Hydrazinyl-substituted heteroaryl compounds and methods for producing a conjugate

Patent metadata

Field	Value
Publication number	US-11376334-B2
Application number	US-202016936265-A
Country	US
Kind code	B2
Filing date	Jul 22, 2020
Priority date	Mar 18, 2016
Publication date	Jul 5, 2022
Grant date	Jul 5, 2022

Abstract

The present disclosure provides conjugate structures and hydrazinyl-substituted heteroaryl compounds used to produce these conjugates. The disclosure also encompasses methods of production of such conjugates and compounds, as well as methods of using the same.

First claim

What is claimed is:

1. A method of delivering a conjugate to a subject, the method comprising:
administering to the subject an effective amount of a conjugate comprising at least one modified amino acid residue of formula (I):

wherein:
R 1 and R 2 are each independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl;
one of R 3 and R 4 is a polypeptide and the other is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl;
R 5 and R 6 are each independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acyl amino, amino acyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, or R 5 and R 6 are cyclically linked to form a 5 or 6-membered heterocyclyl;
Z 1 is selected from CR 7 , N, O and S;
Z 2 is C or N;
R 7 is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acyl amino, amino acyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl;
L is a linker; and
W is a drug or a detectable label.

2. The method of claim 1 , wherein Z 1 and Z 2 are each N.

3. The method of claim 1 , wherein Z 1 is CR 7 and Z 2 is N.

4. The method of claim 1 , wherein Z 1 is O and Z 2 is C.

5. The method of claim 1 , wherein R 3 is the polypeptide.

6. The method of claim 1 , wherein R 4 is the polypeptide.

7. The method of claim 1 , wherein R 5 and R 6 are each independently selected from alkyl and substituted alkyl.

8. The method of claim 1 , wherein R 7 is hydrogen.

9. The method of claim 1 , wherein:
the linker is of the formula -(T 1 -V 1 ) a -(T 2 -V 2 ) b -(T 3 -V 3 ) c -(T 4 -V 4 ) d -(T 5 -V 5 ) e —, wherein a, b, c, d and e are each independently 0 or 1, where the sum of a, b, c, d and e is 1 to 5;
T 1 , T 2 , T 3 , T 4 and T 5 are each independently selected from (C 1 -C 12 )alkyl, substituted (C 1 -C 12 )alkyl, (EDA) w , (PEG) n , (AA) p , —(CR 13 0H) h -, 4-amino-piperidinyl (4AP), para-aminobenzyl (PAB), para-amino-benzyloxy (PABO), meta-amino-benzyloxy (MABO), para-amino-benzyloxycarbonyl (PABC), meta-amino-benzyloxycarbonyl (MABC), an acetal group, a disulfide, a hydrazine, a carbohydrate, a beta-lactam, an ester, (AA) p -MABO, (AA) p -MABC, (AA) p -PABO, (AA) p -PABC, MABO-(AA) p , MABC-(AA) p , PABO-(AA) p , PABC-(AA) p , (AA) p -MABO-(AA) p , (AA) p -MABC-(AA) p , (AA) p -PABO-(AA) p , and (AA) p -PABC-(AA) p ;
V 1 , V 2 , V 3 , V 4 and V 5 are each independently selected from the group consisting of a covalent bond, —CO—, —NR 11 —, —CONR 11 —, —NR 11 CO—, —C(O)O—, —OC(O)—, —O—, —S—, —S(O)—, —SO 2 —, —SO 2 NR 11 —, —NR 11 SO 2 — and —P(O)OH—;
each R 11 and R 13 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acyl amino, amino acyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl;
w is an integer from 1 to 20;
n is an integer from 1 to 30;
p is an integer from 1 to 20; and
h is an integer from 1 to 12.

10. The method of claim 9 , wherein:
EDA is an ethylene diamine having the structure:

wherein q is an integer from 1 to 6, r is 0 or 1, and each R 12 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acyl amino, amino acyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, or wherein two adjacent R 12 groups are cyclically linked to form a piperazinyl ring;
PEG is a polyethylene glycol or a substituted polyethylene glycol;
AA is an amino acid residue; and
4AP is

wherein each R 14 is independently selected from hydrogen, alkyl, substituted alkyl, polyethylene glycol, substituted polyethylene glycol, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acyl amino, amino acyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl.

11. The method of claim 10 , wherein each R 11 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl.

12. The method of claim 10 , wherein each R 12 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, or wherein two adjacent R 12 groups are cyclically linked to form a piperazinyl ring.

13. The method of claim 10 , wherein each R 13 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, and substituted aryl.

14. The method of claim 10 , wherein each R 14 is independently selected from hydrogen, alkyl, substituted alkyl, polyethylene glycol, substituted polyethylene glycol, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl.

15. The method of claim 10 , wherein T 1 , T 2 , T 3 , T 4 and T 5 and V 1 , V 2 , T 3 , V 4 and V 5 are selected from the following table:

T 1
V 1
T 2
V 2
T 3
V 3
T 4
V 4
T 5
V 5

Assignees

• Scherer Technologies Llc R P

Inventors

• Chuprakov Stepan
• Kudirka Romas Alvydas
• Mcfarland Jesse M
• Garafalo Albert W
• Rabuka David

Classifications

• C07D498/18 Primary

  Bridged systems · CPC title

• A61K47/68033

  the drug being a maytansine · CPC title

• A61K47/545

  Heterocyclic compounds (A61K47/558 takes precedence) · CPC title

• A61K47/6803 Primary

  Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates · CPC title