Claims for Patent: 5,431,900

Summary for Patent: 5,431,900

Title:	Ester-substituted diaminedithiols and radiolabeled complexes thereof
Abstract:	Radiopharmaceuticals consisting essentially of a lipophilic, charge neutral radionuclide complex of a diaminedithiol ligand having 1-4 ester groups of the formula --A--COOR where A is a straight or branched chain alkylene of 0-10 carbon atoms and R is an alkyl group of 1-10 carbon atoms are useful in radioimaging brain perfusion in primates. Ester-substituted diaminedithiols in sterile, pharmaceutically acceptable form, and kits of the diaminedithiols and sterile, non-pyrogenic reducing agents for reducing preselected radionuclides are also provided. Technetium-99m is a preferred radionuclide.
Inventor(s):	Bergstein; Paul L. (Norwood, MA), Cheesman; Edward H. (Townsend, MA), Watson; Alan D. (Andover, MA)
Assignee:	The Du Pont Merck Pharmaceutical Company (Wilmington, DE)
Application Number:	08/139,894
Patent Claims:	1. An ester-substituted diaminedithiol of the formula: ##STR12## or a pharmaceutically suitable salt thereof wherein: each of R.sub.1 -R.sub.12 individually is selected from the group consisting of H, alkyl of 1-10 carbon atoms and --A--COOR wherein A is a straight or branched chain alkylene of 0-10 carbon atoms, n, o, and p are independently 1 or 2, and R is (a) alkyl of 1-10 carbon atoms, (b) phenyl or benzyl optionally substituted with up to 5 ring substituents each selected from alkyl of 1-4 carbon atoms, fluoro, chloro, bromo, nitro, alkoxy of 1-4 carbon atoms, carboxyl, or a carboxylic acid ester of 1-4 carbon atoms, said ester-substituted diaminedithiol in sterile, pharmaceutically acceptable form. 2. An ester-substituted diaminedithiol of the formula: ##STR13## or a pharmaceutically suitable salt thereof wherein: each of R.sup.1 -R.sup.12 individually is selected from the group consisting of H, alkyl of 1-10 carbon atoms and --A--COOR wherein A is a straight or branched chain alkylene of 1-10 carbon atoms, n, o, and p are independently 1 or 2, and R is (a) alkyl of 1-10 carbon atoms, with the proviso that at least on of R.sup.1 -R.sup.12 is --A--COOR, said ester-substituted diaminedithiol in sterile, pharmaceutically acceptable form. 3. A diaminedithiol of claim 2 wherein R and any alkyl in R.sup.1 -R.sup.12 is from 1-3 carbon atoms. 4. A diaminedithiol of claim 2 wherein A is a straight chain alkylene of 0-3 carbon atoms. 5. A diaminedithiol of claim 2 wherein R.sup.3 and R.sup.10 are --A--COOR and R.sup.4 and R.sup.9 are H. 6. A diaminedithiol of claim 2 wherein A is a bond and R is ethyl. 7. A diaminedithiol of claim 2 wherein n, o and p are 1, R.sup.3 and R.sup.10 are --A--COOR where A is a straight chain alkylene of 0-3 carbon atoms and R is alkyl of 1-3 carbon atoms, R.sup.4 and R.sup.9 are H, and R.sup.1, R.sup.2, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.11 and R.sup.12 individually are selected from the group consisting of H, and alkyl of 1-3 carbon atoms. 8. A diaminedithiol of claim 2 wherein 1-4 of R.sup.1 -R.sup.12 is --A--COOR. 9. A diaminedithiol of claim 2 wherein A is a bond and the stereochemistry at the position where that bond is attached to the diaminedithiol backbone is L. 10. The sterile, pharmaceutically acceptable diaminedithiol of claim 2 which is N,N'-1,2-ethylenediylbis-L-cysteine diethylester, dihydrochloride. 11. The sterile, pharmaceutically acceptable diaminedithiol of claim 2 which is N,N'-1,2-ethylenediylbis-L-cysteine, dimethylester, dihydrochloride. 12. The sterile pharmaceutically acceptable diaminedithiol of claim 2 which is N,N'-1,2-ethylenediylbis-L-cysteine, di-n-propylester, dihydrochloride. 13. A kit comprising a predetermined quantity of a sterile, pharmaceutically acceptable ester-substituted diaminedithiol of claim 1 and a predetermined quantity of a sterile, non-pyrogenic reducing agent for reducing a preselected radionuclide. 14. A kit comprising a predetermined quantity of a sterile, pharmaceutically acceptable ester-substituted diaminedithol of claim 2 and a predetermined quantity of a sterile, non-pyrogenic reducing agent for reducing a preselected radionuclide. 15. A kit of claim 14 wherein the reducing agent is a stannous salt for reducing technetium-99m. 16. A kit of claim 15 wherein the diaminedithiol is a diaminedithiol of claim 3. 17. A kit of claim 15 wherein the diaminedithiol is a diaminedithiol of claim 4. 18. A kit of claim 15 wherein the diaminedithiol is a diaminedithiol of claim 5. 19. A kit of claim 15 wherein the diaminedithiol is a diaminedithiol of claim 6. 20. A kit of claim 15 wherein the diaminedithiol is a diaminedithiol of claim 7. 21. A kit of claim 15 wherein the diaminedithiol is a diaminedithiol of claim 8. 22. A kit of claim 15 wherein the diaminedithiol is the diaminedithiol of claim 9. 23. A kit of claim 15 wherein the diaminedithiol is the diaminedithiol of claim 10. 24. A kit of claim 15 wherein the diaminedithiol is the diaminedithiol of claim 11. 25. A kit of claim 15 wherein the diaminedithiol is the diaminedithol of claim 12.