CA2991661A1 - Solution phase synthesis and crystallization of beta-turn peptidomimetic cyclic salts - Google Patents
Solution phase synthesis and crystallization of beta-turn peptidomimetic cyclic salts Download PDFInfo
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- CA2991661A1 CA2991661A1 CA2991661A CA2991661A CA2991661A1 CA 2991661 A1 CA2991661 A1 CA 2991661A1 CA 2991661 A CA2991661 A CA 2991661A CA 2991661 A CA2991661 A CA 2991661A CA 2991661 A1 CA2991661 A1 CA 2991661A1
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- 239000000816 peptidomimetic Substances 0.000 title claims abstract description 90
- 125000004122 cyclic group Chemical group 0.000 title abstract description 14
- 230000015572 biosynthetic process Effects 0.000 title description 27
- 238000002425 crystallisation Methods 0.000 title description 24
- 230000008025 crystallization Effects 0.000 title description 23
- 238000003786 synthesis reaction Methods 0.000 title description 10
- 238000000034 method Methods 0.000 claims abstract description 119
- 150000003839 salts Chemical class 0.000 claims abstract description 101
- 150000001875 compounds Chemical class 0.000 claims abstract description 71
- 150000001413 amino acids Chemical class 0.000 claims description 57
- 150000001923 cyclic compounds Chemical class 0.000 claims description 52
- 229940024606 amino acid Drugs 0.000 claims description 46
- 235000001014 amino acid Nutrition 0.000 claims description 46
- 239000000243 solution Substances 0.000 claims description 46
- 125000006239 protecting group Chemical group 0.000 claims description 41
- 239000000203 mixture Substances 0.000 claims description 40
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 37
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 30
- -1 NR9 Inorganic materials 0.000 claims description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- 239000001257 hydrogen Substances 0.000 claims description 23
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 22
- 239000002253 acid Substances 0.000 claims description 22
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 21
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 20
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 20
- 125000003118 aryl group Chemical group 0.000 claims description 18
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 17
- 239000004472 Lysine Substances 0.000 claims description 17
- 230000008878 coupling Effects 0.000 claims description 16
- 238000010168 coupling process Methods 0.000 claims description 16
- 238000005859 coupling reaction Methods 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 15
- 235000013922 glutamic acid Nutrition 0.000 claims description 15
- 239000004220 glutamic acid Substances 0.000 claims description 15
- 230000008569 process Effects 0.000 claims description 15
- 125000001424 substituent group Chemical group 0.000 claims description 15
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 15
- 239000004475 Arginine Substances 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 14
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 14
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 13
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 claims description 13
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 13
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 claims description 12
- 239000004473 Threonine Substances 0.000 claims description 12
- 239000003637 basic solution Substances 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 claims description 11
- 230000002378 acidificating effect Effects 0.000 claims description 11
- 125000000524 functional group Chemical group 0.000 claims description 11
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims description 10
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 claims description 10
- 229960000310 isoleucine Drugs 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 9
- 150000002431 hydrogen Chemical group 0.000 claims description 9
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims description 9
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 claims description 9
- BNCJEZWKLUBUBB-QXEWZRGKSA-N 5-[(3as,4s,6ar)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]-n-(2-aminoethyl)pentanamide Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)NCCN)SC[C@@H]21 BNCJEZWKLUBUBB-QXEWZRGKSA-N 0.000 claims description 8
- 108010016626 Dipeptides Proteins 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 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 claims description 8
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 7
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 claims description 7
- 239000002585 base Substances 0.000 claims description 7
- 238000010647 peptide synthesis reaction Methods 0.000 claims description 7
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 7
- UMRUUWFGLGNQLI-QFIPXVFZSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-6-[(2-methylpropan-2-yl)oxycarbonylamino]hexanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(O)=O)C3=CC=CC=C3C2=C1 UMRUUWFGLGNQLI-QFIPXVFZSA-N 0.000 claims description 6
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 6
- 235000009582 asparagine Nutrition 0.000 claims description 6
- 229960001230 asparagine Drugs 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 5
