Compounds and their uses

Details Compounds and their uses Compounds and their uses

2001-03-02

2004-07-06

Henley, III, Raymond (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S004100, C536S017200, C536S018400

Reexamination Certificate

active

06759390

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to compounds and their uses, and in particular to compounds which have a mimetic or antagonistic property of an inositol phosphoglycan, and the uses of these compounds, e.g. to treat a condition ameliorated by administration of an IPG second messenger or an IPG antagonist thereof.
BACKGROUND OF THE INVENTION
Many of the actions of growth factors on cells are thought to be mediated by a family of inositol phosphoglycan (IPG) second messengers
[13]
. It is thought that the source of IPGs is a “free” form of glycosyl phosphatidylinositol (GPI) situated in cell membranes. IPGs are thought to be released by the action of phosphatidylinositol-specific phospholipases following binding of growth factors to receptors on the cell surface. There is evidence that IPGs mediate the action of a large number of growth factors including insulin, nerve growth factor, hepatocyte growth factor, insulin-like growth factor I (IGF-I), fibroblast growth factor, transforming growth factor &bgr;, the action of IL-2 on B-cells and T-cells, ACTH signalling of adrenocortical cells, IgE, FSH and hCG stimulation of granulosa cells, thyrotropin stimulation of thyroid cells, cell proliferation in the early developing ear and rat mammary gland.
Partially characterised inositolphosphoglycans (IPGs) have been postulated to mediate the action of a number of growth factors including insulin and insulin-like growth factor I (IGF-I)
[1]
. Despite their isolation from several tissues type, the precise chemical structures of these IPGs are, however, still unknown and two main structural groups have been proposed on the basis of the chemical composition
[2,3]
which display different biological activity and tissue distribution
[4]
; the family of glucosamine-myo-inositol containing IPGs (IPG-A) and the family of chiro-inositol-galactosamine containing IPGs (IPG-P).
In an attempt to establish the minimal structural requirements for biological activity, a number of compounds containing some of the basic structural motifs that have been postulated for IPG mediators have been synthesised in the art
[5]
. These synthetic compounds include O-(2-amino-2-deoxy-D-glucopyranosyl)-&agr;(1-6)-chiro-inositol 1-phosphate and O-(2-amino-2-deoxy-D-glucopyranosyl)-&agr;(1-6)-myo-inositol 1-phosphate
[6]
.
U.S. Pat. No. 6,004,938 (Hoechst) discloses a group of synthetic inositol glycans having insulin-like action. The compounds are based on 2-6 monsaccharide units linked to an inositol moiety. The examples in the patent all employ myo-inositol and are composed of 5 or 6 units apart from two pseudo-trisaccharide compounds G and H. Compounds G and H are HO—PO(H)O-6Man-&agr;(1-4)-GluN-&agr;(1-6)-(L)inositol-1,2(cyclic) phosphate and HO—PO(H)O-6Man-&agr;(1-4)-GluN-&agr;(1-6)-(L)inositol, otherwise known as O-(6-hydrogenphosphonate-&agr;-D-mannopyranosyl)-(1-4)-(2-ammonio-2-deoxy-&agr;-D-glucopyranosyl)-(1-6)-L-myo-inositol-1,2-cyclic phosphate and O-(6-hydrogenphosphonate-&agr;-D-mannopyranosyl)-(1-4)-(2-amino-2-deoxy-&agr;-D-glucopyranosyl)-L-myo-inositol. The properties of exemplified compounds are investigated in lipogenesis and glucose transport assays employing rat fat cells.
WO96/14075 (University of Virginia) discloses a generic family of compounds D-hexosamines linked to an inositol via a &bgr;1,4-linkage. The inositols can be myo or chiro-inositol or pinitol, while the hexosamines are glucosamine or galactosamine. However, this application describes the synthesis of just two compounds 4-O-(2-deoxy-2-amino-&bgr;-D-galactopyranosyl)-D-pinitol and 4-O-(2-deoxy-2-amino-&bgr;-D-galactopyranosyl)-D-chiro-inositol, or in IUPAC notation O-(2-amino-2-deoxy-&bgr;-D-galactopyranosyl)-(1-4)-D-pinitol and O-(2-amino-2-deoxy-&bgr;-D-galactopyranosyl)-(1-4)-D-chiro-inositol.
