Methods for inhibiting the growth of tumors with...

Details Methods for inhibiting the growth of tumors with... Methods for inhibiting the growth of tumors with...

2000-08-22

2001-10-23

Rotman, Alan L. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S051000, C546S048000

Reexamination Certificate

active

06306868

ABSTRACT:

The present invention relates to derivatives of camptothecin, to a process for their preparation, to their use as active ingredients for the preparation of medicament useful in the treatment of tumors, and to pharmaceutical preparations containing them.
The antitumoral agent 20S-camptothecin, of formula
where R
1
, R
2
and R
3
are hydrogen, discovered in 1966 by M. E. Wall et al. (J. Amer. Chem. Soc. 88, 3888-90 (1966), after a preliminary clinical evaluation was withdrawn as a therapeutic agent because of its toxicity for man and of its low solubility, which made difficult its administration in suitable pharmaceutical preparations. The attention of academic and industrial researchers was then devoted to the synthesis of camptothecin analogues with improved therapeutic profile. Two out of the numerous analogues described by the above drawn formula, namely Topotecan, where R
1
is hydrogen, R
2
is the —CH
2
—NH(CH
3
)
2
group, R
3
is OH, and CPT-11, where R
1
is ethyl, R
2
is hydrogen, and R
3
is
have recently become available to the oncologist for the treatment of some tumors (J. of Clinical Oncology, 10, 1775-80 (1992); J. of the National Cancer Inst. 85, 271 (1993). Other derivatives presently in clinical trials are 9-aminocamptothecin and the analogue of formula:
(Cancer Treatment Reviews 20, 73-96 (1994)).
Most synthetic efforts have been devoted to the introduction of suitable substituents to overcome the problem of the scarce water solubility that characterizes this class of compounds, and that can lead to difficulties in their formulation and to unpredictable plasma levels of the drug. Moreover, the persistence of the lactone ring in closed form is an important factor for the antitumor efficacy.
The relevance of this class of compounds is also due to their peculiar mechanism of action: in fact they display their antitumoral effects by inhibiting topoisomerase I, an enzyme that regulates DNA topology and therefore plays a critical role in essential cellular pathways such as DNA replication, transcription, recombination and repair (C. Capranico and F. Zunino, Current Pharm. Design, 1, 1-14 (1995). The need for new drugs effective against colorectal, non small cell lung carcinoma, ovarian tumors and prostatic carcinoma, still little responsive to chemotherapeutic treatment, makes rewarding the search for new camptothecin derivatives with improved pharmacological properties.
It has now been found that derivatives of camptothecin and of 10-hydroxycamptothecin carrying substituents at carbon C-7 exhibit antitumor activity and possess favourable physico-chemical properties that allow their formulation in suitable pharmaceutical compositions.
The present invention comprises compounds of formula (I),
wherein:
R
1
is —CN, —CH(CN)—R
4
, —CH═C(CN)—R
4
, —CH
2
—CH(CN)—R
4
, —C(═NOH)—NH
2
, —C(═NH)—NH
2
, —CH═C(NO
2
)—R
4
, —CH(CN)—R
5
, —CH(CH
2
NO
2
)—R
5
; 5-tetrazolyl, 2-(4,5-dihydrooxazolyl), 1,2,4-oxadiazolin-3-yl-5-one;
R
2
is hydrogen;
R
3
is hydrogen, OR
6
;
R
4
is hydrogen, C
1
-C
6
linear or branched alkyl, CN, COOR
7
;
R
5
is hydrogen, OR
8
;
R
6
is hydrogen, C
1
-C
6
linear or branched alkyl, (C
6
-C
12
) aryl (C
1
-C
4
) alkyl, (C
1
-C
4
) alkoxy (C
1
-C
4
) alkyl, (C
1
-C
4
) alkyl (C
6
-C
12
) aryl, (C
6
-C
12
) aryl (C
2
-C
4
) acyl, (C
2
-C
4
) acyl, amino (C
1
-C
4
) alkyl, amino (C
2
-C
4
) acyl, glycosyl;
R
7
is hydrogen, C
1
-C
6
linear or branched alkyl, (C
6
-C
12
) aryl (C
1
-C
4
) alkyl, (C
1
-C
4
) alkoxy (C
1
-C
4
) alkyl, (C
1
-C
4
) alkyl (C
6
-C
12
) aryl;
R
5
has the same meanings of R
6
, independently of the latter;
their N
1
-oxides, their isomers, diastereoisomers, enantiomers and mixtures thereof, as well as their metabolites, in particular active metabolites.
The present invention includes also the pharmaceutically acceptable salts.
