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Details for Patent: 5,053,394

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Details for Patent: 5,053,394

Title: Targeted forms of methyltrithio antitumor agents
Abstract:This disclosure describes a method for constructing carrier-drug conjugates from the family of methyltrithio antibacterial and antitumor agents.
Inventor(s): Ellestad; George A. (Pearl River, NY), McGahren; William J. (Demarest, NJ), Sassiver; Martin L. (Spring Valley, NY), Hamann; Philip R. (Garnerville, NY), Hinman; Lois M. (Tarrytown, NY), Upeslacis; Janis (Pomona, NY)
Assignee: American Cyanamid Company (Stamford, CT)
Filing Date:Apr 14, 1989
Application Number:07/339,343
Claims:1. A carrier-drug conjugate of the formula ##STR22## prepared from a compound of formula CH.sub.3 SSS-W wherein CH.sub.3 SSS-W is an antitumor antibiotic designated as LL-E33288.alpha..sub.1.sup.Br, .alpha..sub.1.sup.I, .alpha..sub.2.sup.Br, .alpha..sub.3.sup.Br, .alpha..sub.3.sup.I, .alpha..sub.4.sup.Br, .beta..sub.1.sup.Br, B.sub.1.sup.I, .beta..sub.2.sup.Br, .beta..sub.2.sup.I, .gamma..sub.1.sup.Br, .gamma..sub.1.sup.I, .delta..sub.1.sup.I, the iodo or bromo pseudoaglycones, their dihydro or N-acyl counterparts, BBM-1675, FR-900405, FR-900406, PD 114759, PD 115028, CL-1577A, CL-1577B, CL-1577D, CL-1577E, CL-1724 or their N-acetyl counterparts comprising:

reacting CH.sub.3 SSS-W with a compound of general formula A-Sp-SH, wherein Sp is a straight or branched-chain divalent or trivalent (C.sub.1 -C.sub.18) radical, divalent or trivalent aryl or heteroaryl radical, divalent or trivalent (C.sub.3 -C.sub.18) cycloalkyl or heterocycloalkyl radical, divalent or trivalent aryl-or heteroaryl-alkyl (C.sub.1 -C.sub.18) radical, divalent or trivalent cycloalkyl- or heterocycloalkyl-alkyl (C.sub.1 -C.sub.18) radical or divalent or trivalent (C.sub.2 -C.sub.18) unsaturated alkyl radical, wherein if Sp is a trivalent radical, it can be additionally substituted by amino, alkylamino, arylamino, heteroarylamino, carboxyl, lower alkoxy, hydroxy, thiol, or lower alkylthio groups; and Q is, or can be subsequently converted to, halogen, amino, alkylamino, carboxyl, carboxaldehyde, hydroxy, tiol, .alpha.-haloacetyloxy, lower alkyldicarboxyl, --CONHNH.sub.2, --NHCONHNH.sub.2, --NHCSNHNH.sub.2, --ONH.sub.2, --CON.sub.3, ##STR23## to produce an intermediate of formula Q-Sp-SS-W, wherein Q, Sp, and W are as hereinbefore defined,

reacting Q-Sp-SS-W with a molecule of the formula Tu-(Y).sub.n wherein the carrier Tu is defined as a mono- or polyclonal antibody, its fragments, its chemically or genetically manipulated counterparts, or growth factors or steroids; Y is a side-chain amino, carboxy, or thiol group of a protein, an aldehyde derived from glycoprotein carbohydrate residues, or an amidoalkylathio group; and n is an integer of from 1 to 100, to produce a compound of the formula: ##STR24## wherein Tu, Y, Sp, W, and n are as hereinbefore defined, and Z is formed from covalent reaction of the groups Q and Y directly or after subsequent reduction, and Z is --CONH--, --CONHN.dbd.CH--, --CONHNHCH.sub.2 --, --NHCONHN.dbd.CH--, --NHCONHNHCH.sub.2, --NHCSNHN.dbd.CH--, --NHCSNHNHCH.sub.2 --, --OH.dbd.CH--, --NH--, --NHCH.sub.2 --, --N.dbd.CH--, --CO.sub.2 --, --NHCH.sub.2 CO.sub.2 --, --SS--, ##STR25## and m is 0.1 to 15.

