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  • C07D495/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/32—One oxygen, sulfur or nitrogen atom
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  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • 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
  • C07D405/12—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 linked by a chain containing hetero atoms as chain links
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  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—Ortho-condensed systems
  • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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Definitions

• Bax-induced cell death is a major cause of many types of degenerative diseases.
• Bax is a 21-kDa member of the conserved Bcl-2 family of proteins involved in regulating programmed cell death.
• Bax plays a key role in the intrinsic pathway of apoptosis.
• Bcl-2 family proteins are characterized by the presence of four Bcl-2 homology (BH) domains.
• Antiapoptotic members e.g., Bcl-2, Bcl-XL and Mcl-1 have all four BH domains (BH1-4).
• the proapoptotic members are further divided into multi-domain proteins (e.g., Bax, Bak and Bok) containing three BH domains (BH 1-3) or BH3-only proteins (e.g., Bim, Bid and PUMA, etc.,) containing just the BH-3 domain.
• multi-domain proteins e.g., Bax, Bak and Bok
• BH3-only proteins e.g., Bim, Bid and PUMA, etc.
• Embodiments described herein relate to compounds for use in inhibiting Bax mediated cell death and/or apoptosis and to their use in treating conditions, disorders, and/or diseases associate with Bax mediated cell death and/or apoptosis.
• the Bax inhibiting compounds described herein suppressed Bax-induced cell death at 1 nM -1000 nM (e.g., Bax- induced death of mouse embryonic fibroblasts (MEFs)) compared to previously reported Bax inhibitors that required at least 200 nM to inhibit Bax-induced death of MEFs, and have Bax binding affinity (Kd) ranging from 1 nM-1000 nM.
• the Bax inhibiting compound can include the following formula (I): or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:
• R 1 and R 2 are each independently -H, alkyl, -F, -CN, -O-alkyl, cycloalkyl, oxetanyl, or tetrahydrofuranyl, or R 1 together with R 2 forms a phenyl ring optionally substituted with one or two R 8 groups, or R 1 together with R 2 forms a five or six-membered heteroaromatic ring containing one or two heteroatoms chosen from N, O and S, optionally substituted with one or two R 8 groups;
• R 8 is halo, alkyl, cycloalkyl, oxetanyl, tetrahydrofuranyl,
• R 3 is absent, -H, -D, -F, -Cl, -CF 3 , -alkyl, cyclopropyl -O-alkyl, or -CN;
• R 4 is -H, alkyl, cyclopropyl, or -CF 3 ;
• R 5 is absent, -H, or alkyl
• R 5 and the nitrogen atom to which it is attached may be replaced by an oxygen atom
• V, W, X, Y and Z are each independently -CH, or N;
• X 1 and Z 1 are each independently -CH or N;
• W 1 and Y 1 are each independently C or N, and when Y 1 is N, R 3 is absent;
• X 2 is O or N, when X 2 is O, R 5 is absent;
• R 6 is -H, halo, alkyl, cycloalkyl, -CN, -O-alkyl, -O-cycloalkyl, -O- heterocyclyl, -S0 2 -alkyl, -CH2S 0 2 -alkyl, -CONH2, -CONH-alkyl, or -CON(alkyl)2;
• R 7 is -H, halo, alkyl, cycloalkyl, -CN, -O-alkyl, -O-cycloalkyl, -O- heterocyclyl, -S0 2 -alkyl, -CH2S 0 2 -alkyl, -CONH2, -CONH-alkyl, or -CON(alkyl)2 ; alternatively, R 6 or R 7 can be an aryl optionally substituted with one or two R 9 groups;
• R 6 or R 7 can be a 4-6 membered ring heterocycle containing one or two heteroatoms chosen from the group consisting of N, O and S, and optionally substituted with one or two R 9 groups, excluding unstable heterocycles;
• R 6 or R 7 can be a 5-6 membered ring heteroaryl group containing one to four heteroatoms chosen from the group consisting of N, O and S, and optionally substituted with one or two R 9 groups, excluding unstable heterocycles;
• R 9 is H, halo, alkyl, cycloalkyl, alkyl-CO-, oxetanyl,
• R 6 together with R 7 and the phenyl ring or heteroaryl ring to which they are attached, may be a benzimidazole ring, benzotriazole ring, azaindole ring, azaindazole, or benzodioxolane, with N of the rings bearing an optional substituent R 10 , and with Cs of the rings optionally substituted with R 11 ;
• R 10 is -H, alkyl, or cycloalkyl
• R 11 is -H, alkyl, or cycloalkyl.
• the Bax inhibiting compound having formula (I) can include a compound having the following formula:
• R 1 and R 2 are each independently -H, Ci-C 6 -alkyl, -F, -CN, -0-Ci-C 6 -alkyl, C3-C7-cycloalkyl, 3-oxetanyl, or 3-tetrahydrofuranyl, or R 1 together with R 2 forms a phenyl ring optionally substituted with one or two R 8 groups, or R 1 together with R 2 forms a five or six-membered heteroaromatic ring containing one or two heteroatoms chosen from N, O and S, optionally substituted with one or two R 8 groups;
• R 8 is halo, Ci-C 6 -alkyl, C3-C7-cycloalkyl, 3-oxetanyl, 3-tetrahydrofuranyl, - CN, -O-Ci-Ce-alkyl, -0-C 3 -C 7 -cycloalkyl, -S0 2 -Ci-C 6 -alkyl, or -CH 2 S0 2 -Ci-C 6 -alkyl;
• R 3 is -H, -D, -F, -Cl, -CF3, -Ci-C 6 -alkyl, cyclopropyl -0-Ci-C 6 -alkyl, or -CN;
• R 4 is -H, -Ci-C 6 -alkyl, -cyclopropyl, or -CF3;
• R 5 is -H, or -Ci-C 6 -alkyl
• R 5 and the nitrogen atom to which it is attached may be replaced by an oxygen atom
• X, Y and Z are each independently -CH, or N;
• R 6 is -H, halo, Ci-Ce-alkyl, C 3 -C 7 -cycloalkyl, -CN, -O-Ci-Ce-alkyl, -0-C 3 -C 7 - cycloalkyl, -O-heterocyclyl, -S0 2 -Ci-C 6 -alkyl, -CH 2 S0 2 -Ci-C 6 -alkyl, -CONH 2 , -CONH-Ci- Ce-alkyl, or -CON(Ci-C 6 -alkyl) 2 ;
• R 7 is -H, halo, Ci-Ce-alkyl, C 3 -C 7 -cycloalkyl, -CN, -O-Ci-Ce-alkyl, -0-C 3 -C 7 - cycloalkyl, -O-heterocyclyl, -S0 2 -Ci-C 6 -alkyl, -CH 2 S0 2 -Ci-C 6 -alkyl, -CONH 2 , -CONH-Ci- Ce-alkyl, or -CON(Ci-C 6 -alkyl) 2;
• R 6 or R 7 can be an aryl optionally substituted with one or two R 9 groups;
• R 6 or R 7 can be a 4-6 membered ring heterocycle containing one or two heteroatoms chosen from the group consisting of N, O and S, and optionally substituted with one or two R 9 groups, excluding unstable heterocycles;
• R 6 or R 7 can be a 5-6 membered ring heteroaryl group containing one to four heteroatoms chosen from the group consisting of N, O and S, and optionally substituted with one or two R 9 groups, excluding unstable heterocycles;
• R 9 is halo, Ci-C 6 -alkyl, C3-C 7 -cycloalkyl, Ci-Cs-alkyl-CO-, 3-oxetanyl, 3- tetrahydrofuranyl, -CN, -0-Ci-C 6 -alkyl, -0-C 3 -C 7 -cycloalkyl, -CONH 2 , -CONH-alkyl, or - CON(alkyl) 2 ;
• R 6 together with R 7 and the phenyl ring or heteroaryl ring to which they are attached, may be a benzimidazole ring, benzotriazole ring, azaindole ring, azaindazole, or benzodioxolane, with N of the rings bearing an optional substituent R 10 , and with Cs of the rings optionally substituted with R 11 ;
• R 10 is -H, Ci-C 6 -alkyl, or C3-C7-cycloalkyl;
• R 11 is -H, Ci-C 6 -alkyl, or C3-C7-cycloalkyl.
• R 1 and R 2 are each independently -H, Ci-C 6 -alkyl, -F, - CN, -0-Ci-C 6 -alkyl, C3-C7-cycloalkyl, 3-oxetanyl, or 3-tetrahydrofuranyl, or R 1 together with R 2 forms a phenyl ring optionally substituted with one or two R 8 groups, or R 1 together with R 2 forms a saturated five or six-membered hetero aromatic ring containing one or two heteroatoms chosen from N, O and S, optionally substituted with one or two R 8 groups.
• R 8 is halo, Ci-C 6 -alkyl, C3-C7-cycloalkyl, 3-oxetanyl, 3- tetrahydrofuranyl, -CN, -0-Ci-C 6 -alkyl, -0-C 3 -C 7 -cycloalkyl, -S0 2 -Ci-C 6 -alkyl, or -CH2SO2- Ci-Ce-alkyl.
• R 3 is absent, -H, -D, -F, -Cl, -CF3, -Ci-C 6 -alkyl, cyclopropyl -0-Ci-C 6 -alkyl, or -CN.
• R 4 is -H, -Ci-C 6 -alkyl, -cyclopropyl, or -CF 3 .
• R 5 is absent, -H, or -Ci-C 6 -alkyl.
• R 6 is -H, halo, Ci-C 6 -alkyl, C3-C7-cycloalkyl, -CN, -O-
• R 7 is -H, halo, Ci-C 6 -alkyl, C3-C7-cycloalkyl, -CN, -O- Ci-Ce-alkyl, -0-C 3 -C 7 -cycloalkyl, -S0 2 -Ci-C 6 -alkyl, -CH 2 S0 2 -Ci-C 6 -alkyl, -CONH2, - CONH-Ci-Ce-alkyl, or -CON(Ci-C 6 -alkyl).
• R 9 is H, halo, Ci-C 6 -alkyl, C3-C7-cycloalkyl, C 1 -C 5 - alkyl-CO-, 3-oxetanyl, 3-tetrahydrofuranyl, -CN, -0-Ci-C 6 -alkyl, or -0-C 3 -C 7 -cycloalkyl.
• R 10 is -H, Ci-C 6 -alkyl, or C3-C7-cycloalkyl.
• R 11 is -H, Ci-C 6 -alkyl, or C3-C7-cycloalkyl.
• R 1 together with R 2 can form a phenyl ring optionally substituted with one or two R 8 groups, or R 1 together with R 2 can form a saturated five or six- membered heteroaromatic ring containing one or two heteroatoms chosen from N, O and S, optionally substituted with one or two R 8 groups.
• R 4 is -Ci-C 6 -alkyl or -CF 3 and R 5 is -H.
• X and Y are independently H; and Z is N.
• R 6 or R 7 is a 4-6 membered ring saturated heterocycle containing one or two heteroatoms chosen from the group consisting of N, O and S, and optionally substituted with one or two R 9 groups, excluding unstable heterocycles, or R 6 or R 7 is a 5-6 membered ring heteroaryl group containing one to three heteroatoms chosen from the group consisting of N, O and S, and optionally substituted with one or two R 9 groups, excluding unstable heterocycles.
