Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-01-02
2004-04-13
Lambkin, Deborah C. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S304000, C560S019000, C562S433000, C564S084000, C564S085000, C564S088000
Reexamination Certificate
active
06720424
ABSTRACT:
TECHNICAL FIELD
The present invention relates to VEGF-receptor antagonists inhibiting VEGF, which corresponds to specific growth factors of vascular endothelial cells, from binding to receptors.
The present application is based on patent applications in Japan (Japanese Patent Application No. Hei 11-188271 and Japanese Patent Application No. Hei 11-188272), the disclosure of which is incorporated herein by reference as a part of the present description.
BACKGROUND ART
VEGF (vascular endothelial growth factor) is a growth factor exhibiting extremely high specificity to vascular endothelial cells. VEGF and the receptors thereof play main roles in physiologic angiogenesis such as placentation or development. As VEGF receptors, Flt-1 (fms-like tyrosine kinase) and KDR (kinase insert domain containing receptor) have been reported (
Advances in Cancer Research
, vol. 67, pp. 281-316, 1995).
It is suggested that VEGF and the receptors thereof play main roles not only in physiologic angiogenesis but also in pathologic angiogenesis observed in diseases such as diabetic retinopathy, chronic rheumatism, and solid tumors (
Advances in Cancer Research
, vol. 67, pp. 281-316, 1995), and are involved in progress of these diseases. In addition, it is known that VEGF and the receptors thereof are involved not only in angiogenesis but also in vascular hyperpermeability. It is suggested that vascular hyperpermeability due to VEGF is involved in pathologic symptoms such as carcinomatous ascites retention or cerebral edema upon ischemia reperfusion injury (
J. Clin. Invest
., vol. 104, pp. 1613-1620, 1999).
Therefore, it is believed that substances which inhibit binding between VEGF and the receptors thereof are considered to be useful in treatment of various diseases in which pathologic angiogenesis due to VEGF is involved, and amelioration of pathologic symptoms in which vascular hyperpermeability due to VEGF is involved.
DISCLOSURE OF THE INVENTION
An objective of the present invention is to provide compounds for use as a VEGF-receptor antagonist for treating diseases in which angiogenesis induced by VEGF is involved, and for ameliorating pathologic symptoms in which vascular hyperpermeability induced by VEGF is involved.
The compounds according to the present invention correspond to aminobenzoic acid derivatives represented by Formula (1) as follows:
{in Formula (1), R
1
represents a hydrogen atom or a C
1-6
alkyl group;
R
2
represents a hydrogen atom, a C
1-6
alkyl group, a C
3-8
cycloalkyl C
1-3
alkyl group, a phenyl C
1-3
alkyl group, a group represented by CH
2
CO
2
R
5
(wherein R
5
represents a hydrogen atom or a C
1-6
alkyl group), or a group represented by CH
2
CON(R
6
)R
7
(wherein R
6
and R
7
independently represent a hydrogen atom or a C
1-6
alkyl group);
R
3
represents a C
8-25
alkyl group, a group represented by (CH
2
)
p
CO
2
R
11
(wherein p is an integer of 1 to 20, and R
11
represents a hydrogen atom or a C
1-6
alkyl group), or a group represented by (CH
2
)
3
CONHCH(R
12
) CONHR
13
(wherein R
12
represents a hydrogen atom or a group represented by CH
2
CO
2
R
14
group (wherein R
14
represents a hydrogen atom or a C
1-6
alkyl group), and R
13
represents a C
1-20
alkyl group);
R
4
represents a hydrogen atom or a group represented by OR
9
or CO
2
R
10
(wherein R
9
and R
10
independently represent a hydrogen atom or a C
1-6
alkyl group),
A represents a group represented by S(O)
q
R
15
(wherein q is 0, 1, or 2, R
15
represents a C
1-6
alkyl group, a phenyl C
1-3
alkyl group, or a group represented by (CH
2
)
m
OR
16
(wherein m is 2 or 3, and R
16
represents a hydrogen atom or a methoxymethyl group)), a group represented by Formula (2) as follows:
(in the formula, R
17
represents a hydrogen atom or a group represented by CO
2
R
19
, CH
2
CO
2
R
20
, CH
2
CH
2
CO
2
R
21
, or CH═CHCO
2
R
22
(wherein R
19
, R
20
, R
21
, and R
22
independently represent a hydrogen atom or a C
1-6
alkyl group), R
18
represents a hydrogen atom or a group represented by CO
2
R
23
(wherein R
23
represents a hydrogen atom or a C
1-6
alkyl group), Y′ represents O, S, or NR
24
(wherein R
24
represents a hydrogen atom or a C
1-6
alkyl group), and Z represents CH or N), or a group represented by Formula (3) as follows:
(in the formula, R
25
represents a hydrogen atom or a group represented by CO
2
R
26
(wherein R
26
represents a hydrogen atom or a C
1-6
alkyl group));
X represents O, a single bond, or a group represented by NR
27
(wherein R
27
represents a hydrogen atom or a t-butoxycarbonyl group);
Y represents O, CONH, NHCO, or a group represented by NR
28
(wherein R
28
represents a hydrogen atom or a t-butoxycarbonyl group, with the proviso that when Y represents NHCO, A is not represented by Formula (2) described above); and
n is an integer of 0 to 15}
or pharmaceutically acceptable salt of the same.