2. A protein-drug conjugate according to claim 1 of the formula ##STR26## prepared from the class of antitumor antibiotics designated LL-E33288 (CH.sub.3 SSS-W) comprising: p1 displacing the dithiomethyl moiety with a compound of formula Q-Sp-SH, wherein Sp is straight or branched-chain divalent or trivalent (C.sub.2 -C.sub.10) radicals or divalent or trivalent aryl- or heteroaryl-alkyl (C.sub.2 --C.sub.5) radicals, wherein if Sp is a trivalent radical, it can be additionally substituted by amino, heteroarylamino, hydroxy, or thiol groups; and Q is, or can be subsequently converted to, carboxyl, lower alkyldicarboxylanhydride, --CONHNH.sub.2, or ##STR27## to produce an intermediate of general formula A-Sp-SS-W, wherein Q, Sp, and W are as hereinbefore defined,

reacting Q-Sp-SS-W with a molecule of the formula Tu-(Y).sub.n wherein Tu is a monoclonal antibody which exhibits preferential reactivity with a human tumor-associated antigen, Y is a side-chain amino group on the antibody, or an aldehyde generated by oxidation of the carbohydrate groups of the antibody, and n is an integer of from 1 to 100, to produce a compound of the formula: ##STR28## wherein Tu, Y, Sp, W, and n are as hereinbefore defined, and Z is formed from covalent reaction of the groups Q and Y directly or after subsequent reduction, and Z is --CONH--, --CONHN.dbd.CH--, --CONHNHCH.sub.2 --, or ##STR29## and m is 0.1 to 15.

3. A protein-drug conjugate according to claim 2 wherein CH.sub.3 SSS-W is the antitumor antibiotic designated LL-E33288.delta..sub.1.sup.I having:

a) ultraviolet spectrum as shown in FIG. I;

b) a proton magnetic resonance spectrum as shown in FIG. II; and

c) an infrared spectrum as shown in FIG. III.

4. A protein-drug conjugate according to claim 2 wherein CH.sub.3 SSS-W is the antitumor antibiotic designated LL-E33288.alpha..sub.2.sup.I having:

a) a proton magnetic resonance spectrum as shown in FIG. IV; and

b) a carbon-13 nuclear magnetic resonance spectrum as shown in FIG. V.

5. A protein-drug conjugate according to claim 2 wherein CH.sub.3 SSS-W is the antitumor antibiotic designated LL-E33288.alpha..sub.3.sup.I having:

a) ultraviolet spectrum as shown in FIG. VI;

b) an infrared spectrum as shown in FIG. VII;

c) a proton magnetic resonance spectrum as shown in FIG. VIII; and

d) a carbon-13 nuclear magnetic resonance spectrum as shown in FIG. IX.

6. A protein-drug conjugate according to claim 2 wherein CH.sub.3 SSS-W is the antitumor antibiotic designated N-acetyl LL-E33288.delta..sub.1.sup.I having:

a) ultraviolet spectrum as shown in FIG. X;

b) an infrared spectrum as shown in FIG. XI;

c) a proton magnetic resonance spectrum as shown in FIG. XII; and

d) a carbon-13 nuclear magnetic resonance spectrum as shown in FIG. XIII.

7. A protein-drug conjugate according to claim 2 wherein CH.sub.3 SSS-W is the antitumor antibiotic designated iodo LL-E33288 pseudoaglycone having:

a) ultraviolet spectrum as shown in FIG. XIV;

b) an infrared spectrum as shown in FIG. XV;

c) a proton magnetic resonance spectrum as shown in FIG. XVI; and

d) a carbon-13 nuclear magnetic resonance spectrum as shown in FIG. XVII.

8. A protein-drug conjugate according to claim 2 wherein Tu is the monoclonal antibody designated Lym 1.

9. A protein-drug conjugate according to claim 2 wherein Tu is the monoclonal antibody designated Lym 2.

10. A protein-drug conjugate according to claim 2 wherein Tu is the monoclonal antibody designated CT-M-01.

11. A protein-drug conjugate according to claim 2 wherein Tu is the monoclonal antibody designated B72.3.

12. A protein-drug conjugate according to claim 2 wherein Tu is the monoclonal antibody designated MAC-68.

13. A protein-drug conjugate according to claim 2 wherein Q is the hydroxysuccinimide ester of a carboxyl group, Sp is --CH.sub.2 CH.sub.2 --, Y is --NH.sub.2, Z is --CONH--, and m is 0.5 to 15.

14. A protein-drug conjugate according to claim 2 wherein Q is the hydroxysuccinimide ester of a carboxyl group, Sp is --CH.sub.2 CH(CH.sub.3)--, Y is --NH.sub.2, Z is --CONH--, and m is 0.5 to 15.

15. A protein-drug conjugate according to claim 2 wherein Q is the 4-nitrophenyl ester of a carboxyl group, Sp is --CH.sub.2 CH.sub.2 --, Y is --NH.sub.2, Z is --CONH--, and m is 0.5 to 15.

16. A protein-drug conjugate according to claim 2 wherein Q is the hydroxysuccinimide ester of a carboxyl group, Sp is --CH.sub.2 C(CH.sub.3).sub.2 --, Y is --NH.sub.2, Z is --CONH--, and m is 0.5 to 15.

