Methods and compositions for treating diseases associated with pathogenic proteins
OwnerPeter Chiang, Daniel Levy +3inventors
InventorsPeter Chiang, Daniel Levy, Meng Guo, Valeri Martichonok, Brian Sefton
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Abstract
Methods and compositions are provided comprising a therapeutically effective amount of a compound of formula I wherein R1-4, W, X, Y and Z are as defined in the specification, for inhibiting and treating diseases and disorders associated with pathogenic proteins causing neurodegenerative diseases and amyloid diseases, such as protease resistant prion proteins (PrPSc) and those associated with transmissible spongiform encephalopathies (TSEs), Alzheimer's Disease, amyloidosis, and the like.
Claims38
A method of treating an animal suffering from a disease or condition associated with pathogenic proteins, comprising administering to said mammal a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I
- wherein R1 is selected from the group consisting of H, Cl, Br, I, NO, NO2, CN, C1-C6 alkyl, L1-R18 or CF3;
- R2 is selected from the group consisting of H, Cl, Br, I, NO, NO2, CN, C1-C6 alkyl, L2-(C1-C6 alkyl) or CF3;
- R3 is selected from the group consisting of H, Cl, Br, I, NO, NO2, CN, C1-C6 alkyl, L3-(C1-C6 alkyl) or CF3;
- R4 is selected from the group consisting of H, Cl, Br, I, NO, NO2, CN, C1-C6 alkyl, L4-(C1-C6 alkyl), L4-aryl or CF3, and each aryl is optionally substituted with 0-3 groups independently selected from F, Cl, Br, I, OR29 NH2, CO2H, CF3, CN, C1-C6 alkyl;
- R5 is selected from the group consisting of H, L5-R32 or C(R7)2R28;
- R6 is selected from the group consisting of H, Cl, Br, I, C1-C6 alkyl, L6-R8, CF3 or aryl, and each aryl is optionally substituted with 0-3 groups independently selected from F, Cl, Br, I, OH, NH2, CO2H, CF3, CN, C1-C6 alkyl;
- R7 is independently selected from the group consisting of H, F, C1-C6 alkyl, OR9, SR10, S(═O)R11, S(═O)2R12 or NR13R14;
- R8 is selected from the group consisting of H or C1-C6 alkyl;
- R9 is selected from the group consisting of H or C1-C6 alkyl;
- R10 is selected from the group consisting of H or C1-C6 alkyl;
- R11 is C1-C6 alkyl;
- R12 is selected from the group consisting of OH, C1-C6 alkyl or O—(C1-C6 alkyl);
- R13 is selected from the group consisting of H, C1-C6 alkyl or (C═O)—(C1-C6 alkyl);
- R14 is selected from the group consisting of H, C1-C6 alkyl or (C═O)—(C1-C6 alkyl);
- R15 is selected from the group consisting of H, C1-C6 alkyl or (C═O)—(C1-C6 alkyl);
- R16 is selected from the group consisting of R6 or aryl, and each aryl is optionally substituted with 0-3 groups independently selected from F, Cl, Br, I, OH, NH2, CO2H, CF3, CN, C1-C6 alkyl;
- R17 is selected from the group consisting of H, C1-C6 alkyl or aryl, and each aryl is optionally substituted with 0-3 groups independently selected from F, Cl, Br, I, OH, NH2, CO2H, CF3, CN, C1-C6 alkyl;
- R18is H, C1-C6 alkyl or —(CH2)nCR19R20(CH2)o CR30R31(CH2)p—R21;
- R19 is selected from the group consisting of H, C1-C6 alkyl, OH or O—(C1-C6 alkyl);
- R20 is selected from the group consisting of H, C1-C6 alkyl, OH or O—(C1-C6 alkyl);
- R21 is selected from the group consisting of H, C(═NH)NH2, OR22, SR23, S(═O)R24, S(═O)2R25 or NR26R27;
- R22 is selected from the group consisting of H or C1-C6 alkyl;
- R23 is selected from the group consisting of H or C1-C6 alkyl;
- R24 is C1-C6 alkyl;
- R25 is selected from the group consisting of OH, C1-C6 alkyl or O—(C1-C6 alkyl);
- R26 is selected from the group consisting of H, (CH2)qOH, C(═NH)NH2, C1-C8 alkyl or (C═O)—(C1-C6 alkyl) where both R26 and R27 are not simultaneously OH and are not simultaneously C(═NH)NH2;
- R27 is selected from the group consisting of H, (CH2)rOH, C(═NH)NH2, C1-C8 alkyl or (C═O)—(C1-C6 alkyl) where both R26 and R27 are not simultaneously OH and are not simultaneously C(═NH)NH2;
- R28 is selected from the group consisting of H, F and a cyclic amine selected from the following
