Imidazopyridine derivatives

Details Imidazopyridine derivatives Imidazopyridine derivatives

2001-04-26

2002-06-11

Dentz, Bernard (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S300000, C514S303000, C544S236000, C546S119000, C546S120000, C546S121000

Reexamination Certificate

active

06403588

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to imidazolidine derivatives which are useful as medicaments, more particularly as phosphatidylinositol-3-kinase (PI3K) inhibitors and antitumor agents.
BACKGROUND OF THE INVENTION
Phosphatidylinositol (hereinafter abbreviated as “PI”) is one of a number of phospholipids found in cell membranes. In recent years it has become clear that PI plays an important role in intracellular signal transduction. It is well recognized in the art that especially PI (4,5) bisphosphate (PI(4,5)P2) is degraded into diacylglycerol and inositol (1,4,5) triphosphate by phospholipase C to induce activation of protein kinase C and intracellular calcium mobilization, respectively [M. J. Berridge et al., Nature, 312, 315 (1984); Y Nishizuka, Science, 225, 1365 (1984)].
Turning back to the late 1980s, a PI3 kinase (PI3K) was found to be an enzyme to phosphorylate the 3-position of the inositol ring of phosphatidylinositol [D. Whitrnan et al., Nature, 332, 664 (1988)].
PI3K was originally considered to be a single enzyme at the time when PI3K was discovered. Recently it was clarified that a plurality of subtypes are present in the PI3K. Three major classes of PI3Ks have now been identified on the basis of their in vitro substrate specificity [B. Vanhaesebroeck, Trend in Biol. Sci., 22, 267(1997)].
Substrates for class I PI3Ks are PI, PI(4)P and PI(4,5)P2. In these substrates, PI(4,5)P2 is the most advantageous substrate in cells. Class I PI3Ks are further divided into two groups, class Ia and class Ib, in terms of their activation mechanism. Class Ia PI3Ks, which include PI3K p110&agr;, p110&bgr; and p110&dgr; subtypes, are activated in the tyrosine kinase system. Class Ib PI3K includes a p110&ggr; subtype activated by a G protein-coupled receptor.
PI and PI(4)P are known as substrates for class II PI3Ks but PI(4,5)P2 is not a substrate for the enzymes of this class. Class II PI3Ks include PI3K C2&agr;, C2&bgr; and C2&ggr; subtypes, which are characterized by containing C2 domains at the C terminus, implying that their activity will be regulated by calcium ions. The substrate for class III PI3Ks is PI only. A mechanism for activation of the class III PI3Ks is not clarified yet. Since each subtype has its own mechanism for regulating activity, it is considered that the respective subtypes will be activated depending on their respective stimuli specific to each of them.
In the PI3K subtypes, the class la subtype has been most extensively investigated to date. The three subtypes of class la are hetero dimers of a catalytic 110 kDa subunit and regulatory subunits of 85 kDa and 55 kDa. The regulatory subunits contain SH2 domains and bind to tyrosine residues phosphorylated by growth factor receptors with a tyrosine kinase activity or oncogene products thereby inducing the PI3K activity of the p110 catalytic subunit. Thus, the class Ia subtypes are considered to be associated with cell proliferation and carcinogenesis. Furthermore, the class Ia PI3K subtypes bind to activated ras oncogene to express their enzyme activity. It has been confirmed that the activated ras oncogene is found to be present in many cancers, suggesting a role of class Ia PI3Ks in carcinogenesis.
As explained above, the PI3K inhibitors are expected to be a new type of medicaments useful for cell proliferation disorders, in particular antitumor agents. As the PI3K inhibitor, wortnannin[H. Yano et al., J. Biol. Chem., 263, 16178 (1993)] and Y294002 [J. Vlahos et al., J. Biol. Chem., 269, 5241(1994)] which is represented by the formula below are known. However, creation of PI3K inhibitors are sincerely desired having a more potent and excellent cancer cell growth inhibiting activity.
