Melphalan derivatives

Details Melphalan derivatives Melphalan derivatives

1987-12-21

1991-12-24

Russel, Jeffrey E.

Drug, bio-affecting and body treating compositions

Lymphokine

530388, 530390, 530391, 435174, 514155, 562450, 560 41, A61K 3944, C07K 1528, C07K 1700

Patent

active

050751085

DESCRIPTION:

BRIEF SUMMARY
This invention relates to melphalan derivatives. Formulas are set out in the accompanying drawings. The present invention provides a compound of formula I ##STR4## wherein R.sub.1 is of formula II ##STR5## wherein R.sub.4 and R.sub.5, which may be the same or different, are bromo, chloro, iodo or alkylsulphonyl; ##STR6## wherein R.sub.6 and R.sub.7, which may be the same or different, are H, alkyl, aryl, carboxy, hydroxy or amino and n is 0-10; and radical having an antigen binding site or R.sub.3 is a radical having an antigen binding site.
Preferred alkyl groups are those containing 6 or less carbon atoms. Preferred aryl groups are those containing 12 or less carbon atoms.
The R.sub.1 group may occur in ortho-, meta- or para-position.
Preferred compounds of formula I are those where --R.sub.3 is a group capable of being cleared and replaced by a antibody. Such --R.sub.3 groups include those which with the adjacent --CO-group are active ester groups. A particular group as R.sub.3 is N-hydroxysuccinimide. Other R.sub.3 groups include mixed anhydrides, N-hydroxysolphosuccinimides, azides and p-nitrophenyl esters.
It is preferred that R.sub.3 is an antibody.
The antibody may be a monoclonal antibody. Antibodies useful in the present invention included those showing specificity for breast, brain, melanoma, lung, pancreas and colon tumours.
The antibody may be an intact immunogobulin or a fragment of an immunogobulin maintaining a sufficiency of an antigen binding site such that it is preferentially absorbed by a tumour cell as compared to a non tumour cell.
Thus, in addition to whole antibodies, it is also possible to utilize F(ab').sub.2 and F(ab') fragments.
Still further antibody polymers such as antibody pentamers IgM and derivatives of these such as immunogobulin monomers may be used.
Also usable are IgC.sub.2a, IgG.sub.2b, IgG.sub.1, and IgG.sub.3.
The compounds of formula I, II and III may be coupled indirectly to monoclonal antibodies via an inert carrier molecule such as human serum albumin or synthetic polymers.
The compounds of this invention may be combined with pharmaceutically acceptable carriers.
The mode of administration of the compounds of this invention will be as selected. In particular, the compounds of this invention may be administered intravenously, intraperitonealy, intrapleuraly, intrapericardialy, and intracerebo spinal fluid.
Compounds in accordance with the present invention can be prepared by acylating a starting compound of the formula ##STR7## with an acylating compound containing the R.sub.2 -CO-group to obtain a compound of formula IV. ##STR8##
The compound of formula IV may be reacted with a compound containing a group R.sub.3 which may be cleaved and replaced by an antibody radical.
The present invention also provides a pharmacological composition comprising a compound of formula I above wherein R.sub.3 is an antibody and R.sub.1, R.sub.2 and R.sub.4-7 have the meaning given above and a pharmaceutically acceptable diluent.
The compounds of this invention where R.sub.3 is an antibody have utility in tumour treatment.


PART A

Melphalan (MEL) is an aromatic alkylating agent which by virtue of its derivation from phenylalanine enters cells by an amino acid transport system. The compounds of this invention are certain derivatives of melphalan prepared with a view to targeting tumour cells.
By acylating the amino group of MEL, an N-acyl derivative was synthesized that was 100 times less toxic than MEL to tumour cells in vitro. An active ester of N-acyl Melphalan (NaM) was then reacted with monolonal antibodies (MoAbs) to the human transferrin receptor (TFR) or the murine Ly-2.1 alloantigen, both of which appear to be internalized. Up to 30 molecules of NaM were specifically bound with retention of alkylating activity and minimal loss in antibody activity. The in vitro cytotoxicity of the conjugate was tested by the inhibition of (.sup.3 H)-thymidine incorporation into tumour cells which demonstrated the conjugate to be specifically cytotoxic towards antibody reactive cell lines

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Chemical Abstract No. 156683d, vol. 82, No. 23 (1975).
Arm. Khim. Zh., vol. 27, No. 11, pp. 997-999(1974) and translation thereof.

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