US20090099242A1 - Heterocyclic inhibitors of necroptosis - Google Patents

Heterocyclic inhibitors of necroptosis Download PDF

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US20090099242A1
US20090099242A1 US12/228,750 US22875008A US2009099242A1 US 20090099242 A1 US20090099242 A1 US 20090099242A1 US 22875008 A US22875008 A US 22875008A US 2009099242 A1 US2009099242 A1 US 2009099242A1
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compound
pharmaceutically acceptable
stereoisomer
solvate
acceptable salt
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Gregory D. Cuny
Xin Teng
Junying Yuan
Alexei Degterev
John A. Porco, JR.
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Harvard College
Boston University
Brigham and Womens Hospital Inc
Tufts University
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Priority to US12/228,750 priority Critical patent/US20090099242A1/en
Assigned to PRESIDENT AND FELLOWS OF HARVARD COLLEGE, TUFTS UNIVERSITY reassignment PRESIDENT AND FELLOWS OF HARVARD COLLEGE ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DEGTEREV, ALEXEI
Assigned to PRESIDENT AND FELLOWS OF HARVARD COLLEGE reassignment PRESIDENT AND FELLOWS OF HARVARD COLLEGE ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: YUAN, JUNYING
Assigned to THE BRIGHAM AND WOMEN'S HOSPITAL, INC. reassignment THE BRIGHAM AND WOMEN'S HOSPITAL, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: TENG, XIN, CUNY, GREGORY D.
Assigned to TRUSTEES OF BOSTON UNIVERSITY reassignment TRUSTEES OF BOSTON UNIVERSITY ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PORCO, JOHN A., JR.
Publication of US20090099242A1 publication Critical patent/US20090099242A1/en
Assigned to NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT reassignment NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT CONFIRMATORY LICENSE (SEE DOCUMENT FOR DETAILS). Assignors: BRIGHAM AND WOMEN'S HOSPITAL
Priority to US12/859,997 priority patent/US8278344B2/en
Priority to US13/589,867 priority patent/US8658689B2/en
Priority to US14/152,703 priority patent/US9108955B2/en
Priority to US14/796,378 priority patent/US20160102053A1/en
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Definitions

  • the invention relates to heterocyclic compounds and to cell death, in particular through necrosis and necroptosis, and regulation thereof by heterocyclic compounds.
  • necrotic and/or necrotic pathways In many diseases, cell death is mediated through apoptotic and/or necrotic pathways. While much is known about the mechanisms of action that control apoptosis, control of necrosis is not as well understood. Understanding the mechanisms regulating both necrosis and apoptosis in cells is essential to being able to treat conditions, such as neurodegenerative diseases, stroke-coronary heart disease, kidney disease, and liver disease. A thorough understanding of necrotic and apoptotic cell death pathways is also crucial to treating AIDS and the conditions associated with AIDS, such as retinal necrosis.
  • Cell death has traditionally been categorized as either apoptotic or necrotic based on morphological characteristics (Wyllie et al., Int. Rev. Cytol. 68: 251 (1980)). These two modes of cell death were also initially thought to occur via regulated (caspase-dependent) and non-regulated processes, respectively. More recent studies, however, demonstrate that the underlying cell death mechanisms resulting in these two phenotypes are much more complicated and under some circumstances interrelated. Furthermore, conditions that lead to necrosis can occur by either regulated caspase-independent or non-regulated processes.
  • necroptosis One regulated caspase-independent cell death pathway with morphological features resembling necrosis, called necroptosis, has recently been described (Degterev et al., Nat. Chem. Biol. 1:112 (2005)). This manner of cell death can be initiated with various stimuli (e.g., TNF- ⁇ and Fas ligand) and in an array of cell types (e.g., monocytes, fibroblasts, lymphocytes, macrophages, epithelial cells and neurons).
  • TNF- ⁇ and Fas ligand e.g., monocytes, fibroblasts, lymphocytes, macrophages, epithelial cells and neurons.
  • Necroptosis may represent a significant contributor to and in some cases predominant mode of cellular demise under pathological conditions involving excessive cell stress, rapid energy loss and massive oxidative species generation, where the highly energy-dependent apoptosis process is not operative.
  • necrostatins for anti-necroptosis therapeutics.
  • the discovery of compounds that prevent caspase-independent cell death would also provide useful therapeutic agents for treating or preventing conditions in which necrosis occurs. These compounds and methods would be particularly useful for the treatment of neurodegenerative diseases, ischemic brain and heart injuries, and head trauma.
