Aminoacyl prodrug derivatives and medicaments for the treatment of thromboembolitic disorders
View Patent ↗The present application relates to prodrug derivatives of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-morpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide, processes for their preparation, their use for the treatment and/or prophylaxis of diseases, and their use for the manufacture of medicaments for the treatment and/or prophylaxis of diseases, especially of thromboembolic disorders.
1. A compound of formula (I)
in which
R 1 is hydrogen or (C 1 -C 4 )-alkyl which may be substituted by hydroxy or (C 1 -C 4 )-alkoxy,
R 2 is hydrogen or (C 1 -C 4 )-alkyl,
and
L is a (C 1 -C 4 )-alkanediyl group in which one CH 2 group may be replaced by an O atom, or is a group of the formula
in which
* means the point of linkage to the N atom,
R 3 is the side group of a natural α-amino acid or its homologues or isomers,
or
R 3 is linked to R 1 and the two together form a (CH 2 ) 3 or (CH 2 ) 4 group,
R 4 is hydrogen or methyl,
R 5 is (C 1 -C 4 )-alkyl,
and
R 6 is hydrogen or (C 1 -C 4 )-alkyl,
or a salt thereof.
2. A compound according to claim 1 , in which
R 1 is hydrogen or (C 1 -C 4 )-alkyl,
R 2 is hydrogen,
and
L is a (C 2 -C 4 )-alkanediyl group or is a group of the formula
in which
* means the point of linkage to the N atom,
R 3 is hydrogen, methyl, propan-2-yl, propan-1-yl, imidazol-4-ylmethyl, hydroxy-methyl, 1-hydroxyethyl, carbamoylmethyl, 2-carbamoylethyl, 4-aminobutan-1-yl, 3-aminopropan-1-yl or 3-guanidinopropan-1-yl,
or
R 3 is linked to R 1 and the two together form a (CH 2 ) 3 or (CH 2 ) 4 group,
R 4 is hydrogen or methyl,
R 5 is methyl,
and
R 6 is hydrogen or methyl,
or a salt thereof.
3. A compound according to claim 1 , in which
R 1 is hydrogen, methyl or n-butyl,
R 2 is hydrogen,
and
L is a CH 2 CH 2 group or is a group of the formula
in which
* means the point of linkage to the N atom,
R 3 is hydrogen, methyl, propan-2-yl, propan-1-yl, imidazol-4-ylmethyl, hydroxy-methyl, 1-hydroxyethyl, carbamoylmethyl, 2-carbamoylethyl, 4-aminobutan-1-yl, 3-aminopropan-1-yl or 3-guanidinopropan-1-yl,
or
R 3 is linked to R 1 and the two together form a (CH 2 ) 3 or (CH 2 ) 4 group,
R 4 is hydrogen or methyl,
and
R 6 is hydrogen or methyl,
or a salt thereof.
4. A method for preparing a compound of claim 1 , characterized in that either
[A] the compound (A)
is initially converted in an inert solvent in the presence of a base with a compound of the formula (II)
in which R 2 has the meaning indicated in claim 1 ,
and
Q is a leaving group such as, for example, chlorine, bromine or iodine, into a compound of the formula (III)
in which Q and R 2 have the meanings indicated above,
the latter is then reacted in an inert solvent with the caesium salt of an α-amino carboxylic acid or α-amino thiocarboxylic acid of the formula (IV)
in which R 1 , R 3 and R 4 each have the meanings indicated in claim 1 ,
PG is an amino protective group such as, for example, tert-butoxycarbonyl (Boc) or benzyloxycarbonyl (Z),
and
X is O or S,
to give a compound of the formula (V)
in which R 1 , R 2 , R 3 , R 4 , PG and X each have the meanings indicated above,
and subsequently the protective group PG is removed to result in a compound of the formula (I-A)
in which R 1 , R 2 , R 3 , R 4 and X each have the meanings indicated above,
or
[B] compound (A) is reacted in an inert solvent in the presence of a base with a compound of the formula (VI)
in which PG has the meaning indicated above,
R 1A is (C 1 -C 4 )-alkyl which may be substituted by hydroxy or (C 1 -C 4 )-alkoxy,
and
L 1 is a (C 1 -C 4 )-alkanediyl group in which one CH 2 group may be replaced by an O atom,
to give a compound of the formula (VII)
in which R 1A , L 1 and PG each have the meanings indicated above,
and subsequently the protective group PG is removed to result in a compound of the formula (I-B)
in which R 1A and L 1 have the meanings indicated above,
or
[C] the compound (B)
is initially converted into a compound of the formula (VIII)
in which PG, R 1 , R 2 and R 5 each have the meanings indicated in claim 1 ,
and
L 2 is a (CH 2 ) 2 or CR 3 R 4 group in which R 3 and R 4 each have the meanings indicated in claim 1 ,
the latter is then reacted in an inert solvent in the presence of a base with a compound of the formula (IX)
to give a compound of the formula (X)
in which PG, L 2 , R 1 , R 2 and R 5 each have the meanings indicated above,
and subsequently the protective group PG is removed to result in a compound of the formula (I-C)
in which L 2 , R 1 , R 2 and R 5 each have the meanings indicated above,
or
[D] compound (A) is reacted in an inert solvent in the presence of a base with a compound of the formula (XI)
in which
L 1 is a (C 1 -C 4 )-alkanediyl group in which one CH 2 group may be replaced by an O atom,
and
PG 1 and PG 2 are independently of one another an amino protective group such as, for example, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Z) or p-methoxybenzyl (PMB) and may be identical or different,
to give a compound of the formula (XII)
in which L 1 , PG 1 and PG 2 each have the meanings indicated above,
and subsequently the protective groups PG 1 and PG 2 are removed, simultaneously or sequentially, to result in a compound of the formula (I-D)
in which L 1 has the meaning indicated above,
and the compound of the formula (I-A), (I-B), (I-C) or (I-D) resulting in each case is optionally converted with the appropriate (i) solvents and/or (ii) acids into a salt thereof.