The present invention includes the use of compounds of formula (I) as active ingredients for the preparation of medicaments, in particular medicaments useful for the treatment of tumors.
The present invention includes pharmaceutical compositions containing compounds of formula (I) as active ingredients.
The present invention includes a process for the preparation of compounds of formula (I).
The present invention includes the use of compounds of formula (I) wherein R
1
is CN as intermediates for the preparation of other compounds of formula (I), wherein R
1
is —C═(NOH)—NH
2
, —C(═NH)—NH
2
, 5-tetrazolyl, 2-(4,5-dihydrooxazolyl).
Examples of C
1
-C
6
alkyl are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, 2-methylbutyl, isopentyl, hexyl, 3-methylpentyl, 2-ethylbutyl.
Example of (C
6
-C
12
) aryl (C
1
-C
4
) alkyl are: benzyl, mono or polysubstituted C
1
-C
6
alkyl benzyl, &agr;- or &bgr;-phenylethyl, mono- or poly C
1
-C
4
alkyl-substituted &agr;- or &bgr;-phenylethyl, mono or poly C
1
-C
4
alkyl-substituted &agr;-, &bgr;- or &ggr;-phenylpropyl, &agr;- or &bgr;-naphthylmethyl, mono or poly C
1
-C
2
alkyl substituted &agr;- or &bgr;-naphthylmethyl.
Examples of (C
1
-C
2
) alkoxy (C
1
-C
4
) alkyl are methoxymethyl, ethoxyethyl, ethoxymethyl, propoxyethyl, butoxyethyl.
Examples of (C
1
-C
4
) alkyl (C
6
-C
12
) aryl are tolyl, xylyl, ethylphenyl, isopropylphenyl, terbutylphenyl, methylnaphthyl.
Examples of (C
6
-C
12
) aryl (C
2
-C
4
) acyl are phenylacetyl, naphthylacetyl, 2-phenylpropionyl, 3-phenylpropionyl, 2-, 3- or 4-phenylbutirryl, mono, di- or tri (C
1
-C
4
) alkyl substituted phenylacetyl.
Examples of C
2
-C
4
acyl are acetyl, propionyl, butirryl and their isomers.
Examples of amino (C
1
-C
4
) alkyl and amino (C
2
-C
4
) acyl are C
1
-C
4
alkyl and C
2
-C
4
acyl wherein the amino substituents can be in any position of the carbon chain.
Examples of pharmaceutically acceptable salts are:
in case of a basic nitrogen atom, salts with pharmaceutically acceptable acids, both inorganic and organic, such as hydrochloric acid, sulfuric acid, acetic acid, in case of an acid group, such as —COOH, salts with pharmaceutically acceptable bases, both inorganic and organic, such as alkali and alkaline earth hydroxides, ammonium hydroxide, amines.
The compounds of formula (1) may be in the form of pharmaceutically acceptable salts and/or of N
1
-oxides. A list of preferred groups of compounds is given below.
A first group of preferred compounds includes compounds of formula (I) where R
3
is hydrogen.
A second group of preferred compounds includes compounds of formula (I) where R
3
is OR
6
and R
6
is as above defined.
A third group of preferred compounds includes compounds of formula (I) wherein R
1
is CN, R
3
is hydrogen or OR
6
, and R
6
is as above defined.
A fourth group of preferred compounds includes compounds of formula (I) wherein R
1
is CH(CN)—R
4
, wherein R
4
is preferably CN or COOR
7
, R
7
being as above defined.
A fifth group of preferred compounds includes compounds of formula (I) wherein R
1
is CH(═NOH)NH
2
, R
3
is OR
6
, as defined above.
A sixth group of preferred compounds includes compounds of formula (I) wherein R
1
is CH(═NH)NH
2
, R
3
is OR
6
, as defined above.
A seventh group of preferred compounds includes compounds of formula (I) wherein R
1
is CH=C(CN)R
4
, wherein R
4
is preferably CN or COOR
7
, R
7
being as above defined, in particular R
4
is CN, R
2
and R
3
are hydrogen.
An eighth group of preferred compounds includes compounds of formula (I) wherein R
1
is CH(CH
2
NO
2
)R
5
, R
5
is OR
8
according to the above definitions.
A ninth group of preferred compounds includes compounds of formula (I) wherein R
1
is CH═C(NO
2
)—R
4
, wherein R
4
is H, R
3
is OR
6
according to the above definitions.
Compounds of formula (I) particularly preferred are those where R
1
is CN or CH═C(CN)
2
or —CH
2
CH(CN)—R
4
and R
2
and R
3
are hydrogen.
The compounds of formula (I) can be obtained starting from camptothecin-7-methanol (II, R
1
=CH
2
OH, R
2
=H, R
3
=H) or from 10-hydroxycamptothecin-7-methanol (II, R
1
=CH
2
OH, R
2
=H, R
3
&e

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