Aminomethyl-functionalized denatonium derivatives, their preparation and use

Patent metadata

Field	Value
Publication number	US-11891352-B2
Application number	US-201916975077-A
Country	US
Kind code	B2
Filing date	Feb 20, 2019
Priority date	Feb 21, 2018
Publication date	Feb 6, 2024
Grant date	Feb 6, 2024

Abstract

The present invention is directed to compounds of the general formula (I) and salts thereof

wherein X − is halide, pseudohalide, sulphate, benzoate, acetate, trifluoroacetate, hydroxide, saccharinate or capsaicinate; R 10 is hydrogen or C1-C10-alkyl; and R 1 -R 9 independently are hydrogen, halogen, C1-C5-alkyl, C1-C4-alkoxy, C1-C20-alkoxycarbonyl. The invention is furthermore directed to a method for the preparation of these compounds. The compounds can be used as bitter substances in medicine, pharmaceutics and/or diagnostics. They can furthermore be used for the coupling to proteins and peptides by means of forming a peptide bond between the amino-group of the compounds of the present invention and a carboxyl-group of the protein or peptide.

First claim

The invention claimed is:

1. A compound of general formula (I)

or a salt thereof, wherein:
X − is selected from the group consisting of a halide, pseudohalide, sulphate, benzoate, acetate, trifluoroacetate, hydroxide, saccharinate and capsaicinate;
R 10 is hydrogen or a C1-C10-alkyl; and
R 1 -R 9 independently are selected from the group consisting of hydrogen, halogen, C1-C5-alkyl, C1-C4-alkoxy, and C1-C20-alkoxycarbonyl.

2. The compound according to claim 1 , wherein:
X − is selected from the group consisting of a halide, pseudohalide, sulphate, benzoate, acetate and trifluoroacetate;
R 10 is a C1-C4-alkyl;
R 1 -R 4 are each hydrogen;
R 5 is a C1-C4-alkyl;
R 9 is a C1-C4-alkyl; and
R 6 -R 8 are each hydrogen.

3. The compound according to claim 1 , wherein:
X − is trifluoroacetate;
R 10 is ethyl;
R 5 is methyl;
R 9 is methyl;
R 1 -R 4 are each hydrogen; and
R 6 -R 8 are each hydrogen.

4. The compound according to claim 1 , wherein said compound is formulated for use as a bitter substance in medicine, pharmaceutics and/or diagnostics.

5. A method for preparing a compound of general formula (I)

or a salt thereof, said method comprising the following steps:
a) reacting a compound of general formula (II):

with a compound of general formula (III):

resulting in a compound of general formula (IV):

 and

b) deprotecting the compound of general formula (IV) to form the compound of general formula (I) or a salt thereof, wherein, in the compounds of general formulae (I), (II), (III) and (IV):
R 1 -R 10 and X − are as defined in claim 1 ;
Y is a halogen or pseudohalogen;
Y − is a halide or pseudohalide corresponding to Y; and
PG is an amino protection group selected from the group consisting of tert-butyloxycarbonyl (Voc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc) and allyloxycarbonyl (alloc).

6. The method according to claim 5 , wherein step a) is performed in a solvent-free melt.

7. The method according to claim 6 , wherein a mixture of the compound of general formula (II) and the compound of general formula (III) is heated for 1 to 30 minutes at temperatures in the range of 60 to 120° C.

8. The method according to claim 5 , wherein 1 molar equivalent of the compound of general formula (II) is reacted with 1.4 to 1.8 molar equivalents of the compound of general formula (III).

9. The method according to claim 5 , wherein, in the compound of general formula (II), Y is Br and, in the compound of general formula (IV), Y − is Br − .

10. The method according to claim 5 , wherein PG in the compound of general formulae (II) and (IV) is tert-butyloxycarbonyl (Boc).

11. The method according to claim 10 , wherein the step of deprotecting the compound of general formula (IV) set forth in step b) is performed solvent-free using trifluoroacetic acid.

12. The method according to claim 5 , wherein:
X − is selected from the group consisting of a halide, pseudohalide, sulphate, benzoate, acetate and trifluoroacetate;
R 10 is a C1-C4-alkyl;
R 1 -R 4 are each hydrogen;
R 5 is a C1-C4-alkyl;
R 9 is a C1-C4-alkyl; and
R 6 -R 8 are each hydrogen.

13. The method according to claim 5 , wherein:
X − is trifluoroacetate;
R 10 is ethyl;
R 5 is methyl;
R 9 is methyl;
R 1 -R 4 are each hydrogen; and
R 6 -R 8 are each hydrogen.

14. A coupling product for use in medicine, pharmaceutics and/or diagnostics, said coupling product comprising the compound according to general formula (I) as defined in claim 1 and a peptide or a protein, wherein the compound of general formula (I) and the peptide or the protein are connected via a peptide bond between the aminomethyl-group of the compound of general formula (I) and a carboxyl-group (COOH-group) of the peptide or protein.

15. A method for producing a coupling product comprising the compound according to general formula (I) or a salt thereof as defined in claim 1 and a peptide or protein, said method comprising the step of coupling the compound of general formula (I) or a salt thereof with the peptide or protein by forming a peptide bond between the aminomethyl-group of the compound of general formula (I) or the salt thereof and a carboxyl-group of the protein or peptide.

16. The method according to claim 15 , wherein the peptide or protein used in the coupling with the compound of general formula (I) or the salt thereof is protected by a protection group, and the protection group is cleaved after the coupling.

17. The method according to claim 15 , wherein the compound of general formula (I) or the salt thereof and the peptide or protein is coupled in the presence of a coupling agent and a base.

18. The method according to claim 17 , wherein the coupling agent is O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorphosphate (HATU) and the base is diisopropylethylamine (DIPEA).

Assignees

• Univ Wuerzburg J Maximilians
• Julius Maximilians Univ

Inventors

• Meinel Lorenz
• Luehmann Tessa
• Raschig Martina

Classifications

• C07C237/04 Primary

  the carbon skeleton being acyclic and saturated · CPC title

• C07C231/12

  by reactions not involving the formation of carboxamide groups · CPC title

• C07K1/10

  using coupling agents {(C07K1/006 takes precedence)} · CPC title

• C07C231/10

  from compounds not provided for in groups C07C231/02 - C07C231/08 · CPC title