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US 2019/0330264 A1Published application
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), reacting a compound of formula (V) with a thiol-containing molecule of formula (VI), resulting in a compound of formula (VII).
Claims26
Process for the preparation of alkene- or alkyne-phosphonamidates comprising the steps of
- (I) Reacting a compound of formula (III)
- wherein
- represents a double or triple bond;
- X represents R3—C when is a triple bond;
- or
- X represents (R3 R4)C when is a double bond;
- R1 independently represents an optionally substituted aliphatic or aromatic residue, such as phenyl;
- 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 such as
- wherein # represents the position of O in formula (III);
- 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 such as pyridyl;
- preferably, R1 represents C1-C8-alkyl, C1-C8-alkyl substituted with —S—S—(C1-C8-alkyl), C1-C8-alkyl substituted with (C1-C8-alkoxy)n wherein n is 1, 2, 3, 4, 5 or 6, C1-C8-alkyl substituted with optionally substituted phenyl, phenyl or phenyl substituted with —NO2;
- R3 represents H or C1-C8-alkyl;
- and
- R4 represents H or C1-C8-alkyl;
- with an azide of formula (IV)
- ●-N3 (IV)
- wherein
- ● represents an aliphatic or aromatic residue;
- to prepare a compound of formula (V)
- wherein ●, , R1, and X are as defined above;
- (II) Reacting a compound of formula (V) with a thiol-containing molecule of formula (VI)
- -SH (VI)
- wherein represents an optionally substituted C1-C8-alkyl, an optionally substituted Phenyl, an optionally substituted aromatic 5- or 6-membered heterocyclic system, an amino acid, a peptide, a protein, an antibody, a saccharide, a polysaccharide, a nucleotide, a oligonucleotide or a polymer;
- resulting in a compound of formula (VII)
- wherein
- represents a bond if in a compound of formula (V) represents a double bond;
- or
- represents a double bond if in a compound of formula (V) represents a triple bond;
- and
- , ●, R1 and X are as defined above.
30 more elements
Process for the preparation of alkene-phosphonamidates comprising the steps of:
- (I) Reacting a compound of formula (III)
- wherein
- V represents C1-C8-alkyl, preferably methyl, ethyl or propyl, more preferably methyl;
- R1 independently represents an optionally substituted aliphatic or aromatic residue, such as phenyl;
- 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 such as
- wherein # represents the position of O in formula (III*);
- 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 such as pyridyl;
- preferably, R1 represents C1-C8-alkyl, C1-C8-alkyl substituted with —S—S—(C1-C8-alkyl), C1-C8-alkyl substituted with (C1-C8-alkoxy)n wherein n is 1, 2, 3, 4, 5 or 6, C1-C8-alkyl substituted with optionally substituted phenyl, phenyl or phenyl substituted with —NO2;
- 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 ●, V, and R1 are as defined above;
- X is (R3 R4)C;
- and
- R3 and R4 are as defined above;
- (II) Reacting a compound of formula (V*) with a thiol-containing molecule of formula (VI)
- -SH (VI)
- wherein represents an optionally substituted C1-C8-alkyl, an optionally substituted Phenyl, an optionally substituted aromatic 5- or 6-membered heterocyclic system, an amino acid, a peptide, a protein, an antibody, a saccharide, a polysaccharide, a nucleotide, a oligonucleotide or a polymer;
- resulting in a compound of formula (VII*)
- wherein , ●, V, R1 and X are as defined above.
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Dependencies are inferred from the claim text.