Streptospirole derivatives
View Patent ↗The invention relates to streptospirole derivatives of the general formula (I), wherein R 1 , R 2 , R 3 , X 1 , X 2 , Y 1 and Y 2 are as defined herein, a process for the preparation of said compounds by fermenting the microorganism Streptomyces sp. ST 108140 (DSM 19369) and optionally derivatizing the compounds produced by said microorganism, a pharmaceutical composition comprising at least one compound of the formula (I), and the use of a compound of the formula (I) for the preparation of a medicament for the treatment and/or prophylaxis of bacterial infections.
1. A compound of formula (I),
wherein
R 1 is (C 6 -C 7 )alkyl,
R 2 is H, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkylene-OH,
R 3 is H or (C 1 -C 6 )alkyl,
X 1 is selected from halogen, O—(C 1 -C 6 )alkyl, NH[(C 1 -C 6 )alkyl], NH[C 1 -C 4 )alkylene-(C 6 -C 10 )-aryl], NH[(C 1 -C 4 )alkylene-(C 6 -C 10 )-heteroaryl], and S—(C 1 -C 4 )alkylene-N[(C 1 -C 4 )alkyl] 2 ,
X 2 is halogen, and
Y 1 and Y 2 are independently selected from H; OH; NH[(C 1 -C 6 )alkyl]; NH[C 1 -C 4 )alkylene-(C 6 -C 10 )-aryl], wherein the (C 6 -C 10 )-aryl group is optionally substituted by halogen;
NH[C 1 -C 4 )alkylene-(C 6 -C 10 -heteroaryl]; and a saturated or unsaturated heterocyclic ring system containing 5 to 6 ring atoms optionally substituted by (C 1 -C 6 )alkyl, wherein one or two ring atoms are selected from N, O, and S; or Y 1 and Y 2 together are ═O,
or a physiologically tolerated salt of a compound of the formula (I).
2. A compound of formula (I) according to claim 1 , wherein R 1 is selected from n-hexyl, 4-methyl-pentyl, n-heptyl, and 4-methyl-hexyl.
3. A compound of formula (I) according to claim 1 , wherein R 2 is selected from H, (C 1 -C 4 )alkyl, and (C 1 -C 4 )alkylene-OH.
4. A compound of formula (I) according to claim 1 , wherein R 3 is H or (C 1 -C 4 )alkyl.
5. A compound of formula (I) according to claim 1 , wherein X 1 is selected from Cl, Br, O—(C 1 -C 4 )alkyl, NH[(C 1 -C 4 )alkyl], NH[(C 1 -C 4 )alkylene-pyridyl], and S—(C 1 -C 4 )alkylene-N[(C 1 -C 4 )alkyl] 2 .
6. A compound of formula (I) according to claim 1 , wherein X 1 and X 2 are independently selected from Cl and Br.
7. A compound of formula (I) according to claim 1 , wherein X 1 and X 2 are both Cl.
8. A compound of formula (I) according to claim 1 , wherein Y 1 and Y 2 are independently of each other selected from the group consisting of H; OH; NH[(C 1 -C 6 )alkyl]; NH—CH 2 -phenyl wherein the phenyl group is optionally substituted by halogen; and a saturated heterocyclic ring system containing 5 to 6 ring atoms optionally substituted by (C 1 -C 6 )alkyl; or Y 1 and Y 2 are together ═O.
9. A compound of formula (I) according to claim 1 , wherein
R 1 is (C 6 -C 7 )alkyl,
R 2 is H, (C 1 -C 4 )alkyl, or (C 1 -C 4 )alkylene-OH,
R 3 is H or (C 1 -C 4 )alkyl,
X 1 is halogen, O—(C1-C4)alkyl, NH[(C 1 -C 6 )alkyl], NH[(C 1 -C 4 )alkylene-heteroaryl] or S—(C 1 -C 4 )alkylene-N[(C 1 -C 4 )alkyl] 2 ,
X 2 is halogen, and
Y 1 and Y 2 are independently of each other selected from H; OH; NH[(C 1 -C 6 )alkyl]; NH—CH 2 -phenyl wherein the phenyl group is optionally substituted by halogen; and a saturated heterocyclic ring system containing 5 to 6 ring atoms optionally substituted by (C 1 -C 6 )alkyl; or
Y 1 and Y 2 together are ═O,
or a physiologically tolerated salt of a compound of the formula (I).
