IPC분류정보
국가/구분 |
United States(US) Patent
등록
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국제특허분류(IPC7판) |
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출원번호 |
US-0941530
(2010-11-08)
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등록번호 |
US-8614253
(2013-12-24)
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발명자
/ 주소 |
- Patterson, John Bruce
- Lonergan, David Gregory
- Flynn, Gary A.
- Zeng, Qingping
- Pallai, Peter V.
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출원인 / 주소 |
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대리인 / 주소 |
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인용정보 |
피인용 횟수 :
6 인용 특허 :
90 |
초록
Compounds which directly inhibit IRE-1α activity in vitro, prodrugs, and pharmaceutically acceptable salts thereof. Such compounds and prodrugs are useful for treating diseases associated with the unfolded protein response and can be used as single agents or in combination therapies.
대표청구항
▼
1. A method of inhibiting IRE-1α activity, comprising contacting IRE-1α with a compound represented by structural formula (I): wherein: the OH substituent is located ortho to the aldehyde substituent;Q is an aromatic isocyclic or heterocyclic ring system selected from benzene, naphthalene, pyridine
1. A method of inhibiting IRE-1α activity, comprising contacting IRE-1α with a compound represented by structural formula (I): wherein: the OH substituent is located ortho to the aldehyde substituent;Q is an aromatic isocyclic or heterocyclic ring system selected from benzene, naphthalene, pyridine, pyridine N-oxide, thiophene, benzo[b]thiophene, benzo[c]thiophene, furan, pyrrole, pyridazine, pyrmidine, pyrazine, triazine, isoxazoline, oxazoline, thiazoline, pyrazoline, imidazoline, fluorenyl, biphenyl, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, benzofuran, indole, isoindole, isobenzofuran, benzimidazole, 1,2-benzisoxazole, and carbazole;RX and Rz can be present or absent and are independently selected from hydrogen, aryl, heterocyclic, -A″Ra, —OH, —OA″Ra, —NO2, —NH2, —NHA″Ra, —N(A″Ra)(A′″Rb), —NHCOA″Ra, —NHCOOA″Ra, —NHCONH2, —NHCONHA″Ra, —NHCON(A″Ra)(A′″Rb), halogen, —COOH, —COOA″Ra, —CONH2, —CONHA″Ra, —CON(A″Ra)(A′″Rb), and Rycan be present or absent and is selected from hydrogen, aryl, heterocyclic, -A″Ra, —OA″Ra, —NO2, —NH2, —NHA″Ra, —N(A″Ra)(A′″Rb), —NHCOA″Ra, —NHCOOA″Ra, —NHCONH2, —NHCONHA″Ra, —NHCON(A″Ra)(A′″Rb), halogen, —COOH, —COOA″Ra, —CONH2, —CONHA″Ra, —CON(A″Ra)(A″′Rb), and Ra is hydrogen, —COOH, —COOA, —CONH2, —CONHA, —CONAA′, —NH2, —NHA, —NAA′, —NCOA, —NCOOA, or —OA;Rb is hydrogen, —COOH, —COOA, —CONH2, —CONHA, —CONAA′, —NH2, —NHA, —NAA′, —NCOA, —NCOOA, —OH, or —OA;Y is C1-C10 alkylene or C2-C8 alkenylene, in which (a) one, two or three CH2 groups may be replaced by O, S, SO, SO2, NH, or NRc and/or (b) 1-7 H atoms may be independently replaced by F or Cl;A and A′ are: (a) independently C1-C10 alkyl or C2-C8 alkenyl, in which (i) one, two or three CH2 groups may be replaced by O, S, SO, SO2, NH, or NRc and/or (ii) 1-7 H atoms may be independently replaced by F or Cl, aryl or heterocyclic; or(b) A and A′ together are alternatively C2-C7 alkylene, in which one, two or three CH2 groups may be replaced by O, S, SO, SO2, NH, NRc, NCORc or NCOORc, to form, for example, an alkylenedioxy group;A″, A′″ are independently (a) absent, (b) C1-C10 alkylene, C2-C8 alkenylene, or C3-C7 cycloalkyl in which one, two or three CH2 groups may be replaced by O, S, SO, SO2, NH or NRc and/or 1-7 H atoms may be replaced by F and/or Cl; or (c) together are C2-C7 alkyl in which one, two or three CH2 groups may be replaced by O, S, SO, SO2, NH, NRc, NCORc or NCOORc,Rc is C1-C10 alkyl, C3-C7 cycloalkyl, C4-C8 alkylenecycloalkyl, or C2-C8 alkenyl in which one, two or three CH2 groups may be replaced by O, S, SO, SO2, NH, NMe, NEt and/or by —CH═CH— groups, 1-7 H atoms may be replaced by F and/or Cl, and/or 1 H atom may be replaced by Ra;aryl is phenyl, benzyl, naphthyl, fluorenyl or biphenyl, each of which is unsubstituted or