CC-1065 analogs having two CPI subunits

Details CC-1065 analogs having two CPI subunits CC-1065 analogs having two CPI subunits

1991-03-08

1996-07-30

Richter, Johann

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

548433, C07C48702

Patent

active

055413390

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

Antibiotic CC-1065, (7bR,8aS)-7-[[1,6-dihydro-4-hydroxy-5-methoxy-7-[(4,5,8,8a-tetrahydro-7-me thyl-4-oxocyclopropa[c]pyrrolo[3,2-e]indol-2(1H)-yl)carbonyl]benzo[1,2-b:4, 3-b']dipyrrol-3(2H)-yl]carbonyl]1,6-dihydro-4-hydroxy-5-methoxy-benzo[1,2-b :4,3-b']dipyrrole-3(2H)-carboxamide, is disclosed and claimed in L. J. Hanka et al. U.S. Pat. No. 4,169,888 together with a process for preparing antibiotic CC-1065 by aerobic fermentation procedures, and recovering antibiotic CC-1065 therefrom.
In The Journal of Antibiotics, 1985, 38, 746, D. G. Martin et al reported that acetic acid adds across the spirocyclopropylcyclohexadienyl (SCPCH) system of CC-1065 to produce the phenolic, acetic acid product (AAP), 7-[[7-[[1-[(acetyloxy)methyl]-1,6-dihydro-5-hydroxy-8-methylbenzo[1,2-b:4, 3-b']dipyrrol-3(2H)-yl]carbonyl]-1,6-dihydro-4-hydroxy-5-methoxybenzo[1,2-b :4,3-b']-dipyrrol-3(2H)-yl]carbonyl]-1,6-dihydro-4-hydroxy-5-methoxy-benzo[ 1,2-b:4,3-b']dipyrrole-3(2H)-carboxamide. AAP was tested in vitro and in vivo and found to be less potent than CC-1065 by a factor of 10.sup.3 to 10.sup.4 depending upon the particular test system and therefore tended to divert attention from adducts of the SCPCH system as useful antitumor agents or as prodrugs to CC-1065 analogs.
In J. Am. Chem. Soc., 103, No. 18, 1981, W. Wierenga published a "Synthesis of the Left-Hand Segment of the Antitumor Agent CC-1065".
EP Application 0 154 445 (published Nov. 9, 1985) discloses various analogs of antibiotic CC-1065, including compounds of formula EP-I and EP-II (see General Formula chart of EP 0154 445), wherein R.sub.1 in formula EP-II is CH.sub.3 --, --CH.sub.2 Ph, CH.dbd.CHCH.sub.2 --, --CH.sub.2 SCH.sub.3, --CH.sub.2 OCH.sub.3, --CH.sub.2 OCH.sub.2 CH.sub.2 OCH.sub.3, --CH.sub.2 CCl.sub.3, --CH.sub.2 CH.sub.2 Si(R.sub.2).sub.3, or H, where Ph is phenyl; R is alkyl(C.sub.1 -C.sub.5), phenyl, or H; R.sub.2 ' is C.sub.1 to C.sub.5 -alkyl, phenyl or hydrogen, and is not necessarily the same as R in one compound; R.sub.3 is alkyl(C.sub.1 -C.sub.5), phenyl, or H; and X is Cl, Br, I or OSO.sub.2 R.sub.40, where R.sub.40 is C.sub.1 to C.sub.5 -alkyl, phenyl, tolyl, bromophenyl, nitrophenyl, or trifluromethyl. The O-protected compounds of formula EP-II are chemically stable and only removable under specific chemical conditions. However, when the compounds of formula EP-II are O-deprotected, they can be cyclized to yield the compounds of EP-I.
EP Application 0 154 445 also discloses CPI dimers joined by --CO--(CH.sub.2).sub.n1 --CO-- where n.sub.1 is 2-12 and CPI dimers joined by the tether --C(O)--(--R.sub.11 --)--C(O)--X.sub.7 --(CH.sub.2 CH.sub.2 --X.sub.7)n4--C(O)--(--R.sub.11 --)--C(O)-- where R.sub.11 =CH.sub.2 CH.sub.2, CH.dbd.CH; and X.sub.7 --O, NH, and n4=1-4, and the HCl and MeI salts for X.sub.7 =NH.
Additional dimers of CPI prodrugs joined by --CO--(CH.sub.2).sub.n1 --CO-- where n.sub.1 is 2-2 and CPI dimers Joined by the tether --C(O)--(--R.sub.11 --)--C(O)--X.sub.7 --(--CH.sub.2 CH.sub.2 --X.sub.7)n4--C(O)--(--R.sub.11)--C(O)-- where R.sub.11 =CH.sub.2 CH.sub.2, CH.dbd.CH; and X.sub.7 =O, NH, and n4=1-4, and the HCl and MeI salts for X.sub.7 =NH are disclosed in U.S. patent application Ser. No. 944,633, filed 19 Dec. 1986, now abandoned, and PCT/U.S. application Ser. No. 87/03227, filed 11 Dec. 1987, published 14 Jul. 1988.
Various oral and poster presentations of material in U.S. patent application Ser. No. 944,633, filed 19 Dec. 1986, have been made.


SUMMARY OF THE INVENTION

This invention provides some new synthetically obtained compounds of formula I (see General Formulae Chart), as defined hereinafter, which are useful as uv light absorber substances, or as chemical intermediates. Representative formula I compounds have also been shown to possess useful ranges of antitumor activity in standard laboratory animal tests. The compounds of this invention are obtained by chemical processes shown in Schemes 1-6 and detailed in the examples.


DETAILED DESCRIPTION OF THE INVENTION

More specifically, this i

REFERENCES:
patent: 4169888 (1979-10-01), Hanka et al.
patent: 4413132 (1983-11-01), Werenga et al.
patent: 4912227 (1990-03-01), Kelly et al.
Martin, D. G. et al, "CC-1065 Transformations", J. Antibiotics, 1985, vol. 38, pp. 746-752.
Weirenga, W., "Synthesis of the Left-Hand Segment of the Antitumor Agent CC-1065", J. Am. Chem. Soc. 103, No. 18, 1981, pp. 5621-5623.
Werenga, JACS 103, pp. 5621-5623 (1981).
PCT/US87/03227 dated Dec. 12, 1987.

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