National Research Development Corporation

British Technology Group Limited

Andrew M Creighton

William A Jeffery

Brian Maurice Foxwell

Peter Parker

Further improvements relating to radiolabelling of proteins

Nucleoside thiotriphosphates carrying .sup.32 P in the gamma-thiophosphate group, prepared by reaction between a nucleoside diphosphate and .sup.32 p labelled thiophosphate salt, are used as thiophosphorylating agents for antibodies that bind to tumour-associated antigens. The labelled thiotriphosphates can be used to introduce a therapeutically useful .sup.32 P atom into an antibody that has been modified by the incorporation into its structute of a peptide region capable of acting as a substrate for a phosphokinase. The resulting labelled antibody can then be used for injection in anti-tumour therapy and has clinical advantages over the corresponding phosphoylated analogue.

Radio-labelling of proteins

Nucleoside thiotriphosphates carrying .sup.32 P in the gamma-thiophosphate group, prepared by reaction between a nucleoside diphosphate and a .sup.32 P labelled thiophosphate salt, are used as thiophosphorylating agents for antibodies that bind to tumour-associated antigens. The labelled thiotriphosphates can be used to introduce a therapeutically useful .sup.32 P atom into an antibody that has been modified by the incorporation into its structure of a peptide region capable of acting as a substrate for a phosphokinase. The resulting labelled antibody can then be used for injection in anti-tumour therapy and has clinical advantages over the corresponding phosphorylated analogue.

(gamma)-[.sup.32 p](gamma) -thioribonucleoside-5.sup.1 -triphosphates

A compound of formula (II): ##STR1## in which R.sub.1 and R.sub.2 together form a methylene or ethylene bridging group and R.sub.3 is a hydrogen, an acyclic aliphatic hydrocarbon group having a maximum of six carbon atoms or a group CH.sub.2 R.sub.4 in which R.sub.4 is a C.sub.1-5 alkyl group substituted by a hydroxy group or by a C.sub.1-6 alkoxy group, or a salt thereof formed with a physiologically acceptable inorganic or organic acid, are of value for use in therapy, particularly as cardioprotective agents.

Pharmaceutical compositions

.sup.32 P thiophosphate preparation

Compounds of formula (II) ##STR1## wherein R.sub.1 and R.sub.2 are each separately selected from hydrogen, alkyl, alkenyl and alkynyl groups having up to a maximum of four carbon atoms and being unsubstituted, and alkyl, alkenyl and alkynyl groups having up to a maximum of three carbon atoms and being substituted by one, or in the case of fluoro by one or more, substituents but with the proviso that when R.sub.1 is hydrogen then R.sub.2 is hydrogen or methyl, or R.sub.1 and R.sub.2 together constitute an ethylene bridging group, and R.sub.3 is a group which under physiological conditions undergoes elimination with the formation of a 3,5-dioxopiperazinyl ring, with the further proviso that the compound is in the meso or erythro configuration when each of R.sub.1 and R.sub.2 is the same or different unsubstituted or substituted alkyl, alkenyl or alkynyl group, and salts thereof with a physiologically acceptable inorganic or organic acid, are of value as prodrugs, particularly for effecting cardioprotection.

Compounds of formula (II) ##STR1## wherein R.sub.1 and R.sub.2 are each separately selected from hydrogen, alkyl, alkenyl and alkynyl groups having up to a maximum of four carbon atoms and being unsubstituted, and alkyl, alkenyl and alkynyl groups having up to a maximum of three carbon atoms and being substituted by one, or in the case of fluoro by one or more, substituents but with the proviso that when R.sub.1 is hydrogen then R.sub.2 is hydrogen or methyl, or R.sub.1 and R.sub.2 together constitute an ethylene bridging group, and R.sub.3 is a group which under physiological conditions undergoes elimination with the formation of a 3,5-dioxopiperazinyl ring, with the further proviso that the compound is in the meso or erythro configuration when each of R.sub.1 and R.sub.2 is the same or different unsubstituted or substituted alkyl, alkenyl or alkynyl group, and salts thereof with a physiologically acceptable inorganic or organic acid, are of value as prodrugs, particularly in the therapy of cancers sensitive to the compounds of formula (II) and psoriasis.

