Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-05-08
2002-07-02
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S212080, C540S524000, C540S526000, C540S527000
Reexamination Certificate
active
06413954
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the area of chemotherapeutic agents and, more particularly, relates to certain substituted caprolactam carbonates and ethers, and the use of said caprolactam carbonates and ethers in treating tumors.
BACKGROUND OF THE INVENTION
Cancer is a serious health problem throughout the world. Cancer incidence in the U.S. has increased 30% during the past 30 years, and is expected to continue to increase into the next century. This is attributable to increased prevalence of cigarette smoking by women, general aging of the population, enhanced diagnostic capabilities and, as well, potential decreases in mortality from other causes. As a result, an extensive number of research endeavors have been undertaken in an effort to develop therapies appropriate to the treatment and prevention of cancer in humans.
In the chemotherapeutic area, research has been conducted to develop anti-tumor agents effective against various types of cancer. Oftentimes, anti-tumor agents which have been developed and found effective against cancer cells are, unfortunately, also toxic to normal cells. This toxicity manifests itself in weight loss, nausea, vomiting, hair loss, fatigue, itching, hallucinations, loss of appetite, etc., upon administration of the anti-tumor agent to a patient in need of cancer chemotherapy.
Furthermore, conventionally used chemotherapeutic agents do not have the effectiveness desired or are not as broadly effective against different types of cancers as desired. As a result, a great need exists for chemotherapeutic agents which are not only more effective against all types of cancer, but which have a higher degree of selectivity for killing cancer cells with no or minimal effect on normal cells. In addition, highly effective and selective anti-tumor agents, in particular, against cancers of the colon, bladder, prostate, stomach, pancreas, breast, lung, liver, brain, testis, ovary, cervix, skin, vulva and small intestine are desired. Moreover, anti-tumor activity against colon, breast, lung and prostate cancers as well as melanomas are particularly desired because of the lack of any particular effective chemotherapy at the present time.
DESCRIPTION OF THE PRIOR ART
U.S. Pat. No. 4,831,135 discloses novel &dgr;-caprolactam derivatives with anti-tumor, antibiotic and anthelmintic activity.
J. Org. Chem.,
Vol. 51, pages 4494-4496 (1986) discloses the isolation and identification of certain caprolactam natural products which exhibit antiproliferative activity against eucaryotic cells, nematodes, and bacteria.
J. Am. Chem. Soc.,
Vol.111, pages 647-654 (1989) discloses the isolation and identification of certain caprolactam natural products.
J. Org. Chem.,
Vol. 55, pages 240-242 (1990) discloses the isolation and identification of certain caprolactam natural products which exhibit antiproliferative activity against nematodes and bacteria.
J. Nat. Prod.,
Vol. 60, pages 814-816 (1997) discloses the isolation and identification of certain caprolactam marine natural products.
J. Chem. Soc., Perkin Trans.
1 Issue 22, pages 2849-2854 (1995) discloses a process for preparing the caprolactam compound (+)-bengamide E.
J. Org. Chem.,
Vol. 60, pages 5910-5918 (1995) discloses a process for preparing the caprolactam compound (+)-bengamide E.
Heterocycles,
Vol. 38, pages 2383-2388 (1994) discloses a process for preparing the caprolactam compound bengamide B.
Tetrahedron Lett.,
Vol. 35, pages 6899-6902 (1994) discloses a process for preparing the caprolactam compound bengamide E.
Syn. Lett.,
Issue 12, pages 1007-1008 (1992) discloses a process for preparing the caprolactam compound bengamide E.
J. Chem. Soc., Chem. Commun.,
Issue 15, pages 1064-1066 (1992) discloses a process for preparing the caprolactam compound bengamide A.
J. Org. Chem.,
Vol.57, pages 5042-5044 (1992) discloses a process for preparing the caprolactam compound bengamide E.
Tetrahedron Lett.,
Vol. 32 pages 5907-5910 (1991) discloses a process for preparing the caprolactam compounds bengamide E and B.
Tetrahedron Left.,
Vol. 32, pages 3409-3412 (1991) discloses a process for preparing an intermediate useful for preparing the bengamide class of caprolactam compounds.
Tetrahedron Lett.,
Vol. 32, pages 1063-1066 (1991) discloses a process for preparing the caprolactam compound bengamide E.