WO99/06421 (University of Virginia) describes synthetic insulin mimetic substances and includes a general formula I showing &bgr;1,4-linked disaccharides. However, despite this the compounds synthesised in this application are exactly the same as those disclosed in the applicant's earlier application, WO96/14075.
A multi-step synthesis of a IPG-P mimetic from glucose has been previously reported in Jaramillo et al
[6]
, which discloses a compound called C4, 1-D-6-O-(2-amino-2-deoxy-&agr;-D-glucopyranosyl)-chiro-inositol 1-phosphate. A further synthesis of C4 is described in our co-pending International Patent Application PCT/GB99/03715 (Rademacher Group Limited). Zapata et al
[16]
discloses three other compounds C1-C3 which are:
C1 1-D-4-O-(2-amino-2-deoxy-&agr;-D-glucopyranosyl)-myo-inositol 1-phosphate.
C2 1-D-6-O-(2-amino-2-deoxy-&agr;-D-glucopyranosyl)-myo-inositol 1-phosphate.
C3 1-D-6-O-(2-amino-2-deoxy-&agr;-D-glucopyranosyl)-myo-inositol 1,2 cyclic-phosphate.
It remains a significant problem in the art to produce synthetic compounds which can mimic one or more of the activities of inositol phosphoglycans or which act as antagonists of IPGs.
SUMMARY OF THE INVENTION
Broadly, the present invention relates to IPG mimetic and antagonist compounds and to methods of producing the compounds and to their medical uses. The compounds disclosed herein are useful as synthetic mimetics of IPG-P or IPG-A second messengers and/or growth factors whose action is mediated by IPGs, or a competitive antagonists of IPGs In particular, the present invention is based on surprising finding that compounds comprising a sugar residue linked to a cyclitol, wherein the sugar residue is substituted with one or more negatively charged groups, such as phosphate or other phosphoryl groups, have one or more as IPG or IPG antagonists biological activities.
Accordingly, in a first aspect, the present invention provides a compound represented by the general formula:
X-cyclitol
wherein:
X represents a sugar residue;
the sugar residue is substituted with one or more negatively charged groups;
the sugar residue and cyclitol are linked by an &agr; or &bgr; linkage other than a &bgr;1,4 linkage;
the sugar residue is optionally further substituted with between one and three groups, and the cyclitol is unsubstituted or is substituted with between one and five groups, the group or groups independently selected from:
(a) phosphoryl groups such as phosphate —O—P(O)(OH)
2
; thiophosphate —O—P(S)(O)
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)OR
1
R
2
; substituted thiophosphonate —O—P(S)OR
1
R
2
; —O—P(S)(OH)(SH); cyclic phosphate;
(b) other phosphorus containing compounds such as phosphoramidite —O—P(OR)—NR
1
R
2
and phosphoramidate —O—P(O)(OR)—NR
1
R
2
;
(c) sulphur groups such as —O—S(O)(OH), —SH, —SR, —S(—O)—R, —S(O)
2
R, RO—S(O)
2
−
, —O—SO
2
NH
2
, —O—SO
2
R
1
R
2
or sulphamide —NHSO
2
NH
2
;
(d) amino groups such as —NHR, —NR
1
R
2
, —NHAc, —NHCOR, —NH—O—COR, —NHSO
3
−
, —NHSO
2
R, —N(SO
2
R)
2
, and/or amidino groups such as —NH—C(═NH)NH
2
and/or ureido groups such as —NH—CO—NR
1
R
2
or thiouriedo groups such as —NH—C(S)—NH
2
;
(e) hydroxy groups and substituted hydroxy groups such as —OR
3
, where R
3
is C
1-10
unsubstituted or substituted alkyl, e.g. CHF
2
or CF
3
, 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, R
1
and R
2
are independently hydrogen or C
1-10
unsubstituted or substituted alkyl or aryl.
The compounds may be provided as racemic or diasteromeric mixtures, resolved or partially resolved optical isomers, and as pharmaceutically acceptable salts, esters and derivatives as discussed in more detail below.
Examples of groups which may be negatively charged depending on the pH conditions include phosphoryl groups such as phosphate —O—P(O)(OH)
2
; thiophosphate —O—P(S)(OH)
2
; ph

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