EP2173709A2 - Verfahren und zwischenprodukte zur synthese selektiver dpp-iv-inhibitoren - Google Patents
Verfahren und zwischenprodukte zur synthese selektiver dpp-iv-inhibitorenInfo
- Publication number
- EP2173709A2 EP2173709A2 EP08743692A EP08743692A EP2173709A2 EP 2173709 A2 EP2173709 A2 EP 2173709A2 EP 08743692 A EP08743692 A EP 08743692A EP 08743692 A EP08743692 A EP 08743692A EP 2173709 A2 EP2173709 A2 EP 2173709A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- compound
- formula
- cbz
- salt
- crystalline form
- 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- Withdrawn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
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- MOILFCKRQFQVFS-VUMZSGCYSA-N (3r,4s)-4,6,6-trimethylbicyclo[3.1.1]heptane-3,4-diol Chemical compound C1C2C(C)(C)C1C[C@@H](O)[C@]2(O)C MOILFCKRQFQVFS-VUMZSGCYSA-N 0.000 description 1
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical class CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- UTQNKKSJPHTPBS-UHFFFAOYSA-N 2,2,2-trichloroethanone Chemical group ClC(Cl)(Cl)[C]=O UTQNKKSJPHTPBS-UHFFFAOYSA-N 0.000 description 1
- RKHAWKWXFLWSTL-UHFFFAOYSA-N 3-oxo-3-phenylmethoxy-2-phenylmethoxycarbonyl-2-(pyrrolidin-3-ylamino)propanoic acid Chemical compound C(=O)(OCC1=CC=CC=C1)C(NC1CNCC1)(C(=O)O)C(=O)OCC1=CC=CC=C1 RKHAWKWXFLWSTL-UHFFFAOYSA-N 0.000 description 1
- 125000002672 4-bromobenzoyl group Chemical group BrC1=CC=C(C(=O)*)C=C1 0.000 description 1
- 125000000242 4-chlorobenzoyl group Chemical group ClC1=CC=C(C(=O)*)C=C1 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-OUBTZVSYSA-N Carbon-13 Chemical compound [13C] OKTJSMMVPCPJKN-OUBTZVSYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 102100036969 Dipeptidyl peptidase 9 Human genes 0.000 description 1
- 101710087005 Dipeptidyl peptidase 9 Proteins 0.000 description 1
- 102000003779 Dipeptidyl-peptidases and tripeptidyl-peptidases Human genes 0.000 description 1
- 108090000194 Dipeptidyl-peptidases and tripeptidyl-peptidases Proteins 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 1
- VTLYFUHAOXGGBS-UHFFFAOYSA-N Fe3+ Chemical compound [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 description 1
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical group NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 1
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- OKIZCWYLBDKLSU-UHFFFAOYSA-M N,N,N-Trimethylmethanaminium chloride Chemical compound [Cl-].C[N+](C)(C)C OKIZCWYLBDKLSU-UHFFFAOYSA-M 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical group ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- 150000001204 N-oxides Chemical group 0.000 description 1
- 208000028389 Nerve injury Diseases 0.000 description 1
- FFJQEBWLOFIREW-UHFFFAOYSA-N OBO.OBO Chemical group OBO.OBO FFJQEBWLOFIREW-UHFFFAOYSA-N 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 206010057430 Retinal injury Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 description 1
- JFRKIFOHHPKORS-UHFFFAOYSA-N [C].N1CCCC1 Chemical group [C].N1CCCC1 JFRKIFOHHPKORS-UHFFFAOYSA-N 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000005076 adamantyloxycarbonyl group Chemical group C12(CC3CC(CC(C1)C3)C2)OC(=O)* 0.000 description 1
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 description 1
- 229910001413 alkali metal ion Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 150000001409 amidines Chemical class 0.000 description 1
- 125000006242 amine protecting group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 150000003974 aralkylamines Chemical class 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 125000003828 azulenyl group Chemical group 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 125000002529 biphenylenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C12)* 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 125000005620 boronic acid group Chemical group 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 125000002676 chrysenyl group Chemical group C1(=CC=CC=2C3=CC=C4C=CC=CC4=C3C=CC12)* 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 125000005265 dialkylamine group Chemical group 0.000 description 1
- 125000005266 diarylamine group Chemical group 0.000 description 1
- YLELLFWQFUPLCO-UHFFFAOYSA-N dicyclohexylazanium;2-[phenylmethoxycarbonyl-(1-phenylmethoxycarbonylpyrrolidin-2-yl)amino]acetate Chemical compound C1CCCCC1[NH2+]C1CCCCC1.C=1C=CC=CC=1COC(=O)N(CC(=O)[O-])C1CCCN1C(=O)OCC1=CC=CC=C1 YLELLFWQFUPLCO-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229910001447 ferric ion Inorganic materials 0.000 description 1
- 229910001448 ferrous ion Inorganic materials 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000009969 flowable effect Effects 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 150000002357 guanidines Chemical class 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000002192 heptalenyl group Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 1
- 150000007857 hydrazones Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- DCPMPXBYPZGNDC-UHFFFAOYSA-N hydron;methanediimine;chloride Chemical compound Cl.N=C=N DCPMPXBYPZGNDC-UHFFFAOYSA-N 0.000 description 1
- 150000002443 hydroxylamines Chemical group 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 125000003427 indacenyl group Chemical group 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 150000008040 ionic compounds Chemical class 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 150000002773 monoterpene derivatives Chemical class 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000008764 nerve damage Effects 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000003232 p-nitrobenzoyl group Chemical group [N+](=O)([O-])C1=CC=C(C(=O)*)C=C1 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 230000003132 peptidolytic effect Effects 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- 125000006678 phenoxycarbonyl group Chemical group 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- XOJVVFBFDXDTEG-UHFFFAOYSA-N pristane Chemical compound CC(C)CCCC(C)CCCC(C)CCCC(C)C XOJVVFBFDXDTEG-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 125000001725 pyrenyl group Chemical group 0.000 description 1
- WGBPCMYISDZTQA-UHFFFAOYSA-N pyrrolidin-1-ylboronic acid Chemical compound OB(O)N1CCCC1 WGBPCMYISDZTQA-UHFFFAOYSA-N 0.000 description 1
- VEBQYHFHXCAREJ-UHFFFAOYSA-N pyrrolidin-2-ylboronic acid Chemical compound OB(O)C1CCCN1 VEBQYHFHXCAREJ-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000029964 regulation of glucose metabolic process Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- IGLNJRXAVVLDKE-UHFFFAOYSA-N rubidium atom Chemical compound [Rb] IGLNJRXAVVLDKE-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000010956 selective crystallization Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- YJMLRPJMPXRDTD-UHFFFAOYSA-M sodium 3-oxo-3-phenylmethoxy-2-phenylmethoxycarbonyl-2-(pyrrolidin-3-ylamino)propanoate Chemical compound [Na+].C(=O)(OCC1=CC=CC=C1)C(NC1CNCC1)(C(=O)[O-])C(=O)OCC1=CC=CC=C1 YJMLRPJMPXRDTD-UHFFFAOYSA-M 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 description 1
- 229910001427 strontium ion Inorganic materials 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000000565 sulfonamide group Chemical group 0.000 description 1
- 125000001174 sulfone group Chemical group 0.000 description 1
- 125000003375 sulfoxide group Chemical group 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000001935 tetracenyl group Chemical group C1(=CC=CC2=CC3=CC4=CC=CC=C4C=C3C=C12)* 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000000101 thioether group Chemical group 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- 229910001428 transition metal ion Inorganic materials 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 125000005259 triarylamine group Chemical group 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- SZYJELPVAFJOGJ-UHFFFAOYSA-N trimethylamine hydrochloride Chemical compound Cl.CN(C)C SZYJELPVAFJOGJ-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003960 triphenylenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C3=CC=CC=C3C12)* 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 150000003673 urethanes Chemical class 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
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- 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
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/14—Nitrogen atoms not forming part of a nitro radical
Definitions
- the enzyme dipeptidyl peptidase IV is a member of the dipeptidyl peptidase family, which cleaves N-terminal dipeptide residues from proteins, particularly where the dipeptide includes an N-terminal penultimate proline or alanine residue.
