Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Patent
1999-07-19
2000-06-27
Ramsuer, Robert W.
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
544 69, 544142, 544373, 546199, 548433, 5142352, A61K 315377, C07D41314
Patent
active
060808594
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to novel pyrroloindole derivatives having a carbamoyloxy group which have antimicrobial and antitumor activities, optical isomers thereof, and pharmacologically acceptable salts thereof; and intermediates for production thereof.
BACKGROUND ART
CC-1065, which is an antibiotic having antimicrobial activity and antitumor activity, is disclosed in J.Antibiotics, vol.31, p.1211 (1978), and vol.34, p.1119 (1981); and U.S. Pat. No. 4,169,888. Duocarmycin A having analogous structure, and analogues thereof are disclosed in WO87/06265; EP0318056; J.Antibiotics, vol.42, p.1229 (1989); and JP-A-4-99774. Derivatives of CC-1065 are disclosed in EP0359454, JP-A-60-193989, and published Japanese translation of PCT application (Kohyo) 2-502005. Derivatives of duocarmycins are disclosed in JP-A-3-7287, JP-A-3-128379, EP0354583, and EP0406749. These are derived by utilizing directly a basic skeleton of a natural substance, or modification of a natural product. Further, a chemically synthesized pyrroloindole derivative having a trifluoromethyl group on the pyrroloindole ring is disclosed by the inventors of the present invention in JP-A-6-116269.
The inventors of the present invention made comprehensive researches on pyrroloindole derivatives which are effective against solid tumor and is less toxic. Consequently, The inventors found a derivative having a trifluoromethyl group in the pyrroloindole ring, and disclosed it in JP-A-6-116269. In JP-A-6-116269, a prodrug represented by Formula A having a carbamoyl group containing a cyclic amine is disclosed. ##STR3##
The present invention intends to provide a prodrug which forms an active species (a compound of Formula A in which B is hydrogen) in vivo more readily than the prodrug shown in Examples of JP-A-6-116269, and is effective against solid tumor and is less toxic.
DISCLOSURE OF INVENTION
It was found by the inventors of the present invention that the pyrroloindole derivatives having a carbamoyloxy group represented by the following general formula (1) below, optically active isomers thereof, and pharmacologically acceptable salts thereof are useful as the aforementioned prodrug. ##STR4## where R.sup.1 is OH, or a pyrrolidinyl group; n is 1 or 2; R.sup.2 is a lower alkyl group of C.sub.1 -C.sub.4 ; X--Y or Y--X is CH.sub.2, CHOH, CH.sub.2 -CH.sub.2, O--CH.sub.2, or NMe--CH.sub.2 ; Z.sup.1 is Cl or Br; and Ar.sup.1 is ##STR5## (wherein Z.sup.2 is O or NH, m is 0 or an integer of 1 to 4), ##STR6## (wherein m is 0 or an integer of 1 to 4), ##STR7## (wherein m is 0 or an integer of 1 to 4), ##STR8## (wherein Z.sup.3 is O or NH; Ar.sup.2 is any of the above groups a, b, c, and d). Consequently the present invention has been completed.
The present invention further relates to protected pyrroloindole derivatives represented by the following general formula (2): ##STR9## where R.sup.1 is OR.sup.3 (R.sup.3 is a protecting group for the hydroxyl group); n is 1 or 2; R.sup.2 is a lower alkyl of C.sub.1 -C.sub.4 ; X--Y is CH.sub.2, CHOH, CH.sub.2 --CH.sub.2, O--CH.sub.2, or NMe--CH.sub.2 ; Z.sup.1 is Cl or Br; and Ar.sup.1 is ##STR10## (wherein Z.sup.2 is O or NH, m is 0 or an integer of 1 to 4), ##STR11## (wherein m is 0 or an integer of 1 to 4), ##STR12## (wherein m is 0 or an integer of 1 to 4), ##STR13## (wherein Z.sup.3 is O or NH; Ar.sup.3 is any of the above groups of a, b, c, and d), and further relates to protected pyrroloindole derivatives represented by the following general formula (2): ##STR14## where R.sup.1 is OR.sup.3 (R.sup.3 is a protecting group for the hydroxyl group), n is 1, R.sup.2 is methyl, X--Y is O--CH.sub.2, Z.sup.1 is Cl, and Ar.sup.1 is ##STR15##
These derivatives are useful as an intermediate for production of the aforementioned carbamoyl group-containing pyrroloindole derivative.
The present invention further relates to an intermediate for production of the aforementioned protected pyrroloindole derivative represented by the following general formula (3), optically active isomers thereof, and salts th
REFERENCES:
patent: 5629430 (1997-05-01), Terashima et al.
Fukuda Yasumichi
Oomori Yasuo
Shimazawa Rumiko
Terashima Shiro
Kyorin Pharmaceutical Co. Ltd.
Ramsuer Robert W.
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