  • the invention features a compound having a structure according to Formula (I)
  • X 1 and X 2 are, independently, N or CR 4 ;
  • X 3 is selected from O, S, NR 5 , or —(CR 5 ) 2 ;
  • Y is selected from C(O) or CH 2 ;
  • Z is (CR 6 R 7 ) n ,
  • R 1 is selected from H, halogen, optionally substituted C 1-6 lower alkyl, or optionally substituted C 1-6 cycloalkyl, or optionally substituted aryl;
  • R 2 is selected from H or optionally substituted C 1-6 lower alkyl
  • R 3 is optionally substituted aryl
  • each R 4 is selected from H, halogen, carboxamido, nitro, cyano, optionally substituted lower C 1-6 alkyl, or optionally substituted aryl;
  • R 5 is selected from H, halogen, optionally substituted lower C 1-6 alkyl, or optionally substituted aryl;
  • each R 6 and R 7 is, independently, selected from H, optionally substituted aryl, or optionally substituted C 1-6 lower alkyl;
  • n 0, 1, 2, or 3;
  • both X 1 and X 2 are N or both X 1 and X 2 are CR 4 , wherein X 3 is not NR 5 when X 1 and X 2 are N.
  • X 1 and X 2 are N and X 3 is S.
  • X 1 and X 2 are CR 4 and X 3 is NR 5 .
  • R 1 is C 1-6 cycloalkyl or branched C 1-6 lower alkyl.
  • R 2 is H.
  • R 3 is a substituted phenyl group having the structure
  • each R 8 , R 9 , R 10 , R 11 , and R 12 is selected, independently, from H, lower C 1-6 alkyl, halogen, amino, carboxamido, alkoxy, nitro, and cyano, and at least one of R 8 , R 9 , R 10 , R 11 , and R 12 is not hydrogen.
  • R 8 and R 12 are, independently, halogen. In other embodiments, R 8 and R 12 are, independently, fluorine or chlorine. In certain embodiments, R 8 is fluorine and R 12 is chlorine.
  • R 9 , R 10 , and R 11 are hydrogen.
  • R 1 is C 1-6 cycloalkyl or branched C 1-6 lower alkyl, or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof.
  • the compound of Formula (I) has a structure according to Formula (I-a)
  • R 1 , R 2 , R 3 , R 6 , and R 7 are as defined for Formula (I), or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof.
  • R 3 is a substituted phenyl group having the structure
  • each R 8 , R 9 , R 10 , R 11 , and R 12 is selected, independently, from H, lower C 1-6 alkyl, halogen, amino, carboxamido, alkoxy, nitro, and cyano, and at least one of R 8 , R 9 , R 10 , R 11 , and R 12 is not hydrogen.
  • R 8 and R 12 are, independently, halogen. In other embodiments, R 8 and R 12 are, independently, fluorine or chlorine. In certain embodiments, R 8 is fluorine and R 12 is chlorine.
  • R 9 , R 10 , and R 11 are hydrogen, or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof.
  • R 1 is C 1-6 cycloalkyl or branched C 16 lower alkyl, or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof. In certain embodiments, R 1 is cyclopropyl, cyclobutyl, or isopropyl.
  • R 2 is H, or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof.
  • R 6 and R 7 are both hydrogen, or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof.
  • R 6 is hydrogen and R 7 is lower C 1-6 alkyl, or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof.
  • carbon bearing R 6 and R 7 has the (S)-configuration.
  • the compound of Formula (I) has a structure according to Formula (I-b)
  • 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.
  • Y is C(O). In other embodiments, Y is CH 2 .
  • R is halogen. In certain embodiments, R is chlorine, or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof.
  • Z is CH 2 . In other embodiments, Z is CHR 7 , where R 7 is C 1-6 lower alkyl. In certain embodiments, the carbon bearing R 7 has the S-configuration.
  • the compound having a structure according to (I-b) is
  • the compound of Formula (I) has a structure according to Formula (I-c)
  • R 1 , R 2 , and R 7 are as defined for Formula (I);
  • R 4A and R 4B are selected, independently, from hydrogen, halogen, carboxamido, nitro, and cyano;
  • R 5 is H or optionally substituted C 1-6 lower alkyl
  • each of R 8 , R 9 , R 10 , R 11 , and R 12 is selected, indepdently, from H, lower C 1-6 alkyl, halogen, amino, amido, alkoxy, nitro, and cyano, and at least one of R 8 , R 9 , R 10 , R 11 , and R 12 is not hydrogen;
  • R 1 is H.
  • R 2 is H.
  • R 4A is H and R 4B is CN. In other embodiments, R 4A is CN and R 4B is H.
  • R 5 is unsubstituted C 1-6 lower alkyl.
  • R 7 is C 1-6 lower alkyl. In other embodiments, the carbon bearing R 7 has the S-configuration.
  • R 8 and R 12 are each, independently, halogen.
  • R 9 , R 10 , and R 11 are hydrogen.
