Heterocyclic inhibitors of necroptosis

• US 20090099242A1
• Filed: 08/15/2008
• Published: 04/16/2009
• Est. Priority Date: 08/15/2007
• Status: Abandoned Application

• Current Assignee: Brigham and Women's Hospital Incorporated, President and Fellows of Harvard College (Harvard Corporation), Trustees of Boston University, Tufts University
• Original Assignee: Brigham and Women's Hospital Incorporated
• Inventors: Porco, John A. JR., Cuny, Gregory D., Yuan, Junying, Degterev, Alexei, Teng, Xin
• Application Number:
  US12/228,750
• Publication Number:
  US 20090099242A1
• Time in Patent Office: Days
• US Class Current: 514/361
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/16 for influenza or rhinoviruses
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 31/22 for herpes viruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• 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: C07D 207/34 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 231/14 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 241/24 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 263/34 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 277/56 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 285/06 : 1,2,3-Thiadiazoles; Hydrogenated 1,2,3-thiadiazoles
• CPC Class Codes: C07D 307/68 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 307/84 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 333/38 : 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 417/12 : linked by a chain containing hetero atoms as chain links

Abstract

The invention features a series of heterocyclic derivatives that inhibit tumor necrosis factor alpha (TNF-α) induced necroptosis. The heterocyclic compounds of the invention are described by Formulas (I) and (Ia)-(Ie) and are shown to inhibit TNF-α induced necroptosis in FADD-deficient variant of human Jurkat T cells. The invention further features pharmaceutical compositions featuring the compounds of the invention. The compounds and compositions of the invention may also be used to treat disorders where necroptosis is likely to play a substantial role.

Claims

1. A compound having a structure according to Formula (I)

wherein

X₁ and X₂ are, independently, N or CR⁴;

X₃ is selected from O, S, NR⁵, or —

(CR⁵)₂;

Y is selected from C(O) or CH₂; and

Z is (CR⁶R⁷)_n,

R¹ is selected from H, halogen, optionally substituted C_1-6 lower alkyl, or optionally substituted C_1-6 cycloalkyl, or optionally substituted aryl;

R² is selected from H or optionally substituted C_1-6 lower alkyl;

R³ is optionally substituted aryl;

each R⁴ is selected from H, halogen, carboxamido, nitro, cyano, optionally substituted lower C_1-6 alkyl, or optionally substituted aryl;

R⁵ is selected from H, halogen, optionally substituted lower C_1-6 alkyl, or optionally substituted aryl;

each R⁶ and R⁷ is, independently, selected from H or optionally substituted C_1-6 lower alkyl; and

n is 0, 1, 2, or 3;

wherein when X₁ and X₂ are N, X₃ is S, Y, is C(O), Z is CH₂, R² is H, and R³ is 2-chloro-6-fluoro-phenyl, R¹ is not methyl;

or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof.

2. The compound of claim 1, wherein both X₁ and X₂ are N or both X₁ and X₂ are CR⁴ and X₃ is S or NR⁵, or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof.

3. The compound of claim 1, wherein said compound has a structure according to Formula (I-a)

wherein R¹, R², R³, R⁶, and R⁷ are as defined for Formula (I), or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof.

4. The compound of claim 3, wherein R³ is a substituted phenyl group having the structure

wherein each R⁸, R⁹, R¹⁰, R¹¹, and R¹² is selected, independently, from H, lower C_1-6 alkyl, halogen, amino, carboxamido, alkoxy, nitro, and cyano, wherein at least one of R⁸, R⁹, R¹⁰, R¹¹, and R¹² is not hydrogen, or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof.

5. The compound of claim 4, wherein R¹ is C_1-6 cycloalkyl or branched C_1-6 lower alkyl, R⁸ and R¹² are halogens, and R⁹, R¹⁰, and R¹¹ are hydrogen, or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof.

6. The compound of claim 5, wherein R¹ is cyclopropyl, cyclobutyl, or isopropyl, R⁸ is fluorine, and R¹² is chlorine, or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof.

7. The compound of claim 1, wherein R² is H, or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof.

8. The compound of claim 1, wherein R⁶ and R⁷ are both hydrogen, or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof.

9. The compound of claim 1, wherein R⁶ is hydrogen and R⁷ is lower C_1-6 alkyl, or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof.

10. The compound of claim 9, wherein the carbon bearing R⁶ and R⁷ has the (S)-configuration, or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof.

11. The compound of claim 1, wherein said compound has a structure according to Formula (I-b)

wherein Y and Z are as defined for Formula (I) and R is selected from:

hydrogen, halogen, azido, cyano, nitro, optionally substituted lower C_1-6 alkyl, aryl, alkoxy, aryloxy, amino, carboxylic group, ketone, carbonate, ester, carboxamide, or carbamate, or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof.

12. The compound of claim 1, wherein said compound is

13. The compound of claim 1, wherein said compound has a structure according to Formula (I-c)

wherein

R¹, R², and R⁷ are as defined for Formula (I);

R^4A and R^4B are selected, independently, from hydrogen, halogen, carboxamido, nitro, and cyano;

R⁵ is H or optionally substituted C_1-6 lower alkyl;

each of R⁸, R⁹, R¹⁰, R¹¹, and R¹² is selected, indepdently, from H, lower C_1-6 alkyl, halogen, amino, amido, alkoxy, nitro, and cyano, wherein at least one of R⁸, R⁹, R¹⁰, R¹¹, and R¹² is not hydrogen;

or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof.

14. The compound of claim 13, wherein said compound has a structure according to Formula (I-d)

wherein R^4B, R⁵, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are as defined in Formula (I-c), or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof.

15. The compound of claim 14, wherein R⁸ and R¹² are each halogen and R⁹, R¹⁰, and R¹¹ are hydrogen, or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof.

16. The compound of claim 13, wherein said compound has a structure according to Formula (I-e)

wherein R¹, R², R^4A, R^4B, R⁵, and R⁷ are as defined in Formula (I-c), or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof.

17. The compound of claim 16, wherein said compound is

18. The compound of claim 13, wherein R⁷ is hydrogen, or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof.

19. The compound of claim 13, wherein R⁷ is optionally substituted lower C_1-6 alkyl, or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof.

20. The compound of claim 13, wherein the carbon bearing R⁷ has the (S)-configuration, or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof.

21. The compound of claim 1, selected from the group consisting of:

or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof.

22. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and the compound of claim 1, or the compound having the formula:

or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof.

23. A method of treating a condition in a subject, said method comprising the step of administering the compound of claim 1, or the compound having the formula:

or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof, to said subject in a dosage sufficient to decrease necroptosis.

24. The method of claim 23, wherein said condition is a neurodegenerative disease or is caused by alteration in cell proliferation, differentiation, or intracellular signalling.

25. A method of decreasing necroptosis comprising contacting a cell with the compound of claim 1, or the compound having the formula:

or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof.

26. A kit comprising

(a) a pharmaceutically acceptable composition comprising the compound of claim 1, or the compound having the formula

 

or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof, and

(b) instructions for the use of the pharmaceutical composition of (a) to treat a condition in a subject.

27. The method of claim 23, wherein said condition is stroke, retinal or brain ischemic injury, head trauma, coronary heart disease, or the result of cell death of cardiac muscle.