EP1406913A2 - Composes et utilisations associees - Google Patents

Composes et utilisations associees

Info

Publication number
EP1406913A2
EP1406913A2 EP01934120A EP01934120A EP1406913A2 EP 1406913 A2 EP1406913 A2 EP 1406913A2 EP 01934120 A EP01934120 A EP 01934120A EP 01934120 A EP01934120 A EP 01934120A EP 1406913 A2 EP1406913 A2 EP 1406913A2
Authority
EP
European Patent Office
Prior art keywords
inositol
deoxy
glucopyranosyl
phosphate
amino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01934120A
Other languages
German (de)
English (en)
Inventor
Manuel Martin-Lomas
Thomas William Rademacher
Hugo Norbert Caro
Irene Francios
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Rodaris Pharmaceuticals Ltd
Original Assignee
Rodaris Pharmaceuticals Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB0011594A external-priority patent/GB0011594D0/en
Priority claimed from US09/798,005 external-priority patent/US6953781B2/en
Application filed by Rodaris Pharmaceuticals Ltd filed Critical Rodaris Pharmaceuticals Ltd
Publication of EP1406913A2 publication Critical patent/EP1406913A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin

Definitions

  • 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 or a free GPI precursor of an IPG, 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.
  • IPG inositol phosphoglycan
  • 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 ⁇ , 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.
  • IGF-I insulin-like growth factor I
  • fibroblast growth factor transforming growth factor ⁇
  • 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.
  • IPGs Partially characterised inositolphosphoglycans
  • IGF-I insulin and insulinlike growth factor I
  • 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 c zz ' r ⁇ -inositol- galactosamine containing IPGs (IPG-P).
  • US Patent No: 6,004,938 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 my ⁇ -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- ⁇ (l ⁇ 4)-GluN- ⁇ (l ⁇ 6)-(L)inositol- l,2(cyclic) phosphate and HO-PO(H)O-6Man- ⁇ (l ⁇ 4)-GluN- ⁇ (l ⁇ 6)-(L)inositol, otherwise known as O-(6-hydrogenphosphonate- ⁇ -D-mannopyranosy ⁇ )-(l->4)-(2- ammonio-2-deoxy- ⁇ -D-glucopyranosyl)-( 1 - 6)-L-my ⁇ -inositol- 1 ,2-cyclic phosphate and O-(6-hydrogenphosphonate- ⁇ -D-mannopyranosyl)-(l ⁇ 4)-(2-amino-2-deoxy- ⁇ -D- glucopyranosyl)-L-mj/ ⁇ -inositol.
  • the properties of exemplified compounds are investigated in Ii
  • WO96/14075 discloses a generic family of compounds D- hexosamines linked to an inositol via a ⁇ l,4-linkage.
  • the inositols can be myo or c/zzr ⁇ -inositol or pinitol, while the hexosamines are glucosamine or galactosamine.
  • this application describes the synthesis of just two compounds 4-O-(2- deoxy-2-amino- ⁇ -D-galactopyranosyl)-D-pinitol and 4-O-(2-deoxy-2-amino- ⁇ -D- galactopyranosyl)-D-c/ztr ⁇ -inositol.
  • W ⁇ 99/06421 (University of Virginia) describes synthetic insulin mimetic substances and includes a general formula I showing ⁇ l,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.
  • 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, as synthetic mimetics of GPI precursors of IPGs, or as competitive antagonists of IPGs.
  • the compounds are based on the 1,6 linkage of a sugar residue and a cyclitol.
  • the present invention provides a compound represented by the general formula:
  • X represents a sugar residue; 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 as defined herein; with the proviso that the compound is not l-D-4-O-(2-amino-2-deoxy- ⁇ -D- glucopyranosyl)-my ⁇ -inositol 1 -phosphate, 1 -D-6-O-(2-arnino-2-deoxy- ⁇ -D- glucopyranosyl)-my ⁇ -inositol 1 -phosphate, 1 -D-6-O-(2-arnino-2-deoxy- ⁇ -D- glucopyranosyl)-my ⁇ -inositol 1,2 cyclic-phosphate, l-D-6-O-(2-amino-2-deoxy- ⁇ -D- glucopyranosyl)-c z/r ⁇ -
  • the present invention provides the present invention provides a compound represented by the general formula:
  • X represents a sugar residue; 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 as defined herein; with the proviso that the compound is not l-D-4-O-(2-amino-2-deoxy- ⁇ -D- glucopyranosyl)-my ⁇ -inositol 1 -phosphate, l-D-6-O-(2-arnino-2-deoxy- ⁇ -D- glucopyranosyl)-my ⁇ -inositol 1 -phosphate, 1 -D-6-O-(2-arnino-2-deoxy- ⁇ -D- glucopyranosyl)-my0-inositol 1,2 cyclic-phosphate, l-D-6-O-(2-arnino-2-deoxy- ⁇ -D- glucopyranosyl)-cw ' ro-
  • the present invention provides the present invention provides a compound represented by the general formula:
  • X represents a sugar residue; 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 as defined herein.
  • the sugar residue is a hexose or a pentose, and may be an aldose or a ketose.
  • the sugar residue can be a member of the D or L series and can include amino sugars, deoxy sugars and their uronic acid derivatives.
  • the sugar residue is a hexose
  • it is selected from the group consisting of glucose, galactose or mannose, or substituted hexose sugar residues such as an amino sugar residue such as hexosamine, galactosamine or glucosamine, and more preferably D-glucosamine (2- amino-2-deoxy-D-glucose) or D-galactosamine (2-amino-2-deoxy-D-galactose).
  • Preferred pentose sugar residues include arabinose, fucose and ribose.
  • the sugar residue is optionally substituted at one, two, three or four positions, other than the position of linkage to the cyclitol moiety.