  • the compound of Formula (I) has a structure according to Formula (I-d)
  • R 4B , R 5 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are as defined in Formula (I-c), or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof.
  • R 4B is CN.
  • R 5 is unsubstituted C 1-6 lower alkyl.
  • R 7 is C 1-6 lower alkyl. In certain embodiments, the carbon bearing R 7 has the S-configuration.
  • R 8 and R 12 are each, independently, halogen.
  • R 9 , R 10 , and R 11 are hydrogen.
  • the compound of Formula (I) has a structure according to Formula (I-e)
  • R 1 , R 2 , R 4A , R 4B , R 5 , and R 7 are as defined in Formula (I-c), or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof.
  • R 1 is H or unsubstituted C 1-6 lower alkyl.
  • R 2 is H.
  • R 4A is H and R 4B is CN.
  • R 4A is CN and R 4B is H.
  • R 7 is hydrogen
  • R 7 is C 1-6 lower alkyl.
  • the carbon bearing R 7 has the S-configuration, or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof.
  • the compound of Formula (I) is selected from the group consisting of:
  • the compounds of Formulas (I), (I-a), (I-b), (I-c), (I-d), or (I-e) also include any pharmaceutically acceptable salts or solvates thereof, or stereoisomers thereof.
  • the invention features a pharmaceutical composition including a pharmaceutically acceptable excipient and the compound of any of Formulas (I), (I-a), (I-b), (I-c), (I-d), or (I-e), or the compound having the formula:
  • the invention features a method of treating a condition in a subject, where the method includes the step of administering the compound of any of Formulas (I), (I-a), (I-b), (I-c), (I-d), or (I-e), or the compound having the formula:
  • the condition is a neurodegenerative disease or is caused by alteration in cell proliferation, differentiation, or intracellular signalling.
  • the invention features a method of decreasing necroptosis including the step of contacting a cell with the compound of any of Formulas (I), (I-a), (I-b), (I-c), (I-d), or (I-e), or the compound having the formula:
  • the condition is a neurodegenerative disease or is a condition caused by alteration in cell proliferation, differentiation, or intracellular signalling.
  • the condition caused by alteration in cell proliferation, differentiation, or intracellular signalling is cancer or infection (e.g., by viruses (e.g., acute, latent and persistent), bacteria, fungi, or other microbes).
  • the viruses are human immunodeficiency virus (HIV), Epstein-Barr virus (EBV), cytomegalovirus (CMV)5 human herpesviruses (HHV), herpes simplex viruses (HSV), human T-Cell leukemia viruses (HTLV)5 Varicella-Zoster virus (VZV), measles virus, papovaviruses (JC and BK), hepatitis viruses, adenovirus, parvoviruses, and human papillomaviruses.
  • HSV human immunodeficiency virus
  • EBV Epstein-Barr virus
  • CMV cytomegalovirus
  • HSV herpes simplex viruses
  • HSV herpes simplex viruses
  • HSV human T-Cell leukemia viruses
  • VZV Varicella-Zoster virus
  • measles virus papovaviruses
  • JC and BK hepatitis viruses
  • adenovirus adenovirus
  • parvoviruses
  • the condition is a neurodegenerative disease that 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, Fahr disease, or muscular dystrophies or related diseases (e.g., Becker's muscular dystrophy, Duchenne muscular dystrophy, myotonic dystrophy, limb-girdle muscular dystrophy, Landouzy-Dejerine muscular dystrophy, facioscapulohumeral muscular dystrophy (Steinert's disease), myotonia congenita, Thomsen's disease, and Pompe's disease).
  • the neurodegerative disease is muscle wasting.
  • muscle wasting is associated with cancer, AIDS, congestive heart failure, chronic obstructive pulmonary disease, and necrosis, and a
  • the invention features a method of screening compounds to identify inhibitors of necroptosis, where the method includes the following steps:
  • an inhibitor of necroptosis is identified when the inhibition of necroptosis observed in (b) exceeds the inhibition of necroptosis by the compound of any of Formulas (I), (I-a), (I-b), (I-c), (I-d), or (I-e), or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof.
  • the invention features a kit including
  • the compounds of Formulas (I), (I-a), (I-b), (I-c), (I-d), or (I-e) are used to boost the immune system in a patient.
  • the patient has an immunocompromising condition. In other embodiments, the patient does not have an immunocompromising condition.
  • alkoxy is meant a group having the structure —O(lower C 1-6 alkyl), where the lower C 1-6 alkyl may be brached, linear, or cyclic. The lower C 1-6 alkyl may also be substituted or unsubstituted.
  • amino is meant a group having a structure selected from: —NH 2 , —NH(lower C 1-6 alkyl), —N(lower C 1-6 alkyl) 2 , —NH(aryl), —N(lower C 1-6 alkyl)(aryl), and —N(aryl) 2 .
