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Claims for Patent: 5,606,040

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Claims for Patent: 5,606,040

Title: Antitumor and antibacterial substituted disulfide derivatives prepared from compounds possessing a methyl-trithio group
Abstract:This disclosure describes disulfide analogs of the family of antibacterial and antitumor agents known collectively as the LL-E33288 complex.
Inventor(s): McGahren; William J. (Demarest, NJ), Sassiver; Martin L. (Spring Valley, NY), Ellestad; George A. (Pearl River, NY)
Assignee: American Cyanamid Company (Wayne, NJ)
Application Number:08/155,179
Patent Claims: 1. A substituted disulfide of formula Q--Sp--SS--W, prepared from a compound of formula CH.sub.3 SSS--W and designated as L-E33288.alpha..sub.1 -Br, .alpha..sub.1 -I, .alpha..sub.2 -Br, .alpha..sub.2 -I, .alpha..sub.3 -Br, .alpha..sub.3 -I, .alpha..sub.4 -Br, .beta..sub.1 -Br, .beta..sub.1 -I, .beta..sub.2 -Br, .beta..sub.2 -I, .gamma..sub.1 -Br, .gamma..sub.1 -I, .delta..sub.1 -I, the iodo or bromo pseudoaglycones, their dihydro or N-acyl counterparts, BBM-1675, FR-900405, FR-900406, PD114759, PD115028, CL-1577A, CL-1577B, CL-1577D, CL-1577E, CL-1724, or their N-acetyl counterparts, wherein ##STR14## R.sub.5 is CH.sub.3, C.sub.2 H.sub.5, or (CH.sub.3).sub.2 CH; R.sub.8 is OH and R.sub.9 is H, or R.sub.8 and R.sub.9 together is a carbonyl group; X is an iodine or bromine atom; R.sub.5, is a hydrogen or the group RCO, wherein R is hydrogen, CH.sub.3 or a mono-substituted C.sub.6 -C.sub.11 aryl group; Sp is a straight or branched-chain divalent or trivalent (C.sub.1 -C.sub.18) radical, divalent or trivalent (C.sub.6 -C.sub.11) aryl or heteroaryl radical, divalent or trivalent cyclo-alkyl (C.sub.3 -C.sub.18) radical, divalent or trivalent (C.sub.6 -C.sub.11)aryl- or heteroaryl-alkyl (C.sub.4 -C.sub.18) radical, divalent or trivalent (C.sub.3 -C.sub.18) cycloalkyl-alkyl (C.sub.4 -C.sub.18) radical, or divalent or trivalent (C.sub.2 -C.sub.18) unsaturated alkyl radical, wherein heteroaryl is (4-methyl-coumarinyl-7-yl)amino; and wherein if Sp is a trivalent radical, it can be additionally substituted by amino, C.sub.1 -C.sub.10 alkylamino, C.sub.6 -C.sub.11 arylamino, heteroarylamino, carboxyl, lower alkoxy, hydroxy, thiol, or lower alkylthio groups; Q is hydrogen, halogen, amino, C.sub.1 -C.sub.10 alkylamino, C.sub.1 -C.sub.10 dialkylamino, piperidino, pyrrolidino, piperazino, carboxyl, carboxaldehyde, lower alkoxy, hydroxy, thiol, lower alkyldicarboxyl, --CONHNH.sub.2, --NHCONHNH.sub.2, --CSNHNH.sub.2, --NHCSNHNH.sub.2, or --ONH.sub.2 ; with the proviso that when Sp is ethylidine, Q cannot be hydrogen.

2. A substituted disulfide of formula Q--Sp--SS--W, according to claim 1 prepared from a compound of formula CH.sub.3 SSS--W wherein: ##STR15## R.sub.5 is CH.sub.3, C.sub.2 H.sub.5, or (CH.sub.3).sub.2 CH; X is an iodine or bromine atom: R.sub.5 ' is a hydrogen or the group RCO, wherein R is hydrogen, CH.sub.3, or a mono-substituted C.sub.6 -C.sub.11 aryl group wherein the substituents are as defined in claim 1; and Sp and Q are as defined in claim 1.

