Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – 8 to 10 amino acid residues in defined sequence
Reexamination Certificate
2001-04-11
2004-08-10
Low, Christopher S. F. (Department: 1653)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
8 to 10 amino acid residues in defined sequence
C514S015800
Reexamination Certificate
active
06774211
ABSTRACT:
TECHNICAL FIELD
The invention relates to novel compounds having activity useful for treating conditions which arise or are exacerbated by angiogenesis, pharmaceutical compositions comprising these compounds, a method of treating using said compounds, and a method of inhibiting angiogensis.
BACKGROUND OF THE INVENTION
Angiogenesis is the fundamental process by which new blood vessels are formed and is essential to a variety of normal body activities (such as reproduction, development and wound repair). Although the process is not completely understood, it is believed to involve a complex interplay of molecules which both stimulate and inhibit the growth of endothelial cells, the primary cells of the 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 however (such as during wound repair), these same cells can undergo rapid proliferation and turnover within a five day period. (Folkman, J. and Shing, Y.,
The Journal of Biological Chemistry
, 267(16): 10931-10934, 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 exascerbate an existing pathological condition. For example, ocular neovacularization has been implicated as the most common cause of blindness. 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 angiogenesis-dependent (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)).
Although 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)), there are disadvantages associated with several of these compounds. For example, suramin is a potent angiogenesis inhibitor, but causes (at doses required to reach antitumor activity) severe systemic toxicity in humans. Other compounds, such as retinoids, interferons and antiestrogens are safe for human use but have only a weak anti-angiogenic effect.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a compound the formula of:
A
0
-A
1
-A
2
-A
3
-A
4
-A
5
-A
6
-A
7
-A
8
-A
9
-A
10
(I)
or a pharmaceutically acceptable salt, ester, solvate, or prodrug thereof, wherein:
A
0
is hydrogen or an acyl group selected from:
(1) R—(CH
2
)
n
—C(O)—; wherein n is an integer from 0 to 8 and R is selected from hydroxyl; methyl; N-acetylamino; methoxyl; carboxyl; cyclohexyl optionally containing a one or two double bonds and optionally substituted with one to three hydroxyl groups; and a 5- or 6-membered ring aromatic or nonaromatic ring optionally containing one or two heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the ring is optionally substituted with a moiety selected from alkyl, alkoxy, and halogen; and
(2) R
1
—CH
2
CH
2
—(OCH
2
CH
2
O)
p
—CH
2
—C(O)—; wherein R
1
is selected from hydrogen, alkyl and N-acetylamino, and p is an integer from 1 to 8;
A
1
is an amino acyl residue selected from:
(1) alanyl,
(2) asparaginyl,
(3) citrullyl,
(4) glutaminyl,
(5) glutamyl,
(6) N-ethylglycyl,
(7) methionyl,
(8) N-methylalanyl,
(9) prolyl,
(10) pyro-glutamyl,
(11) sarcosyl,
(12) seryl,
(13) threonyl,
(14)—HN—(CH
2
)
q
—C(O)—, wherein q is 1 to 8, and
(15)—HN—CH
2
CH
2
—(OCH
2
CH
2
O)
r
—CH
2
—C(O)—, wherein r is 1 to 8;
A
2
is an amino acyl residue selected from:
(1) alanyl,
(2) asparaginyl,
(3) aspartyl,
(4) glutaminyl,
(5) glutamyl,
(6) leucyl,
(7) methionyl,
(8) phenylalanyl,
(9) prolyl,
(10) seryl,
(11)—HN—(CH
2
)
q
—C(O)—, wherein q is 1 to 8, and
(12)—HN—CH
2
CH
2
—(OCH
2
CH
2
O)
r
—CH
2