- DPP-IV is believed to be involved in glucose control, as its peptidolytic action inactivates the insulotropic peptides glucagon-like peptide I (GLP-I) and gastric inhibitory protein (GIP).
- GLP-I glucagon-like peptide I
- GIP gastric inhibitory protein
- Inhibition of DPP-IV such as with synthetic inhibitors in vivo, can serve to increase plasma concentrations of GLP-I and GIP, and thus improve glucose control. Such synthetic inhibitors would therefore be useful in the treatment of Diabetes Mellitus and related conditions.
- DPP-VII DPP-VIII
- DPP-IX DPP-IX
- FAP fibroblast activation protein
- R a and R b are OH thereby providing a boronic acid, or its salt or a protected form, is disclosed.
- the compounds are referred to as pyrrolidin-3-yl- glycyl-boro-proline and derivatives, or more generally, pyrrolidin-3- ylglycylaminoalkylboronates.
- U.S. Pat. No. 7,317,109, issued Jan. 8, 2008 claims a compound of this structure and further claims the use of the compound for selectively inhibiting DPP-IV, for example in a mammal with a malcondition that can be regulated or normalized by inhibition of DPP-IV, such as diabetes or other errors of glucose metabolism.
- boro-proline derivative an analog of proline wherein the carboxylic acid moiety of the aminoacid has been replaced by a boronic acid moiety or a protected form thereof, such as a boronic ester.
- R a and R b are protected hydroxyl groups, which can be deprotected to yield N- (pyrrolidin-3-ylglycyl)Z>oro-proline or a salt thereof.
- the 1- carbobenzyloxypyrrolidin-S-yl-N-carbobenzyloxyglycine is therefore a key intermediate in the preparation of the selective DPP-IV inhibitor N-(pyrrolidin- 3 -ylglycyl)boro-proline.
- Embodiments of the present invention are directed to methods of synthesis of certain DPP-IV inhibitory compounds of the pyrrolidin-3-yl-glycyl- boro-proline class, and to intermediates useful in carrying out the methods of synthesis.
- An embodiment of the invention provides a method of preparation of a compound of formula (I):
- each PG is independently a nitrogen protecting group
- R a and R b are each hydroxyl or a salt thereof, or a group that can be converted to hydroxyl or a salt thereof, or R a and R b together with a boron atom to which they are attached form a cyclic structure that can be converted to B(OH) 2 or a salt thereof; comprising contacting a carboxylate salt of formula (II)
- An embodiment of the invention provides a method of preparation of a compound of formula (IV):
- each PG is independently a nitrogen protecting group
- R a and R b are each hydroxyl or a salt thereof, or a group that can be converted to hydroxyl or a salt thereof, or R a and R b together with a boron atom to which they are attached form a cyclic structure that can be converted to B(OH) 2 or a salt thereof;
- a carboxylate salt of formula (V) namely an (R)- stereoisomer of the compound of formula (II):
- An embodiment of the invention provides a method of preparation of a compound of formula (VII):
- each PG is independently a nitrogen protecting group
- R a and R b are each hydroxyl or a salt thereof, or a group that can be converted to hydroxyl or a salt thereof, or R a and R b together with a boron atom to which they are attached form a cyclic structure that can be converted to B(OH) 2 or a salt thereof; comprising contacting a carboxylate salt of formula (V):
- An embodiment of the invention provides a sodium salt of the formula (II-Cbz-Na):
- Another embodiment of the invention provides a sodium salt of formula (V-Cbz-Na):
- Another embodiment of the invention provides a crystalline form of the above-displayed compound.
- the crystalline form can be characterized, inter alia, by X-ray powder diffraction data, provided herein.
- An embodiment of the invention provides a method of preparation of a compound of formula (II-Cbz-Na) or (V-Cbz-Na), or of a crystalline form thereof, the method including recovery from an organic extract of an aqueous saponification reaction mixture, the aqueous saponification mixture having previously been adjusted to a pH of about 5.5-7.5.
- the aqueous saponification mixture can be the reaction product of the sodium hydroxide mediated saponification of the corresponding ester, such as a methyl ester.
- Another embodiment of the invention provides a dicyclohexylammonium salt of the formula (II-Cbz-DCHA):
- the invention provides a dicyclohexylammonium salt of the formula (V-Cbz-DCHA):
- Another embodiment provides a crystalline form of the above-displayed formula, that can be characterized, inter alia, by X-ray powder diffraction data, provided herein.
- Various embodiments provide methods of preparation of compounds (II- Cbz-DCHA) and (V-Cbz-DCHA).
- the invention provides a method of preparation of the dicyclohexylammonium salt, comprising contacting a carboxylic acid of the formula:
- the (R)-stereoisomer of the above-displayed carboxylic acid can be contacted with dicyclohexylamine in an organic solvent to provide the (R)-stereoisomer of the dicyclohexylammonium salt.
- methods are provided for use of the sodium salt or of the dicyclohexylammonium salt of the racemate or of respective (R)- stereoisomer enriched forms in carrying out a coupling reaction with a protected boro-proline derivative of the formula (X):
- the compounds of formulas (XV) and (XVI) can be isolated as salts thereof.
- the compounds can be isolated and purified as their citrate or tartrate salts, or more specifically, as their L-tartrate salts.
