Fused bicyclic pyrimidine derivatives

Details Fused bicyclic pyrimidine derivatives Fused bicyclic pyrimidine derivatives

1999-05-19

2002-07-02

Ramsuer, Robert W. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C544S117000, C544S279000, C544S280000

Reexamination Certificate

active

06413971

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to novel bicyclic pyrimidine derivatives that are useful in the treatment of hyperproliferative diseases, such as cancers, in mammals. This invention also relates to a method of using such compounds in the treatment of hyperproliferative diseases in mammals, especially humans, and to pharmaceutical compositions containing such compounds.
Compounds that are useful in the treatment of hyperproliferative diseases are also disclosed in the following co-pending patent applications: PCT international patent application number PCT/IB97/100675 (filed Jun. 11, 1997), United States provisional patent application No. 60/028881 (filed Oct. 17, 1996), PCT international patent application number PCT/IB97/00584 (filed May 22, 1997), U.S. patent application Ser. No. 08/653,786 (filed May 28, 1996), PCT international patent application publication number WO 96/40142 (published Dec. 19, 1996), and PCT international patent application publication number WO 95/23141 (published Aug. 31, 1995). Each of the foregoing United States and PCT international patent applications is incorporated herein by reference in its entirety.
It is known that a cell may become cancerous by virtue of the transformation of a portion of its DNA into an oncogene (i.e., a gene that upon activation leads to the formation of malignant tumor cells). Many oncogenes encode proteins which are aberrant tyrosine kinases capable of causing cell transformation. Alternatively, the overexpression of a normal proto-oncogenic tyrosine kinase may also result in proliferative disorders, sometimes resulting in a malignant phenotype.
Receptor tyrosine kinases are large enzymes that span the cell membrane and possess an extracellular binding domain for growth factors such as epidermal growth factor, a transmembrane domain, and an intracellular portion that functions as a kinase to phosphorylate specific tyrosine residue in proteins and hence to influence cell proliferation. It is known that such kinases are often aberrantly expressed in common human cancers such as breast cancer, gastrointestinal cancer such as colon, rectal or stomach cancer, leukemia, and ovarian, bronchial or pancreatic cancer. It has also been shown that epidermal growth factor receptor (EGFR), which possesses tyrosine kinase activity, is mutated or overexpressed in many human cancers such as brain, lung, squamous cell, bladder, gastric, breast, head and neck, oesophageal, gynecological and thyroid cancers. Thus, it is believed that inhibitors of receptor tyrosine kinases, such as the compounds of the present invention, are useful as selective inhibitors of the growth of mammalian cancer cells.
It has also been shown that EGFR inhibitors may be useful in the treatment of pancreatitis and kidney disease (such as proliferative glomerulonephritis and diabetes-induced renal disease), and may reduce successful blastocyte implantation and therefore may be useful as a contraceptive. See PCT international application publication number WO 95/19970 (published Jul. 27, 1995).
It is known that polypeptide growth factors such as vascular endothelial growth factor (VEGF) having a high affinity to the human kinase insert-domain-containing receptor (KDR) or the murine fetal liver kinase 1 (FLK-1) receptor have been associated with the proliferation of endothelial cells and more particularly vasculogenesis and angiogenesis. See PCT international application publication number WO 95/21613 (published Aug. 17, 1995). Agents, such as the compounds of the present invention, that are capable of binding to or modulating the KDR/FLK-1 receptor may be used to treat disorders related to vasculogenesis or angiogenesis such as diabetes, diabetic retinopathy, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula
and to pharmaceutically acceptable salts thereof, wherein;
Z is a group of the formula
wherein n is an integer from 0 to 2 and p is an integer from 0 to 3;