Japanese patent KOKAI (Laid-Open) No. H09-176165 discloses imidazopyridine derivatives having an ACAT inhibitory activity. WO93/25553 discloses imidazopyridine derivatives having an activity to treat atherosclerosis or hypercholesterolemia. U.S. Pat. No. 4,713,381 discloses imidazopyridine derivatives as reaction intermediates. However, all of these have a different structure from those of the compounds of the present invention. Further, these references do not disclose or imply a PI3K inhibiting and antitumor activity.
Hungarian patent publication No. HU 43066A2 and Eur. J. Med. Chem. (1989), 24(1), 97-9 discloses imidazopyridine derivatives substituted by a substitited-amino-substituted-1,3,5-triazinyl group having a cardiotonic activity. Arch. Pharm. (Weinheim, Ger.) (1992), 325(9), 623-4 discloses imidazopyridine derivatives substituted by a substitited-amino-substituted-1,3,4-oxadiazolyl which are useful as anticonvulsants. Moreover, the Maybridge catalogue (order No. SPB-04848) discloses imidazopyridine derivatives substituted by an alkylthio-substituted-pyrimidinyl group.
SUMMARY OF THE INVENTION
The present inventors have performed extensive investigations on compounds with a PI3K inhibiting activity. As a result, it has been discovered that novel imidazopyridine derivatives have an excellent PI3K inhibiting activity and cancer cell growth inhibiting activity. Based on the discovery, it has been found that the imidazopyridine derivatives could be excellent PI3K inhibitors and cancinostatic agents. The present invention has thus been achieved.
Therefore, the present invention relates to novel imidazopyridine derivatives or salts thereof which are useful as PI3K inhibitors and antitumor agents. The imidazopyridine derivatives are represented by the following general formula (I):
wherein R
1
represents —H, -a lower alkyl, -a lower alkenyl, -a lower alkynyl, -a cycloalkyl, -a cycloalkenyl, -a halogen, —NO
2
, —CN, -a halogenated lower alkyl, —OR
a
, —SR
a
, —SO
2
R
a
, —SOR
a
, —CO
2
R
a
, —CO—R
a
, -an aryl, -a lower alkylene-an aryl, —O-a lower alkylene-an aryl, —CONR
a
R
b
, —CO-(a nitrogen-containing saturated heterocyclic group which may be substituted by a lower alkyl group), —SO
2
NR
a
R
b
, —SO
2
-(a nitrogen-containing saturated heterocyclic group which may be substituted by a lower alkyl group), —SO
3
H, -(a nitrogen-containing saturated heterocyclic group which may be substituted by a lower alkyl group), —NR
a
R
b
, —CONR
a
-a lower alkylene-OR
b
, —CONR
a
-a lower alkylene-NR
b
R
c
, —CONR
a
-a lower alkylene-(a nitrogen-containing saturated heterocyclic group which may be substituted by a lower alkyl group), —O-a lower alkylene-OR
a
, —O-a lower alkylene-O-a lower alkylene-O
a
, —O-a lower alkylene-NR
a
R
b
, —O-a lower alkylene-(a nitrogen-containing saturated heterocyclic group which may be substituted by a lower alkyl group), —O-a lower alkylene-O-a lower alkylene-NR
a
R
b
, —O-a lower alkylene-O-a lower alkylene-(a nitrogen-containing saturated heterocyclic group which may be substituted by a lower alkyl group), —O-a lower alkylene-NR
c
-a lower alkylene-NR
a
R
b
, —O-a lower alkylene-NR
c
-a lower alkylene-(a nitrogen-containing saturated heterocyclic group which may be substituted by a lower alkyl group), —OCO—NR
a
R
b
, —OCO-(a nitrogen-containing saturated heterocyclic group which may be substituted by a lower alkyl group), —NR
a
—SO
2
R
b
, —NR
c
-a lower alkylene-NR
a
R
b
, —NR
c
-a lower alkylene-(a nitrogen-containing saturated heterocyclic group which may be substituted by a lower alkyl group), —N(a lower alkylene-NR
a
R
b
)
2
, —N(a lower alkylene-(a nitrogen-containing saturated heterocyclic group which may be substituted by a lower alkyl group))
2
, —CONR
a
—OR
b
, —NR
a
—COR
b
, —NR
a
CO—NR
b
R
c
, —NR
a
—CO-(a nitrogen-containing saturated heterocyclic group which may be substituted by a lower alkyl group), or —OCOR
a
;
R
a
, R
b
and R
c
which may be the same or different, represent —H, -a lower alkyl or -an aryl;
T represents N or CR
1a
;
U represents N or CR
3
;
n represents an integer, 1, 2 or 3;
in Y . . . Y
2
. . . Y
3
,
i) . . . represents a single bond on one side and a single or double bond on the other side, Y
1
represents CR
5
or CR
5a
R
5b
, Y
2
represents N, NH, CR
4a
or CR
4b
R
4c
, and Y
3
represents

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