US2020223860A1PendingUtilityA1
The total synthesis of glucosepane and related chemical reactions, compounds and compositions and obtained therefrom and methods of treatment
Est. expirySep 25, 2035(~9.2 yrs left)· nominal 20-yr term from priority
Y02P20/55C07C 281/16A61K 31/55A61K 45/06C07D 487/04C07D 491/048
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Claims
Abstract
Glucosepane is a structurally complex protein post-translational modification (PTM) believed to exist in all living organisms. Research in humans suggests that glucosepane plays a critical role in the pathophysiology of both diabetes and human aging; yet comprehensive biological investigations of this metabolite have been greatly hindered by a scarcity of chemically homogeneous material available for study. Glucosepane possesses a unique chemical structure that incorporates a surprising, never-before-prepared non-aromatic tautomer of imidazole (hereafter termed an “iso-imidazole”), rendering it a challenging target for chemical synthesis. In this application, the inventors report the first total synthesis of glucosepane, enabled by the development of a novel one-pot method for preparation of the iso-imidazole core. The synthesis of the present invention is concise (8-steps starting from commercial materials), convergent, high-yielding (12% overall), and enantioselective. These results should prove useful to the art and practice of heterocyclic chemistry, and critical for the study of glucosepane and its role in human health and disease, especially the treatment of diabetic disorders or its impact on aging processes. Methods of synthesis, compounds obtained therefrom, pharmaceutical compositions and methods of treatment provide embodiments of the present invention.
Claims
exact text as granted — not AI-modified1 . A method of synthesizing gluocosepane or a glucosepane derivative comprising reacting an azepin-one compound according to the chemical structure (14)
where R is a C 1 -C 12 optionally substituted hydrocarbon group or a heterocyclic group, with a semicarbazone compound according to the chemical structure:
Where X is optionally substituted S-alkyl, an optionally substituted S-aryl, an optionally substituted S-heterocyclyl, an optionally substituted O-alkyl, an optionally substituted O-aryl, an optionally substituted O-heterocyclyl, a NR 1 R 2 group where R 1 and R 2 are each independently H, an optionally substituted alkyl group, including an alkyl group which forms an amino acid group of ornithine or lysine where the distal amine of the side chain of each amino acid is linked to the semicarbazone and the amine or the amine and carboxylic groups are protected with a protecting group, an optionally substituted aryl group or an optionally substituted heterocyclyl, or X is an amino acid group obtained from a D- or L-amino acid according to the chemical structure;
where the amine group of the amino acid is linked to the semicarbazone and the amine group and/or the carboxylic group is optionally protected and R a is H, C 1 -C 6 alkyl or alkanol or R a forms a cyclic ring with R 3 (proline) or R 3 is a side chain derived from an amino acid preferably selected from the group consisting of alanine (methyl), arginine (propyleneguanidine), asparagine (methylenecarboxyamide), aspartic acid (ethanoic acid), cysteine (thiol, reduced or oxidized di-thiol), glutamine (ethylcarboxyamide), glutamic acid (propanoic acid), glycine (H), histidine (methyleneimidazole), isoleucine (1-methylpropane), leucine (2-methylpropane), lysine (butyleneamine), methionine (ethylmethylthioether), phenylalanine (benzyl), proline (R 3 forms a cyclic ring with R a and the adjacent nitrogen group to form a pyrrolidine group), hydroxyproline, serine (methanol), threonine (ethanol, 1-hydroxyethane), tryptophan (methyleneindole), tyrosine (methylene phenol) or valine (isopropyl) (where the R 3 side chain is optionally protected) to provide compound 24A:
where R and X are the same as above;
Compound 24A is further reacted with trimethylsilyl chloride (TMSCl) in the presence of solvent (preferably chloroform, methylene chloride) at elevated temperature (generally, above room temperature and often at the reflux temperature of the solvent used) to provide compound 28A
or an alternative pharmaceutical salt, non-salt compound or stereoisomer thereof,
Where Y′ is H and R and X are the same as above; and optionally, deprotecting the protected compound, which can be performed in the same pot or separated prior to deprotection.