• R 6 is selected from the group consisting of:
• a Bax inhibiting compound can include the following formula (II):
• a 1 and A 2 are independently CH or N;
• the heterocycle comprising V 3 , W 3 , X 3 , Y 3 and Z 3 and its substituents R 15 , R 16 , R 20 , and R 21 is a heteroaromic ring with two double bonds, including, for example, pyrrole, imidazole, pyrazole or triazole;
• V 3 , W 3 , X 3 , Y 3 and Z 3 can independently be CH or N, with 1- 3 of these atoms being N;
• X 4 is N or O; Y 4 is N or C;
• R 15 , R 16 , R 20 , and R 21 are independently absent, H, alkyl, cycloalkyl, bicyclyl, phenyl, or heteroaryl each optionally substituted with one or more R 18 , or a heterocyclic ring with one or two heteroatoms chosen from the group consisting of N, O, S;
• R 18 is halo, alkyl, cycloalkyl, -CN, -O-alkyl, -O-cycloalkyl, -O-alkyl-alkynyl, - SOi-alkyl, -CH 2 S0 2 -alkyl, -CONH 2 , -CONH-alkyl, or -CON(alkyl) 2 ; and
• R 19 is halo, alkyl, cycloalkyl, -CN, -O-alkyl, -O-cycloalkyl, -S0 2 -alkyl, or -
• the Bax inhibiting compound have formula (II) can include the following formula:
• a 1 and A 2 are independently CH or N;
• the heterocycle comprising V 1 , W 1 , X 1 , Y 1 and Z 1 and its substituents R 15 and R 16 is a heteroaromic ring with two double bonds, including, for example, pyrrole, imidazole, pyrazole or triazole;
• V 1 , W 1 , X 1 , Y 1 and Z 1 can independently be CH or N, with 1-3 of these atoms being N;
• R 15 and R 16 are independently Ci-C 6 -alkyl, C3-C7-cycloalkyl, phenyl, or C5-C6 heteroaryl each optionally substituted with R 18 , or a C4-C6 heterocyclic ring with one or two heteroatoms chosen from the group consisting of N, O, S;
• R 17 is -H, Ci-C 6 -alkyl, C3-C7-cycloalkyl, 3-oxetanyl, or 3-tetrahydrofuranyl; alternatively, R 15 together with R 16 and the ring to which they are attached can form a benzimidazole ring in which V 1 and X 1 are N and W 1 is CH and Y 1 and Z 1 are C atoms at the ring fusion; the benzimidazole ring being optionally substituted with one or two R 19 substituents;
• R 18 is halo, Ci-Ce-alkyl, C 3 -C 7 -cycloalkyl, -CN, -O-Ci-Ce-alkyl, -O-C3-C7- cycloalkyl, -S0 2 -Ci-C 6 -alkyl, -CH 2 S02-Ci-C 6 -alkyl, -CONH2, -CONH-Ci-Ce-alkyl, or - CON(Ci-C 6 -alkyl) 2 ; and
• R 19 is halo, Ci-Ce-alkyl, C 3 -C 7 -cycloalkyl, -CN, -O-Ci-Ce-alkyl, -O-C3-C7- cycloalkyl, -S0 2 -Ci-C 6 -alkyl, or -CH 2 S0 2 -Ci-C 6 -alkyl.
• R 15 , R 16 , R 20 , and R 21 are independently Ci-C 6 -alkyl, C 3 - C7-cycloalkyl, phenyl or C 5 -C 6 heteroaryl optionally substituted with R 18 , or a C 4 -C 6 heterocyclic ring with one or two heteroatoms chosen from the group consisting of N, O, S.
• R 18 is halo, Ci-C 6 -alkyl, C3-C7-cycloalkyl, -CN, -O-Ci- Ce-alkyl, -0-C 3 -C 7 -cycloalkyl, -S0 2 -Ci-C 6 -alkyl, -CH 2 S0 2 -Ci-C 6 -alkyl, -CONH 2 , -CONH- Ci-Ce-alkyl, or -CON(Ci-C 6 -alkyl) 2 .
• R 19 is halo, Ci-Ce-alkyl, C3-C7-cycloalkyl, -CN, -O-Ci-Ce-alkyl, -0-C 3 -C 7 -cycloalkyl, -S0 2 -Ci-C 6 -alkyl, or -CH 2 S0 2 -Ci-C 6 -alkyl.
• a 1 and A 2 are independently CH.
• R 12 0
• a Bax inhibiting compound having formula (II) can include the following formula: or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:
• a 1 and A 2 are independently CH or N;
• the heterocycle comprising V 3 , W 3 , X 3 , Y 3 and Z 3 and its substituents R 15 and R 16 is a heteroaromic ring with two double bonds, including, for example, pyrrole, imidazole, pyrazole or triazole;
• V 3 , W 3 , X 3 , Y 3 and Z 3 can independently be CH or N, with 1-3 of these atoms being N;
• R 15 and R 16 are independently Ci-C 6 -alkyl, C3-C7-cycloalkyl, phenyl or C5-C6 heteroaryl optionally substituted with R 18 , or a C4-C6 heterocyclic ring with one or two heteroatoms chosen from the group consisting of N, O, S;
• R 17 is -H, -NH, Ci-C 6 -alkyl, C3-C7-cycloalkyl, 3-oxetanyl, or 3- tetrahydrofuranyl ;
• R 15 together with R 16 and the ring to which they are attached can form a benzimidazole ring in which V 3 and X 3 are N and W 3 is CH and Y 3 and Z 3 are C atoms at the ring fusion; the benzimidazole ring being optionally substituted with one or two R 19 substituents;
• R 18 is halo, Ci-C 6 -alkyl, C 3 -C 7 -cycloalkyl, -CN, -0-Ci-C 6 -alkyl, -O-C 3 -C 7 - cycloalkyl, -S0 2 -Ci-C 6 -alkyl, -CH 2 S0 2 -Ci-C 6 -alkyl, -CONH 2 , -CONH-Ci-Ce-alkyl, or - CON(Ci-C 6 -alkyl) 2 ; and
• R 19 is halo, Ci-C 6 -alkyl, C3-C 7 -cycloalkyl, -CN, -0-Ci-C 6 -alkyl, -O-C3-C7- cycloalkyl, -S0 2 -Ci-C 6 -alkyl, or -CH 2 S0 2 -Ci-C 6 -alkyl.
• the Bax inhibiting compound of formula (II) can have the following formula:
• R 13 and R 14 are independently -H, Ci-C 6 -alkyl, C3-C7-cycloalkyl, 3-oxetanyl, 3-tetrahydrofuranyl;
• R 15 and R 16 are independently Ci-C 6 -alkyl, C3-C7-cycloalkyl, phenyl or C5-C6 heteroaryl optionally substituted with R 18 , or a C4-C6 heterocyclic ring with one or two heteroatoms chosen from the group consisting of N, O, S;
• R 17 is -H, Ci-C 6 -alkyl, C3-C7-cycloalkyl, 3-oxetanyl, or 3-tetrahydrofuranyl; or R 15 together with R 16 and the ring to which they are attached can be a benzimidazole ring; the benzimidazole ring can be optionally substituted with one or two R 19 substituents;
• R 18 is halo, Ci-Ce-alkyl, C 3 -C 7 -cycloalkyl, -CN, -O-Ci-Ce-alkyl, -O-C3-C7- cycloalkyl, -S0 2 -Ci-C 6 -alkyl, -CH 2 S0 2 -Ci-C 6 -alkyl, -CONH 2 , -CONH-Ci-Ce-alkyl, or -
• R 19 is halo, Ci-Ce-alkyl, C 3 -C 7 -cycloalkyl, -CN, -O-Ci-Ce-alkyl, -O-C3-C7- cycloalkyl, -S0 2 -Ci-C 6 -alkyl, or -CH 2 S0 2 -Ci-C 6 -alkyl.
• the Bax inhibiting compound having formula (II) can have the following formula:
• R 14 is -H, Ci-C 6 -alkyl, C3-C7-cycloalkyl, 3-oxetanyl, 3- tetrahydrofuranyl
• R 15 and R 16 are independently Ci-C 6 -alkyl, C3-C7-cycloalkyl, phenyl or C5-C6 heteroaryl optionally substituted with R 18 , or a C4-C6 heterocyclic ring with one or two heteroatoms chosen from the group consisting of N, O, S;
• R 17 is -H, Ci-C 6 -alkyl, C3-C7-cycloalkyl, 3-oxetanyl, or 3-tetrahydrofuranyl; or
• R 15 together with R 16 and the ring to which they are attached can be a benzimidazole ring; the benzimidazole ring being optionally substituted with one or two R 19 substituents;
• R 18 is halo, Ci-Ce-alkyl, C 3 -C 7 -cycloalkyl, -CN, -O-Ci-Ce-alkyl, -O-C3-C7- cycloalkyl, -S0 2 -Ci-C 6 -alkyl, -CH 2 S0 2 -Ci-C 6 -alkyl, -CONH 2 , -CONH-Ci-Ce-alkyl, or -CON(Ci-C 6 -alkyl) 2 ; and
• R 19 is halo, Ci-Ce-alkyl, C 3 -C 7 -cycloalkyl, -CN, -O-Ci-Ce-alkyl, -O-C3-C7- cycloalkyl, -S0 2 -Ci-C 6 -alkyl, or -CH 2 S0 2 -Ci-C 6 -alkyl.
• the Bax inhibiting compounds can be provided in a pharmaceutical composition that includes the Bax inhibiting compound and a
• the compound or Bax inhibiting compounds described herein can inhibit the Mouse Embryonic Fibroblasts (MEFs) from Bax-induced cell death Bax at an IC50 of less than or equal to 1 mM, an IC50 of less than or equal to 250 nM, an IC50 of less than or equal to 50 nM, an IC50 of less than or equal to 10 nM, an IC50 of less than or equal to 5 nM, an IC50 of about 2.5 nM to about 10 nM, or an IC50 of less than or equal to about 2.5 nM.
• MEFs Mouse Embryonic Fibroblasts
• the Bax inhibiting compound can be administered to a subject to inhibit cell death in the eyes associated with the degenerative eye diseases.
• the degenerative eye disease can include, for example, at least one of Stargardt’s disease, cone- rod dystrophy, retinitis-pigmentosis, macular degeneration, geographic atrophy, glaucoma, optic nerve injury, and Fuchs endothelial corneal dystrophy.
• the Bax inhibiting compound can be administered to a subject to inhibit cell death associated with or treat at least one of a disease, disorder, and/or condition of the nervous system.
• the disease, disorder, and/or condition of the nervous system can include at least one of a neurological disorder, neural injury, neural toxicity disorder, and neural degenerative disorders.
• the neurological disorder can include at least one of traumatic or toxic injuries to peripheral or cranial nerves, spinal cord or to the brain, cranial nerves, traumatic brain injury, stroke, cerebral aneurism, and spinal cord injury.
• the neurological disorder can include at least one of Alzheimer's disease, dementias related to Alzheimer's disease, Parkinson's, Lewy diffuse body diseases, senile dementia, Huntington's disease, Gilles de la Tourette's syndrome, multiple sclerosis, amyotrophic lateral sclerosis, hereditary motor and sensory neuropathy, diabetic neuropathy, progressive supranuclear palsy, epilepsy, or Jakob-Creutzfieldt disease.
• the neural injury can be caused by or associated with at least one of epilepsy, cerebrovascular diseases, autoimmune diseases, sleep disorders, autonomic disorders, urinary bladder disorders, abnormal metabolic states, disorders of the muscular system, infectious and parasitic diseases neoplasms, endocrine diseases, nutritional and metabolic diseases, immunological diseases, diseases of the blood and blood-forming organs, mental disorders, diseases of the nervous system, diseases of the sense organs, diseases of the circulatory system, diseases of the respiratory system, diseases of the digestive system, diseases of the genitourinary system, diseases of the skin and subcutaneous tissue, diseases of the musculoskeletal system and connective tissue, congenital anomalies, or conditions originating in the perinatal period.
• epilepsy cerebrovascular diseases, autoimmune diseases, sleep disorders, autonomic disorders, urinary bladder disorders, abnormal metabolic states, disorders of the muscular system, infectious and parasitic diseases neoplasms, endocrine diseases, nutritional and metabolic diseases, immunological diseases, diseases of the blood and blood-forming organs, mental disorders, diseases of
• the Bax inhibiting compound can be administered to a subject to inhibit cell death associated with or treat at least one symptom associated with an ischemic tissue or a tissue damaged by ischemia.
