US 2006/0148724 A1Published application

Genipin derivatives and uses thereof

AssigneesBeth Israel Deaconess Medical Center, Inc., Trustees of Boston University

InventorsChen-Yu Zhang, Bradford Lowell, John Porco, Ruichao Shen, Cheng Lin, Stefan Krauss

Life of this patent

Estimating the term…

Abstract

Genipin derivatives and pharmaceutical compositions thereof that inhibit the activity of uncoupling protein-2 (UCP2) and are useful in treating deficient first-phase insulin secretion, non-insulin dependent diabetes mellitus, and ischemia in a mammal are disclosed.

Claims22

Dependent claims

A method of treating a disorder selected from ischemia, deficient first-phase insulin secretion, non-insulin dependent diabetes mellitus, or a combination of deficient first-phase insulin secretion and non-insulin dependent diabetes mellitus in a mammal, comprising

i) administering to the mammal a compound represented by the following structural formula:
or pharmaceutically acceptable salts thereof, wherein:
- - - - is a single or double bond;
X1 is ═CR18—, X2 is ═CR12—, and X3 is CR13R14;
X2 is ═CR18—, X3 is ═CR12—, and X1 is CR13R14;
or X1 is CR6R7, X2 is CR8R9 and X3 is CR10R11;
X4 is —O— or —NR—;
each R is independently H or a C1-C5 alkyl;
R1 is —H, —OH, ═O, —OSi(R19)3, a hexose or pentose;
or R1, taken together with a substituent of X3 selected from R10, R11, R12, R13, R14, and R18, together with C7a, the carbon to which R1 is attached, and the carbon represented by X3, form a cyclic ether;
R2 is —OR, or —NR4R5;
or when X1 is CR13R14, R2 and R13, together with C4, C4a, the carbon to which R13 is attached and the carbonyl group to which R2 is attached, form a lactone ring;
R3is —H, —OH, or —OR, or, optionally when - - - - is a single bond, ═O;
R4 and R5 are each, independently, —H or a C1-C5 alkyl;
or R4 and R5 together with the nitrogen to which they are attached form a heterocyclic ring, wherein the C1-C5 alkyl or the heterocyclic ring are optionally substituted with one or more of hydroxy, a halo, a C1-C5 alkyl, phenyl, or cyano;
R6, R7, R8, R9, R10, R11, R13, R14 and R99 are independently —H, —OH, —F, —Cl, —Br, —I, —NO2, —NR2, —C(O)NR2, a C1-C5 alkyl, a hydroxyalkyl, —CH2OC(O)NR15R16, or —CH2OC(O)R17;
or R13 and R14 together are ═O;
or R8 and R10 together with two adjacent carbons to which they are attached, form an epoxy ring;
or R6 and R8 together with two adjacent carbons to which they are attached, form an epoxy ring;
R12 and R18 are each, independently, —H, a C1-C5 alkyl, hydroxyalkyl, —CH2OC(O)NR15R16, —CH2OC(O)R17, or —CH2OH;
R15 and R16 are each, independently, —H or a C1-C5 alkyl;
R17 is a C1-C5 alkyl;
and
R19 for each occurrence is, independently, a C1-C5 alkyl or an aryl, provided that when the disorder is ischemia:
X4 is —O—;
R1 is a hexose or —OH;
and X2 is ═CR18—, X3 is ═CR12—, and X1 is CR13R14, or X1 is CR6R7, X2 is CR8R9 and X3 is CR10R11, none of R10, R11, and R12 is —CH2OH;
and
provided that when the disorder is deficient first-phase insulin secretion, non-insulin dependent diabetes mellitus, or a combination of deficient first-phase insulin secretion, non-insulin dependent diabetes mellitus:
X4 is —O—, R2 is —OCH3, and R1 is ═O, —OH, —OC(O)CH3, glucosyl, O-tetraacetylglucosyl, O-tetramethylglucosyl, or t-butyldimethylsiloxy, and X3 is ═CR12 or CR10R11, none of R10, R11, or R12 is —CH2OH, —CH2OC(O)CH3, or —CH3;
when X4 is —O—, R2 is —OCH3, and R1 is —H, ═O, —OH or t-butyldimethylsiloxy, and X3 is CR10R11, none of R10 and R11 is —CH2OH, and R10 and R11 are not both —H;
and
the compound is not
ii) administering to the mammal a compound represented a structural formula selected from:
or pharmaceutically acceptable salts thereof, wherein:
Ring A is optionally substituted with one or more of —OH, a halo, nitro, cyano, or carboxy;
X4 is —O— or —NR—;
R is H or a C1-C5 alkyl;
R1 is —OH, ═O, —OSi(R19)3, a hexose or pentose;
R20 is —OR, or —NR4R5;
and
R4 and R5 are each, independently, —H or a C1-C5 alkyl;
or R4 and R5 together with the nitrogen to which they are attached form a heterocyclic ring, wherein the C1-C5 alkyl or the heterocyclic ring are optionally substituted with one or more of hydroxy, a halo, a C1-C5 alkyl, phenyl, or cyano.

