WO2001027085A1 - Utilisation de comme inhibiteurs de la caspase-3 nicotinyl aspartyl ketones as inhibitors of caspase-3 - Google Patents

Utilisation de comme inhibiteurs de la caspase-3 nicotinyl aspartyl ketones as inhibitors of caspase-3 Download PDF

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WO2001027085A1
WO2001027085A1 PCT/CA2000/001196 CA0001196W WO0127085A1 WO 2001027085 A1 WO2001027085 A1 WO 2001027085A1 CA 0001196 W CA0001196 W CA 0001196W WO 0127085 A1 WO0127085 A1 WO 0127085A1
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3alkyl
6alkyl
aryl
hetcy
4alkenyl
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PCT/CA2000/001196
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English (en)
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Cameron Black
Erich L. Grimm
Elise Isabel
Johanne Renaud
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Merck Frosst Canada & Co.
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Priority to AU77669/00A priority Critical patent/AU7766900A/en
Priority to CA002386411A priority patent/CA2386411A1/fr
Publication of WO2001027085A1 publication Critical patent/WO2001027085A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • Apoptotic cell suicide is a fundamentally important biological process that is required to maintain the integrity and homeostasis of multicellular organisms. Inappropriate apoptosis, however, underlies the etiology of many of the most intractable of human diseases. In only the last few years, many of the molecules that participate in a conserved biochemical pathway that mediates the highly ordered process of apoptotic cell suicide have been identified.
  • cysteine proteases At the heart of this pathway are a family of cysteine proteases, the 'caspases', that are related to mammalian interleukin-l ⁇ converting enzyme (ICE/caspase-1) and to CED-3, the product of a gene that is necessary for apoptotic suicide in the nematode C. elegans (Nicholson et al., 1997, Trends Biochem Sci 22:299-306).
  • the role of these proteases in cell suicide is to disable critical homeostatic and repair processes as well as to cleave key structural components, resulting in the systematic and orderly disassembly of the dying cell.
  • Caspase inhibitors would thus be useful for the treatment of human diseases including, but not limited to, acute disorders such as cardiac and cerebral ischemia/ reperfusion injury (e.g. stroke), spinal cord injury and organ damage during transplantation, as well as chronic disorders such as neurodegenerative diseases (e.g. Alzheimer's, polyglutamine-repeat disorders, Down's, spinal muscular atrophy, multiple sclerosis), immunodeficiency (e.g. HTV), diabetes, alopecia and aging.
  • Chronic disorders such as neurodegenerative diseases (e.g. Alzheimer's, polyglutamine-repeat disorders, Down's, spinal muscular atrophy, multiple sclerosis), immunodeficiency (e.g. HTV), diabetes, alopecia and aging.
  • Ten caspases have so far been identified in human cells.
  • Each is synthesized as a catalytically dormant proenzyme containing an amino-terminal prodomain followed by the large and small subunits of the heterodimeric active enzyme.
  • the subunits are excised from the proenzyme by cleavage at Asp-X junctions (Nicholson et al., 1997, Trends Biochem Sci 22:299-306).
  • the strict requirement by caspases for Asp in the PI position of substrates is consistent with a mechanism whereby proenzyme maturation can be either autocatalytic or performed by other caspases.
  • the three dimensional crystal structures of mature caspase- 1 and - 3 show that the large subunit contains the principle components of the catalytic machinery, including the active site Cys residue which is harbored within the conserved pentapeptide motif, QACxG,l and residues that stabilize the oxyanion of the tetrahedral transition state (Wilson et al., 1994, Nature 370:270-75; Walker et al., 1994, Cell 78:342-52; Rotonda et al., 1996, Nat Struct Biol 3:619-25).
  • Both subunits contribute residues which stabilize the PI Asp of substrates while the small subunit appears to contain most of the determinants that dictate substrate specificity and, in particular, those which form the specificity-determining S4 subsite.
  • One distinctive feature of these proteases is the absolute requirement for an aspartic acid residue in the substrate PI position.
  • the carboxylate side chain of the substrate PI Asp is tethered by four residues in caspase- 1 (Argl79, Gln238 from p20 and Arg341, Ser347 from plO) that are absolutely conserved in all caspase family members.
  • Catalysis involves a typical cysteine protease mechanism involving a catalytic dyad, composed of His237 and Cys285 (contained within an absolutely conserved QACxG pentapeptide) and an Oxyanion hole' involving Gly238 and Cys285.
  • Inhibitors bind, however, in an unexpected non-transition state configuration (which raises important considerations for inhibitor design) with the oxyanion of the thiohemiacetal being stabilized by the active site His237.
  • caspase family can be divided into three functional subgroups based on their substrate specificities which have been defined by a positional-scanning combinatorial substrate approach.
  • the principle effectors of apoptosis (group II caspases, which include caspases-2, -3 and -7 as well as C. elegans CED-3) have specificity for [P4]DExD[Pl], a motif found at the cleavage site of most proteins known to be cleaved during apoptosis.
  • group -TJ caspases caspases-6, -8, -9 and -10, as well as CTL-derived granzyme B
  • group III caspases function as upstream activators of group II caspases in a proteolytic cascade that amplifies the death signal.
  • group I caspases (caspases- 1, -4 and -5) appears to be to mediate cytokine maturation and their role in apoptosis, if any, has not been substantiated.
  • a tetrapeptide corresponding to the substrate P4-P1 residues is sufficient for specific recognition by caspases and as a consequence has formed the basis for inhibitor design.
  • the P4 residue in particular appears to be most important for substrate recognition and specificity.
  • Caspase- 1 prefers a hydrophobic residue such as Tyr in P4 (which corresponds to its YVHD cleavage site within proIL-l ⁇ ) whereas caspase-3 (and other group II enzymes) has a preference for an anionic Asp residue (which corresponds to the DXXD cleavage sites within most polypeptides that are cleaved by these enzymes during apoptosis).
  • Peptide aldehydes, nitriles and ketones are potent reversible inhibitors of these proteases while compounds that form thiomethylketone adducts with the active site cysteine (e.g. peptide (acyloxy)methylketones) are potent irreversible inhibitors.