- the compound of formula (XVI-T), the L-tartrate salt of the compound of formula (XVI) possesses particularly favorable properties, as it is a stable salt that can readily be purified, stored, dispensed, formulated and orally ingested by a patient in need thereof.
- Compound (XVI-T) is a potent and selective inhibitor of DPP-IV. These salt forms can be administered to patients in the treatment of errors of glucose metabolism, such as diabetes.
- An embodiment of the invention is directed to a crystalline form of compound (XIV):
- Compound (XIV) is the stereochemically defined isomer 2(R)-l- ⁇ 2- [(3R)-pyrrolidinylamino]-acetyl ⁇ -pyrrolidine-2-boronic acid (IS, 2S, 3R,5S)- pinanediol ester.
- An embodiment of the inventive crystalline form includes THF solvent. It is believe that this embodiment of a crystalline form is a crystalline THF solvate of the compound of formula (XIV).
- the crystalline form is characterized by spectral data such as X-ray powder diffraction, nuclear magnetic resonance (NMR), infrared absorption spectroscopy (IR), and differential scanning calorimetry (DSC), as are provided herein.
- An embodiment of the invention concerns a method of preparing the inventive crystalline form of compound (XIV) by crystallization from a solvent, such as tetrahydrofuran.
- a solvent such as tetrahydrofuran.
- a sample of material such as a crude reaction product from a hydrogenolytic removal of Cbz nitrogen protecting groups, can be dissolved in warm THF, the volume reduced under vacuum, and the solution cooled to provide the crystalline material. The material can be further dried.
- Another embodiment of the invention provides a method whereby the crystalline material can be used in the synthesis of a DPP-IV inhibitory material compound (XVI), (2(R)- 1 - ⁇ [(3R)-pyrrolidinylamino]-acetyl ⁇ -pyrrolidine-2- boronic acid):
- Figure 1 is a differential scanning calorimetry (DSC) trace of a crystalline form of the sodium salt of (l-carbobenzyloxypyrrolidin-3-yl)-N- carbobenzyloxyglycine according to the invention.
- DSC differential scanning calorimetry
- Figure 2 is an X-ray powder diffraction pattern of the sodium salt of Figure 1.
- Figure 3 is a solution proton NMR spectrum of the sodium salt of Figure 1.
- Figure 4 is a DSC trace of a crystalline form of the dicyclohexylammonium salt of (l-carbobenzyloxypyrrolidin-3-yl)-N- carbobenzyloxyglycine according to the invention.
- Figure 5 is an X-ray powder diffraction pattern of the dicyclohexylammonium salt of Figure 4.
- Figure 6 is a solution proton NMR spectrum of the dicyclohexylammonium salt of Figure 4.
- Figure 7 is a solution 13 C NMR spectrum of the dicyclohexylammonium salt of Figure 4.
- Figure 8 shows a proton nuclear magnetic resonance (NMR) spectrum of a CDCl 3 solution of the crystalline form of compound (XIV).
- Figure 9 shows an infrared absorption (IR) spectrum of the crystalline form of Figure 8.
- Figure 10 shows a Differential Scanning Calorimetry (DSC) trace of the crystalline form of Figure 8.
- Figure 11 shows an X-ray powder diffraction pattern of the crystalline form of Figure 8.
- treatment is defined as the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes administering a compound of the present invention to prevent the onset of the symptoms or complications, or alleviating the symptoms or complications, or eliminating the disease, condition, or disorder, in the present application referring to a disease, condition, or disorder that can be mediated by selective inhibition of the enzyme DPP-IV, or can be mediated by any other biochemical attribute of an embodiment of a compound of the invention.
- Treating within the context of the instant invention means an alleviation of symptoms associated with a disorder or disease, or inhibition of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder.
- treating a disorder or error of glucose metabolism includes the control, alleviation or prevention of symptoms of the malcondition such as diabetes.
- an "effective amount” or a “therapeutically effective amount” of a compound of the invention refers to an amount of the compound that alleviates, in whole or in part, symptoms associated with the disorder or condition, or halts or slows further progression or worsening of those symptoms, or prevents or provides prophylaxis for the disorder or condition.
- a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result by inhibition of DPP-IV activity.
- a therapeutically effective amount is also one in which any toxic or detrimental effects of compounds of the invention are outweighed by the therapeutically beneficial effects.
- a therapeutically effective amount of a DPP-IV inhibitor of the invention is an amount sufficient to provide a beneficial effect to a patient suffering from the symptoms associated with diabetes, including without limitation elevated blood glucose levels, hypoglycemia, retinal damage, renal failure, nerve damage, microvascular damage, and cardiovascular disease.
- individual isomers can be enriched to various degrees in a sample of the material; a sample of a compound can be racemic, wherein both enantiomers are present in equal amounts, or can be enriched to any degree above equality in a particular isomer.
- a sample can be about 60% enriched, or about 75% enriched, or about 90% enriched, or about 99% enriched, in a particular stereoisomer.
- chiral or “chiral center” is meant an asymmetric center, usually at a carbon atom, or a molecule containing such an asymmetric center, as is well known in the art.
- stereoisomer refers to a molecule that possesses a chiral center, wherein a single configuration at each chiral center is present. When there is only a single chiral center, a pure stereoisomer is referred to as an "enantiomer.” More than a single chiral center results in the possibility of "diastereomers” being present, which can exist as dl pairs or can be a meso form, as is well known in the art.
- a “racemate” or “racemic mixture” contains, in the event of a single chiral center being present, both stereoisomers in equal amounts; in the event of multiple chiral centers each enantiomeric pair of a given diastereomer will be present in equal amounts, although the relative amounts of different diastereomers may differ.
- “Stereochemically pure” and “stereochemically enriched” respectively refer to situations where a single stereoisomer of a molecule is present in a sample, or where there is a predominance of one stereoisomer over another in the sample.
- one enantiomer can predominate over another on a percentage basis; for example a stereochemically enriched sample can be 80% of one enantiomer and 20% of the other, or 90% of one enantiomer and 10% of the other, and so forth.
- Stereochemical purity is a relative term in that even a sample of 99% stereochemical purity still contains 1% of another isomeric form.
- boro-proline is meant an analog of the amino acid proline wherein the carboxylate group is replaced by a boronic acid (boronate) group.
- boronate boronic acid
- the terms encompasses all positional isomers and stereoisomers of the structure of pyrrolidine boronic acid, also including substituted derivatives.
- a “boronic acid” or a “boronate” as the term is used herein refers, respectively, to compounds of the formula RB(OH) 2 or a salt thereof, wherein R is a group bonded to the boron atom via a carbon atom.
- a “boronate” may also refer to a boronate ester, wherein one or both of the OH groups is substituted with a carbon group, for example a methyl group. Therefore, compounds of formula RB(OR') 2 , wherein R' is a group bonded to an oxygen atom via a carbon atom, are also boronates within the meaning herein; these can also be termed "boronate esters".