17. A protein-drug conjugate according to claim 2 wherein Q is the hydroxysuccinimide ester of a carboxyl group, Sp is ##STR30## Y is --NH.sub.2, Z is --CONH--, and m is 0.5 to 15.

18. A protein-drug conjugate according to claim 2 wherein Q is --CONHNH.sub.2, Sp is --CH.sub.2 CH.sub.2 --, Y is --CHO, Z is --CONHN.dbd.CH--, and m is 0.1 to 10.

19. A protein-drug conjugate according to claim 2 wherein Q is --CONHNH.sub.2, Sp is --CH.sub.2 CH.sub.2 --, Y is --CHO, Z is --CONHNHCH.sub.2 --, and m is 0.1 to 10.

20. A protein-drug conjugate according to claim 2 wherein Q is --CONHNH.sub.2, Sp is --CH.sub.2 CH(CH.sub.3)--, Y is --CHO, Z is --CONHN.dbd.CH--, and m is 0.1 to 10.

21. A protein -drug conjugate according to claim 2 wherein Q is --CONHNH.sub.2, Sp is --CH.sub.2 CH(CH.sub.3)--, Y is --CHO, Z is --CONHNHCH.sub.2, and m is 0.1 to 10.

22. A protein-drug conjugate according to claim 2 wherein Q is --CONHNH.sub.2, Sp is --CH.sub.2 C(CH.sub.3).sub.2 --, Y is --CHO, Z is --CONHN.dbd.CH--, and m is 0.1 to 10.

23. A protein-drug conjugate according to claim 2 wherein Q is --CONHNH.sub.2, Sp is --CH.sub.2 C(CH.sub.3).sub.2 --, Y is --CHO, Z is --CONHNHCH.sub.2 --, and m is 0.1 to 10.

24. A protein-drug conjugate according to claim 2 wherein Q is --CONHNH.sub.2, Sp is ##STR31## Y is --CHO, Z is --CONHN.dbd.CH--, and m is 0.1 to 10.

25. A protein-drug conjugate according to claim 2 wherein Q is --CONHNH.sub.2, Sp is ##STR32## Y is --CHO, Z is --CONHNHCH.sub.2 --, and m is 0.1 to 10.

26. A protein-drug conjugate according to claim 2 wherein Q is --CONHNH.sub.2, Sp is ##STR33## Y is --CHO, Z is --CONHN.dbd.CH--, and m is 0.1 to 10.

27. A protein-drug conjugate according to claim 2 wherein Q is --CONHNH.sub.2, Sp is ##STR34## Y is --CHO, Z is --CONHNHCH.sub.2 --, and m is 0.1 to 10.

28. A protein-drug conjugate according to claim 8 wherein CH.sub.3 SSS-W is LL-E33288.delta..sub.1.sup.I, Q is --CONHNH.sub.2, Sp is --CH.sub.2 CH.sub.2 --, Y is --CHO, Z is --CONHNHCH.sub.2, and m is 0.1 to 10.

29. A protein-drug conjugate according to claim 10 wherein CH.sub.3 SSS-W is LL-E33288.alpha..sub.3.sup.I, Q is --CONHNH.sub.2, Sp is --CH.sub.2 CH.sub.2 --, Y is --CHO, Z is --CONHNHCH.sub.2 --, and m is 0.1 to 10.

30. A protein-drug conjugate according to claim 10 wherein CH.sub.3 SSS-W is N-acetyl LL-E33288.delta..sub.1.sup.I, Q is --CONHNH.sub.2, Sp is --CH.sub.2 CH.sub.2 --, Y is --CHO, Z is --CONHNHCH.sub.2 --, and m is 0.1 to 10.

31. A protein-drug conjugate according to claim 8 wherein CH.sub.3 SSS-W is LL-E33288.delta..sub.1.sup.I, Q is --CONHNH.sub.2, Sp is --CH.sub.2 CH(CH.sub.3)--, Y is --CHO, Z is --CONHNHCH.sub.2 --, and m is 0.1 to 10.

32. A protein-drug conjugate to claim 10 wherein CH.sub.3 SSS-W is LL-E33288.alpha..sub.3.sup.I, Q is --CONHNH.sub.2, Sp is --CH.sub.2 C(CH.sub.3).sub.2 --, Y is --CHO--, Z is --CONHNHCH.sub.2 --, and m is 0.1 to 10.

33. A protein-drug conjugate according to claim 10 wherein CH.sub.3 SSS-W is N-acetyl LL-E33288.delta..sub.1.sup.I, Q is --CONHNH.sub.2, Sp is ##STR35## Y is --CHO, Z is --CONHNHCH.sub.2 --, and m is 0.1 to 10.
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