2 . The method according to claim 1 wherein R is a C 1 -C 12 optionally substituted hydrocarbon group (preferably an optionally substituted alkyl or aryl group) or a heterocyclic group (preferably a heteroaryl group); and
X is an optionally substituted S-alkyl, O-alkyl or a NH—R 1 group where R 1 is an optionally substituted C 1 -C 10 alkyl group, including an ornithine or lysine moiety, which contains a protecting group on the free amine and/or carboxylic acid group, wherein said reaction steps occur in multiple steps or in a single pot where all of the steps are performed or where the compound is optionally separated prior to deprotection.
3 . The method of claim 1 wherein the entire method is performed in a single pot.
4 . The method of claim 1 wherein the method is performed in a single pot except for the final deprotection step.
5 . The method according to claim 1 wherein X is S-Me, Y′ is H and R is a C 2 or C 3 alkylene group substituted with an amino group and a carboxylic acid group obtained from ornithine or lysine wherein said amino group and/or said carboxylic acid group is protected.
6 . The method according to claim 1 wherein X is a NH—R 1 group where R 1 is a C 3 or C 4 alkylene group substituted with an amino group and a carboxylic acid group obtained from ornithine or lysine wherein said amino group and/or said carboxylic acid group is protected.
7 . The method according to claim 1 wherein said compound 28A is reacted with SiO 2 or a weak base in the presence of aqueous solvent to convert Y′ to a OH group.
8 . The method according to claim 7 wherein X is S-Me.
9 . The method according to claim 8 wherein Y′ is OH and X is S-Me and said compound is further reacted with a protected ornithine or lysine amino acid at the S-Me position of the imidazole to provide a compound wherein Y′ is OH and X is an ornithine or lysine moiety linked to said imidazole group by the amine in the side chain of ornithine or lysine and the remaining amino group and/or carboxylic acid group of said omithine or said lysine group is protected.
10 . The method according to claim 9 wherein said OH group at Y′ is reduced to a hydrogen.
11 . The method according to claim 10 wherein Y is reduced a borohydride reducing agent.
12 . The method according to claim 11 wherein said borohydride reducing agent is Na(OAc) 3 BH).
13 . The method according to claim 9 wherein said compound is deprotected.
14 . A method of synthesizing glucosepane or a derivative thereof comprising reacting a compound 8 according to the chemical structure:
with a protected lysine or ornithine derivative according to the chemical structure:
BL-NH—CH 2 R
Where BL is a protecting group and R is an alkylene amino acid group obtained from lysine or ornithine which is protected on the free amine and carboxylic acid groups of R in the presence of solvent at elevated temperature in a first step, followed by exposure to a trifluoroacetic acid solution (e.g. 5%) in solvent in the presence of a hydrosilane to provide compound 10:
Exposing compound 10 to aqueous acid at elevated temperature to provide a compound which spontaneously undergoes amadori rearrangement and intramolecular trapping to provide compound 13:
which is reacted with 2,2-dimethoxypropane (DMP) in the presence of pyridinium salt (preferably pyridinium p-toluenesulfonateor PPTS) in solvent to provide compound 14,
where R is the same as above;
reacting compound 14 with a semicarbazone compound according to the chemical structure:
Where X is an optionally substituted S-alkyl (preferably, S-Me), O-alkyl or a NH—R 1 group where R 1 is an optionally substituted C 1 -C 10 alkyl group (preferably, NHR 1 is an ornithine or lysine moiety with the distal amine of the side chain linked to the semicarbozone and the remaining amine and/or acid groups being optionally protected to form the compound 24A
where R and X are the same as above;
further reacting compound 24A with trimethylsilyl chloride (TMSCl) in the presence of solvent at elevated temperature to provide compound 28A:
or an alternative pharmaceutical salt, non-salt compound or stereoisomer thereof,
Where Y′ is H and R and X are the same as above, and optionally, deprotecting the protected compound.
