COMPOUNDS, SCREENS, AND METHODS OF TREATMENT

• US 20100087453A1
• Filed: 10/09/2007
• Published: 04/08/2010
• Est. Priority Date: 10/10/2006
• Status: Abandoned Application

• Current Assignee: Shanghai Institute of Organic Chemistry Chinese Academy of Sciences (Chinese Academy of Sciences), President and Fellows of Harvard College (Harvard Corporation)
• Original Assignee: Shanghai Institute of Organic Chemistry Chinese Academy of Sciences (Chinese Academy of Sciences), President and Fellows of Harvard College (Harvard Corporation)
• Inventors: Yuan, Chengye, Yuan, Junying, Degterev, Alexei
• Application Number:
  US12/444,822
• Publication Number:
  US 20100087453A1
• Time in Patent Office: Days
• US Class Current: 514/260.100
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: C07D 495/04 Ortho-condensed systems

Abstract

The present invention features compounds of Formula (I), pharmaceutical compositions, methods of synthesis, and methods for treating diseases and conditions associated with cellular necrosis. Screening assays for identifying compounds useful for treating these conditions are also described.

Claims

1. A compound of Formula (I):

or a pharmaceutically acceptable salt or solvate thereof, wherein

Q is selected from the group consisting of —

S—

, —

S(O)—

, and —

S(O)₂—

;

R₁ is selected from the group consisting of C₁-C₉ alkyl, C₂-C₉ alkyenyl, C₂-C₉ alkynyl, C₆-C₁₂ aryl, and C₁-C₁₂ carbonyl;

R₂ is selected from the group consisting of C₁-C₉ alkaryl, and C₆-C₁₂ aryl; and

R₃ and R₄ are, independently, selected from the group consisting of C₁-C₉ alkyl, C₂-C₉ alkenyl, C₂-C₉ alkynyl, C₁-C₉ alkyloxy, and C₁-C₁₂ carbonyl, or R₃ and R₄, combined, form an C₃-C₉ carbocyclic, C₂-C₉ heterocyclic, C₆-C₁₂ aryl, or C₂-C₁₂ heteroaryl, ring system;

with the proviso that compounds wherein Q is —

S—

, R₁ is —

CH₂CN, R₂ is —

C₆H₄(4-OMe), and R₃ and R₄, combined, form an unsubstituted C₆-carbocyclic six-membered ring, are specifically excluded.

2. The compound of claim 1, said compound having the Formula (II):

wherein

R₅ is selected from the group consisting of H, C₁-C₉ alkyl, C₂-C₉ alkenyl, C₂-C₉ alkynyl, C₃-C₉ carbocyclyl, C₂-C₉ heterocyclyl, C₂-C₉ heteroaryl, C₆-C₁₂ aryl, C₁-C₉ alkyloxy, C₁-C₉ alkylthio, C₆-C₁₂ arylthio, C₁-C₉ hydroxyalkyl, C₁-C₉ alkyloxy, C₆-C₁₂ aryloxy, C_1-12 carbonyl, C₁-C₉ fluoroalkyl, C₁-C₉ perfluoroalkyl, halogen, —

SH, —

OH, —

N₃, —

NH₂, —

NO₂, and —

CN; and

n is 1, 2, 3, or 4;

or a pharmaceutically acceptable salt or solvate thereof.

3. The compound of claim 1, said compound having the Formula (III):

wherein

m is 1, 2 or 3;

or a pharmaceutically acceptable salt or solvate thereof.

4. The compound of claim 1, said compound having the Formula (IV):

wherein

R₆ is selected from the group consisting of H, C₁-C₉ alkyl, C₂-C₉ alkenyl, C₂-C₉ alkynyl, C₃-C₉ carbocyclyl, C₂-C₉ heterocyclyl, C₂-C₉ heteroaryl, C₆-C₁₂ aryl, C₁-C₉ alkyloxy, C₁-C₉ alkylthio, C₆-C₁₂ arylthio, C₁-C₉ hydroxyalkyl, C₁-C₉ alkyloxy, C₆-C₁₂ aryloxy, C_1-12 carbonyl, C₁-C₉ fluoroalkyl, C₁-C₉ perfluoroalkyl, halogen, —

SH, —

OH, —

N₃, —

NH₂, —

NO₂, and —

CN; and

n is 1, 2, 3, or 4;

or a pharmaceutically acceptable salt or solvate thereof.

