Process for the preparation of 7-substituted-3...

Details Process for the preparation of 7-substituted-3... Process for the preparation of 7-substituted-3...

2003-04-29

2004-08-24

Seaman, D. Margaret (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S159000, C546S160000

Reexamination Certificate

active

06780996

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to a process for the preparation of 7-substituted-3-quinolinecarbonitriles and intermediates useful in a process to prepare 7-substituted-3-quinolinecarbonitriles and pharmaceutically acceptable salts thereof.
Protein kinases are enzymes that catalyze the transfer of a phosphate group from ATP to an amino acid residue, such as tyrosine, serine, threonine, or histidine on a protein. Regulation of these protein kinases is essential for the control of a wide variety of cellular events including proliferation and migration. Specific protein kinases have been implicated in diverse conditions including cancer [Traxler, P. M., Exp. Opin. Ther. Patents, 8, 1599 (1998); Bridges, A. J., Emerging Drugs, 3, 279 (1998)], restenosis [Mattsson, E., Trends Cardiovas. Med. 5, 200 (1995); Shaw, Trends Pharmacol. Sci. 16, 401 (1995)], atherosclerosis [Raines, E. W., Bioessays, 18, 271 (1996)], angiogenesis [Shawver, L. K., Drug Discovery Today, 2, 50 (1997); Folkman, J., Nature Medicine, 1, 27 (1995)] and osteoporosis [Boyce, J. Clin. Invest., 90, 1622 (1992)] and stroke (Paul, R. et al, Nature Medicine, 7(2), 222(2001). An effective preparation of compounds which are inhibitors of protein tyrosine kinases and are useful in the treatment of cancer is important.
The compounds disclosed in WO9843960 (U.S. Pat. No. 6,002,008) are 3-quinolinecarbonitrile derivatives which are inhibitors of protein tyrosine kinases and useful in the treatment of cancer. The aforementioned compounds have been prepared by processes which are effective for the initial preparation of targeted compounds. However, a new and effective alternate source of important intermediates useful in the preparation of 3-quinolinecarbontrile derivatives is desired. Additionally desired is an alternate process to prepare 7-substituted-3-quinolinecarbonitriles.
A further series of new 3-quinolinecarbonitriles which are also highly effective inhibitors of protein tyrosine kinases and useful in the treatment of cancer are disclosed in published application WO 00/18740. Suitable processes for the preparation of 3-quinolinecarbonitriles are described therein, however, there is still a need in the art for yet more suitable methods for the preparation of important intermediates and final products useful in the preparation of 3-quinolinecarbonitriles useful in the treatment of cancer.
Therefore, methods to prepare 7-substituted-3-quinolinecarbonitriles and intermediates to facilitate their preparation are of great value.
It is an object of this invention to provide an alternate process to prepare 7-substituted-3-quinolinecarbonitriles and intermediates useful in a process to prepare 7-substituted-3-quinolinecarbonitriles which are highly effective as inhibitors of protein kinases useful in the treatment of cancer.
It is an object of this invention to provide a novel process for the preparation of 7-substituted-3-quinolinecarbonitriles by displacement of the 7-fluoro group of 7-fluoro-4-(substituted amino)quinolinecarbonitriles.
It is a further object of this invention to provide a novel process for the preparation of 7-substituted-4-oxo-1,4-dihydro-3-quinolinecarbonitriles by displacement of the 7-fluoro group of 7-fluoro-4-oxo-1,4-dihydro-3-quinolinecarbonitriles.
BRIEF SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of 7-substituted-3-quinolinecarbonitriles of Formula (I)
wherein:
X is selected from —O—, —S—, —NH—, and —NR
2′
—;
W′ is H or —OR
3
;
q is an integer of 0-5;
m is an integer of 0-2;
n is an integer of 2-5;
R
1
is an alkyl group of 1 to 6 carbon atoms, a cycloalkyl group of 3 to 10 carbon atoms, or an aryl of 6 to 12 carbon atoms, or heteroaryl ring, said aryl or heteroaryl ring is optionally fused to an additional aryl or heteroaryl ring, wherein heteroaryl is defined as a 5 or 6 membered aromatic ring moiety containing at least one and up to 4 heteroatoms selected from O, S, and N; said aryl or heteroaryl rings optionally fused may optionally be substituted with 1 to 4 substituents independently selected from the group consisting of —J, —NO