40 more elements

A compound represented by the following structural formula:

or pharmaceutically acceptable salts thereof, wherein:
- - - - is a single or double bond;
X1 is ═CR18—, X2 is ═CR12—, and X3 is CR13R14;
X2 is ═CR18—, X3 is ═CR12—, and X1 is CR13R14;
or X1 is CR6R7, X2 is CR8R9 and X3 is CR10R11;
X4is —O— or —NR—;
each R is independently H or a C1-C5 alkyl;
R1 is —H, —OH, ═O, —OSi(R19)3, a hexose or pentose;
X1 is CR13R14;
and R2 and R13, together with C4, C4a, the carbon to which R13 is attached and the carbonyl group to which R2 is attached, form a lactone ring;
or, R1, taken together with a substituent of X3 selected from R10, R11, R12, R13, R14, and R18, together with C7a, the carbon to which R1 is attached, and the carbon represented by X3, form a cyclic ether;
and R2 is —OR or —NR4R5;
or, R1, taken together with a substituent of X3 selected from R10, R11, R12, R13, R14, and R18, together with C7a, the carbon to which R1 is attached, and the carbon represented by X3, form a cyclic ether;
X1 is CR13R14;
and R2 and R13, together with C4, C4a, the carbon to which R13 is attached and the carbonyl group to which R2 is attached, form a lactone ring;
R3is —H, —OH, or —OR, or, optionally when - - - - is a single bond, ═O;
R4 and R5 are each, independently, —H or a C1-C5 alkyl;
or R4 and R5 together with the nitrogen to which they are attached form a heterocyclic ring, wherein the C1-C5 alkyl or the heterocyclic ring are optionally substituted with one or more of hydroxy, a halo, a C1-C5 alkyl, phenyl, or cyano;
R6, R7, R8, R9, R10, R11, R13, R14 and R99 are independently —H, —OH, —F, —Cl, —Br, —I, —NO2, —NR2, —C(O)NR2, a C1-C5 alkyl, a hydroxyalkyl, —CH2OC(O)NR15R16, or —CH2OC(O)R17;
or R13 and R14 together are ═O;
or R8 and R10 together with two adjacent carbons to which they are attached, form an epoxy ring;
or R6 and R8 together with two adjacent carbons to which they are attached, form an epoxy ring;
R12 and R18 are each, independently, —H, a C1-C5 alkyl, hydroxyalkyl, —CH2OC(O)NR15R16, —CH2OC(O)R17, or —CH2OH;
R15 and R16 are each, independently, —H or a C1-C5 alkyl;
R17 is a C1-C5 alkyl;
and
R19 for each occurrence is, independently, a C1-C5 alkyl or an aryl, provided that:
when X4 is —O—, R2is —OCH3, and R1 is ═O, —OH, —OC(O)CH3, glucosyl, O-tetraacetylglucosyl, O-tetramethylglucosyl, or t-butyldimethylsiloxy, and X3 is ═CR12 or CR10R11, none of R10, R11, or R12 is —CH2OH, —CH2OC(O)CH3, or —CH3;
when X4 is —NR—, R2 is —OCH3, and R1, taken together with a substituent of X3 selected from R13, and R14, together with C7a, the carbon to which R1 is attached, and the carbon represented by X3, form the cyclic ether;
none of R13 and R14 is —OH;
when X1 is CR6R7, X2 is CR8R9 and X3 is CR10R11, the cyclic ether is unsubstituted, and R8, R9, and R11 are independently —F, —Cl, —Br, —I, —NO2, —NR2, —C(O)NR2, a C1-C5 alkyl, or —CH2OC(O)NR15R16;
when X4 is —O—;
R1 is a hexose or —OH;
and X2 is ═CR18—, X3 is ═CR12—, and X1 is CR13R14, or X1 is CR6R7, X2 is CR8R9 and X3 is CR10R11, none of R10, R11, and R12 is —CH2OH;
and
the compound is not