- 125000003368 amide group Chemical group 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 239000007791 liquid phase Substances 0.000 claims description 5
- 150000007522 mineralic acids Chemical class 0.000 claims description 5
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 5
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- OTKXCALUHMPIGM-FQEVSTJZSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-5-[(2-methylpropan-2-yl)oxy]-5-oxopentanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(O)=O)C3=CC=CC=C3C2=C1 OTKXCALUHMPIGM-FQEVSTJZSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 125000002947 alkylene group Chemical group 0.000 claims description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 3
- 239000003880 polar aprotic solvent Substances 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 3
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 150000002012 dioxanes Chemical class 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 claims description 2
- 239000000347 magnesium hydroxide Substances 0.000 claims description 2
- 235000012254 magnesium hydroxide Nutrition 0.000 claims description 2
- 229910001862 magnesium hydroxide Inorganic materials 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 229910052698 phosphorus Inorganic materials 0.000 claims description 2
- 235000015320 potassium carbonate Nutrition 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 125000006413 ring segment Chemical group 0.000 claims description 2
- 229910052711 selenium Inorganic materials 0.000 claims description 2
- 150000003840 hydrochlorides Chemical group 0.000 claims 5
- OSWULUXZFOQIRU-UHFFFAOYSA-N tert-butyl 2-aminoacetate;hydrochloride Chemical compound Cl.CC(C)(C)OC(=O)CN OSWULUXZFOQIRU-UHFFFAOYSA-N 0.000 claims 2
- 239000013078 crystal Substances 0.000 description 35
- 239000002002 slurry Substances 0.000 description 25
- 238000007363 ring formation reaction Methods 0.000 description 21
- 238000004458 analytical method Methods 0.000 description 17
- 238000002411 thermogravimetry Methods 0.000 description 16
- 230000009466 transformation Effects 0.000 description 15
- 239000003929 acidic solution Substances 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 14
- 239000012467 final product Substances 0.000 description 13
- 239000012535 impurity Substances 0.000 description 13
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 8
- 108091006629 SLC13A2 Proteins 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 238000010511 deprotection reaction Methods 0.000 description 8
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 7
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 238000000113 differential scanning calorimetry Methods 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 238000001179 sorption measurement Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- PECYZEOJVXMISF-UHFFFAOYSA-N 3-aminoalanine Chemical compound [NH3+]CC(N)C([O-])=O PECYZEOJVXMISF-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- 235000008206 alpha-amino acids Nutrition 0.000 description 4
- 238000012937 correction Methods 0.000 description 4
- 230000001351 cycling effect Effects 0.000 description 4
- 108010037444 diisopropylglutathione ester Proteins 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 4
- 230000001788 irregular Effects 0.000 description 4
- 238000001000 micrograph Methods 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 239000002516 radical scavenger Substances 0.000 description 4
- 238000010189 synthetic method Methods 0.000 description 4
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000004471 Glycine Substances 0.000 description 3
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 3
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 3
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 238000013019 agitation Methods 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 3
- 235000014304 histidine Nutrition 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 3
- 238000000386 microscopy Methods 0.000 description 3
- 239000012038 nucleophile Substances 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 3
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 239000012265 solid product Substances 0.000 description 3
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 2
- UKAUYVFTDYCKQA-UHFFFAOYSA-N -2-Amino-4-hydroxybutanoic acid Natural products OC(=O)C(N)CCO UKAUYVFTDYCKQA-UHFFFAOYSA-N 0.000 description 2
- 102000001189 Cyclic Peptides Human genes 0.000 description 2
- 108010069514 Cyclic Peptides Proteins 0.000 description 2
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- C07K—PEPTIDES
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- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1021—Tetrapeptides with the first amino acid being acidic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/02—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length in solution
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/14—Extraction; Separation; Purification
- C07K1/30—Extraction; Separation; Purification by precipitation
- C07K1/306—Extraction; Separation; Purification by precipitation by crystallization
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1027—Tetrapeptides containing heteroatoms different from O, S, or N
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Analytical Chemistry (AREA)
- Crystallography & Structural Chemistry (AREA)