  • the Ac-DEVD-CHO tetrapeptide aldehyde (which was designed to mimic the caspase-3 recognition site) is a very potent inhibitor of caspase-3 (Ki ⁇ 1 nM) although it is also a weaker but reasonable inhibitor of caspase- 1, presumably owing to promiscuity in the S4 subsite of this enzyme (Nicholson et al., 1995, Nature 376:37-43).
  • caspase-3 Ki ⁇ 1 nM
  • the present invention relates to compounds represented by formula I:
  • Rl represents H, NH2, NHCi -6alkyl, NHC(O)Ci -6alkyl,
  • NHC(O)OCi-6alkyl or NHC(O)Aryl, said alkyl and the alkyl and aryl portions of which are optionally substituted with 1-3 members selected from the group consisting of: CO2H, CO2Ci-6alkyl, aryl, NH2, NHCi-3alkyl, NH-Aryl, N(C ⁇ -.3alkyl)2 and
  • Hetcy; R2 is selected from the group consisting of:
  • Ci-6alkyl and N(Ci-6alkyl)SO2C3-6alkenyl said Ci-6alkyl, C2-6 a lkenyl, C3-6alkenyl and C2-6alkynyl groups and portions in (a) through (i) above being optionally substituted with 1-6 members selected from the group consisting of: halo, OH, NH2, CN, CO2H, Hetcy, Aryl, CO2Ci-6alkyl, OC ⁇ _6alkyl, O-Aryl, CO2C3 ⁇ alkenyl, C(O)NH2, C(O)NHC ⁇ _3alkyl, C(O)N(Ci-3alkyl)2, C(O)NH-Aryl, C(O)N(Ci-3alkyl)-Aryl, C(O)Ci -3alkyl, C(O)C3_ 4alkenyl, -S(O)yCi -3alkyl, -S(O) y C3_
  • R3 represents H, halo or Ci-3alkyl
  • R4 is selected from the group consisting of: H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl and Hetcy, said Ci -6alkyl, C2-6alkenyl and C2-6alkynyl groups being optionally substituted with 1-6 members selected from the group consisting of: halo, OH, NH2, NHCi-ioalkyl, N(C ⁇ _i0alkyl)2, CN, CO2H, Hetcy, Aryl, CO2Ci-6alkyl, OC ⁇ _6alkyl, Oaryl, CO2Ci-3alkyl, CO2C3_4alkenyl, C(O)NH2, C(O)NHCi-3alkyl, C(O)N(Ci-3alkyl)2, C(O)NH-Aryl, C(O)N(C ⁇ _3alkyl)-A ⁇ yl, C(O)Ci -3alkyl, C(O)C3_ 4al
  • Aryl represents a 6-14 membered aromatic ring system and Hetcy represents a 5-10 membered ring system, aromatic or non- aromatic, containing at least one heteroatom and optionally containing up to 2 additional heteroatoms, said heteroatoms being selected from O, S(O)y with y as defined above and N, said Aryl and Hetcy groups and portions thereof being optionally substituted with 1-6 members selected from the group consisting of: -(CH2) ⁇ -4- CO2H, -(CH2)0-3CO2Ci-3alkyl, halo, CN, NH2, phenyl, pyrrolidinyl, NHCH3, Ci . 6alkyl, SO2NH2 and SO2CH3.
  • the invention also encompasses a pharmaceutical composition comprising a compound of formula I in combination with a pharmaceutically acceptable carrier.
  • the invention also encompasses a method of treating cardiac and cerebral ischemia/reperfusion injury (e.g. stroke), type I diabetes, immune deficiency syndrome (including AIDS), cerebral and spinal cord trauma injury, organ damage during transplantation, alopecia, aging, Parkinson's disease, Alzheimer's disease, Down's syndrome, spinal muscular atrophy, multiple sclerosis and neurodegenerative disorders, comprising administering to a mammalian patient in need of such treatment an effective amount of a compound of formula I.
  • cardiac and cerebral ischemia/reperfusion injury e.g. stroke
  • type I diabetes e.g. stroke
  • immune deficiency syndrome including AIDS
  • cerebral and spinal cord trauma injury e.g. stroke
  • organ damage during transplantation e.g., alopecia, aging, Parkinson's disease, Alzheimer's disease, Down's syndrome, spinal muscular atrophy, multiple sclerosis and neurodegenerative disorders
  • alkyl means linear, branched or cyclic structures and combinations thereof, containing one to twenty carbon atoms unless otherwise specified.
  • alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s- and t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, eicosyl, 3,7-diethyl-2,2-dimethyl- 4-propylnonyl, cyclopropyl, cyclopentyl, cycloheptyl, adamantyl, cyclododecylmethyl, 2-ethyl-l- bicyclo[4.4.0]decyl and the like.
  • Alkylcarbonyl signifies groups having the formula -C(O)-alkyl, wherein alkyl is defined as above.
  • Alkylsulfonyl signifies groups having the formula -S(O)2-alkyl, wherein alkyl is defined as above.
  • Fluoroalkyl means linear, branched or cyclic alkyl groups and combinations thereof, of one to ten carbon atoms, in which one or more hydrogen but no more than six is replaced by fluorine. Examples are -CF3, -CH2CH2F, and - CH2CF3 and the like.
  • Haloalkyl means linear, branched or cyclic alkyl groups having up to six halo groups attached.
  • Alkoxy means alkoxy groups of one to ten carbon atoms of a straight, branched or cyclic configuration. Examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy and the like.
  • Alkoxycarbonyl signifies groups having the formula -C(O)-alkoxy, wherein alkoxy is defined as above.
  • Alkylthio means alkylthio groups of one to ten carbon atoms of a straight, branched or cyclic configuration. Examples of alkylthio groups include methylthio, propylthio, isopropylthio, etc. By way of illustration, the propylthio group signifies -SCH2CH2CH3.
  • Aryl represents a 6-14 membered aromatic ring system, optionally substituted with 1-6 members selected from the group consisting of: -(CH2)0-6- CO2H, -(CH2)0-6CO2Ci-6alkyl, OH, halo, CN, NH2, phenyl, naphthyl, pyrrolyl, pyridyl, piperidyl, pyrrolidinyl, furanyl, thienyl, NHCH3, Ci-6alkyl, NHSO3H, SO2NH2, and SO2CH3.
