Biologically active compounds obtainable from Sorangium cellulosum

• US 20070021480A1
• Filed: 07/13/2006
• Published: 01/25/2007
• Est. Priority Date: 07/15/2005
• Status: Active Grant

• Current Assignee: Helmholtz-Zentrum FüR Umweltforschung GmbH - UFZ (Bundesrepublik Deutschland)
• Original Assignee: Gesellschaft Fur Biotechnologische Forschung mbH
• Inventors: Irschik, Herbert, Sasse, Florenz, Jansen, Rolf
• Granted Patent: US 7,947,719 B2
• Time in Patent Office: Days
• US Class Current: 514/375
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 498/18 Bridged systems
• CPC Class Codes: C07D 498/22 in which the condensed system contains four or more hetero rings

Abstract

The present invention relates to a novel group of compounds having antibiotic, antifungal and/or cytostatic properties, which are obtainable from myxobacteria, especially of the genus Sorangium, preferably Sorangium cellulosum. One representative of this group of compoundsis currently named Disorazole Z and Disorazole Z-epoxide, respectively, with specific substituents and specific unsaturated bonds to its cyclic core structure:

Claims

1. Compound comprising structure a structure according to formula I,

wherein substituents R1 to R32 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, halogen, hydroxyl, carbonyl, acetyl, alkoxyl, aryloxyl, arylalkyloxyl, amino, imino, hydroxylamino, mono-alkylamino, di-alkylamino, hydrazinyl, cyano, alkylcyano, sulfhydryl, disulfidylalkyl, sulfatidyl, and alkylsulfidyl.

2. Compound according to claim 1, wherein the substituents R1 to R32 are further substituted in their alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, carbonyl, acetyl, alkoxyl, aryloxyl, arylalkyloxyl, mono-alkylamino, di-alkylamino, alkylcyano, disulfidylalkyl, and/or alkylsulfidyl groups by 1, 2 or 3 substituents independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, halogen, fluoro, chloro, bromo, iodo, —

N₃, NO₂, ═

O, ═

S, ═

S(O)₂, hydroxyl, carbonyl, acetyl, alkoxyl, aryloxyl, arylalkyloxyl, amino, imino, hydroxylamino, mono-alkylamino, di-alkylamino, hydrazinyl, cyano, alkylcyano, sulfhydryl, disulfidylalkyl, sulfatidyl and alkylsulfidyl.

3. Compound according to claim 1, comprising a structure according to formula III:

wherein R33 to R70 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, halogen, hydroxyl, carbonyl, acetyl, alkoxyl, aryloxyl, arylalkyloxyl, amino, imino, hydroxylamino, mono-alkylamino, di-alkylamino, hydrazinyl, cyano, alkylcyano, sulfhydryl, disulfidylalkyl, sulfatidyl, and alkylsulfidyl.

4. Compound according to claim 3, wherein the substituents R33 to R70 are further substituted in their alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, carbonyl, acetyl, alkoxyl, aryloxyl, arylalkyloxyl, mono-alkylamino, di-alkylamino, alkylcyano, disulfidylalkyl, and/or alkylsulfidyl groups by 1, 2 or 3 substituents independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, halogen, fluoro, chloro, bromo, iodo, —

N₃, NO₂, ═

O, ═

S, ═

S(O)₂, hydroxyl, carbonyl, acetyl, alkoxyl, aryloxyl, arylalkyloxyl, amino, imino, hydroxylamino, mono-alkylamino, di-alkylamino, hydrazinyl, cyano, alkylcyano, sulfhydryl, disulfidylalkyl, sulfatidyl and alkylsulfidyl.

5. Compound according to claim 1, comprising a structure according to formula V:

wherein substituents Z1 to Z32 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, halogen, hydroxyl, carbonyl, acetyl, alkoxyl, aryloxyl, arylalkyloxyl, amino, imino, hydroxylamino, mono-alkylamino, di-alkylamino, hydrazinyl, cyano, alkylcyano, sulfhydryl, disulfidylalkyl, sulfatidyl, and alkylsulfidyl.

6. Compound according to claim 5, wherein the substituents Z1 to Z32 are further substituted in their alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, carbonyl, acetyl, alkoxyl, aryloxyl, arylalkyloxyl, mono-alkylamino, di-alkylamino, alkylcyano, disulfidylalkyl, and/or alkylsulfidyl groups by 1, 2 or 3 substituents independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, halogen, fluoro, chloro, bromo, iodo, —

N₃, NO₂, ═

O, ═

S, ═

S(O)₂, hydroxyl, carbonyl, acetyl, alkoxyl, aryloxyl, arylalkyloxyl, amino, imino, hydroxylamino, mono-alkylamino, di-alkylamino, hydrazinyl, cyano, alkylcyano, sulfhydryl, disulfidylalkyl, sulfatidyl and alkylsulfidyl.

7. Compound according to claim 1, comprising a structure according to formula VII:

wherein substituents Z33 to Z70 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, halogen, hydroxyl, carbonyl, acetyl, alkoxyl, aryloxyl, arylalkyloxyl, amino, imino, hydroxylamino, mono-alkylamino, di-alkylamino, hydrazinyl, cyano, alkylcyano, sulfhydryl, disulfidylalkyl, sulfatidyl, and alkylsulfidyl.