  • Each lower C 1-6 alkyl and aryl may be, independently, unsubstituted or substituted.
  • Each lower C 1-6 alkyl may be, independently, brached, linear, or cyclic.
  • aryl is meant is an optionally substituted C 6 -C 14 cyclic group with [4n+2] ⁇ electrons in conjugation and where n is 1, 2, or 3.
  • Non-limiting examples of arenes include heteroaryls and benzene, naphthalene, anthracene, and phenanthrene.
  • Aryls may be unsubstituted or substituted.
  • a substituted aryl may be optionally substituted with 1, 2, 3, 4, 5, or 6 substituents located at any position of the ring.
  • aryloxy is meant a group having the structure —O(aryl).
  • Aryl may be unsubstituted or substituted.
  • azido is meant a group having the structure —N 3 .
  • carboxylate is meant a group having the structure —OCONH 2 , —OCONH(lower C 1-6 alkyl), —OCON(lower C 1-6 alkyl) 2 , —OCON(lower C 1-6 alkyl)(aryl), —OCONH(aryl), or —OCON(aryl) 2 .
  • Each lower C 1-6 alkyl and aryl may be, independently, unsubstituted or substituted.
  • Each lower C 1-6 alkyl may be, independently, brached, linear, or cyclic.
  • carbonate is meant a group having a the structure —OCO 2 (lower C 1-6 alkyl) or —OCO 2 (aryl). Each lower C 1-6 alkyl and aryl may be unsubstituted or substituted.
  • carboxamide is meant a group having the structure —CONH 2 , —CON(lower C 1-6 alkyl), —CON(lower C 1-6 alkyl) 2 , —CON(lower C 1-6 alkyl)(aryl), —CONH(aryl), or —CON(aryl) 2 .
  • Each lower C 1-6 alkyl and aryl may be, independently, unsubstituted or substituted.
  • Each lower C 1-6 alkyl may be, independently, brached, linear, or cyclic.
  • carboxylic group is meant a group having a structure selected from: —CO 2 H, —CO 2 (lower C 1-6 alkyl), and —CO 2 (aryl). Each lower C 1-6 alkyl and aryl may be unsubstituted or substituted. Each lower C 1-6 alkyl may be, independently, brached, linear, or cyclic.
  • cyano is meant a group having the structure —CN.
  • an effective amount or “therapeutically effective amount” of an agent is that amount sufficient to effect beneficial or desired results, such as clinical results, and, as such, an effective amount depends upon the context in which it is being applied.
  • an effective amount of an agent is, for example, an amount sufficient to achieve a reduction in necroptosis as compared to the response obtained without administration of the agent.
  • esters is meant a group having a structure selected from —OCO(lower C 1-6 alkyl) or —OCO(aryl). Each lower C 1-6 alkyl and aryl may be unsubstituted or substituted. Each lower C 1-6 alkyl may be, independently, brached, linear, or cyclic.
  • halogen or “halo” is meant fluorine (—F), chlorine (—Cl), bromine (—Br), or iodine (—I).
  • heteroaryl is mean an aryl group that contains 1, 2, or 3 heteroatoms in the cyclic framework.
  • exemplary heteroaryls include, but are not limited to, furan, thiophene, pyrrole, thiadiazole (e.g., 1,2,3-thiadiazole or 1,2,4-thiadiazole), oxadiazole (e.g., 1,2,3-oxadiazole or 1,2,5-oxadiazole), oxazole, benzoxazole, isoxazole, isothiazole, pyrazole, thiazole, benzthiazole, triazole (e.g., 1,2,4-triazole or 1,2,3-triazole), benzotriazole, pyridines, pyrimidines, pyrazines, quinoline, isoquinoline, purine, pyrazine, pteridine, triazine (e.g, 1,2,3-triazine, 1,2,4-tria
  • ketone is meant a group having the structure —CO(lower C 1-6 alkyl) or —CO(aryl). Each lower C 1-6 alkyl and aryl may be unsubstituted or substituted. Each lower C 1-6 alkyl may be, independently, brached, linear, or cyclic.
  • lower alkyl or “lower C 1-6 alkyl” is meant hydrocarbon chains of from 1 to 6 carbon atoms. Lower alkyls may include 1, 2, 3, 4, 5, or 6 carbon atoms.
  • a lower C 1-6 alkyl may be linear, branched or cyclic (“cycloalkyls”). Examples of linear lower alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl. Examples of branched lower alkyl groups include, but are not limited to: isopropyl, s-, i- and t-butyl, and isoamyl.
  • cyclic lower alkyl groups include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclobutylmethyl.