  • Aryl is, for example, phenyl or naphthyl. When aryl is present in a substituent on alkyl, alkenyl, alkynyl or Hetcy, it is optionally substituted as described above.
  • the groups -(CH2)0-6-CO2H and -(CH2)0-6CO2Ci -6alkyl refer to carboxylic acids and esters, alkanoic acids and alkyl esters thereof. Thus, these include CO2H and CO2Ci-6alkyl.
  • Hetcy as used herein refers to a 5-14 membered ring system that is aromatic, non-aromatic or partially aromatic, and that contains at least one heteroatom. Up to 3 additional heteroatoms selected from O, S(O)y and N, with y representing 0, 1 or 2 are included.
  • Hetcy is optionally substituted with 1-6 members selected from the group consisting of: -(CH2)0-6-CO2H, -(CH2)0-6CO2Ci- alkyl, OH, halo, CN, NH2, phenyl, naphthyl, pyrrolyl, pyridyl, piperidyl, pyrrolidinyl, furanyl, thienyl, NHCH3, Ci _6alkyl, NHSO3H, SO2NH2, and SO2CH3.
  • 1-6 members selected from the group consisting of: -(CH2)0-6-CO2H, -(CH2)0-6CO2Ci- alkyl, OH, halo, CN, NH2, phenyl, naphthyl, pyrrolyl, pyridyl, piperidyl, pyrrolidinyl, furanyl, thienyl, NHCH3, Ci _6alkyl, NHSO3H, SO
  • Heteroaryl is an aromatic subset of Hetcy, and thus includes, e.g., , pyridyl, furyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, benzothienyl, pyrazolyl, indolyl, purinyl, isoxazolyl, oxazolyl and coumarinyl.
  • Halo includes F, Cl, Br and I.
  • BOC t-butyloxycarbonyl
  • DIBAL diisobutyl aluminum hydride
  • DIEA N,N-diisopropylethylamine
  • EDCI l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • EDTA ethylenediaminetetraacetic acid, tetrasodium salt hydrate
  • FAB fast atom bombardment
  • HMPA hexamethylphosphoramide
  • HATU O-(7-Azabenzotriazol-l-yl)N,N,N',N'- tetramethyluronium hexafluorophosphate
  • HOBt 1 -hydroxybenzotriazole
  • KHMDS potassium hexamethyldisilazane
  • MCPBA metachloroperbenzoic acid
  • NBS N-bromosuccinimide
  • NMM 4-methylmorpholine
  • PCC pyridinium chlorochromate
  • Ph phenyl
  • PPTS pyridinium p-toluene sulfonate
  • pTSA p-toluene sulfonic acid
  • r.t. room temperature
  • rac. racemic
  • Rl represents H, NH2, NHCi -6alkyl, NHC(O)Ci -6alkyl, NHC(O)OC ⁇ _6alkyl, or NHC(O)Aryl, said alkyl and the alkyl and aryl portions of which are optionally substituted with 1-3 members selected from the group consisting of: CO2H, C ⁇ 2C ⁇ _6alkyl, aryl, NH2, NHCi -3alkyl, NH-Aryl, N(C ⁇ _3alkyl)2 and Hetcy;
  • R2 is selected from the group consisting of: (a) H, OH, halo, NH2, CN, Ci -6alkyl, C2-6alkenyl, C2-6alkynyl, CO2H, Aryl and Hetcy; (b) OC ⁇ _6alkyl and OC3-6alkenyl;
  • R3 represents H, halo or Ci-3alkyl
  • R4 is selected from the group consisting of: H, Cl-6alkyl, C2-6alkenyl, C2-6alkynyl and Hetcy, said Ci -6alkyl, C2-6 a lkenyl and C2-6alkynyl groups being optionally substituted with 1-6 members selected from the group consisting of: halo, OH, NH2, NHCi-ioalkyl, N(Ci -ioalkyl)2, CN, CO2H, Hetcy, Aryl, CO2Ci_6alkyl, OCi-6alkyl, Oaryl, CO2Ci -3alkyl, CO2C3_4alkenyl, C(O)NH2, C(O)NHC ⁇ _3alkyl, C(O)N(C ⁇ _3alkyl)2, C(O)NH-Aryl, C(O)N(Ci-3aIkyl)-A ⁇ yl, C(O)C ⁇ _3alkyl, C(
  • Aryl represents a 6-14 membered aromatic ring system
  • Hetcy represents a 5-10 membered ring system, aromatic or non- aromatic, containing at least one heteroatom and optionally containing up to 2 additional heteroatoms, said heteroatoms being selected from O, S(O)y with y as defined above and N, said Aryl and Hetcy groups and portions thereof being optionally substituted with 1-6 members selected from the group consisting of: -(CH2) ⁇ -4- CO2H, -(CH2)0-3CO2Ci_3alkyl, halo, CN, NH2, phenyl, pyrrolidinyl, NHCH3, Cl- 6alkyl, SO2NH2 and SO2CH3.
  • Rl represents H, NH2, NHCi -6alkyl, NHC(O)Ci -6alkyl, NHC(O)OCi -6alkyl or NHC(O)Aryl, said alkyl and the alkyl and aryl portions of which are optionally substituted with 1-2 members selected from the group consisting of: CO2H, CO2C1 - ⁇ alkyl, aryl, NH2, NHCi -3alkyl, NH-Aryl and N(C ⁇ _3alkyl)2.
  • R2 is selected from the group consisting of:
  • Aryl represents a 6-14 membered aromatic ring system and Hetcy represents a 5-14 membered ring system, aromatic, non-aromatic or partially aromatic, containing at least one heteroatom and optionally containing up to 3 additional heteroatoms, said heteroatoms being selected from O, S(O)y with y as defined above and N, said Aryl and Hetcy groups and portions thereof being optionally substituted with 1-6 members selected from the group consisting of: -(CH2) ⁇ -4- CO2H, -(CH2)0-3CO2Ci_3alkyl, halo, CN, NH2, phenyl, pyrrolidinyl, NHCH3, Ci . ⁇ alkyl, SO2NH2 and SO2CH3. Within this subset, all other variables are as originally defined.
