Trifluoromethylpyrroloindolecarboxylic acid ester and process fo

Details Trifluoromethylpyrroloindolecarboxylic acid ester and process fo Trifluoromethylpyrroloindolecarboxylic acid ester and process fo

1995-06-14

1997-05-13

Haley, Jacqueline

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

548425, 548433, 544363, 546 85, 546 87, 546135, 546140, 546146, 546148, 546174, 546187, C07D48704

Patent

active

056294301

DESCRIPTION:

BRIEF SUMMARY
This is a National Stage Application of PCT/JP93/01159 filed Aug. 19, 1993 and published as WO 94/04535 on Mar. 3, 1994.


TECHNICAL FIELDS

The present invention relates to novel antibacterial and antineoplastic 7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo[3,2-e]indole-8-carboxylic acid ester derivatives, 6-trifluoromethyl-1,2,8,8a-tetrahydrocyclopropa[c]pyrrolo-[3,2-e]indol-4 (5H)-one-7-carboxylic acid ester derivatives, optically active isomers thereof, and pharmaceutically acceptable salts thereof.


BACKGROUND TECHNIQUE

CC-1065 is disclosed as an antibacterial and antineoplastic antibiotic in J. Antibiotics, 31 1211 (1978) and ibid, 34 1119 (1981); and USP 4169888. Further, duocarmycin A having a similar structure thereto and analogues thereof are disclosed in WO87/06265, EP0318056, J. Antibiotics 42 1229 (1989), and JP-A-4-99774.
Further derivatives of CC-1065 are disclosed in JP-A-60-193989, and Japan Patent Kohyo 2-502005. Derivatives of duocarmycins are disclosed in JP-A-3-7287, JP-A-3-128379, EP0354583, and EP0406749. All of these compounds are derived by utilizing the base skeleton of an unmodified natural substance or by modifying chemically a natural substance.
The clinical therapy of cancer includes surgical excision, X-ray radiotherapy, pharmacotherapy using a chemotherapeutic agent(chemotherapy), and so forth. Of these therapies, chemotherapy is the one and only therapy for cancer having wide-spread metastasis in several body regions and for cancer at the terminal stage. Originally, chemotherapy is expected to be the least to burden a patient, while in facts, chemotherapeutic agents hitherto known impose severe suffer on patients due to strong adverse reactions. Further, there are several effective chemotherapeutic agents against leukemia which grows rapidly, but most of them are less effective for solid tumor which grows slowly. From these reasons, chemotherapy so far is not always primarily adopted for cancer.
In view of the present status of the chemotherapeutic agents, the inventors of the present invention have conducted comprehensively the investigation on compounds which exhibit high selectivity to cancer cells and exhibit high efficacy also on solid tumor with less toxicity.


DISCLOSURE OF INVENTION

It was found by the inventors of the present invention that the trifluoromethylpyrroloindolecarboxylic acid ester derivatives represented by the general formula (1) and (2) below, optical isomers thereof, and pharmaceutically acceptable salts thereof exhibit excellent antibacterial effects and antineoplastic effects, and further has high selectivity to cancer cells with low toxicity: ##STR3## [In the formulas, R is a lower alkyl group of C.sub.1 .about.C.sub.4, ##STR4## (X.sup.1, X.sup.2, and X.sup.3 are independently a hydrogen atom, OH, OR.sup.3 (R.sup.3 is a substituted or unsubstituted linear or branched lower alkyl group of C.sub.1 .about.C.sub.6, or a substituted or unsubstituted aryl group), OCOR.sup.3 (R.sup.3 is the same as above), CHO, NO.sub.2, ##STR5## (R.sup.4 and R.sup.5 are independently a hydrogen atom, a substituted or unsubstituted linear or branched lower alkyl group of C.sub.1 .about.C.sub.6, or a substituted or unsubstituted aryl group (R.sup.3 is the same as above)), ##STR6## (X.sup.4, X.sup.5 and X.sup.6 are independently a hydrogen atom, or OR.sup.3, or ##STR7## (R.sup.3, R.sup.4, and R.sup.5 are the same as above)), ##STR8## (R.sup.4, and R.sup.5 are the same as above), ##STR9## (R.sup.4, and R.sup.5 are the same as above), Z.sup.1 is O, S, or NR.sup.4 (R.sup.4 is the same as above), n is 0.about.2), ##STR10## (X.sup.7 is O, S, or NH, X.sup.8 is CH or N (X.sup.1, X.sup.2, X.sup.3, and Z.sup.1 are the same as above)), ##STR11## (X.sup.9, and X.sup.10 are independently CH or N (X.sup.1, X.sup.2, X.sup.3, X.sup.8, and Z.sup.1 are the same as above)), ##STR12## (X.sup.11, and X.sup.12 are independently CH or N (X.sup.1, X.sup.2, X.sup.3, X.sup.7 and Z.sup.1 are the same as above)), ##STR13## (R.sup.6 is represented by the above formula a, b, c, or d (X.sup.1, X.sup

REFERENCES:
patent: 4978757 (1990-12-01), Kelly et al.
patent: 5101038 (1992-03-01), Nakano et al.

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