Water soluble analogues of 20(S)-camptothecin

Details Water soluble analogues of 20(S)-camptothecin Water soluble analogues of 20(S)-camptothecin

1996-12-19

2001-01-23

Kifle, Bruck (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S048000

Reexamination Certificate

active

06177439

ABSTRACT:

The present invention relates to novel water soluble C-ring analogues of 20(S)-Camptothecin having the general formula 1.
In the above formula 1, R
1
, R
2
, R
3
, R
4
are independently the same or different and represent hydrogen, hydroxy, aryloxy, lower alkoxy, lower alkanoyl, nitro, cyano, halo, carboxy, carbonyloxy, amino, substituted amino, lower alkyl, substituted lower alkyl, or R
2
, R
3
together represent —O—(CH
2
)
n
—O— where n=1 or 2; R
5
represents hydrogen, lower alkyl, substituted lower alkyl, lower aralkyl, hydroxymethyl, carboxymethyl, aminomethyl, substituted aminomethyl where the amino group may be mono or disubstituted in which both substituents are independent or combined together to form a cyclic ring system of a total of 5-6 atoms containing carbon and optionally one or two heteroatoms selected from oxygen, nitrogen or sulfur; and R
6
represents hydrogen, phenyl or benzyl where the phenyl group may be unsubstituted or substituted with mono, di or trisubstituents which may be selected from halogen, hydroxy, lower alkoxy, cyano, carboxyl, nitro, amino or substituted amino, lower alkyl, substituted lower alkyl; cycloalkyl or cycloalkyl lower alkyl where the cyclic ring is in the range of 3 membered to 7 membered ring system containing all carbon atoms; lower alkyl groups substituted with heterocyclic rings where the heterocyclic ring system has a total of 3 to 7 atoms, the heterocyclic rings containing carbon with at least one heteroatom such as oxygen, nitrogen or sulfur; lower alkanoyl; benzoyl where the phenyl group can be unsubstituted or substituted; lower alkenyl; lower alkyl; substituted lower alkyl, substituted lower alkenyl or substituted lower alkanoyl where the substituents can be halogen, hydroxy, lower alkoxy, aryloxy, thio, thioalkyl, thioaryl, aryl, heteroaryl, carboxy, cyano, nitro, amido or amino in which the amino group can be unsubstituted or mono, or disubstituted in which both substituents are independent or combined together to form 5 or 6 membered cyclic ring system containing carbon, and optionally contain one or two heteroatoms selected from oxygen, nitrogen or sulfur, the total number of atoms in the cyclic ring system is 5 or 6; with the proviso that (i) when R
1
is methoxy group, R
6
is not hydrogen or lower alkyl group; (ii) when R
2
is hydroxy, lower alkoxy, thioalkyl, nitro, amino, alkylamino, acylamino or halogen, R
6
is not hydrogen or lower alkyl group; (iii) when R
5
is lower alkyl, lower aralkyl, CH
2
OH, COOH, COOMe or CH
2
OR″ where R″ represents lower alkyl or acyl group, R
6
is not hydrogen or lower alkyl group; (iv) when R
1
is methoxy group, R
2
is hydroxy, lower alkoxy, thioalkyl, nitro, amino, alkylamino, acylamino, or halogen, R
5
is lower alkyl, lower aralkyl, CH
2
OH, COOH, COOMe or CH
2
OR″ where R″ represents lower alkyl or acyl group, R
6
is not hydrogen or lower alkyl group; (v) when R
1
through R
5
represent hydrogen, R
6
is not hydrogen or lower alkyl group.
All these compounds of the formula 1 are prepared from the compounds of the general formula 2 having 20(S)-chiral center,
where R
1
to R
5
have the meaning described above. Camptothecin having the formula 3, is an alkaloid with strong antitumor activity,
and was isolated from
Camptotheca acuminata
by Wall and co-workers in 1966. However, its development as a potential drug for cancer treatment had been abandoned due to unacceptable side effects on humans and due to its low water solubility as well as high toxicity problems. Since the discovery of its mechanism of action as an inhibitor of topoisomerise I by Liu and co-workers in 1985 [L. F. Liu, et al.,
J. Biol. Chem.,
260, 14873 (1985)], the research interest on camptothecin has once again taken momentum.