  • R3 represents H or Ci-3alkyl. Within this subset, all other variables are as originally defined. Another subset of compounds of the present invention that is of interest relates to compounds of formula I wherein:
  • R4 is selected from the group consisting of: H, Ci -6alkyl, C2-6alkenyl, C2-6alkynyl and Hetcy, said Ci-6alkyl, C2-6alkenyl and C2-6alkynyl groups being optionally substituted with 1-6 members selected from the group consisting of: halo, OH, NH2, CN, CO2H, Hetcy, N(Ci -io alkyl)2, Aryl, CO2Ci-6alkyl, OCi -6alkyl, Oaryl, CO2Ci-3alkyl, CO2C3_4alkenyl, C(O)NH2, C(O)NHCi -3alkyl, C(O)N(Ci-3alkyl)2, C(O)NH-Aryl, C(O)N(Ci -3alkyl)-Aryl, C(O)Ci-3alkyl, C(O)C3_4alkenyl, -S(O)
  • 3alkyl -S(O) y C3-4alkenyl, S(O)y-(Ci-3alkyl-aryl), wherein y is as previously defined; OCi -3alkyl-aryl, NH(Ci-3alkyl-aryl), N(Ci -3alkyl)C(O)Ci-3alkyl, N(C ⁇ .
  • 3alkyl)Aryl S(O)2N(C ⁇ _3alkyl)Hetcy, NHSO3H, NHSO2Ci -3alkyl, NHSO2C3. 4alkenyl, NHSO2A17I, NHSO2Hetcy, N(Ci _3alkyl)SO3H, N(Ci -3alkyl)SO2Ci . 3alkyl, N(Ci-3alkyl)SO2C3-4alkenyl, N(Ci-3alkyl)SO2Aryl and N(C ⁇ . 3alkyl)SO2Hetcy;
  • Aryl represents a 6-14 membered aromatic ring system and Hetcy represents a 5-10 membered ring system, aromatic or non- aromatic, containing at least one heteroatom and optionally containing up to 2 additional heteroatoms, said heteroatoms being selected from O, S(O)y with y as defined above and N, said Aryl and Hetcy groups and portions thereof being optionally substituted with 1-3 members selected from the group consisting of: -(CH2)0-4-
  • Rl is selected from the group consisting of: H, NH2, NHC ⁇ _6alkyl, NHC(O)C ⁇ - ⁇ alkyl, NHC(O)OCi -6alkyl and NHC(O)Aryl, said alkyl and the alkyl and aryl portions of which are optionally substituted with 1-2 members selected from the group consisting of: CO2H and CO2Ci -6alkyl, .
  • R2 is selected from the group consisting of:
  • Aryl represents a 6-10 membered aromatic ring system
  • Hetcy represents a 5-10 membered ring system, aromatic or non- aromatic, containing at least one heteroatom and optionally containing up to 3 additional heteroatoms, said heteroatoms being selected from O, S and N, said Aryl and Hetcy groups and portions thereof being optionally substituted with 1-6 members selected from the group consisting of: -(CH2)0-6 _ CO2H and -(CH2)0-6CO2Ci-6alkyl.
  • R4 is selected from the group consisting of: H and Ci-4alkyl, optionally substituted with a member selected from the group consisting of: Hetcy, N(Ci-ioalkyl)2, Aryl, O-Aryl, OCi -6alkyl, S(O)yC ⁇ .3alkyl, S(O)y-(Ci-3alkyl-aryl), wherein y is 0 or 2, OC ⁇ _3alkyl-aryl and NH(Ci-3alkyl-aryl), wherein Aryl represents phenyl optionally substituted with 1-3 halo groups.
  • Rl is selected from the group consisting of: H, NH2. NHCi -6alkyl, NHC(O)Ci _6alkyl, NHC(O)OC ⁇ _6alkyl and NHC(O)Aryl, said alkyl and the alkyl and aryl portions of which are optionally substituted with 1-2 members selected from the group consisting of: CO2H and CO2Ci_6alkyl;
  • R2 is selected from the group consisting of:
  • Hetcy represents a 5-10 membered ring system, aromatic or non- aromatic, containing at least one heteroatom and optionally containing up to 3 additional heteroatoms, said heteroatoms being selected from O, S and N, said Aryl and Hetcy groups and portions thereof being optionally substituted with 1-6 members selected from the group consisting of: -(CH2) ⁇ -6- CO2H and -(CH2)0-6C ⁇ 2C ⁇ _6alkyl;
  • R3 represents H
  • R4 is selected from the group consisting of: H and Ci-4alkyl optionally substituted with a member selected from the group consisting of: Hetcy, Aryl, O- Aryl, OC ⁇ _6alkyl, S(O)yC 1.3 alkyl, N(Ci -ioalkyl)2, S(O)y-(Ci -3alkyl-aryl), wherein y is 0 or 2, OCi-3alkyl-aryl and NH(Ci-3alkyl-aryl), wherein Aryl represents phenyl optionally substituted with 1-3 halo groups.
  • Representative examples of compounds of formula I are found in Table
  • the invention encompasses a method of treating a caspase-3 mediated disease in a mammalian patient in need of such treatment, comprising administering to said patient a compound of formula I in an amount effective to treat said caspase-3 mediated disease.
  • the invention encompasses a method of treating cardiac and cerebral ischemia/reperfusion injury (e.g. stroke), type I diabetes, immune deficiency syndrome (including AIDS), cerebral and spinal cord trauma injury, organ damage during transplantation, alopecia, aging, Parkinson's disease, Alzheimer's disease, Down's syndrome, spinal muscular atrophy, multiple sclerosis and neurodegenerative disorders, comprising administering to a mammalian patient in need of such treatment an effective amount of a compound of formula I.
  • cardiac and cerebral ischemia/reperfusion injury e.g. stroke
  • type I diabetes e.g., immune deficiency syndrome (including AIDS)
  • cerebral and spinal cord trauma injury e.g. stroke
  • organ damage during transplantation e.g. stroke
  • the invention encompasses a method of treating acute disorders, including cardiac and cerebral ischemia/ reperfusion injury (e.g. stroke), spinal cord injury and organ damage during transplantation, in a mammalian patient in need of such treatment, comprising administering to said patient a compound of formula I in an amount effective to treat said acute disorder.
