Nitrogen-based camptothecin derivatives

Details Nitrogen-based camptothecin derivatives Nitrogen-based camptothecin derivatives

2002-05-23

2004-11-30

Kifle, Bruck (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S048000

Reexamination Certificate

active

06825207

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to novel camptothecin derivatives that are useful for treating various types of cancer.
BACKGROUND OF THE INVENTION
Camptothecin (often abbreviated as “CPT”), a phytotoxic alkaloid first isolated from the wood and bark of
Camptotheca acuminata
(Nyssaceae) by Wall and coworkers in 1966, was shown to have antitumor activity against the mouse leukemia L1210 system. The compound has a pentacyclic ring system with an asymmetric center in ring E with a 20 S configuration. The pentacyclic ring system includes a pyrrolo [3, 4-b] quinoline (rings A, B and C), a conjugated pyridone ring D), and six membered lactone (ring E) with an 20S-hydroxyl group. Camptothecin itself is essentially insoluble in water. Therefore, camptothecin was evaluated clinically as a water soluble sodium carboxylate salt in the early stages. It appears that the carboxylate salt was actually the compound where the E ring was open to form the sodium salt. This sodium salt produced severe toxicity and had very little anticancer activity. Thus early work on camptothecin was discontinued after starting phase II trials. However, interest in the compound revived when it was found to inhibit topoisomerase, an enzyme that is required for its swiveling and relaxation of DNA during molecular events such as replication and transcription. A number of syntheses and modifications of the molecule have been reported in the literature and new derivatives have been prepared over the years. For example, topotecan (9-dimethylaminomethyl-10-hydroxy CPT) and irinotecan (7-ethyl-10[4-(1-piperidino)-1-piperidino] carbonyloxy CPT) show clinical useful activity. This invention defines a new series of 20 S esters that are useful for treating various types of cancer. The novel compounds have higher potency and lower toxocity than CPT and other CPT derivatives.
SUMMARY OF THE INVENTION
One aspect of this invention is a compound of the formula (I), below,
wherein R is R
a
R
b
N(CH
2
)
m
, m is an integer of 1-10 (preferably 2), and each of R
a
and R
b
is independently
lower alkyl substituted with one to five substituents independently selected from the group consisting of halo, lower alkoxy, hydroxy, cyano, nitro, or amino;
phenyl optionally substituted with from one to five substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, formyl, lower alkyl carbonyl, hydroxycarbonyl, lower alkylcarbonyloxy, benzyloxy, optionally substituted piperidino, lower alkoxycarbonyl, and lower alkylcarbonylamino;
cycloalkyl of 3-7 carbons, optionally substituted with one to five substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, and lower alkylcarbonylamino;
lower alkoxy; or
R
a
R
b
together with N form a cyclic amine or imide ring;
R
2
is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RC(O)O (R defined hereinbefore), cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, —C(O)H, lower alkoxycarbonyl, tri lower alkylsilyl, lower alkylcarbonyloxy, lower alkylcarbonylamino, lower alkylcarbonyloxymethyl, substituted vinyl, 1-hydroxy-2-nitroethyl, alkoxycarbonylethyl, aminocarbonyl, alkylcarbonyl, alkylcarbonylmethyl, benzoylmethyl, benzylcarbonyloxymethyl, or mono- or di lower alkoxymethyl.
R
3
is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RC(O)O (R defined hereinbefore) cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, CH
2
NR
7
R
8
(where each of R
7
and R
8
is independently H—, alkyl of 1-6 carbons, optionally substituted phenyl, hydroxy lower alkyl, amino lower alkyl, or mono- or dialkylamino lower alkyl, or R
7
and R
8
taken together with —N— represent a cyclic amino-), —C(O)H, CH
2
R
9
(where R
9
is lower alkoxy, CN, amino lower alkoxy, mono- or di-lower alkylamino lower alkoxy, lower alkylthio, amino lower alkylthio, for mono- or di-lower alkylamino lower alkylthio), or NR
10
R
11
(where each of R
10
and R
11
is independently hydrogen, lower alkyl, phenyl, hydroxy lower alkyl, amino lower alkyl, or mono- or di-lower alkyl, or R
10
and R
11
taken together with —N— represent a cyclic amino), dialkylamino alkyl, lower alkylcarbonyloxy, or lower alkylcarbonylamino; and
R
4
is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RC(O)O (R defined hereinbefore) cyano, nitro, amino, amino lower alkyl, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, carbamoyloxy, lower alkylcarbonyloxy, or lower alkylcarbonylamino, or R
4
together with R
5
is methylenedioxy;
R
5
is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RC(O)O (R defined hereinbefore), cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, or lower alkylcarbonylamino; and
R
6
is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RC(O)O (R defined hereinbefore), cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxcarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, or lower alkylcarbonylamino.
Another aspect of the invention is a pharmaceutical composition useful for treating cancer in a warm-blooded animal, which composition comprises compound of the invention as defined herein in combination with a pharmaceutically acceptable excipient.
Another aspect of this invention is a method for treating cancer in a warm-blooded animal, which method comprises administering a therapeutically effective amount of a compound of the invention as defined herein. The compound is administered in a therapeutically effective dose by appropriate administration, e.g. orally, topically, or parenterally.
Another aspect of this invention is process for preparing compounds of this invention by reacting camptothecin (CPT) or a CPT analog with a compound of the formula R—C(O)X, wherein R is R
a
R
b
N(CH
2
)
2
, where R
a
and R
b
are as defined herein, and X is e.g. bromide, chloride, hydroxy, alkoxy of 1-11 carbons.
Other aspects of this invention will be apparent to one of skill in the art by reviewing the ensuing specification.


REFERENCES:
patent: 5916896 (1999-06-01), Wall et al.
patent: 5965566 (1999-10-01), Greenwald et al.
patent: 6207832 (2001-03-01), Curran et al.
patent: 6339091 (2002-01-01), Bigg et al.
patent: 6350756 (2002-02-01), Yang et al.
patent: 6403604 (2002-06-01), Yang et al.
patent: 0 861 842 (1998-09-01), None
patent: WO 98/28304 (1998-07-01), None
patent: WO 03/014069 (2003-02-01), None
Salmon et al. Oncology (1999), Chapter 162, Principles of Cancer Therapy.*
Balasubramanian et al. (Recent Developments in Cancer Cytotoxics) (Annual reprts in Medicinal Chemistry—33) (1998), pp. 151-159.*
Abstract of Keskin et al. (Anti-cancer Drug Res. (2000), 15(2), 79-98).*
Abstract of Singer et al. (Annals of the New York Academy of Sciences (2000), 922 (Camptothecins), 136-150).*
Shabat D et al., “Multiple event activation of a generic prodrug trigger by antibody catalysis”, Proceedings of the National Academy of Sciences of USA, 96:6925-6930, Jun. 1999.
Keskin, O. et al., “Characterization of anticancer agents by their growth inhibitory activity and relationships to mechanism of action and structrure”, Anti Cancer Drug Design, 15:2:78-98 (2000).
Bomgaars, et al., “The Development of Camptothecin Analogs in Childhood Cancers,” Oncologist 6:506-516 (2001).
Lerchen, “Milestones in Camptothecin Research,” Drugs of the Future 27:869-876 (2002).
Garcia-Carbonero et al., “Current Perspectives on the Clinical Experience, Pharmacology and Continued Development of the Camptothecins”,Clinical Cancer Research, Mar. 2002, vol. 8, 641-661.
Maliepaard et al., “Circumvention of breast cancer resistance protein (BCRP)-mediated resistance to camptothecins in vitro using non-sub

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