JP2020537648A - (r)−9−(2,5−ジフルオロフェネチル)−4−エチル−2−メチル−1−オキサ−4,9−ジアザスピロ[5.5]ウンデカン−3−オンの塩 - Google Patents
(r)−9−(2,5−ジフルオロフェネチル)−4−エチル−2−メチル−1−オキサ−4,9−ジアザスピロ[5.5]ウンデカン−3−オンの塩 Download PDFInfo
- Publication number
- JP2020537648A JP2020537648A JP2020520801A JP2020520801A JP2020537648A JP 2020537648 A JP2020537648 A JP 2020537648A JP 2020520801 A JP2020520801 A JP 2020520801A JP 2020520801 A JP2020520801 A JP 2020520801A JP 2020537648 A JP2020537648 A JP 2020537648A
- Authority
- JP
- Japan
- Prior art keywords
- oxa
- difluorophenethyl
- diazaspiro
- undecane
- ethyl
- 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.)
- Pending
Links
- 150000003839 salts Chemical class 0.000 title claims description 193
- -1 2,5-difluorophenethyl Chemical group 0.000 title description 182
- YNMZZHPSYMOGCI-UHFFFAOYSA-N undecan-3-one Chemical compound CCCCCCCCC(=O)CC YNMZZHPSYMOGCI-UHFFFAOYSA-N 0.000 title description 36
- KALIKXMQWFLZKB-CQSZACIVSA-N (2R)-9-[2-(2,5-difluorophenyl)ethyl]-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one Chemical class FC1=C(CCN2CCC3(CN(C([C@H](O3)C)=O)CC)CC2)C=C(C=C1)F KALIKXMQWFLZKB-CQSZACIVSA-N 0.000 claims abstract description 111
- 238000011282 treatment Methods 0.000 claims abstract description 43
- 108020001612 μ-opioid receptors Proteins 0.000 claims abstract description 25
- 230000002265 prevention Effects 0.000 claims abstract description 24
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 20
- 102000051367 mu Opioid Receptors Human genes 0.000 claims abstract description 19
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 13
- 201000010099 disease Diseases 0.000 claims abstract description 11
- 208000002193 Pain Diseases 0.000 claims description 83
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 59
- 230000036407 pain Effects 0.000 claims description 55
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 42
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 31
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 30
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 30
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 27
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 claims description 26
- 229910019142 PO4 Inorganic materials 0.000 claims description 25
- 239000003814 drug Substances 0.000 claims description 24
- IWYDHOAUDWTVEP-ZETCQYMHSA-N (S)-mandelic acid Chemical class OC(=O)[C@@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-ZETCQYMHSA-N 0.000 claims description 23
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 23
- 229910002651 NO3 Inorganic materials 0.000 claims description 23
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 23
- 239000010452 phosphate Substances 0.000 claims description 23
- 239000007787 solid Substances 0.000 claims description 23
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 22
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 21
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 claims description 18
- 208000000094 Chronic Pain Diseases 0.000 claims description 17
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 17
- 229950004221 besilate Drugs 0.000 claims description 16
- 206010020751 Hypersensitivity Diseases 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 15
- 208000026935 allergic disease Diseases 0.000 claims description 15
- 230000009610 hypersensitivity Effects 0.000 claims description 15
- 208000004296 neuralgia Diseases 0.000 claims description 14
- 208000021722 neuropathic pain Diseases 0.000 claims description 14
- 230000001404 mediated effect Effects 0.000 claims description 13
- 208000005298 acute pain Diseases 0.000 claims description 11
- 229950007655 esilate Drugs 0.000 claims description 11
- 102000005962 receptors Human genes 0.000 claims description 10