  • acute disorders including cardiac and cerebral ischemia/ reperfusion injury (e.g. stroke), spinal cord injury and organ damage during transplantation, in a mammalian patient in need of such treatment, comprising administering to said patient a compound of formula I in an amount effective to treat said acute disorder.
  • the invention encompasses a method of treating chronic disorders, including neurodegenerative diseases (e.g. Alzheimer's, polyglutamine-repeat disorders, Down's, spinal muscular atrophy, multiple sclerosis), immunodeficiency (e.g. HTV), diabetes, alopecia and aging, in a mammalian patient in need of such treatment, comprising administering to said patient a compound of formula I in an amount effective to treat said chronic disorder.
  • neurodegenerative diseases e.g. Alzheimer's, polyglutamine-repeat disorders, Down's, spinal muscular atrophy, multiple sclerosis
  • immunodeficiency e.g. HTV
  • diabetes alopecia and aging
  • the invention encompasses a method of treating a caspase-3 mediated disease in a mammalian patient in need of such treatment, comprising administering to said patient a compound of formula I in an amount effective to treat said caspase-3 mediated disease.
  • these compounds are preferably useful to treat, prevent or ameliorate in mammals and especially in humans, diseases including but not limited to: cardiac and cerebral ischemia/reperfusion injury (e.g. stroke) type I diabetes immune deficiency syndrome (including AIDS) cerebral and spinal cord trauma injury organ damage during transplantation alopecia aging
  • cardiac and cerebral ischemia/reperfusion injury e.g. stroke
  • type I diabetes immune deficiency syndrome including AIDS
  • Alzheimer's disease Down's syndrome spinal muscular atrophy multiple sclerosis neurodegenerative disorders.
  • the compound is administered to a mammalian patient in need of such treatment or prevention an amount of a compound as described herein that is effective to treat or prevent the disease or condition.
  • the compounds described typically contain asymmetric centers and may thus give rise to diastereomers and optical isomers.
  • the present invention includes all such possible diastereomers as well as their racemic and resolved, enantiomerically pure forms and pharmaceutically acceptable salts thereof.
  • compositions of the present invention comprise a compound of formula I as an active ingredient or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier, and optionally other therapeutic ingredients.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable bases including inorganic bases and organic bases.
  • Representative salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, ammonium, potassium, sodium, zinc and the like. Particularly preferred are the calcium, magnesium, potassium, and sodium salts.
  • Representative salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
  • basic ion exchange resins such as argin
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
  • Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids.
  • reference to the compounds of formula I are meant to also include the pharmaceutically acceptable salts.
  • the ability of the compounds of formula I to inhibit caspase-3 make them useful research tools in the field of apoptosis.
  • the magnitude of therapeutic dose of a compound of formula I will, of course, vary with the nature of the severity of the condition to be treated and with the particular compound of formula I and its route of administration and vary upon the clinician's judgement. It will also vary according to the age, weight and response of the individual patient. An effective dosage amount of the active component can thus be determined by the clinician after a consideration of all the criteria and using his/her best judgement on the patient's behalf.
  • a representative dose will range from 0.001 mpk/d to about 100 mpk/d.
  • An ophthalmic preparation for ocular administration comprising 0.001- 1% by weight solutions or suspensions of the compounds of formula I in an acceptable ophthalmic formulation may be used.
  • Any suitable route of administration may be employed for providing an effective dosage of a compound of the present invention.
  • oral, parenteral and topical may be employed.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
  • compositions suitable for oral, parenteral and ocular (ophthalmic) may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.
  • the compounds of formula I can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • any of the usual pharmaceutical media may be employed, such as, for example, water, alcohols, oils, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case or oral solid preparations such as, for example, powders, capsules and tablets, with the solid oral preparations being preferred over the liquid preparations. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaque
  • compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil emulsion.
  • Such compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into active ingredient with the carrier which constitutes one or more necessary ingredients.
  • the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • each dosage unit may contain from about 0.01 mg to about 1.0 g of the active ingredient.
  • Aspartyl aldehyde 1 is prepared as illustrated in Scheme 1. Reaction of N-fluorenylmethyloxycarbonyl-L-aspartic acid ⁇ -tert-butyl ester (Fmoc-L-Asp (OtBu)-OH) (2) (Novabiochem) with iso-butyl chloroformate (IBCF) followed by treating the reaction mixture with sodium borohydride gives alcohol 3. This is oxidized under Swem conditions to give 1.
  • the semicarbazide Resin D is prepared according to Scheme 3. Treatment of compound 6 (Webb et al, J. Am. Chem. Soc. 114, 3156 (1992)) with a commercial amino-Merrifield resin in the presence of EDCI and HOBT in dichloromethane followed by removal of the Boc group with trifluoroacetic acid (TFA) in dichloromethane afforded Resin D.
  • Aspartyl ketone derivatives could be prepared as shown in Scheme 4.
  • An organometallic reagent such as an alkyl Grignard (RMgBr) can be added to aldehyde 7 (prepared in direct analogy to aldehyde 1), and the resulting alcohol oxidized to the ketone with an oxidizing agent such as Dess-Martin periodinane.
  • Ketone 9 can be loaded onto Resin D with catalytic HO Ac in THF to provide Resin E.
  • Cleavage of the Alloc group may be accomplished with Pd(PPh3)4 in the presence of pyrrolidine or tributyltin hydride, generating Resin F. This may be coupled with pyridine carboxylic acid derivatives as shown in Scheme 2 to generate compounds of the present invention.
  • Scheme 4 Preparation of Ketone Derivatives
  • ketone derivatives containing a heteroatom in the D- position could be prepared from bromomethylketone 11.
  • reaction of N-fluorenylmethyloxycarbonyl-L-aspartic acid D-tert-butyl ester (Fmoc-L- Asp (OtBu)-OH) (1) (Novabiochem) with iso-butyl chloroformate (IBCF) followed by treating the reaction mixture with an excess of diazomethane yields the diazomethylketone intermediate 10.