• the ischemia can be associated with at least one of acute coronary syndrome, acute lung injury (ALI), acute myocardial infarction (AMI), acute respiratory distress syndrome (ARDS), arterial occlusive disease,
• arteriosclerosis arteriosclerosis, articular cartilage defect, aseptic systemic inflammation, atherosclerotic cardiovascular disease, autoimmune disease, bone fracture, bone fracture, brain edema, brain hypoperfusion, Buerger's disease, burns, cancer, cardiovascular disease, cartilage damage, cerebral infarct, cerebral ischemia, cerebral stroke, cerebrovascular disease, chemotherapy- induced neuropathy, chronic infection, chronic mesenteric ischemia, claudication, congestive heart failure, connective tissue damage, contusion, coronary artery disease (CAD), critical limb ischemia (CLI), Crohn's disease, deep vein thrombosis, deep wound, delayed ulcer healing, delayed wound-healing, diabetes (type I and type II), diabetic neuropathy, diabetes induced ischemia, disseminated intravascular coagulation (DIC), embolic brain ischemia, graft- versus-host disease, hereditary hemorrhagic telengiectasiaischemic vascular disease, hyperoxic injury, hypoxia
• the Bax inhibiting compound can be administered ex vivo to at least one of cells, tissue, or organs to increase fitness of the cells, tissue, or organs as a donor graft or transplantation, or enhance cell, tissue, or organ engraftment or transplantation.
• the Bax inhibiting compound can be administered to a subject or to a tissue graft of a subject to mitigate graft rejection or enhance graft
• the Bax inhibiting compound can be administered to a subject or to a tissue graft of a subject to enhance graft engraftment following treatment of the subject with radiation therapy, chemotherapy, or immunosuppressive therapy.
• the Bax inhibiting compound can be administered to a subject to confer resistance to toxic or lethal effects of exposure to radiation.
• the Bax inhibiting compound being administered to a subject to confer resistance to the toxic effect of chemotherapy, or the toxic effect of immunosuppressive therapy.
• the Bax inhibiting compound can be administered to a subject to treat stroke, myocardial infarction, degenerative disease, and an infectious agent.
• Fig. 1 is a graph illustrating Bax inhibiting compounds described herein
• Fig. 2 illustrates images showing a Bax inhibiting compound described herein protected mouse embryonic fibroblast (MEF) cells from Bax induced cell death.
• Fig. 3 illustrates images showing a Bax inhibiting compound described herein inhibited Bax-induced apoptosis without significant impact on expression levels of Bax, Bcl- 2, Bcl-XL and Mcl-1.
• FIG. 4 illustrates the results showing Bax inhibiting compound described herein protected ARPE19 (Human Retinal cells) cells from atRAL induced cell death (Fig. 4A) and mouse retina from the bright light- induced cell deah in vivo (Stargadrdt’s disease mouse model) (Fig. 4B,C).
• the verb“comprise” as is used in this description and in the claims and its conjugations are used in its non-limiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded.
• the present invention may suitably“comprise”,“consist of’, or“consist essentially of’, the steps, elements, and/or reagents described in the claims.
• pharmaceutically acceptable means suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use within the scope of sound medical judgment.
• salts include those obtained by reacting the active compound functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc.
• acid addition salts may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.
• pharmaceutically acceptable salts also includes those obtained by reacting the active compound functioning as an acid, with an inorganic or organic base to form a salt, for example salts of ethylenediamine, N-methyl- glucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine,
• inorganic or metal salts include lithium, sodium, calcium, potassium, magnesium salts and the like.
• the salts of the compounds described herein can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules.
• Non-limiting examples of hydrates include monohydrates, dihydrates, etc.
• Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.
• solvates means solvent addition forms that contain either
• stoichiometric or non- stoichiometric amounts of solvent Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as H 2 O, such combination being able to form one or more hydrate.
• the compounds and salts described herein can exist in several tautomeric forms, including the enol and imine form, and the keto and enamine form and geometric isomers and mixtures thereof.
• Tautomers exist as mixtures of a tautomeric set in solution. In solid form, usually one tautomer predominates. Even though one tautomer may be described, the present application includes all tautomers of the present compounds.
• a tautomer is one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. This reaction results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that are interconvertable by tautomerizations is called tautomerism.
• keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs.
• Tautomerizations can be catalyzed by: Base: 1. deprotonation; 2. formation of a delocalized anion (e.g an enolate); 3. protonation at a different position of the anion; Acid:
• Amino refers to the -NH2 radical.
• Halo or“halogen” refers to bromo, chloro, fluoro or iodo radical.
• “Hydroxy” or“hydroxyl” refers to the -OH radical.
• Niro refers to the -NO2 radical.
• Alkyl or“alkyl group” refers to a fully saturated, straight or branched hydrocarbon chain radical having from one to twelve carbon atoms, and which is attached to the rest of the molecule by a single bond. Alkyls comprising any number of carbon atoms from 1 to 12 are included. An alkyl comprising up to 12 carbon atoms is a C 1 -C 12 alkyl, an alkyl comprising up to 10 carbon atoms is a C 1 -C 10 alkyl, an alkyl comprising up to 6 carbon atoms is a C 1 -C 6 alkyl and an alkyl comprising up to 5 carbon atoms is a C 1 -C 5 alkyl.
• a C 1 -C 5 alkyl includes C 5 alkyls, C 4 alkyls, C 3 alkyls, C 2 alkyls and Ci alkyl (i.e., methyl).
• a C 1 -C 6 alkyl includes all moieties described above for C 1 -C 5 alkyls but also includes C 6 alkyls.
• a C 1 -C 10 alkyl includes all moieties described above for C 1 -C 5 alkyls and C 1 -C 6 alkyls, but also includes C7, Cs, C9 and C10 alkyls.
• a C1-C12 alkyl includes all the foregoing moieties, but also includes Cn and C12 alkyls.
• Non-limiting examples of C1-C12 alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, t-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl.
• an alkyl group can be optionally substituted.
• Alkylene or“alkylene chain” refers to a fully saturated, straight or branched divalent hydrocarbon chain radical, and having from one to twelve carbon atoms.
• C1-C12 alkylene include methylene, ethylene, propylene, n-butylcnc, ethenylene, propenylene, n-butcnylcnc, propynylene, n-butynylcnc, and the like.
• the alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
• the points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene chain can be optionally substituted.
• Alkenyl or“alkenyl group” refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms, and having one or more carbon-carbon double bonds. Each alkenyl group is attached to the rest of the molecule by a single bond. Alkenyl group comprising any number of carbon atoms from 2 to 12 are included.
• An alkenyl group comprising up to 12 carbon atoms is a C2-C12 alkenyl
• an alkenyl comprising up to 10 carbon atoms is a C2-C10 alkenyl
• an alkenyl group comprising up to 6 carbon atoms is a C2-C6 alkenyl
• an alkenyl comprising up to 5 carbon atoms is a C2-C5 alkenyl.
• a C2-C5 alkenyl includes C5 alkenyls, C4 alkenyls, C3 alkenyls, and C2 alkenyls.
• a C2-C6 alkenyl includes all moieties described above for C2-C5 alkenyls but also includes C 6 alkenyls.
• a C2-C10 alkenyl includes all moieties described above for C2-C5 alkenyls and C2-C6 alkenyls, but also includes C7, Cs, C9 and C10 alkenyls.
• a C2-C12 alkenyl includes all the foregoing moieties, but also includes Cn and C12 alkenyls.
• Non-limiting examples of C2-C12 alkenyl include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), iso- propenyl, 2-methyl- 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl,
• an alkyl group can be optionally substituted.
• alkenylene or“alkenylene chain” refers to a straight or branched divalent hydrocarbon chain radical, having from two to twelve carbon atoms, and having one or more carbon-carbon double bonds.
• C2-C12 alkenylene include ethene, propene, butene, and the like.
• the alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
• the points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkenylene chain can be optionally substituted.
• Alkynyl or“alkynyl group” refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms, and having one or more carbon-carbon triple bonds. Each alkynyl group is attached to the rest of the molecule by a single bond. Alkynyl group comprising any number of carbon atoms from 2 to 12 are included.
• An alkynyl group comprising up to 12 carbon atoms is a C2-C12 alkynyl
• an alkynyl comprising up to 10 carbon atoms is a C2-C10 alkynyl
• an alkynyl group comprising up to 6 carbon atoms is a C2-C6 alkynyl
• an alkynyl comprising up to 5 carbon atoms is a C2-C5 alkynyl.
• a C2-C5 alkynyl includes C5 alkynyls, C4 alkynyls, C3 alkynyls, and C2 alkynyls.
• a C2-C6 alkynyl includes all moieties described above for C2-C5 alkynyls but also includes C 6 alkynyls.
• a C2-C10 alkynyl includes all moieties described above for C2-C5 alkynyls and C2-C6 alkynyls, but also includes C7, Cs, C9 and C10 alkynyls.
• a C2-C12 alkynyl includes all the foregoing moieties, but also includes Cn and C12 alkynyls.
• Non-limiting examples of C2-C12 alkenyl include ethynyl, propynyl, butynyl, pentynyl and the like. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted.
• Alkynylene or“alkynylene chain” refers to a straight or branched divalent hydrocarbon chain radical, having from two to twelve carbon atoms, and having one or more carbon-carbon triple bonds.
• C2-C12 alkynylene include ethynylene, propargylene and the like.
• the alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
• the points of attachment of the alkynylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain.
• an alkynylene chain can be optionally substituted.
• Alkoxy refers to a radical of the formula -OR a where R a is an alkyl, alkenyl or alknyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkoxy group can be optionally substituted.
• Alkylamino refers to a radical of the formula -NHR a or -NR a R a where each R a is, independently, an alkyl, alkenyl or alkynyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkylamino group can be optionally substituted.
• R a is an alkyl, alkenyl or alkynyl radical as defined above.
• a non-limiting example of an alkyl carbonyl is the methyl carbonyl (“acetal”) moiety.
• Alkylcarbonyl groups can also be referred to as“C w -C z acyl” where w and z depicts the range of the number of carbon in R a , as defined above.
• “Ci-Cio acyl” refers to alkylcarbonyl group as defined above, where R a is Ci-Cio alkyl, C2-C10 alkenyl, or C2-C10 alkynyl radical as defined above. Unless stated otherwise specifically in the specification, an alkyl carbonyl group can be optionally substituted.
• Aryl refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring.
• the aryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems.
• Aryl radicals include, but are not limited to, aryl radicals derived from phenyl (benzene), aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, chrysene, fluoranthene, fluorene, a.s-indaccnc, .s-indaccnc, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
• aryl is meant to include aryl radicals that are optionally substituted.
• Alkyl or“arylalkyl” refers to a radical of the formula -R b -R c where R b is an alkylene group as defined above and R c is one or more aryl radicals as defined above.
• Aralkyl radicals include, but are not limited to, benzyl, diphenylmethyl and the like. Unless stated otherwise specifically in the specification, an aralkyl group can be optionally substituted.
• “Aralkenyl” or“arylalkenyl” refers to a radical of the formula -R b -R c where R b is an alkenylene group as defined above and R c is one or more aryl radicals as defined above. Unless stated otherwise specifically in the specification, an aralkenyl group can be optionally substituted.
• Alkynyl or“arylalkynyl” refers to a radical of the formula -R b -R c where R b is an alkynylene group as defined above and R c is one or more aryl radicals as defined above. Unless stated otherwise specifically in the specification, an aralkynyl group can be optionally substituted.
• Carbocyclyl “carbocyclic ring” or“carbocycle” refers to a ring structure, wherein the atoms which form the ring are each carbon. Carbocyclic rings can comprise from 3 to 20 carbon atoms in the ring. Carbocyclic rings include aryls and cycloalkyl.
