Aminoacyl prodrug derivatives and medicaments for treatment of thromboembolic disorders
View Patent ↗The present application relates to prodrug derivatives of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-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 the formula
in which
n is 1 or 2,
X is an oxygen atom, a sulphur atom or NH,
R 1 is the side group of a natural a-amino acid or of its homologs or isomers,
R 2 is hydrogen or methyl,
R 3 is hydrogen,
or
R 1 and R 2 are linked via a (CH 2 ) 3 or (CH 2 ) 4 group and combine with the nitrogen or carbon atom to which they are attached to form a 5- or 6-membered ring, respectively, and salts thereof.
2. The compound of claim 1 , in which
n is 1 or 2,
X is an oxygen atom, a sulphur atom or NH,
R 1 is hydrogen, methyl, propan-2-yl, propan-1-yl, 2-methylpropan-1-yl, imidazol-4-yl-methyl, hydroxymethyl, 1-hydroxyethyl, carboxymethyl, 2-carboxyethyl, carbamoylmethyl, 2-carbamoylethyl, 4-aminobutan-1-yl, 3-aminopropan-1-yl, 3-guanidinopropan-1-yl, benzyl or 4-hydroxybenzyl,
R 2 is hydrogen or methyl, and
R 3 is hydrogen
or
R 1 and R 3 are linked via a (CH 2 ) 3 or (CH 2 ) 4 group and combine with the nitrogen or carbon atom to which they are attached to form a 5- or 6-membered ring, respectively.
3. The compound of claim 1 , in which
n is 1 or 2,
X is NH,
R 1 is hydrogen, methyl, propan-2-yl, 2-methylpropan-1-yl, imidazol-4-ylmethyl, hydroxymethyl, 1-hydroxyethyl, carboxymethyl, 2-carboxyethyl, carbamoylmethyl, 2-carbamoylethyl, 4-aminobutan-1-yl, benzyl or 4-hydroxybenzyl,
R 2 is hydrogen, and
R 3 is hydrogen.
4. A process for preparing a compound of the formula (I) of claim 1 , or salts thereof, comprising:
[A] converting a compound of the formula (A):
in an inert solvent in the presence of a base with a compound of the formula (II):
in which n has the meaning indicated in claim 1 ,
and
Q is a leaving group,
into a compound of the formula (III):
in which n has the meaning indicated in claim 1 , and
Q has the meaning indicated in this claim,
reacting the compound of formula (III) according to process [A1] 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 2 and R 3 have the meaning indicated in claim 1 ,
PG is an amino protective group,
and
Y is O or S,
to give a compound of the formula (V)
in which n, R 1 , R 2 and R 3 have the meaning indicated in claim 1 ,
PG has the meaning indicated in this claim, and
X is O or S,
and removing the protective group PG according to conventional methods to obtain a compound of the formula (I-A)
in which n, R 1 , R 2 and R 3 have the meaning indicated in claim 1 , and
X is O or S, or
reacting the compound of formula (III) according to process [A2] in an inert solvent in the presence of a base with an a-amino thiocarboxylic acid of the formula (VI)
in which R 1 , R 2 and R 3 have the meaning indicated in claim 1 ,
and PG is an amino protective group, to give a compound of the formula (V-A)
in which n, R 1 , R 2 and R 3 have the meaning indicated in claim 1 , and
PG has the meaning indicated in this claim, and
removing the protective group PG according to conventional methods to obtain a compound of the formula (I-A)
in which n, R 1 , R 2 and R 3 have the meaning indicated in claim 1 ,
or
[B] reacting compound (A) in an inert solvent in the presence of a base with a compound of the formula (VII)
in which n has the meaning indicated in claim 1 ,
to give a compound of the formula (VIII)
in which n has the meaning indicated in claim 1 ,
and removing the protective groups according to conventional methods to obtain a compound of the formula (IX):
in which n has the meaning indicated in claim 1 , and
combining the compound of formula (IX) in the presence of a base with a compound of the formula (X)
in which R 1 , R 2 and R 3 have the meaning indicated in claim 1 ,
AG is hydroxyl or halogen, or
with the carbonyl group of formula (X) forms an active ester, or a mixed anhydride, and
PG is an amino protective group,
to obtain a compound of the formula (XI)
in which n, R 1 , R 2 and R 3 have the meaning indicated in claim 1 , and
PG has the meaning indicated in this claim,
and removing the protective group PG from the compound of formula (XI) according to conventional methods to obtain a compound of the formula (I-B)
in which n, R 1 , R 2 and R 3 have the meaning indicated in claim 1
and optionally converting the compounds of the formula (I-A) or (I-B) with the appropriate (i) solvents and/or (ii) acids into their salts.
5. A pharmaceutical composition comprising a compound of the formula (I) as defined in claim 1 and an inert, non-toxic, pharmaceutically suitable excipient.