WO2012021800A2 - Inhibiteurs de la caspase utilisés comme agents thérapeutiques contre une lésion neurale ou d'organe et pour l'imagerie - Google Patents

Inhibiteurs de la caspase utilisés comme agents thérapeutiques contre une lésion neurale ou d'organe et pour l'imagerie Download PDF

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WO2012021800A2
WO2012021800A2 PCT/US2011/047579 US2011047579W WO2012021800A2 WO 2012021800 A2 WO2012021800 A2 WO 2012021800A2 US 2011047579 W US2011047579 W US 2011047579W WO 2012021800 A2 WO2012021800 A2 WO 2012021800A2
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substituted
unsubstituted
injury
alkyl
compound
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WO2012021800A3 (fr
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Kevin Ka-Wang Wang
Zhiqun Zhang
Xue-Min Cheng
Bradley Caprathe
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Banyan Biomarkers
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C07K5/06052—Val-amino acid

Definitions

  • Acute brain injury can take on different forms. Nerve cells
  • nerve cells in the nervous system including the brain and spinal cord and the peripheral nervous system can become injured.
  • nerve cells can be injured following traumatic brain injury (TBI), stroke (ischemic or hemorrhagic), spinal cord injury, electrical discharge-induced injury such as epilepsy, exposure to acute drug overdose or to substance abuse (such as "recreational drugs") of even a single recreational use of abused substances such as "Speed” or methamphetamine (Meth) or chemically related
  • Ecstasy or 3,4-methylenedioxy-methamphetamine (MDMA). Yet, currently there are no simple, rapid and non-invasive methods to assess the extent of neurotoxic cell loss or brain damage resulting from these conditions in the emergency room and to monitor the long-term neurotoxic impact of such conditions.
  • the neural pathways of a mammal are particularly at risk if neurons are subjected to mechanical or chemical trauma or to neuropathic degeneration sufficient to put the neurons that define the pathway at risk of dying.
  • a host of neuropathies some of which affect only a subpopulation or a system of neurons in the peripheral or central nervous systems have been identified to date.
  • the neuropathies which may affect the neurons themselves or the associated glial cells, may result from cellular metabolic dysfunction, infection, exposure to toxic agents, autoimmunity dysfunction, malnutrition or ischemia. In some cases the cellular dysfunction is thought to induce cell death directly. In other cases, the neuropathy may induce sufficient tissue necrosis to stimulate the body's
  • Stroke is a leading cause of death in the developed world. It may be caused by reduced blood flow or ischemia that results in deficient blood supply and death of tissues in one area of the brain (infarction).
  • causes of ischemic strokes include blood clots that form in the blood vessels in the brain (thrombus) and blood clots or pieces of atherosclerotic plaque or other material that travel to the brain from another location (emboli). Bleeding (hemorrhage) within the brain may also cause symptoms that mimic stroke. The ability to detect such injury is lacking in the prior art.
  • Mammalian neural pathways also are at risk due to damage caused by neoplastic lesions.
  • Neoplasias of both the neurons and glial cells have been identified.
  • Transformed cells of neural origin generally lose their ability to behave as normal differentiated cells and can destroy neural pathways by loss of function.
  • the proliferating tumors may induce lesions by distorting normal nerve tissue structure, inhibiting pathways by compressing nerves, inhibiting cerebrospinal fluid or blood supply flow, and/or by stimulating the body's immune response.
  • Metastatic tumors which are a significant cause of neoplastic lesions in the brain and spinal cord, also similarly may damage neural pathways and induce neuronal cell death.
  • proteases include cysteine proteases (calpain-1 and -2, caspase-3, cathepsin-B and -L [Yamashima, (2000). Prog. Neurobiol. 62, 273-295], metalloproteases (e.g., MMP-2 and -9) [Asahi., Asahi Jung del Fini Lo (2000). J. Cereb. Blood Flow Metab. 20, 1681 -1689; Clark, Bou., Chapman Edwards (1997) Neurosci. Lett.
  • Calpain inhibitors have demonstrated neuroprotective effects against brain injury [Kupina, Nath, Bernath, Inoue, Azuma, Yuen, Wang, and. Hall, (2001 ) J. Neurotrauma. 18, 1229-1240; Li, Howlett, He, Miyashita, Siddiqui MShuaib. (1998) Neurosci Lett. 1998 May 8; 247(1 ):17-20; Markgraf, Velayo, Johnson, McCarty, Medhi, Koehl,
  • proteases are also known.
  • organ injury comprises any damage, injury or infection, functional failure to specific organs such as liver, kidney, prostate, lung, skeletal muscle, heart, pancreas, stomach, small and large intestine, bladder and the reproductive system (Sindram et al.
  • neural or organ injury-specific imaging agents can be detected by positron emission tomography (PET), single photon emission computed tomography (SPECT), radioscintigraphy, magnetic resonance imaging (MRI), computed tomography (CT scan).
  • PET positron emission tomography
  • SPECT single photon emission computed tomography
  • MRI magnetic resonance imaging
  • CT scan computed tomography
  • compositions useful as caspase inhibitors are useful for the treatment of neural or organ injury.
  • Other compounds are useful as neural and organ-specific imaging agents.
  • neural and organ damage is detected via proteases and inhibitors that are specific to injury or damage to the central and peripheral nervous system as well as other organs.
  • TBI and MethlMDMA exposure differentially trigger the over- activation of two cellular proteases (calpain and caspase) in injured neurons, leading to two different forms of cell death (necrosis-acute cell death and apoptosis-delayed cell death).
  • other protease might also be over-activated, including cathepsins, proteasome,
  • protease inhibitor-based imaging ligands e.g. withradionuclide label
  • neural or organ injury-specific imaging agents e.g. withradionuclide label
  • the compounds disclosed herein may be represented by formula (a-l) or salts thereof:
  • R and R are as defined below and the compound optionally comprises a radionuclide selected from the group consisting of 11 C, 14 C, 3 H,
  • the compounds disclosed herein may be represented by formula (b-l) or salts thereof:
  • R an onally comprises a radionuclide selected from the group consisting of 11 C, 14 C, 3 H, 18 F, 99m Tc, 186 Re, 188 Re, 111 ln, 67 Ga, 68 Ga, 201 TI, 52 Fe, 203 Pb, 58 Co, 64 Cu, 123 l, 124 l, 125 l, 131 l, 210 At, 76 Br, 77 Br, 32 P, 33 P and 35 S.
  • the compounds disclosed herein may be represented by formula (I) or salts thereof:
  • R and tionally comprises a radionuclide selected from the group consisting of 11 C, 14 C, 3 H, 8F, 99m Tc, 186 Re, 188 Re, 111 ln, 67 Ga, 68 Ga, 201 TI, 52 Fe, 203 Pb, 58 Co, 64 Cu, 123 l, 124 l, 125 l, 3 l, 210 At, 76 Br, 77 Br, 32 P, 33 P and 35 S.
  • a radionuclide selected from the group consisting of 11 C, 14 C, 3 H, 8F, 99m Tc, 186 Re, 188 Re, 111 ln, 67 Ga, 68 Ga, 201 TI, 52 Fe, 203 Pb, 58 Co, 64 Cu, 123 l, 124 l, 125 l, 3 l, 210 At, 76 Br, 77 Br, 32 P, 33 P and 35 S.
  • this disclosure further provides methods for neural imaging in a patient.
  • One method comprises administering a neural injury specific imaging agent to a patient, wherein the neural injury specific imaging agent comprises said compound or salt of formula (I); and detecting the neural injury specific imaging agent; wherein the neural injury comprises any one of: damage to the nervous system, including retinal ganglion cells; a traumatic brain injury; a stroke related injury; cerebral ischemia, shaken baby syndrome, a cerebral aneurism related injury; demyelinating diseases; a spinal cord injury, including monoplegia, diplegia, paraplegia, hemiplegia and quadriplegia; a neuroproliferative disorder or neuropathic pain syndrome; stroke, concussion, post-concussion syndrome, cerebral ischemia,
  • neurodegenerative diseases brain injuries, infection or neuropathies; and imaging neural damage in the patient or animal.
  • the present disclosure also discloses a method of organ or multiple-organ injury imaging in a patient.
  • the method comprises administering to a patient an organ injury specific imaging agent wherein the organ injury or multi-organ injury specific imaging agent comprises said compound or salt of formula (I); and detecting said organ injury specific imaging agent; thereby imaging organ damage in the patient.
  • a method of determining the location of organ or multi-organ injury in a patient comprises administering the imaging agent of formula (lb) to a patient suspected of having an organ or multi-organ injury; and detecting the location of the imaging agent in the patient thereby locating the organ or multi-organ injury.
  • neural injury is caused by traumatic brain injury, stroke, cerebral ischemia, shaken baby syndrome, cerebral aneurism, demyelinating disease, spinal cord injury, a neuroproliferative disorder, neuropathic pain, concussion, infection, or neuropathy.
  • disclosed compounds may be represented by formula (a-ll) or salts thereof:
  • disclosed compounds may be represented by formula (b-ll) or salts thereof:
  • disclosed compounds may be represented by formula (II) or salts thereof:
  • Activity of an enzyme is the amount of product produced per unit time at a fixed temperature and pH.
  • Specific activity of an enzyme is the amount of product produced per unit time per mg protein.
  • Substrate is the target protein that the enzyme catalyzes.
  • the International Union of Biochemistry (I.U.B.) initiated standards of enzyme nomenclature which recommend that enzyme names indicate both the substrate acted upon and the type of reaction catalyzed.
