Dipeptoid prodrugs and the use thereof
View Patent ↗The present application relates to prodrug derivatives of 2-amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}thio)-4-[4-(2-hydroxyethoxy)phenyl]pyridine-3,5-dicarbonitrile, 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 cardiovascular disorders.
1. A compound of the formula (I)
in which
R A is a group of the formula
in which
* means the point of linkage to the O atom,
L 1 and L 2 are independently of one another a bond or —CH 2 —,
R 1 , R 2 and R 3 are independently of one another hydrogen or methyl,
R 4 and R 6 are identical or different and are independently of one another hydrogen or the side group of a natural α-amino acid or its homologs or isomers,
R 5 and R 7 are independently of one another hydrogen or methyl,
L 3 is straight-chain or branched (C 2 -C 4 )-alkanediyl which is additionally substituted by amino,
R 8 , R 9 and R 10 are independently of one another hydrogen or methyl,
m is the number 2, 3, 4, 5 or 6,
L 4 is straight-chain or branched (C 2 -C 4 )-alkanediyl, which is additionally substituted by carboxyl,
R 11 is hydrogen or methyl,
and
n is the number 1, 2, 3 or 4,
and the salts thereof.
2. The compound of the formula (I) as claimed in claim 1 , in which
R A is a group of the formula
in which
* means the point of linkage to the O atom,
L 1 is a bond,
L 2 is a bond or —CH 2 —,
R 1 and R 3 are independently of one another hydrogen or methyl,
R 4 is hydrogen, methyl, propan-2-yl, propan-1-yl, 2-methylpropan-1-yl, 1-methyl-propan-1-yl, butan-1-yl, benzyl, p-hydroxybenzyl, imidazol-4-ylmethyl, hydroxymethyl, 1-hydroxyethyl, carbamoylmethyl or 2-carbamoylethyl,
R 6 is hydrogen, imidazol-4-ylmethyl, 4-aminobutan-1-yl, 3-aminopropan-1-yl, 2-aminoethyl, aminomethyl or 3-guanidinopropan-1-yl,
L 3 is straight-chain (C 2 -C 4 )-alkanediyl which is additionally substituted by amino,
R 8 and R 10 are independently of one another hydrogen or methyl,
m is the number 2, 3 or 4,
L 4 is straight-chain (C 2 -C 4 )-alkanediyl which is additionally substituted by carboxyl,
R 11 is hydrogen or methyl,
and
n is the number 2, 3 or 4.
3. The compound of the formula (I) as claimed in claim 1 , in which
R A is a group of the formula
in which
* means the point of linkage to the O atom,
L 1 and L 2 are each a bond,
R 4 is hydrogen, methyl, propan-2-yl, propan-1-yl, 2-methylpropan-1-yl, 1-methyl-propan-1-yl, butan-1-yl, benzyl, p-hydroxybenzyl, imidazol-4-ylmethyl, hydroxymethyl, 1-hydroxyethyl, carbamoylmethyl or 2-carbamoylethyl,
R 6 is imidazol-4-ylmethyl, 4-aminobutan-1-yl, 3-aminopropan-1-yl, 2-aminoethyl, aminomethyl or 3-guanidinopropan-1-yl,
L 3 is a group of the formula —CH(NH 2 )—CH 2 —, —CH 2 —CH(NH 2 )—, —CH 2 —CH(NH 2 )—CH 2 —, —CH(NH 2 )—CH 2 —CH 2 — or —CH 2 —CH 2 —CH(NH 2 )—,
m is the number 2, 3 or 4,
L 4 is a group of the formula **—CH 2 —CH(COOH)— or **—CH 2 —CH 2 —CH(COOH)—, in which
** represents the point of linkage to the adjoining carbonyl group,
and
n is the number 2 or 3.
4. The compound of the formula (I) as claimed in claim 1 , in which
R A is a group of the formula
in which
* means the point of linkage to the O atom,
L 1 and L 2 are each a bond,
R 4 is hydrogen, methyl, propan-2-yl, 2-methylpropan-1-yl, benzyl, hydroxymethyl or 1-hydroxyethyl,
and
R 6 is imidazol-4-ylmethyl, 4-aminobutan-1-yl, 3-aminopropan-1-yl, 2-aminoethyl, aminomethyl or 3-guanidinopropan-1-yl.
5. The compound of the formula (I) as claimed in claim 1 , in which
R A is a group of the formula
in which
* means the point of linkage to the O atom,
L 3 is a group of the formula —CH(NH 2 )—CH 2 —, —CH 2 —CH(NH 2 )—, —CH(NH 2 )—CH 2 —CH 2 — or —CH 2 —CH 2 —CH(NH 2 )—,
and
m is the number 2 or 3.
6. A process for preparing compounds of the formula (I) as defined in claim 1 , characterized in that the compound (A)
either
[A] is esterified in an inert solvent in the presence of a condensing agent initially with a carboxylic acid of the formula (II), (III) or (IV)
in which L 1 , L 3 , L 4 , R 1 , R 4 , R 5 and R 11 each have the meanings indicated in claim 1 , and
PG 1 is a temporary amino protective group such as, for example, tert-butoxycarbonyl
and
PG 2 is a temporary carboxyl protective group such as, for example, tert-butyl,
to give compounds of the formula (V), (VI) or (VII),
in which L 1 , L 3 , L 4 , R 1 , R 4 , R 5 , R 11 , PG 1 and PG 2 each have the meanings indicated above,
then, after elimination of the protective group PG 1 or PG 2 , is coupled in an inert solvent in the presence of a condensing agent in the case of compound (V) with a compound of the formula (VIII), in the case of compound (VI) with a compound of the formula (IX) and in the case of compound (VII) with a compound of the formula (X)
in which L 2 , R 6 , R 7 , R 8 , PG 2 , m and n each have the meanings indicated in claim 1 ,
and
R 2a and R 3a , and R 9a and R 10a , are in each case identical or different and have the meanings of respectively R 2 , R 3 , R 9 and R 10 indicated in claims 1 to 5 , or are a temporary amino protective group such as, for example, tert-butoxycarbonyl,
and subsequently protective groups which are present where appropriate are removed again,
or
[B] is coupled in an inert solvent in the presence of a condensing agent with a compound of the formula (XI), (XII) or (XIII)
in which L 1 , L 2 , L 3 , L 4 , R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 11 , m and n each have the meanings indicated in claim 1 ,
R 2a and R 3a , and R 9a and R 10a , are in each case identical or different and have the meanings of respectively R 2 , R 3 , R 9 and R 10 indicated in claim 1 , or are a temporary amino protective group such as, for example, tert-butoxycarbonyl,
and
PG 2 is a temporary carboxyl protective group such as, for example, tert-butyl,
and subsequently protective groups which are present where appropriate are removed again,
and the resulting compounds of the formula (I) are converted where appropriate with the appropriate (i) solvents and/or (ii) acids or bases into the solvates, salts and/or solvates of the salts thereof.
7. A medicament comprising a compound as defined in claim 1 in combination with one or more inert, non-toxic pharmaceutically suitable excipients.
8. A method for the treatment and/or prophylaxis of cardiovascular disorders in humans and animals by administering to a human or animal a compound as defined in claim 1 .