33 more elements

A compound represented by a structural formula selected from:

wherein:
Ring A is optionally substituted with one or more of —OH, a halo, nitro, cyano, or carboxy;
X5 is ═CR18—, X2 is ═CR12—, and X3 is CR13R14;
X2 is ═CR18—, X3 is ═CR12—, and X5 is CR21R22;
or X1 is CR6R7, X2 is CR8R9 and X3 is CR10R11;
X4 is —O— or —NR—;
R is H or a C1-C5 alkyl;
R1 is —OH, ═O, —OSi(R19)3, a hexose or pentose;
R2 is —OR, or —NR4R5;
R4 and R5 are each, independently, —H or a C1-C5 alkyl;
or R4 and R5 together with the nitrogen to which they are attached form a heterocyclic ring, wherein the C1-C5 alkyl or the heterocyclic ring are optionally substituted with one or more of hydroxy, a halo, a C1-C5 alkyl, phenyl, or cyano;
R6, R7, R8, R9, R10, R11, R13, R14, R21 and R22 are independently —H, —OH, a C1-C5 alkyl, a hydroxyalkyl, —CH2OC(O)NR15R16, —CH2OC(O)R17, or —CH2OH;
or R21 and R22 together are ═O;
or R8 and R10 together with two adjacent carbons to which they are attached, form an epoxy ring;
R12 and R18 are each, independently, —H, a C1-C5 alkyl, hydroxyalkyl, —CH2OC(O)NR15R16, —CH2OC(O)R17, or —CH2OH;
R15 and R16 are each, independently, —H or a C1-C5 alkyl;
R17 is a C1-C5 alkyl;
R19 for each occurrence is, independently, a C1-C5 alkyl or an aryl;
R20 is —OR, or —NR4R5;
and
R23, R24, R25, R26 are each, independently, selected from the group consisting of —H, —OH, a C1-C5 alkyl, a hydroxyalkyl, —CH2OC(O)NR15R16, —CH2OC(O)R17, or —CH2OH;
provided that when the compound is represented by structural formula:
when R1 is glucosyl and R25 is —H, R26 is not methyl;
provided that when the compound is
when R1 is glucosyl Ring A is not 3,4-dihydroxyphenyl;
and
provided that when the compound is
when X4 is —O—, R1 is not glucosyl.

25 more elements

Dependencies are inferred from the claim text.

Facts

Application: 11/241,768Filed 29 Sep 2005
Priority: 31 Mar 2003
Published: 6 Jul 2006
Term ends: Not estimatedThe source records don’t support an estimate.

Classification17 codes

C07D 221/04
Condensed with carbocyclic rings or ring systems: ortho- or peri-condensed ring systems
A61K 31/352
Having six-membered rings with one oxygen as the only ring hetero atom: condensed with carbocyclic rings, e.g. methantheline
A61K 31/353
Condensed with carbocyclic rings, e.g. methantheline: 3,4-Dihydrobenzopyrans, e.g. chroman, catechin
A61K 31/365
Having oxygen as the only ring hetero atom, e.g. fungichromin: lactones

Family

Application60/459,278Us provisional application · filed 31 Mar 2003
Application11/241,768Continuation · filed 29 Sep 2005
US 2008/0009450 A9Published application
US 7,649,014 B2Related patent
US 2006/0148724 A1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