- Peptides Or Proteins (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201562190596P | 2015-07-09 | 2015-07-09 | |
| US62/190,596 | 2015-07-09 | ||
| PCT/EP2016/066281 WO2017005902A1 (en) | 2015-07-09 | 2016-07-08 | Solution phase synthesis and crystallization of beta-turn peptidomimetic cyclic salts |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2991661A1 true CA2991661A1 (en) | 2017-01-12 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2991661A Pending CA2991661A1 (en) | 2015-07-09 | 2016-07-08 | Solution phase synthesis and crystallization of beta-turn peptidomimetic cyclic salts |
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| EP (2) | EP3319978B1 (OSRAM) |
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| KR (1) | KR102056257B1 (OSRAM) |
| CN (2) | CN114874288A (OSRAM) |
| AU (1) | AU2016290654C1 (OSRAM) |
| CA (1) | CA2991661A1 (OSRAM) |
| TW (1) | TWI708779B (OSRAM) |
| WO (1) | WO2017005902A1 (OSRAM) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| JP6801835B2 (ja) | 2015-07-09 | 2020-12-16 | ミメトゲン ファーマシュウティカルズ インコーポレイテッドＭｉｍｅｔｏｇｅｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ， Ｉｎｃ． | β−ターンペプチド模倣環状塩の液相合成及び結晶化 |
| PL3464336T3 (pl) | 2016-06-01 | 2022-05-16 | Athira Pharma, Inc. | Związki |
| MX2020012629A (es) * | 2018-05-31 | 2021-01-29 | Sederma Sa | Metodo para sintesis de peptido en fase de solucion y estrategias protectoras de la misma. |
| US11427612B2 (en) * | 2018-08-21 | 2022-08-30 | Wayne State University | Epimerization-free N to C solid-phase peptide synthesis |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AUPP254898A0 (en) * | 1998-03-24 | 1998-04-23 | University Of Queensland, The | Peptide turn mimetics |
| WO2001052843A1 (en) | 2000-01-18 | 2001-07-26 | Mcgill University | β-TURN PEPTIDOMIMETIC CYCLIC COMPOUNDS |
| BR0311558A (pt) * | 2002-06-11 | 2007-04-27 | Lilly Co Eli | composto ou sal farmaceuticamente aceitável do mesmo, processo para preparar o mesmo, métodos para afetar os receptores de glutamato metabotrópicos ligados a camp, para administrar uma quantidade eficaz de um composto e para tratar um distúrbio neurológico e psiquiátrico em um paciente, e, formulação farmacêutica |
| KR101565185B1 (ko) * | 2008-04-04 | 2015-11-02 | 미메토젠 파르마슈티칼스 인크. | 건안증을 치료하기 위한 베타-턴 펩티도미메틱 환상 화합물 |
| ES2512717T3 (es) * | 2009-02-27 | 2014-10-24 | Mimetogen Pharmaceuticals Inc. | Compuestos cíclicos peptidomiméticos para el tratamiento de la retinitis pigmentosa |
| WO2012013281A1 (de) * | 2010-07-29 | 2012-02-02 | Merck Patent Gmbh | Flüssigkristallines medium enthaltend thiophenderivate |
| JP5710436B2 (ja) * | 2011-09-26 | 2015-04-30 | 株式会社東芝 | パターン形成方法 |
| KR102061382B1 (ko) * | 2012-06-22 | 2019-12-31 | 미메토젠 파르마슈티칼스 인크. | 베타-턴 펩티도미메틱 환상 화합물의 합성 |
| JP6516974B2 (ja) * | 2013-06-14 | 2019-05-22 | 豊田合成株式会社 | ゴム組成物及びゴム製品 |
| US9200100B2 (en) * | 2013-06-20 | 2015-12-01 | Exxonmobil Chemical Patents Inc. | Long-bridged salen catalyst |
| JP6801835B2 (ja) * | 2015-07-09 | 2020-12-16 | ミメトゲン ファーマシュウティカルズ インコーポレイテッドＭｉｍｅｔｏｇｅｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ， Ｉｎｃ． | β−ターンペプチド模倣環状塩の液相合成及び結晶化 |
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2016
- 2016-07-08 JP JP2017567608A patent/JP6801835B2/ja active Active
- 2016-07-08 KR KR1020187003965A patent/KR102056257B1/ko active Active
- 2016-07-08 CN CN202210654769.XA patent/CN114874288A/zh active Pending
- 2016-07-08 CA CA2991661A patent/CA2991661A1/en active Pending
- 2016-07-08 CN CN201680040450.0A patent/CN107849089B/zh active Active
- 2016-07-08 EP EP16739073.1A patent/EP3319978B1/en active Active
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- 2016-07-08 EP EP25158656.6A patent/EP4549450A3/en active Pending
- 2016-07-08 US US15/205,909 patent/US10125165B2/en active Active
- 2016-07-08 WO PCT/EP2016/066281 patent/WO2017005902A1/en not_active Ceased
- 2016-07-11 TW TW105121814A patent/TWI708779B/zh active
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2018
- 2018-11-08 US US16/184,485 patent/US11078234B2/en active Active
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2021
- 2021-06-02 US US17/337,383 patent/US11753441B2/en active Active
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2023
- 2023-07-18 US US18/354,076 patent/US12281179B2/en active Active
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| US11078234B2 (en) | 2021-08-03 |
| CN107849089B (zh) | 2022-07-05 |
| CN114874288A (zh) | 2022-08-09 |
| EP3319978A1 (en) | 2018-05-16 |
| US20210300966A1 (en) | 2021-09-30 |
| TW201716425A (zh) | 2017-05-16 |
| US20170008923A1 (en) | 2017-01-12 |
| EP4549450A2 (en) | 2025-05-07 |
| WO2017005902A1 (en) | 2017-01-12 |
| AU2016290654A1 (en) | 2018-01-25 |
| EP4549450A3 (en) | 2025-07-02 |
| HK1255355A1 (en) | 2019-08-16 |
| US11753441B2 (en) | 2023-09-12 |
| US20190194251A1 (en) | 2019-06-27 |
| US12281179B2 (en) | 2025-04-22 |
| KR20180036982A (ko) | 2018-04-10 |
| TWI708779B (zh) | 2020-11-01 |
| KR102056257B1 (ko) | 2019-12-16 |
| AU2016290654C1 (en) | 2021-11-11 |
| JP6801835B2 (ja) | 2020-12-16 |
| CN107849089A (zh) | 2018-03-27 |
| EP3319978C0 (en) | 2025-02-19 |
| JP2018528928A (ja) | 2018-10-04 |
| EP3319978B1 (en) | 2025-02-19 |
| AU2016290654B2 (en) | 2021-07-08 |
| US20230357318A1 (en) | 2023-11-09 |
| US10125165B2 (en) | 2018-11-13 |
| AU2016290654A2 (en) | 2020-08-06 |
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