Pyridazine compounds, compositions and methods
The invention relates to novel chemical compounds, compositions and methods of making and using the same. In particular, the invention provides pyridazine compounds and/or related heterocyclic derivatives, compositions comprising the same, and methods of making and using pyridazine compounds and/or related heterocyclic derivatives and compositions comprising the same, for modulation of cellular pathways (e.g., signal transduction pathways), for treatment or prevention of inflammatory diseases (e.g., Alzheimer's disease), for research, drug screening, and therapeutic applications.
1. A compound of Formula Ib:
wherein:
R 1 is a substituted amino group;
R 2 is cycloalkyl, cycloalkenyl, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl, heterocyclic, acyl, acyloxy, sulfonyl, sulfinyl, sulfenyl, amino, imino, azido, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, ureido, cyano, halo, silyl, silyloxy, silylalkyl, silylthio, carboxyl, carbonyl, carbamoyl, or carboxamide,
wherein heteroaryl is a fully unsaturated heteroatom-containing ring-shaped aromatic radical having one, two or three rings attached in a pendant manner or fused, having 5 or 6 members in each ring and having at least one heteroatom selected from carbon, nitrogen, sulfur and oxygen, and heterocyclic is a saturated or partially saturated heteroatom-containing ring-shaped radical having one, two or three rings attached in a pendant manner or fused, having 3 to 6 members in each ring and having at least one heteroatom selected from carbon, nitrogen, sulfur and oxygen, and each of heteroaryl and heterocyclic is optionally substituted by halogen, hydroxy, thio, nitro, amino, ketone, aldehyde, ester, amide, alkyl, aryl, or cycloalkyl,
R 3 is hydrogen, and
R 4 , R 5 and R 6 are independently hydrogen, alkyl, alkoxy, halo or nitro;
or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
3. A compound according to claim 1 , wherein the substituted amino group for R 1 has the formula —NR21R22, where R21 and R22 are any combination of hydrogen, hydroxyl, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, carbonyl, carboxyl, amino, silyl, heteroaryl or heterocyclic, each of which are optionally substituted, provided that R21 and R22 are not both hydrogen.
4. A compound according to claim 1 , wherein the substituted amino group for R 1 is methylamino, ethylamino, dimethylamino, 2-propylamino, butylamino, isobutylamino, cyclopropylamino, benzylamino, allylamino, hydroxylamino, cyclohexylamino, piperidinyl, hydrazinyl, diphenylmethylamino, tritylamino, trimethylsilylamino or dimethyl-tert.-butylsilylamino, each of which are optionally substituted.
5. A compound according to claim 1 , wherein R 2 is pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl or tetrazolyl.
6. A compound according to claim 1 , wherein the compound is one of the following two compounds:
or a pharmaceutically acceptable salt thereof.
7. A compound according to claim 1 , wherein R 2 is pyridinyl.
8. A method for reducing neuroinflammation to treat a disease or condition which presents neuroinflammation in a subject, comprising administering to the subject a compound of claim 1 .
9. A method for reducing neuroinflammation to treat a disease or condition which presents neuroinflammation in a subject, comprising administering to the subject a compound of claim 2 .
10. The method of claim 8 , wherein progression of said disease or condition is ameliorated or progresses to a less severe stage.
11. The method of claim 8 , wherein said compound reduces neuroinflammation associated with any one of traumatic brain injury, intracerebral hemorrhage, or Alzheimer's disease.
12. The method of claim 8 , wherein said compound decreases neuroinflammation by acting on one or more of cell signaling molecule production, activation of glia or glial activation pathways and responses, proinflammatory cytokines or chemokines, oxidative stress-related responses, acute phase proteins, components of the complement cascade, protein kinase activity, cell damage and cell death signal transduction pathways.
13. The method of claim 8 , wherein said disease includes mild cognitive impairment (MCI).
14. The method of claim 8 , further comprising: administering a pharmaceutically acceptable carrier, excipient, or vehicle to said subject and wherein kinase activity, glial activation, neuronal cell damage, and/or neuronal cell death is reduced or inhibited.
15. The method of claim 8 , wherein the progression of said disease is delayed.
16. The method of claim 8 , wherein the disease or condition treated is Alzheimer's disease, intracerebral hemorrhage or traumatic brain injury, which disease or condition presents neuroinflammation.
17. The method of claim 8 , wherein the compound inhibits pro-inflammatory cytokines or chemokines.
18. The method of claim 8 , wherein the compound inhibits IL-1β, TNF-α and/or S100β.
19. The method of claim 9 , wherein the disease or condition treated is Alzheimer's disease, intracerebral hemorrhage or traumatic brain injury, which disease or condition presents neuroinflammation and/or wherein the compound reduces neuroinflammation associated with any one of traumatic brain injury, intracerebral hemorrhage, or Alzheimer's disease.
20. A method for reducing neuroinflammation to treat a disease or condition which presents neuroinflammation in a subject, comprising administering to the subject a compound of claim 6 .
21. The method of claim 20 , wherein the disease or condition treated is Alzheimer's disease, intracerebral hemorrhage or traumatic brain injury, which disease or condition presents neuroinflammation and/or wherein the compound reduces neuroinflammation associated with any one of traumatic brain injury, intracerebral hemorrhage, or Alzheimer's disease.