Organic compounds -- part of the class 532-570 series – Organic compounds – Chalcogen in the nitrogen containing substituent
Reexamination Certificate
1998-07-15
2001-02-06
Woodward, Michael P. (Department: 1654)
Organic compounds -- part of the class 532-570 series
Organic compounds
Chalcogen in the nitrogen containing substituent
C530S313000, C530S333000, C546S001000, C546S249000, C548S400000, C568S591000, C568S604000
Reexamination Certificate
active
06184374
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention is in the field of the chemistry of targeting anticancer anthracycline derivatives. More particularly, it concerns doxorubicin (DOX) or its daunosamine modified derivatives (DM-DOX) linked covalently to analogs of peptide hormones such as LH-RH, bombesin and somatostatin. These covalent conjugates are targeted to various tumors bearing receptors for the peptide hormone analogs.
2. Discussion of the Prior Art
LH-RH Analogs which have cytotoxic moieties at the sixth position are shown in Schally, Janaky and Bajusz, European Patent Publication number 0 450 461 B1, grant publication Sep. 6, 1995.
GnRH (LH-RH) analogs for destroying gonadotrops are described in Nett and Glode, European Patent, international Publication No.: WO 90/09799 published on September 7, 1990.
The patent describes toxins, like ricin, linked to analogs of LH-RH for destroying gonadotrophs and thus curing sex hormone dependent cancers. LH-RH doxorubicin derivative is also mentioned without specification of the chemistry of linking.
Cytotoxic somatostatin analogs are described by Schally et al. in U.S. Patent application filed on Apr. 6, 1990 and refiled in Jul. 15, 1993 under Ser. No. 08/076,846.
A review by A. V. Schally in
Anti-Cancer Drugs
5, 115-130 (1994) gives details about the presence of receptors on the cell membranes of a wide variety of tumors for analogs of LH-RH, bombesin or somatostatin.
G. Weckbecker lists several references that show the presence of receptors and receptor subtypes for somatostatin analogs on several normal and tumorous tissues in his review in
Farmac. Ther.
60, 245-264 (1993).
Bombesin-like peptides and the presence of bombesin/GRP receptors for them on various normal and tumorous tissues are discussed in the review by N. Bunnett in
Gut Peptides: Biochemistry and Physiology
423-445 (1994) Ed.: J. Walsh and G. J. Dockray, Raven Press, New York and by E. Spindell in
Recent Progress in Hormone Research
48, (1993) (Academic Press).
Doxorubicin is, at this time, the most widely used, and very potent anticancer agent. However, certain tumors do not respond to it at all and its use is also limited by multidrug resistance (MDR) and cardiotoxicity as well as neutropenia, which are the results of chronic treatment. In order to overcome these drawbacks and to further exploit the enormous tumoricidal potential inherent in the structure of anthracycline antibiotics, thousands of synthetic derivatives have been described, including their targeted analogs linked to various carrier macromolecules.
Most of the history of DOX and its analogs is described in “Adriamyc-in”, David W. Henry,
ACS Symposium Series, No.
30,
Cancer Chemotherapy, American Chemical Society,
pp. 15-57 (1976) and in the book Doxorubicin, Federico Arcamone, Academic Press, (1981).
Highly active, alkylating, non-cross resistant 3′-deamino-3′-(3″-cyano-4″-morpholinyl)DOX and derivatives thereof which have antitumor activity are described in Mosher, et al., U.S. Pat. No. 4,464,529, Aug. 7, 1984. The synthesis and biological evaluation of these “Intensely Potent Morpholinyl Anthracyclines” are also described in
J. Med. Chem.
1984, 27, 638-645.
In
Proc. Natl. Acad. Sci. USA
Vol. 88, pp. 4845-4849, June 1991. Gao et al. describe formaldehyde-mediated alkylation of a DNA sequence by a daunorubicin derivative.
Anthracycline analogues bearing latent alkylating substituents are described in
J. Med. Chem.
35, 3208-3214 (1992).
The use of an &agr;-,&ohgr;-diiodo compound for the alkylation of the daunosamine nitrogen of DOX and thus the formation of a new morpholinyl DOX derivative is described in European Patent EP 434 960, filed by Pharmacia Carlo Erba on Dec. 12, 1989.