  • the enzyme uricase is called urate: 0 2 oxidoreductase
  • the enzyme glutamic oxaloacetic transaminase (GOT) is called L-aspartate: 2- oxoglutarate aminotransferase.
  • Inhibitors refers to any molecule that inhibits the activity of any enzyme that is indicative of neural damage. Examples of the desired target families are shown in Table 1 .
  • “Inhibitory concentration” is intended to mean the concentration at which the "potential inhibitor of caspase” compounds screened in the enzyme assays inhibit a measurable percentage of caspase-3.
  • “inhibitory concentration” values range from IC50 to IC90, and are preferably, IC50, ICeo, IC 70 , ICso, or IC 90 , which represent 50%, 60%, 70%, 80% and 90% reduction in caspase mediated damage.
  • the concentration ranges the concentration at which the "potential inhibitor of caspase” compounds screened in the enzyme assays inhibit a measurable percentage of caspase-3.
  • Examples of “inhibitory concentration” values range from IC50 to IC90, and are preferably, IC50, ICeo, IC 70 , ICso, or IC 90 , which represent 50%, 60%, 70%, 80% and 90% reduction in caspase mediated damage.
  • the inhibitor concentration ranges the concentration at which the “potential inhibitor of caspase” compounds screened in the
  • inhibitor concentration is measured as the IC50 value. It is understood that a designation for IC50 is the half maximal inhibitory concentration.
  • Neuronal cells are cells that reside in the brain, central and peripheral nerve systems, including, but not limited to, nerve cells, glial cell, oligodendrocyte, microglia cells or neural stem cells.
  • Neuronal/organ injury specific or neuronally enriched proteins are defined herein, as proteins that are present in neural cells and not in non- neuronal cells, such as, for example, cardiomyocytes, myocytes, in skeletal muscles, hepatocytes, kidney cells and cells in testis.
  • Neurodegenerative disorders Parkinson's; Alzheimer's or autoimmune disorders (multiple sclerosis) of the central nervous system; memory loss; long term and short term memory disorders; learning disorders; autism, depression, benign forgetfulness, childhood learning disorders, close head injury, and attention deficit disorder; autoimmune disorders of the brain, neuronal reaction to viral infection; brain damage; depression; psychiatric disorders such as bi-polarism, schizophrenia; narcolepsy/sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy); severance of nerves or nerve damage; severance of the cerebrospinal nerve cord (CNS) and any damage to brain or nerve cells; neurological deficits associated with AIDS; tics (e.g. Giles de la Tourette's syndrome);
  • Huntington's chorea schizophrenia, traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, MS and motor neuron disease, ataxias, muscular rigidity (spasticity) and temporomandibular joint dysfunction; Reward Deficiency Syndrome (RDS) behaviors in a subject.
  • diseases such as diabetes, MS and motor neuron disease, ataxias, muscular rigidity (spasticity) and temporomandibular joint dysfunction
  • RDS Reward Deficiency Syndrome
  • “Injury or neural injury” is intended to include a damage which directly or indirectly affects the normal functioning of the CNS or PNS.
  • the injury can be damage to retinal ganglion cells; a traumatic brain injury; a stroke related injury; a cerebral aneurism related injury;
  • demyelinating diseases such as multiple sclerosis; a spinal cord injury, including monoplegia, diplegia, paraplegia, hemiplegia and quadriplegia; a neuroproliferative disorder or neuropathic pain syndrome.
  • CNS injuries or disease include TBI, stroke, concussion (including post- concussion syndrome), cerebral ischemia, neurodegenerative diseases of the brain such as Parkinson's disease, Dementia Pugilistica, Huntington's disease and Alzheimer's disease, brain injuries secondary to seizures which are induced by radiation, exposure to ionizing or iron plasma, nerve agents, cyanide, toxic concentrations of oxygen, neurotoxicity due to CNS malaria or treatment with anti-malaria agents, malaria pathogens, injury due to trypanosomes, and other CNS traumas.
  • PNS injuries or diseases include neuropathies induced either by toxins (e.g. cancer chemotherapeutic agents) diabetes, peripheral trauma or any process that produced pathological destruction of peripheral nerves and/or their myel
  • Stroke is art recognized and is intended to include sudden diminution or loss of consciousness, sensation, and voluntary motion caused by rapture or obstruction (e.g. by a blood clot) of an artery of the brain.
  • Traumatic Brain Injury is art recognized and is intended to include the condition in which, a traumatic blow to the head causes damage to the brain, often without penetrating the skull.
  • the initial trauma can result in expanding hematoma, subarachnoid hemorrhage, cerebral edema, raised intracranial pressure (ICP), and cerebral hypoxia, which can, in turn, lead to severe secondary events due to low cerebral blood flow (CBF).
  • ICP intracranial pressure
  • CBF cerebral blood flow
  • metal means a pharmaceutical comprising a metal.
  • the metal is the cause of the imagable signal in diagnostic applications and the source of the cytotoxic radiation in radiotherapeutic applications. Radiopharmaceuticals are
  • Radionuclide coordination sphere is composed of one or more chelators or bonding units from one or more reagents and one or more ancillary or co-ligands, provided that there are a total of two types of ligands, chelators or bonding units.
  • a radiopharmaceutical comprised of one chelator or bonding unit from one reagent and two of the same ancillary or co-ligands and a
  • radiopharmaceutical comprised of two chelators or bonding units from one or two reagents and one ancillary or co-ligand are both considered to be comprised of binary ligand systems.
  • the radionuclide coordination sphere is composed of one or more chelators or bonding units from one or more reagents and one or more of two different types of ancillary or co-ligands, provided that there are a total of three types of ligands, chelators or bonding units.
  • a radiopharmaceutical comprised of one chelator or bonding unit from one reagent and two different ancillary or co-ligands is considered to be comprised of a ternary ligand system.
  • radiopharmaceuticals and in diagnostic kits useful for the preparation of said radiopharmaceuticals can comprise one or more oxygen, nitrogen, carbon, sulfur, phosphorus, arsenic, selenium, and tellurium donor atoms.
  • a ligand can be a transfer ligand in the synthesis of a radiopharmaceutical and also serve as an ancillary or co-ligand in another radiopharmaceutical. Whether a ligand is termed a transfer or ancillary or co-ligand depends on whether the ligand remains in the radionuclide coordination sphere in the
  • radiopharmaceutical which is determined by the coordination chemistry of the radionuclide and the chelator or bonding unit of the reagent or reagents.
  • a "chelating group” is a moiety or group that binds to a metal ion through the formation of chemical bonds with one or more donor atoms. In some embodiments, the chelating group binds or complexes the metal ion via two or more separate bindings. In some embodiments, the chelating group binds or complexes the metal ion via four or more separate bindings. In some embodiments, the chelating group bind or complexes the metal ion via six or more separate bindings.
  • Radionuclide refers to an atom with an unstable nucleus which undergoes radioactive decay.
  • Alkyl by itself or as part of another substituent refers to a hydrocarbon group which may be linear, cyclic, or branched or a combination thereof having the number of carbon atoms designated (i.e., d- 8 means one to eight carbon atoms).
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, cyclopentyl, (cyclohexyl)methyl, cyclopropylmethyl,
  • Alkyl groups can be substituted or unsubstituted, unless otherwise indicated. Examples of substituted alkyl include haloalkyl, thioalkyl, aminoalkyl, and the like.
  • Alkoxy refers to -O-alkyl. Examples of an alkoxy group include methoxy, ethoxy, n-propoxy etc.
  • Alkenyl refers to an unsaturated hydrocarbon group which may be linear, cyclic or branched or a combination thereof. In some
  • alkenyl groups with 2-8 carbon atoms can be used.
  • the alkenyl group may contain 1 , 2 or 3 carbon-carbon double bonds.
  • alkenyl groups include ethenyl, n-propenyl, isopropenyl, n-but-2-enyl, n- hex-3-enyl, cyclohexenyl, cyclopentenyl and the like.
  • Alkenyl groups can be substituted or unsubstituted, unless otherwise indicated.
  • Alkynyl refers to an unsaturated hydrocarbon group which may be linear, cyclic or branched or a combination thereof. In some
  • alkynyl groups with 2-8 carbon atoms can be used.
  • the alkynyl group may contain 1 , 2 or 3 carbon-carbon triple bonds.
  • Examples of alkynyl groups include ethynyl, n-propynyl, n-but-2-ynyl, n-hex-3-ynyl and the like.
  • Alkynyl groups can be substituted or unsubstituted, unless otherwise indicated.
  • Aryl refers to a polyunsaturated, aromatic hydrocarbon group having a single ring (monocyclic) or multiple rings (bicyclic), which can be fused together or linked covalently.
  • aryl groups with 6-10 carbon atoms can be used, where this number of carbon atoms can be designated by C 6 -io, for example.
  • Examples of aryl groups include phenyl and naphthalene-1 -yl, naphthalene-2-yl, biphenyl and the like.
  • Aryl groups can be substituted or unsubstituted, unless otherwise indicated.
  • Halo or "halogen”, by itself or as part of a substituent refers to a chlorine, bromine, iodine, or fluorine atom.
  • Haloalkyl as a substituted alkyl group, refers to a monohaloalkyl or polyhaloalkyl group, most typically substituted with from 1-3 halogen atoms. Examples include 1-chloroethyl, 3-bromopropyl, trifluoromethyl and the like.
  • Heterocyclyl refers to a saturated or unsaturated non-aromatic ring containing at least one heteroatom (typically 1 to 5 heteroatoms) selected from nitrogen, oxygen or sulfur.
