Dolastatin 15 derivatives

Details Dolastatin 15 derivatives Dolastatin 15 derivatives

2000-07-18

2002-10-01

Jones, Dwayne C. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S002600, C514S017400, C530S329000, C530S330000

Reexamination Certificate

active

06458765

ABSTRACT:

BACKGROUND OF THE INVENTION
A number of short peptides with significant activity as inhibitors of cell growth have been isolated from the Indian Ocean sea hare
Dolabella auricularia
(Bai et al.,
Biochem. Pharmacology
, 40: 1859-1864 (1990); Beckwith et al.,
J. Natl. Cancer Inst
., 85: 483-488 (1993) and references cited therein). These include Dolastatins 1-10 (U.S. Pat. No. 4,816,444, issued to Pettit et al.) and Dolastatin-15 (European Patent Application No. 398558). Dolastatin 15, for example, markedly 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.
The exceedingly small amounts of the various 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 these compounds (Roux et al.,
tetrahedron
50: 5345-5360 (1994); Shioiri et al.,
tetrahedron
49: 1913-24 (1993); Patino et al.,
tetrahedron
48: 4115-4122 (1992) and references cited therein). Synthetic Dolastatin 15, however, suffers from drawbacks which include poor solubility in aqueous systems and the need for expensive starting materials for its synthesis. These, in turn, have led to the synthesis and evaluation of structurally modified Dolastatin 15 derivatives [cf.:
Biorg. Med. Chem. Lett
. 4: 1947-50 (1994); WO 93 03054; JP-A-06234790; WO 93 23424].
However, there is a need for synthetic compounds with the biological activity of Dolastatin 15 which have useful aqueous solubility and can be produced efficiently and economically.
SUMMARY OF THE INVENTION
Compounds of the present invention include cell growth inhibitors which are peptides of Formula I,
A-B-D-E-F-(G)
r
-(K)
s
,-L   (I),
and acid salts thereof, wherein A, B, D, E, F, G and K are &agr;-amino acid residues, and s and r are each, independently, 0 or 1 L is a monovalent radical, such as, for example, an amino group, an N-substituted amino group, a &bgr;-Phydroxylamino group, a hydrazido group, an alkoxy group, a thioalkoxy group, an aminoxy group, or an oximato group.
Another aspect of the present invention includes pharmaceutical compositions comprising a compound of Formula I and a pharmaceutically acceptable carrier.
An additional embodiment of the present invention is a method for treating cancer in a mammal, such as a human, comprising administering to the mammal an effective amount of a compound of Formula I in a pharmaceutically acceptable composition.
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 15, 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 15 is also expensive to synthesize and suffers from poor aqueous solubility. As shown herein, however, Dolastatin 15 can serve as a starting point for the development of compounds which overcome these disadvantages while retaining antineoplastic activity or exhibiting greater antineoplastic activity than the natural product. Applicants have discovered that certain structural modifications of Dolastatin 15 provide compounds with a surprisingly improved therapeutic potential for the treatment of neoplastic diseases as compared to Dolastatin 10 and Dolastatin 15. Furthermore, the compounds of the present invention can be conveniently synthesized, as described below in detail.
For the purposes of the present invention, the term “monovalent radical” is intended to mean an electrically neutral molecular fragment capable of forming one covalent bond with a second neutral molecular fragment. Monovalent radicals include the hydrogen atom, alkyl groups, such as methyl, ethyl and propyl groups, halogen atoms, such as fluorine, chlorine and bromine atoms, aryl groups, such as phenyl and naphthyl groups, and alkoxy groups, such as methoxy and ethoxy groups. Two monovalent radicals on adjacent sigma-bonded atoms can also together form a pi bond between the adjacent atoms. Two monovalent radicals may also be linked together, for example, by a polymethylene unit, to form a cyclic structure. For example, the unit-N(R)R′, wherein R and R′ are each a monovalent radical, can, together with the nitrogen atom, form a heterocyclic ring. In addition, two monovalent radicals bonded to the same atom can together form a divalent radical, such as an oxygen atom or an alkylidene group, for example, a propylidene group.
For the purposes of the present invention, the term “normal alkyl” refers to an unbranched, or straight chain, alkyl group, for example, normal propyl (n-propyl,—CH
2
CH
2
CH
3
).
The compounds of the present invention can be represented by Formula I,
A-B-D-E-F-(G)
r
-(K)
s
-L   (I),
wherein A, B, D, E, F, G, and K are &agr;-amino acid residues; s and r are each, independently, 0 or 1; and L is a monovalent radical such as an amino group, an N-substituted amino group, a &bgr;-Phydroxylamino group, a hydrazido group, an alkoxy group, a thioalkoxy group, an aminoxy group, or an oximato group.
The peptides of Formula I are generally composed of L-amino acids but they can contain one or more D-amino acids. In the following discussion, reference to a particular amino acid includes both enantiomers unless a specific enantiomer is indicated. The present compounds can also be present as salts with physiologically-compatible 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.
The following is a description of the present invention, including a detailed description of individual components and of methods of using the claimed compounds.
Compounds of the Present Invention
Identity of A
In one embodiment, A is a proline derivative of Formula II
a
,
where n
a
is an integer, preferably 0, 1, 2, or 3. R
a
is a monovalent radical, such as a hydrogen atom or an unsubstituted or fluorine-substituted alkyl group, for example a normal, branched or cyclic C
1
-C
3
-alkyl group which is, optionally, substituted by from 1 to about 3 fluorine atoms; suitable examples include methyl, ethyl, isopropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, 1-methyl-2-fluoroethyl, 1-fluoromethyl-2-fluoroethyl or cyclopropyl; methyl, ethyl or isopropyl are preferred;
In this embodiment, R
1
a
is a monovalent radical, such as a hydrogen atom, an alkyl group, such as a methyl, ethyl or propyl group, or a phenyl group. The phenyl group can be substituted; suitable substituents include one or more halogen atoms, with fluorine, chlorine and bromine atoms preferred, C
1
-C
4
-alkyl groups, methoxy, ethoxy, trifluoromethyl or nitro groups. R
a
and R
1
a
together can also form a propylene bridge. R
2
a
, R
3
a
, R
4
a
and R
5
a
are each, independently, a monovalent radical, such as a hydrogen atom or an alkyl, preferably, methyl, group.
In another embodiment, A is a substituted glycine derivative of Formula III
a
,
where R
a
has the meaning stated for R
a
in Formula II
a
and, R
1
a
is a monovalent radical, for example, a hydrogen atom or a C
1
-C
6
-alkyl group, preferably a methyl, ethyl or propyl group.
In this embodiment, R
6
a
is a monovalent radical, such as an alkyl, substituted alkyl, alkenyl, phenyl or substituted phenyl group. Suitable examples include methoxymethyl, 1-methoxyethyl, 1,1-dimethyl-hydroxymethyl, 1-trifluoromethylethyl, 1-trifluoromethyl-2,2,2-trifluoroethyl

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