Pharmaceutically active disubstituted triazine derivatives

Patent metadata

Field	Value
Publication number	US-9226929-B2
Application number	US-201214002730-A
Country	US
Kind code	B2
Filing date	Mar 1, 2012
Priority date	Mar 2, 2011
Publication date	Jan 5, 2016
Grant date	Jan 5, 2016

Abstract

The present invention relates to disubstituted triazine derivatives and/or pharmaceutically acceptable salts thereof, the use of these derivatives as pharmaceutically active agents, especially for the prophylaxis and/or treatment of infectious diseases, including opportunistic diseases, immunological diseases, autoimmune diseases, cardiovascular diseases, cell proliferative diseases, inflammation, erectile dysfunction and stroke, and pharmaceutical compositions containing at least one of said disubstituted triazine derivatives and/or pharmaceutically acceptable salts thereof. Furthermore, the present invention relates to the use of said disubstituted triazine derivatives as inhibitors for a protein kinase.

First claim

The invention claimed is:

1. A compound having the general formula (I)

wherein

R 1 is
L is a bond or —CR 5 R 6 —, —CR 5 R 6 —CR 7 R 8 —, —CR 5 R 6 —CR 7 R 8 —CR 9 R 10 —, —CR 5 R 6 —CR 7 R 8 —CR 9 R 10 —CR 11 R 12 —;
R 5 —R 12 represent independently of each other —H, —CH 3 , —C 2 H 5, —C 3 H 7 , —F, —CI, —Br, —I;
R 3 is selected from —H, —NO 2 , —CN, —Br, —I, —C 2 H 5 , —C 3 H 7 , —CH(CH 3 ) 2, —C 4 H 9 , —CH 2 —CH(CH 3 ) 2 , —CH(CH 3 )—C 2 H 5 , —CR 13 R 14 R 21 , —CR 13 R 14 —CR 15 R 16 R 21 , —CR 13 R 14 —CR 15 R 16 —CR 17 R 18 R 21 , —CR 13 R 14 —CR 15 R 16 —CR 17 R 18 —CR 19 R 20 R 21 , —SO 2 R 22 , —CONR 23 R 24 , —NR 25 SO 2 NR 23 R 24 , —NR 25 SO 2 R 22 , —NR 25 CONR 23 R 24 , —SO 2 NR 23 R 24 , —SO(NR 26 )R 22;
R 13 - R 21 and R 29 - R 32 represent independently of each other —H, —CH 3 , -C 2 H 5 , -C 3 H 7 , -C 4 H 9 , —F, —CI, —Br, —I;
R 22 and R 28 are independently selected from R 27 ′, —CR 13 R 14 R 21 , —CR 13 R 14 —CR 15 R 16 R 21 , —CR 13 R 14 —CR 15 R 16 —CR 17 R 18 —CR 19 R 20 —CR 29 R 30 R 21 , —CR 13 R 14 —CR 15 R 16 —CR 17 R 18 R 21 , —CR 13 R 14 —CR 15 R 16 —CR 17 R 18 —CR 19 R 20 R 21 , —CR 13 R 14 —CR 15 R 16 —CR 17 R 18 —CR 19 R 20 —CR 29 R 30 —CR 31 R 32 R 21 ,—CH 2 Ph; —CH 2 Ph the phenyl group of which may further be substituted by one, two, three, four or five substituents selected from the group consisting of —CH 3 , —C 2 H 5, —C 3 H 7 , —F, —CI, —Br and —I;
R 23 and R 24 are independently selected from —H, —CR 13 R 14 R 21 , —CR 13 R 14 —CR 15 R 16 R 21 , —CR 13 R 14 —CR 15 R 16 —CR 17 R 18 —CR 19 R 20 —CR 29 R 30 R 21 , —CR 13 R 14 —CR 15 R 16 —CR 17 R 18 R 21 , —CR 13 R 14 —CR 15 R 16 —CR 17 R 18 —CR 19 R 20 R 21 , —CR 13 R 14 —CR 15 R 16 —CR 17 R 18 —CR 19 R 20 —CR 29 R 30 —CR 31 R 32 R 21 , —CR 13 R 14 —CR 15 R 16 —O—R 33 , —CR 13 R 14 —CR 15 R 16 —CR 17 R 18 —O—R 33 , —CR 13 R 14 —CR 15 R 16 —NR 33 R 34 , —CR 13 R 14 —CR 15 R 16 —CR 17 R 18 —NR 33 R 34 , —CR 13 R 14 —CR 15 R 16 —CR 17 R 18 —CR 19 R 20 —NR 33 R 34 , —CR 13 R 14 —CR 15 R 16 —CR 17 R 18 —CR 19 R 20 —CR 29 R 30 —NR 33 R 34 , —Ph, —CH 2 PH, phenyl group which may further be substituted by one, two, three, four or five substituents selected from the group consisting of —CH 3 , —C 2 H 5 , —C 3 H 7 , —F, —CI, —Br and —I; —CH 2 Ph the phenyl group of which may further be substituted by one, two, three, four or five substituents selected from the group consisting of —CH 3 , —C 2 H 5, —C 3 H 7 , —F, —CI, —Br and —I; or both residues R 23 and R 24 together form with the nitrogen atom to which they are attached an azetidine, pyrrolidine, piperidine, piperazine, azepane, or morpholine ring;
R 25 is selected from —H, —CH 3 , —C 2 H 5 , —C 3 H 7 , —CH(CH 3 ) 2 , —C 4 H 9, —CH 2 —CH(CH 3 ) 2 , —CH(CH 3 )—C 2 H 5 or —C(CH 3 ) 3;
R 26 is —H, —CH 3 , —C 2 H 5 , —C 3 H 7 , —CH(CH 3 ) 2 , —C 4 H 9 , —CH 2 —CH(CH 3 ) 2, —CH(CH 3 )—C 2 H 5 , —C(CH 3 ) 3 , —C 5 H 11 , —CH(CH 3 )—C 3 H 7, —CH 2 —CH(CH 3 )—C 2 H 5 , —CH(CH 3 )—CH(CH 3 ) 2 , —C(CH 3 ) 2 —C 2 H 5, —CH 2 —C(CH 3 ) 3 , —CH(C 2 H 5 ) 2 , —C 2 H 4 —CH(CH 3 ) 2 , —C 6 H 13 , —C 3 H 6 —CH(CH 3 ) 2 , —C 2 H 4 —CH(CH 3 )—C 2 H 5 , —CH(CH 3 )—C 4 H 9, —CH 2 —CH(CH 3 )—C 3 H 7 , —CH(CH 3 )—CH 2 —CH(CH 3 ) 2, —CH(CH 3 )—CH(CH 3 )—C 2 H 5 , —CH 2 —CH(CH 3 )—CH(CH 3 ) 2 , —CH 2 —C(CH 3 ) 2 C 2 H 5 , —C(CH 3 ) 2 —C 3 H 7 , —C(CH 3 ) 2 —CH(CH 3 ) 2 , —C 2 H 4 —C(CH 3 ) 3 , —CH(CH 3 )—C(CH 3 ) 3 , —CR 13 R 14 R 21 , —COR 28, —CR 13 R 14 —CR 15 R 16 R 21 , —CR 13 R 14 —CR 15 R 16 —CR 17 R 18 —CR 19 R 20 —CR 29 R 30 R 21 , —CR 13 R 14 —CR 15 R 16 —CR 17 R 18 R 21 , —CR 13 R 14 —CR 15 R 16 —CR 17 R 18 —CR 19 R 20 R 21 , —CR 13 R 14 —CR 15 R 16 —CR 17 R 18 —CR 19 R 20 —CR 29 R 30 —CR 31 R 32 R 21 , —COOR 28 , —R 27;
R 27 , R 27′ and R 27″ are independently selected from

