ZA200207850B - Antitumoral ecteinascidin derivatives. - Google Patents

Description

i . )

ANTITUMORAL ECTEINASCIDIN DERIVATIVES

The present invention relates to antitumoral ecteinascidin derivatives.

BACKGROUND OF THE INVENTION

The ecteinascidins are exceedingly potent antitumour agents isolated from the marine tunicate Ecteinascidia turbinata. Several ecteinascidins have been reported previously in the patent and scientific literature.

U.S. Patent N° 5,256,663 describes pharmaceutical compositions comprising matter extracted from the tropical marine invertebrate, Ecteinascidia turbinata, and designated therein as ecteinascidins, and the use of such compositions as antibacterial, anti-viral, and/or antitumour agents in mammals.

U.S. Patent N° 5,089,273 describes novel compositions of matter extracted from the tropical marine invertebrate, Ecteinascidia turbinata, and designated therein as ecteinascidins 729, 743, 745, 759A, 759B and 770. These compounds are useful as antibacterial and / or antitumour agents in mammals.

U.S. Patent N° 5,478,932 describes ecteinascidins isolated from the Caribbean tunicate Ecteinascidia turbinata, which provide in vivo protection against P388 lymphoma, B16 melanoma, M5076 ovarian sarcoma, Lewis lung carcinoma, and the LX- 1 human lung and MX-1 human mammary carcinoma xenografts.

U.S. Patent N° 5,654,426 describes several ecteinascidins isolated from the

Caribbean tunicate Ecteinascidia turbinata, which provide in vivo protection against

. 7 WO 01/77115 PCT/GBU1/01667

P388 lymphoma, B16 melanoma, M5076 ovarian sarcoma, Lewis lung carcinoma, and the LX-1 human lung and MX-1 human mammary carcinoma xenografts.

U.S. Patent N°. 5,721,362 describes a synthetic process for the formation of ecteinascidin compounds and related structures.

WO 00/69862, from which the present application claims priority, describes the synthesis of ecteinascidin compounds from cyanosafracin B.

The interested reader is also referred to: Corey, E.J., J. Am. Chem. Soc., 1996, 118 pp. 9202-9203; Rinehart, et al., Journal of National Products, 1990, “Bioactive

Compounds from Aquatic and Terrestrial Sources”, vol. 53, pp. 771-792; Rinehart et al,,

Pure and Appl. Chem., 1990, “Biologically active natural products”, vol 62, pp. 1277- 1280; Rinehart, et al, J. Org. Chem., 1990, “Ecteinascidins 729, 743, 745, 759A, 759B, and 770: Potent Antitumour Agents from the Caribbean Tunicate Ecteinascidia turbinata”, vol. 55, pp. 4512-4515; Wright et al, J. Org. Chem., 1990, “Antitumour

Tetrahydroisoquinoline Alkaloids from the Colonial Ascidian Ecteinascidia turbinata’, vol. 55, pp. 4508-4512; Sakai et al., Proc. Natl. Acad. Sci. USA 1992, “Additional antitumour ecteinascidins from a Caribbean tunicate: Crystal structures and activities in vivo™, vol. 89, 11456-11460; Science 1994, “Chemical Prospectors Scour the Seas for

Promising Drugs”, vol. 266,pp. 1324; Koenig, K.E., “Asymmetric Synthesis”, ed.

Morrison, Academic Press, Inc., Orlando, FL, vol. 5, 1985,p. 71; Barton, et al., J. Chem

Soc. Perkin Trans. 1, 1982, “Synthesis and Properties of a Series of Sterically Hindered

Guanidine Bases”, pp. 2085; Fukuyama et al., J. Am Chem. Soc., 1982, “Stereocontrolled :

Total Synthesis of (+) — Saframycin B”, vol. 104,pp. 4957; Fukuyama et al., J. Am Chem

Soc., 1990, “Total Synthesis of (+) — Saframycin A”, vol. 112, p. 3712; Saito, et al., J.