• Cycloalkyl refers to a stable non-aromatic monocyclic or polycyclic fully saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, which can include fused, bridged, or spiral ring systems, having from three to twenty carbon atoms, preferably having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond.
• Monocyclic cycloalkyl radicals include, for example,
• Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl, decalinyl,
• Cycloalkenyl refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon double bonds, which can include fused, bridged, or spiral ring systems, having from three to twenty carbon atoms, preferably having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond.
• Monocyclic cycloalkenyl radicals include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, cycloctenyl, and the like.
• Polycyclic cycloalkenyl radicals include, for example, bicyclo[2.2.1]hept-2-enyl and the like. Unless otherwise stated specifically in the specification, a cycloalkenyl group can be optionally substituted.
• Cycloalkynyl refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon triple bonds, which can include fused, bridged, or spiral ring systems, having from three to twenty carbon atoms, preferably having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond.
• Monocyclic cycloalkynyl radicals include, for example, cycloheptynyl, cyclooctynyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkynyl group can be optionally substituted.
• Cycloalkylalkyl refers to a radical of the formula -R b -R d where R b is an alkylene, alkenylene, or alkynylene group as defined above and R d is a cycloalkyl, cycloalkenyl, cycloalkynyl radical as defined above. Unless stated otherwise specifically in the specification, a cycloalkylalkyl group can be optionally substituted.
• Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl,
• haloalkyl group can be optionally substituted.
• Haloalkenyl refers to an alkenyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., 1-fluoropropenyl, 1,1-difluorobutenyl, and the like. Unless stated otherwise specifically in the specification, a haloalkenyl group can be optionally substituted.
• Haloalkynyl refers to an alkynyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., 1-fluoropropynyl, 1-fluorobutynyl, and the like. Unless stated otherwise specifically in the specification, a haloalkynyl group can be optionally substituted.
• Heterocyclyl “heterocyclic ring” or“heterocycle” refers to a stable 3- to 20-membered non-aromatic, partially aromatic, or aromatic ring radical which consists of two to twelve carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Heterocyclycl or heterocyclic rings include heteroaryls as defined below.
• the heterocyclyl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused, bridged, and spiral ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical can be optionally oxidized; the nitrogen atom can be optionally quatemized; and the heterocyclyl radical can be partially or fully saturated.
• heterocyclyl radicals include, but are not limited to, aziridinyl, oextanyl, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiomorph
• 1,1-dioxo-thiomorpholinyl 1,1-dioxo-thiomorpholinyl, pyridine-one, and the like.
• the point of attachment of the heterocyclyl, heterocyclic ring, or heterocycle to the rest of the molecule by a single bond is through a ring member atom, which can be carbon or nitrogen.
• a heterocyclyl group can be optionally substituted.
• Heterocyclylalkyl refers to a radical of the formula -R b -R e where R b is an alkylene group as defined above and R e is a heterocyclyl radical as defined above. Unless stated otherwise specifically in the specification, a heterocyclylalkyl group can be optionally substituted.
• Heterocyclylalkenyl refers to a radical of the formula -R b -R e where R b is an alkenylene group as defined above and R e is a heterocyclyl radical as defined above. Unless stated otherwise specifically in the specification, a heterocyclylalkenyl group can be optionally substituted.
• Heterocyclylalkynyl refers to a radical of the formula -R b -R e where R b is an alkynylene group as defined above and R e is a heterocyclyl radical as defined above. Unless stated otherwise specifically in the specification, a heterocyclylalkynyl group can be optionally substituted.
• V-heterocyclyl refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. Unless stated otherwise specifically in the specification, an /V-heterocyclyl group can be optionally substituted.
• Heteroaryl refers to a 5- to 20-membered ring system radical one to thirteen carbon atoms and one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, as the ring member.
• the heteroaryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems, wherein at least one ring containing a heteroatom ring member is aromatic.
• the nitrogen, carbon or sulfur atoms in the heteroaryl radical can be optionally oxidized and the nitrogen atom can be optionally quaternized.
• Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[h][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl
• V-heteroaryl refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. Unless stated otherwise specifically in the specification, an /V-heteroaryl group can be optionally substituted.
• Heteroarylalkyl refers to a radical of the formula -R b -R f where R b is an alkylene chain as defined above and R f is a heteroaryl radical as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkyl group can be optionally substituted.
• Heteroarylalkenyl refers to a radical of the formula -R b -R f where R b is an alkenylene, chain as defined above and R f is a heteroaryl radical as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkenyl group can be optionally substituted.
• Heteroarylalkynyl refers to a radical of the formula -R b -R f where R b is an alkynylene chain as defined above and R f is a heteroaryl radical as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkynyl group can be optionally substituted.
• Thioalkyl refers to a radical of the formula -SR a where R a is an alkyl, alkenyl, or alkynyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, a thioalkyl group can be optionally substituted.
• substituted means any of the above groups (e.g ., alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, alkoxy, alkylamino, alkylcarbonyl, thioalkyl, aryl, aralkyl, carbocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, heterocyclyl, /V-heterocyclyl, heterocyclylalkyl, heteroaryl, /V-heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, etc) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atoms such as, but not limited to: a halogen atom such as F, Cl, Br, and I;
• “Substituted” also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles.
• a higher-order bond e.g., a double- or triple-bond
• nitrogen in groups such as imines, oximes, hydrazones, and nitriles.
• “substituted” includes any of the above groups in which one or more hydrogen atoms are replaced with:
• R and R h are the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, /V-heterocyclyl, heterocyclylalkyl, heteroaryl, V-heteroaryl and/or heteroarylalkyl.
• “Substituted” further means any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, /V-heterocyclyl, heterocyclylalkyl, heteroaryl, /V-heteroaryl and/or heteroarylalkyl group.
• each of the foregoing substituents can also be optionally substituted with one or more of the above substituents.
• a point of attachment bond denotes a bond that is a point of attachment between two chemical entities, one of which is depicted as being attached to the point of attachment bond and the other of which is not depicted as being attached to the point of attachment bond.
• “ L '” indicates that the chemical entity“A” is bonded to another chemical entity via the point of attachment bond.
• the specific point of attachment to the non-depicted chemical entity can be specified by inference.
• the compound , ” infers that the point of attachment bond is the bond by which X is depicted as being attached to the phenyl ring at the ortho position relative to fluorine.
• parenteral administration and “administered parenterally” are art-recognized terms, and include modes of administration other than enteral and topical administration, such as injections, and include, without limitation, intravenous, intramuscular, intrapleural, intravascular, intrapericardial, intraarterial, intrathecal, intracapsular,
• intraorbital intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra- articular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion.
• treating includes inhibiting a disease, disorder or condition in a subject, e.g., impeding its progress; and relieving the disease, disorder or condition, e.g., causing regression of the disease, disorder and/or condition. Treating the disease or condition includes ameliorating at least one symptom of the particular disease or condition, even if the underlying pathophysiology is not affected.
• preventing is art-recognized and includes stopping a disease, disorder or condition from occurring in a subject, which may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it. Preventing a condition related to a disease includes stopping the condition from occurring after the disease has been diagnosed but before the condition has been diagnosed.
• a "patient,” “subject,” or “host” to be treated by the subject method may mean either a human or non-human animal, such as a mammal, a fish, a bird, a reptile, or an amphibian.
• the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent.
• the term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered.
• the subject is a mammal.
• a patient refers to a subject afflicted with a disease or disorder.
• prophylactic or“therapeutic” treatment is art-recognized and includes administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g ., disease or other unwanted state of the host animal) then the treatment is prophylactic, i.e., it protects the host against developing the unwanted condition, whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).
• the unwanted condition e.g ., disease or other unwanted state of the host animal
• physiologically, or pharmacologically active substances that act locally or systemically in a patient or subject to treat a disease or condition.
• the terms include without limitation pharmaceutically acceptable salts thereof and prodrugs.
• Such agents may be acidic, basic, or salts; they may be neutral molecules, polar molecules, or molecular complexes capable of hydrogen bonding; they may be prodrugs in the form of ethers, esters, amides and the like that are biologically activated when administered into a patient or subject.
• terapéuticaally effective amount or“pharmaceutically effective amount” is an art-recognized term.
• the term refers to an amount of a therapeutic agent that produces some desired effect at a reasonable benefit/risk ratio applicable to any medical treatment.
• the term refers to that amount necessary or sufficient to eliminate, reduce or maintain a target of a particular therapeutic regimen.
• the effective amount may vary depending on such factors as the disease or condition being treated, the particular targeted constructs being administered, the size of the subject or the severity of the disease or condition.
• One of ordinary skill in the art may empirically determine the effective amount of a particular compound without necessitating undue experimentation.
• a therapeutically effective amount of a therapeutic agent for in vivo use will likely depend on a number of factors, including: the rate of release of an agent from a polymer matrix, which will depend in part on the chemical and physical characteristics of the polymer; the identity of the agent; the mode and method of administration; and any other materials incorporated in the polymer matrix in addition to the agent.
• compositions are described as having, including, or comprising, specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components.
• methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps.
• order of steps or order for performing certain actions is immaterial so long as the compositions and methods described herein remains operable. Moreover, two or more steps or actions can be conducted simultaneously.
• Embodiments described herein relate to compounds for use in inhibiting Bax mediated cell death and/or apoptosis and to their use in treating conditions, disorders, and/or diseases associate with Bax mediated cell death and/or apoptosis.
• the Bax inhibiting compounds described herein suppressed Bax-induced cell death at 1 nM -10 nM (in culture medium) compared to previously reported Bax inhibitors that required at least 1 mM (1000 nM in cell culture medium), and have Bax binding affinity (Kd) ranging from 1 nM-100 nM.
• Bax inhibiting compounds described herein showed a dose-dependent effect to rescue cells from Bax, protected mouse embryonic fibroblast (MEF) cells from Bax induced cell death, inhibited Bas-induced apoptosis without significant impact on expression levels of Bax, Bcl-2, Bcl-XL and Mcl-1, andprotected ARP19 (Retinal cells) cells from atRAL induced cell death.
• the Bax inhibiting compounds described herein can be used to help subjects suffering from cell death-related diseases and/or apoptosis including, for example, retinal degenerative diseases, cardiovascular diseases, neurodegenerative diseases, and other diseases caused by unwanted Bax-induced
• the Bax inhibiting compounds described herein can also be used as Bax inhibitors to extend the survival of cells, tissues, and/or organs ex vivo and after transplantation and engraftment. Therefore, the Bax inhibiting compounds canbe beneficial in improving the efficiency of the storage and transplantation of cells, tissues, and organs.