- 108020003175 receptors Proteins 0.000 claims description 10
- 206010065390 Inflammatory pain Diseases 0.000 claims description 9
- 208000019695 Migraine disease Diseases 0.000 claims description 9
- 230000004064 dysfunction Effects 0.000 claims description 9
- 206010027599 migraine Diseases 0.000 claims description 9
- 208000009935 visceral pain Diseases 0.000 claims description 9
- 230000006806 disease prevention Effects 0.000 claims description 6
- 150000007522 mineralic acids Chemical class 0.000 claims description 4
- 150000002823 nitrates Chemical class 0.000 claims description 4
- 150000007524 organic acids Chemical group 0.000 claims description 4
- 235000005985 organic acids Nutrition 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical class OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims 1
- 108010085082 sigma receptors Proteins 0.000 abstract description 13
- 238000000634 powder X-ray diffraction Methods 0.000 description 102
- 238000005160 1H NMR spectroscopy Methods 0.000 description 38
- 150000001875 compounds Chemical class 0.000 description 34
- 235000021317 phosphate Nutrition 0.000 description 23
- 239000000203 mixture Substances 0.000 description 22
- 238000004519 manufacturing process Methods 0.000 description 19
- 238000000113 differential scanning calorimetry Methods 0.000 description 17
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 15
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 14
- 238000000034 method Methods 0.000 description 14
- GMDHSZCKOQCULK-BTJKTKAUSA-N C(\C=C/C(=O)O)(=O)O.CCC(CCCCCCCC)=O Chemical compound C(\C=C/C(=O)O)(=O)O.CCC(CCCCCCCC)=O GMDHSZCKOQCULK-BTJKTKAUSA-N 0.000 description 13
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 13
- GOWMWURPCDISQR-UHFFFAOYSA-N C(C(=O)O)(=O)O.CCC(CCCCCCCC)=O Chemical compound C(C(=O)O)(=O)O.CCC(CCCCCCCC)=O GOWMWURPCDISQR-UHFFFAOYSA-N 0.000 description 12
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 12
- 238000009472 formulation Methods 0.000 description 11
- 230000001225 therapeutic effect Effects 0.000 description 11
- 239000012458 free base Substances 0.000 description 10
- 239000003446 ligand Substances 0.000 description 10
- 238000003860 storage Methods 0.000 description 10
- IQKYFWNEGWSXPI-UHFFFAOYSA-N Cl.CCC(CCCCCCCC)=O Chemical compound Cl.CCC(CCCCCCCC)=O IQKYFWNEGWSXPI-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 230000000694 effects Effects 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 8
- 150000007513 acids Chemical class 0.000 description 7
- 230000001154 acute effect Effects 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- UZILMRSSGKFWTO-UHFFFAOYSA-N 1-oxa-4,9-diazaspiro[5.5]undecan-3-one Chemical compound C1NC(=O)COC11CCNCC1 UZILMRSSGKFWTO-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- FYSUZRDELDXCAV-UHFFFAOYSA-N P(=O)(O)(O)O.CCC(CCCCCCCC)=O Chemical compound P(=O)(O)(O)O.CCC(CCCCCCCC)=O FYSUZRDELDXCAV-UHFFFAOYSA-N 0.000 description 6
- KMKIYDLDQLSRPM-UHFFFAOYSA-N [N+](=O)(O)[O-].CCC(CCCCCCCC)=O Chemical compound [N+](=O)(O)[O-].CCC(CCCCCCCC)=O KMKIYDLDQLSRPM-UHFFFAOYSA-N 0.000 description 6
- 239000002671 adjuvant Substances 0.000 description 6
- 230000000202 analgesic effect Effects 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 238000004090 dissolution Methods 0.000 description 6
- 239000003937 drug carrier Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 239000003981 vehicle Substances 0.000 description 6
- ACNIDEXTOGQVLU-OAHLLOKOSA-N (2R)-9-[2-(2,5-difluorophenyl)ethyl]-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecane Chemical compound FC1=C(CCN2CCC3(CN(C[C@H](O3)C)CC)CC2)C=C(C=C1)F ACNIDEXTOGQVLU-OAHLLOKOSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- XYFOOSLGXWUFKX-UHFFFAOYSA-N S(=O)(=O)(O)O.CCC(CCCCCCCC)=O Chemical compound S(=O)(=O)(O)O.CCC(CCCCCCCC)=O XYFOOSLGXWUFKX-UHFFFAOYSA-N 0.000 description 5
