EP0354904A1 - Inositol phosphate analogues - Google Patents
Inositol phosphate analoguesInfo
- Publication number
- EP0354904A1 EP0354904A1 EP88902179A EP88902179A EP0354904A1 EP 0354904 A1 EP0354904 A1 EP 0354904A1 EP 88902179 A EP88902179 A EP 88902179A EP 88902179 A EP88902179 A EP 88902179A EP 0354904 A1 EP0354904 A1 EP 0354904A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- inositol
- general formula
- formula
- myo
- zero
- 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- Withdrawn
Links
- INAPMGSXUVUWAF-GCVPSNMTSA-N [(2r,3s,5r,6r)-2,3,4,5,6-pentahydroxycyclohexyl] dihydrogen phosphate Chemical class OC1[C@H](O)[C@@H](O)C(OP(O)(O)=O)[C@H](O)[C@@H]1O INAPMGSXUVUWAF-GCVPSNMTSA-N 0.000 title description 5
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 23
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 15
- -1 inositol phosphorothioates Chemical class 0.000 claims abstract description 15
- 239000002904 solvent Substances 0.000 claims abstract description 5
- 150000001451 organic peroxides Chemical class 0.000 claims abstract description 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims abstract 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 15
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical group CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 claims description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 14
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 13
- 239000005864 Sulphur Substances 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 11
- WSGYTJNNHPZFKR-UHFFFAOYSA-N 3-hydroxypropanenitrile Chemical compound OCCC#N WSGYTJNNHPZFKR-UHFFFAOYSA-N 0.000 claims description 7
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 7
- 229910019142 PO4 Inorganic materials 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
- 239000011734 sodium Substances 0.000 claims description 7
- 229910052708 sodium Inorganic materials 0.000 claims description 7
- 125000006239 protecting group Chemical group 0.000 claims description 6
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 claims description 6
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 claims description 5
- 239000010452 phosphate Substances 0.000 claims description 3
- INAPMGSXUVUWAF-UHFFFAOYSA-L (2,3,4,5,6-pentahydroxycyclohexyl) phosphate Chemical compound OC1C(O)C(O)C(OP([O-])([O-])=O)C(O)C1O INAPMGSXUVUWAF-UHFFFAOYSA-L 0.000 claims description 2
- QWTBDIBOOIAZEF-UHFFFAOYSA-N 3-[chloro-[di(propan-2-yl)amino]phosphanyl]oxypropanenitrile Chemical compound CC(C)N(C(C)C)P(Cl)OCCC#N QWTBDIBOOIAZEF-UHFFFAOYSA-N 0.000 claims description 2
- 150000004001 inositols Chemical class 0.000 claims description 2
- 239000007800 oxidant agent Substances 0.000 claims 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims 1
- 125000001424 substituent group Chemical group 0.000 claims 1
- 229960000367 inositol Drugs 0.000 abstract description 19
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 abstract description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 6
- 230000003647 oxidation Effects 0.000 abstract description 4
- 238000007254 oxidation reaction Methods 0.000 abstract description 4
- 230000002285 radioactive effect Effects 0.000 abstract description 2
- 239000007795 chemical reaction product Substances 0.000 abstract 1
- 150000003014 phosphoric acid esters Chemical class 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 150000005691 triesters Chemical class 0.000 description 10
- 239000000047 product Substances 0.000 description 9
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 8
- 235000021317 phosphate Nutrition 0.000 description 6
- 150000003536 tetrazoles Chemical class 0.000 description 6
- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 description 5
- 238000004679 31P NMR spectroscopy Methods 0.000 description 5
- 238000005915 ammonolysis reaction Methods 0.000 description 5
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- 150000003863 ammonium salts Chemical class 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 125000001309 chloro group Chemical group Cl* 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 239000003456 ion exchange resin Substances 0.000 description 4
- 229920003303 ion-exchange polymer Polymers 0.000 description 4
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 3
- 229920005654 Sephadex Polymers 0.000 description 3
- 239000012507 Sephadex™ Substances 0.000 description 3
- RYYWUUFWQRZTIU-UHFFFAOYSA-N Thiophosphoric acid Chemical group OP(O)(S)=O RYYWUUFWQRZTIU-UHFFFAOYSA-N 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- IMQLKJBTEOYOSI-GPIVLXJGSA-N Inositol-hexakisphosphate Chemical group OP(O)(=O)O[C@H]1[C@H](OP(O)(O)=O)[C@@H](OP(O)(O)=O)[C@H](OP(O)(O)=O)[C@H](OP(O)(O)=O)[C@@H]1OP(O)(O)=O IMQLKJBTEOYOSI-GPIVLXJGSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 2
