Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-11-17
2001-05-29
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
Reexamination Certificate
active
06239127
ABSTRACT:
The present invention relates to the area of chemotherapeutic agents and, more particularly, relates to certain substituted caprolactams, pharmaceutical compositions comprising said caprolactams, a method of treating tumors, the use of said caprolactams in the chemotherapy of tumors, and a process for preparing said compounds.
Cancer is a serious health problem throughout the world. As a result, an extensive number of research endeavors has been undertaken in an effort to develop therapies appropriate to the treatment and alleviation 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 healthy 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 therapy at the present time.
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 caprolactams which exhibit a high degree of selectivity in killing cancer cells. The essence of the instant invention is the finding that certain substituted caprolactams are useful in treating tumors.
The invention relates to caprolactams 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;
X is (C
1-12
) alkylene; (C
2-12
) alkenylene; or (C
2-12
) alkynylene;
m is 0 or 1; and
R
3
is (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 of formula I are those where
R
1
is (C
1-6
) alkyl;
R
2
is hydrogen or (C
1-4
) alkyl;
X is (C
1-6
) alkylene or (C
2-6
) alkenylene;
m is 0 or 1; and
R
3
is (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.
More preferred compounds are those of formula I where
R
1
is i-propyl or t-butyl;
R
2
is hydrogen or methyl;
m is 0 or 1;
X is (C
1-6
) alkylene; and
R
3
is (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;
or a pharmaceutically acceptable acid addition salt thereof, where possible.
Even more preferred compounds are those of formula I where
R
1
is i-propyl or t-butyl;
R
2
is hydrogen or methyl;
m is 0 or 1;
X is methylene or ethylene; and
R
3
is (C
5-7
)cycloalkyl, phenyl, 3,4-dichlorophenyl, 4-methoxyphenyl, 4-n-decylphenyl, 4-n-decyloxyphenyl or 3-pyridyl;
with the proviso that when m is 0, R
3
is (C
5-7
)cycloalkyl, 4-n-decylphenyl or 4-n-decyloxyphenyl;
or a pharmaceutically acceptable acid addition salt thereof, where possible.
In another embodiment, the instant invention provides pharmaceutical compositions, especially for the treatment of tumors in warm-blooded animals, comprising a pharmaceutically acceptable carrier or diluent and a antitumorally effective dose of a compound of formula I above, preferably 3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-[hexahydro-2-oxo-6(cyclohexylcarbonyl)oxy-2H-azepin-3-yl]non-6-enamide or 3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-[hexahydro-2-oxo-6-(1-oxo-3-phenylpropoxy)-2H-azepin-3-yl]non-6-enamide, or a pharmaceutically acceptable acid addition salt thereof, where possible.
In still another embodiment, the instant invention provides a method for treating tumors comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula I above, or a pharmaceutically acceptable acid addition salt thereof, where possible.
In another embodiment, the instant invention relates to the use of a compound of formula I or of a pharmaceutically acceptable salt of such a compound for the preparation of a pharmaceutical composition for use in the chemotherapy of tumors.
Furthermore, the instant invention relates to the use of a compound of formula I or of a pharmaceutically acceptable salt of such a compound for the chemotherapy of tumors.
In the above definitions: 1) the alkyl groups containing 1 to 6 carbon atoms are either straight or branched chain, of which examples of the latter include isopropyl, isobutyl, t-butyl, isopentyl, neopentyl, isohexyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 1,1,2,2-tetramethylethyl; and 2) the alkyl and alkoxy groups containing 1 to 18 carbon atoms are either straight or branched chain.
The term “(C
1-12
) alkylene” as used herein refers to a straight or branched chain divalent group consisting solely of carbon and hydrogen and having from 1 to 12 carbon atoms. Examples of “alkylene” groups include methylene, ethylene, propylene, butylene, pentylene, 3-methypentylene, etc.
The term “(C
2-12
) alkenylene” as used herein refers to a straight or branched chain divalent group consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having from 2 to 12 carbon atoms. Examples of “alkenylene” groups include ethenylene, propenylene, butenylene, pentenylene, 3-methylpentenylene, etc.
The term “(C
2-12
) alkynylene” as used herein refers to a straight or branched chain divalent group consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having from 2 to 12 carbon atoms. Examples of “alkynylene” groups include acetylene, propynylene, butynylene, pentynylene, 3-methylpentynylene, etc.
The acid addition salts of the compounds of formula I may be those of pharmaceutically acceptable organic or inorganic acids. Although the preferred acid addition salts are those of hydrochloric and methanesulfonic acid, salts of sulfuric, phosphoric, citric, fumaric, maleic, benzoic, benzenesulfonic, succinic, tartaric, lactic and acetic acid may also be utilized.
The caprolactams of formula I may be prepared as depicted below:
where each R
1
, R
2
, X, m and R
3
is as defined above.
As to the individual steps, Step A involves the acylation of an aminocaprolactam of formula VI with a lactone compound of formula VII to obtain a diamide compound of formula VIII. The acylation is conducted in a polar, organic solvent, preferably a protic polar solvent such as isopropanol, at a temperature slightly below or at the reflux temperature of the solvent employed for a period of between 4 and 48 hours.
Step B concerns the hydrolysis of the 1,3-dioxane group common to a diamide compound of formula VIII, to obtain a substituted caprolactam compound of formula I. The hydrolysis is typically carried out by dissolving the diamide in
Bair Kenneth Walter
Jagoe Christopher Turchik
Kinder, Jr. Frederick Ray
Versace Richard William
Wattanasin Sompong
Borovian Joseph J.
Kifle Bruck
Novartis AG
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