N-alkylated peptides having antiangiogenic activity

Details N-alkylated peptides having antiangiogenic activity N-alkylated peptides having antiangiogenic activity

2000-10-31

2004-08-17

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

06777535

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 the compounds, methods of treatment using the compounds, and methods of inhibiting angiogenesis.
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 thesc molecules appear to maintain the microvasculature in a quiescent state (i.e., one of no capillary growth) for prolonged periods that may last for weeks, or in some cases, decades. However, when necessary, such as during wound repair, these same cells can undergo rapid proliferation and turnover within as little as five days (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 exacerbate an existing pathological condition. For example, ocular neovascularization 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 the liver, the lung, and the bones (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)). A number of disadvantages have been associated with many of these compounds. A potent angiogenesis inhibitor, for example suramin, can cause severe systemic toxicity in humans at doses required to reach antitumor activity. Other compounds, such as retinoids, interferons, and antiestrogens are safe for human use, but have only a weak anti-angiogenic effect.
A new class of compounds having particularly effective in vitro and in vivo angiogenesis inhibiting properties, as well as a promising toxicity profile, has been described in commonly-owned U.S. patent application Ser. No. 09/316,888, filed May 21, 1999. Novel changes in position 3 of the new angiogenesis inhibitors is described in copending provisional U.S. Patent Application Ser. No. 60/166,791, filed Nov. 22, 1999. Although the compounds have demonstrated satisfactory enzymatic stability and bioavailability, it would be desirable to prepare analogs of the antiangiogenic peptides having enhanced stability against in vivo enzymatic cleavage, improved pharmacokinetics, increased water solubility, and potentially better oral bioavailability.
SUMMARY OF THE INVENTION
The present invention relates to a novel class of compounds having angiogenesis-inhibiting properties. The invention provides nona- and decapeptides wherein the nitrogen atom of at least one of the amide bonds of an amino acid residue in positions 2 through 9 of the peptide is N-alkylated. Compounds of the invention exhibit enhanced metabolic stability, improved pharmacokinetics, increased water solubility, and potentially better oral bioavailability.
In one aspect, the present invention provides a compound of formula (I)
Xaa
1
-Xaa
2
-Xaa
3
-Xaa
4
-Xaa
5
-Xaa
6
-Xaa
7
-Xaa
8
-Xaa
9
-Xaa
10
-Xaa
11
(I), (SEQ ID NO:1)
     1    2    3     4    5    6    7    8    9
or a pharmaceutically acceptable salt, prodrug, ester, or solvate thereof, wherein
at least one amide bond of an amino acid residue represented by Xaa
3
, Xaa
4
, Xaa
5
, Xaa
6
, Xaa
7
, Xaa
8
, Xaa
9
, and Xaa
10
is N-alkylated;
Xaa
1
is absent or Xaa
1
is selected from the group consisting of hydrogen, N-methylprolyl, and an acyl group, wherein the acyl group is selected from the group consisting of
R
1
—(CH
2
)
n
—C(O)—, wherein n is an integer from 0 to 8 and R
1
is selected from the group consisting of N-acetylamino, alkoxy, alkyl, aryl, carboxy, cycloalkenyl, cycloalkyl, heterocycle, and hydroxy; and
R
2
—CH
2
CH
2
—O—(CH
2
CH
2
O)
p
—CH
2
—C(O)—, wherein p is an integer from 1 to 8 and R
2
is selected from the group consisting of hydrogen, N-acetylamino, and alkyl;
provided that Xaa
1
is absent only when Xaa
2
is N-(R
3
)-prolyl;
Xaa
2
is an N-alkylated amino acid selected from the group consisting of N-(R
3
)-alanyl, N-(R
3
)-glycyl, N-(R
3
)-norvalyl, and N-(R
3
)-prolyl, wherein R
3
is C
1
-C
5
-alkyl; or Xaa
2
is an N-unalkylated amino acid selected from the group consisting of
&bgr;-alanyl,
D-alanyl,
4-aminobutyryl,
(1R,3S)-1-aminocyclopentane-3-carbonyl,
(1S,3R)-1-aminocyclopentane-3-carbonyl,
(1R,4S)-1-aminocyclopent-2-ene-4-carbonyl,
(1S,4R)-1-aminocyclopent-2-ene-4-carbonyl,
asparaginyl,
3-(4-chlorophenyl)alanyl,
3-(4-cyanophenyl)alanyl,
glutaminyl,
glutamyl,
glycyl,
4-hydroxyprolyl,
3-(4-methylphenyl)alanyl,
prolyl,
seryl, and
threonyl;
Xaa
3
is an N-alkylated amino acid selected from the group consisting of N-(R
3
)-alanyl, N-(R
3
)-glycyl, N-(R
3
)-leucyl, and N-(R
3
)-phenylalanyl, wherein R
3
is as defined above; or Xaa
3
is an N-unalkylated amino acid selected from the group consisting of
alanyl,
(1S,3R)-1-aminocyclopentane-3-carbonyl,
(1S,4R)-1-aminocyclopent-2-ene-4-carbonyl,
asparaginyl,
aspartyl,
3-(3-cyanophenyl)alanyl,
3-(4-cyanophenyl)alanyl,
glutaminyl,
glycyl,
leucyl,
lysyl(N-epsilon-acetyl),
3-(4-methylphenyl)alanyl,
norvalyl,
prolyl, and
phenylalanyl;
Xaa
4
is an N-alkylated amino acid selected from the group consisting of N-(R
3
)-alanyl, N-(R
3
)-glycyl, N-(R
3
)-homophenylalanyl, N-(R
3
)-isoleucyl, N-(R
3
)-leucyl, N-(R
3
)-norvalyl, N-(R
3
)-phenylalanyl, N-(R
3
)-D-phenylalanyl, N-(R
3
)-seryl, N-(R
3
)-tyrosyl, N-(R
3
)-valyl, and N-(R
3
)-D-valyl, wherein R
3
is as defined above; or Xaa
4
is an N-unalkylated amino acid selected from the group consisting of
alanyl,
alloisoleucyl,
allylglycyl,
2-aminobutyryl,
(1R,4S)-aminocyclopent-2-ent-4-carbonyl,
asparaginyl,
aspartyl,
3-[2-(5-bromothienyl)]alanyl,
3-(3-chlorophenyl)alanyl,
3-(4-chlorophenyl)alanyl,
3-(3-cyanophenyl)alanyl,
cyclohexylalanyl,
3-(3,4-dimethoxyphenyl)alanyl,
3-(3-fluorophenyl)alanyl,
3-(4-fluorophenyl)alanyl,
glutaminyl,
glycyl,
histidyl,
homophenylalanyl,
homoseryl,
isoleucyl,
leucyl,
lysyl(N-epsilon-acetyl),
methionyl,
methionyl(sulfone),
3-(4-methylphenyl)alanyl,
3-(naphth-1-yl)alanyl,
3-(naphth-2-yl)alanyl,
noronithyl,
norvalyl,
phenyalanyl,
phenylglycyl,
prolyl,
3-(3-pyridyl)alanyl,
3-(4-thiazolyl)alanyl,
3-(2-thienyl)alanyl,
seryl,
seryl(O-benzyl),
styrylalanyl,
tryptyl,
tyrosyl,
valyl, and
D-valyl;
Xaa
5
is an N-alkylated amino acid selected from the group consisting of N-(R
3
)-D-homophenylalanyl, N-(R
3
)-D-isoleucyl, N-(R
3
)-D-leucyl, and N-(R
3
)-D-phenyllalanyl, wherein R
3
is as defined above;

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