Insulin derivatives for diabetes treatment

Patent metadata

Field	Value
Publication number	US-9867869-B2
Application number	US-201314652011-A
Country	US
Kind code	B2
Filing date	Dec 12, 2013
Priority date	Dec 12, 2012
Publication date	Jan 16, 2018
Grant date	Jan 16, 2018

Abstract

Compounds, compositions, and methods for “smart” delivery of a therapeutic, prophylactic or diagnostic agent, such as glucose-mediated delivery of insulin through glucose-sensing insulin derivatives, are provided. The insulin derivatives bind serum albumin or agglomerate in vivo. The insulin derivatives effectively dissociate to release insulin in a hyperglycemic condition, where the complexation of glucose to a glucose-sensing element alters properties of the insulin derivative leading to the dissociation. The compounds, compositions, and methods provide a delivery strategy for both self-regulated and long-term diabetes management.

First claim

We claim:

1. An insulin conjugate having the formula:
X 1 -X 2
wherein X 1 is insulin, an insulin analog, glucagon, GLP-1, or a GLP-1 agonist,
X 2 is:
(i) —CO—(CH 2 ) 1 —NH—CO—CR 1 R 2 ,
wherein j is an integer from 3-25
R 1 is —NH—R 12 or —NH—CO—CH 2 —CH 2 —CNR 12 —C(O)R 32 , where R 32 is glucamine, gluconic acid, glucosamine, fructosamine, galactosamine, mannosamine, or other hexosamines,
R 12 is selected from the group consisting of hydrogen, —SO 2 alkyl, —SO 2 cycloalkyl, —SO 2 heterocycloalkyl, —SO 2 aryl, —SO 2 heteroaryl, —COalkyl, —COcycloalkyl, —COheterocycloalkyl, —COaryl, —COheteroaryl, —CONHalkyl, —CONHcycloalkyl, —CONHheterocycloalkyl, —CONHaryl, —CONHheteroaryl,

wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are substituted or unsubstituted,
R 2 is —(CH 2 ) n —NH—CO—R 11 or —(CH 2 ) n —NH—SO 2 R 11 ,
n is an integer from 3-25, and
R 11 is an organic borate group;

(ii) an oligomer comprising a plurality of monomers, wherein the monomers comprise a side chain, wherein the side chain comprises one or more organic borate groups, hydrophobic groups, hydrophilic neutral groups, hydrophilic charged groups, diol groups, fluorescent groups, and combinations thereof, wherein at least one of the side chains comprises an organic borate group;
(iii) —CO—R 6 —R 7 ,
wherein R 6 is a linker or is not present,
wherein R 7 is a diol-containing group complexed to a hydrophobic organic borate group, wherein the diol-containing group comprises one or more diols, wherein the hydrophobic organic borate group comprises one or more organic borate groups covalently linked to a hydrophobic group, wherein at least one diol and one hydrophobic organic borate group form a boronic ester; or

(iv) —CO—R 8 , wherein R 8 is:
(a) -alkenyl-R 9 , wherein R 9 is a phenylboronic acid group, wherein the alkenyl group can be substituted or unsubstituted, wherein the number of carbons in the alkenyl group is from 3 to 25,
(b) —R 13 , wherein R 13 is a bile acid, wherein one or more hydroxyls on the bile acid are derivatized with an organic borate group, or
(c) —(CH 2 ) r —NH—CO—CHR 14 —NH—CO—(CH 2 ) s , wherein r is an integer from 3-25, wherein s is an integer from 3-25, wherein R 14 is an amine-containing group comprising an organic borate group.

2. The derivatized insulin of claim 1 , wherein n is 4.

3. The derivatized insulin of claim 1 , wherein each monomer residue of the oligomer is —CO—O—R 3 —, wherein R 3 is:
—CR 4 —(CH 2 ) m —NH— or pyrrolidine substituted with R 4 , wherein m is an integer from 0-25,
wherein R 4 is —CO—NH—R 5 or —CO—NH—C(CH—CO—NH—R 5 ) 2 ,
wherein each R 5 is independently:
(a) an organic borate group,
(b) C 8-18 alkyl,
(c) —CH 2 -phenyl,
(d) —(CH 2 —CH 2 —O) p —H or —(CH 2 —CH 2 —O) p —CH 3 , wherein p is an integer from 1-500,
(e) —CH 2 -dioxane,
(f) —CH 2 —CH 2 -oxazane,
(g) —CH 2 —CH 2 —N(CH 2 —CH 3 ) 2 ,
(h) —CH 2 —CH 2 -pyrazole,
(i) a fluorescent group,
(j) -piperidine-phenyl,
(k) -piperidine-oxazane,
(l) -piperidine-CH 2 —CH 2 —N(CH 2 —CH 3 ) 2 ,
(m) -piperidine-CH 2 —CH 2 -pyrazole,
(n) -dimethylaminobenzyl, or
(o) -pyridine,
wherein at least one R s is a phenylboronic acid group.

