Indolinone derivatives

Details Indolinone derivatives Indolinone derivatives

2002-12-20

2004-02-03

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C544S144000, C544S391000, C544S373000, C546S187000, C546S201000, C548S468000, C514S235200, C514S323000, C514S418000

Reexamination Certificate

active

06686362

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel indolinone derivatives useful as pharmaceuticals, to processes for preparing the compounds, to intermediates useful in the preparation of the compounds, to pharmaceutical compositions comprising the compounds, and to the use of the compounds as pharmaceuticals.
BACKGROUND OF THE INVENTION
WO 96/40116 disclose that certain pyrrole substituted 2-indolinone derivatives are receptor tyrosine kinase inhibitors useful in the treatment of conditions responsive to receptor tyrosine kinase inhibitors, for example proliferative disorders such as cancer. A preferred compound, disclosed on page 17, is 3-(2,3-dimethylpyrrol-5-yl)methylene]-2-indolinone, also known as SU5416. Unfortunately, this compound has been found to exhibit poor solubility in water and low bioavailability upon oral and intravenous administration.
WO 99/61422 discloses further pyrrole substituted 2-indolinone derivatives as receptor tyrosine kinase inhibitors. A preferred compound, disclosed as compound 5 on page 214, is 3-[2,4-dimethyl-5-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrol-3-yl]propionic acid, also known as SU6668. This compound has been found to possess superior oral activity to SU5416, but has been reported to lack the ability of that compound to inhibit the receptor tyrosine kinase Flt-3 (Abstract 497, Anne-Marie O'Farrell et al., America Society of Hematology Meeting, Orlando, Fla., USA, Dec. 7-11, 2001). Flt-3 is an important target for a tyrosine kinase inhibitor, especially for the treatment of Acute Myeloid Leukemia (AML), because about 30% of AML patients have been found to possess mutant forms of Flt-3 which lead to constitutive tyrosine phosphorylation of Flt-3 (Levis et al.,
Blood
, Aug. 1, 2001, Vol. 98. No. 3, pp 885-887).
WO 01/60814 discloses pyrrole substituted 2-indolinone derivatives bearing certain amido substituents directly attached to the pyrrole ring as receptor tyrosine kinase inhibitors.
WO 02/055517 discloses indolinones substituted with aryl substituents at the 4 position which exhibit protein kinase modulating ability.
WO 01/42243 discloses that certain compounds containing two or more pyrrole substituted 2-indolinone groups covalently linked together through the 3 position on each pyrrole by one or more linker groups are also useful as receptor tyrosine kinase inhibitors.
Nonetheless, in view of the severity of conditions responsive to receptor tyrosine kinase inhibitors and of the recent identification of specific kinase inhibitor targets, a need exists for new receptor tyrosine kinase inhibitors with diverse properties.
SUMMARY OF THE INVENTION
Pyrrole substituted 2-indolinone derivatives bearing certain carboxamidoethyl groups at the 4 position on pyrrole have now been found that are inhibitors of receptor tyrosine kinases with particularly desirable properties.
Accordingly, the present invention provides a compound of formula (I):
in which:
(i) R
1
represents a hydrogen atom or a (1-4C)alkyl group; and R
2
represents a group of formula -A
1
-NR
5
R
6
in which each of R
5
and R
6
independently represents a hydrogen atom or a (1-4C)alkyl group and A
1
represents (CH
2
)
m
, (CH
2
)
n
-A
2
-(CH
2
)
p
or (CH
2
CH
2
O)
q
CH
2
CH
2
in which m is an integer of from 2 to 10, each of n and p is an integer of from 1 to 6, A
2
is CH═CH, phenylene, biphenylene, cyclohexylene or piperazinylene and q is 1, 2 or 3;
(ii) R
1
and R
2
together represent -A
3
-NR
7
-A
4
- in which each of A
3
and A
4
independently represents (CH
2
)
r
or (CH
2
CH
2
O)
s
CH
2
CH
2
in which r is an integer of from 2 to 6, s is 1, 2 or 3, and R
7
represents a hydrogen atom or a (1-4C)alkyl group;
(iii) R
1
and R
2
together with the nitrogen atom to which they are attached represent a piperidinyl group, which piperidinyl group bears a substituent of formula -A
5
-R
8
at the 4 position, in which A
5