Org. Chem., 1989, “Synthesis of Saframycins. Preparation of a Key Tricyclic Lactam

Intermediate to Saframycin A”, vol. 54, 5391; Still, et al., J. Org. Chem., 1978, “Rapid

Chromatographic Technique for Preparative Separations with Moderate Resolution”, vol. 43, p. 2923; Kofron, W.G.; Baclawski, L.M., J. Org. Chem, 1976, vol. 41, 1879; Guan et al., J. Biomolec. Struc. & Dynam., vol. 10 pp. 793-817 (1993); Shamma et al., “Carbon-

: , \ 13 NMR Shift Assignments of Amines and Alkaloids”, p. 206 (1979); Lown et al.,

Biochemistry, 21, 419-428 (1982); Zmijewski et al., Chem. Biol. Interactions, 52, 361- 375 (1985); Ito, CRC CRIT. Rev. Anal. Chem., 17, 65-143 (1986); Rinchart et al., “Topics in Pharmaceutical Sciences 1989” pp. 613-626, D. D. Breimer, DJ. A.

Cromwelin, K.K. Midha, Eds., Amsterdam Medical Press B.V., Noordwijk, The

Netherlands (1989); Rinehart et al, “Biological Mass Spectrometry,” 233-258 eds.

Burlingame et al., Elsevier Amsterdam (1990); Guan et al., Jour. Biomolec. Struct. &

Dynam., vol. 10 pp. 793-817 (1993); Nakagawa et al, J. Amer. Chem. Soc., 111: 2721- 2722 (1989); Lichter et al., “Food and Drugs from the Sea Proceedings” (1972), Marine

Technology Society, Washington, D.C.1973, 117-127; Sakai et al, J. Amer. Chem. Soc. 1996, 118, 9017; Garcia-Rocha et al., Brit. J. Cancer, 1996, 73: 875-883; and Pommier et al., Biochemistry, 1996, 35: 13303-13309; Rinehart, K.L., Med. Res. Rev., 2000, 20, 1-27 and I. Manzanares et al, Org. Lezt., 2000, 2(16), 2545-2548.

The most promising ecteinascidin is ecteinascidin 743, which is undergoing clinical trials for treatment of cancers. Et 743 has a complex tris(tetrahydroisoquinolinephenol) structure of the following formula (I):

OCH;

HO CH;

OCOCH;

H

CH, : nN

Qo : 0 OH oO 6.

CH30

NH

HO

It is currently prepared by isolation from extracts of the marine tunicate

Ecteinascidin turbinata. The yield is low, and alternative preparative processes have been sought.

o WO 01/77115 PCT/GB01/01667

The ecteinascidins include a fused system of five rings (4) to (£) as shown in the following structure of formula (XIV): 17 18 16 4 n 2 Oo 15 p 10 3 2 po

B C 14 7 0 N i 8 1 21

In ecteinascidin 743, the 1,4 bridge has the structure of formula (IV): ( (0) ? oo

HO

Other known ecteinascidins include compounds with a different bridged cyclic ring system, such as occurs in ecteinascidin 722 and 736, where the bridge has the structure of formula (V): ( \ o= J

HN S NH ecteinascidins 583 and 597, where the bridge has the structure of formula (VI):

{ \ =

H” “NH, and ecteinascidin 594 and 596, where the bridge has the structure of formula (VII): 4 ( 0 = J

Oo

The complete structure for these and related compounds is given in J. Am. Chem.

Soc. (1996) 118, 9017-9023.

Further compounds are known with the fused five ring system. In general, they lack the bridged cyclic ring system which is present in the ecteinascidins. They include the bis(tetrahydroisoquinolinequinone) antitumor-antimicrobial antibiotics safracins and saframycins, and the marine natural products renieramicins and xestomycin isolated from cultured microbes or sponges. They all have a common dimeric tetrahydroisoquinoline carbon framework. These compounds can be classified into four types, types I to IV, with respect to the oxidation pattern of the aromatic rings.

