B, W and X cannot be all heteroatom moieties unless B, W and X are all nitrogen based or B and X are independently O or N and W is PR11, POR12, PO2, S(Y4)m and m is 1 or 2;
- and
- wherein B and W or W and X cannot both be of the general formula C(Y), POR12, PO2, S(═Y4)t and t is 1 or 2;
- optionally in a pharmaceutically acceptable carrier.
23 more elements
A method for treatment of a host infected with a Flaviviridae virus comprising administering an effective amount of an andrographolide or its derivative of the formula:
- or its cis isomer, or its pharmaceutically acceptable salt, ester, salt of an ester or prodrug;
- wherein:
- B1, B2 and B3 are independently CR1R2, C(Y1), O, NR4, PR5, P(═Y2)R6, P(═Y3)2, S(═Y4)k, a spacer group or a covalent bond;
- and k can be 0, 1 or 2;
- and
- W1, W2 and W3 are independently CR7R8, CR9, C, C(Y5), O, NR10, PR11, P(═Y6)R12, P(═Y7)2, S(═Y8)f or a covalent bond;
- and f can be 0, 1 or 2;
- or
- B1—W1, B2—W2, and/or B3—W3 are independently CR3═CR9 or C≡C;
- and
- X1, X2 and X3 are independently hydrogen, CR18R19R20, C═R21R22, C≡R23, C≡N, C(═Y9)R24, OR25, NR26R27, N═NR28, P(═Y10)d(R29)V, S(═Y11)d(R30)i or NO2;
- and d can be 0, 1 or 2;
- and v can be 0, 1 or 2;
- and i can be independently 0 or 1;
- and
- Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10 and Y11 are independently O, S or NZ;
- and Z can be independently hydrogen, R13, OR14, SR15 or NR16R17;
- and
- R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31 and R32 are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, alkaryl, arylalkyl, heterocyclic, heteroaromatic, acyl, aldehyde, carbamide, alkoxy, amino, halogen, silyl, thiol, sulfoxy, sulfinyl, sulfamoyl, hydroxyl, ester, carboxylic acid, amide, nitro, cyano, phosphonyl, phosphinyl, phosphoryl, imide, thioester, ether, acid halide, oxime, carbamate, thioether, residue of a natural or synthetic amino acid or a carbohydrate, any of which can be optionally attached to the targeting moiety or oxygen radical through a spacer group;
- or alternatively,
- R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31 and R32 can individually come together to form a bridged compound comprising of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, alkaryl, aryl alkyl, heterocyclic, heteroaromatic, acyl, carbamide, alkoxy, amino, halogen, silyl, thiol, sulfinyl, sulfamoyl, ester, amide, phosphonyl, phosphinyl, phosphoryl, imide, thioester, ether, oxime, carbamate, thioether, residue of a natural or synthetic amino acid or a carbohydrate, any of which can be optionally attached to the targeting moiety or oxygen radical through a spacer group;
- and
- each carbon atom cannot be covalently bound to more than two heteroatoms;
- and wherein B, W and X cannot be all heteroatom moieties unless B, W and X are all nitrogen based or B and X are independently O or N and W is PR11, POR12, PO2, S(Y4)m and m is 1 or 2;
- and
- wherein B and W or W and X cannot both be of the general formula C(Y), POR12, PO2, S(═Y4)t and t is 1 or 2;
- optionally in a pharmaceutically acceptable carrier.
24 more elements
A method for treatment of a host infected with a Flaviviridae virus comprising administering an effective amount of a derivative or andrographolide of the formula:
- or its cis isomer, or its pharmaceutically acceptable salt, ester, salt of an ester or prodrug;
- wherein
- B1, B2 and B3 are independently CR1R2, C(Y1), O, NR4, PR5, P(═Y2)R6, P(═Y3)2, S(═Y4)k, a spacer group or a covalent bond;
- and k can be 0, 1 or 2;
- and
- W1, W2 and W3 are independently CR7R8, CR9, C, C(Y5), O, NR10, PR11, P(═Y6)R12, P(═Y7)2, S(═Y8)f or a covalent bond;
- and f can be 0, 1 or 2;
- or
- B1—W1, B2—W2, and/or B3—W3 are independently CR3═CR9 or C≡C;
- and
- X1, X2 and X3 are independently hydrogen, CR18R19R20, C═R21R22, C≡R23, C≡N, C(═Y9)R24, OR25, NR26R27, N═NR28, P(═Y10)d(R29)V, S(═Y11)d(R30)i or NO2;
- and d can be 0, 1 or 2;
- and v can be 0, 1 or 2;
- and i can be independently 0 or 1;
- and
- Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10 and Y11 are independently O, S or NZ;
- and Z can be independently hydrogen, R13, OR14, SR15 or NR16R17;
- and
- R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31 and R32 are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, alkaryl, arylalkyl, heterocyclic, heteroaromatic, acyl, aldehyde, carbamide, alkoxy, amino, halogen, silyl, thiol, sulfoxy, sulfinyl, sulfamoyl, hydroxyl, ester, carboxylic acid, amide, nitro, cyano, phosphonyl, phosphinyl, phosphoryl, imide, thioester, ether, acid halide, oxime, carbamate, thioether, residue of a natural or synthetic amino acid or a carbohydrate, any of which can be optionally attached to the targeting moiety or oxygen radical through a spacer group;
- or alternatively,
- R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31 and R32 can individually come together to form a bridged compound comprising of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, alkaryl, aryl alkyl, heterocyclic, heteroaromatic, acyl, carbamide, alkoxy, amino, halogen, silyl, thiol, sulfinyl, sulfamoyl, ester, amide, phosphonyl, phosphinyl, phosphoryl, imide, thioester, ether, oxime, carbamate, thioether, residue of a natural or synthetic amino acid or a carbohydrate, any of which can be optionally attached to the targeting moiety or oxygen radical through a spacer group;
- and
- each carbon atom cannot be covalently bound to more than two heteroatoms;
- and wherein B, W and X cannot be all heteroatom moieties unless B, W and X are all nitrogen based or B and X are independently O or N and W is PR11, POR12, PO2, S(Y4)m and m is 1 or 2;
- and
- wherein B and W or W and X cannot both be of the general formula C(Y), POR12, PO2, S(═Y4)t and t is 1 or 2;
- optionally in a pharmaceutically acceptable carrier.