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 2
- IMQLKJBTEOYOSI-UHFFFAOYSA-N Phytic acid Natural products OP(O)(=O)OC1C(OP(O)(O)=O)C(OP(O)(O)=O)C(OP(O)(O)=O)C(OP(O)(O)=O)C1OP(O)(O)=O IMQLKJBTEOYOSI-UHFFFAOYSA-N 0.000 description 2
- 238000007068 beta-elimination reaction Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 2
- AFQIYTIJXGTIEY-UHFFFAOYSA-N hydrogen carbonate;triethylazanium Chemical compound OC(O)=O.CCN(CC)CC AFQIYTIJXGTIEY-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 150000008300 phosphoramidites Chemical class 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 238000001394 phosphorus-31 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000001665 trituration Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- MMWCIQZXVOZEGG-MLQGYMEPSA-N 1D-myo-inositol 1,3,4-trisphosphate Chemical compound O[C@@H]1[C@@H](O)[C@H](OP(O)(O)=O)[C@@H](OP(O)(O)=O)[C@@H](O)[C@H]1OP(O)(O)=O MMWCIQZXVOZEGG-MLQGYMEPSA-N 0.000 description 1
- MNZDCOHDXOTQON-UHFFFAOYSA-N 3-[chloro-[di(propan-2-yl)amino]phosphanyl]propanenitrile Chemical compound CC(C)N(C(C)C)P(Cl)CCC#N MNZDCOHDXOTQON-UHFFFAOYSA-N 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 229930091051 Arenine Natural products 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- MMWCIQZXVOZEGG-XJTPDSDZSA-N D-myo-Inositol 1,4,5-trisphosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](OP(O)(O)=O)[C@H](OP(O)(O)=O)[C@@H](O)[C@@H]1OP(O)(O)=O MMWCIQZXVOZEGG-XJTPDSDZSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- MMWCIQZXVOZEGG-HOZKJCLWSA-N [(1S,2R,3S,4S,5R,6S)-2,3,5-trihydroxy-4,6-diphosphonooxycyclohexyl] dihydrogen phosphate Chemical compound O[C@H]1[C@@H](O)[C@H](OP(O)(O)=O)[C@@H](OP(O)(O)=O)[C@H](O)[C@H]1OP(O)(O)=O MMWCIQZXVOZEGG-HOZKJCLWSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 238000012925 biological evaluation Methods 0.000 description 1
- DWISNYLUFCHIKU-UHFFFAOYSA-N bis(2-cyanoethyl) hydrogen phosphite Chemical compound N#CCCOP(O)OCCC#N DWISNYLUFCHIKU-UHFFFAOYSA-N 0.000 description 1
- 125000005340 bisphosphate group Chemical group 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 210000001638 cerebellum Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical class NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 229910052816 inorganic phosphate Inorganic materials 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 230000037427 ion transport Effects 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 230000007257 malfunction Effects 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 102000006240 membrane receptors Human genes 0.000 description 1
- 108020004084 membrane receptors Proteins 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 150000004712 monophosphates Chemical class 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 238000005731 phosphitylation reaction Methods 0.000 description 1
- 150000003906 phosphoinositides Chemical class 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 229940068041 phytic acid Drugs 0.000 description 1
- 235000002949 phytic acid Nutrition 0.000 description 1
- 239000000467 phytic acid Substances 0.000 description 1
- 102000040430 polynucleotide Human genes 0.000 description 1
- 108091033319 polynucleotide Proteins 0.000 description 1
- 239000002157 polynucleotide Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 238000001525 receptor binding assay Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- JLEXUIVKURIPFI-UHFFFAOYSA-N tris phosphate Chemical compound OP(O)(O)=O.OCC(N)(CO)CO JLEXUIVKURIPFI-UHFFFAOYSA-N 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/16—Esters of thiophosphoric acids or thiophosphorous acids
- C07F9/165—Esters of thiophosphoric acids
- C07F9/177—Esters of thiophosphoric acids with cycloaliphatic alcohols
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- This invention relates to analogues of inositol phosphate esters and to a method for the preparation thereof.
- Inositol [C 6 H 6 (OH) 6 ] is hexahydroxycyclohexane of which there are nine isomeric forms.
- Myo- inositol is cis-1,2,3,5-trans-4,6-hexahydroxycyclohexane.
- inositol phosphates are known, One well-known derivative of commercial importance is phytic acid (inositol hexaphosphoric acid). Also known are D-myo-inositol-1,3,4-trisphosphate , the 1,4,5-isomer and the 1,4,5,6- and 1,3,4,5-tetrakisphosphates. These molecules are of biological importance although their precise biological roles have not yet been fully elucidated. They may be isolated with some difficulty and in low yield from natural sources.
- inositol phosphates The biological significance of inositol phosphates is the subject of much current interest and research.