5. The compound of claim 1, wherein said compound is selected from the group consisting of compounds 6 to 31 of Table 2;

compounds 32 to 51 of Table 3;

compounds 52 to 62 of Table 4;

compounds 63 to 78 of Table 5;

compounds 79 to 92 of Table 6;

compounds 93 to 103 of Table 7;

compounds 104 to 118 of Table 8;

compounds 119 to 122 of Table 9;

compounds 123 to 126 of Table 10;

compounds 127 to 129 of Table 11;

compounds 130 to 132 of Table 12;

compounds 133 to 136 of Table 13;

compounds 137 to 139 of Table 14;

compounds 140 to 142 of Table 15;

compounds 143 to 148 of Table 16;

compounds 149 to 153 of Table 17;

compounds to 154 to 157 of Table 18;

compounds 158 to 161 of Table 19;

compounds 162 to 169 of Table 20;

compounds 170 to 172 of Table 21; and

compounds 173 to 182 of Table 22;

or a pharmaceutically acceptable salt or solvate thereof.

6. The compound of claim 1, wherein said compound is selected from the group consisting of compounds 6, 13, 24, and 25 of Table 2;

compounds 33 to 35, 38 to 41, 43, 44, and 47 to 49 of Table 3;

compounds 53, 55, and 58 of Table 4;

compounds 67, 68, and 72 to 76 of Table 5;

compounds 87 and 90 of Table 6;

compounds 98 and 103 of Table 7;

compounds 106 and 114 of Table 8;

compounds 119 and 121 of Table 9;

compounds 123 and 125 of Table 10;

compounds 127 to 129 of Table 11;

compound 130 of Table 12;

compounds 133 to 136 of Table 13;

compounds 137 and 138 of Table 14;

compounds 144 and 146 of Table 16;

compound 150 of Table 17;

compounds 154 and 156 of Table 18; and

compound 167 of Table 20;

or a pharmaceutically acceptable salt or solvate thereof.

7. The compound of claim 6, wherein said compound is an active Nec-5 compound;

or a pharmaceutically acceptable salt or solvate thereof.

14. A method of treating a subject with a disease or condition, said disease or condition provided in Table 1, said method comprising administering to said subject an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof.

15. The method of claim 14, wherein said disease or condition is chronic, neurodegenerative disease;

acute neurological disease;

acute neurodegeneration;

the result of cell death associated with renal failure;

the result of retinal neuronal cell death;

the result of cell death of cardiac muscle;

the result of cell death of cells of the immune system;

mycocardial infarction;

cardiac infarction;

stroke;

ischemic stroke;

hemorrhagic stroke;

ischemia;

ischemic liver disease, pancreatic disease, heart disease, brain disease, kidney disease or injury;

ischemic mesenteric, retinal, or neuronal injury;

ischemic injury during organ storage;

delayed ischemic brain injury;

traumatic brain injury;

head trauma;

sepsis;

septic shock;

necroptosis;

necrosis;

ischemic necrosis;

retinal necrosis;

necrotizing myopathy of intensive care;

primary systemic infection;

pancreatitis;

or cell death induced by LPS.

16. The method of claim 15, wherein said chronic neurodegenerative disease is Alzheimer'"'"'s disease;

Huntington'"'"'s disease;

Parkinson'"'"'s disease;

amyotrophic lateral sclerosis;

HIV-associated dementia;

cerebral ischemia;

amyotropic lateral sclerosis;

multiple sclerosis;

Lewy body disease;

Menke'"'"'s disease;

Wilson'"'"'s disease;

Creutzfeldt-Jakob disease;

or Fahr disease.

17. The method of claim 14, wherein said compound is selected from the group consisting of compounds 6 to 31 of Table 2;

compounds 32 to 51 of Table 3;

compounds 52 to 62 of Table 4;

compounds 63 to 78 of Table 5;

compounds 79 to 92 of Table 6;

compounds 93 to 103 of Table 7;

compounds 104 to 118 of Table 8;

compounds 119 to 122 of Table 9;

compounds 123 to 126 of Table 10;

compounds 127 to 129 of Table 11;

compounds 130 to 132 of Table 12;

compounds 133 to 136 of Table 13;

compounds 137 to 139 of Table 14;

compounds 140 to 142 of Table 15;

compounds 143 to 148 of Table 16;

compounds 149 to 153 of Table 17;

compounds to 154 to 157 of Table 18;

compounds 158 to 161 of Table 19;

compounds 162 to 169 of Table 20;

compounds 170 to 172 of Table 21; and

compounds 173 to 182 of Table 22;

or a pharmaceutically acceptable salt or solvate thereof.

18. The method of claim 17, wherein said compound is selected from the group consisting of compounds 6, 13, 24, and 25 of Table 2;

compounds 33 to 35, 38 to 41, 43, 44, and 47 to 49 of Table 3;

compounds 53, 55, and 58 of Table 4;

compounds 67, 68, and 72 to 76 of Table 5;

compounds 87 and 90 of Table 6;

compounds 98 and 103 of Table 7;

compounds 106 and 114 of Table 8;

compounds 119 and 121 of Table 9;

compounds 123 and 125 of Table 10;

compounds 127 to 129 of Table 11;

compound 130 of Table 12;

compounds 133 to 136 of Table 13;

compounds 137 and 138 of Table 14;

compounds 144 and 146 of Table 16;

compound 150 of Table 17;

compounds 154 and 156 of Table 18; and

compound 167 of Table 20;

or a pharmaceutically acceptable salt or solvate thereof.