- 239000000556 agonist Substances 0.000 description 5
- 230000008901 benefit Effects 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 230000001684 chronic effect Effects 0.000 description 5
- 230000008534 mechanical pain sensitivity Effects 0.000 description 5
- UFOUQLJGVGRURV-UHFFFAOYSA-N 1,2-diazaspiro[5.5]undecan-3-one hydrochloride Chemical compound Cl.O=C1CCC2(CCCCC2)NN1 UFOUQLJGVGRURV-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 229950002475 mesilate Drugs 0.000 description 4
- 229940005483 opioid analgesics Drugs 0.000 description 4
- 239000002464 receptor antagonist Substances 0.000 description 4
- 229940044551 receptor antagonist Drugs 0.000 description 4
- 239000001384 succinic acid Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- CEWRPZWPTGADRK-UHFFFAOYSA-N C(CCC(=O)O)(=O)O.CCC(CCCCCCCC)=O Chemical compound C(CCC(=O)O)(=O)O.CCC(CCCCCCCC)=O CEWRPZWPTGADRK-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 208000004454 Hyperalgesia Diseases 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 102100028656 Sigma non-opioid intracellular receptor 1 Human genes 0.000 description 3
- 101710104750 Sigma non-opioid intracellular receptor 1 Proteins 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 238000009509 drug development Methods 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 239000000945 filler Substances 0.000 description 3
- 150000003840 hydrochlorides Chemical class 0.000 description 3
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 238000011813 knockout mouse model Methods 0.000 description 3
- 238000011866 long-term treatment Methods 0.000 description 3
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 3
- IWYDHOAUDWTVEP-UHFFFAOYSA-N mandelic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 3
- 229960005181 morphine Drugs 0.000 description 3
- 235000006408 oxalic acid Nutrition 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 150000003890 succinate salts Chemical class 0.000 description 3
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- OTVCMGMYOYLFCC-UHFFFAOYSA-N 2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one Chemical class C1NC(=O)C(C)OC11CCNCC1 OTVCMGMYOYLFCC-UHFFFAOYSA-N 0.000 description 2
- DGPGXHRHNRYVDH-UHFFFAOYSA-N 4-[2-(5-methyl-1-naphthalen-2-ylpyrazol-3-yl)oxyethyl]morpholine Chemical compound N=1N(C=2C=C3C=CC=CC3=CC=2)C(C)=CC=1OCCN1CCOCC1 DGPGXHRHNRYVDH-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 2
- DLRYNNBRMYFCNB-UHFFFAOYSA-N Br.CCC(CCCCCCCC)=O Chemical compound Br.CCC(CCCCCCCC)=O DLRYNNBRMYFCNB-UHFFFAOYSA-N 0.000 description 2
- QMQPXSMLBWVCHZ-UHFFFAOYSA-N C(CC(=O)O)(=O)O.CCC(CCCCCCCC)=O Chemical compound C(CC(=O)O)(=O)O.CCC(CCCCCCCC)=O QMQPXSMLBWVCHZ-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 2
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 2
- 208000035154 Hyperesthesia Diseases 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 2
- 208000028389 Nerve injury Diseases 0.000 description 2
- 102000003840 Opioid Receptors Human genes 0.000 description 2
- 108090000137 Opioid Receptors Proteins 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000000853 adhesive Substances 0.000 description 2
- 230000001070 adhesive effect Effects 0.000 description 2
- 230000036592 analgesia Effects 0.000 description 2
- 229940035676 analgesics Drugs 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- YKPUWZUDDOIDPM-SOFGYWHQSA-N capsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 230000003828 downregulation Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000012395 formulation development Methods 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 238000007914 intraventricular administration Methods 0.000 description 2