BEST MODE FOR CARRYING OUT THE INVENTION
In the present invention, the term “C
1-6
alkyl group” means a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms. As examples thereof, mention may be made of, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a t-butyl group, a pentyl group, an isopentyl group, a 1-ethylpropyl group, a hexyl group, an isohexyl group, a 1-ethylbutyl group, and the like. The term “C
3-8
cycloalkyl C
1-3
alkyl group” means a straight-chain or branched-chain alkyl group having 1 to 3 carbon atoms, substituted with a cycloalkyl group having 3 to 8 carbon atoms. As examples thereof, mention may be made of, for example, a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, and the like.
The term “C
8-25
alkyl group” means a straight-chain or branched-chain alkyl group having 8 to 25 carbon atoms. As examples thereof, mention may be made of an octyl group, a 7-methyloctyl group, a 7,7-dimethyloctyl group, an octadecyl group, a 17-methyloctadecyl group, a 17,17-dimethyloctadecyl group, a pentacosyl group, a 23-methyltetracosyl group, a 22,22-dimethyltricosyl group, and the like.
The term “C
1-20
alkyl group” means a straight-chain or branched-chain alkyl group having 1 to 20 carbon atoms. As examples thereof, mention may be made of, for example, a methyl group, an ethyl group, a decyl group, a 9-methyldecyl group, a 9,9-dimethyldecyl group, an icosyl group, and the like.
The term “phenyl C
1-3
alkyl group” means a straight-chain or branched-chain alkyl group having 1 to 3 carbon atoms, substituted with a phenyl group. As examples thereof, mention may be made of, for example, a benzyl group, a 2-phenylethyl group, a 3-phenylpropyl group, and the like.
In addition, as examples of the pharmaceutically acceptable salt in the present invention, mention may be made of, for example, a salt with an inorganic acid such as sulfuric acid, hydrochloric acid, or phosphoric acid, or the like; a salt with an organic acid such as acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, or the like; a salt with an amine such as trimethylamine, methylamine, or the like; a salt with a metal ion such as sodium ion, potassium ion, calcium ion, or the like; and the like.
In addition, some of the compounds according to the present invention exhibit crystal polymorphism. The present invention includes any crystal forms thereof.
In Formula (1), it is preferable that A represent a group represented by S(O)
q
R
15
(wherein q and R
15
have the same meanings as described above) or a group represented by Formula (5) as follows:
(in the formula, R
17
R
18
, and Y′ have the same meanings as described above), and it is more preferable that A represent a group represented by SR
15
(wherein R
15
has the same meaning as described above) or a group represented by Formula (5) wherein R
17
represents CO
2
R
19
(wherein R
19
has the same meaning as described above) and R
18
represents a hydrogen atom. In addition, it is most preferable that A represent a group represented by SR
1
Asanuma Hajime
Sato Masakazu
Shibuya Masabumi
Takayama Tetsuo
Wada Hisaya
Lambkin Deborah C.
Taisho Pharmaceutical Co. Ltd.
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