- where the attachment point is at any available carbon or nitrogen atom, and all available carbon or nitrogen atoms are optionally substituted with a group independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl and (C═O)—(C1-C6 alkyl), where no more than two substitutions are not H;
- R29 is selected from the group consisting of H and C1-C6 alkyl;
- R30 is selected from the group consisting of H and C1-C6 alkyl;
- R31 is selected from the group consisting of H and C1-C6 alkyl;
- R32 is either C1-C6 alkyl or (CH2)sR21;
- L1, L2, L3, L4, L5 and L6 are independently selected from the group consisting of O, S, S(═O), S(═O)2 and NR15;
- W is N or CR5;
- X is N or CR16;
- Y is N or CR6;
- Z is N or CR17;
- n is an integer from 0-10;
- o is an integer from 0-10;
- p is an integer from 0-10;
- n+o+p is an integer from 0-12;
- q is an integer from 0-4;
- r is an integer from 0-4;
- and
- s is either 0 or an integer from 2-6;
- and
- pharmaceutically acceptable salts, hydrates, and polymorphs thereof.
A composition for treating livestock having a disease or condition associated with pathogenic proteins, wherein said composition comprises:
- livestock feed;
- and a compound of formula I.
A method of treating a disease characterized by pathogenic protein formation, the method comprising administering a therapeutically effective amount of a compound of formula I.
A method of preventing disease in a mammal that has been exposed to a protease resistant prion protein, the method comprising administering to said mammal a therapeutically effective amount of a compound of formula I.
A method of preventing disease in an animal that is in danger of being exposed to a protease resistant prion protein, the method comprising administering to said animal a therapeutically effective amount of a compound of formula I.
A method of treating disease in an animal that is exhibiting signs, symptoms or laboratory evidence of a transmissible spongiform encephalopathy, the method comprising administering to said animal a therapeutically effective amount of a compound of formula I.
A method for reducing or retarding degeneration in a cell population of a tissue or organ subject to damage in an amyloid disease, comprising exposing the cell population to a therapeutically effective amount of a compound of formula I.
A method for reducing necrosis or apoptosis in a cell population of a tissue or organ subject to necrotic or apoptotic damage in an amyloid disease, comprising exposing the cell population to a therapeutically effective amount of a compound of formula I.
A method of blocking amyloid toxicity in cells, said method comprising contacting said cells with an effective amount of at least one compound of formula I.
A method for reducing or retarding neurodegeneration in a cell population comprising neurons which have been exposed to an amount of a stimulus sufficient to produce at least partially protease resistant proteins resulting in neurodegeneration, the method comprising:
- exposing the cell population to a therapeutically effective amount of a compound of formula I.
A method for inhibition of neuronal cell death in a cell population that is exposed to a protease resistant prion protein stimulus, the method comprising:
- administering a therapeutically effective amount of a compound of formula I to the cell population.
A method of treating a product derived from a human source to reduce the risk of transmission of an infectious pathogenic protein, the method comprising:
- combining a compound of formula I with said product.
A method for slowing, arresting, or reversing the development of a neurodegenerative disease in a human patient, the method comprising:
- administering a therapeutically effective amount of a compound of formula I to the patient to inhibit progression of the disease over a therapeutically effective period of time.
The kit of claim 32, wherein the kit further comprises an additional pharmaceutical composition comprising an active agent useful in treating the disease or disorder.