• the Bax inhibiting compound can include the following formula (I):
• R 1 and R 2 are each independently -H, alkyl, -F, -CN, -O-alkyl, cycloalkyl, oxetanyl, or tetrahydrofuranyl, or R 1 together with R 2 forms a phenyl ring optionally substituted with one or two R 8 groups, or R 1 together with R 2 forms a five or six-membered heteroaromatic ring containing one or two heteroatoms chosen from N, O and S, optionally substituted with one or two R 8 groups;
• R 8 is halo, alkyl, cycloalkyl, oxetanyl, tetrahydrofuranyl,
• R 3 is absent, -H, -D, -F, -Cl, -CF3, -alkyl, cyclopropyl -O-alkyl, or -CN;
• R 4 is -H, alkyl, cyclopropyl, or -CF3;
• R 5 is absent, -H, or alkyl; altematively, R 5 and the nitrogen atom to which it is attached may be replaced by an oxygen atom;
• V, W, X, Y and Z are each independently -CH, or N;
• X 1 and Z 1 are each independently -CH or N;
• W 1 and Y 1 are each independently C or N, and when Y 1 is N, R 3 is absent;
• X 2 is O or N, when X 2 is O, R 5 is absent;
• R 6 is -H, halo, alkyl, cycloalkyl, -CN, -O-alkyl, -O-cycloalkyl, -O- heterocyclyl, -S0 2 -alkyl, -CH2S 0 2 -alkyl, -CONH2, -CONH-alkyl, or -CON(alkyl)2;
• R 7 is -H, halo, alkyl, cycloalkyl, -CN, -O-alkyl, -O-cycloalkyl, -O- heterocyclyl, -S0 2 -alkyl, -CH2S 0 2 -alkyl, -CONH2, -CONH-alkyl, or -CON(alkyl)2 ;
• R 6 or R 7 can be an aryl optionally substituted with one or two R 9 groups;
• R 6 or R 7 can be a 4-6 membered ring heterocycle containing one or two heteroatoms chosen from the group consisting of N, O and S, and optionally substituted with one or two R 9 groups, excluding unstable heterocycles;
• R 6 or R 7 can be a 5-6 membered ring heteroaryl group containing one to four heteroatoms chosen from the group consisting of N, O and S, and optionally substituted with one or two R 9 groups, excluding unstable heterocycles;
• R 9 is H, halo, alkyl, cycloalkyl, alkyl-CO-, oxetanyl,
• R 6 together with R 7 and the phenyl ring or heteroaryl ring to which they are attached, may be a benzimidazole ring, benzotriazole ring, azaindole ring, azaindazole, or benzodioxolane, with N of the rings bearing an optional substituent R 10 , and with Cs of the rings optionally substituted with R 11 ;
• R 10 is -H, alkyl, or cycloalkyl
• R 11 is -H, alkyl, or cycloalkyl.
• R 1 and R 2 are each independently -H, Ci-C 6 -alkyl, -F, - CN, -0-Ci-C 6 -alkyl, C3-C7-cycloalkyl, 3-oxetanyl, or 3-tetrahydrofuranyl, or R 1 together with R 2 forms a phenyl ring optionally substituted with one or two R 8 groups, or R 1 together with R 2 forms a saturated five or six-membered hetero aromatic ring containing one or two heteroatoms chosen from N, O and S, optionally substituted with one or two R 8 groups.
• R 8 is halo, Ci-C 6 -alkyl, C3-C7-cycloalkyl, 3-oxetanyl, 3- tetrahydrofuranyl, -CN, -0-Ci-C 6 -alkyl, -0-C 3 -C 7 -cycloalkyl, -S0 2 -Ci-C 6 -alkyl, or -CH2SO2- Ci-Ce-alkyl.
• R 3 is absent, -H, -D, -F, -Cl, -CF3, -Ci-C 6 -alkyl, cyclopropyl -0-Ci-C 6 -alkyl, or -CN.
• R 4 is -H, -Ci-C 6 -alkyl, -cyclopropyl, or -CF 3 .
• R 5 is absent, -H, or -Ci-C 6 -alkyl.
• R 6 is -H, halo, Ci-C 6 -alkyl, C3-C7-cycloalkyl, -CN, -O-
• R 7 is -H, halo, Ci-C 6 -alkyl, C3-C7-cycloalkyl, -CN, -O- Ci-Ce-alkyl, -0-C3-C 7 -cycloalkyl, -S0 2 -Ci-C 6 -alkyl, -CH 2 S02-Ci-C 6 -alkyl, -CONH2, - CONH-Ci-Ce-alkyl, or -CON(Ci-C 6 -alkyl) 2 .
• R 9 is H, halo, Ci-C 6 -alkyl, C3-C7-cycloalkyl, C1-C5- alkyl-CO-, 3-oxetanyl, 3-tetrahydrofuranyl, -CN, -0-Ci-C 6 -alkyl, or -0-C 3 -C 7 -cycloalkyl.
• R 10 is -H, Ci-C 6 -alkyl, or C3-C7-cycloalkyl.
• R 11 is -H, Ci-C 6 -alkyl, or C3-C7-cycloalkyl.
• R 1 together with R 2 can form a phenyl ring optionally substituted with one or two R 8 groups, or R 1 together with R 2 can form a saturated five or six- membered heteroaromatic ring containing one or two heteroatoms chosen from N, O and S, optionally substituted with one or two R 8 groups.
• R 4 is -Ci-C 6 -alkyl or -CF 3 and R 5 is -H.
• X and Y are independently H; and Z is N.
• R 6 or R 7 is a 4-6 membered ring saturated heterocycle containing one or two heteroatoms chosen from the group consisting of N, O and S, and optionally substituted with one or two R 9 groups, excluding unstable heterocycles, or R 6 or R 7 is a 5-6 membered ring heteroaryl group containing one to three heteroatoms chosen from the group consisting of N, O and S, and optionally substituted with one or two R 9 groups, excluding unstable heterocycles.
• R 6 is selected from the group consisting of: [00126]
• the Bax inhibiting compound having formula (I) can include a compound having the following formula:
• R 1 and R 2 are each independently -H, Ci-C 6 -alkyl, -F, -CN, -0-Ci-C 6 -alkyl, C3-C7-cycloalkyl, 3-oxetanyl, or 3-tetrahydrofuranyl, or R 1 together with R 2 forms a phenyl ring optionally substituted with one or two R 8 groups, or R 1 together with R 2 forms a five or six-membered heteroaromatic ring containing one or two heteroatoms chosen from N, O and S, optionally substituted with one or two R 8 groups;
• R 8 is halo, Ci-C 6 -alkyl, C3-C7-cycloalkyl, 3-oxetanyl, 3-tetrahydrofuranyl, - CN, -O-Ci-Ce-alkyl, -0-C3-C 7 -cycloalkyl, -S0 2 -Ci-C 6 -alkyl, or -ClfeSCfc-Ci-Ce-alkyl;
• R 3 is -H, -D, -F, -Cl, -CF3, -Ci-C 6 -alkyl, cyclopropyl -0-Ci-C 6 -alkyl, or -CN;
• R 4 is -H, -Ci-C 6 -alkyl, -cyclopropyl, or -CF3;
• R 5 is -H, or -Ci-C 6 -alkyl; alternatively, R 5 and the nitrogen atom to which it is attached may be replaced by an oxygen atom;
• X, Y and Z are each independently -CH, or N;
• R 6 is -H, halo, Ci-Ce-alkyl, C 3 -C 7 -cycloalkyl, -CN, -O-Ci-Ce-alkyl, -O-C3-C7- cycloalkyl, -O-heterocyclyl, -S0 2 -Ci-C 6 -alkyl, -CH 2 S0 2 -Ci-C 6 -alkyl, -CONH2, -CONH-Ci- Ce-alkyl, or -CON(Ci-C 6 -alkyl) 2 ;
• R 7 is -H, halo, Ci-Ce-alkyl, C 3 -C 7 -cycloalkyl, -CN, -O-Ci-Ce-alkyl, -O-C3-C7- cycloalkyl, -O-heterocyclyl, -S0 2 -Ci-C 6 -alkyi, -CH 2 S0 2 -Ci-C 6 -alkyi, -CONH 2 , -CONH-Ci- Ce-alkyl, or -CON(Ci-C 6 -alkyl) 2;
• R 6 or R 7 can be an aryl optionally substituted with one or two R 9 groups;
• R 6 or R 7 can be a 4-6 membered ring heterocycle containing one or two heteroatoms chosen from the group consisting of N, O and S, and optionally substituted with one or two R 9 groups, excluding unstable heterocycles;
• R 6 or R 7 can be a 5-6 membered ring heteroaryl group containing one to four heteroatoms chosen from the group consisting of N, O and S, and optionally substituted with one or two R 9 groups, excluding unstable heterocycles;
• R 9 is halo, Ci-C 6 -alkyl, C3-C7-cycloalkyl, Ci-Cs-alkyl-CO-, 3-oxetanyl, 3- tetrahydrofuranyl, -CN, -0-Ci-C 6 -alkyl, -0-C 3 -C 7 -cycloalkyl, -CONH 2 , -CONH-alkyl, or - CON(alkyl) 2 ;
• R 6 together with R 7 and the phenyl ring or heteroaryl ring to which they are attached, may be a benzimidazole ring, benzotriazole ring, azaindole ring, azaindazole, or benzodioxolane, with N of the rings bearing an optional substituent R 10 , and with Cs of the rings optionally substituted with R 11 ;
• R 10 is -H, Ci-C 6 -alkyl, or C3-C7-cycloalkyl
• R 11 is -H, Ci-C 6 -alkyl, or C3-C7-cycloalkyl.
• R 1 together with R 2 can form a phenyl ring optionally substituted with one or two R 8 groups, or R 1 together with R 2 can form a saturated five or six- membered heteroaromatic ring containing one or two heteroatoms chosen from N, O and S, optionally substituted with one or two R 8 groups.
• R 4 is -Ci-C 6 -alkyl or -CF3 and R 5 is -H.
• X and Y are independently H; and Z is N.
• R 6 or R 7 is a 4-6 membered ring saturated heterocycle containing one or two heteroatoms chosen from the group consisting of N, O and S, and optionally substituted with one or two R 9 groups, excluding unstable heterocycles, or R 6 or R 7 is a 5-6 membered ring heteroaryl group containing one to three heteroatoms chosen from the group consisting of N, O and S, and optionally substituted with one or two R 9 groups, excluding unstable heterocycles.
• R 6 is selected from the group consisting of:
• the Bax inhibiting compound having formula (I) can be selected from the group consisting of:
• a Bax inhibiting compound can include the following
• a 1 and A 2 are independently CH or N;
• the heterocycle comprising V 3 , W 3 , X 3 , Y 3 and Z 3 and its substituents R 15 , R 16 , R 20 , and R 21 is a heteroaromic ring with two double bonds, including, for example, pyrrole, imidazole, pyrazole or triazole;
• V 3 , W 3 , X 3 , Y 3 and Z 3 can independently be CH or N, with 1- 3 of these atoms being N;
• X 4 is N or O
• Y 4 is N or C
• R 15 , R 16 , R 20 , and R 21 are independently alkyl, cycloalkyl, bicyclyl, phenyl or heteroaryl optionally substituted with one or more R 18 , or a heterocyclic ring with one or two heteroatoms chosen from the group consisting of N, O, S;
• R 18 is halo, alkyl, cycloalkyl, -CN, -O-alkyl, -O-cycloalkyl, -O-alkyl-alkynyl, -SOi-alkyl, -CH 2 S0 2 -alkyl, -CONH 2 , -CONH-alkyl, or -CON(alkyl) 2 ; and
• R 19 is halo, alkyl, cycloalkyl, -CN, -O-alkyl, -O-cycloalkyl, -S0 2 -alkyl, or -
• R 15 , R 16 , R 20 , and R 21 are independently Ci-C 6 -alkyl, C3- C7-cycloalkyl, phenyl or C5-C6 heteroaryl optionally substituted with R 18 , or a C4-C6 heterocyclic ring with one or two heteroatoms chosen from the group consisting of N, O, S.
• R 18 is halo, Ci-C 6 -alkyl, C3-C7-cycloalkyl, -CN, -O-Ci- Ce-alkyl, -0-C 3 -C 7 -cycloalkyl, -S0 2 -Ci-C 6 -alkyl, -CH 2 S0 2 -Ci-C 6 -alkyl, -CONH 2 , -CONH- Ci-Ce-alkyl, or -CON(Ci-C 6 -alkyl) 2 .
• R 19 is halo, CYCValkyl, C3-C7-cycloalkyl, -CN, -O-Ci-Ce-alkyl, -0-C 3 -C 7 -cycloalkyl, -SCk-Ci-Ce-alkyl, or -CHiSCk-Ci-Ce-alkyl.
• a 1 and A 2 are independently CH.