- One area in which the inositol phosphates have been found to be involved is in calcium ion transport mechanisms in cells.
- an inositol phosphorothioate having the general formula I;
- n is zero or an integer from 1 to 5 and, m is an integer from 1 to 6.
- the present invention provides an inositol molecule in which one or more of its six hydroxyl groups is esterified by a phosphorothioate group, the remaining positions being occupied by hydroxyl or phosphate ester groups.
- the sulphur atom, of the thioate group may be a radioisotope of sulphur to provide radiolabelled compounds for use as research reagents.
- the present invention also provides a method of preparing an inositol phosphorothioate having the general formula I;
- n is zero or an integer from 1 to 5 and, m is an integer from 1 to 6, said method comprising reacting an inositol derivative having the general formula II ;
- n is zero or an integer from 1 to 5 and B represents a hydroxyl-protecting group, with a solution of elemental sulphur in a solvent therefor, and removing the protecting groups from the product of the reaction.
- the hydroxyl-protecting group represented by B in formula II is a benzyl group.
- a divalent group such as isopropylidene may be utilised when n is an even number and the hydroxyl groups are thereby protected in pairs.
- Bz is a benzyl group
- iPr' is an isopropylidenyl group
- n is zero or an integer from 1 to 5
- m is zero or 1 or 2
- p is 2 or 4 or 6.
- the compound of general formula II above may be oxidised with, for example a hydroperoxide such as tert- butylhydroperoxide, to form a compound having the formula VI;
- the starting material that is, the inositol derivative having the general formula II defined above, may be prepared by a method comprising reacting a compound having the general formula III:
- the benzylated inositol starting material (formula III above) may be prepared from inositol, via the isopropylidene derivatives, according to the method described in J. Gigg, R. Gigg, S. Payne & R. Conant;
- the present invention also provides a method of preparing an inositol phosphate having the general formula I;
- n is zero or an integer from 1 to 5 and, m is zero, said method comprising reacting an inositol derivative having the general formula II; '
- n is zero or an integer from 1 to 5 and B represents a hydroxyl-protecting group, with an organic peroxide, and removing the protecting groups from the product of the reaction.
- the organic preroxide is preferably tert-butyl hydroperoxide.
- (+,-)- 1,2,4-tri-O-benzyl-myo-inositol (0.20 mmole) was treated with 0.66 mmole of chloro (2-cyanoethoxy)- N,N diisopropylamino phosphine and diisopropylethylamine ((0.60 mmole) in dichloromethane to yield the trisphosphoramidite.
- Reaction of the trisphosphoramidite with tetrazole and 2-cyanoethanol yielded the trisphosphite triester in about 90% yield.
- 31P NMR spectroscopy showed 5 Jpp spin-spin coupling in the form of an AB system for two of the phosphite triesters confirming the phosphitylation of the vicinal 4,5-diol system.
- (+,-)-1,2,3,4-tetra-O-benzyl myo-inositol was treated with 2 equivalents of chloro(2-cyanoethoxy)- N,N diisopropylamino phosphine in dichloromethane to yield the bisphosphoramidite.
- Treatment of the bisphosphoramidite with tetrazole and 2-cyanoethanol gave the bisphosphite triester.
- 31 P NMR spectroscopy showed that about 90% of the phosphorus could be accounted for by an AB system assignable to the 4, 5-bis ⁇ hosphite triester system.
- the 4,5-bisphosphite triester prepared as described in Example 2 above, was reacted with a solution of sulphur in pyridine to yield the bisphosphoro-thioate triester and subsequent removal of the protecting groups using sodium in liquid ammonia yielded (+,-)myo-inositol 4,5-bisphos ⁇ horothioate.
- the sulphur may be radioactive.
- (+ , -) -1,2,4,5-Bisisopropylidene-myo-inositol was reacted with chloro(2-cyanoethoxy)-N,N diisopropylamino phosphine (0.715 mmole) and diisopropylethylamine (0.715 mmole) in dichloromethane (1 ml) for one hour to yield the bisphosphoramidite.
- Reaction of the phosphoramidite with tetrazole and 2-cyanoethanol (0.715 mmole of each) gave the 1,4-bisphosphite triester.
- Oxidation with tert-butyl hydroperoxide (1 ml) gave the bisphosphate triester.
- (+) -1,2,4-tri-O-benzyl-myo- inositol was converted to the corresponding tri [di(2-cyanoethyl)]phosphite via the phosphoramidite as previously described and then oxidised using sulphur in pyridine.
- Complete deprotection of all the protecting groups was accomplished using sodium in liquid ammonia, the 2-cyanoethyl groups being removed by beta-elimination and the benzyl groups cleaved to yield a crude product.