- a "cyclic boronate diester” is a compound of formula RB(OR') 2 wherein the two R' groups are covalently bonded to each other.
- an ethylene glycol diester of a boronic acid is a cyclic boronate diester within the meaning herein.
- the term "coupling reaction” refers to the formation of an amide bond between the carboxylate salt and the boro-proline derivative, as shown herein.
- amino protecting group or "N-protected” as used herein refers to those groups intended to protect an amino group against undesirable reactions during synthetic procedures and which can later be removed to reveal the amine. Commonly used amino protecting groups are disclosed in Protective Groups in Organic Synthesis, Greene, T.W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999).
- Amino protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2- bromoacetyl, trifluoroacetyl, trichloroacetyl, o-nitrophenoxyacetyl, ⁇ - chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; alkoxy- or aryloxy-carbonyl groups (which form urethanes with the protected amine) such as benzyloxycarbonyl (Cbz), p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbony
- Amine protecting groups also include cyclic amino protecting groups such as phthaloyl and dithiosuccinimidyl, which incorporate the amino nitrogen into a heterocycle.
- amino protecting groups include formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, Alloc, Teoc, benzyl, Fmoc, Boc and Cbz. It is well within the skill of the ordinary artisan to select and use the appropriate amino protecting group for the synthetic task at hand.
- substituted refers to an organic group as defined herein in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to a non-hydrogen atom such as, but not limited to, a halogen (i.e., F, Cl, Br, and I); an oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, aralkyloxy groups; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups such as amines, hydroxylamines, N-oxides, hydrazides, azides, and enamines; and other heteroatoms in various other groups.
- a halogen i.e., F, Cl, Br, and I
- an oxygen atom in groups such as hydroxyl groups, alkoxy groups,
- Substituted alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl groups as well as other substituted groups also include groups in which one or more bonds to a hydrogen atom are replaced by one or more bonds, including double or triple bonds, to a carbon atom, or to a heteroatom such as, but not limited to, oxygen in carbonyl (oxo), carboxyl, ester, amide, imide, urethane, and urea groups; and nitrogen in imines, hydroxyimines, oximes, hydrazones, amidines, guanidines, and nitriles.
- Alkyl groups include straight chain and branched alkyl groups and cycloalkyl groups having from 1 to about 20 carbon atoms, and typically from 1 to 12 carbons or, in some embodiments, from 1 to 8 carbon atoms.
- straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups.
- branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups.
- Representative substituted alkyl groups may be substituted one or more times with any of the groups listed above, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.
- Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms.
- aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups.
- aryl groups contain 6-14 carbons in the ring portions of the groups.
- Aryl groups can be unsubstitued, or can be substituted as discussed above.
- Representative substituted aryl groups may be mono- substituted or substituted more than once, such as, but not limited to, 2-, 3-, A-, 5-, or 6-substituted phenyl or 2-8 substituted naphthyl groups, which may be substituted with carbon or non-carbon groups such as those listed above.
- alkoxy refers to an oxygen atom connected to an alkyl group as defined above.
- linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like.
- branched alkoxy include but are not limited to isopropoxy, sec- butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like.
- cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
- aryloxy and arylalkoxy refer to, respectively, an aryl group bonded to an oxygen atom and an aralkyl group bonded to the oxygen atom at the alkyl. Examples include but are not limited to phenoxy, naphthyloxy, and benzyloxy.
- amine includes primary, secondary, and tertiary amines having, e.g., the formula N(group) 3 wherein each group can independently be H or non-H, such as alkyl, aryl, and the like.
- Amines include but are not limited to R-NH 2 , alkylamines, arylamines, alkylarylamines, R 2 NH wherein each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, heterocyclylamines and the like, and R3N wherein each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, and the like.
- amino group is a substituent of the form -NH 2 , - NHR, -NR 2 , -NR 3 + , wherein each R is independently selected, and protonated forms of each.
- amine also includes ammonium ions as used herein.
- ammonium ion includes the unsubstituted ammonium ion NH 4 + , but unless otherwise specified, it also includes any protonated or quaternarized forms of amines. Thus, trimethylammonium hydrochloride and tetramethylammonium chloride are both ammonium ions within the meaning herein.
- amide includes C- and N-amide groups, i.e., -C(O)NR 2 , and -NRC(O)R groups, respectively.
- Amide groups therefore include but are not limited to carbamoyl groups (-C(O)NH 2 ) and formamide groups (-NHC(O)H).
- a “cation” as the term is used herein with respect to the carboxylate salts used in the inventive method refers to a positively charged ionic molecular entity such as a metal ion or an ammonium ion.
- Cationic metal ions include alkali metal ions such as lithium, sodium, potassium and rubidium, alkali earth metal ions such as magnesium, calcium, and strontium, and transition metal ions such as ferrous or ferric ion, zinc ion, and the like.
- Cationic ammonium ions include ammonium ions as defined above, unsubstituted or substituted, including cationic (protonated or quaternarized) forms of amines, such as dicyclohexylammonium ion.
- N-acylated boro-proline compounds known to be biologically active as selective inhibitors of the enzyme dipeptidyl peptidase IV (DPP-IV), an enzyme important in regulation of glucose metabolism.
- DPP-IV dipeptidyl peptidase IV
- synthetic intermediates useful in carrying out the inventive methods are provided.
- An embodiment of the invention provides a method of preparation of a compound of formula (I):
- each PG is independently a nitrogen protecting group
- R a and R b are each hydroxyl or a salt thereof, or a group that can be converted to hydroxyl or a salt thereof, or R a and R b together with a boron atom to which they are attached form a cyclic structure that can be converted to B(OH) 2 or a salt thereof; comprising contacting a carboxylate salt of formula (II)
- a compound of formula (II) is a salt of a carboxylic acid, the carboxylic acid being a doubly N-protected form of pyrrolidin-3-yl-glycine, also known as 3-(carboxymethylamino)-pyrrolidine or 3-(N-glycyl)pyrrolidine.
- the N-protecting groups can be any suitable groups that are stable to reaction conditions used in the coupling of the carboxylate salt with the boro-proline derivative of formula (III) or a salt thereof.
- PG can be a benzyloxycarbonyl group, also known as a carbobenzoxy (Cbz) group, or PG can be a t-butoxycarbonyl (tBoc) group, or an allyloxycarbonyl (alloc) group, or any of the many suitable N-protecting groups known in the art.
- the protecting group is stable to the coupling reaction conditions, but can be removed under conditions that do not destroy the coupled product of formula (I):
- the two PG groups need not be the same, although they can have the same identity.