Type 1, dimeric isoquinolinequinones, is a system of formula (VIII) most commonly occuring in this class of compounds, see the following table I.

Table I

Structure of Type I Saframycin Antibiotics

OCH, 0) CHa, 0] H H

N——CH,

CH;0 > ~~ R14b

H : HH

[0] R21

HN

R258" ‘r2sb

Substituents

Compound R'% R%® R?! R>*? R?%® R>* saframycin A H H CN 0 oO CH; saframycin B H H H 0) @) CH; saframycin C H OCH; H Oo O CH; saframycin G H OH CN 0) 0] CH, saframycin H H H CN OH CH,;COCH; CH, saframycin S H H OH oO 8) CH; saframycin Y3 H H CN NH; H CH; saframycin Yd, H H CN NH; H C,H; saframycin Ad, H H CN oO Oo C,H; saframycin Yd, H H CN NH, H H saframycin Yap H Q° CN NH, H CH; saframycin Yau H Q° CN NH, H CH; saframycin AH, H H CN H° OH’ CH, saframycin AH,;Ac H H CN H OAc CH; saframycin AH, H H CN OH’ H* CH; saframycin AH,Ac H H CN OAc H CH; saframycin AR; H H H H OH CH;

¢ assignments are interchangeable. ® where the group Q is of formula (IX):

OCH; o H

H-=

CHa, Pe 0

CHO 7 "H

H H oO CN

HN

AH

0

CH;

Type I aromatic rings are seen in saframycins A, B and C; G and H; and S isolated from Streptomyces lavendulae as minor components. A cyano derivative of saframycin A, called cyanoquinonamine, is known from Japanese Kokai JP-A2 59/225189 and 60/084288. Saframycins Y3, Ydi, Ad; and Yd, were produced by S. lavendulae by directed biosynthesis, with appropriate supplementation of the culture medium. Saframycins Yap, and Yq dimers formed by linking the nitrogen on the C-25 of one unit to the C-14 of the other,have also been produced in supplemented culture medium of S. lavendulae. Saframycins AR; (=AH,), a microbial reduction product of saframycin A at C-25 produced by Rhodococcus amidophilus, is also prepared by nonstereoselective chemical reduction of saframycin A by sodium borohydride as a 1:1 mixture of epimers followed by chromatographic separation (the other isomer AH, is less polar). The further reduction product saframycin AR, 21-decyano-25-dihydro- saframycin A, (= 25-dihydrosaframycin B) was produced by the same microbial conversion. Another type of microbial conversion of saframycin A using a Nocardia species produced saframycin B and further reduction by a Mycobacterium species produced saframycin AH'Ac. The 25-O-acetates of saframycin AH, and AH, have also been prepared chemically for biological studies.

Type I compounds of formula (X) have also been isolated from marines sponges, see Table II.

Table II

Structures of Type I Compounds from Marine Sponges

OCH; o CH, 0] H

H=

CHj : O

CH,0 » 7% R14b

H H H

0 R21 0) or

Substituents

IE C.J [= =

R™ R R R renieramycin A OH H H -C(CH;)=CH-CH; renieramycin B OC,H; H H -C(CH;3)=CH-CH, renieramycin C OH 0 0 -C(CH;)=CH-CH; renieramycin D OC,H; 0) 0) -C(CH;)=CH-CH;, renieramycin E H H OH -C(CH;)=CH-CH; renieramycin F OCH; H OH -C(CH;)=CH-CH; xestomycin OCH; H H -CH;

Renieramycins A-D were isolated from the antimicrobial extract of a sponge, a

Reniera species collected in Mexico, along with the biogenetically related monomeric isoquinolines renierone and related compounds. The structure of renieramycin A was initially assigned with inverted stereochemistry at C-3, C-11, and C-13. However, careful examination of the 'H NMR data for new, related compounds renieramycins E and F, isolated from the same sponge collected in Palau, revealed that the ring junction of renieramycins was identical to that of saframycins. This result led to the conclusion that the formerly assigned stereochemistry of renieramycins A to D must be the same as that of saframycins.