3. A substituted disulfide compound according to claim 2 prepared from the antitumor antibiotic of the formula CH.sub.3 SSS--W and designated LL-E33288.sub..gamma.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 substituted disulfide compound according to claim 2 prepared from the antitumor antibiotic of the formula CH.sub.3 SSS--W and designated LL-E33288.sub..alpha.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 substituted disulfide compound according to claim 2 prepared from the antitumor antibiotic of the formula CH.sub.3 SSS--W and designated LL-E33288.sub..alpha.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 substituted disulfide compound according to claim 2 prepared from the antitumor antibiotic of the formula CH.sub.3 SSS--W and designated N-acetyl LL-E33288.sub..gamma.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 substituted disulfide compound according to claim 2 prepared from the antitumor antibiotic of the formula CH.sub.3 SSS--W and designated iodo LL-E33288 pseudoglycone 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 compound Q--Sp--SS--W according to claim 2 wherein Sp is --CH.sub.2 -- and Q is H.

9. A compound Q--Sp--SS--W according to claim 2 wherein Sp is --CH.sub.2 CH.sub.2 -- and Q is H.

10. A compound Q--Sp--SS--W according to claim 2 wherein Sp is --CH.sub.2 CH(CH.sub.3)-- and Q is H.

11. A compound Q--Sp--SS--W according to claim 2 wherein Sp is --CH.sub.2 C(CH.sub.3).sub.2 -- and Q is H.

12. A compound Q--Sp--SS--W according to claim 2 wherein Sp is --CH.sub.2 CH.sub.2 -- and Q is ##STR16##

13. A compound Q--Sp--SS--W according to claim 2 wherein Sp is --CH.sub.2 CH.sub.2 CH.sub.2 -- and Q is H.

14. A compound Q--Sp--SS--W according to claim 2 wherein Sp is --CH.sub.2 CH.sub.2 -- and Q is --CO.sub.2 H.

15. A compound Q--Sp--SS--W according to claim 2 wherein Sp is --CH.sub.2 CH.sub.2 -- and Q is ##STR17##

16. A compound Q--Sp--SS--W according to claim 2 wherein Sp is --CH.sub.2 CH.sub.2 -- and Q is --CONHNH.sub.2.

17. A compound Q--Sp--SS--W according to claim 2 wherein Sp is --CH.sub.2 CH(CH.sub.3)-- and Q is --CO.sub.2 H.

18. A compound Q--Sp--SS--W according to claim 2 wherein Sp is --CH.sub.2 CH(CH.sub.3)-- and Q is --CONHNH.sub.2.

19. A compound Q--Sp--SS--W according to claim 2 wherein Sp is --CH.sub.2 C (CH.sub.3)2-- and Q is --CO.sub.2 H.

20. A compound Q--Sp--SS--W according to claim 2 wherein Sp is --CH.sub.2 C (CH.sub.3).sub.2 -- and Q is --CONHNH.sub.2.

21. A compound Q--Sp--SS--W according to claim 2 wherein Sp is ##STR18## and Q is --CO.sub.2 H.

22. A compound Q--Sp--SS--W according to claim 2 wherein Sp is ##STR19## and Q is --CONHNH.sub.2.

23. A compound Q--Sp--SS--W according to claim 2 wherein Sp is ##STR20## and Q is --CONHNH.sub.2.

24. The ethyl disulfide of LL-E33288.gamma..sub.1 -I having the structure ##STR21##

25. The propyl disulfide of LL-E33288.gamma..sub.1 -I having:

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

b) a mass spectrum as shown in FIG. XXIII having the structure ##STR22##

26. The 1-methyl-1-propyl disulfide of LL-E33288.gamma..sub.1 -I having the structure ##STR23##

27. The t-butyl disulfide of LL-E33288.gamma..sub.1 -1 having the structure ##STR24##

28. The 3-mercaptoproprionyl hydrazide disulfide of LL-E33288.gamma..sub.1 -I having the structure ##STR25##

29. The 3-mercaptobutyryl hydrazide disulfide of LL-E33288.alpha..sub.3 -I having the structure ##STR26##

30. The 3-mercaptoisovaleryl hydrazide disulfide of N-acetyl LL-E33288.gamma..sub.1 -I having the structure ##STR27##

31. The p-mercaptodihydrocinnamyl hydrazide disulfide of N-acetyl LL-E33288.gamma..sub.1 -I having the structure ##STR28##

32. The compound LL-E33288.gamma..sub.2 -I having:

a) ultraviolet spectrum as shown in FIG. XVIII;

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

c) an infrared spectrum as shown in FIG. XX;

d) a mass spectrum as shown in FIG. XXI; and

e) having the structure ##STR29##

33. The compound LL-E33288.gamma..sub.2 -Br having the structure ##STR30##
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