Insulin conjugates

Patent metadata

Field	Value
Publication number	US-11098102-B2
Application number	US-201916709208-A
Country	US
Kind code	B2
Filing date	Dec 10, 2019
Priority date	Dec 11, 2018
Publication date	Aug 24, 2021
Grant date	Aug 24, 2021

Abstract

The present invention relates to a conjugate comprising a sulfonamide of formula (I) and an active pharmaceutical ingredient such as an insulin analog comprising at least one mutation relative to the parent insulin, wherein the insulin analog comprises a mutation at position B16 which is substituted with a hydrophobic amino acid and/or a mutation at position B25 which is substituted with a hydrophobic amino acid. The present invention further relates to a sulfonamide of formula (A). Moreover, the present invention relates to an insulin analog comprising at least one mutation relative to the parent insulin.

First claim

The invention claimed is:

1. A conjugate comprising an active pharmaceutical ingredient and a sulfonamide of formula (I-1-2)

wherein in the sulfonamide of formula (I-1-2):
X is a nitrogen atom or a —CH— group;
m is an integer in the range from 5 to 15;
r is an integer in the range from 1 to 6;
q is zero or 1; and
the HOOC—(CH 2 ) m —O— group is situated in meta or para position on phenyl ring Ph with respect to the —S(O) 2 — group,

wherein the sulfonamide of formula (I-1-2) is covalently bound to the active pharmaceutical ingredient in that the terminal carboxy group “a” of the sulfonamide of formula (I-1-2) is covalently bound to an amino group of the active pharmaceutical ingredient, and
wherein the active pharmaceutical ingredient is selected from the group consisting of insulin, insulin analog, GLP-1, and GLP-1 analog.

2. The conjugate according to claim 1 , wherein the sulfonamide has the formula (I-1-2a)

the formula (I-1-2b)

or the formula (I-1-2c)

3. The conjugate of claim 1 , wherein the conjugate has one of the following structures:

(conjugate 1), or

(conjugate 3), or

(conjugate 4).

4. The conjugate of claim 1 , wherein the active pharmaceutical ingredient is an insulin or insulin analog.

5. The conjugate according to claim 4 , wherein the insulin analog comprises an A chain having an amino acid sequence of GIVEQCCTSICSLEQLENYCN (SEQ ID NO: 47) and a B chain having an amino acid sequence of FVNQHLCGSHLVEALYLVCGERGFVYTPK (SEQ ID NO: 48).

6. The conjugate according to claim 4 , wherein the insulin analog comprises an A chain having an amino acid sequence of GIVEQCCTSICSLEQLENYCN (SEQ ID NO: 77) and a B chain having an amino acid sequence of FVEQHLCGSHLVEALVLVCGERGFVYTPK (SEQ ID NO: 78).

7. The conjugate according to claim 4 , wherein the insulin analog comprises at least one mutation relative to a parent insulin, wherein the insulin analog comprises a mutation at position B25 which is substituted with a hydrophobic amino acid.

8. The conjugate according to claim 7 , wherein the parent insulin is human insulin, porcine insulin, or bovine insulin.

9. The conjugate according to claim 7 , wherein the insulin analog further comprises a mutation at position A14 which is substituted with an amino acid selected from the group consisting of glutamic acid (Glu), aspartic acid (Asp) and histidine (His).

10. The conjugate according to claim 7 , wherein the hydrophobic amino acid is a branched-chain amino acid selected from the group consisting of valine (Val), isoleucine (Ile), and leucine (Leu).

11. The conjugate according to claim 4 , wherein the amino group to which the sulfonamide is covalently bound is an epsilon amino group of a lysine present in the insulin or insulin analog.

12. The conjugate according to claim 4 , wherein the amino group to which the sulfonamide is covalently bound is the N-terminal amino group of the B chain of the insulin or insulin analog.

13. A pharmaceutical composition comprising in a pharmaceutically effective amount the conjugate of claim 1 in a pharmaceutically acceptable carrier.

14. A conjugate having the following structure:

(conjugate 1).

15. A pharmaceutical composition comprising in a pharmaceutically effective amount the conjugate of claim 14 in a pharmaceutically acceptable carrier.

16. A conjugate having the following structure:

(conjugate 3).

17. A pharmaceutical composition comprising in a pharmaceutically effective amount the conjugate of claim 16 in a pharmaceutically acceptable carrier.

18. A conjugate having the following structure:

(conjugate 4).

19. A pharmaceutical composition comprising in a pharmaceutically effective amount the conjugate of claim 18 in a pharmaceutically acceptable carrier.

20. The conjugate according to claim 4 , wherein the insulin analog comprises at least one mutation relative to a parent insulin, and wherein the insulin analog comprises a mutation at position B16 which is substituted with a hydrophobic amino acid.

21. The conjugate according to claim 20 , wherein the parent insulin is human insulin, porcine insulin, or bovine insulin.

22. The conjugate according to claim 4 , wherein the insulin analog comprises an A chain having an amino acid sequence of GIVEQCCTSICSLEQLENYCN (SEQ ID NO: 43) and a B chain having an amino acid sequence of FVNQHLCGSHLVFALYLVCGERGFIYTPK (SEQ ID NO: 44).

23. The conjugate according to claim 20 , wherein the insulin analog further comprises a mutation at position A14 which is substituted with an amino acid selected from the group consisting of glutamic acid (Glu), aspartic acid (Asp) and histidine (His).

24. The conjugate according to claim 20 , wherein the hydrophobic amino acid is a branched-chain amino acid selected from the group consisting of valine (Val), isoleucine (Ile), and leucine (Leu).

Assignees

• Sanofi Sa

Inventors

• Mendez Perez Maria
• Rackelmann Nils
• Bialy Laurent
• Guessregen Stefan
• Will Martin
• Boehme Thomas
• Villar Garea Ana
• Korn Marcus Hermann
• Besenius Melissa
• Riedel Jens
• Werner Ulrich
• Podeschwa Michael

Classifications

• C07K14/62 Primary

  Insulins · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61K38/28

  Insulins · CPC title

• A61K31/18 Primary

  Sulfonamides (compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63) · CPC title

• A61K47/542

  Carboxylic acids, e.g. a fatty acid or an amino acid · CPC title