15 . The method according to claim 14 wherein X in said compound 28A is S-Me, Y′ is H and R is the same as in claim 14
Wherein said compound is reacted with SiO 2 or weak base in the presence of aqueous solvent to provide an intermediate where Y′ is OH, and R and X are the same as above, followed by reacting the hydroxyl-containing intermediate with a protected NH-Lys (lysine) or NH-Orn (ornithine) amino acid wherein the distil amine of the side chain of the lysine or ornithine is a free amine and the remaining amine or the amine and carboxylic acid groups in the amino acid are protected to displace the S-Me group at X and substitute a protected NH-Lys or NH-Orn group, followed by reducing the hydroxyl group at Y′ to a hydrogen group where R is the same as above and X is a protected NH-Lys or NH-Orn group.
16 . (canceled)
17 . (canceled)
18 . (canceled)
19 . A method of synthesizing a compound according to the chemical structure:
or a non-salt form, alternative salt form or stereoisomer thereof
Where R is a C 2 or C 3 alkylene group substituted with an optionally protected amine and carboxylic acid group at the distal carbon of the alkylene group, X is a —NHR 1 group where R 1 is a C 3 or C 4 alkylene group of ornithine or lysine containing an amine group and/or carboxylic acid group of said omithine or lysine being optionally protected;
Comprising reacting a compound according to the chemical structure:
Where R is a C 2 or C 3 alkyl group of omithine or lysine containing an amine group and a carboxylic group either of which or both are optionally protected, with a semicarbazone compound according to the chemical structure:
Where X is S-methyl or —NHR 1 , where R 1 is a C 3 or C 4 alkylene group of ornithine or lysine containing an amine group and/or carboxylic acid group of said ornithine or lysine being optionally protected to provide a compound according to the chemical structure:
Where R and X are the same as above;
Reacting said semicarbozone substituted compound above with trimethylsilyl chloride in solvent at elevated temperature to provide a compound according to the chemical structure
where X is S-Me or —NHR 1 , and Y′ is H, or
a non-salt, an alternative salt or a stereoisomer thereof.
20 . The method according to claim 19 wherein X is S-Me and said compound is reacted with SiO 2 or weak base in the presence of aqueous solvent to convert the bridge hydrogen (Y′═H) to a hydroxyl group (Y′ is OH).
21 . The method according to claim 20 wherein after said bridge hydrogen is converted to a hydroxyl group, the compound is reacted with a protected ornithine or lysine compound and the S-Me group is converted to a NHR 1 group, where R 1 is the same as in claim 19 , and wherein said hydroxyl group is converted to a hydrogen group under reducing conditions using a borohydride reducing agent and said protecting groups are removed to provide glucosepane or a glucosepane derivative according to the chemical structure:
Where R is a C 2 or C 3 alkylene group substituted with an amine and carboxylic acid group at the distal carbon of the alkylene group, X is a —NHR 1 group where R 1 is a C 3 or C 4 alkylene group of ornithine or lysine containing an amine group and a carboxylic acid group and Y′ is H, or
A non-salt form, an alternative salt form or a stereoisomer thereof.
22 . (canceled)
23 . A method for synthesizing a substituted imidazole from an aldehyde or ketone of the general formula 1k:
Where Z 1 is H, an optionally substituted C 1 -C 12 hydrocarbon group, a 3-20 membered heterocyclic group, a NR 1 R 2 group, a SR 1 or OR 1 group or together Z 1 and Z 2 form an optionally substituted 5- to 7-membered ring which is carbocyclic or heterocyclic;
Z 2 is H, an optionally substituted C 1 -C 12 hydrocarbon group, a 3-20 membered heterocyclic group or together Z 1 and Z 2 are linked to form an optionally substituted 5- to 8-membered ring which is carbocyclic or heterocyclic;
