Intermediates for the synthesis of camptothecin derivatives

Details Intermediates for the synthesis of camptothecin derivatives Intermediates for the synthesis of camptothecin derivatives

1999-03-26

2001-01-23

Low, Christopher S. F. (Department: 1653)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S048000, C564S305000, C548S181000, C562S405000

Reexamination Certificate

active

06177568

ABSTRACT:

TECHNICAL FIELD
This invention relates to camptothecin derivatives and pharmaceutically acceptable salts thereof, expressed by the following chemical formula (I), its manufacturing method and antineoplastic agent containing it as an active ingredient
Wherein;
R is hydrogen or —(CH )
2
—NR
1
R
2
, (R
1
is hydrogen or a general protecting group of amine; R
2
is a lower alkyl, hydroxyethyl or acetoxyethyl; further, R
2
may form heterocyclic compound by binding with an adjacent nitrogen);
n is 1 or 2; R
3
is hydrogen or —OR
4
[R
4
is hydrogen or
(R
5
is methyl or CH
3
OCH
2
—);
(R
6
is isopropyl, phenyl or —CH
2
CH
2
Cl.); CH
2
OR
7
(R
7
is methyl, ethyl or CH
3
OCH
2
CH
2
—)];
wherein;
When n is 2 and R
4
is hydrogen, R is not hydrogen;
and when n is 2 and R
3
is H, R is not hydrogen;
also, when R is —CH
2
CH
2
NHCH
3
, R
3
is not hydrogen.
BACKGROUND OF ART
Since the isolation of camptothecin from the Chinese tree,
Camptotheca acuminata
, by Wall and co-workers (J. Am. Chem. Soc., 1966, 88, 3888), there had been many approaches to synthesize camptothecin. However, the development of camptothecin as an effective antineoplastic agent was unsuccessful due to its severe toxicity in the first clinical trial in 1970.
Thereafter, Liu et al. reported in 1985 that camptothecin had a specific mode of action to inhibit topoisomerase I. Thus, considerable interest has focused on this compound. In particular, since topoisomerase I inhibitor itself was not used clinically, it is expected that with its actual development, camptothecin may be very efficiently used in combination with other antineoplastic chemotherapeutics having different modes of action.
Recently, various studies for the development of camptothecin derivatives have been proposed in order to reduce the toxicity of camptothecin and to further enhance its antineoplastic activities. Among these related studies, the clinical trial of CPT-11(Irinotecan) synthesized by Yakurt-Honsha Co. of Japan in 1986 showed that it exhibited excellent antineoplastic activities with less toxicity (Japanese Patent Laid Open Publication No. 64-61482) and followed by other pharmaceutical companies such as Smithkline Beecham (Topotecan) and Glaxo (MDO-camptothecin and 9-aminocamptothecin). Among them, CPT-11 is launched. In particular, it is noticeable that said CPT-11 compound has exhibited excellent antineoplastic activities in the treatment of incurable solid tumors such as the lung cancer.
Since a majority of camptothecin derivatives developed hitherto were semi-synthetic compounds which were obtained from the chemical modification of camptothecin, there were some difficulties in procuring camptothecin and in developing derivatives with a variety of structures because of restrictions of said chemical modification. In addition, these reported total synthesis are not satisfactory in view of both chemical and optical yields.
DISCLOSURE OF INVENTION
Accordingly, the inventor et al. have confirmed that through the total synthesis for a series of novel compounds expressed by said general formula (I) and followed by in vitro test, these compounds with different mode of action may be used as effective antineoplastic agents. Thus, the present invention has been completed.
Camptothecin is a fused ring system, composed of a quinoline (A and B), fused to a pyrrolidine ring (C), fused to an alpha-pyridone ring (D) which in turn is fused to a lactone ring(E).
In particular, further careful review has been made on camptothecin's mode of action to inhibit topoisomerase I and various structures of camptothecin derivatives developed hitherto, and attempts have been also made in such a manner to modify the substituents of B-ring or E-ring in camptothecin.
In consideration of the fact that the conventionally developed derivatives have suffered from some side effects such as nausea, vomiting and cystitis due to extremely poor water solubility, the introduction of side chain at B-ring of camptothecin was made in such a manner that in order to enhance the solubility. Hence, the side chain including amino groups was introduced at the 7-position of camptothecin.