4. An insulin conjugate having the formula:
X 1 -X 2
wherein X 1 is insulin, an insulin analog, glucagon, GLP-1, or a GLP-1 agonist,
X 2 is:
(i) —CO—(CH 2 ) j —NH—CO—CR 1 R 2 ,
wherein j is an integer from 3-25
R 1 is —NH—R 12 or —NH—CO—CH 2 —CH 2 —CNR 12 —C(O)R 32 , where R 32 is glucamine, gluconic acid, glucosamine, fructosamine, galactosamine, mannosamine, or other hexosamines,
R 12 is selected from the group consisting of hydrogen, —SO 2 alkyl, —SO 2 cycloalkyl, —SO 2 heterocycloalkyl, —SO 2 aryl, —SO 2 heteroaryl, —COalkyl, —COcycloalkyl, —COheterocycloalkyl, —COaryl, —COheteroaryl, —CONHalkyl, —CONHcycloalkyl, —CONHheterocycloalkyl, —CONHaryl, —CONHheteroaryl,

wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are substituted or unsubstituted,
R 2 is —(CH 2 ) n —NH—CO—R 11 or —(CH 2 ) n —NH—SO 2 R 11 ,
n is an integer from 3-25, and
R 11 is an organic borate group;

(ii) an oligomer comprising a plurality of monomers, wherein the monomers comprise a side chain, wherein the side chain comprises one or more organic borate groups, hydrophobic groups, hydrophilic neutral groups, hydrophilic charged groups, diol groups, fluorescent groups, and combinations thereof, wherein at least one of the side chains comprises an organic borate group;
(iii) —CO—R 6 —R 7 ,
wherein R 6 is a linker or is not present,
wherein R 7 is a diol-containing group complexed to a hydrophobic organic borate group, wherein the diol-containing group comprises one or more diols, wherein the hydrophobic organic borate group comprises one or more organic borate groups covalently linked to a hydrophobic group, wherein at least one diol and one hydrophobic organic borate group form a boronic ester; or

(iv) —CO—R 8 , wherein R 8 is:
(a) -alkenyl-R 9 , wherein R 9 is a phenylboronic acid group, wherein the alkenyl group can be substituted or unsubstituted, wherein the number of carbons in the alkenyl group is from 3 to 25,
(b) —R 13 , wherein R 13 is a bile acid, wherein one or more hydroxyls on the bile acid are derivatized with an organic borate group, or
(c) —(CH 2 ) r —NH—CO—CHR 14 —NH—CO—(CH 2 ) s , wherein r is an integer from 3-25, wherein s is an integer from 3-25, wherein R 14 is an amine-containing group comprising an organic borate group,

wherein the diol-containing group is -(DOPA-Gly) i —NH 2 , wherein i is an integer from 1-5.

5. The derivatized insulin of claim 1 , wherein the diol-containing group is 6-methyl-6-deoxy-D-galactose, 1-deoxy-β-D-lactopyranoside, α-D-Mannopyranosyl, or adenosine.

6. An insulin conjugate having the formula:
X 1 -X 2
wherein X 1 is insulin, an insulin analog, glucagon, GLP-1, or a GLP-1 agonist,
X 2 is:
(i) —CO—(CH 2 ) j —NH—CO—CR 1 R 2 ,
wherein j is an integer from 3-25
R 1 is —NH—R 12 or —NH—CO—CH 2 —CH 2 —CNR 12 —C(O)R 32 , where R 32 is glucamine, gluconic acid, glucosamine, fructosamine, galactosamine, mannosamine, or other hexosamines,
R 12 is selected from the group consisting of hydrogen, —SO 2 alkyl, —SO 2 cycloalkyl, —SO 2 heterocycloalkyl, —SO 2 aryl, —SO 2 heteroaryl, —COalkyl, —COcycloalkyl, —COheterocycloalkyl, —COaryl, —COheteroaryl, —CONHalkyl, —CONHcycloalkyl, —CONHheterocycloalkyl, —CONHaryl, —CONHheteroaryl,

wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are substituted or unsubstituted,
R 2 is —(CH 2 ) n —NH—CO—R 11 or —(CH 2 ) n —NH—SO 2 R 11 ,
n is an integer from 3-25, and
R 11 is an organic borate group;

(ii) an oligomer comprising a plurality of monomers, wherein the monomers comprise a side chain, wherein the side chain comprises one or more organic borate groups, hydrophobic groups, hydrophilic neutral groups, hydrophilic charged groups, diol groups, fluorescent groups, and combinations thereof, wherein at least one of the side chains comprises an organic borate group;
(iii) —CO—R 6 —R 7 ,
wherein R 6 is a linker or is not present,
wherein R 7 is a diol-containing group complexed to a hydrophobic organic borate group, wherein the diol-containing group comprises one or more diols, wherein the hydrophobic organic borate group comprises one or more organic borate groups covalently linked to a hydrophobic group, wherein at least one diol and one hydrophobic organic borate group form a boronic ester; or

(iv) —CO—R 8 , wherein R 8 is:
(a) -alkenyl-R 9 , wherein R 9 is a phenylboronic acid group, wherein the alkenyl group can be substituted or unsubstituted, wherein the number of carbons in the alkenyl group is from 3 to 25

Assignees

• Massachusetts Inst Technology
• The Children'S Medical Center Corp

Inventors

• Anderson Daniel G
• Chou Hung-Chieh
• Webber Michael J
• Tang Benjamin C
• Levi Yair
• Zhang Yunlong
• Kanasty Rosemary Lynn
• Vegas Arturo Jose
• Langer Robert S

Classifications

• G01N2333/62

  Insulins · CPC title

• A61K47/54

  the modifying agent being an organic compound · CPC title

• A61K47/549

  Sugars, nucleosides, nucleotides or nucleic acids · CPC title

• A61K47/554

  the modifying agent being a steroid plant sterol, glycyrrhetic acid, enoxolone or bile acid · CPC title

• A61K38/28 Primary

  Insulins · CPC title