Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
1999-05-21
2003-10-14
Low, Christopher S. F. (Department: 1653)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C514S019300, C562S553000, C562S562000
Reexamination Certificate
active
06632961
ABSTRACT:
TECHNICAL FIELD
The present invention relates to compounds which are useful for treating pathological states which arise from or are exacerbated by angiogenesis, to pharmaceutical compositions comprising these compounds, and to methods of inhibiting angiogenesis in a mammal.
BACKGROUND OF THE INVENTION
Angiogenesis, the process by which new blood vessels are formed, is essential for normal body activities including reproduction, development and wound repair. Although the process is not completely understood, it is believed to involve a complex interplay of molecules which regulate the growth of endothelial cells (the primary cells of capillary blood vessels). Under normal conditions, these molecules appear to maintain the microvasculature in a quiescent state (i.e. one of no capillary growth) for prolonged periods which may last for as long as weeks or, in some cases, decades. When necessary (such as during wound repair), these same cells can undergo rapid proliferation and turnover within a 5 day period (Folkman, J. and Shing, Y., The Journal of Biological Chemistry, 267(16), 10931-10934, (1992) and Folkman, J. and Klagsbrun, M., Science, 235, 442-447 (1987).
Although angiogenesis is a highly regulated process under normal conditions, many diseases (characterized as angiogenic diseases) are driven by persistent unregulated angiogenesis. Otherwise stated, unregulated angiogenesis may either cause a particular disease directly or exacerbate an existing pathological condition. For example, ocular neovascularization has been implicated as the most common cause of blindness and dominates approximately twenty eye diseases. In certain existing conditions, such as arthritis, newly formed capillary blood vessels invade the joints and destroy cartilage. In diabetes, new capillaries formed in the retina invade the vitreous, bleed, and cause blindness. Growth and metastasis of solid tumors are also dependent on angiogenesis (Folkman, J., Cancer Research, 46, 467-473 (1986), Folkman, J., Journal of the National Cancer Institute, 82, 4-6 (1989). It has been shown, for example, that tumors which enlarge to greater than 2 mm must obtain their own blood supply and do so by inducing the growth of new capillary blood vessels. Once these new blood vessels become embedded in the tumor, they provide a means for tumor cells to enter the circulation and metastasize to distant sites such as liver, lung or bone (Weidner, N., et al., The New England Journal of Medicine, 324(1), 1-8 (1991).
Several angiogenesis inhibitors are currently under development for use in treating angiogenic diseases (Gasparini, G. and Harris, A. L., J. Clin. Oncol., 13(3): 765-782, (1995), but there are disadvantages associated with these compounds. Suramin, for example, is a potent angiogenesis inhibitor but causes severe systemic toxicity in humans at doses required for antitumor activity. Compounds such as retinoids, interferons and antiestrogens are relatively safe for human use but have weak antiangiogenic effects. Irsogladine, an anti-tumor drug with low toxicity, has only weak anti-angiogenic effects. Thus there is still a need for compounds useful in treating angiogenic diseases in mammals.
SUMMARY OF THE INVENTION
In one embodiment of the present invention are disclosed compounds represented by Formula I
or a pharmaceutically acceptable salt or prodrug thereof, where
L
1
is selected from
(1) a covalent bond,
(2) —C(O)NR
5
(CH
2
)
m
—, where m is an integer from 0 to 4, and
R
5
is selected from
(a) hydrogen
and
(b) alkyl,
and
(3) —N(R
5
)C(O)(CH
2
)
m
—, where (2) and (3) are drawn with their left ends attached to R
1
;
R
1
is selected from
(1) alkyl,
