Protein kinase C inhibitors

{
  "publication_number": "US5624949A",
  "country": "US",
  "kind": "A",
  "title": "Protein kinase C inhibitors",
  "abstract": "This invention provides novel bis-indolemaleimide macrocycle derivatives of the formula: The invention further provides the preparation, pharmaceutical formulations and the methods of use for inhibiting Protein Kinase C in mammals.",
  "claims": [
    "1. A method of inhibiting protein kinase C, which comprises administering to a mammal in need of such treatment a pharmaceutically effective amount of a compound of the formula: ##STR71## wherein: W is --O--, --S--, --SO--, --SO 2 --, --CO--, C 2 -C 6 alkylene, substituted alkylene, C 2 -C 6 alkenylene, -aryl-, -aryl(CH 2) m O- -heterocycle-, -heterocycle-(CH 2) m O-, -fused bicyclic-, -fused bicyclic-(CH 2) m O-, --NR 3 --, --NOR 3 --, --CONH--, or --NHCO--; X and Y are independently C 1 -C 4 alkylene, substituted alkylene, or together X, Y, and W combine to form --(CH 2) n -AA-; R 1 is independently hydrogen, halo, C 1 -C 4 alkyl, hydroxy, C 1 -C 4 -alkoxy, haloalkyl, nitro, NR 4 R 5, or --NHCO(C 1 -C 4 alkyl); R 2 is hydrogen, CH 3 CO--, NH 2, or hydroxy; R 3 is hydrogen, (CH 2) m aryl, C 1 -C 4 alkyl, --COO(C 1 -C 4 alkyl), --CONR 4 R 5, --(C═NH)NH 2, --SO(C 1 -C 4 alkyl), --SO 2 (NR 4 R 5), or --SO 2 (C 1 -C 4 alkyl); R 4 and R 5 are independently hydrogen, C 1 -C 4 alkyl, phenyl, benzyl, or combine to the nitrogen to which they are bonded to form a saturated or unsaturated 5 or 6 member ring; AA is an amino acid residue; m is independently 0, 1, 2, or 3; and n is independently 2, 3, 4, or 5; or a pharmaceutically acceptable salt or solvate thereof.",
    "2. A method of claim 1, wherein R 2 is hydrogen.",
    "3. A method of claim 2, wherein the moieties --X--W--Y-- contain 4 to 8 atoms, said atoms being substituted or unsubstituted.",
    "4. A method of claim 3, wherein W is a substituted alkylene, --O--, --S--, or --NR 3 --; and R 3 is hydrogen, (CH 2) m aryl, C 1 -C 4 alkyl; and m is 0, 1, 2, or 3.",
    "5. A method of claim 4, wherein the compound is of the formula: ##STR72## wherein: Y is C 1 -C 4 alkylene or substituted alkylene; W' is --O--, --S--, or --NR 3 --; R 3 is hydrogen, (CH 2) m aryl, C 1 -C 4 alkyl; and m is independently 2 or 3.",
    "6. A method of claim 5, wherein W' is --O--; and Y is substituted alkylene.",
    "7. A method of claim 6, wherein the compound is of the formula: ##STR73## wherein: Z is --(CH 2) p -- or --(CH 2) p --O--(CH 2) p --; R 6 is hydroxy, --SH, C 1 -C 4 alkyl, (CH 2) m aryl, --NH(aryl), --NR 4 R 5, --NH(CF 3) or N(CF 3)(CH 3); R 4 is hydrogen or C 1 -C 4 alkyl; R 5 is hydrogen, C 1 -C 4 alkyl, benzyl, or combines with R 4 and the nitrogen to which they are bonded to form a saturated or unsaturated 5 or 6 member ring; p is independently 0, 1 or 2; and m is independently 0, 1, 2, or 3.",
    "8. A method of claim 7, wherein Z is --CH 2 --; R 6 is --NR 4 R 5, --NH(CF 3) or N(CF 3)(CH 3), and R 4 and R 5 are methyl.",