- GJRQTCIYDGXPES-UHFFFAOYSA-N isobutyl acetate Chemical compound CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- 150000002688 maleic acid derivatives Chemical class 0.000 description 2
- 150000002690 malonic acid derivatives Chemical class 0.000 description 2
- 238000007726 management method Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000002756 mu opiate receptor agonist Substances 0.000 description 2
- 229940126487 mu opioid receptor agonist Drugs 0.000 description 2
- 230000008764 nerve damage Effects 0.000 description 2
- 230000007823 neuropathy Effects 0.000 description 2
- 201000001119 neuropathy Diseases 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 150000003891 oxalate salts Chemical class 0.000 description 2
- 230000008533 pain sensitivity Effects 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 208000033808 peripheral neuropathy Diseases 0.000 description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000005180 public health Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 238000013341 scale-up Methods 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- ZTGMHFIGNYXMJV-SQTRZTOVSA-N (1R)-1,13-dimethyl-10-prop-2-enyl-10-azatricyclo[7.3.1.02,7]trideca-2(7),3,5-trien-4-ol hydrochloride Chemical compound CC1C2CC3=C([C@@]1(CCN2CC=C)C)C=C(C=C3)O.Cl ZTGMHFIGNYXMJV-SQTRZTOVSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical class O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical group N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 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
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 206010002942 Apathy Diseases 0.000 description 1
- WJZOXVLFSONJLR-UHFFFAOYSA-N C(C)S(=O)(=O)O.CCC(CCCCCCCC)=O Chemical compound C(C)S(=O)(=O)O.CCC(CCCCCCCC)=O WJZOXVLFSONJLR-UHFFFAOYSA-N 0.000 description 1
- JGKHQWYNAJYMEL-BTJKTKAUSA-N C(\C=C/C(=O)O)(=O)O.C(C)C1(OC2(CNC1=O)CCNCC2)C Chemical compound C(\C=C/C(=O)O)(=O)O.C(C)C1(OC2(CNC1=O)CCNCC2)C JGKHQWYNAJYMEL-BTJKTKAUSA-N 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 206010058019 Cancer Pain Diseases 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 102100037709 Desmocollin-3 Human genes 0.000 description 1
- 206010058314 Dysplasia Diseases 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 101000968042 Homo sapiens Desmocollin-2 Proteins 0.000 description 1
- 101000880960 Homo sapiens Desmocollin-3 Proteins 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 229940127450 Opioid Agonists Drugs 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 1
- 206010038678 Respiratory depression Diseases 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 235000017663 capsaicin Nutrition 0.000 description 1
- 229960002504 capsaicin Drugs 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 210000003703 cisterna magna Anatomy 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229940000425 combination drug Drugs 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000011903 deuterated solvents Substances 0.000 description 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 1
- ORPJQSFBLBHKPN-UHFFFAOYSA-N dichloromethane;methylsulfinylmethane Chemical compound ClCCl.CS(C)=O ORPJQSFBLBHKPN-UHFFFAOYSA-N 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- LJQKCYFTNDAAPC-UHFFFAOYSA-N ethanol;ethyl acetate Chemical compound CCO.CCOC(C)=O LJQKCYFTNDAAPC-UHFFFAOYSA-N 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000008394 flocculating agent Substances 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 229960003878 haloperidol Drugs 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000000185 intracerebroventricular administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 description 1