19. The method of claim 18, wherein said compound is an active Nec-5 compound, or a pharmaceutically acceptable salt or solvate thereof.

8. A pharmaceutical composition comprising a compound of Formula (I):

or a pharmaceutically acceptable salt or solvate thereof, wherein

Q is selected from the group consisting of —

S—

, —

S(O)—

, and —

S(O)₂—

;

R₁ is selected from the group consisting of C₁-C₉ alkyl, C₂-C₉ alkyenyl, C₂-C₉ alkynyl, C₆-C₁₂ aryl, and C₁-C₁₂ carbonyl;

R₂ is selected from the group consisting of C₁-C₉ alkaryl, and C₆-C₁₂ aryl; and

R₃ and R₄ are, independently, selected from the group consisting of C₁-C₉ alkyl, C₂-C₉ alkenyl, C₂-C₉ alkynyl, C₁-C₉ alkyloxy, and C₁-C₁₂ carbonyl, or R₃ and R₄, combined, form an C₃-C₉ carbocyclic, C₂-C₉ heterocyclic, C₆-C₁₂ aryl, or C₂-C₁₂ heteroaryl, ring system;

and a pharmaceutically acceptable excipient.

9. The pharmaceutical composition of claim 8, wherein said compound, or a pharmaceutically acceptable salt or solvate thereof, is selected from the group consisting of compounds 1 and 6 to 31 of Table 2;

compounds 32 to 51 of Table 3;

compounds 52 to 62 of Table 4;

compounds 63 to 78 of Table 5;

compounds 79 to 92 of Table 6;

compounds 93 to 103 of Table 7;

compounds 104 to 118 of Table 8;

compounds 119 to 122 of Table 9;

compounds 123 to 126 of Table 10;

compounds 127 to 129 of Table 11;

compounds 130 to 132 of Table 12;

compounds 133 to 136 of Table 13;

compounds 137 to 139 of Table 14;

compounds 140 to 142 of Table 15;

compounds 143 to 148 of Table 16;

compounds 149 to 153 of Table 17;

compounds to 154 to 157 of Table 18;

compounds 158 to 161 of Table 19;

compounds 162 to 169 of Table 20;

compounds 170 to 172 of Table 21; and

compounds 173 to 182 of Table 22.

10. The pharmaceutical composition of claim 9, wherein said compound, or a pharmaceutically acceptable salt or solvate thereof, is selected from the group consisting of compounds 1 and 6, 13, 24, and 25 of Table 2;

compounds 33 to 35, 38 to 41, 43, 44, and 47 to 49 of Table 3;

compounds 53, 55, and 58 of Table 4;

compounds 67, 68, and 72 to 76 of Table 5;

compounds 87 and 90 of Table 6;

compounds 98 and 103 of Table 7;

compounds 106 and 114 of Table 8;

compounds 119 and 121 of Table 9;

compounds 123 and 125 of Table 10;

compounds 127 to 129 of Table 11;

compound 130 of Table 12;

compounds 133 to 136 of Table 13;

compounds 137 and 138 of Table 14;

compounds 144 and 146 of Table 16;

compound 150 of Table 17;

compounds 154 and 156 of Table 18; and

compound 167 of Table 20.

11. The pharmaceutical composition of claim 10, wherein said compound, or a pharmaceutically acceptable salt or solvate thereof, is an active Nec-5 compound.

20. A method of treating a subject with a disease or condition, said disease or condition provided in Table 1, said method comprising administering to said subject an effective amount of a pharmaceutical composition of claim 8.

21. The method of claim 20, wherein said disease or condition is chronic neurodegenerative disease;

acute neurological disease;

acute neurodegeneration;

the result of cell death associated with renal failure;

the result of retinal neuronal cell death;

the result of cell death of cardiac muscle;

the result of cell death of cells of the immune system;

mycocardial infarction;

cardiac infarction;

stroke;

ischemic stroke;

hemorrhagic stroke;

ischemia;

ischemic liver disease, pancreatic disease, heart disease, brain disease, kidney disease or injury;

ischemic mesenteric, retinal, or neuronal injury;

ischemic injury during organ storage;

delayed ischemic brain injury;

traumatic brain injury;

head trauma;

sepsis;

septic shock;

necroptosis;

necrosis;

ischemic necrosis;

retinal necrosis;

necrotizing myopathy of intensive care;

primary systemic infection;

pancreatitis;

or cell death induced by LPS.