  • a lower C 1-6 alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, or cyclopropyl.
  • a lower alkyl may be unsubstituted or substituted.
  • a substituted lower alkyl may be optionally substituted with 1, 2, 3, 4, 5, or 6 substituents located at any carbon of the lower alkyl.
  • nitro is meant a group having the structure —NO 2 .
  • a “pharmaceutically acceptable excipient” as used herein refers any ingredient other than the compounds described herein (for example, a vehicle capable of suspending or dissolving the active compound) and having the properties of being nontoxic and non-inflammatory in a patient.
  • Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, or waters of hydration.
  • excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, B
  • pharmaceutically acceptable salt represents those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66:1-19.
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting the free base group with a suitable organic acid.
  • Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphersulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pe
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like.
  • solvates refers to compounds that retain non-covalent associations to residual solvent molecules in the solid state.
  • solvates may be prepared by crystallization, recrystallization, or precipitation from a solution that includes organic solvents, water, or a mixture thereof.
  • Solvates include, but are not limited to, compounds that include solvent molecules in the crystal lattice following recrystallization.
  • the molecular stoichiometry of solvation can vary from, for example, 1:1 solvent:compound to 10:1 solvent:compound. These ratios can include a mixture of associated solvent molecules.
  • NMP N-methylpyrrolidinone
  • DMSO dimethyl sulfoxide
  • DMF N,N′-dimethylformamide
  • DMAC N,N′-dimethylacetamide
  • DMEU 1,3-dimethyl-2-imid
  • composition a composition containing a compound of the invention, formulated with a pharmaceutically acceptable excipient, and manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal. Excipients consisting of DMSO are specifically excluded.
  • Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or any other formulation described herein.
  • stereoisomer is meant a diastereomer, enantiomer, or epimer of a compound.
  • a chiral center in a compound may have the S-configuration or the R-configuration.
  • Diastereomers of a compound include stereoisomers in which some, but not all, of the chiral centers have the opposite configuration as well as those compounds in which substituents are differently oriented in space (for example, trans versus cis).
  • substituents include, but are not limited to: halogen, azido, cyano, nitro, lower C 1-6 alkyl, aryl, alkoxy, aryloxy, amino, carboxylic group, ketone, carbonate, ester, carboxamide, or carbamate.
  • Substituents may be further substituted with 1, 2, 3, 4, 5, or 6 substituents as defined herein.
  • a lower C 1-6 alkyl or an aryl group e.g., heteroaryl, phenyl, or naphthyl
  • FIG. 1 shows cell-type-specific activities of necrostatins.
  • FADD-deficient Jurkat, L929 and mouse adult lung fibroblast cells were treated for 24 hours with 10 ng/mL human TNF- ⁇ and/or 100 ⁇ M zVAD.fmk as indicated in the presence of 30 ⁇ M of necrostatin 1, 2 or 55.
  • heterocyclic derivatives that inhibit tumor necrosis factor alpha (TNF- ⁇ )-induced necroptosis.
  • the heterocyclic compounds of the invention are described by Formulas (I) and (Ia)-(Ie) and are shown to inhibit TNF- ⁇ induced necroptosis in FADD-deficient variant of human Jurkat T cells.
  • Pharmaceutical compositions including the compounds of the invention are also described.
  • the invention also features kits and methods of treatment featuring the compounds and compositions of the invention.
  • X 1 and X 2 are, independently, N or CR 4 ;
  • X 3 is selected from O, S, NR 5 , or —(CR 5 ) 2 ;
  • Y is selected from C(O) or CH 2 ;
  • Z is (CR 6 R 7 ) n ,
  • R 1 is selected from H, halogen, optionally substituted C 1-6 lower alkyl, or optionally substituted C 1-6 cycloalkyl;
  • R 2 is selected from H or optionally substituted C 1-6 lower alkyl
  • R 3 is optionally substituted aryl
  • each R 4 is selected from H, halogen, optionally substituted lower C 1-6 alkyl, or optionally substituted aryl;
  • R 5 is selected from H, halogen, optionally substituted lower C 1-6 alkyl, or optionally substituted aryl;
  • each R 6 and R 7 is, independently, selected from H, optionally substituted aryl, or optionally substituted C 16 lower alkyl;
  • n 0, 1, 2, or 3;
  • the compounds of the invention have the Formula (I-a):
  • R 1 is selected from H, halogen, optionally substituted C 1-6 lower alkyl, optionally substituted C 1-6 cycloalkyl, or optionally substituted aryl;
  • R 2 is selected from H or optionally substituted C 1-6 lower alkyl
  • R 3 is optionally substituted aryl
  • R 6 and R 7 are, independently, selected from H or optionally substituted C 1-6 lower alkyl
  • At least one of R 6 and R 7 is hydrogen.
