Sialic acid analogs

Patent metadata

Field	Value
Publication number	US-10065981-B2
Application number	US-201514944779-A
Country	US
Kind code	B2
Filing date	Nov 18, 2015
Priority date	Oct 24, 2011
Publication date	Sep 4, 2018
Grant date	Sep 4, 2018

Abstract

The present invention provides sialic acid analogs and their compositions useful for the treatment of sialic acid deficiencies.

First claim

What is claimed is:

1. A compound having structural Formula (I):

or a pharmaceutically acceptable salt or solvate thereof;
wherein:
R 2 , R 3 , R 4 , and R 6 are independently hydrogen or a moiety selected from structural formula (a), (b), (c), (f), and (g):

R 1 is structural formula;
X is oxygen or sulfur;
L 1 and L 2 are each independently a covalent bond, —O—, or —NR 10a —;
R 10a is hydrogen or optionally substituted alkyl;
R 1a and R 2a are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, —X a —C(O)—O—R 11a , or —X a —O—C(O)—O—R 11a ;
X a is optionally substituted alkylene;
each R 11a is independently hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl;
R 3a , together with —C(O)—moiety to which it is attached, form a monopeptidyl or dipeptidyl group; wherein the monopeptidyl is derived from naturally occurring amino acid selected from the group consisting of Alanine, Arginine, Asparagine, Aspartic acid, Cysteine, Glutamic acid, Glutamine, Glycine, Histidine, Isoleucine, Leucine, Lysine, Methionine, Phenylalanine, Proline, Serine, Threonine, Tryptophan, Tyrosine, and Valine, or non-naturally occurring amino acid; and the dipeptidyl group is derived from naturally occurring amino acid, non-naturally occurring amino acid, or a combination thereof;
each R 8a and R 9a is independently hydrogen or optionally substituted alkyl;
m is 1 or 2;
Z is hydrogen, lower alkyl, an amide group, a lactam group, an ester group, a lactone group, an urea group, a cyclic urea group, a carbonate group, a cyclic carbonate group, a carbamate group, a cyclic carbamate group, or a moiety selected from (a), (b), (c), and (f);
R 5 is hydrogen, G + , optionally substituted alkyl, or a moiety selected from (a), (b), (c), (f), and (g); and
G + is a charged organic amine moiety; or alternatively,
OR 3 and OR 5 are taken together to form a lactone structure represented by Formula (Ia):

2. The compound of claim 1 , wherein structural Formula (I) is represented by structural Formula (II), and structural Formula (II) is represented by structural Formula (IIa):

R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are defined the same as claim 1 .

3. The compound of claim 1 , wherein the monopeptidyl group is derived from amino acids selected from the group consisting of Alanine, Arginine, Asparagine, Aspartic acid, Cysteine, Glutamic acid, Glutamine, Histidine, Isoleucine, Leucine, Lysine, Methionine, Phenylalanine, Proline, Serine, Threonine, Tryptophan, Tyrosine, and Valine.

4. The compound of claim 1 , wherein the dipeptidyl group is derived from amino acids selected from the group consisting of Alanine, Arginine, Asparagine, Aspartic acid, Cysteine, Glutamic acid, Glutamine, Glycine, Histidine, Isoleucine, Leucine, Lysine, Methionine, Phenylalanine, Proline, Serine, Threonine, Tryptophan, Tyrosine, Valine, and a combination thereof.

5. The compound of claim 1 , wherein
R 1 is structural formula (f), wherein the monopeptidyl group is represented by structural formula (d) or (e);

R 4a is hydrogen, halogen, nitro, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted carbocyclyl, OR, NR 2 , or SR;
each R, R 7a , R 5a , and R 6a is independently hydrogen or optionally substituted alkyl; or alternatively, R 4a and NR 5a R 6a , together with the carbon atom to which they are attached, or R 5a and R 6a , together with the nitrogen atom to which they are attached, form an optionally substituted four- to seven-membered azacyclic ring which optionally contains one or more additional heteroatom(s) selected from oxygen, nitrogen, and sulfur; and
L 3 is optionally substituted alkylene.

6. The compound of claim 1 , wherein
R 1 is structural formula (f), wherein the dipeptidyl group is represented by structural Formula (h) or (i):

R 4a and R 5a are defined the same as claim 1 ;
R 12a is hydrogen, halogen, nitro, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted carbocyclyl, ═O, OR, NR 2 , or SR;
R 13a and R 14a are independently hydrogen or optionally substituted alkyl; or alternatively, R 12a and NR 13a R 14a , together with the carbon atom to which they are attached, or R 13a and R 14a , together with the nitrogen atom to which they are attached, form an optionally substituted four-to seven-membered azacyclic ring which optionally contains one or more additional heteroatom(s) selected from oxygen, nitrogen, and sulfur;
R 15a and R 16a are independently hydrogen or optionally substituted alkyl; and
L 4 and L 5 are independently optionally substituted alkylene.

7. A compound having structural Formula (III):

or a pharmaceutically acceptable salt or solvate thereof;
wherein:
R 1b , R 2b , R 3b , R 4b , R 5b are independently OH, or —O—(CHR b ) n —O—C(O)—Y; with the proviso that at least one of R 1b , R 2b , R 3b , and R 4b and R 5b is not OH;
n is 1 or 2;
R b is hydrogen or lower alkyl;
each —O—C(O)—Y is independently a peptidyl moiety; and
the presence of one or more —O—C(O)—Y in Formula (III) increases the uptake of the compound thereof by peptide transporter 1 (PepT1) as compared to the uptake of a compound of Formula (III) wherein R 1b , R 2b , R 3b , R 4b , and R 5b are OH.

8. The compound of claim 7 , wherein structural Formula (III) is represented by structural Formula (IV):

R 1 , R 2 , R 3 , R 4 , and R 5 are defined the same as claim 7 .

9. A compound having a structural Formula (Ia):

or a pharmaceutically acceptable salt or solvate thereof;
wherein:
R 2 , R 3 , R 4 , and R 6 are independently hydrogen or a moiety selected from structural formula (a), (b), (c), (f), and (g):

R 1 is hydrogen or a moiety selected from structural formula (a), (b), (c), (f), and (g); or a nucleoside phosphate moiety;
X is oxygen or sulfur;
L 1 and L 2 are each independently a covalent bond, —O—, or —NR 10a —;
R 10a is hydrogen or optionally substituted alkyl;
R 1a and R 2a are each independently

Assignees

• Ultragenyx Pharmaceutical Inc

Inventors

• Kakkis Emil
• Jungles Steven
• Zhao He

Classifications

• A61P21/00

  Drugs for disorders of the muscular or neuromuscular system · CPC title

• C07H7/027

  Keto-aldonic acids · CPC title

• C07H13/10

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

• C07H13/04

  having the esterifying carboxyl radicals attached to acyclic carbon atoms · CPC title

• C07H7/02 Primary

  Acyclic radicals · CPC title