  • This intermediate is subjected in situ to a 1:1 mixture of AcOH and 45% aqueous hydrobromic acid (HBr) to give compound 11 as a white powder.
  • HBr aqueous hydrobromic acid
  • the Fmoc group on Resin H is cleaved with 20% (v) piperidine in DMF and the resultant Resin I reacted with a substituted nicotinic acid using O-(7-Azabenzotriazol-l-yl)N,N,N',N'- tetramethyluronium hexafluorophosphate (HATU) as the activating agent and diisopropylethylamine (DIEA) as the base, affording Resin J.
  • HATU O-(7-Azabenzotriazol-l-yl)N,N,N',N'- tetramethyluronium hexafluorophosphate
  • DIEA diisopropylethylamine
  • the final product I is released from solid support by treating Resin J with trifluoroacetic acid (TFA) in water (9/1, v/v).
  • Nicotinic acid derivatives bearing a carboxamide substituent in the 5- postion were prepared as shown in Scheme 7.
  • Nucleophilic displacement of the bromine in Resin G with 4-fluorobenzylmercaptan in the presence of suitable bases followed by Fmoc cleavage with 20% (v) piperidine in DMF gave Resin K.
  • This resin was reacted with pyridinedicarboxylic acid using O-(7-Azabenzotriazol-l- yl)N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) as the activating agent and diisopropylethylamine (DIEA) as the base, affording Resin L.
  • HATU O-(7-Azabenzotriazol-l- yl)N,N,N',N'-tetramethyluronium hexafluorophosphate
  • DIEA diisopropylethylamine
  • This resin may be coupled with primary or secondary amines, or anilines using HATU and DIEA to give the resin-bound amides (Resin M).
  • the final product I is released from solid support by treating Resin M with trifluoroacetic acid (TFA) in water (9/1, v/v).
  • Scheme 7 Preparation of pyridinediamide derivatives
  • Nicotinic acid derivatives containing a sulfone in the 5-position were prepared as shown in Scheme 8.
  • 5-bromonicotinic acid underwent Fischer esterification followed by sodium thiomethoxide displacement of the bromine to give thioether 14.
  • Oxidation of the sufide to the sulfoxide 15 could be accomplished with an oxidant such as MMPP.
  • Pummerer rearrangement was achieved by warming with TFAA, then concentrating and treating the residue with triethylamine in MeOH to give the thiol 16.
  • This thiol may be alkylated with alkyl halides in DMF in the presence of an amine base.
  • the resulting sulfide 17 can be oxidized to the sulfone with an oxidant such as MMPP, and the ester can be hydrolized under basic conditions to give nicotinic acid derivative 18.
  • This acid may be coupled to Resin K as previously described, and the resin cleaved with TFA H2O to provide the sulfone derivatives which are examples of the present invention.
  • Nicotinic acid derivatives containing a sulfonamide in the 5-position were prepared as shown in Scheme 9.
  • the ester moiety of thiol 16 (or its corresponding disulfide) may be hydrolized under basic conditions to give acid 20 (or its corresponding disulfide).
  • Oxidation to the sulfonyl chloride 21 may be accomplished with chlorine gas in HO Ac.
  • Primary or secondary amines may be reacted with 21 to give sulfonamides 22 .
  • These acids may be coupled to Resin K as previously described, and the resin cleaved with TFA H2O to provide the sulfonamide derivatives which are examples of the present invention.
  • Caspase inhibitors containing aryloxymethylketones and acyloxymethyl ketones may be prepared as shown in Scheme 10.
  • Resin G in DMF may be treated with a phenol or substituted phenol in the presence of a base such as cesium carbonate to give Resin M.
  • Resin G in DMF may be treated with a carboxylic acid, preferably an aromatic acid, in the presence of a base such as potassium fluoride to give Resin M.
  • Coupling of an appropriately substituted nicotinic acid under standard conditions then provides Resin N, which may be cleaved with TFA/H2O to provide compounds of the present invention.
  • Caspase inhibitors containing aryloxymethylketones and acyloxymethyl ketones may be prepared as shown in Scheme 11.
  • Resin O is prepared from Alloc-L-Asp (OtBu)-OH as described in Schemes 5 and 6. Treatment of Resin O with a primary amine in DMF followed by Boc protection generates Resin P. The Alloc group may then be removed using a palladium catalyst and a hydride source. The resulting amine may be coupled with an appropriately substituted nicotinic acid under standard conditions to provide Resin Q. This may be cleaved with TFA/H2O to provide compounds of the present invention.
  • N-Fmoc-L-aspartic acid ⁇ -tert-butyl ester 10.01 g, 24.3 mmol
  • THF tetrahydrofuran
  • NMM N- methylmorpholine
  • IBCF isobutyl chloroformate
  • Step 5 Resin B 152 mg of resin was suspended in 2 mL DMF. Piperidine (0.4 mL) was added, and the mixture was rotated for 25 min. The resin was filtered and washed with DMF (3 x), THF (3x) and CH2CI2 (3x)
  • Step 6 (3S)-3-[(5-Bromo-3-pyridyl)carbamoyl]amino-4-oxo-butanoic acid
  • the resin from Step 5 was suspended in 1.6 mL DMF and EDCI (87 mg, 0.45 mmol), HOBt (70 mg, 0.45 mmol) and 5-bromonicotinic acid (77 mg, 0.38 mmol) were added.
  • the mixture was rotated at RT for 3h, then filtered and washed with DMF, THF, CH2CI2 and EtOAc (3x each).
  • the resin was then treated with 9: 1 TFA:H2 ⁇ (2.5 mL) and rotated for 35 min.
  • the resin was filtered and washed with 9:1 TFA:H2 ⁇ (2 x 2.5 mL), and the filtrates were concentrated.
  • the residue was dissolved in 1:1 HOAc:H2 ⁇ and lyophilized to provide 19.3 mg of the title compound.
  • Resin B was reacted with 6-aminonicotinic acid as described in Example 1, Step 6.
  • the resulting resin-bound aniline (104.8 mg) was suspended in 2 mL of pyridine with 77 mg of succinic anhydride and heated to 94°C for 4 h.