  • Compounds of the invention having Formula (I-a) include:
  • Y and Z are as defined for Formula (I) and R is a substituent that may be 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.
  • Compounds of the invention having Formula (I-b) include:
  • R 1 is selected from H, halogen, optionally substituted C 1-6 lower alkyl, optionally substituted C 1-6 cycloalkyl, or optionally substituted aryl;
  • R 2 is selected from H or optionally substituted C 1-6 lower alkyl
  • R 4A and R 4B are selected, independently, from hydrogen, halogen, carboxamido, nitro, and cyano;
  • R 5 is H or optionally substituted C 1-6 lower alkyl
  • R 7 is hydrogen or optionally substituted lower C 1-6 alkyl
  • each of R 8 , R 9 , R 10 , R 11 , and R 12 is selected, indepdently, from H, lower C 1-6 alkyl, halogen, amino, amido, alkoxy, nitro, and cyano;
  • R 8 , R 9 , R 10 , R 11 , and R 12 is not hydrogen.
  • Examples of compounds having Formula (I-c) include those having Formula (I-d):
  • R 4B , R 5 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are as defined in Formula (I-c).
  • R 1 , R 2 , R 4A , R 4B , R 5 , and R 7 are as defined in Formula (I-c).
  • Compounds of the invention where the carbon bearing R 7 is a chiral center may be used as a racemate, stereochemical mixture, or in enantiomerically pure form.
  • a compound where the carbon bearing R 7 is a chiral center has the (S)-configuration.
  • a compound where the carbon bearing R 7 is a chiral center has the (R)-configuration.
  • the compounds of the invention can be formulated into pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo.
  • the present invention provides a pharmaceutical composition comprising a compound of the invention in admixture with a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising a compound of the invention in admixture with a pharmaceutically acceptable excipient.
  • Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington's Pharmaceutical Sciences (2003-20 th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF 19), published in 1999.
  • the compounds of the invention may be used in the form of the free base, in the form of salts, solvates, and as prodrugs. All forms are within the scope of the invention.
  • the described compounds or salts, solvates, or prodrugs thereof may be administered to a patient in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art.
  • the compounds of the invention may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump, or transdermal administration and the pharmaceutical compositions formulated accordingly.
  • Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.
  • Pharmaceutically acceptable excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, or waters of hydration.
  • excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, B
  • a compound of the invention may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet.
  • a compound of the invention may be incorporated with an excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • a compound of the invention may also be administered parenterally.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that may be easily administered via syringe.
  • compositions for nasal administration may conveniently be formulated as aerosols, drops, gels, and powders.
  • Aerosol formulations typically include a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomizing device.
  • the sealed container may be a unitary dispensing device, such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use.
  • the dosage form comprises an aerosol dispenser
  • a propellant which can be a compressed gas, such as compressed air or an organic propellant, such as fluorochlorohydrocarbon.
  • the aerosol dosage forms can also take the form of a pump-atomizer.
  • compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, where the active ingredient is formulated with a carrier, such as sugar, acacia, tragacanth, or gelatin and glycerine.
  • a carrier such as sugar, acacia, tragacanth, or gelatin and glycerine.
  • Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base, such as cocoa butter.
  • the compounds of the invention may be administered to an animal alone or in combination with pharmaceutically acceptable carriers, as noted above, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration, and standard pharmaceutical practice.
  • the amount of active ingredient in the compositions of the invention can be varied.
  • dosage levels of between 0.1 ⁇ g/kg to 100 mg/kg of body weight are administered daily as a single dose or divided into multiple doses.
  • the general dosage range is between 250 ⁇ g/kg to 5.0 mg/kg of body weight per day. Wide variations in the needed dosage are to be expected in view of the differing efficiencies of the various routes of administration.
  • oral administration generally would be expected to require higher dosage levels than administration by intravenous injection. Variations in these dosage levels can be adjusted using standard empirical routines for optimization, which are well known in the art. In general, the precise therapeutically effective dosage will be determined by the attending physician in consideration of the above identified factors.
  • Compounds disclosed herein can be used to treat disorders where necroptosis is likely to play a substantial role (e.g., cerebral ischemia, traumatic brain injury, and other disorders described herein). Compounds of the invention can also be used in screening methods to identify targets of necroptosis and to identify additional inhibitors of necroptosis, as well as in assay development.
  • Compounds disclosed herein can be evaluated for their pharmacological properties in animal models of disease.
  • the compounds identified to decrease necrosis or necroptosis may be structurally modified and subsequently used to decrease necrosis or necroptosis, or to treat a subject with a condition in which necrosis or necroptosis occurs.
  • the methods used to generate structural derivatives of the small molecules that decrease necrosis or necroptosis are readily known to those skilled in the fields of organic and medicinal chemistry.
