MACROLACTONE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND USE THEREOF FOR THE TREATMENT OF CANCER
The present invention relates to the use of a compound of the formula (I), wherein X and Y independently of one another are OH, O—(C 1 -C 6 )-alkyl, NH 2 or NH—(C 1 -C 6 )-alkyl, or X and Y together form a group —O— or wherein X and Y together form a further bond between the C atoms to which they are attached; R1 and R2 independently of one another are H, Cl or Br; R3 is H,(C 1 -C 6 )alkyl, C(═O)—(C 1 -C 6 )-alkyl or (C 1 -C 6 )-alkylene-NH—(C 1 -C 6 )-alkyl; R4 is H, (C 1 -C 6 )-alkyl or C(═O)—(C 1 -C 6 )-alkyl, and R5 is methyl or ethyl; or a physiologically tolerable salt of a compound of the formula (I), for the treatment and/or prophylaxis of cancer diseases, a pharmaceutical composition for the treatment and/or prophylaxis of cancer diseases comprising a compound of the formula (I), a compound of the formula (I) and a process for the preparation of the compound (I).
1 . A method for treating and/or preventing cancer in a patient in need thereof comprising administering to said patient a therapeutically effective amount of a compound of the formula (I),
wherein
X and Y independently of one another are OH, O—(C 1 -C 6 )-alkyl, NH 2 or NH—(C 1 -C 6 )-alkyl, or X and Y together form a group —O— or wherein X and Y together form a further bond between the C atoms to which they are attached,
R1 and R2 independently of one another are H, Cl or Br,
R3 is H, (C 1 -C 6 )-alkyl, C(═O)—(C 1 -C 6 )-alkyl or (C 1 -C 6 )-alkylene-NH—(C 1 -C 6 )-alkyl,
R4 is H, (C 1 -C 6 )-alkyl or C(═O)—(C 1 -C 6 )-alkyl, and
R5 is methyl or ethyl,
or a physiologically tolerable salt thereof.
2 . The method according to claim 1 , wherein X and Y together form a group —O— or wherein X and Y together form a further bond between the C atoms to which they are attached.
3 . The method according to claim 1 , wherein at least one of R1 and R2 is Cl or Br.
4 . The method according to claim 1 , wherein R3 is H or (C 1 -C 6 )-alkyl.
5 . The method according to claim 1 , wherein R4 is H.
6 . The method according to claim 1 , wherein R5 is ethyl.
7 . The method according to claim 1 , wherein
X and Y together form a group —O—, or X and Y form a further double bond between the C atoms to which they are attached,
R1 and R2 independently of one another are H, Cl or Br,
R3 and R4 independently of one another are H, (C 1 -C 6 )-alkyl or C(═O)—(C 1 -C 6 )-alkyl, and
R5 is methyl or ethyl.
8 . The method according to claim 1 , wherein
X and Y together form a group —O—, or X and Y form a further double bond between the C atoms to which they are attached,
R1 and R2 independently of one another are H, Cl or Br,
R3 is H or (C 1 -C 6 )-alkyl,
R4 is H, and
R5 is methyl or ethyl.
9 . The method according to claim 1 , wherein
X and Y together form a group —O—, or X and Y form a further double bond between the C atoms to which they are attached,
R1 and R2 are both Cl,
R3 is H or (C 1 -C 6 )-alkyl,
R4 is H, and
R5 is methyl or ethyl.
10 . A pharmaceutical composition for the treatment and/or prophylaxis of cancer diseases comprising at least one compound of the formula (I) as defined in claim 1 .
11 . A compound of the formula (I),
wherein
X and Y independently of one another are OH, O—(C 1 -C 6 )-alkyl, NH 2 or NH—(C 1 -C 6 )-alkyl, or X and Y together form a group —O— or wherein X and Y together form a further bond between the C atoms to which they are attached,
R1 and R2 independently of one another are H, Cl or Br,
R3 is H, (C 1 -C 6 )-alkyl, C(═O)—(C 1 -C 6 )-alkyl or (C 1 -C 6 )-alkylene-NH—(C 1 -C 6 )-alkyl,
R4 is H, (C 1 -C 6 )-alkyl or C(═O)—(C 1 -C 6 )-alkyl, and
R5 is methyl or ethyl,
provided that when
X and Y independently of one another are OH, O—(C 1 -C 6 )-alkyl, NH 2 or NH—(C 1 -C 6 )-alkyl, or X and Y together form a group —O—,
R1 and R2 independently of one another are H or Cl,
R3 is H, (C 1 -C 6 )-alkyl, C(═O)—(C 1 -C 6 )-alkyl or (C 1 -C 6 )-alkylene-NH—(C 1 -C 6 )-alkyl, and
R4 is H, (C 1 -C 6 )-alkyl or C(═O)—(C 1 -C 6 )-alkyl,
R5 may not be ethyl,
or a physiologically tolerable salt thereof.
12 . A process for the preparation of a compound according to claim 11 , or a physiologically tolerable salt thereof, comprising
1. fermenting the strain Nannocystis sp. ST 201196 (DSM 18870) or one of its variants and/or mutants under suitable conditions in a culture medium which contains a Cl and/or a Br source, until one or more of the compounds of the formula (I) accumulates in the culture medium and
2. isolating a compound of the formula (I) from the culture medium, and
3. optionally derivatizing the compound of the formula (I) and/or converting it into a physiologically tolerable salt.
13 . The process according to claim 12 , wherein at least one Br source is present in the culture medium.
14 . A pharmaceutical composition containing at least one compound of the formula (I) according to claim 11 .