- the coupling reaction can be carried out using a boronate-protected boro- proline derivative, wherein R a and R b are suitably blocked hydroxyl groups.
- R a and R b can each be an alkoxy group, such as methoxy.
- R a and R b together with the boron atom to which they are attached, can form a cyclic group that can ultimately be hydrolyzed to a boronic acid or a salt thereof.
- R a and R b together with the boron atom can include a cyclic boronate diester, such as an ethylene glycol cyclic boronate diester, or a propylene glycol cyclic boronate diester.
- R a and R together with the boron atom can include a monoterpene diol cyclic boronate diester, such as a pinanediol cyclic boronate diester.
- a monoterpene diol can be a chiral form, that is, a monoterpene with at least one chiral center wherein a stereoisomerically pure form is used. This offers the advantage of allowing purification of a preferred chiral form at the pyrrolidine carbon bearing the boron atom (the ⁇ -carbon) by selective crystallization of the desired diastereomeric diester.
- the pinanediol cyclic diester can be a cyclic diester of (1 S, 2S, 3R, 5S)-pinanediol (also known as (+)-pinanediol).
- a stereochemically enriched boro-proline compound of formula (III) can be used in the coupling reaction, for example a protected boro-proline of formula (IX) or a salt thereof
- the coupling reaction can use a carboxylate salt of formula (II)
- the coupling reaction can be carried out between either of a stereochemically unspecified compound of formula (II) or a stereochemically specified compound of formula (V), and a stereochemically unspecified boro- proline derivative of formula (III) or a salt thereof or a stereochemically specified boro-proline derivative of formula (IX) or a salt thereof.
- the reaction product can be the stereochemically undefined product of formula
- the compound of formula (VII) in particular is useful as a direct precursor to a stereochemically defined known inhibitor of DPP-IV, a compound of formula (XVI)
- the pharmaceutically acceptable salt can be a citrate salt, or can be a tartrate salt, such as an L-tartrate salt, as is disclosed by the inventors herein in pending PCT application Ser. No. PCT/US2007/018629.
- the boro-proline reactant of formula (III) or its (R)-enantiomer of formula (IX) can be present in the coupling reaction as a free base, or can be introduced in salt form, for example, as a compound of formula (X), wherein R a , R b , and the boron atom to which they are bonded are the cyclic (+)-pinanediol boronate diester and Y is a suitable counterion:
- a suitable counterion is an anion that is stable and unreactive under the reaction conditions and does not bring about decomposition of reagents used in the coupling reaction.
- a halide, such as chloride, is a non-limiting example of a suitable counterion for the boro-proline ammonium ion as shown for use in the coupling reaction.
- the coupling reaction is carried out under conditions suitable for formation of an amide bond.
- the coupling reaction can be carried out in the presence of a carboxyl activating reagent, for example a hydroxylic compound that can form an activated ester with a carboxyl group.
- the carboxyl activating reagent can be an N-hydroxy compound.
- a specific example is N-hydroxybenztriazole.
- Another example is N- hydroxysuccinimide.
- the coupling reaction can be carried out in the presence of a dehydrating reagent.
- the coupling of the carboxyl group and the amino group yields water as a byproduct, so the presence of a dehydrating reagent can be used to drive the reaction to completion.
- a dehydrating reagent can also serve to bring about the formation of an activated ester from the carboxyl group and the hydroxylic compound used in formation of the activated ester described above.
- An example of a dehydrating reagent is a carbodiimide.
- a specific example is EDAC, N- ethyl-TV-p -(dimethylamino)propyl)carbodiimide hydrochloride.
- a carbodiimide can also serve as a carboxyl activating reagent through formation of an O- acylisourea compound.
- the coupling reaction can be carried out in the presence of a base, such as an organic base.
- a base such as an organic base.
- An example is N-methylmorpholine.
- a base can serve to scavenge a proton from a boro-proline salt.
- Suitable solvents for the coupling reaction include non-hydroxylic and non-amino organic solvents such as dichloromethane or N,N- dimethylformamide .
- the reaction can be carried out at any suitable temperature, for example, at about O 0 C to about 5°C, for example in dichloromethane; or at about 15°C to about 25 0 C, for example in dimethylformamide.
- the reaction can take several hours at these temperatures to reach completion.
- the progress of a reaction can be monitored using techniques well known in the art, such as high pressure liquid chromatography (HPLC).
- HPLC high pressure liquid chromatography
- the carboxylate salt of formula (II) or (V) includes a counterion M + .
- the cation M + can be either a metal ion or a substituted or unsubstituted ammonium ion.
- M + can be a sodium ion.
- M + can be an alkyl-substituted ammonium ion, for example, a dicyclohexylammonium ion.
- the compound or set of compounds, such as are used in the inventive methods can be any one of any of the combinations and/or sub-combinations of the above-listed embodiments.
- the present invention provides a compound of formula (II- Cbz-Na) wherein M + is a sodium ion and both BP groups are Cbz:
- the sodium content supports the structure being a sodium salt, not a free carboxylic acid, although minor amounts, up to about 20% in some examples, of the free carboxylic acid may be present when the sodium salt is prepared by an inventive method.
- An NMR spectrum is also consistent with the proposed structure.
- the crystalline form isolated is found to be highly water-soluble, consistent with the sodium salt structure.
- the compound of formula (II-Cbz-Na) can have an (R)-configuation at the chiral carbon atom, where the 3-amino group is bonded to the pyrrolidine ring. Accordingly, the present invention further provides the (R)-stereoisomer, a compound of formula (V-Cbz-Na), wherein both PG groups are Cbz, and M + is a sodium ion:
- the invention further provides a crystalline form of the compound of formula (V-Cbz-Na), wherein the crystalline form is readily recovered by extraction at a pH of about 5.5-6.5 with an organic solvent from an alkaline hydrolysis reaction mixture of a corresponding ester, which can be a methyl ester.
- the crystalline form which typically can be recovered in a yield of at least about 70% and a purity of at least about 90%, has been characterized by DSC (see Figure 1) and X-ray powder diffraction (XPD) (see Figure 2), as well as by solution proton NMR spectroscopy (Figure 3).
- the DSC trace shows a sharp endotherm peaking at about 178°C, the melting point of the material.
- the XPD pattern includes maxima at 2 ⁇ values selected maxima having approximate values of 9.57, 11.25, 14.37, 16.34, 16.72, 16.96, 17.34, 18.38, 18.61, 18.97, 19.29, 19.51, 20.34, 21.07, 21.24, 21.81, 22.54, 23.11, 23.45, 24.41, 25.33, 25.82, 27.10, 28.02, and 29.97 degrees.
- the crystalline form can contain minor quantities of the free carboxylic acid, for example about 5-10%, or up to about 20% of the free carboxylic acid.