R
1
is H, C
1
-C
6
alkyl or —C(O)(C
1
-C
6
alkyl);
R
2
is phenyl or 1H-indazol-5-yl, wherein said groups are optionally substituted by 1 to 3 R
5
substituents, or R
2
is a group of the formula (Ii) or (Ij)
wherein p is an integer from 0 to 3 and n is an integer from 0 to 2;
or R
1
and R
2
are taken together to form a group of the formula (Ik)
wherein the dashed line indicates a single or double bond and m is an integer from 0 to 4;
each R
3
is independently H, —C(O)OR
9,
or C
1
-C
6
alkyl wherein said alkyl is optionally substituted by halo, —OR
9
, —NR
9
R
10
or —C(O)OR
9
;
R
4
is R
3
—OR
9
, or —NR
9
R
10
;
each R
5
is independently halo, cyano, C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
, alkynyl, —OR
9
, —NR
9
R
10
, nitro, or C
6
-C
10
aryl wherein said alkyl, alkenyl, alkynyl and aryl R
5
groups are optionally substituted by 1 to 3 substituents independently selected from halo, nitro, C
1
-C
4
alkyl and —OR
9
;
R
6
and R
7
are independently H or R
5
;
R
8
is H, —SO
2
(C
6
-C
10
aryl), —(CH
2
)
q
(5-10 membered heterocyclyl), C
2
-C
6
alkenyl, C
1
-C
6
alkyl, —(CH
2
)
q
(CH
2
)
q
(C
1
-C
6
alkoxy), —(CH
2
)
q
(C
1
-C
6
alkoxy), —C(O)(C
1
-C
6
alkoxy), or —SO
2
(C
1
-C
4
alkyl) wherein each q is independently an integer from 2 to 4;
each R
9
and R
10
is independently H or C
1
-C
6
alkyl; and,
R
11
is trifluoromethyl, halo, nitro, —OR
9
, —NR
9
R
10
, cyano, C
1
-C
4
alkyl, —S(O)
x
R
9
wherein x is an integer from 0 to 2,—C(O)OR
9
, —OC(O)(C
1
-C
4
alkyl), —C(O)NR
9
R
10
), —NR
9
C(O)(C
1
-C
4
alkyl), —C(O)NHSO
2
(C
1
-C
4
alkyl), —NHCH
2
C(O)NR
9
R
10
, —NHC(O)(C
1
-C
4
alkoxy), —NHOC(O)(C
1
-C
4
alkyl), —NR
9
OR
10
, anilino, pyrrolidinyl, piperidinyl, azido, guanidino, morpholino, phenyl, —C(O)(C
1
-C
6
alkyl), benzenesulfonyl, allyl, thiophenyl, piperazinyl, 4-(C
1
-C
4
alkyl)-piperazinyl, phenyftnio, benzenesulphonamido, 2-oxopyrrolidin-1-yl, 2,5dioxopyrrolidin-1-yl, phenoxy, benzoyloxy, benzoylamino, —(CH
2
)
w
O(CH
2
)
v
OR
9,
—O(CH
2
)
w
O(CH
2
)
v
OR
9
, —O(CH
2
)
w
C(O)OR
9
, —O(CH
2
)
w
C(O)NR
9
R
10
, —(CH
2
)
w
S(CH
2
)
v
OR
9,
—NH(CH
2
)
v
O(C
1
-C
4
alkyl), —NH(CH
2
)
w
(C
6
-C
10
aryl), —NHC(O)(CH
2
)
w
(C
1
-C
4
alkoxy), or —O(CH
2
)
w
(C
6
-C
10
aryl), wherein w is an integer from 1 to 4 and v is an integer from 2 to 4, and wherein the alkyl, heterocyclic, and aryl moieties of the foregoing R
11
groups are optionally substituted by 1 or 2 substituents independently selected from the group consisting of halo, C
1
-C
4
alkyl, —OR
9,
—NR
9
R
10
, —C(O)OR
9
, —OC(O)(C
1
—C
4
alkyl), —C(O)NR
9
R
10
, —NHC(O)(C
1
-C
4
alkyl), nitro, imidazolyl, piperidino, morpholino, and piperazinyl;
with the proviso that where Z is a group of the formula (Ie), and R
2
is phenyl, then said phenyl is substituted by 1 to 3 substituents independently selected from C
1
-C
6
alkyl, C
2
-C
6
alkynyl and halo, and one of R
4
and R
7
is halo or H and the other is as defined above; and,
with the further proviso that where Z is a group of the formula (Ia), (Ib), (Ic) or (Id), and R
2
is phenyl, then said phenyl is substituted by C
2
-C
6
alkynyl.
Preferred compounds of formula I include those wherein R
2
is optionally substituted phenyl. More preferred are those compounds of formula I wherein R
2
is phenyl substituted by C
2
-C
6
alkynyl, in particular ethynyl.
Other preferred compounds of formula I include those wherein Z is a pyrrolo moiety of formula (Ie) or (If).
Other preferred compounds of formula I include those wherein R
1
and R
2
are taken together to form an indole or indoline moiety of formula (1k),
Specific preferred compounds of formula I include the following:
4-(6-Chloro-2,3dihydro-indol-1-yl)-7H-pyrrolo[2,3-d]pyrimidine;
4-(6-Methyl-2,3dihydro-indol-1-yl)-7H-pyrrolo[2,3-d]pyrimidine;
4 (6-Chloro-5-fluoro-2,3dihydryo-indol-1-yl)-7H-pyrrolo[2,3]pyrimidine:
1-(4-m-Tolylamino-pyrrolo[2,3-d]pyrimidin-7-yl)-ethanone;
4-(6Chlor

Affiliated with

Also associated with

Rating

Fused bicyclic pyrimidine derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Fused bicyclic pyrimidine derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Fused bicyclic pyrimidine derivatives will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2841078