Compounds and their uses

• US 20010053767A1
• Filed: 03/02/2001
• Published: 12/20/2001
• Est. Priority Date: 05/12/2000
• Status: Active Grant

• Current Assignee: Rodaris Pharmaceuticals Limited
• Original Assignee: Rodaris Pharmaceuticals Limited
• Inventors: Rademacher, Thomas William, Francois, Irene, Martin-Lomas, Manuel, Caro, Hugo Norberto
• Granted Patent: US 6,939,857 B2
• Time in Patent Office: Days
• US Class Current: 514/25
• CPC Class Codes: C07H 15/207 Cyclohexane rings not substituted by nitrogen atoms, e.g. kasugamycins
• CPC Class Codes: C07H 5/06 Aminosugars

Abstract

Compounds having a mimetic or antagonistic property of an inositol phosphoglycan, and the uses of these compounds are disclosed, together with the use, e.g. to treat a condition ameliorated by administration of an IPG second messenger or an IPG antagonist thereof. Preferred compounds of the invention are based on the substituted cyclitols, such as the chiro-inositol derivative pinitol (3-O-methyl-chiro-inositol).

Claims

1. A compound represented by the general formula:

X-substituted cyclitol

wherein;

X represents a sugar residue;

the cyclitol is substituted at the 3-position with a substituted or unsubstituted alkyl group;

the sugar residue and cyclitol are linlced other than at position 3 of the cyclitol, wherein the linkage is an α

or β

linkage other than a β

1,4 linkage; and

,

the sugar residue is unsubstituted or substituted with between one and four groups, and the cyclitol is unsubstituted or is further substituted with between one and four groups, the group or groups being independently selected from;

(a) phosphoryl groups such as phosphate —

O—

P(O)(OH)₂;

thiophosphate —

O—

P(S)(OH)₂;

phosphate esters —

O—

P(O)(OR)₂;

thiophosphate esters —

O—

P(S)(OR)₂;

phosphonate —

O—

P(O)OHR;

thiopho sphonate —

O—

P(S)OHR;

substituted phosphonate —

O—

P(O)OR₁R₂;

substituted thiophosphonate —

O—

P(S)OR₁R₂;

—

O—

P(S)(OH)(SH);

cyclic phosphate;

(b) other phosphorus containing compounds such as phosphoramidite —

O—

P(OR)—

NR₁R₂ and phosphoramidate —

O—

P(O)(OR)—

NR₁R₂;

(c) sulphur groups such as —

O—

S(O)(OH), —

SH, —

SR, —

S(—

O)—

R, —

S(O)₂R, RO—

S(O)₂⁻

;

—

O—

SO₂NH₂, —

O—

SO₂R₁R₂ or sulphamide —

NHSO₂NH₂;

(d) amino groups such as —

NHR, —

NR₁R₂, —

NHAc, —

NHCOR, —

NH—

O—

COR, —

NHSO₃, —

NHSO₂R, —

N(SO₂R)₂, and/or amidino groups such as —

NH—

C(═

NH)NH₂ and/or ureido groups such as —

NH—

CO—

NR₁R₂ or thiouriedo groups such as —

NH—

C(S)—

NH₂;

(e) hydroxy groups and substituted hydroxy groups such as —

OR₃, where R₃ is C_1-10 unsubstituted or substituted allcyl, e.g. CHF₂ or CF₃, alkoxyalkyl, aryloxyalkyl, cycloalkyl, alkenyl (unsubstituted alkyl), allcylene (C_3-7 cycloalkyl), —

OCOR, aryl, heteroaryl, acetal, or where two hydroxyl groups are joined as a ketal;

(f) halogen substituents such as fluorine or chlorine;

(g) hydrogen e.g. to provide a deoxy sugar;

wherein R, R₁ and R₂ are independently hydrogen or C_1-10 unsubstituted or substituted alkyl or aryl;

or a derivative of the compound.

2. The compound of

claim 1

, wherein the sugar residue is a hexose or a pentose, or substituted forms thereof.

3. The compound of

claim 2

, wherein the sugar residue is a hexose selected from the group consisting of glucose, galactose or mannose.

4. The compound of

claim 2

, wherein the sugar residue is a hexosamine.

5. The compound of

claim 4

, wherein the hexosamine is galactosamine or glucosamine.