In view of the mode of action suggested by Crow that camptothecin binds covalently with topoisomerase I [
J. Med. Chem.,
1992, 35, 4160-4164], the modification of camptothecin at E-ring was attempted so as to enhance its reactivity.
The processes for manufacturing camptothecin derivatives and its intermediates are described in more detail as set forth hereunder, in accordance with the practice of this invention.
The compounds based upon EXAMPLES can be prepared in accordance with the practice of this invention as specified in the following Scheme 1.
Wherein;
R, n and R
3
are the same as described in the above and R′ is hydrogen or —(CH
2
)
2
—NR
1
R
2
; R
1
is a general protecting group of amine; R
2
is the same as described in the above. Friedlander condensation of aminoketone compound(II) with tricyclic Ketone(III) affords the compound expressed by the general formula (I) [Organic reactions, 28, 37-202, Wiley & Sons Inc, New York (1932)].
The condensation of the compounds (II) and (III) is conducted, in general, in the presence of acid at room temperature or under the heating condition.
The following inert solvents should be used for the reactions so as not to affect the reactions, for example, aromatic hydrocarbons(toluene, benzene, xylene etc.), hydrocarbon halide(dichloromethane, chloroform, 1,1-dichloroethane, 1,2-dichoroethane etc.), lower alcohols, amides (N,N-dimethylformamide etc.), or acetic acid.
The reactions may be conducted using inorganic acid(hydrochloric acid or sulfuric acid) or organic acids (methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, acetic acid, etc.).
The reaction time ranges from 1 to 48 hrs, and the reaction temperature is 30 to 150° C.
As a typical reaction condition, it is most preferable that reflux is made available in the presence of p-toluenesulfonic acid in toluene.
When R is —CH
2
CH
2
NHR
2
(R
1
is hydrogen) in the synthesis of general formula (I), said amino protecting group is removed through the catalytic hydrogenation using platinum or palladium.
When R′ is hydrogen in the compound (II), compound(I) is obtained after carbonyl group of the compound(II) is protected by acetalization with ethylene glycol or by formation of shiff base with p-toluidine according to known process. [Chem. Ber. 76, 1099(1943)].
When R
3
is hydroxy group in the compound(III), thus obtained compound(I), wherein R
3
is hydroxy group, is reacted with such reagents as
and R
7
OCH
2
Cl to produce the compound(I) wherein the hydroxy group of R
3
is thus modified.
In particular, when R
6
NCO is used, the compound expressed by the general formula (I) can be obtained by using the catalytic amounts of tin complex (e.g., di-n-butyltin diacetate, etc.).
The aminoketone(II) can be prepared in accordance with Scheme 2.
Wherein;
R′, R
1
and R
2
are the same as described in the above.
A novel aminoketone compound(II) of this invention can be prepared as follows:
2′-nitroacetophenone reacts with monoalkylamine (e.g., ethylamine, propylamine or isopropylamine), monoarylamine(e.g., benzylamine) or dialkylamine(e.g., morpholine, piperidine or diethylamine) in the presence of conc. hydrochloric acid, through Mannich reaction with paraformaldehyde to give the compound(IV).
The reaction is conducted at 30-80° C. for 1 to 48 hrs.
In case of the compound(IV) having monoalkylamine or monoarylamine, the general protecting group of amine is introduced to give the said compound(IV).
According to this invention, Cbz is a preferable protecting group of amine.
The compound(IV) is treated with sodium dithionite in lower alcohol solvent to give the compound(II).
The reaction is conducted at 30 to 100° C. for 1 to 10 hrs.
As specified in Scheme 3 below, a novel tricyclic ketone(III) of this invention can be prepared from the compound(IX) which is already known.
From the compound(III), tricyclicketone(n is

Affiliated with

Also associated with

Rating

Intermediates for the synthesis of camptothecin derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Intermediates for the synthesis of camptothecin derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Intermediates for the synthesis of camptothecin derivatives will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2487757