Compounds and their uses

• US 6,939,857 B2
• Filed: 03/02/2001
• Issued: 09/06/2005
• Est. Priority Date: 05/12/2000
• Status: Expired due to Fees

• Current Assignee: Rodaris Pharmaceuticals Limited
• Original Assignee: Rodaris Pharmaceuticals Limited
• Inventors: Francois, Irene, Caro, Hugo Norberto, Rademacher, Thomas William, Martin-Lomas, Manuel
• Primary Examiner(s): Wilson, James O.
• Assistant Examiner(s): Krishnan, Ganapathy
• Application Number:
  US09/798,125
• Publication Number:
  US 20010053767A1
• Time in Patent Office: 1,649 Days
• Field of Search: 536/4.1, 536/17.2, 536/18.4, 536/55.1, 536/123.1, 514/25, 514/54, 514/62
• 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-β

1,6-pinitol

wherein,

X represents a sugar residue;

the sugar residue is substituted with one, two or three groups, and the pinitol is unsubstituted or is further substituted with between one and four groups, said substituted groups being substituted on at least one of said sugar residue and said pinitol and being independently selected from the group consisting of;

(a) a phosphoryl group having a formula selected from the group consisting of —

O—

P(O)(OH)₂, —

O—

P(S)(OH)₂, —

O—

P(O)(OR)₂, —

O—

P(S)(OR)₂, —

O—

P(O)OHR, —

O—

P(S)OHR, —

O—

P(O)OR₁R₂, —

O—

P(S)OR₁R₂, —

O—

P(S)(OH)(SH), or a cyclic phosphate;

(b) a phosphorus-containing group having a formula selected from the group consisting of —

O—

P(OR)—

NR₁R₂ and —

O—

P(O)(OR)—

NR₁R₂;

(c) a sulphur-containing group having a formula selected from the group consisting of —

O—

S(O)(OH)₂, —

SH, —

SR, —

S(—

O)—

R, —

S(O)₂R, RO—

S(O)₂⁻

, —

O—

SO₂NH₂, —

O—

SO₂R₁R₂ or —

NHSO₂NH₂;

(d) a substituted amino-containing group having a formula selected from the group consisting of —

NHR, —

NR₁R₂, —

NHAc, —

NHCOR, —

NH—

O—

COR, —

NHSO₃⁻

, —

NHSO₂R, —

N(SO₂R), —

NHC(═

NH)NH₂, —

NH—

CO—

NR₁R₂ or —

NH—

C(S)—

NH₂;

(e) a hydroxy group;

a substituted hydroxy group represented by the formula —

OR₃, where R₃ is C_1-10 unsubstituted alkyl or C_1-10 substituted alkyl, alkoxyalkyl, aryloxyalkyl, cycloalkyl, alkenylalkyl in which the alkyl group is unsubstituted, alkylene-cycoalkyl in which the cycloalkyl group has 3-7 carbon atoms, —

OCOR, aryl, heteroaryl, acetal, or said substituted groups comprise two hydroxyl groups that are joined to form a ketal;

(f) halogen substituents fluorine or chlorine; and

(g) hydrogen, forming a deoxy sugar;

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

or a derivative of the compound, said derivative comprising salts, coordination complexes with metal ions, esters, free acids or bases, hydrates or protecting groups.

2. The compound of claim 1, wherein the sugar residue is unsubstituted hexose or a pentose or said 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 claims 1, wherein the sugar residue and the pinitol are α

-linked.

7. The compound of claim 1, wherein the sugar residue and the pinitol are β

-linked.

8. The compound of claim 1, wherein the pinitol is L-pinitol.

10. A composition comprising a compound of claim 1 in combination with a pharmaceutically acceptable carrier.

11. The compound of claim 1, wherein the pinitol is D-pinitol.

12. The compound of claim 1, wherein said substituted hydroxy group is OR₃ and R₃ is selected from the groups consisting of CHF₂ and CF₃.