monosubstituted, disubstituted or trisubstituted by halogen, —CF3, —Rf, —ORd, —N(Rd)2, —NO2, —CN, —COORd, CON(Rd)2, —NRdCORe, —NRdCON(Re)2, —NRdSO2A, —CORd, —SO2N(Rd)2, —S(O)mRf, AA′ together, or —O(aryl),Rd and Re are independently H or C1-C6 alkyl;Rf is C1-C6 alkyl;heterocyclic is a monocyclic or bicyclic saturated, unsaturated or aromatic heterocyclic ring having 1 to 2 N, O and/or S atoms, which may be unsubstituted or monosubstituted or disubstituted by carbonyl oxygen, halogen, Rf, —ORd, —N(Rd)2, —NO2, —CN, —COORd, —CON(Rd)2, —NRdCORe, —NRdCON(Re)2, —NRfSO2Re, —CORd, —SO2NRd and/or —S(O)mRf; and m is 0, 1 or 2,provided that the compound is not salicylaldehyde. 2. The method of claim 1 wherein the IRE-1α is in a cell. 3. The method of claim 1 wherein the cell has an activated unfolded protein response. 4. The method of claim 2 wherein the cell is a cancer cell. 5. The method of claim 2 wherein the cell is a myeloma cell. 6. The method of claim 2 wherein inhibition of the IRE-1α activity inhibits cell proliferation. 7. The method of claim 2 wherein inhibition of the IRE-1α activity induces apoptosis. 8. The method of claim 2 further comprising contacting the cell with an agent that induces or up-regulates IRE-1α expression. 9. The method of claim 2 further comprising contacting the cell with a biotherapeutic agent, a chemotherapeutic agent, or radiation. 10. The method of claim 2 further comprising contacting the cell with a proteasome inhibitor. 11. The method of claim 1 wherein the compound is provided in the form of a pharmaceutically acceptable salt. 12. A method of inhibiting IRE-1α activity, comprising contacting IRE-1α with a compound represented by structural formula (B): wherein: R1 and R2 independently are hydrogen, phenyl or an optionally benzofused five- or six-membered heterocycle, wherein the phenyl or the optionally benzofused five- or six-membered heterocycle is optionally substituted with —CH2OH, —CHO, —OCH3, halogen, —OH, —CH3, and either:(1) R3 is hydrogen, halogen, —NO2, C1-C3 linear or branched alkyl, C1-C3 linear or branched alkoxy, C1-C3 linear or branched hydroxyl alkyl, and R4 is or(2) R3 is halogen, —NO2, C1-C3 linear or branched alkyl, C1-C3 linear or branched alkoxy, C1-C3 linear or branched hydroxyl alkyl, and R4 is hydrogen, wherein the IRE-1α is in a cell. 13. A method of inhibiting IRE-1α activity, comprising contacting IRE-1α with a compound represented by structural formula (A): wherein: R1 is hydrogen, halogen, or a 5- or 6-membered heterocyclic containing one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur;R2 is hydrogen, phenyl, or a 5- or 6-membered heterocyclic containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heterocyclic is optionally benzofused and wherein the heterocyclic is optionally substituted by 1, 2, or 3 substituents independently selected from C1-C3 linear or branched alkyl, C1-C3 phenylalkyl, C1-C3 alkoxyphenylalkyl, R3 is hydrogen, halogen, —NO2, C1-C3 linear or branched alkoxy, C1-C3 linear or branched hydroxyl alkyl, andQ is a five- or six-membered heterocycle, provided that structural formula (A) does not encompass salicylaldehyde. 14. A method of inhibiting IRE-1α activity, comprising contacting IRE-1α with a compound represented by structural formula (C): wherein: R1 and R2 are independently hydrogen, —CH3, or —OH; andthe hydroxy substitutent in ring A is located ortho to the aldehyde substituent. 15. A method of inhibiting IRE-1α activity, comprising contacting IRE-1α with a compound represented by structural formula (D): wherein R1 is hydrogen, halogen, —NO2, C1-C3 linear or branched alkyl, C1-C3 linear or branched alkoxy, C1-C3 linear or branched hydroxyl alkyl, 16. The method of claim 12, wherein the cell has an activated unfolded protein response. 17. The method of claim 12, wherein the cell is a cancer cell. 18. The method of claim 12, wherein the cell is a myeloma cell. 19. The method of claim 12, wherein inhibition of the IRE-1α activity inhibits cell proliferation. 