R 1 and R 2 are each independently absent (with the proviso that only one of R 1 and R 2 may be absent), H, an optionally substituted C 1 -C 6 alkyl, alkene or alkyne group, an optionally substituted aryl or heterocyclic group or NR 1 R 2 is an optionally protected amino acid group where R 1 is H or a C 1 -C 3 alkyl group and R 2 is a group obtained from a D- or L-amino acid according to the chemical structure:
where R 3 is a side chain derived from an amino acid preferably selected from the group consisting of alanine (methyl), arginine (propyleneguanidine), asparagine (methylenecarboxyamide), aspartic acid (ethanoic acid), cysteine (thiol, reduced or oxidized di-thiol), glutamine (ethylcarboxyamide), glutamic acid (propanoic acid), glycine (H), histidine (methyleneimidazole), isoleucine (1-methylpropane), leucine (2-methylpropane), lysine (butyleneamine), ornithine (propyleneamine), methionine (ethylmethylthioether), phenylalanine (benzyl), proline (R 3 forms a cyclic ring with the adjacent nitrogen group to form a pyrrolidine group), hydroxyproline, serine (methanol), threonine (ethanol, 1-hydroxyethane), tryptophan (methyleneindole), tyrosine (methylene phenol) or valine (isopropyl), where the R 3 group and/or the carboxylic acid group is optionally protected,
The method comprising reacting a compound of formula 1i with a semicarbazone compound of formula S1:
Where X 1 is an optionally substituted S-alkyl, an optionally substituted S-aryl or an optionally substituted S-heterocyclyl, an optionally substituted O-alkyl, an optionally substituted O-aryl, an optionally substituted O-heterocyclyl, a NR 1 R 2 group where R 1 and R 2 are each independently H, an optionally substituted C 1 -C 12 alkyl group, an optionally substituted C 1 -C 6 alkyl, alkene or alkyne group, an optionally substituted aryl or heterocyclic group, or X 1 is an amino acid group preferably obtained from a D- or L-amino acid
where the amine group of the amino acid is linked to the semicarbazone and the amine group and/or the carboxylic group is optionally protected and R a is H, C 1 -C 6 alkyl or alkanol or R a forms a cyclic ring with R 3 (proline) and R 3 is a side chain derived from an amino acid preferably selected from the group consisting of alanine (methyl), arginine (propyleneguanidine), asparagine (methylenecarboxyamide), aspartic acid (ethanoic acid), cysteine (thiol, reduced or oxidized di-thiol), glutamine (ethylcarboxyamide), glutamic acid (propanoic acid), glycine (H), histidine (methyleneimidazole), isoleucine (1-methylpropane), leucine (2-methylpropane), lysine (butyleneamine), methionine (ethylmethylthioether), phenylalanine (benzyl), proline (R 3 forms a cyclic ring with the adjacent nitrogen group to form a pyrrolidine group), hydroxyproline, serine (methanol), threonine (ethanol, 1-hydroxyethane), tryptophan (methyleneindole), tyrosine (methylene phenol) or valine (isopropyl), where the R 3 side chain and/or the carboxylic acid group is optionally protected, to obtain a compound of the formula 1i:
or a salt form (preferably a pharmaceutically acceptable salt form, or stereoisomer thereof
where Z 1 , Z 2 and X 1 are the same as above,
which is thereafter reacted with trimethylsilyl chloride in solvent (e.g. chloroform) at elevated temperature to obtain the compound 1i
Where Y′ is H, and Z 1 , Z 2 and X 1 are the same as above
or a hydrochloride salt form, alternative salt form or stereoisomer thereof),
Wherein said compound is optionally deprotected.
24 . (canceled)
25 . (canceled)
26 . The method according to claim 23 wherein said compound 1i is reacted with SiO 2 or a weak base in aqueous solvent to convert the hydrogen at Y′ to a hydroxyl group.
27 . The method according to claim 26 wherein said hydroxyl group at Y′ is converted to a hydrogen group using a reducing agent, preferably a borohydride reducing agent.