Pharmaceutical compositions for treating certain cancers

Compounds of formula (II) ##STR1## wherein R.sub.1 and R.sub.2 are each separately selected from hydrogen, alkyl, alkenyl and alkynyl groups having up to a maximum of four carbon atoms and being unsubstituted, and alkyl, alkenyl and alkynyl groups having up to a maximum of three carbon atoms and being substituted by one, or in the case of fluoro by one or more, substituents but with the proviso that when R.sub.1 is hydrogen then R.sub.2 is hydrogen or methyl, or R.sub.1 and R.sub.2 together constitute an ethylene bridging group, and R.sub.3 is a group which under physiological conditions undergoes elimination with the formation of a 3,5-dioxopiperazinyl ring, with the further proviso that the compound is in the meso or erythro configuration when each of R.sub.1 and R.sub.2 is the same or different unsubstituted or substituted alkyl, alkenyl or alkynyl group, and salts thereof with a physiologically acceptable inorganic or organic acid, are of value as prodrugs, particularly in the therapy of psoriasis.

Pharmaceutical compositions for treating psoriasis

Compounds of the formula (II) ##STR1## wherein R.sub.1 and R.sub.2 are each separately selected from hydrogen, alkyl, alkenyl and alkynyl groups having up to a maximum of four carbon atoms and being unsubstituted, and alkyl, alkenyl and alkynyl groups having up to a maximum of three carbon atoms and being substituted by one, or in the case of fluoro by one or more, substitutents but with the proviso that when R.sub.1 is hydrogen then R.sub.2 is hydrogen or methyl, or R.sub.1 and R.sub.2 together constitute an ethylene bridging group, and R.sub.3 is a group which under physiological conditions undergoes elimination with the formation of a 3,5-dioxopiperazinyl ring, with the further proviso that the compound is in the meso or erythro configuration when each of R.sub.1 and R.sub.2 is the same or different unsubstituted or substituted alkyl, alkenyl or alkynyl group, and salts thereof with a physiologically acceptable inorganic or organic acid, are of value as prodrugs, particularly in the therapy of cancer and psoriasis.

Compounds of formula (II) ##STR1## wherein R.sub.1 and R.sub.2 are each separately selected from hydrogen, alkyl, alkenyl and alkynyl groups having up to a maximum of four carbon atoms and being unsubstituted, and alkyl, alkenyl and alkynyl groups having up to a maximum of three carbon atoms and being substituted by one, or in the case of fluoro by one or more, substitutents but with the proviso that when R.sub.1 is hydrogen then R.sub.2 is hydrogen or methyl, or R.sub.1 and R.sub.2 together constitute an ethylene bridging group, and R.sub.3 is a group which under physiological conditions undergoes elimination with the formation of a 3,5-dioxopiperazinyl ring, with the further proviso that the compound is in the meso or erythro configuration when each of R.sub.1 and R.sub.2 is the same or different unsubstituted or substituted alkyl, alkenyl or alkynyl group, and salts thereof with a physiologically acceptable inorganic or organic acid, are of value as prodrugs, particularly in the therapy of cancer and psoriasis.

A pharmaceutical composition useful for aiding regression and palliation of sarcoma, lymphosarcoma and leukaemia in mammals comprises a therapeutically effective amount of a compound of formula ##STR1## wherein R.sub.1 and R.sub.2 are each separately selected from hydrogen and methyl or together represent an ethylene bridging group, with the proviso that when both of the groups R.sub.1 and R.sub.2 are methyl they are disposed in the meso configuration, or a non-toxic salt thereof with a physiologically acceptable inorganic or organic acid, in combination with a physiologically acceptable diluent or carrier.

A pharmaceutical composition useful for aiding regression and palliation of cancer in mammals comprises a therapeutically effective amount of a compound of formula ##EQU1## wherein R.sub.1 and R.sub.2 are each separately selected from hydrogen and methyl or together represent an ethylene bridging group, with the proviso that when both of the groups R.sub.1 and R.sub.2 are methyl they are disposed in the meso configuration, or a non-toxic salt thereof with a physiologically acceptable inorganic or organic acid, in combination with a physiologically acceptable diluent or carrier.

Growing community of inventors

London, United Kingdom

Andrew M Creighton