Conjugates of a pharmaceutical agent and a moiety capable of binding to a glucose sensing protein

Patent metadata

Field	Value
Publication number	US-11090364-B2
Application number	US-201716306243-A
Country	US
Kind code	B2
Filing date	Jun 2, 2017
Priority date	Jun 2, 2016
Publication date	Aug 17, 2021
Grant date	Aug 17, 2021

Abstract

The invention describes novel conjugates of formula (I) of a pharmaceutical agent and a moiety capable of binding to a glucose sensing protein allowing a reversible release of the pharmaceutical agent depending on the glucose concentration.

First claim

The invention claimed is:

1. A conjugate consisting of formula (I)
P-[L 1 ] m -[A 1 ] o -[L 2 ] p -[A 2 ] r -[L 3 ] q -S   (I)

wherein:
P is an insulin or an insulinotropic peptide;
L 1 , L 2 , and L 3 are independently a linker having a chain length of 1-20 atoms;
A 1 and A 2 are independently:
a 5 to 6 membered monocyclic ring,
a 9 to 12 membered bicyclic ring,
two 5 to 6 membered monocyclic rings connected to each other,
two 9 to 12 membered bicyclic rings connected to each other, or
a 5 to 6 membered monocyclic ring and a 9 to 12 membered bicyclic ring connected to each other,
wherein each ring is independently a saturated, unsaturated, or aromatic carbocyclic or heterocyclic ring, and wherein each ring is optionally modified with at least one substituent;

S is a sugar moiety which binds to the insulin independent glucose transporter GluT1, wherein the sugar moiety S comprises a terminal pyranose moiety S1 having a backbone structure of Formula (II)

wherein:
1, 2, 3, 4, 5, and 6 denote the positions of the C-atoms in the pyranose moiety;
is a single bond and is a single or a double bond; and
R1 and R3 are H or a protecting group,
wherein S is attached via position 2, 4, or 6 to the conjugate of formula (I), and wherein the sugar moiety S comprises a single terminal saccharide moiety;
and
m, o, p, r, and q are independently 0 or 1, wherein at least one of r and o is 1,
or a pharmaceutically acceptable salt or solvate thereof.

2. The conjugate of formula (I) of claim 1 , wherein P is an insulin which is attached via the amino side chain of an insulin B29Lys residue or via the amino terminus of an insulin B1Phe residue.

3. The conjugate of formula (I) of claim 1 , wherein L 1 , L 2 , and L 3 are independently (C 1 -C 20 ) alkylene, (C 2 -C 20 ) alkenylene, or (C 2 -C 20 ) alkynylene, wherein one or more C-atoms are optionally replaced by heteroatoms or heteroatom moieties selected from the group consisting of O, NH, N(C 1-4 ) alkyl, S, SO, SO 2 , O—SO 2 , O—SO 3 , O—PHO 2 , and O—PO 3 , and/or wherein one or more C-atoms is optionally modified with (C 1-4 ) alkyl, (C 1-4 ) alkyloxy, oxo, carboxyl, halogen, or a phosphorus-containing group.

4. The conjugate of formula (I) of claim 1 , wherein:
(i) L 3 is (C 1 -C 6 ) alkylene, wherein one or two C-atoms are optionally replaced by heteroatoms or heteroatom moieties selected from the group consisting of O, NH, N(C 1-4 ) alkyl, S, SO, SO 2 , O—SO 2 , O—SO 3 , O—PHO 2 , and O—PO 3 , and/or wherein one or more C-atoms is optionally modified with (C 1-4 ) alkyl, (C 1-4 ) alkyloxy, oxo, carboxyl, halogen, or a phosphorus-containing group;
(ii) L 3 is C═O; or
(iii) L 2 is selected from the group consisting of —CO—(CH 2 ) 3 —, —(CH 2 ) 6 —NH—, —(CH 2 ) 2 —CO—(CH 2 —CH 2 —O) 2 —(CH 2 ) 2 —NH— and —CH 2 —O—(CH 2 —CH 2 —O) 3 —.

5. The conjugate of formula (I) of claim 1 , wherein:
(i) A 1 and A 2 are independently a heterocyclic ring, wherein the ring is optionally modified with at least one substituent;
(ii) A 1 and A 2 are independently a 5 to 6 membered monocyclic or a 9 to 12 membered bicyclic ring, wherein the ring is heterocyclic with 1 to 4 heteroatom(s) selected from the group consisting of N, O, and S, and wherein the ring is optionally modified with at least one substituent; or
(iii) A 1 and A 2 are independently a 5 to 6 membered monocyclic ring, wherein the ring is a heteroalkyl ring optionally modified with at least one substituent, or a 9 to 12 membered bicyclic ring wherein the ring is a heterocyclic ring with 1 to 4 heteroatom(s) selected from the group consisting of N, O, and S, and wherein the ring is optionally modified with at least one substituent.