13. The compound of claim 1, wherein said derivative is a coordination complex with a metal ion selected from the group consisting of Mn(+2) and Zn(+2).

9. A compound selected from the group consisting of:

O-(2-amino-2-deoxy-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-inositol; and

1′

-D-6-O-(2′

-amino-2′

-deoxy-β

-D-galactopyranosyl)-3-O-methyl-D-chiro-inositol;

or a derivative of said compound, said derivative comprising salts, coordination complexes with metal ions, free acids or bases, hydrates or protecting groups.

14. A compound represented by the general formula:

 

X-β

1,6-pinitol

wherein;

X represents a sugar residue;

the sugar residue is substituted with between one and four groups, and the pinitol is further substituted with one, two or three groups, said substituted groups being substituted on at least one of said sugar residue and said pinitol and being independently selected from the group consisting of;

(a) a phosphoryl group having a formula selected from the group consisting of —

O—

P(O)(OH)₂, —

O—

P(S)(OH)₂, —

O—

P(O)(OR)₂, —

O—

P(S)(OR)₂, —

O—

P(O)OHR, —

O—

P(S)OHR, —

O—

P(O)₀R₁R₂, —

O—

P(S)OR₁R₂, —

O—

P(S)(OH)(SH), or a cyclic phosphate;

(b) a phosphorus-containing group having a formula selected from the group consisting of —

O—

P(OR)—

NR₁R₂ and —

O—

P(O)(OR)—

NR₁R₂;

(c) a sulphur-containing group having a formula selected from the group consisting of —

O—

S(O)(OH)₂, —

SH, —

SR, —

S(—

O)—

R, —

S(O)₂R, RO—

S(O)₂⁻

, —

O—

SO₂NH₂, —

O—

SO₂R₁R₂ or —

NHSO₂NH₂;

(d) a substituted amino-containing group having a formula selected from the group consisting of —

NHR, —

NR₁R₂, —

NHAc, —

NHCOR, —

NH—

O—

COR, —

NHSO₃⁻

, —

NHSO₂R, —

N(SO₂R), —

NHC(═

NH)NH₂, —

NH—

CO—

NR₁R₂ or —

NH—

C(S)—

NH₂;

(e) a hydroxy group;

a substituted hydroxy group represented by the formula —

OR₃, where R₃ is C_1-10 unsubstituted akyl or C_1-10 substituted alkyl, alkoxyalkyl, aryloxyalkyl, cycloalkyl, alkenylalkyl in which the alkyl group is unsubstituted, alkylene-cycoalkyl in which the cycloalkyl group has 3-7 carbon atoms, —

OCOR, aryl, heteroaryl, acetal, or said substituted groups comprise two hydroxyl groups that are joined to form a ketal;

(f) halogen substituents fluorine or chlorine; and

(g) hydrogen, forming a deoxy sugar;

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

or a derivative of the compound, said derivative comprising salts, coordination complexes with metal ions, esters, free acids or bases, hydrates or protecting groups.

15. The compound of claim 14, wherein the sugar residue is unsubstituted hexose or pentose or said substituted form thereof.

16. The compound of claim 15, wherein the sugar residue is a hexose selected from the group consisting of glucose, galactose or mannose.

17. The compound of claim 15, wherein the sugar residue is a hexosamine.

18. The compound of claim 17, wherein the hexosamine is galactosamine or glucosamine.

19. The compound of claim 14, wherein the sugar residue and the pinitol are α

-linked.

20. The compound of claim 14, wherein the sugar residue and the pinitol are β

-linked.

21. The compound of claim 14, wherein the pinitol is L-pinitol.

22. A compositions comprising a compound of claim 14 in combination with a pharmaceutically acceptable carrier.

23. The compound of claim 14, wherein the pinitol is D-pinitol.

24. The compound of claim 14, wherein said substituted hydroxy group is OR₃ and R₃ is selected from the groups consisting of CHF₂ and CF₃.

25. The compound of claim 14, wherein said derivative is a coordination complex with a metal ion selected from the group consisting of Nn(+2) and Zn(+2).