Modulators of Aldehyde Dehydrogenase and Methods of Use Thereof

• US 20140343045A1
• Filed: 05/23/2014
• Published: 11/20/2014
• Est. Priority Date: 10/28/2008
• Status: Active Grant

• Current Assignee: Board of Trustees of the Leland Stanford Junior University (Stanford Management Co.)
• Original Assignee: Board of Trustees of the Leland Stanford Junior University (Stanford Management Co.)
• Inventors: Mochly-Rosen, Daria, Chen, Che-Hong, Yang, Wenjin
• Granted Patent: US 9,370,506 B2
• Time in Patent Office: Days
• US Class Current: 514/217.03
• CPC Class Codes: A61K 31/4025 not condensed and containing further heterocyclic rings, e.g. cromakalim
• CPC Class Codes: A61K 31/4188 condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
• CPC Class Codes: A61K 31/422 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/4965 Non-condensed pyrazines
• CPC Class Codes: A61K 31/497 containing further heterocyclic rings
• CPC Class Codes: A61K 31/5025 ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/16 Emollients or protectives, e.g. against radiation
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/32 Alcohol-abuse
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/12 for cataracts
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 39/02 Antidotes
• CPC Class Codes: A61P 39/06 Free radical scavengers or antioxidants
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07C 233/29 : having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07D 241/18 : Oxygen or sulfur atoms
• CPC Class Codes: C07D 241/20 : Nitrogen atoms nitro radicals C07D241/16
• CPC Class Codes: C07D 261/08 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 261/14 : Nitrogen atoms
• CPC Class Codes: C07D 317/58 : Radicals substituted by nitrogen atoms nitro radicals C07D317/52
• CPC Class Codes: C07D 317/60 : 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
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 491/052 : the oxygen-containing ring being six-membered

Abstract

The present disclosure provides compounds that function as modulators of aldehyde dehydrogenase (ALDH) enzymatic activity, as well as compositions and formulations comprising the compounds. The present disclosure provides therapeutic methods involving administering a subject compound, or a subject pharmaceutical composition.

Claims

1. A compound of Formula I:

5. The compound of claim 1, wherein the compound is a compound of Formula Ia:

6. The compound of claim 5, wherein the compound has a structure selected from:

7. The compound of claim 1, wherein the compound is a compound of Formula Ib:

9. The compound of claim 1, wherein the compound is a compound of Formula Ic:

10. The compound of claim 9, wherein the compound is

11. The compound of claim 1, wherein the compound is a compound of Formula Id:

12. The compound of claim 11, wherein the compound has a structure selected from:

13. The compound of claim 1, wherein the compound is a compound of Formula Ie:

14. The compound of claim 13, wherein the compound has a structure selected from:

15. The compound of claim 1, wherein the compound is a compound of Formula If:

33. A pharmaceutical composition comprising:

a) a compound of claim 1; and

b) a pharmaceutically acceptable excipient.

44. A method of reducing a level of an aldehyde present at a toxic level in an individual to below the toxic level, the method comprising administering to the individual an effective amount of the composition of claim 33, wherein the aldehyde is a biogenic aldehyde or a xenogenic aldehyde.

47. A method of treating alcohol intolerance, alcohol addiction, or an alcohol abuse disorder, the method comprising administering to an individual who has alcohol intolerance, alcohol addiction, or an alcohol abuse disorder an effective amount of the composition of claim 33.

48. A method of treating an acute or a chronic free-radical associated disease in an individual in need thereof, the method comprising administering to the individual an effective amount of the pharmaceutical composition of claim 33.

51. A method of treating an ocular disorder in an individual, the method comprising administering to the individual an effective amount of the composition of claim 33.

54. A method of treating radiation-induced damage to epithelial cells in an individual, the method comprising administering to the individual a composition comprising an effective amount of the pharmaceutical composition of claim 33.

63. A method of reducing the likelihood that an individual will develop head and neck cancer, the method comprising administering to the individual a composition comprising an effective amount of the pharmaceutical composition of claim 33.

66. A method of treating cancer in an individual, the method comprising administering:

a) a composition comprising the pharmaceutical composition of claim 33; and

b) a cancer chemotherapeutic agent or ionizing radiation,

wherein the pharmaceutical composition and the cancer chemotherapeutic agent, or the pharmaceutical composition and the ionizing radiation, are administered in combined effective amounts to treat the cancer.

74. A method of reducing the likelihood that an individual will develop oral cancer or lung cancer, the method comprising administering to the individual an effective amount of the pharmaceutical composition of claim 33.

2-4. -4. (canceled)

8. (canceled)

16-32. -32. (canceled)

34-43. -43. (canceled)

45-46. -46. (canceled)

49-50. -50. (canceled)

52-53. -53. (canceled)

55-62. -62. (canceled)

64-65. -65. (canceled)

67-73. -73. (canceled)

75-76. -76. (canceled)