- the crystalline form was unexpectedly obtained by crystallization from an organic solvent following its extraction in salt form from the saponification reaction aqueous phase that had been adjusted to a pH of about 5.5-7.5.
- the extraction of the salt form into an organic solvent at the stated pH was unexpected, as carboxylate salts typically partition into an aqueous phase, being ionic compounds.
- the crystalline form as recovered from this process was also unexpected because in other experiments the potassium, cesium, and tetramethylguanidine salts, as well as the free acid form, had all been found to be either non-crystalline waxy solids or oils, which were unsuitable for purification by recrystallization and difficult to handle on a large scale.
- the crystalline form of the sodium salt has particularly favorable properties for a synthetic intermediate, in that it can be readily purified, such as by crystallization, and the crystalline form exists as a relatively stable, flowable powder, as opposed to a wax or an oil. This is advantageous when carrying out the large-scale synthesis of the DPP-IV inhibitor.
- the crystalline form of the compound of formula (II) can have an (R)- configuation at the chiral carbon atom, where the 3 -amino group is bonded to the pyrrolidine ring.
- the crystalline form that is recovered by the inventive process is the (R)- stereoisomer, of formula (V-Cbz-Na).
- the crystalline form of the compound of formula (V-Cbz-Na) is obtained in good yield, and is readily purified.
- the crystalline form of the invention can be obtained from the reaction mixture of a sodium hydroxide mediated saponification of the methyl ester (II- Cbz-E) of the carboxylic acid:
- the pH can be readjusted to maintain a value of about 5.5-7.5 while subsequent organic extractions are carried out.
- the aqueous pH 5.5-7.5 solution is preferably extracted at least twice with the organic solvent.
- the organic, e.g., dichloromethane, solution of the sodium salt of formula (II-Cbz-Na) can be concentrated by evaporation. Then, the residue can be taken up in an ether, for example, the residue can be taken up in methyl t- butyl ether. Alternatively, diethyl ether can be used. Another solvent, for example THF or isopropanol, can be added. In any event after addition of the ether or the alcohol, the mixture is allowed to stand, whereupon crystallization occurs. The crystals that form can be recovered by filtration or other suitable technique, and are then dried.
- a yield of at least about 70% can be obtained of material of formula (II-Cbz-Na) or formula (V-Cbz-Na) of suitable purity for further elaboration to a DPP-IV inhibitor as shown below in Scheme 1.
- the sodium salt as isolated can contain up to about 20% of the free carboxylic acid, for example about 5% or about 10% by weight. This material can be used directly in the inventive coupling reaction described herein without further purification.
- the present invention provides the R- stereoisomer of the compound of formula (II-Cbz-Na), i.e., a compound of formula (V-Cbz-Na) wherein M + is sodium ion and both PG groups are Cbz:
- (V-Cbz-Na) and a method to prepare the (R)-stereoisomer The overall synthesis of the compound can be carried out by coupling of the appropriate stereoisomer of an N(l)-Cbz derivative of 3-aminopyrrolidine with a carboxymethylation reagent such as methyl bromoacetate, then, coupling of a Cbz group to the exocyclic nitrogen such as by use of benzyl chloroformate, followed by ester saponification and crystallization as previously described.
- Another embodiment of the present invention provides a compound of formula (II-Cbz-DCHA) wherein both PG groups are Cbz and M + is dicyclohexylammonium (DCHA) ion:
- V-Cbz-DCHA which can readily be isolated in stable, crystalline form.
- DSC differential scanning calorimetry
- XPD X-ray powder diffraction
- the DSC trace shows a sharp endotherm peaking at about 156 0 C, the melting point of the material.
- the XPD pattern includes maxima at 20 values selected maxima having approximate values of 6.16, 7.47, 8.52, 10.51, 14.24, 16.79, 17.13, 17.81, 18.30, 19.03, 20.51, 20.78, 22.43, 23.69, 25.18, 27.07, and 28.11 degrees.
- the dicyclohexylamine salt can be prepared by crystallization from an organic solution of the free acid combined with dicyclohexylamine.
- the organic solution can comprise isopropyl acetate.
- the organic solution can further comprise tetrahydrofuran (THF).
- THF tetrahydrofuran
- the DCHA salt can have a minor amount of the free carboxylic acid present, typically about 5% to about 10% of the free acid being present as isolated. This material can be used in the practice of an inventive method of synthesis without further purification.
- V-Cbz-A formed with other amines, such as with triethylamine or with morpholine, were not found to have comparable stability or ease of handling and purification.
- the stable, crystalline form of compound (V-Cbz-DCHA) is especially favorable for large-scale preparation of DPP-IV inhibitors of this class, such as preparation of compound (XIV-T), due to the relative ease of purification, handling, and dispensing compound (V-Cbz-DCHA).
- a salt of formula (II) or (V) for example a sodium salt of formula (II-Cbz-Na), its (R) stereoisomer of formula (V-Cbz-Na), or a crystalline form thereof, or a DCHA salt of formula (II-Cbz-DCHA), its (R) stereoisomer of formula (V-Cbz-DCHA), or a crystalline form thereof, can be used in a method for synthesis of a DPP-IV inhibitor of formula (XVI).
- the salt, or the crystalline form of the salt can be used in a coupling reaction as shown in Scheme 1 , wherein the amino group of a protected boroproline derivative (X), or a salt thereof, can be coupled with the carboxylate salt under conditions suitable to bring about formation of an amide bond to provide a compound of formula (XII), or its stereochemically incompletely defined form of formula (XI) having both chiral forms at the pyrrolidine 3 -position.
- Embodiments of the inventive methods can use various protecting groups and counterions.
- Conditions for the coupling reaction yielding compound (XII) can include the use of a carboxyl activating reagent, that is, a reagent that can react with a carboxyl or carboxylate group to provide an activated form, such as an ester of an N-hydroxy compound.
- the carboxyl activating reagent can be N- hydroxybenztriazole.
- These coupling conditions can also include the use of a dehydrating reagent, that is, a reagent that reacts with water in an energetically favorable manner and can serve to drive a reaction that produces water as a byproduct to completion, such as an amide-forming reaction.
- the dehydrating reagent can be a carbodiimide, that can react with water to form a urea product.
- the carbodiimide can be EDAC.
- the coupling conditions can also include the presence of a base in the reaction mixture.
- a base can serve to scavenge acid produced by a coupling reaction, or to liberate an amine free base from its corresponding salt form.
- the coupling conditions can include the presence of a suitable organic solvent, for example dichloromethane or dimethylformide. A suitable solvent does not react to any great extent with any of the reagents in such a way as to interfere with the formation of the desired amide product.