  • the heterocyclyl ring may be monocyclic or bicyclic. In some embodiments, these groups contain 0-5 nitrogen atoms, 0-2 sulfur atoms and 0-2 oxygen atoms. In some
  • these groups contain 0-3 nitrogen atoms, 0-1 sulfur atoms and 0-1 oxygen atoms.
  • heterocycle groups include pyrrolidine, piperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, 1 ,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S- dioxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine and the like.
  • heterocyclic groups are monocyclic, though they may be fused or linked covalently to an aryl or heteroaryl ring system.
  • heterocyclic groups may be represented by formula (AA) below:
  • R A , R B , R C , R D , R E , R F , and R 9 are independently selected from the group consisting of hydrogen, halogen, unsubstituted or substituted d-s alkyl, unsubstituted or substituted C 2 -8 alkenyl, unsubstituted or substituted C 2 -8 alkynyl, -COR H , -C0 2 R H , -CONFER', -NR H COR', -S0 2 R H , -S0 2 NR H R I , -N
  • R n , R° and R p are independently an unsubstituted C-i-s alkyl. Additionally, any two of R a , R b , R c , R d , R e , R f and R 9 may be combined to form a bridged or spirocyclic ring system.
  • the number of R a + R b + R c + R d groups that are other than hydrogen is 0, 1 or 2.
  • each of R a , R b , R c , R d , R e , R f , and R 9 is independently selected from the group consisting of hydrogen, halogen, unsubstituted or substituted Ci_ 8 alkyl, -COR h , -C0 2 R h , -CONR h R h , -NR h COR h , -S0 2 R h , -S0 2 NR h R i , -NS0 2 R h R, -NR h R i , and -OR h , wherein R h and R' are independently selected from the group consisting of hydrogen and unsubstituted Ci-s alkyl and wherein the aliphatic portions of each of the R a , R b , R
  • each of R a , R b , R c , R d , R e , R f , and R 9 is independently hydrogen or Ci -4 alkyl. In another embodiment, at least three of R a , R b , R c , R d , R e , R f , and R 9 are hydrogen.
  • Heteroaryl refers to an aromatic group containing at least one heteroatom, where the heteroaryl group may be monocyclic or bicyclic.
  • Examples include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines, benzothiazolyl, benzofuranyl, benzothienyl, indolyl, azaindolyl, azaindazolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, ind
  • heteroaryl groups are those having at least one aryl ring nitrogen atom, such as quinolinyl, quinoxalinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzothiazolyl, indolyl, quinolyl, isoquinolyl and the like.
  • 6-ring heteroaryl systems include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl and the like.
  • 5-ring heteroaryl systems include isothiazolyl, pyrazolyl, imidazolyl, thienyl, furyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, thiazolyl and the like.
  • Heterocyclyl and heteroaryl can be attached at any available ring carbon or heteroatom.
  • Each heterocyclyl and heteroaryl may have one or more rings. When multiple rings are present, they can be fused together or linked covalently.
  • Each heterocyclyl and heteroaryl must contain at least one heteroatom (typically 1 to 5 heteroatoms) selected from nitrogen, oxygen or sulfur. In some embodiments, these groups contain 0-5 nitrogen atoms, 0-2 sulfur atoms and 0-2 oxygen atoms. In some embodiments, these groups contain 0-3 nitrogen atoms, 0-1 sulfur atoms and 0-1 oxygen atoms. Heterocyclyl and heteroaryl groups can be substituted or unsubstituted, unless otherwise indicated.
  • the substitution may be on a carbon or heteroatom.
  • the resulting group may have either a carbonyl (-C(O)-) or a N-oxide (-N + -0 ).
  • Suitable substituents for substituted aryl, substituted heteroaryl and substituted heterocyclyl include halogen, -CN, -C0 2 R , -C(0)R ,
  • R', R" and R' each independently refer to a variety of groups including hydrogen, substituted or unsubstituted C-i-s alkyl, substituted or unsubstituted C 2 - 8 alkenyl, substituted or unsubstituted C 2 - 8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryloxyalkyl.
  • R' and R" When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring (for example, -NR'R" includes 1 -pyrrolidinyl and 4-morpholinyl). Furthermore, R' and R", R" and R" ⁇ or R' and R'” may together with the atom(s) to which they are attached, form a substituted or unsubstituted 5- ,6- or 7-membered ring.
  • Two of the substituents on adjacent atoms of an aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C(O)- (CH 2 ) q -U-, wherein T and U are independently -NR""-, -0-, -CH 2 - or a single bond, and q is an integer of from 0 to 2.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A'-(CH 2 ) r -B'-, wherein A' and B' are independently -CH 2 -, -0-, -NR""-, -S-, -S(O)-, -S(0) 2 -, -S(0) 2 NR""- or a single bond, and r is an integer of from 1 to 3.
  • One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula - (CH 2 ) s -X-(CH 2 )r, where s and t are independently integers of from 0 to 3, and X is -0-, -NR""-, -S-, -S(O)-, -S(0) 2 -, or -S(0) 2 NR'-.
  • R"" is selected from hydrogen or unsubstituted Ci-s alkyl.
  • Heteroatom is meant to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutically acceptable salt” refers to a salt which is acceptable for administration to a patient, such as a mammal (e.g., salts having acceptable mammalian safety for a given dosage regime). Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids, depending on the particular substituents found on the compounds described herein. When compounds disclosed herein contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • Salts derived from pharmaceutically- acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like.
  • Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary, tertiary and quaternary amines, including substituted amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, ⁇ , ⁇ '- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, proca
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • suitable inert solvent include those derived from inorganic acids such as hydrochloric,
  • the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the
  • salt thereof refers to a compound formed when the hydrogen of an acid is replaced by a cation, such as a metal cation or an organic cation and the like.
  • the salt is a pharmaceutically- acceptable salt, although this is not required for salts of intermediate compounds which are not intended for administration to a patient.
  • compounds disclosed herein can be in a prodrug form.
  • Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds disclosed herein.
  • prodrugs can be converted to the compounds disclosed herein by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
  • Prodrugs may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds.
  • Prodrugs include compounds wherein hydroxyl, amino, sulfhydryl, or carboxyl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, sulfhydryl, or carboxyl group respectively.
  • Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds disclosed herein. Preparation, selection, and use of prodrugs is discussed in T. Higuchi and V.
  • “Therapeutically effective amount” refers to an amount sufficient to effect treatment when administered to a patient in need of treatment.
  • Treating” or “treatment” as used herein refers to the treating or treatment of a disease or medical condition (such as a neural injury, stroke, traumatic brain injury, ischemia, and the like) in a patient, such as a mammal (particularly a human or a companion animal) which includes ameliorating the disease or medical condition, i.e., eliminating or causing regression of the disease or medical condition in a patient; suppressing the disease or medical condition, i.e., slowing or arresting the development of the disease or medical condition in a patient; or alleviating the symptoms of the disease or medical condition in a patient.
  • a disease or medical condition such as a neural injury, stroke, traumatic brain injury, ischemia, and the like
  • a patient such as a mammal (particularly a human or a companion animal) which includes ameliorating the disease or medical condition, i.e., eliminating or causing regression of the disease or medical condition in a patient; suppressing the disease or medical condition, i.e., slowing or arresting
  • Imaging agents comprise a radionuclide.
  • a radionuclide is an atom with an unstable nucleus which undergoes radioactive decay. Any suitable radionuclide known to one skilled in the art which is detectable may be employed.
  • the radionuclide is detectable at low concentrations, usually less than micromolar, possibly less than nanomolar, and can be readily distinguished from other molecules, due to differences in a radioactivity.
  • radionuclides include, for example, 11 C, 14 C, 3 H, 18 F, 99m Tc, 186 Re, 188 Re, 111 ln, 67 Ga, 68 Ga, 201 TI, 52 Fe, 203 Pb, 58 Co, 64 Cu, 123 l, 124 l, 125 l, 131 l, 210 At, 76 Br,
  • the radionuclide is covalently bonded to or ligated to a compound of formula (a-l):
  • R is hydrogen, substituted or unsubstituted d-Cs alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, or L- R Q ;
  • R G is hydrogen, halogen, -OR 2 , -SR 1 , -S(0)R 1 , -S(0) 2 R 1 , -S(0) 2 OR 2 , -OS(0) 2 OR 2 , - P(R 1 ) 2 , P(OR 2 ) 2 , -P(0)(OR 2 ) 2 , -OP(0)OR 2 , substituted or unsubstituted C C 4 alkyl, -0-L-R Q , or L- R Q ,
  • R 1 is selected from the group consisting of substituted or unsubstituted d-Cs alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, aryl, heteroaryl, alkylaryl, and alkylheteroaryl;
  • R 2 is selected from the group consisting of hydrogen, substituted or unsubstituted Ci-C 8 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, aryl, heteroaryl, alkylaryl, and alkylheteroaryl;
  • L is -(CH 2 ) m - or a bond
  • n is 0 or an integer from 1 to 10;
  • R Q is a chelating group
  • the compound or pharmaceutically acceptable salt thereof comprising a radionuclide or covalently bonded or ligated to a radionuclide, wherein said radionuclide is 11 C, 14 C, 3 H, 18 F, 99m Tc, 186 Re, 188 Re, 111 ln, 67 Ga, 68 Ga, 201 TI, 52 Fe, 203 Pb, 58 Co, 64 Cu, 123 l, 124 l, 125 l, 131 l, 210 At, 76 Br, 77 Br, 32 P, 33 P, or 35 S.
