Substituted beta carbolines

Details Substituted beta carbolines Substituted beta carbolines

2001-03-15

2003-09-30

Davis, Zinna Northington (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C544S126000, C546S081000, C514S232800

Reexamination Certificate

active

06627637

ABSTRACT:

This application claims benefit of priority to EP Application no. 00105514.4, filed Mar. 15, 2000, and EP Application no. 00125169.3, filed Nov. 18, 2000, both of which are incorporated herein by reference.
The present invention relates to novel substituted beta-carbolines, a process for their preparation and use thereof as pharmaceuticals.
Art related to the present invention includes U.S. Pat. Nos. 4,631,149 and 5,604,236. U.S. Pat. No. 4,631,149 discloses beta-carbolines useful as antiviral, antibacterial and antitumor agents. U.S. Pat. No. 5,604,236 discloses beta-carboline derivatives containing an acidic group, useful as thromboxane syntheses inhibitors.
NFkB is a heterodimeric transcription factor which can activate a large number of genes which code, inter alia, for proinflammatory cytokines such as IL-1, IL-2, TNF&agr; or IL-6. NFkB is present in the cytosol of cells, building a complex with its naturally occurring inhibitor IkB. The stimulation of cells, for example by cytokines, leads to the phosphorylation and subsequent proteolytic degradation of IkB. This proteolytic degradation leads to the activation of NFkB, which subsequently migrates into the nucleus of the cell and there activates a large number of proinflammatory genes.
In disorders such as rheumatoid arthritis (in the case of inflammation), osteoarthritis, asthma, cardiac infarct, Alzheimer's disease or atherosclerosis, NFkB is activated beyond the normal extent. Inhibition of NFkB is also of benefit in cancer therapy, since it is employed there for the reinforcement of the cytostatic therapy. It has been shown that pharmaceuticals such as glucocorticoids, salicylates or gold salts, which are employed in rheumatic therapy, intervene in an inhibitory manner at various points in the NFkB-activating signal chain or interfere directly with the transcription of the genes.
The first step in the signal cascade mentioned is the degradation of IkB. This phosphorylation is regulated by the specific IkB kinase. To date, no inhibitors are known which specifically inhibit IkB kinase.
In the attempt to obtain active compounds for the treatment of rheumatoid arthritis (in the case of inflammation), osteoarthritis, asthma, cardiac infarct, Alzheimer's disease, carcinomatous disorders (potentiation of cytotoxic therapies) or atherosclerosis, the inventors have surprisingly discovered that the benzimidazoles of the present invention are strong and very specific inhibitors of IkB kinase.
The invention therefore relates to the compounds of the formula I
and/or a stereoisomeric form of the compounds of the formula I and/or a physiologically tolerable salt of the compounds of the formula I, where B
6
, B
7
, B
8
and B
9
are independently selected from the group consisting of carbon atom and nitrogen atom, where B
6
, B
7
, B
8
and B
9
together comprise no more than two nitrogen atoms; wherein
in case a)
the substituents R
1
, R
2
and R
3
may be independently chosen from:
1.1. hydrogen atom,
1.2. halogen,
1.3. —CN,
1.4. —COOH,
1.5. —NO
2
,
1.6. —NH
2
,
1.7. —O—(C
1
-C
10
)-alkyl, wherein alkyl is unsubstituted or mono- to penta-substituted by substituents independently chosen from:
1.7.1 phenyl, which is unsubstituted or mono- to penta-substituted by substituents independently chosen from halogen or —O—(C
1
-C
4
)-alkyl,
1.7.2 halogen,
1.7.3 —NH
2
,
1.7.4 —OH,
1.7.5 —COOR
16
, wherein R
16
is hydrogen atom or —(C
1
-C
10
)-alkyl,
1.7.6 —NO
2
,
1.7.7 —S(O)
y
—R
14
, wherein y is zero, 1 or 2, R
14
is —(C
1
-C
10
)-alkyl, phenyl, which phenyl is unsubstituted or mono- to penta-substituted by substituents independently chosen from those defined under 1.7.1 to 1.7.11, amino or —N(R