22. The method of claim 21, wherein said chronic neurodegenerative disease is Alzheimer'"'"'s disease;

Huntington'"'"'s disease;

Parkinson'"'"'s disease;

amyotrophic lateral sclerosis;

HIV-associated dementia;

cerebral ischemia;

amyotropic lateral sclerosis;

multiple sclerosis;

Lewy body disease;

Menke'"'"'s disease;

Wilson'"'"'s disease;

Creutzfeldt-Jakob disease;

or Fahr disease.

23. The method of claim 20, wherein said compound is selected from the group consisting of compound 1 and compounds 6 to 31 of Table 2;

compounds 32 to 51 of Table 3;

compounds 52 to 62 of Table 4;

compounds 63 to 78 of Table 5;

compounds 79 to 92 of Table 6;

compounds 93 to 103 of Table 7;

compounds 104 to 118 of Table 8;

compounds 119 to 122 of Table 9;

compounds 123 to 126 of Table 10;

compounds 127 to 129 of Table 11;

compounds 130 to 132 of Table 12;

compounds 133 to 136 of Table 13;

compounds 137 to 139 of Table 14;

compounds 140 to 142 of Table 15;

compounds 143 to 148 of Table 16;

compounds 149 to 153 of Table 17;

compounds to 154 to 157 of Table 18;

compounds 158 to 161 of Table 19;

compounds 162 to 169 of Table 20;

compounds 170 to 172 of Table 21; and

compounds 173 to 182 of Table 22;

or a pharmaceutically acceptable salt or solvate thereof.

24. The method of claim 23, wherein said compound is selected from the group consisting of compounds 1, 6, 13, 24, and 25 of Table 2;

compounds 33 to 35, 38 to 41, 43, 44, and 47 to 49 of Table 3;

compounds 53, 55, and 58 of Table 4;

compounds 67, 68, and 72 to 76 of Table 5;

compounds 87 and 90 of Table 6;

compounds 98 and 103 of Table 7;

compounds 106 and 114 of Table 8;

compounds 119 and 121 of Table 9;

compounds 123 and 125 of Table 10;

compounds 127 to 129 of Table 11;

compound 130 of Table 12;

compounds 133 to 136 of Table 13;

compounds 137 and 138 of Table 14;

compounds 144 and 146 of Table 16;

compound 150 of Table 17;

compounds 154 and 156 of Table 18; and

compound 167 of Table 20;

or a pharmaceutically acceptable salt or solvate thereof.

25. The method of claim 24, wherein said compound is an active Nec-5 compound;

or a pharmaceutically acceptable salt or solvate thereof.

12. A method of synthesizing compounds of Formula (I-A):

or a pharmaceutically acceptable salt or solvate thereof, wherein

R₁ is selected from the group consisting of H, C₁-C₉ alkyl, C₂-C₉ alkyenyl, C₂-C₉ alkynyl, C₆-C₁₂ aryl, and C₁-C₁₂ carbonyl;

R₂ is selected from the group consisting of C₁-C₉ alkaryl, and C₆-C₁₂ aryl; and

R₃ and R₄ are, independently, selected from the group consisting of C₁-C₉ alkyl, C₂-C₉ alkenyl, C₂-C₉ alkynyl, C₁-C₉ alkyloxy, and C₁-C₁₂ carbonyl, or R₃ and R₄, combined, form an C₃-C₉ carbocyclic, C₂-C₉ heterocyclic, C₆-C₁₂ aryl, or C₂-C₁₂ heteroaryl, ring system;

R₅ is selected from the group consisting of H, C₁-C₉ alkyl, C₂-C₉ alkenyl, C₂-C₉ alkynyl, C₃-C₉ carbocyclyl, C₂-C₉ heterocyclyl, C₂-C₉ heteroaryl, C₆-C₁₂ aryl, C₁-C₉ alkyloxy, C₁-C₉ alkylthio, C₆-C₁₂ arylthio, C₁-C₉ hydroxyalkyl, C₁-C₉ alkyloxy, C₆-C₁₂ aryloxy, C_1-12 carbonyl, C₁-C₉ fluoroalkyl, C₁-C₉ perfluoroalkyl, halogen, —

SH, —

OH, —

N₃, —

NH₂, —

NO₂, and CN; and

n is 1, 2, 3, or 4;

wherein said method comprises providing a compound of Formula (I-B);

wherein

LG is C₁-C₉ alkyloxy, C₁-C₉ alkylsulfonyloxy, C₆-C₁₂ arylsulfonyloxy, or a halogen; and

reacting said compound of Formula (I-B) with an C₆-C₁₂ aryl isothiocyanate to provide a compound of Formula (I-C);

wherein said compound of Formula (I-C) is thereafter transformed to produce a compound of Formula (I-A).

13. The method of claim 12, wherein said compound of Formula (I-B) is obtained from a compound of Formula (I-E):