  • Treatment may be performed alone or in conjunction with another therapy, for example in combination with apoptosis inhibitors, and may be provided at home, the doctor's office, a clinic, a hospital's outpatient department, or a hospital. Treatment generally begins at a hospital so that the doctor can observe the therapy's effects closely and make any adjustments that are needed. The duration of the therapy depends on the age and condition of the patient, as well as how the patient responds to the treatment. Additionally, a person having a greater risk of developing a condition may receive prophylactic treatment to inhibit or delay symptoms of the disease.
  • the compounds and methods of the invention can be used to treat any of the following disorders where necroptosis is likely to play a substantial role: a neurodegenerative disease of the central or peripheral nervous system, 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; stroke, liver disease, pancreatic disease, the result of cell death associated with renal failure; heart, mesenteric, retinal, hepatic or brain ischemic injury, ischemic injury during organ storage, head trauma, septic shock, coronary heart disease, cardiomyopathy, bone avascular necrosis, sickle cell disease, muscle wasting, gastrointestinal disease, tuberculosis, diabetes, alteration of blood vessels, muscular dystrophy, graft-versus-host disease, viral infection, Crohn's disease, ulcerative colitis, asthma, and any condition in which alteration in cell proliferation, differentiation or intracellular signaling is a causative factor.
  • a neurodegenerative disease of the central or peripheral nervous system the result of retina
  • Conditions in which alteration in cell proliferation, differentiation or intracellular signaling is a causative factor include cancer and infection, e.g., by viruses (e.g., acute, latent and persistent), bacteria, fungi, or other microbes.
  • viruses e.g., acute, latent and persistent
  • exemplary viruses are human immunodeficiency virus (HIV), Epstein-Barr virus (EBV), cytomegalovirus (CMV)5 human herpesviruses (HHV), herpes simplex viruses (HSV), human T-Cell leukemia viruses (HTLV)5 Varicella-Zoster virus (VZV), measles virus, papovaviruses (JC and BK), hepatitis viruses, adenovirus, parvoviruses, and human papillomaviruses.
  • HCV human immunodeficiency virus
  • EBV Epstein-Barr virus
  • CMV cytomegalovirus
  • HSV herpes simplex viruses
  • neurodegenerative diseases are 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, and Fahr disease.
  • Exemplary muscular dystrophies or related diseases are Becker's muscular dystrophy, Duchenne muscular dystrophy, myotonic dystrophy, limb-girdle muscular dystrophy, Landouzy-Dejerine muscular dystrophy, facioscapulohumeral muscular dystrophy (Steinert's disease), myotonia congenita, Thomsen's disease, and Pompe's disease.
  • Muscle wasting can be associated with cancer, AIDS, congestive heart failure, and chronic obstructive pulmonary disease, as well as include necrotizing myopathy of intensive care.
  • Compounds and methods of the invention can additionally be used to boost the immune system, whether or not the patient being treated has an immunocompromising condition.
  • the compounds described herein can be used in a method to strengthen the immune system during immunization, e.g., by functioning as an adjuvant, or by being combined with an adjuvant.
  • kits may include instructions for use of the compounds of the invention in a screening method or as a therapy as described herein.
  • the [1,2,3]thiadiazole derivatives are prepared according to the method outlined in Scheme 1.
  • Meldrum's acid was treated with acyl chlorides in the presence of pyridine to give ⁇ -ketoester (step (a); Oikawa et al., J. Org. Chem. 43: 2087 (1978)).
  • the esters were allowed to react with mono-Boc-hydrazine in the presence of a catalytic amount of p-toluenesulfonic acid (p-TsOH) to give the corresponding imines (step (b); Thomas et al., J. Med. Chem. 28: 442 (1985)).
  • ⁇ -substituted ( ⁇ )-2-chloro-6-fluorobenzylamines were prepared according to Scheme 3 (Polniaszek et al., J. Org. Chem., 55: 215 (1990)). 2-Chloro-6-fluorophenyl ketones were reduced with borane-tetrahydrofuran complex to give the secondary alcohols (step (a)). The alcohols were converted to the corresponding phthalimides via a Mitsonobu reaction (step (b)). The benzylamines were isolated following treatment with hydrazine monohydrate (step (c)).
  • step (d) (S)-1-(2-Chloro-6-fluorophenyl)ethylamine was prepared by treating the benzonitrile starting material with methyl magnesium chloride followed by treatment with acetic anhydride to give ⁇ -enamide (step (d)).
  • step (d) Asymmetric hydrogenation in the presence of the chiral catalyst (S,S)-Me-BPE-Rh gave the corresponding amide (step (e); Burk et al., J. Am. Chem. Soc. 118: 5142 (1996)).