  • the radionuclide is covalently bonded to or ligated to a compound of formula (b-l):
  • R is hydrogen, substituted or unsubstituted d-Cs alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, or L- R Q ;
  • R G is hydrogen, halogen, -OR 2 , -SR 1 , -S(0)R 1 , -S(0) 2 R 1 , -S(0) 2 OR 2 , -OS(0) 2 OR 2 , - P(R 1 ) 2 , P(OR 2 ) 2 , -P(0)(OR 2 ) 2 , -OP(0)OR 2 , substituted or unsubstituted C C 4 alkyl, -0-L-R Q , or L- R Q ,
  • R 1 is selected from the group consisting of substituted or unsubstituted d-Cs alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, aryl, heteroaryl, alkylaryl, and alkylheteroaryl;
  • R 2 is selected from the group consisting of hydrogen, substituted or unsubstituted Ci-C 8 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, aryl, heteroaryl, alkylaryl, and alkylheteroaryl;
  • L is -(CH 2 )m- or a bond
  • n is 0 or an integer from 1 to 10;
  • R Q is a chelating group
  • the compound or pharmaceutically acceptable salt thereof comprising a radionuclide or covalently bonded or ligated to a radionuclide, wherein said radionuclide is 11 C, 14 C, 3 H, 18 F, 99m Tc, 186 Re, 188 Re, 111 ln, 67 Ga, 68 Ga, 201 TI, 52 Fe, 203 Pb, 58 Co, 64 Cu, 123 l, 124 l, 125 l, 131 l, 210 At, 76 Br, 77 Br, 32 P, 33 P, or 35 S.
  • the radionuclide is covalently bonded to or ligated to a compound of formula (I):
  • R is hydrogen, substituted or unsubstituted C-i-Cs alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, or L- R Q ;
  • R G is hydrogen, halogen, -OR 2 , -SR 1 , -S(0)R 1 , -S(0) 2 R 1 , -S(0) 2 OR 2 , -OS(0) 2 OR 2 , - P(R 1 ) 2 , P(OR 2 ) 2 , -P(0)(OR 2 ) 2 , -OP(0)OR 2 , substituted or unsubstituted C C 4 alkyl, -0-L-R Q , or L- R Q ,
  • R 1 is selected from the group consisting of substituted or unsubstituted C-i-Cs alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, aryl, heteroaryl, alkylaryl, and alkylheteroaryl;
  • R 2 is selected from the group consisting of hydrogen, substituted or unsubstituted C-i-Cs alkyl, substituted or unsubstituted Ca-Cs cycloalkyl, aryl, heteroaryl, alkylaryl, and alkylheteroaryl;
  • L is -(CH 2 ) m - or a bond
  • n is 0 or an integer from 1 to 10;
  • R Q is a chelating group; the compound or pharmaceutically acceptable salt thereof comprising a radionuclide or covalently bonded or ligated to a radionuclide, wherein said radionuclide is 11 C, 14 C, 3 H, 18 F, 99m Tc, 186 Re, 188 Re, 111 ln, 67 Ga, 68 Ga, 201 TI, 52 Fe, 203 Pb, 58 Co, 64 Cu, 123 l, 124 l, 125 l, 131 l, 210 At, 76 Br, 77 Br, 32 P, 33 P, or 35 S.
  • heterocyclylcarbonyloxy alkylideneaminooxy, carboxy, alkoxycarbonyl, aryloxycarbonyl, cycloalkyloxycarbonyl, heterocyclylalkyloxycarbonyl- amino, ureido, alkylamino, dialkylamino, arylamino, diarylamino, heterocyclylamino, formylamino, alkylcarbonylamino, arylcarbonylamino, heterocyclylcarbonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, heterocyclylaminocarbonyl, alkoxycarbonylamino, hydroxyaminocarbonyl alkoxyimino,
  • each of the above substituents may be further substituted by one or more of the aforementioned groups.
  • each of the aforementioned groups that is present is either unsubstituted, or is substituted with up to three groups selected from halo, Ci-C 4 alkyl, Ci-C 4 -alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, CN, CONR' 2 , COOR', OH, -NR' 2 , and -S(O) q R', wherein q is 0-2 and each R' is independently H or Ci-C 4 alkyl.
  • R, R G , R 1 , and R 2 is substituted with one or more of the
  • each of the aforementioned groups that is present is either unsubstituted, or is substituted with one group selected from halo, Ci-C 4 alkyl, Ci-C 4 -alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, CN, CONR'2, COOR', OH, -NR' 2 , and -S(O) q R', wherein q is 0-2 and each R' is independently H or Ci-C alkyl.
  • the radionuclide is covalently attached to the compound of formula (I).
  • Radionuclides for covalent attachment to the compounds of formula (I) include 11 C, 14 C, 3 H, 18 F, 123 l, 124 l, 125 l, 3 l , 76 Br, 77 Br, 32 P, 33 P and 35 S.
  • the radionuclides for covalent attachment to the compounds of formula (I) include 18 F, 123 l, 124 l, 125 l, 3 l, 76 Br, and 77 Br.
  • R can be selected from hydrogen, substituted or unsubstituted C-i-Cs alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, aryl, heteroaryl, alkylaryl, or alkylheteroaryl.
  • R can be selected from hydrogen, substituted or unsubstituted Ci-C 8 alkyl; and R G is hydrogen, halogen, -OR 2 , -SR 1 , -S(O)R 1 , -S(O) 2 R 1 , -S(O) 2 OR 2 , -OS(O) 2 OR 2 , - P(R 1 ) 2 , - P(OR 2 ) 2 , -P(O)(OR 2 ) 2 , -OP(O)OR 2 , or substituted or unsubstituted C C 4 alkyl.
  • R G is selected from hydrogen, halogen, and substituted or unsubstituted Ci-C 4 alkyl.
  • R G comprises the radionuclide.
  • R G groups comprising a radionuclide include -OCH 2 18 F, 18 F, 123 l, 124 l, 125 l, 131 l, 76 Br, 77 Br, - 35 SR 1 , - 35 S(O)R 1 , - 35 S(O) 2 R 1 , - 35 S(O) 2 OR 2 , -O 35 S(O) 2 OR 2 , - 32 P(R 1 ) 2 , 32 P(OR 2 ) 2 , - 32 P(O)(OR 2 ) 2 , - 32 OP(O)OR 2 , - 33 P(R 1 ) 2 , 33 P(OR 2 ) 2 , - 33 P(O)(OR 2 ) 2 , - 33 OP(O)OR 2 , where R 1 and R 2 are as defined above.
  • R G is -OCH 2 18 F, 18 F, 123 l, 124 l, 125 l, 3 l, 76 Br, or 77 Br.
  • R G may be attached ortho, meta or para to the amido group on the phenyl ring indicated in formula (I). In some embodiments, R G may be attached para to the amido group.
  • R G comprises the radionuclide
  • R is hydrogen, substituted or unsubstituted Ci-C 8 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, aryl, heteroaryl, alkylaryl, or alkylheteroaryl.
  • R is hydrogen, CH 2 Ph, or substituted or unsubstituted Ci-C 4 alkyl.
  • R comprises the radionuclide and R G is hydrogen, halogen, -OR 2 , or substituted or unsubstituted Ci-C 4 alkyl.
  • R comprises the radionuclide
  • R can be -CH 2 18 F.
  • the compounds of formula (I) have the formula (lb):
  • the radionuclide and the caspase inhibitor must be bound together.
  • the radionuclide is ligated to the compound of formula (I).
  • the radioactive metal may be bound to the peptide by means of a chelating agent.
  • a chelating group may be attached to the compound of formula (II) through a spacing group, as is known in the art.
  • Suitable metallic radionuclides include Antimony-124, Antimony-125, Arsenic- 74, Barium-103, Barium-140, Beryllium-7, Bismuth-206, Bismuth-207, Cadmium-109, Cadmium-1 15m, Calcium-45, Cerium-139, Cerium-141 , Cerium-144, Cesium-137, Chromium-51 , Cobalt-55, Cobalt-56, Cobalt-57, Cobalt-58, Cobalt-60, Cobalt-64, Copper-67, Erbium-169, Europium-152, Gallium-64, Gallium-68, Gadolinium-153, Gadolinium-157 Gold-195, Gold- 199, Hafnium-175, Hafnium-175-181 , Holmium-166, lndium-1 10, Indium- 1 1 1 , lridium-192, lr
  • radionuclides for ligated attachment to the compounds of formula (I) include radiometals such as 99m Tc, 186 Re, 188 Re, 111 In, 67 Ga, 68 Ga, 201 TI, 52 Fe, 203 Pb, 58 Co, 64 Cu, and 210 At.
  • a chelating group is a moiety or group that binds to a metal ion through the formation of a chemical bond with one or more donor atoms.
  • the chelating group binds or complexes the metal ion via two or more separate bindings, more preferably four or more separate bindings, sometimes six or more separate bindings.
  • the chelating group may comprise any chelating moiety known to one skilled in the art.
  • chelating moieties include, but are not limited to amido groups, carboxy groups, amino, hydroxyl, and alkoxy groups.
  • a chelating group capable of binding to the metal at six separate binding spots may comprise three amino groups and three carboxy groups.
  • a chelating group capable of binding the metal at four separate binding spots may comprise four amido groups, or two amido and two hydroxyl groups.
