Dolastatin peptides

Details Dolastatin peptides Dolastatin peptides

2000-03-31

2001-11-27

Oswecki, Jane C. (Department: 1626)

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

4 to 5 amino acid residues in defined sequence

C530S331000, C546S159000, C546S174000, C546S176000, C546S187000, C546S190000, C546S193000, C546S208000, C546S223000, C546S224000, C546S279100, C548S129000, C548S130000, C548S138000, C548S152000, C548S180000, C548S190000, C548S194000, C548S195000, C548S360100, C548S490000, C548S491000, C548S517000, C548S518000, C548S530000, C549S059000, C549S062000, C549S063000, C549S065000, C549S066000, C549S067000, C564S183000, C564S186000, C564S305000, C564S336000, C564S342000, C585S021000, C585S022000

Reexamination Certificate

active

06323315

ABSTRACT:

BACKGROUND OF THE INVENTION
A series of short peptides with significant activity as cell growth inhibitors have been isolated from the Indian Ocean sea hare
Dolabella auricularia
(Pettit et al.,
J. Am. Chem. Soc
. 109: 6883-6885 (1987); Beckwith et al.,
J. Natl. Cancer Inst
. 85, 483-88 (1993); U.S. Pat. No. 4,816,444; European Patent Application Publication No. 398558). These peptides are referred to as Dolastatins 1-15. Of these, Dolastatins 10 and 15 are the most potent cell growth inhibitors. Dolastatin 15, for example, inhibits the growth of the National Cancer Institute's P388 lymphocytic leukemia (PS system) cell line, a strong predictor of efficacy against various types of human malignancies. Dolastatin 10 and Dolastatin 15 effectively inhibit tubulin polymerization and growth of four different human lymphoma cell lines (Bai et al.,
Biochem. Pharmacol
. 39: 1941-1949 (1990); Beckwith et al., supra (1993)).
The minute amounts of the Dolastatin peptides present in
Dolabella auricularia
(about 1 mg each per 100 kg sea hare) and the consequent difficulties in purifying amounts sufficient for evaluation and use, have motivated efforts toward the synthesis of the more promising of these compounds, including Dolastatin 10 (Pettit et al.,
J. Am. Chem. Soc
. 111: 5463-5465 (1989); Roux et al.
Tetrahedron
50: 5345-5360 (1994); Shiori et al.
Tetrahedron
49: 1913-1924 (1993)). Synthetic Dolastatin 10, however, suffers from disadvantages which include poor solubility in aqueous systems and the need for expensive starting materials for its synthesis. These disadvantages, in turn, have led to the synthesis and evaluation of structurally modified Dolastatin 10 derivatives.
A need persists for synthetic compounds with the biological activity of Dolastatin 10 which have useful aqueous solubility and can be produced efficiently and economically.
SUMMARY OF THE INVENTION
The present invention provides compounds of the formula
where R
1
-R
5
are each, independently, a hydrogen atom or a normal or branched C
1
-C
6
-alkyl group; A is a methionyl, phenylalanyl or phenylglycyl residue; n is 0 or 1; R
6
is a hydrogen atom; and R
7
is a carbocyclic group, an aromatic group, a straight chain or branched C
1
-C
4
-alkyl group, a pyridylalkyl group or a heterocyclic group. In another embodiment, R
6
is benzyl or —C(O)OR
8
, where R
8
is a C
1
-C
6
-alkyl group, and R
7
is a heteroaromatic group, such as a 2-tliazolyl group.
In another embodiment, the invention relates to compounds of the formula
where R
1
-R
5
are each, independently, a hydrogen atom or a normal or branched C
1
-C
6
-alkyl group; A is a methionyl, phenylalanyl or phenylglycyl residue; n is 0 or 1; R
6
is a hydrogen atom; and R
7
is an aromatic group.
In yet another embodiment, the invention provides compounds of the formula
where R
1
-R
5
are each, independently, a hydrogen atom or a normal or branched C
1
-C
6
-alkyl group; A is a mcthionyl, phenylalanyl or phenylglycyl residue; n is 0 or 1; and
In yet another embodiment, the present invention provides a method for treating cancer in a patient. The method comprises the step of administering to the patient a therapeutically effective amount of a compound of the invention. The invention also relates to the use of a compound of the invention for the manufacture of a medicament for treating cancer in a patient.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to peptides having antineoplastic activity. It also includes pharmaceutical compositions comprising these compounds and methods for treating cancer in a mammal, including a human, by administration of these compositions to the mammal.