  • the cyclitol moiety is preferably selected from myo-inosito , chiro-inositol or pinitol (3-O-methyl-cfor ⁇ -inositol), in either their D or L forms, and is optionally substituted at one or more of the positions other than the position of linkage to the sugar radical, or in the case of pinitol additionally the 3 -position.
  • the sugar radical is optionally substituted at one, two, three or four positions other than at the position of linkage to the inositol moiety or the anomeric position.
  • the cyclitol moiety is substituted at the 3-position (e.g. is a pinitol or a related compound), preferably the substituent is C,.
  • I0 alkyl and may be a substituted or unsubstituted primary, secondary or tertiary alkyl group.
  • substituted groups include CF 3 , X(CH 2 ) n -O- (where X is hydrogen, or substituted or unsubstituted alkyl), CHF 2 O-.
  • a preferred alkyl group is methyl when the cyclitol is D or L-pinitol (3-O-methyl-c/zz ' r ⁇ -inositol), and is optionally substituted at one or more of the positions other than the 3-position or the position of linkage to the sugar residue.
  • the cyclitol may have one or more of the hydroxyl groups through which the substituents described above are removed so that any substituent(s) are linked to the ring carbon atom.
  • the sugar residue is optionally substituted at one, two, three, four or five positions other than at the position of linkage to the inositol moiety.
  • the compounds of the invention may be either ⁇ or ⁇ linked.
  • substituent group or groups of the cyclitol moiety and the sugar residue are independently selected from:
  • 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)OR ! R 2 ; substituted thiophosphonate -O-
  • 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,R 2 or sulphamide -NHSO 2 NH 2 ;
  • halogen substituents such as fluorine or chlorine
  • hydrogen e.g. to provide a deoxy sugar
  • R, R, and R 2 are independently hydrogen or C,_ 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.
  • the present invention provides a compound represented by the general formula:
  • X represents a sugar residue; the sugar residue is unsubstituted or substituted with between one and four groups, and the inositol is unsubstituted or is further substituted with between one and four groups, the group or groups being as defined herein; with the proviso that the compound is not l-D-4-O-(2-amino-2-deoxy- ⁇ -D- glucopyranosyl)-m O-inositol 1 -phosphate, 1 -D-6-O-(2-arnino-2-deoxy- ⁇ -D- glucopyranosyl)-my ⁇ -inositol 1 -phosphate, 1 -D-6-O-(2-arnino-2-deoxy- ⁇ -D- glucopyranosyl)-m ⁇ -inositol 1,2 cyclic-phosphate.
  • Examples of compounds within this aspect of the invention are RGL1023, RGL1027, RGL1029, RGL1105, RGL1115, RGL1116, RGL1125, RGL1126, RGL1134, RGL1133, RGL1135 and RGL1130.
  • the present invention provides a compound represented by the general formula:
  • X represents a sugar residue; the sugar residue is unsubstituted or substituted with between one and four groups, and the inositol is unsubstituted or is further substituted with between one and four groups, the group or groups being as defined herein; with the proviso that the compound is not lD-6-O-(2-amino-2-deoxy- ⁇ -D- glucopyranosyl)-D-c/7z ' r ⁇ -inositol 1 -phosphate.
  • Examples of compounds within this aspect of the invention are RGL1017, RGL1121 and derivatives thereof.
  • the present invention provides a compound represented by the general formula:
  • 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 as defined herein.
  • Examples of compounds within this aspect of the invention are RGL1024 and RGL1025.
  • the present invention provides a compound represented by the general formula:
  • X represents a sugar residue; the sugar residue is unsubstituted or substituted with between one and four groups, and the inositol is unsubstituted or is further substituted with between one and four groups, the group or groups being as defined herein.
  • Examples of compounds within this aspect of the invention are RGL1002 and RGL1124.
  • the present invention provides a compound represented by the general formula:
  • X represents a sugar residue; the sugar residue is unsubstituted or substituted with between one and four groups, and the inositol is unsubstituted or is further substituted with between one and four groups, the group or groups being as defined herein.
  • Examples of compounds within this aspect of the invention are RGL1018, RGL1019 and RGL1120 and derivatives thereof.
  • the present invention provides a compound represented by the general formula:
  • X represents a sugar residue; the sugar residue is unsubstituted or substituted with between one and four groups, and the inositol is unsubstituted or is further substituted with between one and four groups, the group or groups being as defined herein.
  • Examples of compounds within this aspect of the invention are RGL 1015, RGL 1119 and derivatives thereof.
  • the present invention provides a compound, or a substituted form thereof as defined above, selected from the group consisting of: RGLl 023 O-(2'-amino-2'-deoxy-6'-phosphate-D-glucopyranosyl)- ⁇ (l ,6)-D-myo- inositol.
  • RGL1027 O-(2'-amino-2'-deoxy-4'-phosphate-D-glucopyranosyl)- ⁇ (l,6)-D-my ⁇ - inositol.
  • RGLl 029 O-(2'-arnino-2'-deoxy-3 '-phosphate-D-glucopyranosyl)- ⁇ (l ,6)-D-m ⁇ - inositol.
  • RGL1017 O-(2'-amino-2'-deoxy-D-glucopyranosyl)- ⁇ (l,6)-D-cm * ro-inositol.
  • RGLl 024 O-(2-amino-2-deoxy-D-glucopyranosyl)- ⁇ (l ,6)-D-3-O-methyl-c zt ' r ⁇ - inositol.
  • RGL1025 O-(2-amino-2deoxy-D-galactopyranosyl)- ⁇ (l,6)-D-3-O-methyl-c zz ' r ⁇ - inositol.
  • RGLl 018 O-(2'-amino-2'-deoxy-D-glucopyranosyl)- ⁇ (l ,6)-D-c zz ' r ⁇ -inositol.