• R 12 0
• a Bax inhibiting compound having formula (II) can include the following formula:
• a 1 and A 2 are independently CH or N;
• the heterocycle comprising V 3 , W 3 , X 3 , Y 3 and Z 3 and its substituents R 15 and R 16 is a heteroaromic ring with two double bonds, including, for example, pyrrole, imidazole, pyrazole or triazole;
• V 3 , W 3 , X 3 , Y 3 and Z 3 can independently be CH or N, with 1-3 of these atoms being N;
• R 15 and R 16 are independently Ci-C 6 -alkyl, C3-C7-cycloalkyl, phenyl or C5-C6 heteroaryl optionally substituted with R 18 , or a C4-C6 heterocyclic ring with one or two heteroatoms chosen from the group consisting of N, O, S;
• R 17 is -H, -NH, Ci-C 6 -alkyl, C3-C7-cycloalkyl, 3-oxetanyl, or 3- tetrahydrofuranyl ;
• R 15 together with R 16 and the ring to which they are attached can form a benzimidazole ring in which V 3 and X 3 are N and W 3 is CH and Y 3 and Z 3 are C atoms at the ring fusion; the benzimidazole ring being optionally substituted with one or two R 19 substituents;
• R 18 is halo, Ci-Ce-alkyl, C3-C 7 -cycloalkyl, -CN, -O-Ci-Ce-alkyl, -O-C3-C7- cycloalkyl, -S0 2 -Ci-C 6 -alkyl, -CH 2 S0 2 -Ci-C 6 -alkyl, -CONH 2 , -CONH-Ci-Ce-alkyl, or - CON(Ci-C 6 -alkyl) 2 ; and
• R 19 is halo, Ci-Ce-alkyl, C 3 -C 7 -cycloalkyl, -CN, -O-Ci-Ce-alkyl, -O-C3-C7- cycloalkyl, -S0 2 -Ci-C 6 -alkyl, or -CH 2 S0 2 -Ci-C 6 -alkyl.
• a 1 and A 2 are independently CH.
• R 12 0
• the Bax inhibiting compound of formula (II) can have the following formula:
• R 13 and R 14 are independently -H, Ci-C 6 -alkyl, C3-C7-cycloalkyl, 3- oxetanyl, 3-tetrahydrofuranyl;
• R 15 and R 16 are independently Ci-C 6 -alkyl, C3-C7-cycloalkyl, phenyl or C5-C6 heteroaryl optionally substituted with R 18 , or a C4-C6 heterocyclic ring with one or two heteroatoms chosen from the group consisting of N, O, S;
• R 17 is -H, Ci-C 6 -alkyl, C3-C7-cycloalkyl, 3-oxetanyl, or 3-tetrahydrofuranyl; or R 15 together with R 16 and the ring to which they are attached can be a benzimidazole ring; the benzimidazole ring can be optionally substituted with one or two R 19 substituents;
• R 18 is halo, Ci-Ce-alkyl, C 3 -C 7 -cycloalkyl, -CN, -O-Ci-Ce-alkyl, -O-C3-C7- cycloalkyl, -S0 2 -Ci-C 6 -alkyl, -CH 2 S0 2 -Ci-C 6 -alkyl, -CONH 2 , -CONH-Ci-Ce-alkyl, or - CON(Ci-C 6 -alkyl) 2 ; and
• R 19 is halo, Ci-Ce-alkyl, C 3 -C 7 -cycloalkyl, -CN, -O-Ci-Ce-alkyl, -O-C3-C7- cycloalkyl, -S0 2 -Ci-C 6 -alkyl, or -CH 2 S0 2 -Ci-C 6 -alkyl.
• the Bax inhibiting compound having formula (II) can have the following formula: wherein R 14 is -H, Ci-C 6 -alkyl, C3-C7-cycloalkyl, 3-oxetanyl, 3- tetrahydrofuranyl
• R 15 and R 16 are independently Ci-C 6 -alkyl, C3-C7-cycloalkyl, phenyl or C5-C6 heteroaryl optionally substituted with R 18 , or a C4-C6 heterocyclic ring with one or two heteroatoms chosen from the group consisting of N, O, S;
• R 17 is -H, Ci-C 6 -alkyl, C3-C7-cycloalkyl, 3-oxetanyl, or 3-tetrahydrofuranyl; or R 15 together with R 16 and the ring to which they are attached can be a benzimidazole ring; the benzimidazole ring being optionally substituted with one or two R 19 substituents;
• R 18 is halo, Ci-Ce-alkyl, C3-C 7 -cycloalkyl, -CN, -O-Ci-Ce-alkyl, -O-C3-C7- cycloalkyl, -S0 2 -Ci-C 6 -alkyl, -CH 2 S0 2 -Ci-C 6 -alkyl, -CONH2, -CONH-Ci-Ce-alkyl, or -CON(Ci-C 6 -alkyl) 2 ; and
• R 19 is halo, Ci-Ce-alkyl, C 3 -C 7 -cycloalkyl, -CN, -O-Ci-Ce-alkyl, -O-C3-C7- cycloalkyl, -S0 2 -Ci-C 6 -alkyl, or -CH 2 S0 2 -Ci-C 6 -alkyl.
• the Bax inhibiting compound having formula (II) can be selected from the group consisting of:
• the Bax inhibiting compounds can be provided in a pharmaceutical composition that includes the Bax inhibiting compound and a
• the compound or Bax inhibiting compounds described herein can inhibit the Mouse Embryonic Fibroblasts (MEFs) from Bax-induced cell death Bax at an IC50 of less than or equal to 1 mM, an IC50 of less than or equal to 250 nM, an IC50 of less than or equal to 50 nM, an IC50 of less than or equal to 10 nM, an IC50 of less than or equal to 5 nM, an IC50 of about 2.5 nM to about 10 nM, or an IC50 of less than or equal to about 2.5 nM.
• MEFs Mouse Embryonic Fibroblasts
• the Bas inhibiting compounds e.g., formula I-II
• the Bas inhibiting compounds have a human or mouse microsome stability T1/2 of greater than 50 minutes, greater than 60 minute, greater than 70 minutes, greater than 80 minutes, greater than 90 minutes, or greater than 100 minutes, including all values and ranges there between.
• the Bax inhibiting compounds described herein have a human or mouse microsome stability T1/2 of greater than 110 minutes, greater than 120 minutes, greater than 130 minutes, or greater than 145 minutes, including all values and ranges therebetween.
• the Bax inhibiting compounds described herein have a human or mouse microsome stability T1/2 ranging from 65 to at least 145 (e.g., 65, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, or more, including all values and ranges therebetween). In embodiments, the Bax inhibiting compounds described herein have a human or mouse microsome stability T1/2 of greater than 145 minutes.
• the Bax inhibiting compounds described herein can be used in a method of inhibiting apoptosis in a cell by administering to the cell a therapeutically effective amount of the Bax inhibiting compound.
• An“effective amount” or“therapeutically effective amount” of the Bax inhibiting compound administered to a cell is the amount of the Bax inhibiting compound effective to mitigate Bax mediated apoptosis in the cell.
• the Bax mediated apoptosis is induced by, for example, cell injury, a degenerative disorder or disease, or cytotoxic stresses elicited, for example, by chemo-and radiotherapy delivered to the cell.
• a pharmaceutical composition comprising a compound described herein can be administered to a subject for the treatment of an apoptotic disease.
• the method includes administering a therapeutically effective amount of a pharmaceutical composition comprising the Bax inhibiting compound to the subject.
• a therapeutically effective amount of a pharmaceutical composition including a Bax inhibiting compound described herein encompasses the reduction of Bax mediated cell or tissue death in a subject.
• Apoptotic diseases and related disorders as contemplated herein can include, for example, stroke, heart attack, ischemia, degenerative diseases (neuron and muscle, e.g., Alzheimer disease, Parkinson's disease, cardiomyocyte degeneration, etc), macular degeneration, hypoxia induced apoptosis, ischemia, atrophy, infection by parasitic organisms (virus, bacteria, yeast, or protozoa, etc), side effects of other drugs (e.g., anti-cancer drugs), UV/X-ray irradiation, and several other pathological conditions triggering cell death signals.
• degenerative diseases neurode and muscle, e.g., Alzheimer disease, Parkinson's disease, cardiomyocyte degeneration, etc
• macular degeneration e.g., hypoxia induced apoptosis
• ischemia e.g., atrophy, infection by parasitic organisms (virus, bacteria, yeast, or protozoa, etc)
• side effects of other drugs e.g., anti-cancer drugs
• compositions described herein can be used to inhibit Bax mediated cell death wherein Bax overexpression in the cell is induced by chemo- and radiotherapy.
• a pharmaceutical composition described above can protect megakaryocytes from chemotherapy induced apoptosis without substantially affecting the ability of megakaryocytes to produce and release platelets.
• compositions described herein can be used in a combination therapy or adjunctive therapy with antiproliferative agents or chemotherapeutic agents for the treatment of proliferative disorders, such as neoplastic disorders or cancer.
• combination therapy embraces the administration of the pharmaceutical compositions including the Bax inhibiting compounds described herein and a therapeutic agent as part of a specific treatment regimen intended to provide a beneficial effect from the co-action of these therapeutic agents.
• Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually minutes, hours, days or weeks depending upon the combination selected).
• “Combination therapy” is intended to embrace administration of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner.
• Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules for each of the therapeutic agents.
• each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues.
• the therapeutic agents can be administered by the same route or by different routes.
• a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally.
• all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection.
• the sequence in which the therapeutic agents are administered is not narrowly critical.
• Combination therapy also can embrace the administration of the therapeutic agents as described above in further combination with other biologically active ingredients (such as, but not limited to, a second and different therapeutic agent) and non- drug therapies (such as, but not limited to, surgery or radiation treatment).
• the combination therapy further comprises radiation treatment
• the radiation treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and radiation treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the radiation treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.
• adjunct therapy encompasses treatment of a subject with agents that reduce or avoid side effects associated with the combination therapy of the present invention, including, but not limited to, those agents, for example, that reduce the toxic effect of anticancer drugs, e.g., bone resorption inhibitors, cardioprotective agents; prevent or reduce the incidence of nausea and vomiting associated with chemotherapy, radiotherapy or operation; or reduce the incidence of infection associated with the administration of myelosuppressive anticancer drugs.
• agents that reduce or avoid side effects associated with the combination therapy of the present invention including, but not limited to, those agents, for example, that reduce the toxic effect of anticancer drugs, e.g., bone resorption inhibitors, cardioprotective agents; prevent or reduce the incidence of nausea and vomiting associated with chemotherapy, radiotherapy or operation; or reduce the incidence of infection associated with the administration of myelosuppressive anticancer drugs.
• the apoptotic disease treated by the combination therapy can include proliferative diseases, such as neoplastic disorders (e.g., leukemia) and cancer. Besides being useful for human treatment, the combination therapy is also useful for veterinary treatment of companion animals, exotic and farm animals, including rodents, horses, dogs, and cats.
• the therapeutic agents administered in combination therapy with the Bax inhibiting compounds described herein or pharmaceutical compositions thereof can comprise at least one anti-proliferative agent selected from the group consisting of a chemotherapeutic agent, an antimetabolite, an antitumorgenic agent, an antimitotic agent, an antiviral agent, an antineoplastic agent, an immunotherapeutic agent, and a radiotherapeutic agent.
• the cells, tissue, or organ can be stored in and/or contacted with a composition including a Bax inhibiting compound described herein.
• the effective amount of the Bax inhibiting compound is an amount effective to mitigate Bax mediated apoptosis of the cells, tissue, or organ of interest.
• a composition for storing cells or organs can include an effective amount of the Bax inhibiting compound and an organ preservation solution.
• Organ preservation solutions depend on contacting, storing and/or perfusing the organ with a supportive preservation solution designed to provide pH buffering, osmotic balance and/or some minimal nutritional support, e.g., in the form of glucose and a limited set of other basic nutrients. This approach is typically combined with reduction in organ temperature to just above the freezing point of water. This is intended to reduce the metabolic rate of organ tissues, thus slowing the consumption of nutrients and the production of waste products.