Claims (10)

Printed:23-11-2001 CLMSPAMD19: ~~ 'EPOT919669.0 - PCTGE 0101667 . M&C Folio: WPP82129 Document #: 689944 CLAIMS

1. A compound having a fused ecteinascidin five ring system with a 1.4 bridge having the structure of formula (VIa or VIb): O \ O \ Ss S oA oA! H NH, H OH Via Vib and compounds in which the ~NH. or ~OH of the 1,4 bridge is derivatised; with the exception of ecteinascidin 583, ecteinascidin 597 or N-acetylecteinascidin 597, and with the exception of compounds 14 or 47 of U.S. Patent No 5,721,362.

2. A compound according to claim 1, wherein the fused ecteinascidin five ring system is as in the ecteinasciding, the ring system being of the formula (XIV): : 17 18 16 o 4 y 1 js 15 6 1 H D 20 4 B Cc 14 2 ¢ N 3 ’ 8 23 Where the rings A and E are phenolic; the rings B and D are tetrahydro, and ring C is perhydro. [07-11-2001

Printed.20-11-2004, (CEMSEAMDIS {EF01919668.0 - FCTGE 01 01667. ol 115

:

3. A compound according to claim 2, wherein substituents at positions 5, 6, 7, 8, 12, 16, 17, 18 and 21 are as in a known ecteinascidin.

4. A compound according to claim 3, wherein the substituents at positions 5, 6,7, 8,12, 16, 17 and 18 are as in a known ecteinascidin.

5. A compound according to claim 3 or 4, wherein the known ecteinascidin is ecteinascidin 743.

6. A compound according to any preceding claim, wherein the —NHz or - OH of the 1,4 bridge is derivatised.

7. A compound according to claim 6, in which the group —CHNH,- in the 1,4 bridge is replaced by a group ~C(X.)2 -, where X, is OX, or N(X,)2 wherein the or each X; is independently H, C(=0)R’, substituted or unsubstituted C;-Cis alkyl, substituted or unsubstituted C,-C;s alkenyl, substituted or unsubstituted C,~Cie alkynyl, substituted or unsubstituted aryl, or two X, groups may together form a cyclic substituent on the nitrogen atom.

8. A pharmaceutical composition comprising a compound having a fused : ecteinascidin five ring system with a 1,4 bridge having the structure of formula (VIa or Vib): 1 ( 4 1 ( 4 - \ \ S S oA © o H NH; H OH Via Vib

. : PCT/GB01/01667 ® 116 and compounds in which the ~NH, or ~OH of the 1,4 bridge is derivatised; with the exception of ecteinascidin 583 or 597, together with a pharmaceutically acceptable carrier.

9. The use of a compound having a fused ecteinascidin five ring system with a 1,4 bridge having the structure of formula (VIa or VIb): 1 ( 4 1 ( 4 Oo \ Oo \ S S A oA H NH, H OH Via Vib and compounds in which the —NH; or —-OH of the 1,4 bridge is derivatised; with the exception of ecteinascidin 583 or 597, in the preparation of a medicament for use in the treatment of a tumour.

10. A substance or composition for use in a method of treating a tumour, said substance or composition comprising a compound having a fused ecteinascidin five ring system with a 1,4 bridge having the structure of formula (VIa or VIb): i 1 ( 4 1 ( 4 oO \ Oo \ S S 29 R Oo o H NH, H OH : Via Vib and compounds in which the -NH, or -OH of the 1,4 bridge is derivatised: with the exception of ecteinascidin 583 or 597, said method comprising administering an effective amount of said substance or composition. AMENDED SHEET