  • RGL 1019 O-(2' -amino-2 ' -deoxy-D-glucopyranosyl)- ⁇ ( 1 ,6)-D-c/zzr ⁇ -inositol- 1 - phosphate.
  • RGL1015 O-(2-amino-2-deoxy-D-glucopyranosyl)- ⁇ (l ,6)-3-O-methyl-c/zz ' r ⁇ - inositol.
  • RGL1105 l"-D-4 -O-(6"-phosphate- ⁇ -D-mannopyranosyl)-[l , -D-6-O-(2'- amino-2'-deoxy- ⁇ -D-glucanopyranosyl)-m > ⁇ -inositol].
  • RGLl 116 1 , -D-6-O-(2'-amino-2 , -deoxy- ⁇ -D-glucopyranosyl)-D-5-O-acetyl-my ⁇ - inositol.
  • RGLl 119 1 '-D-6-O-(2'-amino-2 , -deoxy- ⁇ -D-galactopyranosyl)-3-O-rnethyl-D- c zz ' r ⁇ -inositol.
  • RGLl 124 1 '-D-6-O-(2'-amino-2'-deoxy- ⁇ -D-glucopyranosyl)-5-O-acetyl-myo- inositol.
  • RGLl 125 1 '-D-6-O-(2'-amino-2'-deoxy- ⁇ -D-glucopyranosyl)-5-O-butyryl-myo- inositol.
  • RGLl 126 1 '-D-6-O-(2'-amino-2'-deoxy- ⁇ -D-glucopyranosyl)-5-O-palmityl- myo-inositol.
  • RGLl 134 1 '-D-6-O-(2'-amino-3 '-O-benzyl-4'-O-phosphate-2'-deoxy- ⁇ -D- glucopyranosyl)-3 ,4,5-tri-O-benzyl-my ⁇ -inositol- 1 ,2-cyclic phosphate.
  • RGLl 130 1 '-D-6-O-(2'-amino-4'-O-phosphate-2'-deoxy- ⁇ -D-glucopyranosyl)- my ⁇ -inositol-1 ,2-cyclic phosphate.
  • the present invention provides methods for making the compounds of the invention or their intermediates as set out in the following experimental description and the schemes.
  • the present invention further relates to compounds which are the novel intermediates described herein.
  • the present invention provides one or more of the above compounds for use in a method of medical treatment.
  • the compounds may be useful as IPG mimetics or IPG antagonists, e.g. as competitive antagonists.
  • the present invention provides the use of one or more of the above compounds for the preparation of a medicament for the treatment of a condition ameliorated by the administration of an inositol phosphoglycan (IPG) second messenger or an IPG antagonist.
  • IPG inositol phosphoglycan
  • Examples of such conditions are set out in the pharmaceutical uses section below.
  • the present invention provides 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 one or more of the above compounds.
  • IPG inositol phosphoglycan
  • Scheme 1 shows the coupling of diol 2 with trichloroacetimidate 1 resulting in 6-0- glycosylation. Subsequent manipulation of protective groups afforded compound 4.
  • Scheme 2 shows the production of compounds RGLl 023 and RGLl 027 from intermediate 4.
  • Scheme 3 shows the production of compound RGLl 029 by coupling acceptor 2 with trichloroacetimidate 11.
  • Scheme 4 describes the preparation of RGL1019.
  • Scheme 5 describes the preparation of the precursors for RGL1017 and RGLl 018, which are shown in Scheme 6.
  • Scheme 7 shows the synthesis of building block 7 by bis-protection of the trans- diequatorially oriented hydroxyl groups of D-pinitol (5) as cyclohexane 1,2-diacetal and the cis-oriented hydroxyl groups as isopropylidene acetal.
  • Scheme 8 shows the glycosylation of D-pinitol building block 7 with the 2-azido-2- deoxy-D-glucopyranosyl trichloroacetimidate 8 to give the IPG-like compounds 1 and
  • Scheme 9 shows the glycosylation of D-pinitol building block 7 with the 2-azido-2- deoxy-D-galactopyranosyl trichloroacetimidate 13 to give the IPG-like compounds 3 and 4.
  • Scheme 10 shows the synthesis of RGL 1105.
  • Scheme 11 shows the synthesis of RGLl 115 and RGLl 116
  • Scheme 12 shows the synthesis of RGLl 117.
  • Scheme 13 shows the synthesis of RGLl 124.
  • Scheme 14 shows the synthesis of RGLl 125.
  • Scheme 15 shows the synthesis of RGLl 126.
  • Scheme 16 shows the synthesis of RGLl 119.
  • Scheme 17 shows the synthesis of RGLl 134.
  • Scheme 18 shows the synthesis of RGLl 135.
  • Scheme 19 shows the synthesis of RGLl 133.
  • Scheme 20 show the synthesis of RGLl 130.
  • Figure 1 shows a graph of basal lipogenesis stimulation of exemplary compounds of the invention.
  • Figure 2 shows a graph of glucose stimulated lipogenesis stimulation of exemplary compounds of the invention.
  • Figure 3 shows a graph of the PKA inhibition of exemplary compounds of the invention.
  • Figure 4 shows the results of a G6Pase inhibition assay testing the effect of compound RGLl 133 against a known inhibitor, sodium O-vanadate.
  • IPGs Inositol phosphoglvcans
  • IPG-A mediators modulate the activity of a number of insulin-dependent enzymes such as cAMP dependent protein kinase (inhibits), adenylate cyclase (inhibits) and cAMP phospho-diesterases (stimulates).
  • IPG-P mediators modulate the activity of insulin-dependent enzymes such as pyruvate dehydrogenase phosphatase (stimulates) and glycogen synthase phosphatase (stimulates).
  • the A-type mediators mimic the lipogenic activity of insulin on adipocytes, whereas the P-type mediators mimic the glycogenic activity of insulin on muscle.
  • Both A-and P-type mediators are mitogenic when added to fibroblasts in serum free media.
  • the ability of the mediators to stimulate fibroblast proliferation is enhanced if the cells are transfected with the EGF-receptor.
  • A-type mediators can stimulate cell proliferation in the chick cochleovestibular ganglia.
  • Soluble IPG fractions having A-type and P-type activity have been obtained from a variety of animal tissues including rat tissues (liver, kidney, muscle, brain, adipose, heart) and bovine liver. IPG-A and IPG-P biological activity has also been detected in human liver and placenta, malaria parasitized RBC and mycobacteria. The ability of an anti-inositolglycan antibody to inhibit insulin action on human placental cytotrophoblasts and BC3H1 myocytes or bovine-derived IPG action on rat diaphragm and chick cochleovestibular ganglia suggests cross-species conservation of many structural features. However, it is important to note that although the prior art includes these reports of IPG-A and IPG-P activity in some biological fractions, the purification or characterisation of the agents responsible for the activity is not disclosed.