  • the resin was washed with DMF (3 x), THF (3x) and CH2CI2 (3x).
  • the resulting resin was treated with TFA as described in Example 1, Step 6 to provide the title compound as a mixture of cyclic acetals.
  • PYRIDYL)BENZOIC ACID Resin B was reacted with 5-bromonicotinic acid as described in Example 1, Step 6.
  • the resulting resin (0.5 mmol/g, 153 mg) was suspended in DME (2 mL).
  • 4-carboxyphenylboronic acid 64 mg, 0.38 mmol
  • Pd(Ph3P)4 9 mg, 0.008 mmol
  • the resin was filtered and washed with aq NH4CI (3 x), H2O (3x), THF (3x) and CH2CI2 (3x).
  • the resulting resin was treated with TFA as described in Example 1, Step 6 to provide the title compound.
  • N-Fmoc-L-aspartic acid ⁇ -tert-butyl ester 21.0 g, 51.0 mmol
  • THF tetrahydrofuran
  • NMM N-methylmorrJholine
  • IBCF isobutyl chloroformate
  • Resin G 100 mg
  • DMF (3 ml) and thiophenol (26 ⁇ l) were mixed together in a fritted syringe. It was shaken for 30 sec, then (iPr)2NEt (44 ⁇ l) was added. It was rotated for 2h. The resin was washed with DMF (4x), MeOH (4x), THF (4x) and CH2CI2 (4x). It was dried under a N2 flow for 10 min.
  • Step 1 A mixture of Resin K (1.52 g, 0.76 mmol), 3,5-pyridinedicarboxylic acid (1.44g, 8.6 mmol) and HATU (1.10 g, 2.9 mmol) was suspended in 10 mL DMF and shaken. Diethylisopropylamine (1.2 mL, 6.9 mmol) was then added and the mixture rotated for 2.5 h. The resin was washed with DMF (3x), MeOH (3x), THF (3x) and CH2CI2 (3x) and dried to give Resin L. Step 2
  • OXOPENTANOIC ACID A mixture of Resin L (74 mg) and HATU (60 mg) was suspended in DMF (2 mL). Excess diethylamine (-0.5 mL) was added and the mixture was rotated for 1.5h. The resin was washed with DMF (3x), MeOH (3x), THF (3x) and CH2CI2 (3x). The resin was then treated with 9:1 TFA:H2 ⁇ and rotated for 15 min. The resin was filtered and washed with acetonitrile, and the filtrates were concentrated to give 13 mg of the title compound.
  • Step 2 3-Bromo-5-(isopropoxymethyl)pyridine To a 0 °C solution of 3-bromo-5-hydroxymethylpyridine (211 mg, 1.22 mmol) in CH2CI2 (10 mL) was added Et3N (0.4 mL) and MsCl (0.13 mL, 1.7 mmol).
  • the bomb was cooled and depressurized, and the reaction mixture was partitioned between ethyl acetate and aq. ammonium chloride. The organic phase was washed with brine and dried over MgSO4 to give 75 mg of the title compound contaminated with PI13P.
  • Step 4 3S)-5-((4-Fluorobenzyl)sulfanyl)-3-[(5-(isopropoxymethyl)-3- pyridyl)carbonyl]amino-4-oxopentanoic acid
  • OXOPENTANOIC ACID MS (APCI, neg. ion) m/z 502 (M-l, 100), 362 (20), 316 (16).
  • OXOPENTANOIC ACID MS (APCI, neg. ion) m/z 537 (M-l, 100), 397 (40), 351 (45).
  • OXOPENTANOIC ACID MS (APCI, neg. ion) m/z 527 (M-l, 100), 474 (30), 387 (20), 288 (35).
  • PENTANOIC ACID lH NMR 400 MHz, acetone-d6): ⁇ 9.05 (s, IH), 8.50 (m, IH, NH), 8.38 (d, IH), 7.45 (d, IH), 7.39-7.35 (m, 2H), 7.05 (t, 2H), 5.25 (m, IH), 3.72 (s, 2H), 3.50 (dd, ABX, 2H), 3.08 (dd, IH), 2.90 (s, 4H), 2.85 (dd, IH).
  • D MS m/z 492.3 (M+l).
  • Resin I 60 mg was treated with 5-(propylsulfonyl)nicotinic acid (13 mg) as described in Example 12 to provide 15 mg of the title compound.
  • Resin I 80 mg was treated with 5-((pyrrolidino)sulfonyl)nicotinic acid (42 mg) as described in Example 12 to provide 20 mg of the title compound.
  • Resin M 200 mg, 0.086 mmol
  • 5-((cyclopropylamino)sulfonyl) nicotinic acid 46 mg, 0.189 mmol
  • HATU 72 mg, 0.189 mmol
  • the suspension was rotated 2.5 h, then washed with DMF (3x), THF (3x), MeOH (3x), and CH2CI2 (3x).
  • the resulting resin was rotated with 9:1 TFA. ⁇ 2O for 10 min, then filtered and washed with acetonitrile. The filtrate was concentrated to give the title compound.
  • AMC amino-4-methylcoumarin was prepared as follows: i) synthesis of N- Ac-Asp(OBn)-Glu(OBn)-Val-CO2H, ii) coupling with Asp(OBn)-7-amino-4- methylcoumarin, iii) removal of benzyl groups.
  • Standard reaction mixtures 300 ⁇ L final volume
  • Photometric immunoassay for the qualitative and quantitative in vitro determination of cytoplasmic histone-associated-DNA-fragments (mono- and oligonucleosomes) after induced cell death. This assay was performed using the commercially available kit from Boehringer Mannheim, cat. No. 1 920 685.
  • the origin of the left coronary artery was visualized and a 4.0 suture passed under the artery approximately 2 - 3 mm from its origin.
  • the ends of the suture were passed through a short length of 2 mm id tubing and coronary artery occlusion effected by placing tension on the suture such that the tube compressed the artery.
  • the thoracotomy was closed with a small clamp and opened only to effect occlusion and reperfusion of the artery.