these C 3 —C 10 -cycloalkyl groups may further be substituted by one, two, three, four, five or more substituents selected from the group consisting of —F, —CI, —Br and —I;
R 33 and R 34 represent independently of each other —H, —CH 3 , —C 2 H 5, —C 3 H 7 , —C 4 H 9 , —CH 2 Ph, —COOC(CH 3 ) 3 , —COOCH 3 , —COOCH 2 CH 3, —COOCH 2 CH 2 CH 3 , —COOCH(CH 3 ) 2 , —COOCH 2 Ph, —COCH 3;
R 4 is selected from —H, —NO 2 , —CN, —F, —CI, —Br, —I, —CR 35 R 36 R 37 , —CR 35 R 36 —CR 38 R 39 —CR 40 R 41 —CR 42 R 43 R 37 , —O—CR 35 R 36 —CR 38 R 39 R 37 , —O—CR 35 R 36 —CR 38 R 39 —CR 40 R 41 R 37 , —CR 35 R 36 —CR 38 R 39 —CR 40 R 41 R 37 , —O—R 35 R 36 —CR 38 R 39 —CR 40 R 41 —CR 42 R 43 R 37 , —CR 35 R 36 —CR 38 R 39 R 37 , —O—CR 35 R 36 —CR 38 R 39 —CR 40 R 41 —CR 42 R 43 —CR 44 R 45 R 37 , —O—CR 35 R 36 R 37 , —O—CR 35 R 36 —CR 38 R 39 —CR 40 R 41 —CR 42 R 43 —CR 44 R 45 —CR 46 R 47 R 37 , —CR 35 R 36 —CR 38 R 39 —CR 40 R 41 —CR 42 R 43 —CR 44 R 45 R 37 —OCH 2 Ph, —R 27″ , —O—R 27″ , —CR 35 R 36 —CR 38 R 39 —CR 40 R 41 —CR 42 R 43 —CR 44 R 45 —CR 46 R 47 R 37 ,
R 35 —R 47 represent independently of each other —H, —CR 48R 49 R 50 , —CR 48 R 49 —CR 51 R 52 R 50 , —CR 48 R 49 —CR 51 R 52 —CR 53 R 54 R 50 , —CR 48 R 49 —CR 51 R 52 —CR 53 R 54 —CR 55 R 56 R 50 , —F, —CI, —Br, —I;
R 48 R 56 represent independently of each other —H, —F, —Cl, —Br, —I;
R 2 is selected from