  • IPG-A substances are cyclitol-containing carbohydrates, also containing Zn 2+ ions and phosphate and having the properties of regulating lipogenic activity and inhibiting cAMP dependent protein kinase. They may also inhibit adenylate cyclase, be mitogenic when added to EGF-transfected fibroblasts in serum free medium, and stimulate lipogenesis in adipocytes.
  • IPG-P substances are cyclitol-containing carbohydrates, also containing Mn 2+ and/or Zn 2+ ions and phosphate and having the properties of regulating glycogen metabolism and activating pyruvate dehydrogenase phosphatase. They may also stimulate the activity of glycogen synthase phosphatase, be mitogenic when added to fibroblasts in serum free medium, and stimulate pyruvate dehydrogenase phosphatase.
  • Protocols for determining characteristic IPG biological activities such as PDH activation, PKA inhibition, acetylCoA activation, fructose- 1 ,6-bis-phosphatase activity and lipogenesis are well known in the art or provided in the experimental section below.
  • the compounds of the invention may be derivatised in various ways.
  • “derivatives” of the compounds includes salts, coordination complexes with metal ions such as Mn 2+ and Zn 2+ , esters such as in vivo hydrolysable esters, free acids or bases, hydrates, prodrugs or lipids, coupling partners.
  • Salts of the compounds of the invention are preferably physiologically well tolerated and non toxic. Many examples of salts are known to those skilled in the art.
  • Compounds having acidic groups such as phosphates or sulfates, can form salts with alkaline or alkaline earth metals such as Na, K, Mg and Ca, and with organic amines such as triethylamine and Tris (2-hydroxyethyl)amine.
  • Salts can be formed between compounds with basic groups, e.g. amines, with inorganic acids such as hydrochloric acid, phosphoric acid or sulfuric acid, or organic acids such as acetic acid, citric acid, benzoic acid, fumaric acid, or tartaric acid.
  • Compounds having both acidic and basic groups can form internal salts.
  • Esters can be formed between hydroxyl or carboxylic acid groups present in the compound and an appropriate carboxylic acid or alcohol reaction partner, using techniques well known in the art.
  • prodrugs which as prodrugs of the compounds are convertible in vivo or in vitro into one of the parent compounds.
  • at least one of the biological activities of compound will be reduced in the prodrug form of the compound, and can be activated by conversion of the prodrug to release the compound or a metabolite of it.
  • An example of prodrugs are glycolipid derivatives in which one or more lipid moieties are provided as substituents on the sugar residue or the cyclitol moieties, leading to the release of the free form of the compound by cleavage with a phospholipase enzyme.
  • prodrugs include the use of protecting groups which may be removed in situ releasing active compound or serve to inhibit clearance of the drug in vivo. Protecting groups are well known in the art and are discussed further below.
  • An example of a suitable protecting group that might be used as a prodrug is the azido group used in the synthesis below, e.g. on the 2-position of the sugar moiety.
  • Coupled derivatives include coupling partners of the compounds in which the compounds is linked to a coupling partner, e.g. by being chemically coupled to the compound or physically associated with it.
  • Examples of coupling partners include a label or reporter molecule, a supporting substrate, a carrier or transport molecule, an effector, a drug, an antibody or an inhibitor.
  • Coupling partners can be covalently linked to compounds of the invention via an appropriate functional group on the compound such as a hydroxyl group, a carboxyl group or an amino group.
  • Other derivatives include formulating the compounds with liposomes.
  • the compounds described herein or their derivatives can be formulated in pharmaceutical compositions, and administered to patients in a variety of forms, in particular to treat conditions which are ameliorated by the administration of inositol phosphoglycan second messengers or IPG antagonists such as competitive antagonist.
  • compositions for oral administration may be in tablet, capsule, powder or liquid form.
  • a tablet may include a solid carrier such as gelatin or an adjuvant or an inert diluent.
  • Liquid pharmaceutical compositions generally include a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included. Such compositions and preparations generally contain at least 0.1 wt% of the compound.
  • Parental administration includes administration by the following routes: intravenous, cutaneous or subcutaneous, nasal, intramuscular, intraocular, transepithelial, intraperitoneal and topical (including dermal, ocular, rectal, nasal, inhalation and aerosol), and rectal systemic routes.
  • intravenous, cutaneous or subcutaneous injection, or injection at the site of affliction the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability.
