Substituted benzimidazoles

Details Substituted benzimidazoles Substituted benzimidazoles

2000-06-22

2002-03-19

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S211080, C514S211150, C514S217030, C514S227800, C514S233500, C514S252060, C514S254060, C514S256000, C514S314000, C514S394000, C540S553000, C540S603000, C544S060000, C544S132000, C544S238000, C544S333000, C544S366000, C546S199000, C546S152000, C548S304700

Reexamination Certificate

active

06358978

ABSTRACT:

The invention relates to novel substituted benzimidazoles, a process for their preparation, and use thereof as pharmaceuticals.
The application WO 94/12478 describes, inter alia, benzimidazole derivatives that inhibit blood platelet aggregation.
NF&kgr;B is a heterodimeric transcription factor that can activate a large number of genes that code, inter alia, for proinflammatory cytokines such as IL-1, IL-2, TNF&agr;, or IL-6. NF&kgr;B is present in the cytosol of cells, complexed with its naturally occurring inhibitor I&kgr;B. The stimulation of cells, for example, by cytokines, leads to the phosphorylation and subsequent proteolytic degradation of I&kgr;B. This proteolytic degradation leads to the activation of NF&kgr;B, 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, NF&kgr;B is activated beyond the normal extent. The inhibition of NF&kgr;B is also of benefit in cancer therapy, since it is employed there for the reinforcement of the cytostatic therapy. It was possible to show 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 NF&kgr;B-activating signal chain or interfere directly with the transcription of the genes.
The first step in the signal cascade mentioned is the degradation of I&kgr;B. This phosphorylation is regulated by the specific I&kgr;B kinase. To date, no inhibitors are known which specifically inhibit I&kgr;B 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, it has now been found that the benzimidazoles according to the invention are strong and very specific inhibitors of I&kgr;B kinase.
The invention therefore relates to compounds of formula I
or a stereoisomeric form of the compound of formula I or a physiologically tolerable salt of the compound of formula I, where one of the substituents R
1
, R
2
, R
3
, and R
4
is a radical of formula II
in which:
D is —C(O)—, —S(O)—, or —S(O)
2
—;
R
8
is hydrogen or (C
1
-C
4
)-alkyl;
R
9
is
(1) a characteristic radical of an amino acid;
(2) aryl, in which aryl is unsubstituted or substituted;
(3) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted;
(4) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted;
(5) (C
1
-C
6
)-alkyl, in which alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by
(5)(1) aryl, in which aryl is unsubstituted or substituted;
(5)(2) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted;
(5)(3) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted;
(5)(4) —O—R
11
;
(5)(5) ═O;
(5)(6) halogen;
(5)(7) —CN;
(5)(8) —CF
3
;
(5)(9) —S(O)
x
—R
11
, in which x is the integer 0, 1, or 2;
(5)(10) —C(O)—O—R
11
;
(5)(11) —C(O)—N(R
11
)
2
;
(5)(12) —N(R
11
)
2
;
(5)(13) (C
3
-C
6
)-cycloalkyl;
(5)(14) a radical of formula
 or
(5)(15) a radical of formula
 in which
R
11
is
(a) hydrogen;
(b) (C
1
-C
6
)-alkyl, in which alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by
 (1) aryl, in which aryl is unsubstituted or substituted;
 (2) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted;
 (3) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted;
 (4) halogen;
 (5) —N—(C
1
-C
6
)
n
-alkyl, in which n is the integer 0, 1, or 2, and alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by halogen or by —COOH;
 (6) —O—(C
1
-C
6
)-alkyl; or