20. The method of claim 12, wherein inhibition of the IRE-1α activity induces apoptosis. 21. The method of claim 13, further comprising contacting the cell with an agent that induces or up-regulates IRE-1α expression. 22. The method of claim 12, further comprising contacting the cell with a biotherapeutic agent, a chemotherapeutic agent, or radiation. 23. The method of claim 12 further comprising contacting the cell with a proteasome inhibitor. 24. The method of claim 12 wherein the compound is provided in the form of a pharmaceutically acceptable salt. 25. The method of claim 13, wherein the IRE-1α is in a cell. 26. The method of claim 25, wherein the cell has an activated unfolded protein response. 27. The method of claim 25, wherein the cell is a cancer cell. 28. The method of claim 25, wherein the cell is a myeloma cell. 29. The method of claim 25, wherein inhibition of the IRE-1α activity inhibits cell proliferation. 30. The method of claim 25, wherein inhibition of the IRE-1α activity induces apoptosis. 31. The method of claim 25, further comprising contacting the cell with an agent that induces or up-regulates IRE-1α expression. 32. The method of claim 25, further comprising contacting the cell with a biotherapeutic agent, a chemotherapeutic agent, or radiation. 33. The method of claim 25, further comprising contacting the cell with a proteasome inhibitor. 34. The method of claim 25 wherein the compound is provided in the form of a pharmaceutically acceptable salt. 35. The method of claim 14, wherein the IRE-1α is in a cell. 36. The method of claim 35, wherein the cell has an activated unfolded protein response. 37. The method of claim 35, wherein the cell is a cancer cell. 38. The method of claim 35, wherein the cell is a myeloma cell. 39. The method of claim 35, wherein inhibition of the IRE-1α activity inhibits cell proliferation. 40. The method of claim 35, wherein inhibition of the IRE-1α activity induces apoptosis. 41. The method of claim 35, further comprising contacting the cell with an agent that induces or up-regulates IRE-1α expression. 42. The method of claim 35, further comprising contacting the cell with a biotherapeutic agent, a chemotherapeutic agent, or radiation. 43. The method of claim 35, further comprising contacting the cell with a proteasome inhibitor. 44. The method of claim 35, wherein the compound is provided in the form of a pharmaceutically acceptable salt. 45. The method of claim 15, wherein the IRE-1α is in a cell. 46. The method of claim 45, wherein the cell has an activated unfolded protein response. 47. The method of claim 45, wherein the cell is a cancer cell. 48. The method of claim 45, wherein the cell is a myeloma cell. 49. The method of claim 45, wherein inhibition of the IRE-1α activity inhibits cell proliferation. 50. The method of claim 45, wherein inhibition of the IRE-1α activity induces apoptosis. 51. The method of claim 45, further comprising contacting the cell with an agent that induces or up-regulates IRE-1α expression. 52. The method of claim 45, further comprising contacting the cell with a biotherapeutic agent, a chemotherapeutic agent, or radiation. 53. The method of claim 45, further comprising contacting the cell with a proteasome inhibitor. 54. The method of claim 45, wherein the compound is provided in the form of a pharmaceutically acceptable salt. 55. A method of inhibiting IRE-1α activity, comprising contacting IRE-1α with a compound represented by structural formula (B): wherein: R1 and R2 independently are hydrogen, phenyl or an optionally benzofused five- or six-membered heterocycle, wherein the phenyl or the optionally benzofused five- or six-membered heterocycle is optionally substituted with —CH2OH, —CHO, —OCH3, halogen, —OH, —CH3, R3 is halogen, —NO2, C2-C3 linear or branched alkyl, C2-C3 linear or branched alkoxy, C1-C3 linear or branched hydroxyl alkyl, andR4 is hydrogen, 56. The method of claim 55, wherein R3 is C3 alkyl or C3 alkoxy.
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