i) administering to the mammal a compound represented by the following structural formula:
or pharmaceutically acceptable salts thereof, wherein:
- - - - is a single or double bond;
X1 is ═CR18—, X2 is ═CR12—, and X3 is CR13R14;
X2 is ═CR18—, X3 is ═CR12—, and X1 is CR13R14;
or X1 is CR6R7, X2 is CR8R9 and X3 is CR10R11;
X4 is —O— or —NR—;
each R is independently H or a C1-C5 alkyl;
R1 is —H, —OH, ═O, —OSi(R19)3, a hexose or pentose;
or R1, taken together with a substituent of X3 selected from R10, R11, R12, R13, R14, and R18, together with C7a, the carbon to which R1 is attached, and the carbon represented by X3, form a cyclic ether;
R2 is —OR, or —NR4R5;
or when X1 is CR13R14, R2 and R13, together with C4, C4a, the carbon to which R13 is attached and the carbonyl group to which R2 is attached, form a lactone ring;
R3is —H, —OH, or —OR, or, optionally when - - - - is a single bond, ═O;
R4 and R5 are each, independently, —H or a C1-C5 alkyl;
or R4 and R5 together with the nitrogen to which they are attached form a heterocyclic ring, wherein the C1-C5 alkyl or the heterocyclic ring are optionally substituted with one or more of hydroxy, a halo, a C1-C5 alkyl, phenyl, or cyano;
R6, R7, R8, R9, R10, R11, R13, R14 and R99 are independently —H, —OH, —F, —Cl, —Br, —I, —NO2, —NR2, —C(O)NR2, a C1-C5 alkyl, a hydroxyalkyl, —CH2OC(O)NR15R16, or —CH2OC(O)R17;
or R13 and R14 together are ═O;
or R8 and R10 together with two adjacent carbons to which they are attached, form an epoxy ring;
or R6 and R8 together with two adjacent carbons to which they are attached, form an epoxy ring;
R12 and R18 are each, independently, —H, a C1-C5 alkyl, hydroxyalkyl, —CH2OC(O)NR15R16, —CH2OC(O)R17, or —CH2OH;
R15 and R16 are each, independently, —H or a C1-C5 alkyl;
R17 is a C1-C5 alkyl;
and
R19 for each occurrence is, independently, a C1-C5 alkyl or an aryl, provided that when the disorder is ischemia:
X4 is —O—;
R1 is a hexose or —OH;
and X2 is ═CR18—, X3 is ═CR12—, and X1 is CR13R14, or X1 is CR6R7, X2 is CR8R9 and X3 is CR10R11, none of R10, R11, and R12 is —CH2OH;
and
provided that when the disorder is deficient first-phase insulin secretion, non-insulin dependent diabetes mellitus, or a combination of deficient first-phase insulin secretion, non-insulin dependent diabetes mellitus:
X4 is —O—, R2 is —OCH3, and R1 is ═O, —OH, —OC(O)CH3, glucosyl, O-tetraacetylglucosyl, O-tetramethylglucosyl, or t-butyldimethylsiloxy, and X3 is ═CR12 or CR10R11, none of R10, R11, or R12 is —CH2OH, —CH2OC(O)CH3, or —CH3;
when X4 is —O—, R2 is —OCH3, and R1 is —H, ═O, —OH or t-butyldimethylsiloxy, and X3 is CR10R11, none of R10 and R11 is —CH2OH, and R10 and R11 are not both —H;
and
the compound is not
ii) administering to the mammal a compound represented a structural formula selected from:
or pharmaceutically acceptable salts thereof, wherein:
Ring A is optionally substituted with one or more of —OH, a halo, nitro, cyano, or carboxy;
X4 is —O— or —NR—;
R is H or a C1-C5 alkyl;
R1 is —OH, ═O, —OSi(R19)3, a hexose or pentose;
R20 is —OR, or —NR4R5;
and
R4 and R5 are each, independently, —H or a C1-C5 alkyl;
or R4 and R5 together with the nitrogen to which they are attached form a heterocyclic ring, wherein the C1-C5 alkyl or the heterocyclic ring are optionally substituted with one or more of hydroxy, a halo, a C1-C5 alkyl, phenyl, or cyano.

40 more elements

Facts

Application

11/241,768Filed 29 Sep 2005

Priority

31 Mar 2003

Published

6 Jul 2006

Term ends

Not estimatedThe source records don’t support an estimate.

Classification17 codes

C07D 221/04
Condensed with carbocyclic rings or ring systems: ortho- or peri-condensed ring systems
A61K 31/352
Having six-membered rings with one oxygen as the only ring hetero atom: condensed with carbocyclic rings, e.g. methantheline
A61K 31/353
Condensed with carbocyclic rings, e.g. methantheline: 3,4-Dihydrobenzopyrans, e.g. chroman, catechin
A61K 31/365
Having oxygen as the only ring hetero atom, e.g. fungichromin: lactones