  • EDTA ethylene diamine tetra-acetic acid
  • DTPA diethylene triamine penta-acetic acid
  • CDTA cyclohexyl 1 ,2-diamine tetra-acetic acid
  • EGTA ethyleneglycol-0,0'-bis(2-aminoethyl)-N,N,N',N'-tetra acetic acid
  • HBED N,N-bis(hydroxybenzyl)-ethylenediamine-N,N'-diacetic acid
  • TTHA triethylene tetramine hexa-acetic acid
  • HEDTA hydroxyethyldiamine triacetic acid
  • TETA hydroxyethyldiamine triacetic acid
  • DTPA substituted EDTA
  • chelating moieties which a chelating group may comprise include the following:
  • M is a radionuclide
  • EDTA ethylene diamine tetra-acetic acid
  • DTPA diethylene triamine penta-acetic acid
  • CDTA cyclohexyl 1 ,2-diamine tetra-acetic acid
  • EGTA ethyleneglycol-0,0'-bis(2-aminoethyl)-N,N,N',N'-tetra acetic acid
  • HBED N,N-bis(hydroxybenzyl)-ethylenediamine-N,N'-diacetic acid
  • TTHA triethylene tetramine hexa-acetic acid
  • HEDTA hydroxyethyldiamine triacetic acid
  • TETA 1 ,4,8,1 1 -tetra- azacyclotetradecane-N,N',N",N"'-tetra-acetic acid
  • DTPA substituted EDTA
  • Radiolabeled compounds may be prepared using standard radiolabeling procedures well known to those skilled in the art.
  • the calpain inhibitor compounds disclosed herein may be radiolabeled either directly (that is, by incorporating the radiolabel directly into the compounds) or indirectly (that is, by incorporating the radiolabel into the compounds through a chelating agent, where the chelating agent has been incorporated into the compounds).
  • the radiolabeling may be isotopic or nonisotopic. With isotopic radiolabeling, one group already present in the compounds described above is substituted with (exchanged for) the radioisotope. With nonisotopic radiolabeling, the radioisotope is added to the compounds without substituting with (exchanging for) an already existing group.
  • Radiolabeling should also be reasonably stable, both chemically and metabolically, applying recognized standards in the art. Although the compounds disclosed herein may be labeled in a variety of fashions with a variety of different radioisotopes, as those skilled in the art will recognize, such radiolabeling should be carried out in a manner such that the high binding affinity and specificity of the unlabeled or untagged inhibitors of calpain compounds to the macromolecule involved in processing is not significantly affected.
  • Radiolabel calpain inhibitor-imaging agents can be further improved by being synthesized as blood-brain barrier (BBB)-permeable pro-drugs for calpain inhibitor to enhance BBB-permeability and brain residency.
  • BBB blood-brain barrier
  • Neural or organ injury-specific imaging agents can be detected by positron emission tomography (PET), single photon emission computed tomography (SPECT), radioscintigraphy, magnetic resonance imaging (MRI), and computed tomography (CT scan).
  • PET positron emission tomography
  • SPECT single photon emission computed tomography
  • MRI magnetic resonance imaging
  • CT scan computed tomography
  • 18 F is a cyclotron-produced PET isotope.
  • the relatively long half- life 10 min) makes it possible for regional suppliers to ship 18 F-FDG radiotracers to the clinical sites and for clinicians to collect useful images.
  • the target-specific PET 18 F labled radiopharmaceutical can be readily prepared according to the known procedures (Vaidyanathan, G. and
  • an active 18 F- containing intermediate such as N-succinimidyl 4-[18F]fluorobenzoate
  • an amino group of the SR-A receptor antagonist to form the 4- [18F]fluorobenzoyl conjugate.
  • the 18 F -labeled calpain inhibitor can be readily purified by simple filtration, by regular column chromatography, or by HPLC either using a size-exclusion or by reverse phase. In one procedure, the 18F -labeled calpain inhibitor can be prepared in high specific activity and high radiochemical purity.
  • compounds of formula (a-ll) which may or may not comprise a radionuclide:
  • R is hydrogen, substituted or unsubstituted d-Cs alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyi, aryl, heteroaryl, alkylaryl, or alkylheteroaryl;
  • R B is hydrogen, halogen, -OR 2 , -SR 1 , -S(0)R 1 , -S(0) 2 R 1 , -S(0) 2 OR 2 , -OS(0) 2 OR 2 , - P(R 1 ) 2 , P(OR 2 ) 2 , -P(0)(OR 2 ) 2 , -OP(0)OR 2 , or substituted or unsubstituted Ci-C 4 alkyl, -OR L ;
  • R 1 is selected from the group consisting of substituted or unsubstituted d-Cs alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyi, aryl, heteroaryl, alkylaryl, and alkylheteroaryl;
  • R 2 is selected from the group consisting of hydrogen, substituted or unsubstituted Ci-C 8 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyi, aryl, heteroaryl, alkylaryl, and alkylheteroaryl;
  • compounds of formula (b-ll) which may or may not comprise a radionuclide:
  • R A is hydrogen, substituted or unsubstituted d-Cs alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyi, aryl, heteroaryl, alkylaryl, or alkylheteroaryl;
  • R B is hydrogen, halogen, -OR 2 , -SR 1 , -S(0)R 1 , -S(0) 2 R 1 , -S(0) 2 OR 2 , -OS(0) 2 OR 2 , - P(R 1 ) 2 , P(OR 2 ) 2 , -P(0)(OR 2 ) 2 , -OP(0)OR 2 , or substituted or unsubstituted C C 4 alkyl, -OR L ;
  • R 1 is selected from the group consisting of substituted or unsubstituted Ci-C 8 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, aryl, heteroaryl, alkylaryl, and alkylheteroaryl;
  • R 2 is selected from the group consisting of hydrogen, substituted or unsubstituted Ci-C 8 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, aryl, heteroaryl, alkylaryl, and alkylheteroaryl;
  • compounds of formula (II) which may or may not comprise a radionuclide:
  • R A is hydrogen, substituted or unsubstituted Ci-C 8 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, aryl, heteroaryl, alkylaryl, or alkylheteroaryl;
  • R B is hydrogen, halogen, -OR 2 , -SR 1 , -S(0)R 1 , -S(0) 2 R 1 , -S(0) 2 OR 2 , - OS(0) 2 OR 2 , - P(R 1 ) 2 , P(OR 2 ) 2 , -P(0)(OR 2 ) 2 , -OP(0)OR 2 , or substituted or unsubstituted C C 4 alkyl, -OR L ;
  • R 1 is selected from the group consisting of substituted or unsubstituted Ci-C 8 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, aryl, heteroaryl, alkylaryl, and alkylheteroaryl;
  • R 2 is selected from the group consisting of hydrogen, substituted or unsubstituted Ci-C 8 alkyl, substituted or unsubstituted C 3 .C 8 cycloalkyl, aryl, heteroaryl, alkylaryl, and alkylheteroaryl;
  • compounds of formulas (a-ll), (ab-ll), and (II) which may or may not comprise a radionuclide wherein R' is hydrogen, substituted or unsubstituted C C alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, aryl, heteroaryl, alkylaryl, or alkylheteroaryl;
  • R B is hydrogen, halogen, -OR 2 , -SR 1 , -S(0)R 1 , -S(0) 2 R 1 , -S(0) 2 OR 2 , - OS(0) 2 OR 2 , - P(R 1 ) 2 , P(OR 2 ) 2 , -P(0)(OR 2 ) 2 , -OP(0)OR 2 , or substituted or unsubstituted Ci-C 4 alkyl, -OR L ;
  • R 1 is selected from the group consisting of substituted or unsubstituted Ci-C 8 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, aryl, heteroaryl, alkylaryl, and alkylheteroaryl;
  • R 2 is selected from the group consisting of hydrogen, substituted or unsubstituted Ci-C 8 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, aryl, heteroaryl, alkylaryl, and alkylheteroaryl;
  • R A is hydrogen or unsubstituted Ci-C 4 alkyl; and R B is hydrogen or halogen.
  • R A unsubstituted Ci-C 4 alkyl; and R B is halogen.
  • R A is hydrogen; and R B is hydrogen.
  • R A is tert-butyl; and R B is iodo.
  • R A is tert-butyl; and R B is bromo.
  • heterocyclylcarbonyloxy alkylideneaminooxy, carboxy, alkoxycarbonyl, aryloxycarbonyl, cycloalkyloxycarbonyl, heterocyclylalkyloxycarbonyl- amino, ureido, alkylamino, dialkylamino, arylamino, diarylamino, heterocyclylamino, formylamino, alkylcarbonylamino, arylcarbonylamino, heterocyclylcarbonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, heterocyclylaminocarbonyl, alkoxycarbonylamino, hydroxyaminocarbonyl alkoxyimino,
  • each of the above substituents may be further substituted by one or more of the aforementioned groups.
  • each of the aforementioned groups that is present is either unsubstituted, or is substituted with up to three groups selected from halo, Ci-C alkyl, Ci-C -alkoxy, Ci-C haloalkyl, Ci-C haloalkoxy, CN, CONR' 2 , COOR', OH, -NR' 2 , and -S(O) q R', wherein q is 0-2 and each R' is independently H or Ci-C alkyl.
  • R, R G , R 1 , and R 2 is substituted with one or more of the
  • each of the aforementioned groups that is present is either unsubstituted, or is substituted with one group selected from halo, Ci-C alkyl, Ci-C -alkoxy, Ci-C haloalkyl, Ci-C haloalkoxy, CN, CONR' 2 , COOR', OH,
  • compositions [0090] In another aspect, this disclosure provides compositions.
  • compositions will comprise a pharmaceutically acceptable excipient or diluent and a compound having the formula provided above as formula (I) or formula (II).
  • composition as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • compositions for the administration of the compounds disclosed herein may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients.
