Coniosulfides and their derivatives, processes for preparing them, and their use as pharmaceuticals
View Patent ↗The present invention relates to compounds of the formula which are formed during fermentation by the microorganism Coniochaeta ellipsoidea Udagawa, DSM 13856, or by one of its mutations and/or variants, and chemically derivatized if appropriate. The invention furthermore relates to a process for preparing compounds of the formula (I), and to their use as pharmaceuticals. In addition, the invention relates to the use of a compound of the formula (VI) for producing a pharmaceutical for the treatment and prophylaxis of degenerative neuropathics or of Alzheimer's disease.
1. A compound of formula (I)
where
R 1 is
(a) H, or
(b) a radical selected from —C 1 -C 6 -alkyl, —C 2 -C 6 -alkenyl, —C 2 -C 6 -alkynyl or —C 6 -C 10 -aryl, which is substituted once or twice by
(b1) —OH,
(b2) ═O,
(b3) —O—(C 1 -C 6 -alkyl),
(b4) —O—(C 2 -C 6 -alkenyl),
(b5) —C 6 -C 10 -aryl,
(b6) —NH—C 1 -C 6 -alkyl,
(b7) —NH—C 2 -C 6 -alkenyl,
(b8) —NH 2 or
(b9) fluorine, chlorine, bromine or iodine, in which the substituents (b3) to (b8) is optionally substituted by —CN, -amide or -oxime functions, or
(c) —(C 1 -C 4 -alkyl)-(C 6 -C 10 -aryl), or
(d) —NH 2 , —NH—(C 1 -C 6 -alkyl), or —NH—(C 2 -C 6 -alkenyl),
R 2 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl or iso-butyl,
R 3 is a radical which is composed of from 1 to 10 amino acids and which is optionally N-terminally protected,
R 4 is H, —C 1 -C6-alkyl, or —CO—(C 1 -C 6 -alkyl), and
p is an integer 0, 1 or 2,
with the exception of the compounds of the formula (I) in which, at the same time,
R 1 is H,
R 2 is H,
R 3 is —CO—CH 3 ,
R 4 is H, and
p is 0 or 1,
and/or a stereoisomeric form of the compound of the formula (I) and/or mixtures of this form in any ratio,
and/or a physiologically tolerated salt of the compound of the formula (I).
2. A compound of the formula (I) as claimed in claim 1 , where
R 4 is H, and
R 1 , R 2 , R 3 and p are defined as in claim 1 .
3. A compound of the formula (I) as claimed in claim 1 , where
R 4 is H, and
p is 0, and
R 1 , R 2 and R 3 are defined as in claim 1 .
4. A compound of the formula (I) as claimed in claim 1 , where
R 2 is H or methyl,
R 4 is H,
p is 0, and
R 1 and R 3 are defined as in claim 1 .
5. A compound of the formula (I) as claimed in claim 1 , where
R 2 is H or methyl,
R 3 is a radical which is composed of from 1 to 2 amino acids and which can be N-terminally protected,
R 4 is H,
p is 0, and
R 1 is defined as in claim 1 .
6. A compound of the formula (I) as claimed in claim 1 , where
R 1 is H,
R 2 is H or methyl,
R 3 is a radical which is composed of from 1 to 2 amino acids and which can be N-terminally protected,
R 4 is H, and
p is 0.
7. A compound of the formula (II)
and the physiologically tolerated salts thereof.
8. A compound of formula (III):
and the physiologically tolerated salts thereof.
9. A compound of formula (IV)
and the physiologically tolerated salts thereof.
10. A compound of formula (V)
and the physiologically tolerated salts thereof.
11. A process for preparing a compound of formula (I), which comprises fermenting the microorganism Coniochaeta ellipsoidea Udagawa, DSM 13856, or a variant or mutant of Coniochaeta ellipsoidea Udagawa, DSM 13856, in a culture medium until a compound of the formula (I) accumulates in the culture medium, isolating the compound of the formula (I) and then optionally derivatizing it and, where appropriate, converting it into a physiologically tolerated salt.
12. A pharmaceutical comprising at least one compound as claimed in claim 1 and at least one physiologically suitable excipient and/or auxiliary substance.
13. A pharmaceutical comprising at least one compound as claimed in claim 7 and at least one physiologically suitable excipient.
14. A pharmaceutical comprising at least one compound as claimed in claim 8 and at least one physiologically suitable excipient.
15. A pharmaceutical comprising at least one compound as claimed in claim 9 and at least one physiologically suitable excipient.
16. A pharmaceutical comprising at least one compound as claimed in claim 10 and at least one physiologically suitable excipient.