B is a bond, —CH 2 , —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CF 2 —, CH 2 O—, —CH 2 OCH 2 —, —CH 2 CH 2 O—, CH 2 NH—, CH 2 N(CH 3 )—, CH 2 NHCH 2 , —CH 2 N(CH 3 )CH 2 —, CH 2 CH 2 NH—, CH 2 CH 2 N(CH 3 )—;
R 57 is —H, CH 3 , —CF 3 , —CHF 2 , —CH 2 F, —COOCH 3 , —COOCH 2 CH 3 , —COOH, —COOCH 2 Ph, —COOCH 2 CH 2 CH 3 , —COOCH(CH 3 ) 2, —COOCH 2 CH 2 CH 2 CH 3 , —COOCH(CH 3 )(CH 2 CH 3 ), —COOCH 2 CH(CH 3 ) 2 , —COOC(CH 3 ) 3 , —CONH 2 , —Ph, —CONH(CH 3 ), —CON(CH 3 ) 2 , —CN, —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —NH(CH 2 CH 3 ), —N(CH 3 )(CH 2 CH 3 ), —N(CH 2 CH 3 ) 2 , pyrrolidin—1—yl, piperidin—1—yl, azetidin—1—yl, morpholin—4—yl;
R 58 is —H, CH 3 , —F, —CI, —CF 3 , —CH 2 OCH 3;
R 59 is —H, CH 3 , —F, —CI, —CF 3 , —Ph—, CH 2 OCH 3; and
R 60 is —H, —CH 3 , —CF 3 , —COCH 3 , —COOCH 3 , —COOCH 2 CH 3, —COOC(CH 3 ) 3 , —COOCH 2 Ph;
Y is —O—, —SO—, —NH—, or —N(CH 3 )—;
R 61 is —H, CH 3 , —CF 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —COOCH 3 , —COCH 2 CH 3 , —COOH, —CONH 2 , —CN, CH 2 OCH 3 , —CH 2 OH, phenyl, —CH 2 Ph, CH 2 OPh, —CH 2 CH 2 Ph ;
R 62 and R 63 are independently selected from —H, —CH 3 , —CF 3 , —CH 2 CH 3, —CN, —F, —Cl, —Br, —OH, —NH 2 , —OCH 3 , —SCH 3 , —S 02 CH 3;
R 64 and R 65 are independently selected from —H—, CH 3 , —CF 3 , —CH 2 CH 3, —CN, —F, —Cl, —Br, —OH, —NH 2 , —OCH 3;
R 66 and R 67 are independently selected from —H—, CH 3 , —CF 3 , —CH 2 CH 3, —CN, —F, —Cl, —Br;
R 68 is selected from —H, —CH 3 , —CF 3 , —CH 2 CH 3 , —CN, —F, —Cl, —Br, —COOH, —COOCH 3 , —COOCH 2 CH 3 , —CONH 2 , —OH, —OCH 3 , —NH 2;
R 69 is selected from —H, —CH 3 , —CH 2 CH 3;
R 70 and R 71 are independently selected from —H, —CH 3 , —CF 3 , —CH 2 CH 3 , —CN, —F, —Cl, —Br, —COOH, —COOCH 3 , —COOCH 2 CH 3 , —CONH 2 , —NH 2; and
R 72 is selected from —H, —CH 3 , —CF 3 , —CH 2 CH 3;
or a stereoisomer or mixture thereof, a solvate, a tau

Assignees

• Rühter Gerd
• Koch Uwe
• Nussbaumer Peter
• Schulz-Fademrecht Carsten
• Eickhoff Jan
• Bayer Ip Gmbh

Inventors

• Rühter Gerd
• Koch Uwe
• Nussbaumer Peter
• Schulz-Fademrecht Carsten
• Eickhoff Jan

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title