  • a Lead ⁇ electrocardiograph (ECG) signal was obtained by placing subdermal platinum leads and continuously monitored. After a baseline period of 20-30 minutes the left coronary artery was occluded for 45 minutes. The period of reperfusion was 3 hours.
  • the caspase inhibitor or vehicle was administered as a first bolus 5 minutes before the onset of ischemia and a second bolus was administered again at the onset of reperfusion. Additionally, an infusion was initiated immediately after the first bolus dose. Control animals received the vehicle alone in equal volumes to the caspase inhibitor treated animals. At the end of reperfusion the animals were euthanized and infarct size determined using a dual staining technique (1.5% w/v triphenyltetrazolium chloride to demarcate infarct tissue and 0.25% w/v Evan's blue to demarcate the area at risk of infarct. The heart was subsequently cut transversely into 4 slices of equal thickness, and infarct size and area at risk quantified using planimetry.

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Abstract

L'invention concerne des composés inhibiteurs de la caspase-3 représentés par la formule générale (I), ainsi que des compositions pharmaceutiques et des méthodes de traitement. Lesdits composés sont utiles dans le traitement de maladies et d'états induits par la caspase-3, parmi lesquelles les ischémies cardiaques ou cérébrales ou les lésions dues à une reperfusion, le diabète type 1, le syndrome d'immunodéficience, y compris le SIDA, les lésions cérébrales et les traumatismes médullaires, les dommages subits par des organes lors d'une greffe, l'alopécie, le vieillissement, la maladie de Parkinson, la maladie d'Alzheimer, le syndrome de Down, la maladie d'Aran-Duchenne, la sclérose en plaques et les troubles neurodégénératifs.
PCT/CA2000/001196 1999-10-13 2000-10-11 Utilisation de comme inhibiteurs de la caspase-3 nicotinyl aspartyl ketones as inhibitors of caspase-3 WO2001027085A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003024955A2 (fr) * 2001-09-18 2003-03-27 Sunesis Pharmaceuticals, Inc. Inhibiteurs a petites molecules de caspases
WO2004014843A1 (fr) * 2002-08-09 2004-02-19 Takeda Chemical Industries, Ltd. Composés amino substitués et utilisation de ces composés
WO2007011760A2 (fr) * 2005-07-15 2007-01-25 Kalypsys, Inc. Inhibiteurs de la kinesine mitotique
ITRM20080641A1 (it) * 2008-12-02 2010-06-03 Fond Santa Lucia Uso della caspasi-3 per la malattia dell'alzheimer
WO2019163981A1 (fr) * 2018-02-26 2019-08-29 日本化薬株式会社 Agent de prolifération de bases, et composition de résine réactive aux bases contenant ledit agent de prolifération de bases

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998011109A1 (fr) * 1996-09-12 1998-03-19 Idun Pharmaceuticals, Incorporated Nouveaux composes tricycliques permettant d'inhiber la famille de proteases ice/ced-3
WO1999047154A1 (fr) * 1998-03-16 1999-09-23 Cytovia, Inc. Dipeptides inhibiteurs de caspase et leur utilisation
WO1999047545A2 (fr) * 1998-03-19 1999-09-23 Vertex Pharmaceuticals Incorporated Inhibiteurs de caspases

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998011109A1 (fr) * 1996-09-12 1998-03-19 Idun Pharmaceuticals, Incorporated Nouveaux composes tricycliques permettant d'inhiber la famille de proteases ice/ced-3
WO1999047154A1 (fr) * 1998-03-16 1999-09-23 Cytovia, Inc. Dipeptides inhibiteurs de caspase et leur utilisation
WO1999047545A2 (fr) * 1998-03-19 1999-09-23 Vertex Pharmaceuticals Incorporated Inhibiteurs de caspases

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003024955A2 (fr) * 2001-09-18 2003-03-27 Sunesis Pharmaceuticals, Inc. Inhibiteurs a petites molecules de caspases
WO2003024955A3 (fr) * 2001-09-18 2003-08-14 Sunesis Pharmaceuticals Inc Inhibiteurs a petites molecules de caspases
US6878743B2 (en) 2001-09-18 2005-04-12 Sunesis Pharmaceuticals, Inc. Small molecule inhibitors of caspases
WO2004014843A1 (fr) * 2002-08-09 2004-02-19 Takeda Chemical Industries, Ltd. Composés amino substitués et utilisation de ces composés
WO2007011760A2 (fr) * 2005-07-15 2007-01-25 Kalypsys, Inc. Inhibiteurs de la kinesine mitotique
WO2007011760A3 (fr) * 2005-07-15 2007-09-07 Kalypsys Inc Inhibiteurs de la kinesine mitotique
ITRM20080641A1 (it) * 2008-12-02 2010-06-03 Fond Santa Lucia Uso della caspasi-3 per la malattia dell'alzheimer
WO2019163981A1 (fr) * 2018-02-26 2019-08-29 日本化薬株式会社 Agent de prolifération de bases, et composition de résine réactive aux bases contenant ledit agent de prolifération de bases
KR20200128028A (ko) * 2018-02-26 2020-11-11 닛뽄 가야쿠 가부시키가이샤 염기 증식제 및 당해 염기 증식제를 함유하는 염기 반응성 수지 조성물
JPWO2019163981A1 (ja) * 2018-02-26 2021-02-25 日本化薬株式会社 塩基増殖剤及び当該塩基増殖剤を含有する塩基反応性樹脂組成物
US11401370B2 (en) 2018-02-26 2022-08-02 Nippon Kayaku Kabushiki Kaisha Base proliferating agent, and base-reactive resin composition containing said base proliferating agent
JP7199411B2 (ja) 2018-02-26 2023-01-05 日本化薬株式会社 塩基増殖剤及び当該塩基増殖剤を含有する塩基反応性樹脂組成物
KR102602567B1 (ko) 2018-02-26 2023-11-14 닛뽄 가야쿠 가부시키가이샤 염기 증식제 및 당해 염기 증식제를 함유하는 염기 반응성 수지 조성물
US11905361B2 (en) 2018-02-26 2024-02-20 Nippon Kayaku Kabushiki Kaisha Base proliferating agent, and base-reactive resin composition containing said base proliferating agent

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