- the coupling reaction can be carried out with a salt of the (+)-pinanediol-protected boro-proline cyclic diester of formula (X):
- the coupled product (XI) or its 3-(R) stereochemical ⁇ pure form (XII) can then be partially deblocked, removing the two N-Cbz groups by hydrogenolysis, and, in the case of the stereochemically pure 3-(R) enantiomer, the hydrogenolysis product (XIV) can optionally be purified by crystallization, for example from tetrahydrofuran.
- the partially deblocked compound of formula (XIV), or the compound of formula (XIII) having both chiral configurations at the pyyolidine 3 -position can be carried on synthetically by deblocking the boronate moiety to yield stereochemically defined compound (XVI), or compound (XV), respectively.
- Embodiments of the present invention are directed to a crystalline form and a method of purification of a compound of formula (XIV):
- the inventive crystalline form (XIV), named 2(R)- 1-(2-[(3R)- pyrrolidinylamino] -acetyl ⁇ -pyrrolidine-2-boronic acid (IS, 2S, 3R,5S)- pinanediol ester, can be purified by a step of recrystallization from a tetrahydrofuran (THF) solution.
- THF tetrahydrofuran
- the product obtained by recrystallization from THF can contain residual solvent even after drying under vacuum, and is believed to be a crystalline solvate of compound (XIV).
- the crystalline form is believed to be at least about 99% pure, excepting residual solvent.
- a crystalline solvate is meant a crystalline form in which solvent molecules occupy spatially defined positions in the crystalline unit cell.
- An embodiment of the invention provides the crystalline form with the spectral characteristics and physical properties as described herein.
- the proton nuclear magnetic resonance (NMR) spectrum of a CDCl 3 solution of the crystalline form of (XIV) shows the expected resonances, plus resonances attributable to the presence of residual THF.
- Figure 9 shows the infrared (IR) absorption spectrum of the crystalline form of (XIV) as obtained by recrystallization from THF. A strong carbonyl band for the amide bond around 1620 cm "1 is observed.
- Figure 10 shows a Differential Scanning Calorimetry (DSC) trace for the crystalline form. A strong, single endotherm at about 157 0 C is observed.
- Figure 11 shows an X-ray powder diffraction pattern obtained from the crystalline form. Strong scattering peaks at 2 ⁇ values of about 7, 12, 14, 16, 18, and 21° are observed.
- An embodiment of the invention provides a method of preparation of the inventive crystalline form.
- the method includes a step of crystallization of the product from tetrahydrofuran.
- exemplary procedures are given for the synthesis of the crude material and its purification by crystallization from THF, providing the inventive crystalline form of the compound.
- the boronate When the boronate is protected as a diester or a cyclic diester as in compound (XII) or its achiral form, compound (XI), the molecule can then be fully deblocked, for example, by acid catalyzed hydrolysis or transesterification.
- the boronate blocking group is a cyclic pinanediol diester, it can be removed in the presence of phenylboronic acid, as shown in Scheme 2.
- the final product can be isolated and purified as the L-tartrate salt (XIV-T).
- the fully deblocked pyrrolidin-3-ylglycyl-boro-proline (XVI), prepared according to the inventive method, can be used in treatment of a malcondition, or can be converted to a stable salt such as a citrate or tartrate salt (for example compound (XVI-T)) which is then used in treatment of the malcondition.
- a stable salt such as a citrate or tartrate salt (for example compound (XVI-T)
- An embodiment of the present invention provides a method of treatment of a malcondition in a patient, wherein the malcondition can be diabetes or a glucose metabolism disorder, or wherein inhibition of DPP-IV is medically indicated, comprising administering a compound of formula (XV) or (XVI) or salt thereof, prepared from a compound or a crystalline form of formula (II) or formula (V) respectively, or according to a method of the invention, to the patient at a dosage, at a frequency, and over a period of time sufficient to provide a beneficial effect to the patient.
- Discharge the aqueous phase (lower phase) for disposal Add a solution previously prepared by the dilution of hydrochloric acid (0.59 kg ⁇ 1% o 0.51 1 ⁇ 1%) with industrial water (1.5 1 ⁇ 5%) to the organic phase whilst maintaining the temperature between 15 0 C and 25 0 C. Stir for at least 30 minutes at a temperature between 15 0 C and 25°C. Stop stirring and allow layers to separate for at least 30 minutes. Discharge the aqueous phase (lower phase) for disposal.
- the product is isolated after the hydrolysis reaction of the corresponding methyl ester with NaOH, and washing of the organic layer with MTBE.
- the mixture is concentrated to remove the residual solvents (T ⁇ 40°C) and the pH adjusted to 5.9 with 2N HCl.
- the solution is extracted twice with CH2CI2, adjusting the pH to the same value after the first extraction.
- the organic phase is concentrated to a residue and MTBE is added.
- the mixture is refluxed for several hours to remove the water, THF is added, and the mixture is refluxed for Ih at 65°C, cooled to room temperature, stirred for Ih, the precipitate is filtered.
- the product is highly water soluble, dissolving in deionized water in a 1 : 1 weight ratio.
- the reaction mixture was stirred 4 hours at 0 to 5°C.
- the solution was then concentrated on a rotary evaporator, and the residue partitioned between 262 mL ethyl acetate and 111.4 g of 7% aqueous sodium bicarbonate solution.
- the phases were allowed to separate for 10 minutes, the organic phase washed with an additional 53.6 gm of 7% aqueous sodium bicarbonate solution, then with a solution of 7 gm citric acid in 80 mL water.
- the organic phase was separated and the solvent removed on a rotary evaporator under vacuum at less than about 35 0 C.
- the residue was then dissolved in 140 mL of methanol and transferred to a hydrogenation bottle, where 1.6 gm of 5% palladium on carbon was added. After purging six times with hydrogen, the flask was shaken under hydrogen at 28-3O 0 C overnight. The solution was then filtered through 60 gm cellulose and 34 gm sodium sulfate which were then washed with methanol. The filtrate was concentrated under vacuum at a temperature of about 20-35 0 C to a volume of about 40 mL.
- the aqueous (lower) phase was again adjusted to pH 0.7-1.3 with concentrated hydrochloric acid, if necessary, and again extracted with isopropyl acetate (7.0 L) was added, the mixture stirred 30 min at 15-25 0 C, and allowed to stand for 30 min.
- the organic (upper) phase was again separated and combined with the previous organic phase.
- the concentration (C) of the free carboxylic acid in the isopropyl acetate solution was determined by HPLC, and the total weight (W) of the solution was determined.
- the volume of the combined organic phases was adjusted with additional isopropyl acetate to 18 L, then tetrahydrofuran (1.0 L) and dicyclohexylamine (0.615 x C x W kg) were added with stirring.
- ethyl acetate (7.0 L) and deionized water (10.0 L) were added to the reaction mixture, maintaining the reaction temperature at 15-25°C.
- the mixture was stirred for 20 min, the phases allowed to separate, and the aqueous (lower) layer drawn off and discarded.