    "9. A method of claim 7, wherein the compound is selected from the group consisting of (R)-3,4-[(N,N'-1,1'-((2\"-ethoxy)-3'\"(O)-4'\"-(N,N-dimethylamino)-butane)-bis-(3,3'-indolyl)]-1(H)-pyrrole-2,5-dione, (S)-3,4-[(N,N'-1,1'-((2\"-ethoxy)-3'\"(O)-4'\"-(N,N-dimethylamino)-butane)-bis-(3,3'-indolyl)]-1(H)-pyrrole-2,5-dione, a mixture thereof; or a pharmaceutically acceptable salt or solvate thereof.",
    "10. A method of claim 7, wherein the compound is (S)-3,4-[(N,N'-1,1'-((2\"-ethoxy)-3'\"(O)-4'\"-(N,N-dimethylamino)-butane)-bis-(3,3'-indolyl)]-1(H)-pyrrole-2,5-dione or a pharmaceutically acceptable salt or solvate thereof.",
    "11. A method of claim 7, wherein the compound is (R)-3,4-[(N,N'-1,1'-((2\"-ethoxy)-3'\"(O)-4'\"-(N,N-dimethylamino)-butane)-bis-(3,3'-indolyl)]-1(H)-pyrrole-2,5-dione or a pharmaceutically acceptable salt or solvate thereof.",
    "12. A method of claim 7, wherein the compound selected from the group consisting of (S)-3,4-[(N,N'-1,1'-((2\"-ethoxy)-3'\"-(O)-4'\"-(N-pyrrolidine)butane)-bis-(3,3'-indolyl)]-1(H)-pyrrole-2,5-dione, (R)-3,4-[(N,N'-1,1'-((2\"-ethoxy)-3'\"-(O)-4'\"-(N-pyrrolidine)butane)-bis-(3,3'-indolyl)]-1(H)-pyrrole-2,5-dione, a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof.",
    "13. A method of claim 7, wherein the compound is selected from the group consisting of (S)-3,4-[(N,N'-1,1'-((2\"-ethoxy)-3'\"-(O)-4'\"-(N-phenylsulfonamido)-butane)-bis-(3,3'-indolyl)]-1(H)-pyrrole-2,5-dione, (R)-3,4-[(N,N'-1,1'-((2\"-ethoxy)-3'\"-(O)-4'\"-(N-phenylsulfonamido)-butane)-bis-(3,3'-indolyl)]-1(H)-pyrrole-2,5-dione, a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof.",
    "14. A method of inhibiting protein kinase C beta-1 isozyme, which comprises administering to a mammal in need of such treatment a pharmaceutically effective amount of a compound of the formula: ##STR74## wherein; W is --O--, --S--, --SO--, --SO 2 --, --CO--, C 2 -C 6 alkylene, substituted alkylene, C 2 -C 6 alkenylene, -aryl-, -aryl(CH 2) m O- -heterocycle-, -heterocycle-(CH 2) m O-, -fused bicyclic-, -fused bicyclic-(CH 2) m O-, --NR 3 --, --NOR 3 --, --CONH--, or --NHCO--; X and Y are independently C 1 -C 4 alkylene, substituted alkylene, or together X, Y, and W combine to form --(CH 2) n -AA-; R 1 is independently hydrogen, halo, C 1 -C 4 alkyl, hydroxy, C 1 -C 4 alkoxy, haloalkyl, nitro, NR 4 R 5, or --NHCO(C 1 -C 4 alkyl); R 2 is hydrogen, CH 3 CO--, NH 2, or hydroxy; R 3 is hydrogen, (CH 2) m aryl, C 1 -C 4 alkyl, --COO(C 1 -C 4 alkyl), --CONR 4 R 5, --(C═NH)NH 2, --SO(C 1 -C 4 alkyl), --SO 2 (NR 4 R 5), or --SO 2 (C 1 -C 4 alkyl); R 4 and R 5 are independently hydrogen, C 1 -C 4 alkyl, phenyl, benzyl, or combine to the nitrogen to which they are bonded to form a saturated or unsaturated 5 or 6 member ring; AA is an amino acid residue; m is independently 0, 1, 2, or 3; and n is independently 2, 3, 4, or 5; or a pharmaceutically acceptable salt or solvate thereof.",
