Cephem derivatives as anti-metastatic agents

Details Cephem derivatives as anti-metastatic agents Cephem derivatives as anti-metastatic agents

1995-03-08

1998-07-07

Lukton, David

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

540225, 514200, 514 18, 514 19, A61K 31545

Patent

active

057771049

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to the use of cephem derivatives as anti-metastatic agents.
As known, malignancy of cancer is mainly due to metastasis. Because therapy usually fails to destroy multiple secondary tumor, their uncontrolled growth leads to death of patients. Only very few patients die from complications directly arising from primary tumor. Accordingly, there is a need in therapy of drugs able to prevent and/or block the metastatic spread.
Several cephem derivatives were described as having elastase inhibiting activity and can be used in the treatment of inflammatory and degenerative diseases caused by proteolytic enzymes in mammals including humans.
Now we have found that a selected class of compounds previously disclosed can prevent and/or block the metastatic spread of tumors in mammals, including humans.
Accordingly one object of the present invention is the use of a compound of formula (I) ##STR2## wherein n is zero, one or two;
R.sup.1 is hydrogen or an optionally substituted C.sub.1 -C.sub.12 alkyl, C.sub.2 -C.sub.12 alkenyl, C.sub.2 -C.sub.12 alkynyl, C.sub.6 -C.sub.10 aryl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.5 -C.sub.8 cycloalkenyl, or C.sub.7 -C.sub.14 aralkyl, C.sub.8 -C.sub.14 aralkenyl, C.sub.8 -C.sub.14 aralkynyl, (cycloalkyl)alkyl, (cycloalkyl)alkenyl, heterocyclyl, (heterocyclyl)alkyl, (heterocyclyl)alkenyl;
R.sup.2 represents an atom or group selected from the following: R.sup.1 are as defined above .dbd.CHR.sup.1 or .dbd.CH--CO.sub.2 R.sup.1 or .dbd.CH--COR.sup.1 wherein R.sup.1 is as defined above; or R.sup.1 and R.sup.2 taken together with the C-2 carbon atom of the cephem nucleus constitute a carbocyclic or heterocyclyl group;
R.sup.3 represents one of the following: R.sup.1 as defined above above S(O).sub.n R.sup.1 wherein n and R.sup.1 are as defined above defined above or a --CH.sub.2 O--R.sup.7 wherein R.sup.7 is a mono, di- or tripeptide composed of D or L .alpha.-aminoacids chosen from Ala, Gly, Val, Leu, Ile, Phe and with the terminal amino group either free or protected as an amide --NHCOR.sup.1 or sulfonamide --NHSO.sub.2 R.sup.1 wherein R.sup.1 is as defined above defined above R.sup.1 is as defined above --O C(O)-- or --OS(O).sub.2 --, R.sup.1 is as defined above and R.sup.8, being the same or different, is as defined above for R.sup.1 ; or R.sup.1 and R.sup.8 taken together with the nitrogen atom to which they are attached represent a heterocyclic ring; R.sup.1 and R.sup.8 are as defined above and R.sup.9, being the same or different, is as defined for R.sup.1 ; or R.sup.1 is alkyl and R.sup.8 and R.sup.9 together with the nitrogen atom to which they are attached represent a heterocyclic ring;
R.sup.4 is either: above;
R.sup.5 is either R.sup.1 as defined above or halogen or C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkylthio or C.sub.1 -C.sub.6 acylamino;
R.sup.6 is a group selected from the following: are as defined above are as defined above, or R.sup.1 and R.sup.8 taken together with the aminocarbonyl group to which they are attached constitute a heterocyclic ring R.sup.8 and R.sup.9 are as defined above; cephem nucleus constitute a carbocyclic or heterocyclic ring; formula .dbd.CHR.sup.1, .dbd.CH--CO--R.sup.1 or .dbd.CH--SO.sub.2 R.sup.1 wherein R.sup.1 is as defined above medicament for use in preventing and/or treating the metastatic spread of tumors.
A further object the present invention is to provide a compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof, for use in preventing and/or treating the metastatic spread of tumors.
The C.sub.1 -C.sub.12 alkyl group is a straight or branched alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and so on.
The C.sub.2 -C.sub.12 alkenyl group is a straight or branched alkenyl group such as vinyl, allyl, crotyl, 2-methyl-1-propenyl, 1-methyl-1-propenyl, butenyl, pentenyl and so on.
The C.sub.2 -C.sub.12 alkynyl group is a straight or branched alkynyl group such as ethynyl, propargyl, 1-propynyl, 1-butynyl, 2-butynyl a

REFERENCES:
Bioorg Med Chem Lett 1, 21, 1991.

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