24 more elements
A pharmaceutical composition comprising an an andrographolide derivative of the formula:
- or its cis isomer, or its pharmaceutically acceptable salt, ester, salt of an ester or prodrug, wherein:
- B1, B2 and B3 are independently CR1R2, C(Y1), O, NR4, PR5, P(═Y2)R6, P(═Y3)2, S(═Y4)k, a spacer group or a covalent bond;
- and k can be 0, 1 or 2;
- and
- W1, W2 and W3 are independently CR7R8, CR9, C, C(Y5), O, NR10, PR11, P(═Y6)R12, P(═Y7)2, S(═Y8)f or a covalent bond;
- and f can be 0, 1 or 2;
- or
- B1—W1, B2—W2, and/or B3—W3 are independently CR3═CR9 or C≡C;
- and
- X1, X2 and X3 are independently hydrogen, CR18R19R20, C═R21R22, C≡R23, C≡N, C(═Y9)R24, OR25, NR26R27, N═NR28, P(═Y10)d(R29)V, S(═Y11)d(R30)i or NO2;
- and d can be 0, 1 or 2;
- and v can be 0, 1 or 2;
- and i can be independently 0 or 1;
- and
- Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10 and Y11 are independently O, S or NZ;
- and Z can be independently hydrogen, R13, OR14, SR15 or NR16R17;
- and
- R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31 and R32 are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, alkaryl, arylalkyl, heterocyclic, heteroaromatic, acyl, aldehyde, carbamide, alkoxy, amino, halogen, silyl, thiol, sulfoxy, sulfinyl, sulfamoyl, hydroxyl, ester, carboxylic acid, amide, nitro, cyano, phosphonyl, phosphinyl, phosphoryl, imide, thioester, ether, acid halide, oxime, carbamate, thioether, residue of a natural or synthetic amino acid or a carbohydrate, any of which can be optionally attached to the targeting moiety or oxygen radical through a spacer group;
- or alternatively,
- R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31 and R32 can individually come together to form a bridged compound comprising of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, alkaryl, aryl alkyl, heterocyclic, heteroaromatic, acyl, carbamide, alkoxy, amino, halogen, silyl, thiol, sulfinyl, sulfamoyl, ester, amide, phosphonyl, phosphinyl, phosphoryl, imide, thioester, ether, oxime, carbamate, thioether, residue of a natural or synthetic amino acid or a carbohydrate, any of which can be optionally attached to the targeting moiety or oxygen radical through a spacer group;
- and
- each carbon atom cannot be covalently bound to more than two heteroatoms;
- and wherein B, W and X cannot be all heteroatom moieties unless B, W and X are all nitrogen based or B and X are independently O or N and W is PR11, POR12, PO2, S(═Y4)m and m is 1 or 2;
- and
- wherein B and W or W and X cannot both be of the general formula C(Y), POR12, PO2, S(═Y4)t and t is 1 or 2;
- optionally in a pharmaceutically acceptable carrier, in combination with at least a second antiviral agent.