8. Compound according to claim 7, wherein the substituents Z33 to Z70 are further substituted in their alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, carbonyl, acetyl, alkoxyl, aryloxyl, arylalkyloxyl, mono-alkylamino, di-alkylamino, alkylcyano, disulfidylalkyl, and/or alkylsulfidyl groups by 1, 2 or 3 substituents independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, halogen, fluoro, chloro, bromo, iodo, —

N₃, NO₂, ═

O, ═

S, ═

S(O)₂, hydroxyl, carbonyl, acetyl, alkoxyl, aryloxyl, arylalkyloxyl, amino, imino, hydroxylamino, mono-alkylamino, di-alkylamino, hydrazinyl, cyano, alkylcyano, sulfhydryl, disulfidylalkyl, sulfatidyl and alkylsulfidyl.

9. Compound according to claim 1, wherein at least two substituents of R1 to R32, R41 to R70, Z1 to Z32, and Z41 to Z70, respectively, each bound to one of two neighbouring carbon atoms from C5 to C12 and/or from carbon atoms C5′

and C12′

, in combination with the single bond present between the neighbouring carbon atoms, form a group between these carbon atoms selected from the group consisting a double bond, an epoxide(oxiran), an aziran(aziridine), alkyl-, alkenyl-, alkynyl-, a cycloalkyl-, cycloalkylalkyl, heteroaryl-, an arylalkyl-, a heteroarylalkyl-, heterocyclyl-, and/or a heterocyclylalkyl-substituted aziran(aziridine), a thiirane and a thiirane-S-oxide group.

10. Compound according to claim 1, comprising a structure according to formula IV

wherein substituents X3 to X8 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, halogen, hydroxyl, carbonyl, acetyl, alkoxyl, aryloxyl, arylalkyloxyl, amino, imino, hydroxylamino, mono-alkylamino, di-alkylamino, hydrazinyl, cyano, alkylcyano, sulfhydryl, disulfidylalkyl, sulfatidyl, and alkylsulfidyl.

11. Compound according to claim 10, wherein the substituents X3 to X8 are further substituted in their alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, carbonyl, acetyl, alkoxyl, aryloxyl, arylalkyloxyl, mono-alkylamino, di-alkylamino, alkylcyano, disulfidylalkyl, and/or alkylsulfidyl groups by 1, 2 or 3 substituents independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, halogen, fluoro, chloro, bromo, iodo, —

N₃, NO₂, ═

O, ═

S, ═

S(O)₂, hydroxyl, carbonyl, acetyl, alkoxyl, aryloxyl, arylalkyloxyl, amino, imino, hydroxylamino, mono-alkylamino, di-alkylamino, hydrazinyl, cyano, alkylcyano, sulfhydryl, disulfidylalkyl, sulfatidyl and alkylsulfidyl.

12. Compound according to claim 1, comprising a structure according to formula VI:

wherein X11 to X16 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, halogen, hydroxyl, carbonyl, acetyl, alkoxyl, aryloxyl, arylalkyloxyl, amino, imino, hydroxylamino, mono-alkylamino, di-alkylamino, hydrazinyl, cyano, alkylcyano, sulfhydryl, disulfidylalkyl, sulfatidyl, and alkylsulfidyl,

and wherein carbon atom C5 is substituted with R4, carbon atom C6 is substituted with R6, carbon atom C7 is substituted with R8, carbon atom C8 is substituted with R10, carbon atom C9 is substituted with R12, carbon atom C10 is substituted with R14 and carbon atom C11 is substituted with R16, carbon atom C5′

is substituted with C18, carbon atom C6′

is substituted with R20, carbon atom C7′

is substituted with R22, carbon atom C8′

is substituted with R24, carbon atom C9′

is substituted with R26, carbon atom C10′

is substituted with R28, and carbon atom C11′

is substituted with R30.

13. Compound according to claim 6, comprising a structure according to formula II

wherein X1 and X2 are independently selected from the group consisting of

and wherein carbon atom C5 is substituted with R4, carbon atom C6 is substituted with R6, carbon atom C7 is substituted with R8, carbon atom C8 is substituted with R10, carbon atom C9 is substituted with R12, carbon atom C10 is substituted with R14 and carbon atom C11 is substituted with R16, carbon atom C5′

is substituted with C18, carbon atom C6′

is substituted with R20, carbon atom C7′

is substituted with R22, carbon atom C8′

is substituted with R24, carbon atom C9′

is substituted with R26, carbon atom C10′

is substituted with R28, and carbon atom C11′

is substituted with R30.

14. Compound according to claim 7, comprising a structure according to formula

and wherein carbon atom C5 is substituted with Z4, carbon atom C6 is substituted with Z6, carbon atom C7 is substituted with Z8, carbon atom C8 is substituted with Z10, carbon atom C9 is substituted with Z12, carbon atom C10 is substituted with Z14 and carbon atom C11 is substituted with Z16, carbon atom C5′

is substituted with Z18, carbon atom C6′

is substituted with Z20, carbon atom C7′

is substituted with Z22, carbon atom C8′

is substituted with Z24, carbon atom C9′

is substituted with Z26, carbon atom C10′

is substituted with Z28, and carbon atom C11′

is substituted with Z30.

15. Compound according to claim 1, comprising a structure according to formula IX′

;

16. Compound according to claim 1, comprising a structure according to formula X:

17. Pharmaceutical composition, wherein it comprises at least one compound according to claim 1.

18. Process for producing a compound according to claim 1, wherein it involves fermentation of a myxobacterium of the genus Sorangium at a temperature of 20 to 32°

C. under aeration for 8 to 20 days.