(2) alkyl substituted with 1, 2, or 3 substituents selected from
(a) —NO
2
(b) —NR
6
R
7
where R
6
and R
7
are independently selected from
(i) hydrogen,
(ii) alkyl,
(iii) arylalkyl,
(iv) an amino protecting group,
(v) alkanoyl, where the alkanoyl can be optionally substituted with —OR
9
,
(vi) (aryl)oyl,
(vii) alkoxycarbonyl,
and
(viii) (heteroaryl)oyl,
and
(c) alkoxycarbonyl,
(3) aryl substituted with 1, 2, 3, 4, or 5 substituents independently selected from
(a) —NR
6
R
7
,
(b) alkyl,
and
(c) alkyl substituted with 1, 2, or 3 substituents selected from —NR
6
R
7
,
(4) —NR
6
R
7
,
and
(5) —OR
9
;
R
2
and R
3
are selected from
(1) hydrogen
(2) —(CH
2
)
n
C(O)R
8
where n is an integer from 0 to 4, and
R
8
is selected from
(a) —OR
9
where R
9
is selected from
(i) hydrogen,
(ii) alkyl,
and
(iii) alkyl substituted with 1 or 2 substituents selected from the group consisting of aryl
and
(b) —NR
5
R
10
where R
5
is defined previously, and R
10
is selected from
(i) hydrogen,
(ii) alkyl,
(iii) alkyl substituted with 1, 2, or 3 substituents independently selected from
(1′) —CO
2
R
9
and
(2′) —C(O)NR
6
R
7
(iv) aryl,
and
(v) arylalkyl, where (iv) and (v) can be optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from
(1′) alkyl,
(2′) alkanoyl,
(3′) —OR
9
,
(4′) —CO
2
R
9
,
(5′) alkanoyloxy,
(6′) carboxaldehyde,
(7′) cycloalkyl,
(8′) cycloalkenyl,
(9′) halo,
(10′) nitro,
(11′) perfluoroalkyl,
(12′) perfluoroalkoxy,
(13′) —NR
6
R
7
,
(14′) —SO
2
NR
6
R
7
,
(15′) —C(O)NR
6
R
7
,
(16′) aryloxy,
and
(17′) aryl,
and
(3) aryl, wherein the aryl is optionally substituted with 1, 2, or 3 substituents independently selected from
(a) —NR
6
R
7
and
(b) —CO
2
R
9
,
provided that at least one of R
2
and R
3
is other than hydrogen;
R
4
is selected from
(1) hydrogen,
(2) alkyl,
(3) cycloalkyl,
(4) —CO
2
R
5
,
(5) aryl,
and
(6) aryl substituted with at least one of W, X, Y, or Z where W, X, Y, and Z are independently selected from
(a) alkyl,
(b) alkanoyl,
(c) —OR
9
,
(d) —CO
2
R
9
,
(e) alkanoyloxy,
(f) carboxaldehyde,
(g) cycloalkyl,
(h) cycloalkenyl,
(i) halo,
(j)nitro,
(k) perfluoroalkyl,
(l) perfluoroalkoxy,
(m) —NR
6
R
7
,
(n) —SO
2
NR
6
R
7
,
(o) —C(O)NR
6
R
7
,
(p) aryloxy,
and
(q) aryl.
In another embodiment of the invention are disclosed methods of treating diseases comprising administering an effective amount of a compound having Formula I.
In yet another embodiment of the invention are disclosed pharmaceutical compositions containing compounds of Formula I.
Compounds of this invention include, but are not limited to,
N-[4-[N-(acetylglycyl)amino]benzoyl]-L-aspartic acid,
4-[[4-(aminomethyl)benzoyl]amino]-2-phenylbenzoic acid,
N-[4-[(7-amino-1-oxoheptyl)amino]benzoyl]-L-aspartic acid,
(S)-methyl 3-[[6-amino-2-[[(1,1-dimethylethoxy)carbonyl]amino]-1-oxohexyl]amino]-4-(1,1-dimethylethyl)benzoate,
(S)-methyl 3-[[2-(acetylamino)-6-amino-1-oxohexyl]amino]-4-(1,1-dimethylethyl)benzoate,
(S)-3-[[2-(acetylamino)-6-amino-1-oxohexyl)amino]-4-(1,1-dimethylethyl)benzoic acid,
(S)-methyl 4-[[2-[[(1,1-dimethylethoxy)carbonyl]amino]-6-[(phenylmethoxy)carbonyl]amino]-1-oxohexyl]amino]-2-[3-(phenylmethoxy)-phenyl]benzoate,
(S)-1,1-dimethylethyl 4-[[2-[[(1,1-dimethylethoxy)carbonyl]amino]-6-[(phenylmethoxy)carbonyl]amino]-1-oxohexyl]amino]-2-[3-(phenylmethoxy)phenyl]benzoate,
(R)-methyl 4-[[6-amino-2-[[(1,1-dimethylethoxy)carbonyl]amino]-1-oxohexyl]amino]-2-(3-hydroxyphenyl)benzoate,
(R)-methyl 4-[[6-amino-2-[[(1,1-dimethylethoxy)carbonyl]amino]-1-oxohexyl]amino]-2-(2-hydroxyphenyl)benzoate,
(S)-methyl 4-[[2-amino-6-[[(phenylmethoxy)carbonyl]amino]-1-oxohexyl]amino]-2-[(3-(phenylmethoxy)phenyl]benzoate,
(S)-methyl 4-[[2-(acetylamino)-6-[[(phenylmethoxy)carbonyl]amino]-1-oxohexyl]amino]-2-[(3-(phenylmethoxy)phenyl]benzoate
Craig Richard A.
Henkin Jack
Kawai Megumi
Sheppard George S.
Abbott Laboratories
Donner B. Gregory
Low Christopher S. F.
Lukton David
Steele Gregory W.
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