Acrylamide derivatives and process for production thereof

Details Acrylamide derivatives and process for production thereof Acrylamide derivatives and process for production thereof

1997-05-13

1998-07-28

Richter, Johann

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

548433, 548491, 585427, C07D48700, C07D48702, C07D20904, C07C 13465

Patent

active

057864861

DESCRIPTION:

BRIEF SUMMARY
This application is A 371 PCT/JP95/02413 filed Nov. 28, 1995.


TECHNICAL FIELD

The present invention relates to novel acrylamide derivatives, and optically active isomers and pharmaceutically acceptable salts thereof, which have antimicrobial and antitumor activities.


BACKGROUND TECHNIQUES

CC-1065, which has antimicrobial and antitumor activities, 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 a similar structure, and analogues thereof are disclosed in WO87/06265, EP0318056, and 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 Japanese Kohyo 2-502005. Derivatives of duocarmycins are disclosed in JP-A-3-7287, JP-A-3-128379, EP0354583, and EP0406749. All of these substances have a basic skeleton of natural substances, or derived by chemical odification of natural substances.
Compounds having two tetrahydropyrroloindole skeletons in the molecule are included in the claims of JP-A-60-193989 (EP0154445) and Japanese Kohyo-2-502005 (WO8804659). However, no specific compounds is mentioned, and no example is disclosed about the corresponding compounds. Compounds having a -R.sub.5 -T-R'.sub.5 - group as a bridging moiety (where R.sub.5, and R'.sub.5 are respectively a phenyl, heterocyclic, or benzene-condensed heterocyclic group which is substituted by a carbonyl group; T is a group of aminocarbonyl, carbonylamino, carbonyloxy, oxycarbonyl, or the like) are disclosed in Japanese Kohyo 4-500664 (WO9002746), and specific examples thereof include compounds having, as the bridging moiety, a carbonylbis(imino-1H-indole-2-carbonyl) group, or the like.
A compound having two rings and carbonylbis(imino-1-H-indole-2-carbonyl) group as a bridging moiety is disclosed by the inventors of the present invention (JP-A-6-116269).
However, the acrylamide derivatives of the present invention are not known.
The clinical therapy for cancer includes surgical resection, radiotherapy with X-rays or the like, and chemotherapy with a chemotherapeutic. Of these therapies, only the chemotherapy with a chemotherapeutic is effective against the cancers having spread over various parts of the body, and terminal cancers. The chemotherapy, which is considered intrinsically to impose less burden to the patient, causes actually serious pains to the patient owing to the adverse strong side effects. Although most of the current chemotherapeutics are effective against leukemia exhibiting rapid cell growth, they are less effective against solid cancer exhibiting slow cell growth. Therefore, the chemotherapy is not preferentially conducted for cancer therapy.
In such a situation of chemotherapy, the present invention intends to provide a compound which is effective selectively against cancer cells, effective also against solid tumors, and yet less toxic.


DISCLOSURE OF THE INVENTION

After comprehensive investigation to solve the above problems, a novel compound was found, by the inventors of the present invention, which is effective selectively against cancer cells, less toxic, and effective also against solid tumors.
The present invention provides acrylamide derivatives, optical isomers thereof, and pharmaceutically acceptable salts thereof, and a process for production thereof; the acrylamide derivatives being represented by General Formula (1): ##STR2## (wherein X.sup.1 and X.sup.2 are independently a hydrogen atom, a halogen atom, an amino group, an alkylamino group, an aminoalkyl group, a hydroxyl group, OR.sup.3 (R.sup.3 being a linear or branched lower alkyl of C1-C6, or a substituted or unsubstituted aryl group), OCOR.sup.3 (R.sup.3 being the same as above), or a linear or branched lower alkyl of C1-C6, and X.sup.1 and X.sup.2 may be linked together; the ring A is a pyrrole ring, a furan ring, a thiophene ring, a benzene ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, a biphenyl ring, a bipyridine ring, a bipyrimidine ring, a naphthalene rin

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