Dolastatin 10, a peptide isolated from the sea hare
Dolabella auricularia
, is a potent inhibitor of cell growth. This compound, however, is present in trace quantities in the sea hare, and is thus difficult to isolate. Dolastatin 10 is also expensive to synthesize and suffers from poor aqueous solubility. As shown herein, however, Dolastatin 10 can serve as a starting point for the development of compounds which overcome these disadvantaes while retaining antineoplastic activity or exhibiting greater antineoplastic activity than the natural product. Applicants have discovered that certain structural modifications of Dolastatin 10 provide compounds with a surprisingly improved therapeutic potential for the treatment of neoplastic diseases as compared to Dolastatin 10. Furthermore, the compounds of the present invention can be conveniently synthesized, as described below in detail.
The present invention provides antitumor peptides of Formula I,
where R
1
-R
5
are each, independently, a hydrogen atom or a normal or branched C
1
-C
6
-alkyl group. A is a methionyl, phenylalanyl or phenylglycyl residue and n is 0 or 1. In one embodiment, R
6
is a hydrogen atom and R
7
is a carbocylic group, an aromatic group, a C
1
-C
4
-alkyl group, a pyridylalkyl group or a heterocyclic group. In another embodiment, R
6
is benzyl or —C(O)OR
8
, where R
8
is a C
1
-C
6
-alkyl group, and R
7
is a heteroaromatic group, such as a 2-thiazolyl group.
The peptides of Formula I are generally composed of L-amino acids but they can also contain one or more D-amino acids. Preferred compounds of the invention are of Formula I and have the stereochemistry indicated below for a peptide of Formula I wherein n=0.
In the following discussion, compounds of Formula I have the stereochemistry shown above unless otherwise indicated.
The present compounds can also exist as salts with pharmaceutically-acceptable acids, including hydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleic acid, fumaric acid, malic acid, succinic acid, malonic acid, sulfuric acid, L-glutamic acid, L-aspartic acid, pyruvic acid, mucic acid, benzoic acid, glucuronic acid, oxalic acid, ascorbic acid and acetylglycine.
In preferred embodiments, R
1
and R
2
are each methyl, R
3
is an isopropyl or sec-butyl group, R
4
is an isopropyl, sec-butyl or isobutyl group, and R
5
is sec-butyl.
In one embodiment, R
6
is a hydrogen atom and R
7
is selected from among methyl, t-butyl, isopropyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-(3-pyridyl)ethyl, 4-pyridyl and groups a-r, shown below. These and other groups depicted herein are identified by the appropriate letter in Tables 1-11.
In another embodiment, R
6
is —C(O)OCH
3
or benzyl and R
7
is 2-tlhiazolyl.
One subset of compounds of the present invention include pcntapeptides of formula I wherein R
1
and R
2
are each methyl, R
3
is isopropyl, R
4
is isopropyl, R
5
is sec-butyl, n is 1, A is a methionyl residue, R
6
is a hydrogen atom and R
7
is selected from among the groups j, k, m and n, shown above, and groups s, t and u, below.
Another subset of the compounds of the present invention include tetrapeptides of Formula I in which R
1
and R
2
are each methyl, R
3
and R
4
are each isopropyl, R
5
is sec-butyl, n is 0, R
6
is a hydrogen atom and R
7
is selected from among t-butyl, isopropyl, methyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-(3-pyridyl)ethyl, and pyryridyl, or R
7
is selected from among groups k, l, m, o, p, q and r.
Another subset of compounds of the present invention includes tetrapeptides of Formula I wherein R
1
and R
2
are each methyl, R
3
is isopropyl, R
4
and R
5
are each sec-butyl, n is 0, R
6
is a hydrogen atom and R
7
is selected from among groups s and t.
Another subset of the compounds of the present invention includes tetrapeptides of Formula I in which R
1
and R
1
are each methyl, R
3
is isopropyl, R
4
is isopropyl or sec-butyl, R
5
is sec-butyl, n is 0, R
6
is a benzyl group or —C(O)OCH
3
and R
7
is a 2-thiazolyl group.
Another subset of compounds of the invention include pentapeptides of Formula I wherein R
1
and R
2
are each methyl, R
3
is isopropyl, R
4
is isopropyl, R
5
is sec-butyl, n is 1, A is a phenylalanyl residue, R
6
is a hydrogen atom and R
7
is selected from among groups s a

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