28 . (canceled)
29 . (canceled)
30 . A compound according to the chemical structure:
Where Z 1 is H, an optionally substituted C 1 -C 12 hydrocarbon group, a 3-20 membered heterocyclic group, a NR 1 R 2 group, a SR 1 or OR 1 group or together Z 1 and Z 2 link to form an optionally substituted 5- to 8-membered ring which ring is carbocyclic or heterocyclic, including one or more unsaturated bonds;
Z 2 is H, an optionally substituted C 1 -C 12 hydrocarbon group, a 3-20 membered heterocyclic group or together Z 1 and Z 2 are linked to form an optionally substituted 5- to 8-membered ring which is carbocyclic or heterocyclic;
R 1 and R 2 are each independently absent with the proviso that no more than one of R 1 and R 2 is absent, H, an optionally substituted C 1 -C 6 alkyl, alkene or alkyne group, an optionally substituted aryl or heterocyclic group or NR 1 R 2 is an optionally protected amino acid group where R 1 is H or a C 1 -C 3 alkyl group and R 2 is a group according to the chemical structure:
where R 3 is a side chain derived from an amino acid preferably selected from the group consisting of alanine (methyl), arginine (propyleneguanidine), asparagine (methylenecarboxyamide), aspartic acid (ethanoic acid), cysteine (thiol, reduced or oxidized di-thiol), glutamine (ethylcarboxyamide), glutamic acid (propanoic acid), glycine (H), histidine (methyleneimidazole), isoleucine (1-methylpropane), leucine (2-methylpropane), lysine (butyleneamine), ornithine (propyleneamine), methionine (ethylmethylthioether), phenylalanine (benzyl), proline (R 3 forms a cyclic ring with the adjacent nitrogen group to form a pyrrolidine group), hydroxyproline, serine (methanol), threonine (ethanol, 1-hydroxyethane), tryptophan (methyleneindole), tyrosine (methylene phenol) or valine (isopropyl), where said R 3 group is optionally protected;
X 1 is an optionally substituted S-alkyl, an optionally substituted S-aryl or an optionally substituted S-heterocyclyl, an optionally substituted O-alkyl, an optionally substituted O-aryl, an optionally substituted O-heterocyclyl or a NR 1 R 2 group where R 1 and R 2 are each independently H, an optionally substituted C 1 -C 12 alkyl group, an optionally substituted aryl group or an optionally substituted heterocyclyl, or X 1 is an amino acid group according to the chemical structure:
where the amine group of the amino acid is linked to the semicarbazone and the amine group and/or the carboxylic group is optionally protected and R a is H, C 1 -C 6 alkyl or alkanol or R a forms a cyclic ring with R 3 (proline or hydroxyproline) and R 3 is a side chain derived from an amino acid preferably selected from the group consisting of alanine (methyl), arginine (propyleneguanidine), asparagine (methylenecarboxyamide), aspartic acid (ethanoic acid), cysteine (thiol, reduced or oxidized di-thiol), glutamine (ethylcarboxyamide), glutamic acid (propanoic acid), glycine (H), histidine (methyleneimidazole), isoleucine (1-methylpropane), leucine (2-methylpropane), lysine (butyleneamine), methionine (ethylmethylthioether), phenylalanine (benzyl), proline (R 3 forms a cyclic ring with R a and the adjacent nitrogen group to form a pyrrolidine group), hydroxyproline, serine (methanol), threonine (ethanol, 1-hydroxyethane), tryptophan (methyleneindole), tyrosine (methylene phenol) or valine (isopropyl), where the R 3 side chain is optionally protected;
Y′ is H or OH,
or a salt form, stereoisomer, solvate or polymorph thereof.
31 . The compound according to claim 30 wherein X 1 is an optionally substituted heteroaryl, an optionally substituted S—(C 1 -C 12 ) alkyl, an optionally substituted O—(C 1 -C 12 ) alkyl or a NH—R 1 group where R 1 is an optionally substituted C 1 -C 12 alkyl group.
32 . A pharmaceutical composition comprising an effective amount of a compound according to claim 31 , in combination with a pharmaceutically acceptable carrier, additive or excipient, optionally in further combination with an additional bioactive agent useful in the treatment of a diabetic disorder or to inhibit or treat disorders related to the aging process
33 . (canceled)
34 . (canceled)
35 . (canceled)
36 . (canceled)
37 . (canceled)
38 . (canceled)
39 . A compound according to a chemical structure selected from the group consisting of:
where Dod is a Bis(4-methoxyphenyl)methyl group, Cbz is a benzyloxycarbonyl group, Bn is a benzyl group and TFA is a trifluoroacetate group, or
a free amine, tautomer or pharmaceutically acceptable salt thereof.Join the waitlist — get patent alerts
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