• a pharmaceutical composition containing the Bax inhibiting compound described herein can be employed at the hypothermic ranges commonly used in the art, which can range from below 20°C to about 4°C.
• These art-known preservative solutions include, for example, isotonic saline solutions, that may contain, in various proportions, salts, sugars, osmotic agents, local anesthetic, buffers, and other such agents, as described, simply by way of example, by Berdyaev et al., U.S. Pat. No. 5,432,053; Belzer et al., described by U.S. Pat. Nos. 4,798,824, 4,879,283; and 4,873,230; Taylor, U.S. Pat. No. 5,405,742; Dohi et al., U.S. Pat. No. 5,565,317; Stern et al., U.S. Pat. Nos. 5,370,989 and 5,552,267.
• organ encompasses both solid organs, e.g., kidney, heart, liver, lung, pancreas, as well as functional parts of organs, e.g., segments of skin, sections of artery, transplantable lobes of a liver, kidney, lung, and other organs.
• tissue refers herein to viable cellular materials in an aggregate form, e.g., small portions of an organ, as well as dispersed cells, e.g., cells dispersed, isolated and/or grown from heart muscle, liver or kidney, including bone marrow cells and progeny cells, blood born stem cells and progeny, and the various other art-known blood elements, unless otherwise specified.
• Syndromic conditions, traumatic injuries, chronic conditions, medical interventions, or other conditions that cause or are associated with tissue damage and a need for tissue repair, and thus, suitable for treatment or amelioration using the methods described herein, include, but are not limited to, acute coronary syndrome, acute lung injury (ALI), acute myocardial infarction (AMI), acute respiratory distress syndrome (ARDS), arterial occlusive disease, arteriosclerosis, articular cartilage defect, aseptic systemic inflammation, atherosclerotic cardiovascular disease, autoimmune disease, bone fracture, bone fracture, brain edema, brain hypoperfusion, Buerger's disease, bums, cancer, cardiovascular disease, cartilage damage, cerebral infarct, cerebral ischemia, cerebral stroke, cerebrovascular disease, chemotherapy-induced neuropathy, chronic infection, chronic mesenteric ischemia, claudication, congestive heart failure, connective tissue damage, contusion, coronary artery disease (CAD), critical limb ischemia (CLI), Crohn's disease, deep vein thrombosis
• inflammatory bowel disease inflammatory disease, injured tendons, intermittent claudication, intestinal ischemia, ischemia, ischemic brain disease, ischemic heart disease, ischemic peripheral vascular disease, ischemic placenta, ischemic renal disease, ischemic vascular disease, ischemic -reperfusion injury, laceration, left main coronary artery disease, limb ischemia, lower extremity ischemia, myocardial infarction, myocardial ischemia, organ ischemia, osteoarthritis, osteoporosis, osteosarcoma, Parkinson's disease, peripheral arterial disease (PAD), peripheral artery disease, peripheral ischemia, peripheral neuropathy, peripheral vascular disease, pre-cancer, pulmonary edema, pulmonary embolism, remodeling disorder, renal ischemia, retinal ischemia, retinopathy, sepsis, skin ulcers, solid organ transplantation, spinal cord injury, stroke, subchondral-bone cyst, thrombosis, thrombotic brain ischemia, tissue
• the Bax inhibiting compounds described herein can be used for treating ischemia, such as cerebrovascular ischemia, myocardial ischemia, limb ischemia (CLI), myocardial ischemia (especially chronic myocardial ischemia), ischemic cardiomyopathy, cerebrovascular ischemia, renal ischemia, pulmonary ischemia, intestinal ischemia, and the like.
• ischemia such as cerebrovascular ischemia, myocardial ischemia, limb ischemia (CLI), myocardial ischemia (especially chronic myocardial ischemia), ischemic cardiomyopathy, cerebrovascular ischemia, renal ischemia, pulmonary ischemia, intestinal ischemia, and the like.
• the ischemia is associated with at least one of acute coronary syndrome, acute lung injury (ALI), acute myocardial infarction (AMI), acute respiratory distress syndrome (ARDS), arterial occlusive disease, arteriosclerosis, articular cartilage defect, aseptic systemic inflammation, atherosclerotic cardiovascular disease, autoimmune disease, bone fracture, bone fracture, brain edema, brain hypoperfusion,
• ALI acute lung injury
• AMI acute myocardial infarction
• ARDS acute respiratory distress syndrome
• arterial occlusive disease arteriosclerosis
• articular cartilage defect aseptic systemic inflammation
• atherosclerotic cardiovascular disease autoimmune disease
• bone fracture bone fracture
• brain edema brain hypoperfusion
• Buerger's disease burns, cancer, cardiovascular disease, cartilage damage, cerebral infarct, cerebral ischemia, cerebral stroke, cerebrovascular disease, chemotherapy-induced
• CAD coronary artery disease
• CLI critical limb ischemia
• CLI critical limb ischemia
• CLI critical limb ischemia
• DIC disseminated intravascular coagulation
• embolic brain ischemia graft- versus-host disease
• hereditary hemorrhagic telengiectasiaischemic vascular disease hyperoxic injury, hypoxia, inflammation, inflammatory bowel disease, inflammatory disease, injured tendons, intermittent claudication, intestinal ischemia, ischemia, ischemic brain disease, ischemic heart disease, ischemic peripheral vascular disease, ischemic placenta, ischemic renal disease, ischemic vascular disease, ischemic-reperfusion injury, laceration, left main coronary artery disease,
• the Bax inhibiting compounds described herein can be administered to a preparation of hematopoietic stem cells, such as peripheral blood hematopoietic stem cells or umbilical cord stem cells of the subject, to increase the fitness of the stem cell preparation as a donor graft or to decrease the number of units of umbilical cord blood required for transplantation.
• hematopoietic stem cells such as peripheral blood hematopoietic stem cells or umbilical cord stem cells of the subject.
• the hematopoietic stem cells can be administered or contacted ex vivo with one or more Bax inhibiting compounds described herein to provide a therapeutic composition.
• the therapeutic compositions of the can include a population of hematopoietic stem cells treated ex vivo with a one or more of the Bax inhibiting compounds described herein.
• the therapeutic composition comprising the enhanced HSPCs is whole bone marrow, umbilical cord blood, or mobilized peripheral blood.
• Preparations of hematopoietic stem cells administered one or more of the Bax inhibiting Bax inhibiting compounds described herein and/or therapeutic compositions that include hematopoietic stem cells and one or more Bax inhibiting compounds described herein can be used for improving hematopoietic stem cell transplants and in treating ischemia or ischemia-damaged tissue, and in reducing further damage to ischemic tissue and/or repairing damage to ischemic tissue through cell recruitment, improving vascularization in ischemic tissue, improving tissue regeneration at sites of ischemia, decreasing ischemic tissue necrosis or apoptosis, and/or increasing cell survival at sites of ischemia.
• the preparations of the Bax inhibiting compound treated hematopoietic stem cells and/or therapeutic compositions of Bax inhibiting compounds and hematopoietic stem cells are useful to subjects in need of hematopoietic reconstitution, such as subjects that have undergone or are scheduled to undergo myeloablative therapy.
• Subjects which can be treated with the preparations of Bax inhibiting compound treated hematopoietic stem cells and/or therapeutic compositions of Bax inhibiting compounds and hematopoietic stem cells, can include subjects that have or that have been diagnosed with various types of leukemias, anemias, lymphomas, myelomas, immune deficiency disorders, and solid tumors.
• a subject also includes a human who is a candidate for stem cell transplant or bone marrow transplantation, such as during the course of treatment for a malignant disease or a component of gene therapy.
• Subjects may also include individuals or animals that donate stem cells or bone marrow for allogeneic transplantation.
• a subject may have undergone myeloablative irradiation therapy or chemotherapy, or may have experienced an acute radiation or chemical insult resulting in myeloablation.
• a subject may have undergone irradiation therapy or chemotherapy, such as during various cancer treatments.
• Typical subjects include animals that exhibit aberrant amounts (lower or higher amounts than a "normal” or “healthy” subject) of one or more physiological activities that can be modulated by an agent or a stem cell or marrow transplant.
• Subjects which can be treated with the preparations of Bax inhibiting compound treated hematopoietic stem cells and/or therapeutic compositions of Bax inhibiting compounds and hematopoietic stem cells, can also include subjects undergoing chemotherapy or radiation therapy for cancer, as well as subjects suffering from (e.g., afflicted with) non malignant blood disorders, particularly immunodeficiencies (e.g.
• SCID Fanconi's anemia, severe aplastic anemia, or congenital hemoglobinopathies, or metabolic storage diseases, such as Hurler's disease, Hunter's disease, mannosidosis, among others) or cancer, particularly hematological malignancies, such as acute leukemia, chronic leukemia (myeloid or lymphoid), lymphoma (Hodgkin's or non-Hodgkin's), multiple myeloma, myelodysplastic syndrome, or non-hematological cancers such as solid tumors (including breast cancer, ovarian cancer, brain cancer, prostate cancer, lung cancer, colon cancer, skin cancer, liver cancer, or pancreatic cancer).
• hematological malignancies such as acute leukemia, chronic leukemia (myeloid or lymphoid), lymphoma (Hodgkin's or non-Hodgkin's), multiple myeloma, myelodysplastic syndrome, or non-hematological cancers such as solid tumors (including breast cancer
• Subjects may also include subjects suffering from aplastic anemia, an immune disorder (severe combined immune deficiency syndrome or lupus), myelodysplasia, thalassemaia, sickle-cell disease or Wiskott-Aldrich syndrome.
• the subject suffers from a disorder that is the result of an undesired side effect or complication of another primary treatment, such as radiation therapy, chemotherapy, or treatment with a bone marrow suppressive drug, such as zidovadine, chloramphenical or gangciclovir.
• Such disorders include neutropenias, anemias, thrombocytopenia, and immune dysfunction.
• Other subjects may have disorders caused by an infection (e.g., viral infection, bacterial infection or fungal infection) which causes damage to stem or progenitor cells of the bone marrow.
• the Bax inhibiting compounds described herein can be administered to a recipient of a bone marrow transplant, of a hematopoietic stem cell transplant, or of an umbilical cord blood stem cell transplant, in order to decrease the administration of other treatments or growth factors.
• the Bax inhibiting compounds described herein can be administered to a subject to enhance recovery of neutrophils following bone marrow transplantation, following umbilical cord blood transplantation, following transplantation with hematopoietic stem cells, following conventional chemotherapy, following radiation treatment, and in individuals with neutropenias from diseases that include but are not limited to aplastic anemia, myelodysplasia, myelofibrosis, neutropenias from other bone marrow diseases, drug induced neutropenia, immune neutropenias, idiopathic neutropenia, and following infections with viruses that include, but are not limited to, HIV, CMV, and parvovirus.
• the Bax inhibiting compounds described herein can be administered to a subject to enhance recovery of platelets following bone marrow
• thrombocytopenia transplantation, following umbilical cord blood transplantation, following transplantation with hematopoietic stem cells, following conventional chemotherapy, following radiation treatment, and in individuals with neutropenias from diseases that include but are not limited to aplastic anemia, myelodysplasia, myelofibrosis, thrombocytopenias from other bone marrow diseases, drug induced thrombocytopenia, immune thrombocytopenia, idiopathic thrombocytopenic purpura, idiopathic thrombocytopenia, and following infections with viruses that include, but are not limited to, HIV, CMV, and parvovirus.
• viruses that include, but are not limited to, HIV, CMV, and parvovirus.
• the Bax inhibiting compounds described herein can be administered to a subject to enhance recovery of hemoglobin following bone marrow transplantation, following umbilical cord blood transplantation, following transplantation with hematopoietic stem cells, following conventional chemotherapy, following radiation treatment, and in individuals with anemias from diseases that include but are not limited to aplastic anemia, myelodysplasia, myelofibrosis, anemia from other bone marrow diseases, drug induced anemia, immune mediated anemias, anemia of chronic disease, idiopathic anemia, and following infections with viruses that include, but are not limited to, HIV, CMV, and parvovirus.
