Protein kinase C inhibitors

• US 5,624,949 A
• Filed: 03/30/1995
• Issued: 04/29/1997
• Est. Priority Date: 12/07/1993
• Status: Expired due to Fees

• Current Assignee: Eli Lilly and Company
• Original Assignee: Eli Lilly and Company
• Inventors: Jirousek, Michael R., Rito, Christopher J., McDonald, John H. III, Heath, William F. Jr.
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): Sripada, Pavanaram K.
• Application Number:
  US08/413,735
• Time in Patent Office: 761 Days
• Field of Search: 514/183, 514/185, 514/410, 540/472, 540/474, 540/456
• US Class Current: 514/410
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07C 43/1745 having more than one ether bound
• CPC Class Codes: C07C 43/1785 having more than one ether bound
• CPC Class Codes: C07D 487/22 in which the condensed system contains four or more hetero rings
• CPC Class Codes: C07D 498/22 in which the condensed system contains four or more hetero rings
• CPC Class Codes: C07D 513/22 in which the condensed system contains four or more hetero rings
• CPC Class Codes: C07F 7/1804 Compounds having Si-O-C linkages Si-O-acyl linkages C07F7/1896

Abstract

This invention provides novel bis-indolemaleimide macrocycle derivatives of the formula: ##STR1## 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--, --SO₂ --, --CO--, C₂ -C₆ alkylene, substituted alkylene, C₂ -C₆ alkenylene, -aryl-, -aryl(CH₂)_m O- -heterocycle-, -heterocycle-(CH₂)_m O-, -fused bicyclic-, -fused bicyclic-(CH₂)_m O-, --NR₃ --, --NOR₃ --, --CONH--, or --NHCO--;

X and Y are independently C₁ -C₄ alkylene, substituted alkylene, or together X, Y, and W combine to form --(CH₂)_n -AA-;

R₁ is independently hydrogen, halo, C₁ -C₄ alkyl, hydroxy, C₁ -C₄ -alkoxy, haloalkyl, nitro, NR₄ R₅, or --NHCO(C₁ -C₄ alkyl);

R₂ is hydrogen, CH₃ CO--, NH₂, or hydroxy;

R₃ is hydrogen, (CH₂)_m aryl, C₁ -C₄ alkyl, --COO(C₁ -C₄ alkyl), --CONR₄ R₅, --(C═

NH)NH₂, --SO(C₁ -C₄ alkyl), --SO₂ (NR₄ R₅), or --SO₂ (C₁ -C₄ alkyl);

R₄ and R₅ are independently hydrogen, C₁ -C₄ 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 R₂ 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 --NR₃ --;

and R₃ is hydrogen, (CH₂)_m aryl, C₁ -C₄ 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 C₁ -C₄ alkylene or substituted alkylene;

W'"'"' is --O--, --S--, or --NR₃ --;

R₃ is hydrogen, (CH₂)_m aryl, C₁ -C₄ 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 --(CH₂)_p -- or --(CH₂)_p --O--(CH₂)_p --;

R₆ is hydroxy, --SH, C₁ -C₄ alkyl, (CH₂)_m aryl, --NH(aryl), --NR₄ R₅, --NH(CF₃) or N(CF₃)(CH₃);

R₄ is hydrogen or C₁ -C₄ alkyl;

R₅ is hydrogen, C₁ -C₄ alkyl, benzyl, or combines with R₄ 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 --CH₂ --;

R₆ is --NR₄ R₅, --NH(CF₃) or N(CF₃)(CH₃), and R₄ and R₅ 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--, --SO₂ --, --CO--, C₂ -C₆ alkylene, substituted alkylene, C₂ -C₆ alkenylene, -aryl-, -aryl(CH₂)_m O- -heterocycle-, -heterocycle-(CH₂)_m O-, -fused bicyclic-, -fused bicyclic-(CH₂)_m O-, --NR₃ --, --NOR₃ --, --CONH--, or --NHCO--;

X and Y are independently C₁ -C₄ alkylene, substituted alkylene, or together X, Y, and W combine to form --(CH₂)_n -AA-;

R₁ is independently hydrogen, halo, C₁ -C₄ alkyl, hydroxy, C₁ -C₄ alkoxy, haloalkyl, nitro, NR₄ R₅, or --NHCO(C₁ -C₄ alkyl);

R₂ is hydrogen, CH₃ CO--, NH₂, or hydroxy;

R₃ is hydrogen, (CH₂)_m aryl, C₁ -C₄ alkyl, --COO(C₁ -C₄ alkyl), --CONR₄ R₅, --(C═

NH)NH₂, --SO(C₁ -C₄ alkyl), --SO₂ (NR₄ R₅), or --SO₂ (C₁ -C₄ alkyl);

R₄ and R₅ are independently hydrogen, C₁ -C₄ 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.

16. A method of claim 14, wherein the compound is of the formula:

##STR76## wherein;

Z is --(CH₂)_p -- or --(CH₂)_p --O--(CH₂)_p --;

R₆ is hydroxy, --SH, C₁ -C₄ alkyl, (CH₂)_m aryl, --NH(aryl), --NR₄ R₅, --NH(CF₃) or N(CF₃)(CH₃);

R₄ is hydrogen or C₁ -C₄ alkyl;

R₅ is hydrogen, C₁ -C₄ alkyl, benzyl, or combines with R₄ 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.

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--, --SO₂ --, --CO--, C₂ -C₆ alkylene, substituted alkylene, C₂ -C₆ alkenylene, -aryl-, -aryl(CH₂)_m O- -heterocycle-, heterocycle-(CH₂)_m O-, -fused bicyclic-, -fused bicyclic-(CH₂)_m O-, --NR₃ --, --NOR₃ --, --CONH--, or --NHCO--;

X and Y are independently C₁ -C₄ alkylene, substituted alkylene, or together X, Y, and W combine to form --(CH₂)_n -AA-;

R₁ is independently hydrogen, halo, C₁ -C₄ alkyl, hydroxy, C₁ -C₄ alkoxy, haloalkyl, nitro, NR₄ R₅, or --NHCO(C₁ -C₄ alkyl);

R₂ is hydrogen, CH₃ CO--, NH₂, or hydroxy;

R₃ is hydrogen, (CH₂)_m aryl, C₁ -C₄ alkyl, --COO(C₁ -C₄ alkyl), --CONR₄ R₅, --(C═

NH)NH₂, --SO(C₁ -C₄ alkyl), --SO₂ (NR₄ R₅), or --SO₂ (C₁ -C₄ alkyl);

R₄ and R₅ are independently hydrogen, C₁ -C₄ 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.

18. A method of claim 15, wherein the compound is of the formula:

##STR77## wherein;

Z is --(CH₂)_p -- or --(CH₂)_p --O--(CH₂)_p --;

R₆ is hydroxy, --SH, C₁ -C₄ alkyl, (CH₂)_m aryl, --NH(aryl), --NR₄ R₅, --NH(CF₃) or N(CF₃)(CH₃);

R₄ is hydrogen or C₁ -C₄ alkyl;

R₅ is hydrogen, C₁ -C₄ alkyl, benzyl, or combines with R₄ 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.