  • suitable solutions using, for example, solutions of the compounds or a derivative thereof, e.g. in physiological saline, a dispersion prepared with glycerol, liquid polyethylene glycol or oils.
  • compositions can comprise one or more of a pharmaceutically acceptable excipient, carrier, buffer, stabiliser, isotonicizing agent, preservative or anti-oxidant or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient.
  • a pharmaceutically acceptable excipient such materials should be non-toxic and should not interfere with the efficacy of the active ingredient.
  • the precise nature of the carrier or other material may depend on the route of administration, e.g. orally or parentally.
  • Liquid pharmaceutical compositions are typically formulated to have a pH between about 3.0 and 9.0, more preferably between about 4.5 and 8.5 and still more preferably between about 5.0 and 8.0.
  • the pH of a composition can be maintained by the use of a buffer such as acetate, citrate, phosphate, succinate, Tris or histidine, typically employed in the range from about 1 mM to 50 mM.
  • a buffer such as acetate, citrate, phosphate, succinate, Tris or histidine, typically employed in the range from about 1 mM to 50 mM.
  • the pH of compositions can otherwise be adjusted by using physiologically acceptable acids or bases.
  • Preservatives are generally included in pharmaceutical compositions to retard microbial growth, extending the shelf life of the compositions and allowing multiple use packaging.
  • preservatives include phenol, meta-cresol, benzyl alcohol, para-hydroxybenzoic acid and its esters, methyl paraben, propyl paraben, benzalconium chloride and benzethonium chloride.
  • Preservatives are typically employed in the range of about 0.1 to 1.0 % (w/v).
  • the pharmaceutically compositions are given to an individual in a
  • prophylactically effective amount or a “therapeutically effective amount” (as the case may be, although prophylaxis may be considered therapy), this being sufficient to show benefit to the individual. Typically, this will be to cause a therapeutically useful activity providing benefit to the individual.
  • the actual amount of the compounds administered, and rate and time-course of administration, will depend on the nature and severity of the condition being treated. Prescription of treatment, e.g. decisions on dosage etc, is within the responsibility of general practitioners and other medical doctors, and typically takes account of the disorder to be treated, the condition of the individual patient, the site of delivery, the method of administration and other factors known to practitioners. Examples of the techniques and protocols mentioned above can be found in Remington's Pharmaceutical Sciences, 16th edition, Osol, A. (ed), 1980.
  • compositions are preferably administered to patients in dosages of between about 0.01 and lOOmg of active compound per kg of body weight, and more preferably between about 0.5 and lOmg/kg of body weight .
  • the composition may further comprise one or more other pharmaceutically active agents, either further compounds of the invention, inositol phosphoglycans, growth factors such as insulin, NGF or other growth factors listed below, or other drugs, e.g. those in use for the treatment of diabetes or other conditions set out below.
  • IPGs are second messengers for a range of different growth factors, including insulin, nerve growth factor, hepatocyte growth factor, endothelial growth factor, insulin-like growth factor I (IGF-I), fibroblast growth factor, transforming growth factor ⁇ , 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. Consequently, IPGs or their antagonists can be used in the treatment or amelioration of disorders mediated by the growth factors or to mimic specific growth factor biological activities.
  • IGF-I insulin-like growth factor I
  • fibroblast growth factor transforming growth factor ⁇
  • ACTH signalling of adrenocortical cells IgE, FSH and hCG stimulation of granulosa cells
  • thyrotropin stimulation of thyroid cells cell proliferation in the
  • IPGs or IPG antagonists examples include, diabetes, obesity, dyslipidaemia, pre-eclampsia, neurotrophic disorders, hepatic damage and adrenal atrophy.
  • WO98/10791 discloses that pre-eclampsia is characterised by elevated levels of IPG-P and that it can be treated using an IPG-P antagonist.
  • Compounds of the invention which are IPG-P antagonists, e.g. antagonists which compete with wild-type IPG-P but lack one or more of its activities, could be used in the treatment of pre-eclampsia.
  • IPG-P and IPG-A and IPG-A antagonists in the diagnosis and treatment of diabetes is disclosed in WO98/11435.
  • This application discloses that in some forms of diabetes the ratio of P: A-type IPGs is imbalanced and can be corrected by administering a medicament containing an appropriate ratio of IPG-P, IPG-A or antagonist(s) thereof.
  • NIDDM obese type II diabetes
  • IDDM body mass index ⁇ 27
  • P- and A-type IPGs typically in a P:A ratio of about 6:1 for males and 4:1 for females.
  • the compounds and compositions of the present invention can be employed in such types of treatment. More particularly, the compounds are likely to be of use in the treatment of various form of diabetes and diabetic complications including diabetes due to insulin resistance, insulin resistance in type I diabetes and brittle diabetes, obese or lean type II diabetes, and of conditions associated with insulin resistance or insulin underproduction, such as neurotrophic disorders or polycystic ovary syndrome, lipodystrophy, age-related memory loss, and post-ischaemic damage secondary to stroke or post-transplant complications.