• the Bax inhibiting compounds described herein can be administered to a subject to enhance numbers of bone marrow stem cell numbers following bone marrow transplantation, following umbilical cord blood transplantation, following transplantation with hematopoietic stem cells, following conventional chemotherapy, following radiation treatment, in individuals with other bone marrow diseases, in individuals with cytopenias following viral infections, and in individuals with cytopenias.
• the Bax inhibiting compounds described herein can be administered to a subject or to a tissue graft of a subject to mitigate graft rejection, to enhance graft engraftment, to enhance graft engraftment following treatment of the subject or the marrow of the subject with radiation therapy, chemotherapy, or immunosuppressive therapy, to confer resistance to toxic or lethal effects of exposure to radiation, confer resistance to the toxic effect of Cytoxan, the toxic effect of fludarabine, the toxic effect of chemotherapy, or the toxic effect of immunosuppressive therapy, to decrease infection, and/or to decrease pulmonary toxicity from radiation.
• the Bax inhibiting compounds described herein can be administered to a recipient of a tissue stem cell transplant, including but not limited to a transplant with hematopoietic stem cells, neural stem stems, mesenchymal stem cells, or stem cells for other tissues, so as to accelerate tissue regeneration and repair following the transplant.
• the Bax inhibiting compounds described herein can be provided in a
• a pharmaceutical composition containing the Bax inhibiting compounds described herein as an active ingredient may be manufactured by mixing the derivative with a pharmaceutically acceptable carrier(s) or an excipient(s) or diluting the Bax inhibiting compounds described herein with a diluent in accordance with conventional methods.
• the pharmaceutical composition may further contain fillers, anti- cohesives, lubricants, wetting agents, flavoring agents, emulsifying agents, preservatives and the like.
• the pharmaceutical composition may be formulated into a suitable formulation in accordance with the methods known to those skilled in the art so that it can provide an immediate, controlled or sustained release of the Bax inhibiting compounds described herein after being administered into a mammal.
• the pharmaceutical composition may be formulated into a parenteral or oral dosage form.
• the solid dosage form for oral administration may be manufactured by adding excipient, if necessary, together with binder, disintegrants, lubricants, coloring agents, and/or flavoring agents, to the Bax inhibiting compounds and shaping the resulting mixture into the form of tablets, sugar-coated pills, granules, powder or capsules.
• the additives that can be added in the composition may be ordinary ones in the art.
• examples of the excipient include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicate and the like.
• Exemplary binders include water, ethanol, propanol, sweet syrup, sucrose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, shellac, calcium phosphonate and polypyrrolidone.
• the disintegrant examples include dry starch, sodium arginate, agar powder, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, stearic monoglyceride and lactose. Further, purified talc, stearates, sodium borate, and polyethylene glycol may be used as a lubricant; and sucrose, bitter orange peel, citric acid, tartaric acid, may be used as a flavoring agent.
• the pharmaceutical composition can be made into aerosol formulations ( e.g they can be nebulized) to be administered via inhalation.
• the Bax inhibiting compounds described herein may be combined with flavoring agents, buffers, stabilizing agents, and the like and incorporated into oral liquid dosage forms such as solutions, syrups or elixirs in accordance with conventional methods.
• One example of the buffers may be sodium citrate.
• Examples of the stabilizing agents include tragacanth, acacia and gelatin.
• the Bax inhibiting compounds described herein described herein may be incorporated into an injection dosage form, for example, for a subcutaneous, intramuscular or intravenous route by adding thereto pH adjusters, buffers, stabilizing agents, relaxants, topical anesthetics.
• pH adjusters and the buffers include sodium citrate, sodium acetate and sodium phosphate.
• stabilizing agents include sodium pyrosulfite, EDTA, thioglycolic acid and thiolactic acid.
• the topical anesthetics may be procaine HC1, lidocaine HC1 and the like.
• the relaxants may be sodium chloride, glucose and the like.
• the Bax inhibiting compounds described herein may be incorporated into suppositories in accordance with conventional methods by adding thereto pharmaceutically acceptable carriers that are known in the art, for example, polyethylene glycol, lanolin, cacao butter or fatty acid triglycerides, if necessary, together with surfactants such as Tween.
• pharmaceutically acceptable carriers for example, polyethylene glycol, lanolin, cacao butter or fatty acid triglycerides, if necessary, together with surfactants such as Tween.
• the pharmaceutical composition may be formulated into various dosage forms as discussed above and then administered through various routes including an oral, inhalational, transdermal, subcutaneous, intravenous or intramuscular route.
• the dosage can be a pharmaceutically effective amount.
• the pharmaceutically effective amount can be an amount of the Bax inhibiting compounds described herein to treat or inhibit cell death associated with a disease or disorder.
• the pharmaceutically effective amount of the compound will be appropriately determined depending on the kind and the severity of the disease to be treated, age, sex, body weight and the physical condition of the patients to be treated, administration route, duration of therapy and the like. Generally, the effective amount of the compound may be in the range of about 1 to 1,000 mg in the oral
• the daily dosage for adults is in the range of about 0.1 to 5,000 mg, preferably about to 1,000 mg but cannot be determined uniformly because it depends on age, sex, body weight and the physical condition of the patients to be treated.
• the formulation may be administered once a day or several times a day with a divided dose.
• Cosmetic compositions containing the Bax inhibiting compounds described herein can include any substance or preparation intended to be brought into contact with the various superficial parts of the human body (epidermis, body hair and hair system, nails, lips and external genital organs) or with the teeth or the buccal mucous membranes for the purpose, exclusively or mainly, of cleansing them, of giving them a fragrance, of modifying their appearance and/or of correcting body odors and/or protecting them or of maintaining them in good condition.
• the cosmetic composition can comprise a cosmetically acceptable medium that may be water or a mixture of water and at least one solvent selected from among hydrophilic organic solvents, lipophilic organic solvents, amphiphilic organic solvents, and mixtures thereof.
• the cosmetic composition can be administered in the form of aqueous, alcoholic, aqueous-alcoholic or oily solutions or suspensions, or of a dispersion of the lotion or serum type, of emulsions that have a liquid or semi-liquid consistency or are pasty, obtained by dispersion of a fatty phase in an aqueous phase (O/W) or vice versa (W/O) or multiple emulsions, of a free or compacted powder to be used as it is or to be incorporated into a physiologically acceptable medium, or else of microcapsules or microparticles, or of vesicular dispersions of ionic and/or nonionic type.
• aqueous, alcoholic, aqueous-alcoholic or oily solutions or suspensions or of a dispersion of the lotion or serum type, of emulsions that have a liquid or semi-liquid consistency or are pasty, obtained by dispersion of a fatty phase in an aqueous phase (O/W) or vice vers
• the cosmetic compositions may in particular comprise a hair care composition, and in particular a shampoo, a setting lotion, a treating lotion, a styling cream or gel, restructuring lotions for the hair, a mask, etc.
• the cosmetic compositions can be a cream, a hair lotion, a shampoo or a conditioner. These can be used in particular in treatments using an application that may or may not be followed by rinsing, or else in the form of a shampoo.
• a composition in the form of a foam, or else in the form of spray or an aerosol, then comprising propellant under pressure, is also intended. It can thus be in the form of a lotion, serum, milk, cream, gel, salve, ointment, powder, balm, patch, impregnated pad, cake or foam.
• the cosmetic compositions may also contain adjuvants that are normal in the cosmetics field, such as hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic additives, preservatives, antioxidants, solvents, fragrances, fillers, UV-screening agents, odor absorbers and dyestuffs.
• adjuvants that are normal in the cosmetics field, such as hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic additives, preservatives, antioxidants, solvents, fragrances, fillers, UV-screening agents, odor absorbers and dyestuffs.
• the amounts of these various adjuvants are those conventionally used in the cosmetics field, and are for example from 0.1% to 20%, in particular less than or equal to 10%, of the total weight of the composition. According to their nature, these adjuvants can be introduced into the fatty phase, into the aqueous phase and/or into the lipid spherules.
• N-[(lS)-l-(4-bromophenyl)ethyl]thieno[2,3-d]pyrimidin-4-amine (0.5 g, 1.50 mmol, 1 eq), Zn(CN)2 (193 mg, E65 mmol, 104.45 uL, El eq) and Pd(PPh3)4 (173 mg, 149.60 umol, 74.80 uL, 0.1 eq) were taken up into a microwave tube in NMP (10 mL) under N2. The sealed tube was heated at 100°C for 1 hr under microwave. The reaction was added water (20 mL) and extracted with EtOAc (10 mL x 3).
• N-[(lS)-l-(4-bromophenyl)ethyl]thieno[2,3-d]pyrimidin-4-amine 60 mg, 179.52 umol, 1 eq
• 4-cyclopropyl- lH-imidazole 29 mg, 269.27 umol, E5 eq
• Cul 7 mg, 35.90 umol, 0.2 eq
• CS2CO3 117 mg, 359.03 umol, 2 eq
• the premixed catalyst solution was added to a mixture of N-[(lS)-l-(4-bromophenyl)ethyl]thieno[2,3-d]pyrimidin-4-amine (100 mg, 299.19 umol, 1 eq), 4-cyclopropyl- lH-triazole (49 mg, 448.79 umol, 1.5 eq) and K 3 P0 4 (127 mg, 598.38 umol, 2 eq) in toluene (1 ruL) under N2. The mixture was stirred at 120°C for 12 hours. The reaction was concentrated in vacuo.
• the residue was purified by prep-HPLC (column: Nano-micro Kromasil C18 100*30mm 5um;mobile phase: [water(0.1%TFA)-ACN];B%: 5%-25%,10min) to give 1 -(3 -cycloprop ylbenzimidazol-5-yl)ethanamine (0.14 g, 444.04 umol, 28.96% yield, TFA) as a white solid and l-(l-cyclopropylbenzimidazol-5- yl)ethanamine (0.14 g, 444.04 umol, 28.96% yield, TFA) as a white solid.
• N-[(lR)-l-(4-bromophenyl)ethyl]thieno[2,3-d]pyrimidin-4-amine 400 mg, 1.2 mmol, 1 eq
• lH-l,2,4-triazole 124 mg, 1.8 mmol, 1.5 eq
• CS2CO3 780 mg, 2.39 mmol, 2 eq
• Cul 46 mg, 240 umol, 0.2 eq
• N-[(lS)-l-(4-bromophenyl)ethyl]thieno[2,3-d]pyrimidin-4-amine 400 mg, 1.20 mmol, 1 eq), 1H- 1,2, 4-triazole (124 mg, 1.80 mmol, 1.5 eq) and CS2CO3 (780 mg, 2.39 mmol, 2 eq), Cul (46 mg, 239.35 umol, 0.2 eq) were taken up into a microwave tube in DMF (8 mL). The sealed tube was heated at 150°C for 10 hours under microwave. The reaction was added water (30 mL) and extracted with EtOAc (15 mL x 3).
• ESI [M+H] 377.1.
• ESI [M+H] 377.0.
• product 2 was purified again by prep-HPLC (column: Luna C18 100*30 5u;mobile phase: [water(0.04%HCl)- ACN];B%: l%-30%,10min) to give 6-[[4-(2-chlorophenyl)-5-cyclopropyl-imidazol-l- yl] methyl] -1 -methyl-benzimidazole (4.75 mg, 11.37 umol, 4.01% yield, 95.557% purity,
• product 2 was purified again by prep-HPLC (column: Luna C18 100*30 5u;mobile phase: [water(0.04%HCl)- ACN];B%: l%-30%,10min) to give 6-[[4-(2-chlorophenyl)-5-cyclopropyl-imidazol-l- yl] methyl] -1,2-dimethyl-benzimidazole (3.33 mg, 7.50 umol, 2.94% yield, 93.037% purity, HC1) as a white solid.

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