2
, —NH
2
, —OH, —SH, —CN, —N
3
, —COOH, —CONH
2
, —NHC(O)NH
2
, —C(O)H, —CF
3
, —OCF
3
, —R
4
, —OR
4
, —NHR
4
, —NR
4
R
4
, —S(O)
m
R
4
, —NHSO
2
R
4
, —R
5
OH, —R
5
OR
4
, —R
5
NH
2
, —R
5
NHR
4
, —R
5
NR
4
R
4
, —R
5
SH, —R
5
S(O)
m
R
4
, —NHR
6
OH, —N(R
4
)R
6
OH, —N(R
4
)R
6
OR
4
, —NHR
6
NH
2
, —NHR
6
NHR
4
, —NHR
6
NR
4
R
4
, —N(R
4
)R
6
NH
2
, —N(R
4
)R
6
NHR
4
, —N(R
4
)R
6
NHR
4
R
4
,—OR
6
OH, —OR
6
OR
4
, —OR
6
NH
2
, —OR
6
NHR
4
, —OR
6
NR
4
R
4
, —OC(O)R
4
, —NHC(O)R
4
, —NHC(O)NHR
4
, —OR
5
C(O)R
4
, —NHR
5
C(O)R
4
, —C(O)R
4
, —C(O)OR
4
, —C(O)NHR
4
, —C(O)NR
4
R
4
, —R
5
C(O)H, —R
5
C(O)R
4
, —R
5
C(O)OH, —R
5
C(O)OR
4
, —R
5
C(O)NH
2
, —R
5
C(O)NHR
4
, —R
5
C(O)NR
4
R
4
, —R
5
OC(O)R
4
, —R
5
OC(O)NH
2
, —R
5
OC(O)NHR
4
and —R
5
OC(O)NR
4
R
4
, and —YR
7
groups wherein Y is independently selected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO
2
—, —SO
2
NH—, —C(OH)H—, —Q(C(R
8
)
2
)
q
-, —(C(R
8
)
2
)
q
-, —(C(R
8
)
2
)
q
Q—, —C≡C—, cis- and trans —CH═CH— and cycloalkyl of 3-10 carbon atoms;
Q is —O—, —S(O)
m
—, —NH—, or —NR
9
—;
J is halogen selected from fluoro, chloro, bromo and iodo;
R
2
, R
2′
and R
3
are each independently selected from an alkyl group of 1 to 6 carbon atoms, an alkenyl group of 2 to 6 carbon atoms or an alkynyl group of 2 to 6 carbon atoms, wherein each independent alkyl, alkenyl or alkynyl group is optionally substituted with —NO
2
, cyano, or —QR
4
, or R
2
, R
2
and R
3
are each independently selected from —(C(R
8
)
2
)
q
-aryl, —(C(R
8
)
2
)
q
-heteroaryl, —(C(R
8
)
2
)
q
-heterocyclyl, —(C(R
8
)
2
)
n
—Q—(C(R
8
)
2
)
q
-aryl, —(C(R
8
)
2
)
n
—Q—(C(R
8
)
2
)
q
-heteroaryl, —(C(R
8
)
2
)
n
—Q—(C(R
8
)
2
)
q
-heterocyclyl, —(C(R
8
)
2
)
n
—Q—(C(R
8
)
2
)
n
—Q-aryl, —(C(R
8
)
2
)
n
—Q—(C(R
8
)
2
)
n
—Q-heteroaryl, and —(C(R
8
)
2
)
n
—Q—(C(R
8
)
2
)
n
—Q-heterocyclyl, wherein the heterocyclyl group may optionally be substituted on carbon or nitrogen with a group selected from —R
4
, —(C(R
8
)
2
)
q
-aryl, —(C(R
8
)
2
)
q
-heteroaryl, —(C(R
8
)
2
)
q
-heterocyclyl, —(C(R
8
)
2
)
q
—SO
2
R
4
, or the heterocyclyl group may optionally be substituted on carbon by —(C(R
8
)
2
)
q
—QR
4
, or the heterocyclyl group may optionally be substituted on nitrogen by —(C(R
8
)
2
)
n
—QR
4
, and also wherein the aryl or heteroaryl group may optionally be substituted with a group selected from —NO
2
, cyano, —R
4
, —(C(R
8
)2)
q
-aryl, —(C(R
8
)
2
)
q
-heteroaryl, —(C(R
8
)
2
)
q
-heterocyclyl, —(C(R
8
)
2
)
q
—SO
2
R
4
, and —(C(R
8
)
2
)
q
—QR
4
and further provided that R
2
and R
2
′ may optionally be taken together with the nitrogen to which they are attached, forming a heterocyclic ring, that optionally contains an additional heteroatom, selected from nitrogen, oxygen and sulfur, wherein said formed heterocyclic ring may optionally be substituted on carbon or nitrogen with a group —R
4
, or said heterocyclic ring may optionally be substituted on carbon by —(C(R
8
)
2
)
q
—QR
4
, or said heterocyclic ring may optionally be substituted on nitrogen by —(C(R
8
)
2
)
n
—QR
4
;
R
4
is a monovalent group independently selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms;
R
5
is a divalent group independently selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms;
R
6
is a divalent alkyl group of 2 to 6 carbon atoms;
R
7
is a cycloalkyl ring of 3 to 10 carbon atoms optionally substituted with one or more alkyl groups of 1 to 6 carbon atoms or an aryl or heteroaryl ring, optionally fused to an additional aryl or heteroaryl ring, wherein said aryl or heteroaryl ring optionally fused, may optionally be substituted with 1 to 4 substituents selected from the group consisting of aryl, —CH
2
-aryl, —NH-aryl, —O-aryl, —S(O)
m
-aryl, —J, —NO
2
, —NH
2
, —OH, —SH, —CN, —N
3
,

Affiliated with

Also associated with

Rating

Process for the preparation of 7-substituted-3... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Process for the preparation of 7-substituted-3..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for the preparation of 7-substituted-3... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3350988