represents (1-4C)alkylene and R
8
represents piperidin-4-yl; or
(iv) R
1
and R
2
together with the nitrogen atom to which they are attached represent a pyrrolidinyl, piperidinyl or morpholino group; and
R
3
and R
4
each independently represents a hydrogen atom, a halogen atom, a (1-4C)alkyl group, a (1-4C)alkoxy group, a phenyl group which is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, a (1-4C)alkyl group and a (1-4C)alkoxy group, a group of formula R
9
S(O)
2
NR
10
—, a group of formula R
11
N(R
12
)S(O)
2
—, a group of formula R
13
C(O)N(R
14
)— or a group of formula R
15
N(R
16
)C(O)— in which each of R
9,
R
11,
R
16
and R
15
independently represents a (1-4C)alkyl group or a phenyl group which is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, a (1-4C)alkyl group and a (1-4C)alkoxy group, and each of R
10,
R
12
, R
14
and R
16
independently represents a hydrogen atom or a (1-4C)alkyl group;
or a pharmaceutically-acceptable salt thereof.
Compounds of formula (I) have been found to be potent and selective inhibitors of one or more of the receptor tyrosine kinases PDGFR (platelet-derived growth factor), c-Kit, VEGFR (vascular endothelial growth factor) and Flt-3 in whole cell assays.
The invention also provides compounds of formula (Ia):
wherein R is hydrogen, methyl, or ethyl;
or a pharmaceutically-acceptable salt thereof.
The invention also provides pharmaceutical compositions comprising a compound of the invention or a pharmaceutically-acceptable salt thereof and a pharmaceutically-acceptable carrier.
In addition, the invention provides a method of treating a condition responsive to a tyrosine kinase inhibitor, the method comprising administering to a patient in need of treatment an effective amount of a compound of the invention.
Further, the invention provides a compound of the invention as described herein for use in medical therapy, as well as the use of a compound of the invention in the manufacture of a formulation or medicament for treating a disease or condition responsive to a tyrosine kinase inhibitor.
DETAILED DESCRIPTION
The present invention provides novel pyrrole substituted 2-indoline derivatives which are substituted at the 4 position of the pyrrole ring with carboxamidoethyl substituents.
As used herein, the terms alkyl and alkylene refer to a branched or unbranched group. However, the names of specific groups, such as ethyl, ethylene, propyl, propylene, butyl or butylene, signify unbranched groups or radicals, unless indicated otherwise, such as prop-2-yl. Examples of alkyl groups are methyl, ethyl, propyl, prop-2-yl, and butyl. Examples of alkylene groups are methylene, ethylene, propylene and butylene.
The term halogen atom includes fluorine, chlorine and bromine.
The term “therapeutically effective amount” refers to an amount sufficient to effect treatment when administered to a patient in need of treatment.
The term “treatment” as used herein refers to the treatment of a disease or medical condition in a patient, such as a mammal (particularly a human), and includes:
(a) preventing the disease or medical condition from occurring, i.e., prophylactic treatment of a patient;
(b) ameliorating the disease or medical condition, i.e., eliminating or causing regression of the disease or medical condition in a patient;
(c) suppressing the disease or medical condition, i.e., slowing or arresting the development of the disease or medical condition in a patient; or
(d) alleviating the symptoms of the disease or medical condition in a patient.
The term “pharmaceutically-acceptable salt” refers to a salt prepared from a base or acid which is acceptable for administration to a patient, such as a mammal. Such salts can be derived from pharmaceutically-acceptable inorganic or organic acids.
Salts derived from pharmaceutically-acceptable acids include acetic, benzenesulfonic, benzoic, camphosulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pantothenic, phosphoric, succinic, sulf

Affiliated with

Also associated with

Rating

Indolinone 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 Indolinone derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Indolinone derivatives will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3291530