  • the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
  • the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions and self emulsifications as described in U.S. Pat. No. 6,451 ,339, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the active ingredient in admixture with other non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be, for example, inert diluents such as cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate or sodium
  • phosphate granulating and disintegrating agents, for example, corn starch, or alginic acid
  • binding agents for example PVP, cellulose, PEG, starch, gelatin or acacia
  • lubricating agents for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated enterically or otherwise by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Pat. Nos.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • emulsions can be prepared with a non-water miscible ingredient such as oils and stabilized with surfactants such as mono-diglycerides, PEG esters and the like.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium
  • dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example
  • heptadecaethyleneoxycetanol or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as
  • polyoxyethylene sorbitol monooleate or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., sodium EDTA
  • suspending agent e.g., sodium EDTA
  • preservatives e.g., sodium EDTA, sodium bicarbonate, sodium bicarbonate
  • compositions disclosed herein may also be in the form of oil in water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil, arachis oil, a mineral oil (such as liquid paraffin), or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring gums (such as gum acacia or gum tragacanth for example), naturally- occurring phosphatides (such as soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, e.g. sorbitan monooleate), and condensation products of the partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, and flavoring and coloring agents. Oral solutions can be prepared in combination with cyclodextrin, PEG, and surfactants, for example.
  • sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, and flavoring and coloring agents.
  • Oral solutions can be prepared in combination with cyclodextrin, PEG, and surfactants, for example.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example as a solution in 1 ,3-butane diol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, axed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the compounds disclosed herein may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non- irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • a suitable non- irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • the compounds can be administered via ocular delivery by means of solutions or ointments.
  • transdermal delivery of the subject compounds can be accomplished by means of iontophoretic patches and the like.
  • creams, ointments, jellies, solutions or suspensions containing the compounds disclosed herein are employed.
  • topical application is also meant to include the use of mouth washes and gargles.
  • compositions and methods disclosed herein may further comprise other therapeutically active compounds as noted herein, such as those applied in the treatment of the above mentioned pathological conditions.
  • composition consisting of a pharmaceutically acceptable carrier and a compound disclosed herein.
  • a method of neural imaging of a patient comprises administering to a patient a neural injury specific imaging agent of formula (I); and detecting the neural injury specific imaging agent; detecting the neural injury specific imaging agent by positron emission tomography (PET), single photon emission computed tomography (SPECT), radioscintigraphy, magnetic resonance imaging (MRI), or computed tomography (CT scan); and imaging the neural damage in the patient or animal.
  • PET positron emission tomography
  • SPECT single photon emission computed tomography
  • MRI magnetic resonance imaging
  • CT scan computed tomography
  • the neural injury may comprise damage of any one of damage to the nervous system, including retinal ganglion cells; a traumatic brain injury; a stroke related injury; cerebral ischemia, shaken baby syndrome, a cerebral aneurism related injury; demyelinating diseases; a spinal cord injury, including monoplegia, diplegia, paraplegia, hemiplegia and
  • quadriplegia a neuroproliferative disorder or neuropathic pain syndrome
  • stroke concussion
  • post-concussion syndrome cerebral ischemia
  • neurodegenerative diseases brain injuries, infection or neuropathies.
  • a method of organ or multiple-organ injury imaging in a patient comprises administering to a patient an organ injury specific imaging agent wherein the organ injury or multi-organ injury specific imaging agent of formula (I) or salt thereof; and detecting said organ injury specific imaging agent; thereby imaging organ damage in the patient.
  • the organ injury may comprise any damage, injury or infection, functional failure to specific organs such as liver, kidney, prostate, lung, skeletal muscle, heart, pancreas, stomach, small and large intestine, bladder or the reproductive system functional failure to multi-organs, trauma- hemorrhagic shock and sepsis.
  • a method of determining the location of organ or multi-organ injury in a patient comprises administering an imaging agent of formula (I) to a patient suspected of having an organ or multi-organ injury; and detecting the location of the imaging agent in the patient thereby locating the organ or multi-organ injury.
  • the organ injury may include an suitable organ, including for example, the brain, spinal cord, liver, heart, lung, kidney, pancreas, stomach, intestine, prostate, breast, testicle, breast, ovary, and uterus.
  • the organ injury is brain injury.
  • the patient may be male or female.
  • a method of treating a neural injury comprises administering a therapeutically effective amount of a compound or pharmaceutically acceptable salt of the compound of formula (II).
  • Neural injury may be caused by various events including, but not limited to traumatic brain injury, stroke, cerebral ischemia, shaken baby syndrome, cerebral aneurism, demyelinating disease, spinal cord injury, a neuroproliferative disorder, neuropathic pain, concussion, infection, or neuropathy.
  • the neural injury is caused by traumatic brain injury or stroke.
  • Detecting the location of the imaging agent may be conducted by any suitable technique known to one skilled in the art, including, for example, positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), or computed tomography (CT) scan.
  • PET positron emission tomography
  • SPECT single photon emission computed tomography
  • MRI magnetic resonance imaging
  • CT computed tomography
  • the compounds and compositions disclosed herein may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each rouse of administration.
  • administration of the compounds and compositions disclosed herein are a depot formulation.
  • an appropriate dosage level will generally be about 0.001 to 100 mg per kg patient body weight per day which can be administered in single or multiple doses. In some embodiments, the dosage level will be about 0.01 to about 25 mg/kg per day; sometimes about 0.05 to about 10 mg/kg per day. A suitable dosage level may be about 0.01 to 25 mg/kg per day, about 0.05 to
  • the dosage may be 0.005 to 0.05, 0.05 to 0.5, 0.5 to 5.0, or 5.0 to 50 mg/kg per day.
  • the compositions are provided in the form of tablets containing 1 .0 to 1000 milligrams of the active ingredient, particularly 1 .0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • the compounds may be administered on a regimen of 1 to 4 times per day, sometimes once or twice per day.
  • dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, hereditary characteristics, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
  • methods are directed to the treatment of allergic diseases, wherein a compound or composition disclosed herein is administered either alone or in combination with a second therapeutic agent, wherein said second therapeutic agent is an
  • the practitioner can administer a combination of the compound or composition disclosed herein and a second therapeutic agent. Also, the compound or composition and the second therapeutic agent can be administered sequentially, in any order.
  • the compounds and compositions disclosed herein can be combined with other compounds and compositions having related utilities to prevent and treat the condition or disease of interest, such as inflammatory conditions and diseases, including inflammatory bowel disease, allergic diseases, psoriasis, atopic dermatitis and asthma, and those pathologies noted above.
  • Selection of the appropriate agents for use in combination therapies can be made one of ordinary skill in the art.
  • the combination of therapeutic agents may act synergistically to effect the treatment or prevention of the various disorders. Using this approach, one may be able to achieve therapeutic efficacy with lower dosages of each agent, thus reducing the potential for adverse side effects.
  • caspase assay caspase is diluted in 20mM HEPES, 1 mM DTT, 0.5 mM EDTA, and substrate is diluted in 100 mM HEPES, 20mM DTT buffer. The inhibitors are diluted from 1 nM in DMSO and added to a 96-well plate. The reactions are incubated up to 60 min and the fluorescence measured with readings at 15-min intervals with an excitation wavelength of 380 nm and an emission wavelength of 460 nm. IC50 is calculated by sigmaplot software.
  • Cerebrocortical cells are harvested from 1 -day old Sprague- Dawley rat brains are plated on poly-L-lysine coated 24-well culture plates or 6-well culture plates (Erie Scientific, Portsmouth, NH, USA) according to a previously cited method (Nath, R., et al., Evidence for activation of caspase- 3-like protease in excitotoxin- and hypoxia/hypoglycemia-injured neurons. J Neurochem, 1998. 71 (1 ): p.
  • Proteins isolated from brain regions including the cortex, hippocampus are separated by gel electrophoresis, and transferred to PVDF membrane by the semi-dry method. Blots are blocked in 5% nonfat milk in TBST, and then probed with the primary antibody overnight of the total all- spectrin and breakdown products SBDP150, SBDP145 and SBDP120 specific in-house antibodies. Afterward, the blots are incubated with a biotinylated-conjugated secondary antibody then with streptavidin alkaline phosphatase conjugate.
  • Antigenic peptides based on the N'-terminal sequence caspase cleavage site of all-spectrin, were used to produce the SBDP 120 specific rabbit polyclonal antibody that is used as the capture antibody in a standard sandwich ELISA.
  • the antibodies are specific for SBDP 120 (caspase activation produced), and have no cross-reactivity with full-length all-spectrin.
  • the SBDP standard that is used for the calibration curve and as internal standards was obtained by caspase-digestion of full length all- spectrin that had been purified from rat brain tissue. The concentration of the standard was calculated by comparison to a standard calibration curve constructed from purified synthetic antigen of known concentration.
  • the detection antibody is tagged with horse radish peroxidase, which catalyzes the color change of the substrate solution, Ultra-TMB. Color intensity in the assay wells is ready at a wavelength of 652 nm.
  • the SBDPs ELISA have a detection limit of 1 ng/ml and a dynamic range of 3 log units. Inter- and intra- assay coefficients of variation are 13.6% and 14.3% respectively
  • rat cerebrocortical neuronal culture Primary rat cerebrocortical neuronal culture are either untreated, challenged with excitotoxin, or pro-apoptotic challenge that activates both caspase-3 and calpain (staurosporin, STS). Over-activated caspase activity is inhibited using inhibitor concentrations between 1 nM and 300 ⁇ . Western blot and ELISA to analyze cell lysate and cell conditioned media to monitor new inhibitor potency on caspase-3 (SBDP120). IC50's are calculated based on the densitometry of all-spectrin breakdown products.