13
)
2
, wherein R
13
is independently of one another chosen from hydrogen atom, phenyl, —(C
1
-C
10
)-alkyl, —C(O)—(C
1
-C
7
)-alkyl, —C(O)-phenyl, —C(O)—NH—(C
1
-C
7
)-alkyl, —C(O)—O-phenyl, —C(O)—NH-phenyl, —C(O)—O—(C
1
-C
7
)-alkyl,
—S(O)
y
—R
14
, wherein R
14
and y are as defined above,
and wherein the R
13
alkyl or phenyl groups in each case are unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11, or
R
13
together with the nitrogen atom to which it is bonded may be independently chosen to form a heterocycle having 5 to 7 ring atoms,
1.7.8 —O-phenyl, wherein phenyl is unsubstituted or mono- to penta-substituted independently of one another as defined under 1.7.1 to 1.7.11,
1.7.9 a radical selected from pyrrolidine, tetrahydropyridine, piperidine, piperazine, imidazoline, pyrazolidine, furan, morpholine, pyridine, pyridazine, pyrazine, oxolan, imidazoline, isoxazolidine, 2-isoxazoline, isothiazolidine, 2-isothiazoline, thiophene or thiomorpholine,
1.7.10 —(C
3
-C
7
)-cycloalkyl or
1.7.11 ═O,
1.8. —N(R
13
)
2
, wherein R
13
is as defined in 1.7.7 above,
1.9. —NH—C(O)—R
15
, wherein R
15
is
1.9.1 a radical selected from pyrrolidine, tetrahydropyridine, piperidine, piperazine, imidazoline, pyrazolidine, furan, morpholine, pyridine, pyridazine, pyrazine, oxolan, imidazoline, isoxazolidine, 2-isoxazoline, isothiazolidine, 2-isothiazoline, thiophene or thiomorpholine,
wherein said radical is unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11 above, by —CF
3
, by benzyl or by —(C
1
-C
10
)-alkyl, wherein the —(C
1
-C
10
)-alkyl is mono to tri-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11 above,
1.9.2 —(C
1
-C
10
)-alkyl, wherein alkyl is unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11 above or by —O—(C
1
-C
10
)-alkyl, wherein alkyl is unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11 above,
1.9.3 —(C
3
-C
7
)-cycloalkyl,
1.9.4 —N(R
13
)
2
, wherein R
13
is as defined in 1.7.7 above, or
1.9.5 phenyl, wherein phenyl is unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11 above, by —O—(C
1
-C
10
)-alkyl, by —CN, by —CF
3
, by —(C
1
-C
10
)-alkyl, wherein alkyl is mono to tri-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11 above, or by two substituents of said phenyl which form a dioxolan ring,
1.10. —S(O)
y
—R
14
, wherein R
14
and y are as defined in 1.7.7 above,
1.11. —C(O)—R
12
, wherein R
12
is phenyl or —(C
1
-C
7
)-alkyl, wherein alkyl or phenyl are unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under
1.7.1 to 1.7.11 above,
1.12. —C(O)—O—R
12
, wherein R
12
is as defined in 1.11. above,
1.13. —(C
1
-C
10
)-alkyl, wherein alkyl is unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11 above,
1.14. —O—(C
1
-C
6
)-alkyl-O—(C
1
-C
6
)-alkyl,
1.15. —O—(C
0
-C
4
)-alkyl-(C
3
-C
7
)-cycloalkyl,
1.16. —(C
1
-C
4
)-alkyl-N(R
13
)
2
, wherein R
13
is as defined in 1.7.7 above
1.17. —CF
3
or
1.18. —CF
2
—CF
3
,
R
4
is 1. —(C
1
-C
10
)-alkyl, wherein alkyl is mono- to penta-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11 above,
2. —CF
3
,
3. —CF
2
—CF
3
,
4. —CN,
5. —S(O)
y
—R
14
, wherein R
14
and y are as defined in 1.7.7 above,
6. —NH
2
,
7. —O—(C
1
-C
10
)-alkyl, wherein alkyl is mono- to penta-substituted by substituents independently chosen from
7.1 phenyl, which is unsubstituted or mono- to penta-substituted by substituents independently chosen from halogen or —O—(C
1
-C
4
)-alkyl,
7.2 halogen,
7.3 —NH
2
,
7.4 —OH,
7.5 —COOR
16
, wherein R
16
is hydrogen atom or-(C
1
-C
10
)-alkyl,
7.6 —NO
2
,
7.7 —S(O)—R
14
, wherein y is zero, 1 or 2, R
14
is —(C
1
-C
10
)-alkyl, phenyl, which phenyl is unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11, amino or —N(R
13
)
2
,
wherein R
13
is independently of one another chosen from hyd

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