Anti-cancer compounds

Details Anti-cancer compounds Anti-cancer compounds

2001-03-29

2003-03-11

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...

C514S365000, C544S330000, C544S331000, C548S146000, C548S202000, C548S203000, C548S205000

Reexamination Certificate

active

06531479

ABSTRACT:

The present invention relates to 2-substituted 4-heteroaryl-pyrimidines, their preparation, pharmaceutical compositions containing them, and their use in the treatment of proliferative disorders such as cancer, leukemia, psoriasis and the like.
BACKGROUND TO THE INVENTION
Certain 4,5,6-substituted-N-(substituted-phenyl)-2-pyrimidineamines having anti-asthmatic properties are disclosed in EP-A-233,461. Certain 4-heteroaryl-N-(3-substituted-phenyl)-2-pyridineamines possessing anti-proliferative properties and inhibiting protein kinases C, epidermal growth factor receptor-associated tyrosine protein kinase (EGF-R-TPK), as well as CDK1/cyclin B have been disclosed in WO95/09847 wherein the exemplified heteroaryl are pyridyl and indolyl.
J. Med. Chem. (1993) Vol. 36, pages 2716-2725, Paul, R. et al: discloses a further class of phenyl amino-pyrimidines possessing anti-inflammatory activity. These compounds include mono-substituted 2-thienyl groups at the 4-position of the pyrimidine ring and dimethyl-3-furyl groups at this position.
It is an aim of the present invention to provide a further class of N-phenyl-2-pyrimidine anti-proliferative compounds. The compounds of the present invention have surprisingly been found to not to be inhibitors of protein kinase C. As discussed hereinafter, their activity may be demonstrated by inhibition of cell proliferation in cell lines and/or inhibition of cyclin dependent kinase enzymes. Throughout the specification, the term “thienyl” is used interchangeably with “thiophene”
SUMMARY OF THE INVENTION
The first aspect of the present invention relates to compounds of general formula I:
wherein:
X
1
is CH and X
2
is S; or
one of X
1
and X
2
is S, and the other of X
1
and X
2
is N;
Z is NH, NHCO, NHSO
2
, NHCH
2
, CH
2
, CH
2
CH
2
, or CH═CH;
R
1
, R
2
, and R
3
are independently H, alkyl, aryl, aralkyl, heterocycle, halogeno, NO
2
, CN, OH, alkoxy, aryloxy, NH
2
, NH—R′, N—(R′)(R″), NH—COR′, NH-aryl, N-(aryl)
2
, COOH, COO—R′, COO-aryl, CONH
2
, CONH—R′, CON—(R′)(R″), CONH-aryl, CON-(aryl)
2
, SO
3
H, SO
2
NH
2
, CF
3
, CO—R′, or CO-aryl, wherein alkyl, aryl, aralkyl, heterocycle and NH-aryl groups may be further substituted with one or more groups selected from halogeno, NO
2
, CN, OH, O-methyl, NH
2
, COOH, CONH
2
and CF
3
; at least one of the groups R
1
and R
2
being other than H when either X
1
or X
2
is S;
R
4
, R
5
, R
6
, R
7
, and R
8
are independently from each other H, substituted or unsubstituted lower alkyl, halogeno, NO
2
, CN, OH, substituted or unsubstituted alkoxy, NH
2
, NH—R′, alkyl-aryl, alkyl-heteroaryl, NH(C═NH)NH
2
, N(R′)
3
+
, N—(R′)(R″), COOH, COO—R′, CONH
2
, CONH—R′, CON-(R′)(R″), SO
3
H, SO
2
NH
2
, CF
3
or (CH
2
)
n
O(CH
2
)
m
NR′R″, (CH
2
)
n
CO
2
(CH
2
)
m
OR′″ wherein n is 0, 1, 2 or 3 and m is 1, 2 or 3;
wherein R′, R″ and R″′ are each independently alkyl groups that may be the same or different;
and pharmaceutically acceptable salts thereof.


REFERENCES:
patent: 5516775 (1996-05-01), Zimmermann et al.
patent: 6107301 (2000-08-01), Aldrich et al.
patent: 164 204 (1985-12-01), None
patent: 233 461 (1987-08-01), None
patent: 739 341 (1996-10-01), None
patent: WO 95/09847 (1995-04-01), None
patent: WO 95/09852 (1995-04-01), None
patent: WO 95/19358 (1995-07-01), None
patent: WO 97/19065 (1997-05-01), None
patent: WO 00/12485 (2000-03-01), None
Zimmerman er al;Phenyl-pytimidine(PAP) derivatives . . . protein kinase C(PKC);Arch Pharm.329/7,371(1996).*
Zimmermann et al;Phenylamino-pyrimidine(PAP) derivative . . . protein kinase C (PKC);Arch.Pharm.329/7,371(1996).*
Paul, R. et al., “Preparation of substituted N-phenyl-4-aryl-2-pyrimidinamines as mediator release inhibitors,”J. Med. Chem.Sep. 17, 1993;36(19):2716-25.
Zimmermann, J. et al., “Phenylamino-pyrimidine (PAP) derivatives: a new class of potent and selective inhibitors of protein kinase C (PKC),”Arch. Pharm.(Weinheim). Jul. 1996;329(7):371-6.

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