Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-05-03
2001-10-30
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06310210
ABSTRACT:
The present invention relates to new camptothecin derivatives which are water-soluble and excellent in an anti-tumor activity.
BACKGROUND ART
The present inventors have made an exploratory research on new camptothecin (hereinafter referred to CPT) derivatives with excellent anti-tumor activities and already provided many CPT derivatives, and it has been found out that in particular a group of derivatives prepared by a totally synthetic method have an excellent activity, which have a lower alkyl group in 7-position on the B-ring and various hetero substituents and an alkyl group in 9-, 10- and 11-position on the A-ring (see JP, A, H1-186892, U.S. Pat. No. 5,061,800). The present inventors have also made a development research for a method to make them water-soluble by various means in order to solve an administration problem, and found that regarding especially 7-ethyl CPT, the derivatives, in which the part of E-lactone ring is opened by use of the diamine and the hydroxymethyl group is protected by the appropriate acyl group, are excellent in the water solubility without decrease of an anti-tumor activity, contrasting to the E-ring opened water-soluble CPT derivatives known previously (see JP, A, H1-131179, U.S. Pat. No. 4,914,205).
Further, a new group of derivatives which were water-soluble and excellent in an anti-tumor activity were prepared and provided by derivatizing a group of derivatives having a lower alkyl group in 7-position on the B-ring and various hetero substituents and an alkyl group in 9-, 10- and 11-position on the A-ring into derivatives in which the E-lactone ring part is opened by the diamine and further the hydroxymethyl group is protected by an appropriate acyl group (see JP, A, H8-73461, AU, Pat. No. 688547). However, though these derivatives solve the water solubility problem, they are unstable in a basic water solution and not necessarily suitable for making a preparation such as an oral administration agent.
While realizing the water solubility favorable for administration, the creation of a new CPT derivative is needed which is excellent in an anti-tumor activity and in the stability in a basic water solution.
DISCLOSURE OF THE INVENTION
With the object to obtain derivatives having an extremely excellent characteristics in an anti-tumor activity, the present inventors have developed a group of new CPT derivatives in which the water solubility problem is solved and the stability in a basic water solution is improved by derivatizing a group of derivatives having a lower alkyl group in 7-position on the B-ring and various hetero substituents and an alkyl group in 9-, 10- and 11-position on the A-ring into the derivatives in which the E-lactone ring part is opened by the diamine and further the hydroxymethyl group is protected by a carbamate type or carbonate type protecting group.
The present invention provides camptothecin derivatives of the general formula (1)
wherein R
1
represents a hydrogen atom or an alkyl group with 1-6 carbon atoms,
R
2
represents identically or differently 0-4 alkyl groups with 1-6 carbon atoms, a halogen atom, an alkoxyl or hydroxyl group,
R
3
represents a lower alkylamino, di-lower alkylamino, arylamino, cyclic-amino or lower alkoxyl group, and salts thereof.
In the following, the present invention is described in more detail.
BEST MODE FOR CARRYING OUT THE INVENTION
New CPT derivatives according to the present invention can be prepared using as a starting material a derivative having a hydrogen atom or a lower alkyl group in 7-position and various hetero substituents and an alkyl group in 9-12 positions, treating this with N,N-dimethylethylenediamine and subsequently acylating the 17-hydroxyl group with an appropriate acylating agent into a carbonate or carbamate type. Each group of derivatives to be a starting material are the known CPT derivatives of natural origin (9-methoxy-CPT, 10-hydroxy-CPT, 10-methoxy-CPT, 11-hydroxy-CPT, 11-methoxy-CPT, etc.) or those obtained by a known semi-synthetic or totally synthetic method (see the specification in JP, A, 58-39684, JP, A, 58-134095, U.S. Pat. No. 4,473,692, U.S. Pat. No. 4,545,880, JP, A, 59-51287, JP, A, 59-51289, JP, A, H1-279891, U.S. Pat. No. 4,939,255, U.S. Pat. No. 5,061,795, JP, A, H1-186892, U.S. Pat. No. 5,061,800, JP, A, H4-503505, U.S. Pat. No. 4,981,968, JP, A, H5-502017, U.S. Pat. No. 5,049,668, WO91/04260, WO92/11263, U.S. Pat. No. 5,122,606, etc.).
Specifically, as R
1
in the general formula can be selected a hydrogen atom of the natural type, or a lower alkyl group with 1-6 carbon atoms and in these methyl, ethyl or propyl group are particularly preferable.
As R
2
in the general formula can also be selected 0-4 substiuents on the A-ring (9- to 12-position), though specifically, in 9-, 10-, 11- or 12-positions can be selected those substituted independently or together by hydroxyl, a lower alkoxyl group such as methoxyl, a halogen such as fluorine, chlorine or bromine, or a lower alkyl group such as methyl or ethyl, wherein one having fluoro group in 11-position and one having methyl group in 10-position are preferable, in particular one having fluoro group in 11-position and methyl group in 10-position together is preferable.
Further, as R
3
in the general formula can be selected a lower alkylamino group such as methylamino, ethylamino, propylamino or cyclohexylamino group, a lower dialkylamino group such as dimethylamino or diethylamino group, an arylamino group such as phenylamino or fluorophenylamino group, a cyclic-amino group such as 4-isopropylaminocarbonylpiperazinyl group, or a lower alkoxyl group such as methoxyl, ethoxyl or propoxyl group. Among these phenylamino, dimethylamino and methoxyl groups are particularly preferable.
The treatment with N,N-dimethylethylenediamine and the condition of the subsequent acylation of the 17-hydroxyl group by an acylating agent can be carried out in the same method disclosed by the present inventors in JP, A, H1-131179.
Namely, in the ring opening reaction of the E-lactone ring by N,N-dimethylethylenediamine, the reaction is carried out by not using a reaction solvent but by using only an excess amount of N,N-dimethylethylenediamine letting the conversion into a E-ring opening intermediate. Subsequently, an aimed substance can be obtained in a high yield by acylating the 17-hydroxyl group with a desirable acylating agent.
The acylating agents which can be used in the above acylation reaction are not specified, though illustrative of these are the corresponding alkylisocyanates, arylisocyanates, or the corresponding alkylcarbamoylchlorides or chloroalkyl-carbonates.
In the acylation reaction, pyridine, N,N-dimethylamino-pyridine or the like may be present together in the reaction as a catalyst. Further, it is possible to improve the yield of an aimed substance by keeping the condition as anhydrous as possible in processes except the ring opening reaction, that is, the acylation process, or in the later work-up processes such as a pulverization, purification and crystallization processes. The new CPT derivatives according to the invention are excellent in the solubility for water as salts with an appropriate acid such as hydrochloric acid, and excellent in the stability in an basic water solution. Further, the test results for their anti-tumor effects reveal that they have an excellent property and are extremely useful as a new anti-tumor agent.
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pa
Furuta Tomio
Ogawa Takanori
Sawada Seigo
Yaegashi Takashi
Desai Rita
Kabushiki Kaisha Yakul't Honsha
Rotman Alan L.
Wolf Greenfield & Sacks P.C.
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