To overcome this problem of low water solubility and high toxicity of camptothecin, over the last 30 years, several research groups all over the world have prepared and investigated a number of camptothecin analogues involving the modification of rings A-E or the introduction of a variety of substituents on all the five rings of camptothecin of the formula 3 [M. E. Wall et al.,
J. Med. Chem.,
36, 2689 (1993); R. P. Hertzberg et al.,
J. Med. Chem.,
715 (1989); S. W. Sawada et al.,
Chem. Pharm. Bull.,
41(2), 310 (1993)]. Among the various camptothecin analogues prepared to date, only two of them namely, CPT-11 having the formula 4 [
Chem. Pharm. Bull.,
39, 1446 (1991)],
topotecan of the formula 5 [
J. Med. Chem.,
34, 98(1991)]
were introduced as anti-cancer drugs in the market recently. Another compound namely, 9-aminocamptothecin of the formula 6 [
J. Med. Chem. ,
29, 2358 (1986)],
is currently undergoing extensive clinical trials. The extensively studied Structure Activity Relationship (SAR) on camptothecin of the formula 3 [M. E. Wall et al.,
J. Med. Chem.,
36, 2689 (1993)] has revealed that 20(S)-&agr;-hydroxy-&dgr;-lactone (E-ring) moiety in camptothecin is essential for its activity. However, according to recent reports by Ejima et al., replacement of hydroxyl group with an amino group at C-20 position leading to a compound such as 7-ethyl-10-methoxycamptothecin derivative of the formula 7 [A. Ejima et al.,
Chem. Pharm. Bull.,
40(3), 683 (1992)],
exhibited an increased in vivo antitumor activity than 20(RS)-camptothecin of the formula 8. Also in another report (Lawrence Snyder et al.,
J. Org. Chem.,
59, 7033 (1994)], the 18-noranhydrocamptothecin analogue of the formula 9,
exhibited potent camptothecin like inhibition of topoisomerase I activity. Both these reports are contrary to the assumption that 20(S)-&agr;-hydroxy functionality in camptothecin is an essential feature for its biological activity.
Based on the structure-activity results obtained for the camptothecin analogues prepared in the literature, it was established that the modification of substituents at C-9 and C-7 position of camptothecin of the formula 3 plays an important role in the enhancement of anticancer activity by imparting stability to the E-ring lactone [T. G. Burke et al.,
J. Med. Chem.
37, 40 (1994)]. It has also been recognized that the open form of the lactone moiety, namely, ‘the Carboxylate form’ is less effective therapeutically than the closed ‘Lactone form’ [Hertzberg et al.,
J. Med. Chem.,
32, 715(1989); J. M. Covey, C. Jaxel et al.,
Cancer Research.,
49, 5016 (1989); Giovanella et al.,
Cancer Research.,
51, 3052 (1991)]. The recent studies by T. G. Burke et al., on the stability of ‘closed lactone form’ of various camptothecin analogues in the presence of protein called ‘Human Serum Albumin’ (HSA) indicated that the compounds such as CPT-11 of the formula 4 and 7-ethyl-10-hydroxycamptothecin (SN-38) of the formula 7a
and Topotecan of the formula 5, in the presence of HSA at 37° C., exhibited a higher percentage (%) of lactone form at equilibrium than 20(S) camptothecin of the formula 3 and 9-aminocamptothecin of the formula 6 [T. G. Burke and Zihou Mi.,
J. Med. Chem.,
37, 40 (1994); ibid.,
Biochemistry.,
33, 12540 (1994)]. Based on these studies, it was recognized that the understanding of the factors influencing the lactone-carboxylate equilibrium of camptothecin analogues became an important determinant in the design of novel and therapeutically efficacious drug candidates in the camptothecin series.
Although the modification of substituents on rings A and B of camptothecin was taken up at a rapid pace to generate novel CPT analogues, ring ‘C’ analogues of camptothecins were limited presumably because of the research work carried out by Sawada et al., which claimed that the substituents at C-5 position of camptothecin has resulted in the reduction of anti-tumor activity of camptothecins and produced inactive analogues [Sawada S. et al.,
Chem. Pharm. Bull.,
39(10), 2574 (1991)]. The C-5 substituted camptothecins claimed by Sawada et al., (JP 58, 154,584; U.S. Pat. No. 4,513,138; U.S. Pat. No. 4,473,692; U.

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