A pharmaceutical composition for treating a mammal suffering from a disease or condition associated with pathogenic proteins, comprising a therapeutically effective amount of a compound of formula I
- wherein R1 is selected from H, Cl, Br, I, NO, NO2, CN, C1-C6 alkyl, L1-R18 or CF3;
- R2 is selected from H, Cl, Br, I, NO, NO2, CN, C1-C6 alkyl, L2-(C1-C6 alkyl) or CF3;
- R3 is selected from H, Cl, Br, I, NO, NO2, CN, C1-C6 alkyl, L3-(C1-C6 alkyl) or CF3;
- R4 is selected from H, Cl, Br, I, NO, NO2, CN, C1-C6 alkyl, L4-(C1-C6 alkyl), L4-aryl or CF3, and each aryl is optionally substituted with 0-3 groups independently selected from F, Cl, Br, I, OR29 NH2, CO2H, CF3, CN, C1-C6 alkyl;
- R5 is selected from H, L5-R32 or C(R7)2R28;
- R6 is selected from H, Cl, Br, I, C1-C6 alkyl, L6-R8, CF3 or aryl, and each aryl is optionally substituted with 0-3 groups independently selected from F, Cl, Br, I, OH, NH2, CO2H, CF3, CN, C1-C6 alkyl;
- R7 is independently selected from H, F, C1-C6 alkyl, OR9, SR10, S(═O)R11, S(═O)2R12 or NR13R14;
- R8 is selected from H or C1-C6 alkyl;
- R9 is selected from H or C1-C6 alkyl;
- R10 is selected from H or C1-C6 alkyl;
- R11 is C1-C6 alkyl;
- R12 is selected from OH, C1-C6 alkyl or O—(C1-C6 alkyl);
- R13 is selected from H, C1-C6 alkyl or (C═O)—(C1-C6 alkyl);
- R14 is selected from H, C1-C6 alkyl or (C═O)—(C1-C6 alkyl);
- R15 is selected from H, C1-C6 alkyl or (C═O)—(C1-C6 alkyl);
- R16 is selected from R6 or aryl, and each aryl is optionally substituted with 0-3 groups independently selected from F, Cl, Br, I, OH, NH2, CO2H, CF3, CN, C1-C6 alkyl;
- R17 is selected from H, C1-C6 alkyl or aryl, and each aryl is optionally substituted with 0-3 groups independently selected from F. Cl, Br, I, OH, NH2, CO2H, CF3, CN, C1-C6 alkyl;
- R18 is H, C1-C6 alkyl or —(CH2)nCR19R20(CH2)o CR30R31(CH2)p—R21;
- R19 is selected from H, C1-C6 alkyl, OH or O—(C1-C6 alkyl);
- R20 is selected from H, C1-C6 alkyl, OH or O—(C1-C6 alkyl);
- R21 is selected from H, C(═NH)NH2, OR22, SR23, S(═O)R24, S(═O)2R25 or NR26R27.
- R22 is selected from H or C1-C6 alkyl;
- R23 is selected from H or C1-C6 alkyl;
- R24 is C1-C6 alkyl;
- R25 is selected from OH, C1-C6 alkyl or O—(C1-C6 alkyl);
- R26 is selected from H, (CH2)qOH, C(═NH)NH2, C1-C8 alkyl or (C═O)—(C1-C6 alkyl) where both R26 and R27 are not simultaneously OH and are not simultaneously C(═NH)NH2;
- R27 is selected from H, (CH2)rOH, C(═NH)NH2, C1-C8 alkyl or (C═O)—(C1-C6 alkyl) where both R26 and R27 are not simultaneously OH and are not simultaneously C(═NH)NH2;
- R28 is selected from H, F and a cyclic amine consisting of the following structures
- where the attachment point is at any available carbon or nitrogen atom, and all available carbon or nitrogen atoms are optionally substituted with a group independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl and (C═O)—(C1-C6 alkyl), where no more than two substitutions are not H;
- R29 is selected from H and C1-C6 alkyl;
- R30 is selected from H and C1-C6 alkyl;
- R31 is selected from H and C1-C6 alkyl;
- R32 is either C1-C6 alkyl or (CH2)sR21;
- L1, L2, L3, L4, L5 and L6 are independently selected from the group consisting of O, S, S(═O), S(═O)2 and NR15;
- W is N or CR5;
- X is N or CR16;
- Y is N or CR6;
- Z is N or CR17;
- n is an integer from 0-10;
- o is an integer from 0-10;
- p is an integer from 0-10;
- n+o+p is an integer from 0-12;
- q is an integer from 0-4;
- r is an integer from 0-4;
- and
- s is either 0 or an integer from 2-6;
- and
- pharmaceutically acceptable salts, hydrates, and polymorphs thereof;
- and optionally a pharmaceutically acceptable carrier.
Dependencies are inferred from the claim text.