—C(O)—, wherein r is 1 to 8;
A
3
is an amino acyl residue selected from:
(1) alanyl,
(2) asparaginyl,
(3) citrullyl,
(4) cyclohexylalanyl,
(5) cyclohexylglycyl,
(6) glutaminyl,
(7) glutamyl,
(8) glycyl,
(9) isoleucyl,
(10) leucyl,
(11) methionyl,
(12) norvalyl,
(13) phenylalanyl,
(14) seryl,
(15) t-butylglycyl,
(16) threonyl,
(17) valyl,
(18) penicillaminyl, and
(19) cystyl;
A
4
is an amino acyl residue of L or D configuration selected from:
(1) allo-isoleucyl,
(2) glycyl,
(3) isoleucyl,
(4) prolyl,
(5) dehydroleucyl,
(6) D-alanyl,
(7) D-3-(naphth-1-yl)alanyl,
(8) D-3-(naphth-2-yl)alanyl,
(9) D-(3-pyridyl)-alanyl,
(10) D-2-aminobutyryl,
(11) D-allo-isoleucyl,
(12) D-allo-threonyl;
(13) D-allylglycyl,
(14) D-asparaginyl,
(15) D-aspartyl,
(16) D-benzothienyl,
(17) D-3-(4,4′-biphenyl)alanyl,
(18) D-chlorophenylalanyl,
(19) D-3-(3-trifluoromethylphenyl)alanyl,
(20) D-3-(3-cyanophenyl)alanyl,
(21) D-3-(3,4-difluorophenyl)alanyl,
(22) D-citrullyl,
(23) D-cyclohexylalanyl,
(24) D-cyclohexylglycyl,
(25) D-cystyl,
(26) D-cystyl(S-t-butyl),
(27) D-glutaminyl,
(28) D-glutamyl,
(29) D-histidyl,
(30) D-homoisoleucyl,
(31) D-homophenylalanyl,
(32) D-homoseryl,
(33) D-isoleucyl,
(34) D-leucyl,
(35) D-lysyl(Nepsilon-nicotinyl),
(36) D-lysyl,
(37) D-methionyl,
(38) D-neopentylglycyl,
(39) D-norleucyl,
(40) D-norvalyl,
(41) D-ornithyl,
(42) D-penicillaminyl,
(43) D-penicillaminyl(acetamidomethyl),
(44) D-penicillaminyl(S-benzyl),
(45) D-phenylalanyl,
(46) D-3-(4-aminophenyl)alanyl,
(47) D-3-(4-methylphenyl)alanyl,
(48) D-3-(4-nitrophenyl)alanyl,
(49) D-3-(3,4-dimethoxyphenyl)alanyl,
(50) D-3-(3,4,5-trifluorophenyl)alanyl,
(51) D-prolyl,
(52) D-seryl,
(53) D-seryl(O-benzyl),
(54) D-t-butylglycyl,
(55) D-thienylalanyl,
(56) D-threonyl,
(57) D-threonyl(O-benzyl),
(58) D-tryptyl,
(59) D-tyrosyl(O-benzyl),
(60) D-tyrosyl(O-ethyl),
(61) D-tyrosyl, and
(62) D-valyl;
A
5
is an amino acyl residue of L or D configuration selected from:
(1) alanyl,
(2) (3-pyridyl)alanyl,
(3) 3-(naphth-1-yl)alanyl,
(4) 3-(naphth-2-yl)alanyl,
(5) allo-threonyl,
(6) allylglycyl,
(7) glutaminyl,
(8) glycyl,
(9) histidyl,
(10) homoseryl,
(11) isoleucyl,
(12) lysyl(N-epsilon-acetyl),
(13) methionyl,
(14) norvalyl,
(15) octylglycyl,
(16) ornithyl,
(17) 3-(4-hydromethylphenyl)alanyl,
(18) prolyl,
(19) seryl,
(20) threonyl,
(21) tryptyl,
(22) tyrosyl,
(23) D-allo-threonyl,
(24) D-homoseryl,
(25) D-seryl,
(26) D-threonyl,
(27) penicillaminyl, and
(28) cystyl;
A
6
is an amino acyl residue of L or D configuration selected from:
(1) alanyl,
(2) 3-(naphth-1-yl)alanyl,
(3) 3-(naphth-2-yl)alanyl,
(4) (3-pyridyl)alanyl,
(5) 2-aminobutyryl,
(6) allylglycyl,
(7) arginyl,
(8) asparaginyl,
(9) aspartyl,
(10) citrullyl,
(11) cyclohexylalanyl,
(12) glutaminyl,
(13) glutamyl,
(14) glycyl,
(15) histidyl,
(16) homoalanyl,
(17) homoleucyl,
(18) homoseryl,
(19) isoleucyl,
(20) leucyl,
(21) lysyl(N-epsilon-acetyl),
(22) lysyl(N-epsilon-isopropyl),
(23) methionyl(sulfone),
(24) methionyl(sulfoxide),
(25) methionyl,
(26) norleucyl,
(27) norvalyl,
(28) octylglycyl,
(29) phenylalanyl,
(30) 3-(4-carboxyamidephenyl)alanyl,
(31) propargylglycyl,
(32) seryl,
(33) threonyl,
(34) tryptyl,
(35) tyrosyl,
(36) valyl,
(37) D-3-(naphth-1-yl)alanyl,
(38) D-3-(naphth-2-yl)alanyl,
(39) D-glutaminyl,
(40) D-homoseryl,
(41) D-leucyl,
(42) D-norvalyl,
(43) D-seryl,
(44) penicillaminyl, and
(45) cystyl;
A
7
is an amino acyl residue of L or D configuration selected
Bradley Michael F.
Haviv Fortuna
Henkin Jack
Kalvin Douglas M.
Schneider Andrew J.
Abbott Laboratories
Corbin Johanna M.
Low Christopher S. F.
Lukton David
Steele Gregory W.
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