6. The compound of

claim 1

, wherein the sugar residue and the cyclitol axe 1,1 linked, 1,2 linked, 1,5 linked or 1,6 linked.

7. The compound of claims 1, wherein the sugar residue and the cyclitol are α

-linked.

8. The compound of

claim 1

, wherein the sugar residue and the cyclitol are β

-linked.

9. The compound of

claim 1

, wherein the cyclitol is D or L-pinitol (3-O-methyl-chiro-inositol).

10. The compound of

claim 1

which is selected from the group consisting of:

O-(2-amino-2-deoxy-D-glucopyranosyl)-β

(1,6)-D-3-O-methyl-chiro-inositol;

O-(2-amino-2-deoxy-D-glucopyranosyl)-α

(1,6)-D-3-O-methyl-chiro-inositol;

O-(2-amino-2-deoxy-D-galactopyranosyl)-α

(1,6)-D-3- O-methyl-chiro-iaositol; and

1′

-D-6-O-(2′

-amino-2′

-deoxy-β

-D-galactopyranosyl)-O-methyl-D-chiro-inositol;

or a derivative thereof.

12. A composition comprising a compound of

claim 1

in combination with a pharmaceutically acceptable carrier.

14. A method of treating a condition in a mammal ameliorated by an inositol phosphoglycan (IPG) second messenger or an IPG antagonist, the method comprising administering to the mammal a therapeutically effective amount of a compound of

claim 1

.

11. A compound represented by the general formula:

X-1,6-pinitol

wherein,

X represents a sugar residue;

the sugar residue is unsubstituted or substituted with between one and four groups, and the pinitol is unsubstituted or is further substituted with between one and four groups, the group or groups being independently selected from;

(a) phosphoryl groups such as phosphate —

O—

P(O)(OH)₂;

thiophosphate —

O—

P(S)(OH)₂, phosphate esters —

O—

P(O)(OR)₂, thiophosphate esters —

O—

P(S)(OR)₂;

phosphonate —

O—

P(O)OHR;

thiophosphonate —

O—

P(S)OHR;

substituted phosphonate —

O—

P(O)OR₁R₂;

substituted thiophosphonate —

O—

P(S)OR₁R₂, —

O—

P(S)(O)(SH);

cyclic phosphate;

(b) other phosphorus containing compounds such as phosplhoramidite —

O—

P(OR)—

NR₁R₂ and phosphoramidate —

O—

P(O)(OR)—

NR₁R₂;

(c) sulphur groups such as —

O—

S(O)(OH), —

SH, —

SR, —

S(O)—

R, —

S(O)₂R, RO—

S(O)₂⁻

, —

O—

SO₂NH₂, —

O—

SO₂R₁R₂ or sulphamide —

NHSO₂NH₂;

(d) amino groups such as —

NHR, —

NR₁R₂, —

NHAc, —

NHCOR, —

NH—

O—

COR, —

NHSO₃⁻

, —

NHSO₂R, —

N(SO₂R)₂, and/or amidino groups such as —

NH—

C(═

NH)NH₂ and/or ureido groups such as —

NH—

CO—

NR₁R₂ or thiouriedo groups such as —

NH—

C(S)—

NH₂;

(e) hydroxy groups and substituted hydroxy groups such as —

OR₃, where R₃ is C_1-10 unsubstituted or substituted alkyl, e.g. CHF₂ or CF₃, alkoxyalkyl, aryloxyalkyl, cycloalkyl, alkenyl (unsubstituted alkyl), alkylene (C_3-7 cycloalkyl), —

OCOR, aryl, heteroaryl, acetal, or where two hydroxyl groups are joined as a ketal;

(f) halogen substituents such as fluorine or chlorine;

(g) hydrogen, e.g. to provide a deoxy sugar;

wherein R, R₁ and R₂ are independently hydrogen or C_1-10 unsubstituted or substituted alkyl or aryl;

or a derivative of the compound.

13. A composition comprising a compound of

claim 11

in combination with a pharmaceutically acceptable carrier.

15. A method of treating a condition in a mammal ameliorated by an inositol phosphoglycaii (IPG) second messenger or an IPG antagonist, the method comprising administering to the mammal a therapeutically effective amount of a compound of

claim 11

.