Chemoselective thiol-conjugation with alkene or alkyne-phosphonamidates
AssigneesForschungsverbund Berlin E.V., Ludwig-Maximilians-Universitat Munchen
InventorsChristian Hackenberger, Marc André Kasper, Maria Glanz, Tom Sauer, Dominik Schumacher, Jonas Helma-Smets, Heinrich Leonhardt, Andreas Stengl
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Abstract
Disclosed are novel conjugates and processes for the preparation thereof. A process for the preparation of alkene- or alkyne-phosphonamidates comprises the steps of (I) reacting a compound of formula (III) with an azide of formula (IV) to prepare a compound of formula (V) (II) reacting a compound of formula (V) with a thiol-containing molecule of formula (VI) resulting in a compound of formula (VII)
Claims26
A compound of formula (V)
- wherein:
- represents a triple bond;
- X represents R3—C;
- R1 independently represents an optionally substituted aliphatic or aromatic residue;
- optionally, R1 represents C1-C8-alkyl optionally substituted with at least one of (C1-C8-alkoxy)n wherein n is 1, 2, 3, 4, 5 or 6, F, Cl, Br, I, —NO2, —N(C1-C8-alkyl)H, —NH2, —N(C1-C8-alkyl)2, ═O, C3-C8-cycloalkyl, —S—S—(C1-C8-alkyl), hydroxy-(C1-C8-alkoxy)n wherein n is 1, 2, 3, 4, 5 or 6, C2-C8-alkynyl or optionally substituted phenyl;
- or
- optionally, R1 represents phenyl optionally independently substituted with at least one of C1-C8-alkyl, (C1-C8-alkoxy)n wherein n is 1, 2, 3, 4, 5 or 6, F, Cl, I, Br, —NO2, —N(C1-C8-alkyl)H, —NH2 or —N(C1-C8-alkyl)2;
- or
- optionally, R1 represents a 5- or 6-membered heteroaromatic system;
- R3 represents H or C1-C8-alkyl;
- and
- ● represents an aliphatic or aromatic residue.
A process for the preparation of a compound of formula (V), said process comprising the steps of:
- (I) reacting compound of formula (III)
- wherein:
- represents a double bond or a triple bond;
- X represents R3—C when is a triple bond;
- or
- X represents CR3(R4) when is a double bond;
- R1 independently represents an optionally substituted aliphatic or aromatic residue;
- optionally, R1 represents C1-C8-alkyl optionally substituted with at least one of (C1-C8-alkoxy)n wherein n is 1, 2, 3, 4, 5 or 6, F, Cl, Br, I, —NO2, —N(C1-C8-alkyl)H, —NH2, —N(C1-C8-alkyl)2, ═O, C3-C8-cycloalkyl, —S—S—(C1-C8-alkyl), hydroxy-(C1-C8-alkoxy)n wherein n is 1, 2, 3, 4, 5 or 6, C2-C8-alkynyl or optionally substituted phenyl;
- or
- optionally, R1 represents phenyl optionally independently substituted with at least one of C1-C8-alkyl, (C1-C8-alkoxy)n wherein n is 1, 2, 3, 4, 5 or 6, F, Cl, I, Br, —NO2, —N(C1-C8-alkyl)H, —NH2 or —N(C1-C8-alkyl)2;
- or
- optionally, R1 represents a 5- or 6-membered heteroaromatic system;
- R3 represents H or C1-C8-alkyl;
- and
- R4 represents H or C1-C8-alkyl;
- with an azide of formula (IV)
- wherein
- ● represents an aliphatic or aromatic residue;
- to prepare a compound of formula (V)
- wherein ●, , R1, and X are as defined above.
Dependencies are inferred from the claim text.