Pharmaceutically active disubstituted pyridine derivatives

Patent metadata

Field	Value
Publication number	US-9242937-B2
Application number	US-201214002731-A
Country	US
Kind code	B2
Filing date	Mar 1, 2012
Priority date	Mar 2, 2011
Publication date	Jan 26, 2016
Grant date	Jan 26, 2016

Abstract

The present invention relates to disubstituted pyridine 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 pyridine derivatives and/or pharmaceutically acceptable salts thereof. Furthermore, the present invention relates to the use of said disubstituted pyridine derivatives as inhibitors for a protein kinase.

First claim

The invention claimed is:

1. Compounds having the general formula (III)

wherein
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, —Cl, —Br, —I;
R 3 is selected from —H, —NO 2 , —NH 2 , —CN, —F, —Cl, —Br, —I, —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 , —O—CH 3 , —O—C 2 H 5 , —O—C 3 H 7 , —O—CH(CH 3 ) 2 , —O—C 4 H 9 , —O—CH 2 —CH(CH 3 ) 2 , —O—CH(CH 3 )—C 2 H 5 , —O—C(CH 3 ) 3 , —CR 13 R 14 R 21 , —CR 13 R 14 —CR 15 R 16 R 21 , —O—CR 13 R 14 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 , —O—CR 13 R 14 —CR 15 R 16 R 21 , —O—CR 13 R 14 —CR 15 R 16 —CR 17 R 18 R 21 , —SO 2 R 22 , —CONR 23 R 24 , —NR 25 COR 22 , —O—CR 13 R 14 —CR 15 R 16 —CR 17 R 18 —CR 19 R 20 R 21 , —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 , —NR 23 R 24 ;
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, —Cl, —Br, —I;
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 18 —CR 17 R 18 —CR 19 R 20 —CR 29 R 30 —CR 31 R 32 R 21 , —COOR 28 , —R 27 ;
R 22 , and R 28 are independently selected from —R 27′ , —CR 13 R 14 R 21 , —CH 3 , —C 2 H 5 , —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 , —C 3 H 7 , —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, —Cl, —Br and —I;
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, —Cl, —Br and —I;
R 23 , R 24 , R 77 and R 78 are independently of each other selected from —H, —CH 3 , —C 2 H 5 , —CR 13 R 14 R 21 , —C 3 H 7 , —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 —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 —O—R 33 , —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, —Cl, —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, —Cl, —Br and —I; or
both residues R 23 and R 24 together form with the nitrogen atom to which they are attached a azetidine, pyrrolidine, piperidine, piperazine, azepane, or morpholine ring;
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 ;
and 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 4 is selected from —H, —NO 2 , —CN, —F, —Cl, —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—CR 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 , —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 , —OCH 2 Ph, —R 27″ , —O—R 27″ ;
R 35 —R 47 and R 62 —R 74 represent independently of each other —H, —CR 48 R 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, —Cl, —Br, —I;
R 48 —R 56 represent independently of each other —H, —F, —Cl, —Br, —I;
R 4 together with R 22 or R 23 or R 24 or R 25 may form a group —CH 2 CH 2 — or —CH 2 CH 2 CH 2 — if R 4 is attached ortho to -L-R 3 ;
R 2 is

R 57 is selected from —H, —OH, —NO 2 , —CN, —F, —Cl, —Br, —I, —NR 60 R 61 , -D-R 64 , -D-NR 60 R 61 , —O-D-R 64 , —CHO, —CH 2 OH, —CO—R 60 , —CH 2 OR 60 ;
D, D′ and D″ represent independently of each other —CR 62 R 63 —, —CR 62 R 63 —CR 65 R 66 —, —CR 62 R 63 —CR 65 R 66 —CR 67 R 68 —, —CR 62 R 63 —CR 65 R 66 —CR 67 R 68 —CR 69 R 70 —;
R 60 , R 61 , R 75 and R 76 represent independently of each other —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 , -(cyclo-C 3 H 5 );
x is 0, 1, 2 or 3;
B is —OCH 3 , —OC 2 H 5 , —OC 3 H 7 , —O-cyclo-C 3 H 5 , —OCH(CH 3 ) 2 , —OC(CH 3 ) 3 , —OC 4 H 9 ;

and enantiomers, stereoisomeric forms, mixtures of enantiomers, diastereomers, mixtures of diastereomers, acid salt forms, tautomers, and racemates of the above mentioned compounds and pharmaceutically acceptable salts thereof.

2. Compounds according to claim 1 , wherein the substituent-L-R 3 represents —NO 2 , —NH 2 , —SO 2 R 22 , —CONR 23 R 24 , —NR 25 COR 22 , —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 , —NR 23 R 24 , —CH 2 —NO 2 , —CH 2 —NH 2 , —CH 2 —SO 2 R 22 , —CH 2 —CONR 23 R 24 , —CH 2 —NR 25 COR 22 , —CH 2 —NR 25 SO 2 NR 23 R 24 , —CH 2 —NR 25 SO 2 R 22 , —CH 2 —NR 25 CONR 23 R 24 , —CH 2 —SO 2 NR 23 R 24 , —CH 2 —SO(NR 26 )R 22 , —CH 2 —NR 23 R 24 , —CH 2 CH 2 —NO 2 , —CH 2 CH 2 —NH 2 ,

Assignees

• Rühter Gerd
• Nussbaumer Peter
• Choidas Axel
• Schulz-Fademrecht Carsten
• Klebl Bert
• Eickhoff Jan
• Bayer Ip Gmbh
• Lead Discovery Center Gmbh

Inventors

• Rühter Gerd
• Nussbaumer Peter
• Choidas Axel
• Schulz-Fademrecht Carsten
• Klebl Bert
• Eickhoff Jan

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P37/06

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

• A61P35/00

  Antineoplastic agents · CPC title