N-Trifluoroacetyladriamycin
14
-O-hemiglutarate and -hemiadipate are disclosed as analogs of N-trifluoroacetyladriamicyn
14
-O-valerate (AD-32) with improved water solubility in Israel, et al., U.S. Pat. No. 4,299,822, Nov. 10, 1981.
Horton and Priebe (
J. Antibiotics
, XXXVI, 1211-1215.) describe several 14-O-esters of different anthracycline analogs with no dramatic changes in anticancer activity as compared to the 14-OH parent analogs.
In the art of designing targeted chemotherapeutic agents, the following objectives are sought:
1. Stable linkage between the carrier molecule and the chemotherapeutic agent until the target is reached.
2. Retained biological characteristics of the carrier molecule within the conjugate, such as retained binding properties.
3. Retained pharmacological activity of the chemotherapeutic agent within the conjugate, such as retained cytotoxic activity.
4. As a result of conjugation, the production of analogs of more intense activity and/or lower peripheral toxicity relative to the unconjugated moieties.
Conjugation of DOX by NalO
4
oxidation of the daunosamine moiety of DOX followed by reductive alkylation involving a primary amine of a carrier molecule is described in Sela, et al., U.S. Pat. No. 4,263,279, Apr. 21, 1981.
A cis-aconitic acid spacer was used to link the daunosamine nitrogen to macromolecular carriers with a pH-sensitive bond, as described in
Biochem. Biophys. Res. Commun.
1981 102, 1048-1054.
Morpholino-DOX (a highly active, daunosamine modified analog of DOX) was conjugated to antibody via a hydrolyzable (lysosomotrop, pH sensitive) hydrazone linkage, involving the C-13 oxo function of the cytotoxic agent, as described in
Bioconjugate Chemistry
1990 1(5), 325-330.
Sensitivity of the carboxamide bond of a leucine residue to enzymatic degradation was used successfully in conjugates of DOX containing a “spacer arm” peptide, preferentially Ala-Leu-Ala-Leu, where the carboxy terminal Leu acylates the daunosamine nitrogen in DOX and the amino terminal Ala is linked to the carrier through dicarboxylic acid spacer as described in
Proc. Natl. Acad. Sci. USA
1982 79, 626-629.
The daunosamine nitrogen of DOX was acylated by a glutaric acid spacer and linked to LH-RH analogs with a severe loss of cytotoxic activity as described in
Proc. Natl. Acad. Sci. USA
1992 89, 972-976.
All the citations referred to are incorporated herein by reference.
SUMMARY OF THE INVENTION
The compounds of the invention are novel, targeted cytotoxic peptide hormones comprising an anthracycline cytotoxic agent, such as DOX or DM-DOX, conjugated to a peptide hormone, such as analogs of LH-RH, bombesin, and somatostatin. These cytotoxic peptide hormone conjugates are designed for the treatment of tumors bearing specific receptors for the conjugate, such as breast cancer, ovarian, cancer, endometrial cancer, prostate cancer, pancreatic cancer, colon cancer, gastric cancer, and lung cancer. Certain of these (unconjugated) anthracycline cytotoxic agents utilized herein are per se novel, and are highly potent, their level of toxicity however is too high for them to be used in unconjugated form.
Daunosamine modified DOX analogs presented in this invention were developed during a search for new, highly active, non-cross resistant analogs of DOX suitable for the formation of covalent conjugates with peptide carriers.
The formation of stable, covalently linked conjugates with fully retained biological activities of their components was achieved by using a dicarboxylic acid spacer, like glutaric acid. One carboxyl group of the spacer forms an ester bond with the 14-OH group of DOX or DM-DOX and the other carboxyl group of the spacer forms a carboxamide bond with a well chosen free amino group of the peptide carrier.
The compounds of this invention are represented by General Formula
Q
14
—O—R—P I
wherein Q has the general formula
wherein: Q
14
signifies a Q moiety with a side chain at the 14 position, R— is H or —C(O)—(CH
2
)
n
—C(O)— and n=0-7,
R′ is NH
2
or an aromatic, saturated or partially saturated 5 or 6 membered heterocyclic compounds having at least one ring nitrogen and optionally having a butadiene moiety bonded to adjacent carbon atoms of said ring to form a bicyclic system,
P is H or a peptide moiety, suitably an L
Cai Ren-Zhi
Nagy Attila A.
Schally Andrew V.
Behr, Esq. Omri M.
Gupta Anish
The Administrators of the Tulane Educational Fund
Woodward Michael P.
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