Thienopyrimidine and thienopyridine derivatives useful as...

Details Thienopyrimidine and thienopyridine derivatives useful as... Thienopyrimidine and thienopyridine derivatives useful as...

2000-02-10

2002-12-10

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S258100, C544S253000, C546S114000

Reexamination Certificate

active

06492383

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to novel bicyclic pyrimidine and pyridine 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/IB97100675 (filed Jun. 11, 1997), U.S. provisional patent application No. 601041846 (filed Apr. 9, 1997), U.S. provisional patent application No. 60/031862 (filed Nov. 27, 1996), U.S. 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), PCT international patent application publication number WO 97/13771 (published Apr. 17, 1997), 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. The foregoing tyrosine kinases may be classified as growth factor receptor (e.g. EGFR, PDGFR, FGFR and erbB2) or non-receptor (e.g. c-src and bcr-abl) kinases. 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. Aberrant erbB2 activity has been implicated in breast, ovarian, non-small cell lung, pancreatic, gastric and colon cancers. It has also been shown that epidermal growth factor receptor (EGFR) 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 formulas 1 and 2
and to pharmaceutically acceptable salts and hydrates thereof, wherein:
wherein X
1
is N or CH;
R
1
is H, C
1
-C
6
alkyl or —C(O)(C
1
-C
6
alkyl);
R
2
is C
6
-C
10
aryl or 5-13 membered heterocyclic, wherein said R
2
groups are optionally substituted by 1 to 5 R
5
substituents,
each R
5
is independently selected from halo, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, —C(O)R
8
, —C(O)OR
8
, —OC(O)R
8
, —OC(O)OR
8
, —NR
6
C(O)R
7
, —C(O)NR
6
R
7
, —NR
6
R
7
, —OR
9
, —SO
2
NR
6
R
7
, C
1
-C
6
alkyl, —(CH
2
)
j
O(CH
2
)
q
NR
6
R
7
, —(CH
2
)
t
O(CH
2
)
q
OR
9
, —(CH
2
)
t
OR
9
, —S(O)
j
(C
1
-C
6
alkyl), —(CH
2
)
t
(C
6
-C
10
aryl), —(CH
2
)
t
(5-10 membered heterocyclic); —C(O)(CH
2
)
t
(C
6
-C
10
aryl), —(CH
2
)
t
O(CH
2
)
j
(C
6
-C
10
aryl), —(CH
2
)
t
O(CH
2
)
q
(5-10 membered heterocyclic), —C(O)(CH
2
)
t
(5-10 membered heterocyclic), —(CH
2
)
j
NR
7
(CH
2
)
q
NR
6
R
7
, —(CH
2
)
j
NR
7
CH
2
C(O)NR
6
R
7
, —(CH
2
)
j
NR
7
(CH
2
)
q
NR
9
C(O)R
8
, —(CH
2
)
j
NR
7
(CH
2
)
t
O(CH
2
)
q
OR
9
, —(CH
2
)
j
NR
7
(CH
2
)
q
S(O)
j
(C
1
-C
6
alkyl), —(CH
2
)
j
NR
7
(CH
2
)
t
R
6
, —SO
2
(CH
2
)
t
(C
6
-C
10
aryl), and —SO
2
(CH
2
)
t
(5-10 membered heterocyclic), wherein j is an integer ranging from 0 to 2, t is an integer ranging from 0 to 6, q is an integer ranging from 2 to 6, the —(CH
2
)
q
— and —(CH
2
)
t
— moieties of the foregoing R
5
groups optionally include a carbon-carbon double or triple bond where t is an integer between 2 and 6, and the alkyl, aryl and heterocyclic moieties of the foregoing R
5
groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, azido, —C(O)R
8
, —C(O)OR
8
, —OC(O)R
8
, —OC(O)OR
8
, —NR
6
C(O)R
7
, —C(O)NR
6
R
7
, —(CH
2
)
t
NR
6
R
7
, C
1
-C
6
alkyl, —(CH
2
)
t
(C
6
-C
10
aryl), —(CH
2
)
t
(5-10 membered heterocyclic), —(CH
2
)
t
O(CH
2
)
q
OR
9
, and —(CH
2
)
t
OR
9
, wherein t is an integer ranging from 0 to 6 and q is an integer ranging from 2 to 6;
each R
6
and R
7
is independently selected from H, C
1
-C
6
alkyl, —(CH
2
)
t
(C
6
-C
10
aryl), —(CH
2
)
t
(5-10 membered heterocyclic), —(CH
2
)
t
O(CH
2
)
q
OR
9
, and —(CH
2
)
t
OR
9
, wherein t is an integer ranging from 0 to 6 and q is an integer ranging from 2 to 6, and the alkyl, aryl and heterocyclic moieties of the foregoing R
6
and R
7
groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, azido, —C(O)R
8
, —C(O)OR
8
, —CO(O)R
8
, —OC(O)OR
8
, —NR
9
C(O)R
10
, —C(O)NR
9
R
10
, —NR
9
R
10
, C
1
-C
6
alkyl, —(CH
2
)
t
(C
6
-C
10
aryl), —(CH
2
)
t
(5-10 membered heterocyclic), —(CH
2
)
t
O(CH
2
)
q
OR
9
, and —(CH
2
)
t
OR
9
, wherein t is an integer ranging from 0 to 6 and q is an integer ranging from 2 to 6, with the proviso that where R
6
and R
7
are both attached to the same nitrogen, then R
6
and R
7
are not both bonded to the nitrogen directly through an oxygen;
each R
8
is independently selected from H, C
1
-C
10
alkyl, —(CH
2
)
t
(C
6
-C
10
aryl), and —(CH
2
)
t
(5-10 membered heterocyclic), wherein t is an integer ranging from 0 to 6;
each R
9
and R
10
is independently selected from H and C
1
-C
6
alkyl; and,
R
11
is H, C
1
-C
6
alkyl, —C(O)NR
6
R
9
, —C(O)(C
6
-C
10
aryl), —(CH
2
)
t
(C
6
-C
10
aryl), or —(CH
2
)
t
(5-10 membered heterocyclic), wherein t is an integer ranging from 0 to 6, wherein said R
11
groups, other than H, are optionally substituted by 1 to 5 R
5
groups.
Preferred compounds include those of formula 1 wherein R
11
is —(CH
2
)
t
(C
6
-C
10
aryl) or —(CH
2
)
t
(5-10 membered heterocyclic), wherein t is

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