  • the compounds of this invention are also likely to be of use in controlling neuron proliferation or neurite outgrowth, either in vitro or in vivo, e.g. acting as a nerve or neurite growth factor mimetic second messenger. They may thus have applications in the treatment and/or diagnosis of any condition related to neuron proliferation or neurite differentiation.
  • WO99/38516 discloses that IPG-A and synthetic mimetics thereof cause neuron proliferation, mimicking the action of the growth factor IGF-I. In contrast, IPG-P and synthetic mimetics thereof such as compound C4 cause neurite outgrowth.
  • the neurons may be central (brain and spinal cord) neurons, peripheral
  • (sympathetic, parasympathetic, sensory and enteric) neurons e.g. the compounds used in the regeneration of peripheral nerves, or motor neurons.
  • Treatments may involve the treatment of damage to nerve, spinal cord or central nervous system damage secondary to trauma, or autoimmune or metabolic damage, or post-ischaemic damage secondary to stroke or post-transplant complications, motor neuron disease, neurodegenerative disorders or neuropathy.
  • Damage to the nervous system includes the results of trauma, stroke, surgery, infection (e.g. by viral agents), ischemia, metabolic disease, toxic agents, or a combination of these or similar causes.
  • Motor neuron disease includes conditions involving spinal muscular atrophy, paralysis or amyotrophic lateral sclerosis.
  • Neurodegenerative disorders include Parkinson's disease, Alzheimer's disease, epilepsy, multiple sclerosis, Huntingdon's chorea and Meniere's disease.
  • the compounds of the invention may also be useful as hepatocyte growth factor mimetic second messengers, e.g. in the preparation of medicaments for the treatment of hepatic damage caused by infection, alcohol abuse, drug sensitivity, or autoimmunity.
  • the compounds may also be useful as fibroblast growth factor mimetic second messengers or epidermal growth factor mimetic second messengers, e.g. in the preparation of medicaments for the promotion of wound healing following surgery or trauma or tissue damage induced by ischaemia or autoimmunity.
  • the compounds of the invention may be useful as adrenal cell growth factor mimetic second messengers or ACTH mimetic second messengers in the preparation of a medicament for the treatment of disease states involving adrenal atrophy.
  • the compounds of the invention can readily be tested using the assays identified herein to determine their suitability for some or all of the medical uses described above. Thus, even compounds with a relatively low activity in one of the enzymes assays disclosed herein, may be useful by virtue of possessing a different activity, and moreover the pattern of activities can be used to rapidly screen the compounds for suitability in the various medical applications disclosed herein.
  • Phosphoryl groups such as phosphate, cyclic phosphate or substituted phosphate or cyclic phosphate can be substituted into the compounds of the invention by the phosphate or phosphoramidite method, Bannwath et al, Helvetica Chemica Acta, 70:175-186, 1987 and Yu & Fraser-Reid, Tetrahedron Lett, 29:979-982, 1988.
  • Phosphate protecting groups can also be synthesized according to the methods disclosed in Hoeben-Weyl, Methods of Organic Chemistry, volume 12/1 or 12/2, Molheimer, Synthetic Methods of Organic Chemistry, Nol 45.
  • Protecting groups for the OH of sugars include menthoxycarbonyl (MntCO), acetal (in particular, two R groups may together represent a bridging acetal such as O-cyclohexylidene, O- isopropylidene or O-benzylidene), tert-butyldimethylsilyl (TBDMS), benzyl (Bn), tert-butyldiphenylsilyl (TBDPS).
  • MntCO menthoxycarbonyl
  • acetal in particular, two R groups may together represent a bridging acetal such as O-cyclohexylidene, O- isopropylidene or O-benzylidene
  • TDMS tert-butyld
  • the compounds of the invention can be tested for one or more the characteristic IPG- P and/or IPG-A activities mentioned above to determine whether they will be suitable for use a IPG mimetics or antagonists.
  • Preferred assays measure the effect of the compounds on PDH phosphatase, PKA or lipogenesis. Protocols for these assays are provided in Caro et al [14] .
  • the compounds can also be tested to determine whether they activate or inhibit other enzymes involved in insulin signalling mechanism, such as glucose-6-phosphatase.
  • the synthesis of compounds RGL 1023, 1027 and 1029 involved the preparation of a glycosyl acceptor with position 6 free for reaction with the corresponding glycosyl donor.
  • Diol 2 was chosen as the my ⁇ -inositol acceptor [17] as it can be regioselectively glycosylated at position 6.
  • Regio- and stereoselective glycosylation of diol 2 is most conveniently performed using the trichloroacetimidate procedure with 2-azido-2- deoxy glycosyl donors bearing protective group patterns compatible with the further transforamtions required and designed as to provide an acceptable reactivity- selectivity balance in the forthcoming glycosylation reaction.
  • trichloroacetimidate 1 was the glycosyl donor of choice.
  • Oxidation to the phosphate form was achieved in situ by reaction with MPBCA in dichloromethane at room temperature for two hours with good yield.
  • Trifluoracetic acid treatment of compounds 7 and 8 in dichloromethane at room temperature for 4 hours afforded diols 9 and 10 with moderate to good yields.