 (7) —COOH;
(c) aryl, in which aryl is unsubstituted or substituted;
(d) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted; or
(e) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted; and
in the case of (R
11
)
2
, R
11
independently of one another has the meaning of (a) to (e);
Z is
(1) aryl, in which aryl is unsubstituted or substituted;
(2) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted;
(3) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted;
(4) —(C
1
-C
6
)-alkyl, in which alkyl is substituted or unsubstituted independently of one another by
(4)(1) aryl, in which aryl is unsubstituted or substituted;
(4)(2) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted;
(4)(3) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted;
(4)(4) halogen;
(4)(5) —N—(C
1
-C
6
)
n
-alkyl, in which n is the integer 0, 1, or 2, and alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by halogen or by —COOH;
(4)(6) —O—(C
1
-C
6
)-alkyl; or
(4)(7) —COOH; or
(5) —C(O)—R
10
, in which
R
10
is
(1) —O—R
11
; or
(2) —N(R
11
)
2
;
in which R
11
is as defined above; or
R
8
and R
9
, together with the nitrogen and carbon to which they are each bonded, form a heterocyclic ring of formula IIa
 in which:
D, Z, and R
10
are as defined in formula II;
A is nitrogen or —CH
2
—;
B is oxygen, sulfur, nitrogen, or —CH
2
—;
X is oxygen, sulfur, nitrogen, or —CH
2
—;
Y is absent or is oxygen, sulfur, nitrogen, or —CH
2
—; or
X and Y together form a phenyl, 1,2-diazine, 1,3-diazine, or a 1,4-diazine radical;
where the ring system formed by N, A, X, Y, B, and the carbon contains no more than one oxygen; X is not oxygen, sulfur, or nitrogen if A is nitrogen; contains no more than one sulfur; contains 1, 2, 3, or 4 nitrogens; and where oxygen and sulfur do not occur at the same time;
where the ring system formed by N, A, X, Y, B, and the carbon is unsubstituted or mono-, di-, or trisubstituted independently of one another by (C
1
-C
8
)-alkyl, in which alkyl is straight-chain or branched and is unsubstituted or mono- or disubstituted by
(1)(1) —OH;
(1)(2) (C
1
-C
8
)-alkoxy, in which alkoxy is straight-chain or branched;
(1)(3) halogen;
(1)(4) —NO
2
;
(1)(5) —NH
2
;
(1)(6) —CF
3
;
(1)(7) —OH;
(1)(8) methylenedioxy;
(1)(9) —C(O)—CH
3
;
(1)(10) —CH(O);
(1)(11) —CN;
(1)(12) —COOH;
(1)(13) —C(O)—NH
2
;
(1)(14) (C
1
-C
4
)-alkoxycarbonyl, in which alkoxycarbonyl is straight-chain or branched;
(1)(15) phenyl;
(1)(16) phenoxy;
(1)(17) benzyl;
(1)(18) benzyloxy; or
(1)(19) tetrazolyl; or
R
9
and Z together with the carbons to which they each are bonded form a heterocyclic ring of formula IIc
 in which:
D, R
8
, and R
11
are as defined in formula II;
T is oxygen, sulfur, nitrogen, or —CH
2
—;
W is oxygen, sulfur, nitrogen, or —CH
2
—;
V is absent or is oxygen, sulfur, nitrogen, or —CH
2
—; or
T and V together form a phenyl, 1,2-diazine, 1,3-diazine, or a 1,4-diazine radical; or
V and W together form a phenyl, 1,2-diazine, 1,3-diazine, or a 1,4-diazine radical;
where the ring system formed by N, T, V, W, and the two carbons contains no more than one oxygen, no more than one sulfur, and 1, 2, 3, or 4 nitrogen; where oxygen and sulfur do not occur at the same time; and where the ring system formed by N, T, V, W, and the two carbons is unsubstituted or mono-, di-, or trisubstituted independently of one another by the substituents defined above under (1)(1) to (1)(19); and
the other substituents R
1
, R
2
, R
3
, and R
4
are chosen independently of one another, and are
(1) hydrogen;
(2) halogen;
(3) (C
1
-C
4
)-alkyl;
(4) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted;
(5) a heteroc

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