- the proton-coupled 31 P NMR spectrum was similar to that reported for authentic D-myo-inositol-1,4,5-trisphosphate and its synthetic DL-isomer except that the resonances were shifted about 40ppm downfield as would be expected for the phosphorothioates.
- trisphosphorothioate In biological evaluation of trisphosphorothioate, using rat cerebellum membrane receptor-binding assay specific for myo-inositol-1,4,5-tris ⁇ hosphate, the trisphosphorothioate was found to have a high affinity for such receptors, indicating the potential of the sulphur analogues in studies on receptor-linked phosphoinositide metabolism. Additionally it was found to release calcium from permeablised cells as a full agonist with an EC 50 of only three times higher than the 1,4,5-trisphosphate. EXAMPLE 7
- the bisphosphite triester (0.325 mmole) was oxidised to the bisphosphorothioate ester using sulphur (200 mg) in pyridine (2 ml). The reaction mixture was filtered, the liquid evaporated and the residue dissolved in methanol [d P (MeOH) 2s, 65.85, 67.41].
- optical configuration of these products is determined by the optical configuration of the starting materials. If the precursors of the products are optically resolved, the resolution will be reflected in the configuration of the product.
- reaction mixture was then treated with tetrazole (0.014 gram, 200 micromole) and 2-cyanoethanol (0.014 gram, 200 micromole). After a further hour at ambient temperature the resulting phosphite triester was oxidised with sulphur (0.5 gram) in pyridine (2 ml) at room temperature for 16 hours.
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Abstract
De nouvelles phosphorothioates d'inositol ont la formule générale (I) C6H6(OH)n[(OPO2S)2-]m[(OPO2O)2-]6-m-n dans laquelle n représente zéro ou un nombre entier allant de 1 à 5 et, m représente un nombre entier allant de 1 à 6. Elles peuvent être préparées selon un procédé consistant à faire réagir un dérivé d'inositol ayant la formule générale II C6H6(OB)n[OP(OCH2CH2CN)2]6-n, dans laquelle n représente zéro ou un nombre entier allant de 1 à 5 et B représente un groupe protecteur d'hydroxyle, avec une solution de soufre élémentaire, qui peut être radioactive ou non, dans un solvant prévu à cet effet, et à éliminer les groupes protecteurs d'hydroxyle du produit de la réaction. Des esters de phosphates peuvent être préparés par oxydation du composé de formule II avec un peroxyde organique.New inositol phosphorothioates have the general formula (I) C6H6 (OH) n [(OPO2S) 2-] m [(OPO2O) 2-] 6-min in which n represents zero or an integer ranging from 1 to 5 and, m represents an integer ranging from 1 to 6. They can be prepared according to a process consisting in reacting an inositol derivative having the general formula II C6H6 (OB) n [OP (OCH2CH2CN) 2] 6-n, in which n represents zero or an integer ranging from 1 to 5 and B represents a hydroxyl protecting group, with an elemental sulfur solution, which may or may not be radioactive, in a solvent provided for this purpose, and to eliminate the hydroxyl protecting groups of the reaction product. Phosphate esters can be prepared by oxidation of the compound of formula II with an organic peroxide.
Description
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GB8705811 | 1987-03-11 | ||
GB878705811A GB8705811D0 (en) | 1987-03-11 | 1987-03-11 | Inositol derivatives |
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EP (1) | EP0354904A1 (en) |
JP (1) | JPH02502535A (en) |
CA (1) | CA1309415C (en) |
GB (1) | GB8705811D0 (en) |
WO (1) | WO1988007047A1 (en) |
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EP0579957A1 (en) * | 1987-07-02 | 1994-01-26 | 3i RESEARCH EXPLOITATION LIMITED | Preparation of isomers of myoinositol derivatives |
RU2465893C2 (en) * | 2006-08-02 | 2012-11-10 | Йоханнес Гутенберг-Университет Майнц | Anti-poisoning medication |
US20120258936A1 (en) * | 2011-04-06 | 2012-10-11 | The Board Of Regents Of The University Of Texas System | Inositol hexakisphosphate analogs and uses thereof |
CA2849426C (en) * | 2011-09-29 | 2020-03-24 | Eth Zurich | Pharmaceutical compounds for use in the therapy of clostridium difficile infection |
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SE465951B (en) * | 1984-10-23 | 1991-11-25 | Perstorp Ab | ISOMER OF INOSITOL TRIPHOSPHATE PHARMACEUTICAL STATEMENTS FOR SALT FOR USE AS THERAPEUTIC OR PROPHYLACTIC AGENTS AND COMPOSITIONS THEREOF |
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1987
- 1987-03-11 GB GB878705811A patent/GB8705811D0/en active Pending
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1988
- 1988-03-10 JP JP63502236A patent/JPH02502535A/en active Pending
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CA1309415C (en) | 1992-10-27 |
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