J. Nat. Prod.,
Vol. 62, pages 678-680 (1999) discloses the isolation and identification of certain caprolactam marine natural products.
J. Nat Prod.,
Vol. 62, pages 1691-1693 (1999) discloses the isolation and identification of certain caprolactam marine natural products.
SUMMARY OF THE INVENTION
The present invention provides new anti-tumor agents which are effective against a variety of cancer cells. More particularly, the present invention relates to certain substituted caprolactam carbonates and ethers which exhibit a higher degree of selectivity in killing cancer cells. In addition, the present invention provides pharmaceutical compositions useful in treating tumors comprising a therapeutically effective amount of a certain substituted caprolactam carbonates and ethers. Moreover, the present invention provides a method of treating tumors comprising administering to a mammal afflicted therewith a therapeutically effective amount of certain substituted caprolactam carbonates and ethers. Furthermore, the present invention relates to a process for preparing certain substituted caprolactam carbonates and ethers.
DETAILED DESCRIPTION OF THE INVENTION
The essence of the instant invention is the discovery that certain substituted caprolactam carbonates and ethers are useful in treating tumors. In one embodiment, the instant invention provides new anti-tumor agents of formula I:
where
R
1
is (C
1-6
)alkyl or (C
3-6
)cycloalkyl;
R
2
is hydrogen or (C
1-6
)alkyl;
each X, independently, is (C
1-12
) alkylene;
each m, independently, is 0 or 1;
and R
3
is (C
1-12
) alkyl; (C
2-12
) alkenyl; (C
2-12
) alkynyl; (C
3-8
)cycloalkyl; or an aromatic ring system selected from II, III, IV and V:
where R
4
is hydrogen, chloro, or methoxy; R
5
is hydrogen, chloro, (C
1-18
)alkyl or (C
1-18
)alkoxy; and Z is oxygen, sulfur, N—H, or N—CH
3
;
or a pharmaceutically acceptable acid addition salt thereof, where possible.
Preferred compounds are those of formula Ia:
where
each m, independently, and R
3
are as defined above;
R
1
′ is (C
1-6
) alkyl;
R
2
′ is hydrogen or (C
1-4
) alkyl;
and each X′, independently, is (C
1-6
) alkylene;
or a pharmaceutically acceptable acid addition salt thereof, where possible.
More preferred compounds are those of formula Ib:
where
each m, independently, is as defined above;
R
1
″ is i-propyl or t-butyl;
R
2
″ is hydrogen or methyl;
R
3
′ is (C
1-6
)alkyl, (C
2-6
)alkenyl, (C
5-7
)cycloalkyl; or an aromatic ring system selected from IIa and V:
where R
4
′ is in the meta position and is hydrogen or chloro; and R
5
′ is in the para position and is hydrogen, chloro, (C
1-18
)alkyl or (C
1-18
)alkoxy;
and each X″, independently, is (C
1-6
) alkylene;
or a pharmaceutically acceptable acid addition salt thereof, where possible.
Even more preferred compounds are those of formula Ic:
where
each m, independently, is as defined above;
R
3
″ is (C
1-6
)alkyl, (C
5-7
)cycloalkyl, phenyl, 3,4-dichlorophenyl, 4-methoxyphenyl, 4-n-decylphenyl, 4-n-decyloxyphenyl or 3-pyridyl;
and each X″, independently, is as defined above.
In another embodiment, the instant invention provides pharmaceutical compositions useful in treating tumors comprising a pharmaceutically acceptable carrier or diluent and a therapeutically effective amount of a compound of formula I above, or a pharmaceutically acceptable acid addition salt thereof, where possible, preferably a compound of formula Ia above, or a pharmaceutically acceptable acid addition salt thereof, where possible, more preferably a compound of formula Ib above, or a pharmaceutically acceptable salt thereof, where possible, and even more preferably a compound
Bair Kenneth Walter
Kinder, Jr. Frederick Ray
Versace Richard William
Borovian Joseph J.
Kifle Bruck
Novartis AG
LandOfFree
Certain substituted caprolactam carbonates and ethers,... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Certain substituted caprolactam carbonates and ethers,..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Certain substituted caprolactam carbonates and ethers,... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2898154