  • Rat ischemic stroke model with middle cerebral artery occlusion (MCAO) Rat ischemic stroke model with middle cerebral artery occlusion (MCAO)
  • noninvasive filament method of MCAO occlusion is used to produce cerebral ischemia in rats. It consists of blocking blood flow into the MCA with an intraluminal 3-0 monofilament nylon sterile suture with rounded tip introduced through an incision in the external carotid artery (ECA). Under halothane anesthesia (5% halothane via induction chamber followed by 2% halothane via nose cone), the common carotid artery (CCA) is exposed at the level of external and internal carotid artery bifurcation with a midline neck incision.
  • ECA external carotid artery
  • the internal carotid artery (ICA) is followed rostrally to the pterygopalatine branch and the ECA is ligated and cut at its lingual and maxillary branches.
  • the CCA and ICA are temporarily clamped with micro-aneurysm clips.
  • the nylon suture is be introduced into the ICA via an incision on the ECA stump (the path of the suture can be monitored visually through the vessel wall) and advanced through the carotid canal approximately 20 mm from the carotid bifurcation until it becomes lodged in the narrowing of the anterior cerebral artery blocking the origin of the MCA.
  • the skin incision is then closed using sterile autoclips.
  • Rat controlled cortical impact model (in vivo model of traumatic brain injury (TBI))
  • Brain trauma was produced by impacting the right cortex (ipsilateral cortex) with a 5 mm diameter aluminum impactor tip (housed in a pneumatic cylinder) at a velocity of 3.5 m/s with a 1 .6 mm compression and 150 ms dwell time (compression duration).
  • Sham-injured control animals underwent identical surgical procedures, but did not receive an impact injury. Appropriate pre- and post- injury management was maintained to ensure compliance with guidelines set forth by the University of Florida Institutional Animal Care and Use
  • Novel caspase inhibitor is given before CCI trauma surgery by intracerebroventricular (ICV) or intraperitoneal (IP) or subcutaneous injection.
  • the related compounds will be formulated as 1 ml. of a sonicated mixture of DMSO and 100mM sodium phosphate buffer (PBS).
  • PBS sodium phosphate buffer
  • the animals will be allowed to recover. Again at pre-selected time points animals will be sacrificed and ipsilateral cortical and hippocampal tissues will be collected and processed for immunblotting analysis as described before.
  • analyte was dissolved in methanol at 0.01 mg/mL and 10 microliter was infused with the delivery solvent into the mass spectrometer, which scanned from 100 to 1000 daltons. All compounds could be analyzed in the positive APCI mode, using methanol / water as the delivery solvent.
  • Step 1 To a stirring solution at 0 °C under N 2 of Cbz-Val- Asp(OtBu)-OH (8.04 g, 19.03 mmol) and N-methylmorpholine (2.3 mL, 20.9 mmol) in 150 mL of THF was added rapidly /so-butyl chloroformate (2.7 mL, 20.7 mmol). The suspension (solid had formed) was stirred for 15 min, then a freshly prepared diazomethane in diethyl ether solution (-0.25 to 0.5 M solution, 167 mL, -42 to 84 mmol) was added dropwise.
  • Step 2 A mixture of 3-(2-benzyloxycarbonylamino-3-methyl- butyrylamino)-5-bromo-4-oxo-pentanoic acid terf-butyl ester (7.18 g, 14.38 mmol; Step 1 ), 2,3,5,6-tetrafluorophenol (2.87 g, 17.28 mmol) and potassium fluoride (3.34 g, 57.49 mmol) in 30 ml. of DMF was stirred at room
  • Step 3 To a stirring solution at 0 °C under N 2 of 3-(2- benzyloxycarbonylamino-3-methyl-butyrylamino)-4-oxo-5-(2, 3,5,6- tetrafluoro-phenoxy)-pentanoic acid terf-butyl ester (6.16 g, 10.53 mmol; Step 2) in 1 10 ml. of MeOH HF (10:1 ) was added in one portion solid sodium borohydride (1 .00 g, 26.43 mmol). The reaction was stirred cold for 30 min then quenched by dropwise addition of -100 ml. of sat. KH 2 P0 4 solution.
  • Step 4 A solution of 3-(2-benzyloxycarbonylamino-3-methyl- butyrylamino)-4-hydroxy-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid tert- butyl ester (6.97 g, 1 1 .88 mmol; Step 3) in 100 ml. of ethanol was treated with 1 .5 g of palladium, 10 wt% on activated carbon. The sample was hydrogenated (balloon pressure) at room temperature. After -30 min (no starting material left by TLC) the sample was filtered.
  • Step 1 In a pressure vessel (open to the atmosphere), a solution of (4-hydroxy-phenyl)-carbamic acid terf-butyl ester (6.50 g, 31 .06 mmol) in 100 ml. of DMF was treated with potassium carbonate (21 .5 g, 155.6 mmol). The sample was stirred at room temperature for 1 h then cooled to ⁇ -78 °C. Chlorofluoromethane (bp -9.1 °C) was bubbled through the sample for ⁇ 5 min (-15 g, 219 mmol of CICH 2 F was added). The vessel was sealed and stirred at room temperature for 72 h. The sample was cooled, unsealed and allowed to slowly warm to room temperature. The sample was concentrated (to remove most of the DMF) then partitioned between EtOAc and water. The organic extract was washed with sat.
  • Step 2 A solution of (4-fluoromethoxy-phenyl)-carbamic acid terf-butyl ester (6.16 g, 25.53 mmol; Step 1 ) in 20 mL of CH 2 CI 2 was treated with 20 mL of trifluoroacetic acid. The solution was stirred at room temperature for ⁇ 4 h, concentrated then partitioned between CHCI3 and 10% aq. NH 4 OH solution. The organic extract was washed with sat. NaCI solution, dried (MgS0 4 ), filtered and concentrated to give 3.46 g (95%) of 4- fluoromethoxy-phenylamine (compound 8) as a dark yellow liquid. MS (APCI) m/z 142 (M+1 , 100%).
  • Step 3 To a stirring solution at 0 °C under N 2 of 4- fluoromethoxy-phenylamine (3.46 g, 24.50 mmol; Step 2) and 4- methylmorpholine (4.1 mL, 37.3 mmol) in 50 mL of CH 2 CI 2 was added dropwise a solution of methyl oxalyl chloride (2.7 mL, 29.4 mmol) in 20 mL of CH 2 CI 2 . The reaction was allowed to slowly warm to room temperature overnight. The sample was concentrated and partitioned between EtOAc and sat. NaHCC>3 solution. The organic extract was washed with sat.
  • Step 4 A solution of N-(4-fluoromethoxy-phenyl)-oxalamic acid methyl ester (3.52 g, 15.49 mmol; Step 3) in 50 mL of THF was treated with 1 .0 M LiOH solution (19 mL, 19 mmol). The sample was stirred at room temperature for 1 h, concentrated, cooled and slowly acidified with 1 N HCI solution. The solid that formed was filtered, washed with fresh water and vacuum dried to give 2.26 g (68%) of N-(4-fluoromethoxy-phenyl)-oxalamic acid (compound 10) as a tan solid. MS (APCI) m/z 138 (M+1 , 90%) and 1 10 (100%). Scheme III.
  • Compound 13 3- ⁇ (S)-2-[(4-fluoromethoxy-phenylaminooxalyl)- amino]-3-methyl-butyrylamino ⁇ -4-oxo-5-(2,3,5,6-tetrafluoro-phenoxy)- pentanoic acid.
  • Step 1 To a stirring suspension at room temperature under N 2 of N-(4-fluoromethoxy-phenyl)-oxalamic acid (0.96 g, 4.50 mmol; Step 4, Scheme II) in 10 mL of CH 2 CI 2 was added solid 2-(7-aza-1 H-benzotriazole- 1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate (HATU; 1 .71 g, 4.50 mmol).
  • HATU 2-(7-aza-1 H-benzotriazole- 1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate
  • Step 2 A solution of 3- ⁇ 2-[(4-fluoromethoxy- phenylaminooxalyl)-am/no]-3-methyl-butyrylamino ⁇ -4-hydroxy-5-(2, 3,5,6- tetrafluoro-phenoxy)-pentanoic acid terf-butyl ester (1 .00 g, 1 .54 mmol; Step 1 ) in 10 mL of DMSO was treated with solid IBX (2-iodoxybenzoic acid; 0.86 g, 3.07 mmol). The sample was stirred at room temperature under N 2 for 4 h then carefully partitioned between sat. NaHCC>3 and EtOAc (-100 mL of each).
  • Step 3 A solution of 3- ⁇ 2-[(4-fluoromethoxy- phenylaminooxalyl)-amino]-3-methyl-butyrylamino ⁇ -4-oxo-5-(2, 3,5,6- tetrafluoro-phenoxy)-pentanoic acid terf-butyl ester (0.62 g, 0.96 mmol; Step 2) in 25 ml. of CH 2 CI 2 was treated with 5 ml. of trifluoroacetic acid. The solution was stirred at room temperature under N 2 for 2 h, concentrated and diluted with water. The resultant gummy solid was filtered then
  • Compound 20 3- ⁇ 2-[(4-hydroxy-phenylaminooxalyl)-amino]-3- methyl-butyrylamino ⁇ -4-oxo-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid terf-butyl ester.