  • Compounds RGLl 023 and RGLl 027 were obtained after hydrogenolytic debenzylation and concomitant azide reduction of 9 and 10 in buffered medium (Scheme 2).
  • Synthesis of compound RGLl 029 required that the glycosyl donor to be used contained a protecting group in position 3 different from a benzyl group, to be introduced later on in the glycosyl acceptor residue.
  • D-glucopyranoside 1 (1.698 g, 3.217 mmol) and l-D-l,2-O-(L-l,7,7-trimethyl[2.2.1]- bicyclohept-2-ylidene)-3,4-O-(l , 1 ,3,3-tetraisopropyldisiloxanyl)-myo-inositol 2 (2.51 g, 4.507 mmol) in Et 2 O (50 mL) at -20 °C, trimethylsilyl trifluromethanesulfonate (29 ml, 0.160 mmol) was added.
  • CDA CDA
  • MALDI-TOF Calcd. for C 45 H 57 N 3 O 12 +Na + : 855.0, found: 854.3, calcd. for C 45 H 57 N 3 O I2 +K + : 871.1, found: 870.5
  • Disaccharide (9) was dissolved in a mixture of trifluoroacetic acid/water (20:1, 3.7 mL) and stirred at room temperature for 40 min. Then, the reaction mixture was diluted with CH 2 C1 2 (10 mL) and immediately poured into an ice-cold, vigorously stirred solution of saturated aqueous sodium bicarbonate (90 mL). The layers were separated, and the aqueous phase extensively extrated (CH 2 C1 2 , 4x 30 ml), dried over
  • reaction mixture was then stirred at R.T. overnight.
  • TLC analysis (hexane:EtOAc [9:1]) of the reaction mixture suggested that only c.a. 50 % of the ⁇ -1,6 anomer 11 starting material had been consumed.
  • the reaction was therefore heated to 45 °C for 8 hours at which point TLC analysis (hexane: EtOAc [9:1]) indicated complete consumption of the ⁇ -1,6 anomer 11 starting material.
  • the reaction mixture was concentrated to dryness in vacuo, using toluene to azeotropically remove the pyridine.
  • reaction mixture was then stirred at R.T. overnight.
  • TLC analysis (hexane:EtOAc [9:1]) of the reaction mixture suggested that only c.a. 50 % of the ⁇ -1,6 anomer 9 starting material had been consumed.
  • the reaction was therefore heated to 45°C for 9 hours at which point TLC analysis (hexane:EtOAc [9:1]) indicated that only a small quantity of the ⁇ -1,6 anomer 9 starting material remained unreacted.
  • the reaction mixture was concentrated to dryness in vacuo, using toluene azeotropically remove the pyridine.
  • TLC analysis (hexane:EtOAc [10:1]) indicated that approximately 50 % of the ⁇ -1,6 anomer 11 starting material remained. Therefore, the reaction mixture was heated to 110 °C for 6 hours until it was determined by TLC analysis (hexane:EtOAc [10:1]) that approximately 30 % of the ⁇ - 1,6 anomer 11 starting material remained. Butyric anhydride (5 equivalents) and pyridine (1.5 ml) were added and the reaction mixture heated at 110 °C overnight. TLC analysis (hexane:EtOAc [10:1]) then indicated that the ⁇ -1,6 anomer 11 starting material had been consumed.
  • the tetrol 2 (110 mg, 0.15 mmol) was co-evaporated with pyridine (2 x 1 ml) and dissolved in pyridine (2 ml). To the solution was added DMTC1 (78 mg, 1.5 eq) and the reaction stirred for 16 h. The solvent was removed in vacuo and the residue dissolved in DCM (30 ml). The solution was washed with NaHCO 3 (sat, 2 x 20 ml), dried (MgSO 4 ), filtered and concentrated in vacuo. The residual pyridine was removed by co-evaporation with toluene. The product (100 mg, 97 ⁇ mol) was isolated by flash chromatography (silica, 10% ⁇ 50% ethyl acetate/hexanes).
  • Methyldichlorophosphate (30 ⁇ l, 0.29 mmol, 3 eq) was added to pyridine (630 ⁇ l) with stirring under an atmosphere of nitrogen at room temperature. After 30 min compound 1 (100 mg, 0.14 mmol) in pyridine (100 ⁇ l) was added and the reaction stirred for a further 4 h. The reaction was diluted with DCM (10 ml) and quenched by addition of NaHCO 3 solution. The resulting emulsion was separated by the addition of brine and the aqueous phase extracted with DCM (1 x 10 ml). The combined organic solvents were dried (Na 2 SO 4 ), filtered and concentrated in vacuo.
  • FIG. 4 shows the result of an assay measuring the effect of compound RGLl 133 in inhibiting glucose 6-phosphatase, as compared to an known inhibitor, sodium O- vanadate.
  • the results show that RGLl 133 is a good inhibitor of G6Pase activity and would be useful for decreasing hepatic glucose output in diabetic subjects. This suggests that this compound would be useful in the treatment of both type I and type II diabetes.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Diabetes (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Endocrinology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Saccharide Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés possédant une propriété antagoniste ou mimétique d'un inositolphosphoglycanne (IPG), ainsi que l'utilisation de ces composés, de même que l'emploi de ceux-ci, par exemple pour traiter un état amélioré par l'administration d'un second messager IPG ou d'un antagoniste IPG de celui-ci. L'invention concerne notamment des composés comportant une liaison 1,6 d'un reste sucre et d'un cyclitol.
EP01934120A 2000-05-12 2001-05-11 Composes et utilisations associees Withdrawn EP1406913A2 (fr)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
US20359600P 2000-05-12 2000-05-12
US203596P 2000-05-12
GB0011594A GB0011594D0 (en) 2000-05-12 2000-05-12 Compounds and their uses
GB0011594 2000-05-12
US798005 2001-03-02
US09/798,005 US6953781B2 (en) 2000-05-12 2001-03-02 Compounds and their uses
PCT/GB2001/002088 WO2001085740A2 (fr) 2000-05-12 2001-05-11 Composes et utilisations associees