10. A compound of formula (I) according to claim 1 , wherein
R 1 is (C 6 -C 7 )alkyl,
R 2 is H, (C 1 -C 4 )alkyl, or (C 1 -C 4 )alkylene-OH,
R 3 is (C1-C4)alkyl,
X 1 is selected from Cl, Br, NH[(C 1 -C 4 )alkyl], NH[(C 1 -C 4 )alkylene-pyridyl], and S—(C 1 -C 4 )alkylene-N[(C 1 -C 4 )alkyl] 2 ,
X 2 is Cl or Br, and
Y 1 and Y 2 are independently selected from H and OH, or Y 1 and Y 2 are together ═O,
or a physiologically tolerated salt thereof.
11. A compound of formula (I) according to claim 1 , wherein
R 1 is (C 6 -C 7 )alkyl,
R 2 is H, (C 1 -C 2 )alkyl, or (C 1 -C 2 )alkylene-OH,
R 3 is methyl,
X 1 is selected from Cl, Br, NH[butyl], NH[CH 2 -pyridyl], and S-ethylene-N[(C 1 -C 2 )alkyl] 2 ,
X 2 is Cl or Br, and
Y 1 and Y 2 are independently selected from H and OH, or Y 1 and Y 2 are together ═O,
or a physiologically tolerated salt thereof.
12. A compound of formula (I) according to claim 1 , wherein
R 1 is (C 6 -C 7 )alkyl,
R 2 is H,
R 3 is methyl,
X 1 and X 2 are independently selected from Cl and Br,
Y 1 and Y 2 are together ═O,
or a physiologically tolerated salt thereof.
13. A compound of formula (I) according to claim 1 , wherein
R 1 is (C 6 -C 7 )alkyl,
R 2 is H,
R 3 is methyl,
X 1 and X 2 are both Cl,
Y 1 and Y 2 are together ═O,
or a physiologically tolerated salt thereof.
14. A process for preparing a compound of formula (I)
wherein
R 1 is (C 6 -C 7 )alkyl,
R 2 is H, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkylene-OH,
R 3 is H or (C 1 -C 6 )alkyl,
X 1 is selected from halogen, O—(C NH[(C 1 -C 6 )alkyl], NH[(C 1 -C 4 )alkylene-(C 6 -C 10 )-aryl], NH[(C 1 -C 4 )alkylene-(C 6 -C 10 )-heteroaryl], and S—(C 1 -C 4 )alkylene-N[(C 1 -C 4 )alkyl] 2 ,
X 2 is halogen, and
Y 1 and Y 2 are independently selected from H; OH; NH[(C 1 -C 6 )alkyl]; NH[(C 1 -C 4 )alkylene-(C 6 -C 10 )-aryl] wherein the (C 6 -C 10 )-aryl group is optionally substituted by halogen;
NH[(C 1 -C 4 )alkylene-(C 6 -C 10 )-heteroaryl]; and a saturated or unsaturated heterocyclic ring system containing 5 to 6 ring atoms optionally substituted by (C 1 -C 6 )alkyl wherein one or two ring atoms are N, O or S; or Y 1 and Y 2 are together ═O,
or a physiologically tolerated salt of a compound of the formula (I),
the method comprising:
1. fermenting the strain Streptomyces sp. ST 108140 (DSM 19369), or one of its variants and/or mutants, under suitable conditions in a culture medium until one or more of the compounds of the formula (I) accrue(s) in the culture medium,
2. isolating a compound of the formula (I) from the culture medium, and
3. derivatizing the isolated compound of the formula (I) to a compound of the formula (I), where appropriate, and/or, where appropriate, converting the isolated or derivatized compound into a physiologically tolerated salt of a compound of the formula (I).
15. A pharmaceutical composition comprising at least one compound of formula (I) or of a physiologically tolerated salt thereof according to claim 1 .
16. A method for the treatment of an infection in a subject, the method comprising administering to said subject an effective dosage of a compound of the formula (I) or a physiologically tolerated salt thereof according to claim 1 , wherein said infection results from a pathogen selected from Staphylococcus aureus, Escherichia coli, Enterococcus faecalis, Streptococcus pyogenes, Candida albicans , and Mycobacterium smegmatis.
17. A method for the treatment of an infection in a subject, the method comprising administering to said subject an effective dosage of a compound of the formula (I) or a physiologically tolerated salt thereof according to claim 1 , wherein said infection results from a Gram-positive pathogen selected from Streptococci, Staphylococci, and Enterococci.
18. The method of claim 17 , wherein said Gram-positive pathogen is selected from Staphylococcus aureus, Enterococcus faecalis, and Streptococcus pyogenes.