6. The conjugate of formula (I) of claim 1 , wherein:
(i) A 1 and A 2 are independently 1,2,3-triazolyl;
(ii) A 2 is 1,2,3-triazolyl; or
(iii) A 2 is piperazinyl.

7. The conjugate of formula (I) of claim 1 , wherein:
(i) r=1 and A 2 is present and o=0 and A 1 is absent; or
(ii) r=1 and A 2 is present and o=1 and A 1 is present.

8. The conjugate of formula (I) of claim 1 , wherein:
(i) m=1, o=0, p=0, and q=0 or 1; or
(ii) m=1, o=1, p=1, and q=0 or 1.

9. The conjugate of formula (I) of claim 1 , wherein:
(i) A 2 is piperazinyl, L 2 is absent and A 1 is cyclohexanyl;
(ii) A 2 is piperazinyl, L 2 is —CH 2 — and A 1 is cyclohexanyl;
(iii) A 2 is piperazinyl, L 2 is absent and A 1 is phenyl; or
(iv) A 2 is 1,2,3-triazolyl, L 2 is absent and A 1 is phenyl.

10. The conjugate of formula (I) of claim 1 , wherein:
L 3 is —CO—, A 1 is phenyl, L 2 is —O— and A 1 is phenyl, wherein the phenyl ring is unsubstituted or is modified with at least one substituent selected from the group consisting of halogen, NO 2 , CN, (C 1-4 ) alkyl, (C 1-4 ) alkoxy,
(C 1-4 )alkyl-(C 3-7 )cycloalkyl, (C 3-7 ) cycloalkyl, OH, benzyl, —O-benzyl, carboxyl, carboxyester, carboxamide, mono (C 1-4 ) alkyl carboxamide, and di (C 1-4 ) alkyl carboxamide.

11. The conjugate of formula (I) of claim 1 , wherein the group -A 2 -L 3 - is selected from the group consisting of:

12. The conjugate of formula (I) of claim 1 , wherein the terminal pyranose moiety S1 is selected from the group consisting of glucose, galactose, 4-deoxyglucose, and 4,5-dehydroglucose derivatives, attached via position 2, 4, or 6 in the conjugate of formula (I), or selected from mannose attached via position 6.

13. The conjugate of formula (I) of claim 1 , wherein the terminal pyranose moiety S1 is of Formula (IIIa) or (IIIb):

wherein:
R1 is H or a protecting group;
R2 is OR8, NHR8, or an attachment site in the conjugate of formula (I), wherein R8 is H or a protecting group;
R3 is H or a protecting group;
R4 is H, OR8, NHR8, or an attachment site in the conjugate of formula (I), wherein R8 is H or a protecting group;
R5 and R6 are H or form, together with the carbon atom to which they are bound, a carbonyl group;
R7 is OR8, NHR8, or an attachment site in the conjugate of formula (I), wherein R8 is H or a protecting group,
and wherein one of R2, R4, and R7 is the attachment site in the conjugate of formula (I).

14. The conjugate of formula (I) of claim 13 , wherein:
(i) R1 and R3 are each H; or
(ii) R2 is OR8 or an attachment site in the conjugate of formula (I);
R4 is H, OR8, or an attachment site in the conjugate of formula (I);
R7 is OR8 or an attachment site in the conjugate of formula (I); and
wherein R8 is H or a protecting group.

15. The conjugate of formula (I) of claim 13 , wherein position 6 of the pyranose moiety S1 is the attachment site in the conjugate of formula (I).

16. The conjugate of formula (I) of claim 1 , wherein the pyranose moiety S1 is of formula (IVa), (IVb), (IVc), (IVd), or (IVe):

wherein:
R1 is H or a protecting group;
R2 is OR8, NHR8, or an attachment site in the conjugate of formula (I), wherein R8 is H or a protecting grou

Assignees

• Sanofi Sa

Inventors

• Petry Stefan
• Plettenburg Oliver
• Tennagels Norbert
• Werner Ulrich

Classifications

• C07H15/12

  attached to a nitrogen atom of the saccharide radical · CPC title

• C07K14/62 Primary

  Insulins · CPC title

• C07H19/056

  Triazole or tetrazole radicals · CPC title

• C07H13/08

  having the esterifying carboxyl radicals directly attached to carbocyclic rings · CPC title

• C07H13/10

  having the esterifying carboxyl radicals directly attached to heterocyclic rings · CPC title