Publications (1)

Publication Number Publication Date
EP1406913A2 true EP1406913A2 (fr) 2004-04-14

Family

ID=27255717

Family Applications (1)

Application Number Title Priority Date Filing Date
EP01934120A Withdrawn EP1406913A2 (fr) 2000-05-12 2001-05-11 Composes et utilisations associees

Country Status (4)

Country Link
EP (1) EP1406913A2 (fr)
AU (1) AU6042601A (fr)
CA (1) CA2433183A1 (fr)
WO (1) WO2001085740A2 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2878850B1 (fr) 2004-12-02 2008-10-31 Cis Bio Internat Sa Derives de l'inositol-1-phosphate
US20100197625A1 (en) * 2006-12-21 2010-08-05 D Alarcao Marc Synthetic lipophilic inositol glycans for treatment of cancer and glucose-metabolism disorders

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19649350A1 (de) * 1996-11-28 1998-06-04 Hoechst Ag Inositolglykane mit insulinartiger Wirkung

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0185740A2 *

Also Published As

Publication number Publication date
WO2001085740A2 (fr) 2001-11-15
CA2433183A1 (fr) 2001-11-15
WO2001085740A3 (fr) 2002-03-28
AU6042601A (en) 2001-11-20

Similar Documents

Publication Publication Date Title
RU2178794C2 (ru) Инозитолгликаны с инсулиноподобным действием, способ их получения, фармацевтическая композиция и способ ее получения
JP2518739B2 (ja) 腫瘍抑制サツカライド包合体
US6759390B2 (en) Compounds and their uses
US6939857B2 (en) Compounds and their uses
US6716826B2 (en) Compounds and their uses
US7235533B2 (en) Compounds and their uses
WO2001085740A2 (fr) Composes et utilisations associees
EP1409498B1 (fr) Derives de phosphoglycane d'inositol et leurs utilisations en medecine
AU3060600A (en) Inositol-containing hexasaccharides, their synthesis and their uses
EP1409501B1 (fr) Derives d'inositol phosphoglycane et utilisations medicales de ceux-ci
JPH07233186A (ja) 新規ｂｂｍ−１６７５ｄ抗腫瘍性抗生物質
EP1409500B1 (fr) Inositolglycanes alkyles et leur utilisation
WO2001010877A1 (fr) Analogues de c-clycoside et leurs procedes de preparation et d'utilisation
CN1930180B (zh) 左侧葡萄糖脂a类似物
KR100481746B1 (ko) 인슐린-유사작용을갖는이노시톨글리칸및이를포함하는약제학적제제
AU1060200A (en) Carbohydrates and methods for their synthesis
TW200413400A (en) Lipid a derivatives which have glucose back-bone as the reducing sugar part
HK1090379A (en) Levulose glucoselipid a analogue
MXPA97009207A (en) Inositol-glycanos with activity of the type of lainsul
HK1108581A (en) Sulfated oligosaccharide derivatives

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20030328

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

17Q First examination report despatched

Effective date: 20050415

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20121204

R18D Application deemed to be withdrawn (corrected)

Effective date: 20121201