    "15. A method of inhibiting protein kinase C beta-2 isozyme, which comprises administering to a mammal in need of such treatment a pharmaceutically effective amount of a compound of the formula: ##STR75## wherein: W is --O--, --S--, --SO--, --SO 2 --, --CO--, C 2 -C 6 alkylene, substituted alkylene, C 2 -C 6 alkenylene, -aryl-, -aryl(CH 2) m O- -heterocycle-, heterocycle-(CH 2) m O-, -fused bicyclic-, -fused bicyclic-(CH 2) m O-, --NR 3 --, --NOR 3 --, --CONH--, or --NHCO--; X and Y are independently C 1 -C 4 alkylene, substituted alkylene, or together X, Y, and W combine to form --(CH 2) n -AA-; R 1 is independently hydrogen, halo, C 1 -C 4 alkyl, hydroxy, C 1 -C 4 alkoxy, haloalkyl, nitro, NR 4 R 5, or --NHCO(C 1 -C 4 alkyl); R 2 is hydrogen, CH 3 CO--, NH 2, or hydroxy; R 3 is hydrogen, (CH 2) m aryl, C 1 -C 4 alkyl, --COO(C 1 -C 4 alkyl), --CONR 4 R 5, --(C═NH)NH 2, --SO(C 1 -C 4 alkyl), --SO 2 (NR 4 R 5), or --SO 2 (C 1 -C 4 alkyl); R 4 and R 5 are independently hydrogen, C 1 -C 4 alkyl, phenyl, benzyl, or combine to the nitrogen to which they are bonded to form a saturated or saturated or unsaturated 5or 6 member ring; AA is an amino acid residue; m is independently 0, 1, 2, or 3; and n is independently 2, 3, 4, or 5; or a pharmaceutically acceptable salt or solvate thereof.",
    "16. A method of claim 14, wherein the compound is of the formula: ##STR76## wherein: Z is --(CH 2) p -- or --(CH 2) p --O--(CH 2) p --; R 6 is hydroxy, --SH, C 1 -C 4 alkyl, (CH 2) m aryl, --NH(aryl), --NR 4 R 5, --NH(CF 3) or N(CF 3)(CH 3); R 4 is hydrogen or C 1 -C 4 alkyl; R 5 is hydrogen, C 1 -C 4 alkyl, benzyl, or combines with R 4 and the nitrogen to which they are bonded to form a saturated or unsaturated 5 or 6 member ring; p is independently 0, 1 or 2; and m is independently 0, 1, 2, or 3; or a pharmaceutically acceptable salt or solvate thereof.",
    "17. A method of claim 16, wherein the compound is 3,4-[N,N'-1,1'-((2\"-ethoxy)-3'\"(O)-4'\"-(N,N-dimethylamino)-butane)-bis-(3,3'-indolyl)]-1(H)-pyrrole-2,5-dione or a pharmaceutically acceptable salt or solvate thereof.",
    "18. A method of claim 15, wherein the compound is of the formula: ##STR77## wherein: Z is --(CH 2) p -- or --(CH 2) p --O--(CH 2) p --; R 6 is hydroxy, --SH, C 1 -C 4 alkyl, (CH 2) m aryl, --NH(aryl), --NR 4 R 5, --NH(CF 3) or N(CF 3)(CH 3); R 4 is hydrogen or C 1 -C 4 alkyl; R 5 is hydrogen, C 1 -C 4 alkyl, benzyl, or combines with R 4 and the nitrogen to which they are bonded to form a saturated or unsaturated 5 or 6 member ring; p is independently 0, 1 or 2; and m is independently 0, 1, 2, or 3; or a pharmaceutically acceptable salt or solvate thereof.",
    "19. A method of claim 18, wherein the compound is 3,4-[N,N'-1,1'-((2\"-ethoxy)-3'\"(O)-4'\"-(N,N-dimethyiamino)-butane)-bis-(3,3'-indolyl)]-1(H)-pyrrole-2,5-dione or a pharmaceutically acceptable salt or solvate thereof."
  ],
  "cpc": [
    "C07D 487/22",
    "A61P 17/00",
    "A61P 17/06",
    "A61P 25/00",
    "A61P 25/28",
    "A61P 29/00",
    "A61P 3/08",
    "A61P 3/10",
    "A61P 35/00",
    "A61P 43/00",
    "A61P 9/00",
    "A61P 9/08",
    "A61P 9/10",
    "C07C 43/1745",
    "C07C 43/1785",
    "C07D 498/22",
    "C07D 513/22",
    "C07F 7/1804"
  ],
  "assignees": [
    "LILLY CO ELI"
  ],
  "filing_date": "1995-03-30",
  "publication_date": "1997-04-29",
  "grant_date": "1997-04-29",
  "priority_date": "1993-12-07",
  "application_number": "US-41373595-A",
  "family_id": "23638401",
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  ]
}