  • Step 1 To a stirring solution at 0 °C under N 2 of 4- aminophenol (7.00 g, 64.14 mmol) in 300 mL of THF was added dropwise a solution of methyl oxalyl chloride (6.5 mL, 70.7 mmol) in 50 mL of THF. The sample was allowed to slowly warm to room temperature overnight, concentrated and partitioned between EtOAc and sat. NaHC03 solution. The solid that would not go into either phase was filtered, washed with fresh water, fresh EtOAc and vacuum dried to give 7.85 g (63%) of N-(4-hydroxy- phenyl)-oxalamic acid ethyl ester (compound 15) as an off-white solid. MS (APCI) m/z 196 (M+1 , 95%
  • Step 2 A suspension of N-(4-hydroxy-phenyl)-oxalamic acid methyl ester (2.00 g, 10.25 mmol; Step 1 ) and potassium carbonate (3.54 g, 25.61 mmol) in 20 mL of DMF was stirred at room temperature under N 2 for 1 h then benzyl bromide (6.1 mL, 51 .28 mmol) was added. The sample was stirred at room temperature for 72 h then partitioned between EtOAc and water. The organic extract was washed with sat. KH 2 P0 4 and sat. NaCI solutions, dried (MgS0 4 ), filtered and concentrated.
  • Step 3 To a stirring solution at room temperature of N-(4- benzyloxy-phenyl)-oxalamic acid methyl ester (1 .72 g, 6.01 mmol; prepared following the procedure in Step 2) in 100 mL of THF was added 1 .0 M lithium hydroxide solution (9.0 mL, 9.0 mmol). The sample (solid had formed) was stirred at room temperature for 2 h, concentrated (to remove most of the THF), cooled and acidified with 1 M HCI to a pH ⁇ 1 .
  • Step 4 A mixture of 3-(2-amino-3-methyl-butyrylamino)-4- hydroxy-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid terf-butyl ester (1 .82 g, 4.03 mmol; Step 4, Scheme I), N-(4-benzyloxy-phenyl)-oxalamic acid (1 .31 g, 4.83 mmol; Step 3, Scheme IV), 1 -hydroxybenzotriazole hydrate
  • Step 5 To a stirring solution at room temperature of 3- ⁇ 2-[(4- benzyloxy-phenylaminooxalyl)-amino]-3-methyl-butyrylamino ⁇ -4-hydroxy-5- (2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid terf-butyl ester (2.04 g, 2.89 mmol; Step 4, Scheme IV) in 20 mL of DMSO was added solid IBX (2- iodoxybenzoic acid; 4.05 g, 14.46 mmol). The sample was stirred at room temperature under N 2 for 4 h then carefully partitioned between sat. NaHCC>3 and EtOAc (-100 ml. of each).
  • Step 6 A solution of 3- ⁇ 2-[(4-benzyloxy-phenylaminooxalyl)- amino]-3-methyl-butyrylamino ⁇ -4-oxo-5-(2,3,5,6-tetrafluoro-phenoxy)- pentanoic acid terf-butyl ester (1 .05 g, 1 .49 mmol) in 50 ml. of EtOH HF (1 :1 ) was treated with 10% Pd/C. The sample was hydrogenated (balloon pressure) at room temperature for 4 h, filtered and concentrated to a gummy solid.
  • Compound 21 may be radiolabelled with the functional group - CH 2 18 F as shown in Scheme V.
  • the functional group, -CH 2 18 F may be introduced by nucleophilic displacement of 18 FCH 2 Br by the phenol of compound 21 to afford compound 22 by standard nucleophilic displacement conditions known to one skilled in the art.
  • the reagent 18 FCH 2 Br is derived via nucleophilic displacement of bromide in CH 2 Br 2 with 18 F-.
  • Compound 22 is then treated with acid under standard condition to hydrolyze a tert-butyl ester to afford compound 23.
  • Compound 21 may be treated under standard acidic conditions for hydrolyzing tert-butyl esters to afford compound 24.
  • compound X provides a phenolic oxygen and a carboxylate oxygen each of which may be selectively functionalized to afford additional compounds and imaging agents.
  • the carboxylate oxygen may be converted into additional esters under standard chemical transformations. These esters in turn may be radiolabelled by incorporating -CH 2 18 F on to the phenolic oxygen using conditions similar to that described above for compound 22.
  • the -CH 2 18 F group may be introduced on the carboxylate oxygen using conditions known to one skilled in the art to provide an additional imaging agent. Additional imaging agents may be derived alkylating the phenolic oxygen to afford ethers.
  • the ester may be hydrolyzed with acid to afford the carboxylic acid compound 30.
  • esters related to compound 30 may also be formed using standard esterfication conditions for compound 30, or alternatively any of the tert-butyl ester compounds may be transesterifed prior to introduction of the radionuclide to afford other carboxylic esters.
  • Scheme VIII illustrates a method for incorporating a fluoro radionuclide into the left phenyl ring.
  • the synthesis begins by coupling compound 31 with compound 5 under suitable peptide coupling conditions to afford compound 32.
  • Alcohol 32 is then oxidized to the ketone 33.
  • the fluoro radionuclide may then be introduced via nucleophilic displacement of the trimethylammonium leaving group using synthesis procedures known in the art (Journal of Nuclear Medicine, 47(7), 1 153-1 160, 2006; Journal of Labelled Compounds & Radiopharmaceuticals, 47(2), 139-145, 2004; and Journal of Labelled Compounds and Radiopharmaceuticals, 27(7), 823-33, 1989) to afford compound 36.

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Abstract

L'invention concerne des composés, des sels pharmaceutiquement acceptables de ceux-ci, et des compositions utiles comme inhibiteurs de la caspase. Certains composés sont également utiles pour le traitement d'une lésion neurale ou d'organe. D'autres composés sont utiles comme agents d'imagerie neurale ou spécifique d'organes.
PCT/US2011/047579 2010-08-13 2011-08-12 Inhibiteurs de la caspase utilisés comme agents thérapeutiques contre une lésion neurale ou d'organe et pour l'imagerie WO2012021800A2 (fr)

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WO2018119476A1 (fr) 2016-12-23 2018-06-28 The Board Of Trustees Of The Leland Stanford Junior University Composés sondes par activité, compositions et méthodes d'utilisation
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US11828752B2 (en) 2017-03-30 2023-11-28 The Board Of Trustees Of The Leland Stanford Junior University Protease-activated contrast agents for in vivo imaging
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US9074019B2 (en) 2008-09-19 2015-07-07 Henry Ford Health Systems Methods, systems, and compositions for calpain inhibition
US8642558B2 (en) 2008-09-19 2014-02-04 Henry Ford Health Systems Methods, systems, and compositions for calpain inhabition
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KR20150129004A (ko) * 2013-03-15 2015-11-18 더 보드 어브 트러스티스 어브 더 리랜드 스탠포드 주니어 유니버시티 활성 기반 프로브 화합물, 조성물, 및 사용 방법
JP2016518341A (ja) * 2013-03-15 2016-06-23 ザ ボード オブ トラスティーズ オブ ザ レランド スタンフォード ジュニア ユニバーシティー 活性に基づくプローブの化合物、組成物、および使用方法
EP2971065A4 (fr) * 2013-03-15 2016-12-21 Univ Leland Stanford Junior Composés de sonde basée sur l'activité, compositions et méthodes d'utilisation
EP4218829A3 (fr) * 2013-03-15 2023-08-16 The Board of Trustees of the Leland Stanford Junior University Composés de sonde basée sur l'activité, compositions et méthodes d'utilisation
US10100037B2 (en) 2013-03-15 2018-10-16 The Board Of Trustees Of The Leland Stanford Junior University Activity-based probe compounds, compositions, and methods of use
US11655236B2 (en) 2013-03-15 2023-05-23 The Board Of Trustees Of The Leland Stanford Junior University Activity-based probe compounds, compositions, and methods of use
KR102279618B1 (ko) 2013-03-15 2021-07-20 더 보드 어브 트러스티스 어브 더 리랜드 스탠포드 주니어 유니버시티 활성 기반 프로브 화합물, 조성물, 및 사용 방법
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EP3456711A4 (fr) * 2016-05-11 2019-10-16 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Inhibiteur de caspase et composition pharmaceutique, utilisation et procédé thérapeutique associés
CN108884045B (zh) * 2016-05-11 2020-12-04 正大天晴药业集团股份有限公司 Caspase抑制剂及其药物组合物、用途和治疗方法
US10981860B2 (en) 2016-05-11 2021-04-20 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Caspase inhibitor and pharmaceutical composition, use and therapeutic method thereof
CN108884045A (zh) * 2016-05-11 2018-11-23 正大天晴药业集团股份有限公司 Caspase抑制剂及其药物组合物、用途和治疗方法
US10869936B2 (en) 2016-12-23 2020-12-22 The Board Of Trustees Of The Leland Stanford Junior University Activity-based probe compounds, compositions, and methods of use
WO2018119476A1 (fr) 2016-12-23 2018-06-28 The Board Of Trustees Of The Leland Stanford Junior University Composés sondes par activité, compositions et méthodes d'utilisation
EP4310504A2 (fr) 2016-12-23 2024-01-24 The Board of Trustees of the Leland Stanford Junior University Composés sondes à base d'activité, compositions et procédés d'utilisation
US12059482B2 (en) 2016-12-23 2024-08-13 The Board Of Trustees Of The Leland Stanford Junior University Activity-based probe compounds, compositions, and methods of use
US11828752B2 (en) 2017-03-30 2023-11-28 The Board Of Trustees Of The Leland Stanford Junior University Protease-activated contrast agents for in vivo imaging
CN109748843A (zh) * 2017-11-06 2019-05-14 正大天晴药业集团股份有限公司 Caspase抑制剂及其药物组合物、用途和治疗方法
CN109748843B (zh) * 2017-11-06 2022-11-11 正大天晴药业集团股份有限公司 Caspase抑制剂及其药物组合物、用途和治疗方法
WO2023249007A1 (fr) * 2022-06-23 2023-12-28 五稜化薬株式会社 Inhibiteur de calpaïne

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