- An additional 10.0 L of deionized water was added and the extraction repeated.
- a previously prepared solution of sodium bicarbonate (0.37 kg) in deionized water (5.2 L) was added and the mixture stirred at 15-25 0 C, the phases allowed to separate, and the aqueous (lower) phase drawn off and discarded.
- the concentrated solution from the previous reaction was diluted with methanol (7.0 L) at a temperature of 15-25 0 C, then palladium on carbon (5% Pd, 0.04 kg) was added and the mixture stirred. Then, hydrogen gas under a pressure of about 3 to about 9 bar (about 45 to about 135 psi) was introduced and the mixture stirred until the content of starting material was less than 0.4% (GC analysis).
- the reaction mixture was filtered through a bed of cellulose (10.0 kg) and anhydrous sodium sulfate (0.4-1.7 kg) supported on a 0.45 micron filter, then the filter bed rinsed with methanol (1.3 L).
- the methanol solution was concentrated under vacuum at a temperature of no more than 35 0 C to a final volume of about 2.0 L.
- the organic (upper) layer was discharged, and the extraction with MTBE was repeated twice, retaining the aqueous (bottom layer) at each step.
- the aqueous solution was filtered and kept under a vacuum of -0.8 to -0.9 bar for 2 hr at 35- 50 0 C to remove solvent traces.
- the solution was transferred to freeze dryer trays or spray dryer and the water removed by freeze drying or spray drying.
- Compound (XVI) as the tartarate salt was obtained. Purity was in excess of 99% as determined by HPLC.
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Application Number | Priority Date | Filing Date | Title |
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US89384207P | 2007-03-08 | 2007-03-08 | |
US95922607P | 2007-07-12 | 2007-07-12 | |
US2348708P | 2008-01-25 | 2008-01-25 | |
US2950608P | 2008-02-18 | 2008-02-18 | |
PCT/US2008/055927 WO2008109681A2 (en) | 2007-03-08 | 2008-03-05 | Methods and intermediates for synthesis of selective dpp-iv inhibitors |
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EP2173709A2 true EP2173709A2 (de) | 2010-04-14 |
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EP08743692A Withdrawn EP2173709A2 (de) | 2007-03-08 | 2008-03-05 | Verfahren und zwischenprodukte zur synthese selektiver dpp-iv-inhibitoren |
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EP (1) | EP2173709A2 (de) |
CN (1) | CN101679238A (de) |
AR (1) | AR065666A1 (de) |
CA (1) | CA2680133A1 (de) |
MX (1) | MX2009009575A (de) |
TW (1) | TW200843784A (de) |
WO (1) | WO2008109681A2 (de) |
Families Citing this family (13)
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AU2006275697A1 (en) | 2005-08-01 | 2007-02-08 | Phenomix Corporation | Methods of preparing hetercyclic boronic acids and derivatives thereof |
CL2007002499A1 (es) * | 2006-08-30 | 2008-03-14 | Phenomix Corp | Sales citrato y tartrato de compuestos derivados de acido pirrolidinilaminoacetilpirrolidinboronico, inhibidores de dpp-iv; metodo de preparacion; forma solida; combinacion farmaceutica, util para el tratamiento de diabetes. |
UY32030A (es) | 2008-08-06 | 2010-03-26 | Boehringer Ingelheim Int | "tratamiento para diabetes en pacientes inapropiados para terapia con metformina" |
CA2735562C (en) | 2008-08-15 | 2017-10-17 | Boehringer Ingelheim International Gmbh | Dpp-4 inhibitors for wound healing |
AR074990A1 (es) | 2009-01-07 | 2011-03-02 | Boehringer Ingelheim Int | Tratamiento de diabetes en pacientes con un control glucemico inadecuado a pesar de la terapia con metformina |
AR075204A1 (es) | 2009-01-29 | 2011-03-16 | Boehringer Ingelheim Int | Inhibidores de dpp-4 y composiciones farmaceuticas que los comprenden, utiles para tratar enfermedades metabolicas en pacientes pediatricos, particularmente diabetes mellitus tipo 2 |
NZ594044A (en) | 2009-02-13 | 2014-08-29 | Boehringer Ingelheim Int | Antidiabetic medications comprising a dpp-4 inhibitor (linagliptin) optionally in combination with other antidiabetics |
JP2013512229A (ja) | 2009-11-27 | 2013-04-11 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 遺伝子型が同定された糖尿病患者のリナグリプチン等のddp−iv阻害薬による治療 |
WO2011113947A1 (en) | 2010-03-18 | 2011-09-22 | Boehringer Ingelheim International Gmbh | Combination of a gpr119 agonist and the dpp-iv inhibitor linagliptin for use in the treatment of diabetes and related conditions |
BR112012028136A2 (pt) | 2010-05-05 | 2016-08-09 | Boehringer Ingelheim Int | terapia de combinaçao |
EP3725325B1 (de) | 2010-06-24 | 2023-05-31 | Boehringer Ingelheim International GmbH | Diabetestherapie |
WO2013174767A1 (en) | 2012-05-24 | 2013-11-28 | Boehringer Ingelheim International Gmbh | A xanthine derivative as dpp -4 inhibitor for use in modifying food intake and regulating food preference |
CN111533675B (zh) * | 2019-11-29 | 2021-09-28 | 杭州华东医药集团新药研究院有限公司 | 杂环硼酸化合物的杂质及其控制方法 |
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US7317109B2 (en) * | 2003-11-12 | 2008-01-08 | Phenomix Corporation | Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV |
AU2006275697A1 (en) * | 2005-08-01 | 2007-02-08 | Phenomix Corporation | Methods of preparing hetercyclic boronic acids and derivatives thereof |
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- 2008-03-05 MX MX2009009575A patent/MX2009009575A/es not_active Application Discontinuation
- 2008-03-05 CA CA002680133A patent/CA2680133A1/en not_active Abandoned
- 2008-03-05 EP EP08743692A patent/EP2173709A2/de not_active Withdrawn
- 2008-03-05 WO PCT/US2008/055927 patent/WO2008109681A2/en active Application Filing
- 2008-03-05 CN CN200880015066A patent/CN101679238A/zh active Pending
- 2008-03-07 TW TW097108175A patent/TW200843784A/zh unknown
- 2008-03-07 AR ARP080100973A patent/AR065666A1/es not_active Application Discontinuation
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WO2008109681A2 (en) | 2008-09-12 |
TW200843784A (en) | 2008-11-16 |
AR065666A1 (es) | 2009-06-24 |
WO2008109681A3 (en) | 2008-11-13 |
CA2680133A1 (en) | 2008-09-12 |
MX2009009575A (es) | 2009-11-12 |
CN101679238A (zh) | 2010-03-24 |
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