  • Acid hydrolysis of the amide yielded the optically pure amine (step (f)), isolated as the hydrochloride salt.
  • 3-Alkyl pyrrole derivatives were prepared according to the procedure outlined in Scheme 1.
  • Glycine ethyl ester, 5, was treated with p-toluenesulfonyl chloride (Ts—Cl) to give 6, which upon treatment with 4-diethylaminobutan-2-one in the presence of t-BuOK gave 7.
  • Dehydration with POCl 3 yielded the dihydropyrrole derivative 8.
  • Elimination in the presence of sodium ethoxide generated pyrrole derivative 9.
  • the pyrrole nitrogen was deprotonated with sodium hydride and alkylated to give 10.
  • the ester was hydrolyzed with aqueous KOH in MeOH and then the corresponding acid 11 was converted to amides (81), (82), and (83) using EDCI.
  • 1-Alkyl pyrrole derivatives were prepared according to the procedure outlined in Scheme 2. Methyl 2-pyrrolecarboxylate, 100, was deprotonated using sodium hydride and then alkylated to give 101. The ester was hydrolyzed to give acid 102, which was coupled to a 2-chloro-6-fluorobenzylamine utilizing EDCI to give amide 103. Regioselective bromination with NBS gave 104. Finally, conversion of the aryl bromide to a nitrile was accomplished utilizing a palladium-mediated coupling with zinc cyanide to give 105 in excellent yield.
  • Cyano- and halo-substituted pyrrole derivatives were prepared according to the procedure outlined in Scheme 3.
  • 1-Alkylpyrroles 101 were allowed to react with chlorosulfonyl isocyanate to give two readily separable regioisomeric cyanopyrrole derivatives 106 and 107 (1:4). Each was converted the corresponding acid and then coupled with 2-chloro-6-fluorobenzylamine to give 108 and 109, respectively.
  • Methyl 2-pyrrolecarboxylate, 100 was also regioselectively chlorinated with t-butyl hypochlorite to give 110. N-alkylation gave 111 and subsequent ester hydrolysis yielded 112, which was coupled with 2-chloro-6-fluorobenzylamine to give compound (78).
  • necroptosis activity was performed using a FADD-deficient variant of human Jurkat T cells treated with TNF- ⁇ .
  • cells 500,000 cells/mL, 100 ⁇ L per well in a 96-well plate
  • 10 ng/mL of human TNF- ⁇ in the presence of increasing concentration of test compounds for 24 hours at 37° C. in a humidified incubator with 5% CO 2 followed by ATP-based viability assessment.
  • Stock solutions (30 mM) in DMSO were initially prepared and then diluted with DMSO to give testing solutions, which were added to each test well. The final DMSO concentration was 0.5%. Eleven compound test concentrations (0.030-100 ⁇ M) were used. Each concentration was done in duplicate.
  • Cell viability assessments were performed using a commercial luminescent ATP-based assay kit (CellTiter-Glo, Promega, Madison, Wis.) according to the manufacturer's instructions. Briefly, 40 ⁇ L of the cell lysis/ATP detection reagent was added to each well. Plates were incubated on a rocking platform for 10 minutes at room temperature and luminescence was measured using a Wallac Victor 3 plate-reader (Perkin Elmer, Wellesley, Mass.). Cell viability was expressed as a ratio of the signal in the well treated with TNF- ⁇ and compound to the signal in the well treated with compound alone. This was done to account for nonspecific toxicity, which in most cases was ⁇ 10%. EC 50 values were calculated using nonlinear regression analysis of sigmoid dose-response (variable slope) curves from plots of log[I] verses viability values.
  • Table 2 provides EC 50 determinations of necroptosis inhibition in FADD-deficient Jurkat T cells treated with TNF- ⁇ by compounds of the invention having formula (I-a). The standard deviation is ⁇ 10%.
  • Table 3 provides the EC 50 determinations of necroptosis inhibition in FADD-deficient Jurkat T cells treated with TNF- ⁇ by compounds having Formula (I-b).
  • the corresponding secondary amine (13) and imide (16) derivatives of 32 were inactive.
  • the benzylamide was necessary, with the homologous phenethyl amide (51) and the truncated anilide (52) being significantly less active.
  • Compound 52 was prepared in low yield (10%) by allowing 15 to react with 2,6-difluoroaniline in THF and pyridine at room temperature.
  • Microsome stability was determined in pooled mouse liver microsomes.
  • the compounds described herein may show universal activity in a broad range of necroptosis cellular systems or activity may be restricted to specific cell types/stimuli.
  • the compounds described herein are expected to offer advantages, for example, under conditions where molecule specificity may be beneficial, such as treating chronic conditions like neurodegenerative diseases.

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