23 more elements
A pharmaceutical composition comprising an an andrographolide derivative of the formula:
- or its cis isomer, or its pharmaceutically acceptable salt, ester, salt of an ester or prodrug;
- wherein:
- B1, B2 and B3 are independently CR1R2, C(Y1), O, NR4, PR5, P(═Y2)R6, P(═Y3)2, S(═Y4)k, a spacer group or a covalent bond;
- and k can be 0, 1 or 2;
- and
- W1, W2 and W3 are independently CR7R8, CR9, C, C(Y5), O, NR10, PR11, P(═Y6)R12, P(═Y7)2, S(═Y8)f or a covalent bond;
- and f can be 0, 1 or 2;
- or
- B1—W1, B2—W2, and/or B3—W3 are independently CR3═CR9 or C≡C;
- and
- X1, X2 and X3 are independently hydrogen, CR18R19R20, C═R21R22, C≡R23, C≡N, C(═Y9)R24, OR25, NR26R27, N═NR28, P(═Y10)d(R29)V, S(═Y11)d(R30)i or NO2;
- and d can be 0, 1 or 2;
- and v can be 0, 1 or 2;
- and i can be independently 0 or 1;
- and
- Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10 and Y11 are independently O, S or NZ;
- and Z can be independently hydrogen, R13, OR14, SR15 or NR16R17;
- and
- R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31 and R32 are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, alkaryl, arylalkyl, heterocyclic, heteroaromatic, acyl, aldehyde, carbamide, alkoxy, amino, halogen, silyl, thiol, sulfoxy, sulfinyl, sulfamoyl, hydroxyl, ester, carboxylic acid, amide, nitro, cyano, phosphonyl, phosphinyl, phosphoryl, imide, thioester, ether, acid halide, oxime, carbamate, thioether, residue of a natural or synthetic amino acid or a carbohydrate, any of which can be optionally attached to the targeting moiety or oxygen radical through a spacer group;
- or alternatively,
- R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31 and R32 can individually come together to form a bridged compound comprising of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, alkaryl, aryl alkyl, heterocyclic, heteroaromatic, acyl, carbamide, alkoxy, amino, halogen, silyl, thiol, sulfinyl, sulfamoyl, ester, amide, phosphonyl, phosphinyl, phosphoryl, imide, thioester, ether, oxime, carbamate, thioether, residue of a natural or synthetic amino acid or a carbohydrate, any of which can be optionally attached to the targeting moiety or oxygen radical through a spacer group;
- and
- each carbon atom cannot be covalently bound to more than two heteroatoms;
- and wherein B, W and X cannot be all heteroatom moieties unless B, W and X are all nitrogen based or B and X are independently O or N and W is PR11, POR12, PO2, S(Y4)m and m is 1 or 2;
- and
- wherein B and W or W and X cannot both be of the general formula C(Y), POR12, PO2, S(═Y4)t and t is 1 or 2;
- optionally in a pharmaceutically acceptable carrier, in combination with at least a second antiviral agent.
24 more elements
A pharmaceutical composition comprising an an andrographolide derivative of the formula:
- or its cis isomer, or its pharmaceutically acceptable salt, ester, salt of an ester or prodrug;
- wherein
- B1, B2 and B3 are independently CR1R2, C(Y1), O, NR4, PR5, P(═Y2)R6, P(═Y3)2, S(═Y4)k, a spacer group or a covalent bond;
- and k can be 0, 1 or 2;
- and
- W1, W2 and W3 are independently CR7R8, CR9, C, C(Y5), O, NR10, PR11, P(═Y6)R12, P(═Y7)2, S(═Y8)f or a covalent bond;
- and f can be 0, 1 or 2;
- or
- B1—W1, B2—W2, and/or B3—W3 are independently CR3═CR9 or C≡C;
- and
- X1, X2 and X3 are independently hydrogen, CR18R19R20, C═R21R22, C≡R23, C≡N, C(═Y9)R24, OR25, NR26R27, N═NR28, P(═Y10)d(R29)V, S(═Y11)d(R30)i or NO2;
- and d can be 0, 1 or 2;
- and v can be 0, 1 or 2;
- and i can be independently 0 or 1;
- and
- Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10 and Y11 are independently O, S or NZ;
- and Z can be independently hydrogen, R13, OR14, SR15 or NR16R17;
- and
- R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31 and R32 are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, alkaryl, arylalkyl, heterocyclic, heteroaromatic, acyl, aldehyde, carbamide, alkoxy, amino, halogen, silyl, thiol, sulfoxy, sulfinyl, sulfamoyl, hydroxyl, ester, carboxylic acid, amide, nitro, cyano, phosphonyl, phosphinyl, phosphoryl, imide, thioester, ether, acid halide, oxime, carbamate, thioether, residue of a natural or synthetic amino acid or a carbohydrate, any of which can be optionally attached to the targeting moiety or oxygen radical through a spacer group;
- or alternatively,
- R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31 and R32 can individually come together to form a bridged compound comprising of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, alkaryl, aryl alkyl, heterocyclic, heteroaromatic, acyl, carbamide, alkoxy, amino, halogen, silyl, thiol, sulfinyl, sulfamoyl, ester, amide, phosphonyl, phosphinyl, phosphoryl, imide, thioester, ether, oxime, carbamate, thioether, residue of a natural or synthetic amino acid or a carbohydrate, any of which can be optionally attached to the targeting moiety or oxygen radical through a spacer group;
- and
- each carbon atom cannot be covalently bound to more than two heteroatoms;
- and wherein B, W and X cannot be all heteroatom moieties unless B, W and X are all nitrogen based or B and X are independently O or N and W is PR11, POR12, PO2, S(Y4)m and m is 1 or 2;
- and
- wherein B and W or W and X cannot both be of the general formula C(Y), POR12, PO2, S(═Y4)t and t is 1 or 2;
- optionally in a pharmaceutically acceptable carrier, in combination with at least a second antiviral agent.
24 more elements
Dependencies are inferred from the claim text.