Tyrosine based linkers for the releasable connection of peptides
View Patent ↗The invention relates to novel tyrosine based linkers that allow the releasable connection of peptides or proteins with other molecular entities, e.g. polyethylene glycol, to processes for their preparation and their use for preparing medicaments for the treatment and/or prophylaxis of diseases.
1. A compound of the formula
wherein
n represents the number 0, 1, 2, 3 or 4,
m represents the number 0, 1, 2, 3 or 4,
where m and n together are the number 1, 2, 3, 4, 5 or 6,
R 1 represents tert-butyloxycarbonyl or (9H-fluoren-9-ylmethoxy)carbonyl,
R 2 represents tert-butyloxycarbonyl,
R 3 represents hydrogen, methyl, ethyl, n-propyl, isopropyl or benzyl,
R 4 represents a group of the formula
where
* is the point of attachment to the nitrogen,
p represents the number 1, 2, 3, 4 or 5,
R 5 represents hydrogen, aminocarbonyl, (C 1 -C 4 )-alkylaminocarbonyl, phenylaminocarbonyl or a group of the formula
where
# is the point of attachment to the carbon atom,
o represents the number 1, 2, 3, 4 or 5,
R 15 represents hydrogen or (C 1 -C 4 )-alkyl,
R 16 represents hydrogen or (C 1 -C 4 )-alkyl,
R 17 represents the side group of a natural α-amino acid or its homologues or isomers,
and
R 18 represents hydrogen or methyl,
R 6 represents —S-trityl, thiolyl, azidyl, acetylenyl, hydroxycarbonyl or amine,
R 7 represents hydrogen or aminocarbonyl,
R 8 represents —S-trityl, thiolyl, azidyl, acetylenyl, hydroxycarbonyl or amine,
R 9 represents hydrogen or (C 1 -C 4 )-alkyl,
R 10 represents hydrogen or (C 1 -C 4 )-alkyl,
R 11 represents hydrogen or aminocarbonyl,
R 12 represents —S-trityl, thiolyl, azidyl, acetylenyl, hydroxycarbonyl or amine,
R 13 represents the side group of a natural α-amino acid or its homologues or isomers,
and
R 14 represents hydrogen or methyl,
or a salt thereof.
2. The compound of claim 1 , wherein
n represents the number 0, 1, 2 or 3,
m represents the number 0, 1, 2 or 3,
where m and n together are the number 1, 2, 3 or 4,
R 1 represents tert-butyloxycarbonyl or (9H-fluoren-9-ylmethoxy)carbonyl,
R 2 represents tert-butyloxycarbonyl,
R 3 represents hydrogen, methyl, ethyl, n-propyl, isopropyl or benzyl,
R 4 represents a group of the formula
where
* is the point of attachment to the nitrogen,
p represents the number 1, 2, 3, 4 or 5,
R 5 represents hydrogen, aminocarbonyl, phenylaminocarbonyl or —(C═O)NHCH 2 (C═O)NH 2 ,
R 6 represents —S-trityl,
R 7 represents hydrogen or aminocarbonyl,
R 8 represents —S-trityl,
R 9 represents hydrogen,
and
R 10 represents hydrogen.
3. The compound of claim 1 , wherein
n represents the number 2 or 3,
and
m represents the number 0,
or
n represents the number 0,
and
m represents the number 2 or 3,
or
n represents the number 0,
and
m represents the number 1,
R 1 represents tert-butyloxycarbonyl or (9H-fluoren-9-ylmethoxy)carbonyl,
R 2 represents tert-butyloxycarbonyl,
R 3 represents hydrogen, methyl, ethyl, n-propyl, isopropyl or benzyl,
R 4 represents a group of the formula
where
* is the point of attachment to the nitrogen,
p represents the number 1, 2, 3, 4 or 5,
R 5 represents hydrogen, aminocarbonyl, phenylaminocarbonyl or —(C═O)NHCH 2 (C═O)NH 2 ,
R 6 represents —S-trityl,
R 7 represents hydrogen or aminocarbonyl,
R 8 represents —S-trityl,
R 9 represents hydrogen,
and
R 10 represents hydrogen.
4. A process for preparing a compound of the formula (I) or a salt thereof, comprising
reacting a compound of the formula (II)
in which
n, m, R 1 , R 2 , R 3 and R 4 are each as defined in claim 1 ,
with a Palladium(0) source and a reducing agent.
5. A pharmaceutical composition comprising a prodrug prepared with a compound of claim 1 and an inert nontoxic pharmaceutically suitable excipient.
6. The pharmaceutical composition of claim 5 , further comprising a further active ingredient.