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- 230000002981 neuropathic effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 230000008058 pain sensation Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 229940043274 prophylactic drug Drugs 0.000 description 1
- 239000012658 prophylactic medication Substances 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000008844 regulatory mechanism Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 210000003497 sciatic nerve Anatomy 0.000 description 1
- 230000009291 secondary effect Effects 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 210000003625 skull Anatomy 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/10—Spiro-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
Abstract
Description
本発明において、(R)−9−(2,5−ジフルオロフェネチル)−4−エチル−2−メチル−1−オキサ−4,9−ジアザスピロ[5.5]ウンデカン−3−オンの異なる形態についての広範な研究の後、驚くべきことに、その塩のいくつかが有利な製造、取り扱い、保管及び/又は治療特性を提供することが見出され、示された。
(R)−9−(2,5−ジフルオロフェネチル)−4−エチル−2−メチル−1−オキサ−4,9−ジアザスピロ[5.5]ウンデカン−3−オンは、シグマ−1受容体に対してはアンタゴニスト親和性、及びミューオピオイド受容体に対してはアゴニスト親和性の両方を示す化合物である(WO2015185209)。しかしながら、遊離塩基としての(R)−9−(2,5−ジフルオロフェネチル)−4−エチル−2−メチル−1−オキサ−4,9−ジアザスピロ[5.5]ウンデカン−3−オンはオイル状生成物であり、したがって、製剤開発には不便である。塩形成の研究は、この化合物の処方に重要な利便性を提供できる適切な塩を特定するために望ましい。
−遊離塩基をプロトン化するのに十分な酸性度の酸
−製薬上許容される化合物である酸
(R)−9−(2,5−ジフルオロフェネチル)−4−エチル−2−メチル−1−オキサ−4,9−ジアザスピロ[5.5]ウンデカン−3−オン及び約1等量の対応する酸性対イオンを混合し、溶媒を加えて透明な溶液又は懸濁液を得た。
・懸濁液が得られた場合(スラリー)、混合物を室温と40℃の間で一晩攪拌した。
・透明な溶液が調製された場合、溶液を冷却(0〜20℃)して沈殿した固体(沈殿)を得るか、周囲条件下又はロータリーエバポレーター(蒸発)で蒸発乾固した。
・より高い溶解度
・より速い溶解速度
・より低い吸湿性
NMR-1H (CDCl3, 400 MHz, δ): 7.09-6.93 (m, 3H, ArH); 4.11 (q, 1H, J = 6.8 Hz, CH); 3.54-3.43 (m, 4H, CH2); 3.39-3.31 (m, 3H, CH2); 3.20-3.11 (m, 4H, CH2); 2.98-2.89 (m, 1H, CH2); 2.61-2.51 (m, 1H, CH2); 2.48-2.40 (m, 1H, CH2); 2.28-2.24 (m, 1H, CH2); 1.86-1.82 (m, 1H, CH2); 1.44 (d, J = 6.8 Hz, 3H, CH3); 1.13 (t, J = 7.2 Hz, 3H, CH3)。
NMR-1H (CDCl3, 400 MHz, δ): 7.09-6.92 (m, 3H, ArH); 4.10 (q, 1H, J = 6.8 Hz, CH); 3.54-3.43 (m, 4H, CH2); 3.39-3.30 (m, 3H, CH2); 3.20-3.15 (m, 4H, CH2); 2.97-2.89 (m, 1H, CH2); 2.60-2.52 (m, 1H, CH2); 2.47-2.39 (m, 1H, CH2); 2.28-2.24 (m, 1H, CH2); 1.86-1.82 (m, 1H, CH2); 1.44 (d, J = 6.8 Hz, 3H, CH3); 1.12 (t, J = 7.2 Hz, 3H, CH3)。
NMR-1H (DMSO, 400 MHz, δ): 7.24-7.15 (m, 2H, ArH); 7.10-7.04 (m, 1H, ArH); 6.60 (s, 2H, CH=); 4.09 (q, 1H, J = 6.8 Hz, CH); 3.42-3.28 (m, 2H, CH2); 3.23-3.14 (m, 2H, CH2); 2.80-2.76 (m, 2H, CH2); 2.69-2.60 (m, 4H, CH2); 2.48-2.29 (m, 2H, CH2); 1.92-1.87 (m, 1H, CH2); 1.66-1.51 (m, 3H, CH2); 1.25 (d, J = 7.2 Hz, 3H, CH3); 1.01 (t, J = 6.8 Hz, 3H, CH3)。
NMR-1H (CD3OD, 400 MHz, δ): 7.19-7.14 (m, 2H, ArH); 7.11-7.05 (m, 1H, ArH); 4.23 (q, 1H, J = 6.8 Hz, CH); 3.56-3.33 (m, 8H, CH2); 3.28-3.11 (m, 4H, CH2); 2.45-2.35 (m, 1H, CH2); 2.06-1.75 (m, 1H, CH2); 1.93-1.84 (m, 2H, CH2); 1.41 (d, J = 7.2 Hz, 3H, CH3); 1.15 (t, J = 6.8 Hz, 3H, CH3)。
NMR-1H (CD3OD, 400 MHz, δ): 7.19-7.13 (m, 2H, ArH); 7.10-7.04 (m, 1H, ArH); 6.26 (s, 2H, CH=); 4.23 (q, 1H, J = 6.8 Hz, CH); 3.56-3.33 (m, 8H, CH2); 3.28-3.11 (m, 4H, CH2); 2.38-2.33 (m, 1H, CH2); 2.07-1.80 (m, 3H, CH2); 1.41 (d, J = 6.8 Hz, 3H, CH3); 1.15 (t, J = 7.2 Hz, 3H, CH3)。
NMR-1H (CD3OD, 400 MHz, δ): 7.19-7.13 (m, 2H, ArH); 7.10-7.04 (m, 1H, ArH); 6.26 (s, 2H, CH=); 4.23 (q, 1H, J = 6.8 Hz, CH); 3.56-3.33 (m, 8H, CH2); 3.28-3.11 (m, 4H, CH2); 2.38-2.33 (m, 1H, CH2); 2.05-1.77 (m, 3H, CH2); 1.41 (d, J = 6.8 Hz, 3H, CH3); 1.15 (t, J = 7.2 Hz, 3H, CH3)。
NMR-1H (CD3OD, 400 MHz, δ): 7.85-7.82 (m, 2H, ArH); 7.45-7.40 (m, 3H, ArH); 7.19-7.13 (m, 2H, ArH); 7.10-7.04 (m, 1H, ArH); 4.22 (q, 1H, J = 6.8 Hz, CH); 3.55-3.34 (m, 8H, CH2); 3.26-3.11 (m, 4H, CH2); 2.42-2.35 (m, 1H, CH2); 2.05-1.77 (m, 3H, CH2); 1.41 (d, J = 6.8 Hz, 3H, CH3); 1.14 (t, J = 7.2 Hz, 3H, CH3)。
NMR-1H (CD3OD, 400 MHz, δ):7.85-7.82 (m, 2H, ArH); 7.45-7.40 (m, 2H, ArH); 7.18-7.12 (m, 2H, ArH); 7.09-7.03 (m, 1H, ArH); 4.22 (q, 1H, J = 6.8 Hz, CH); 3.54-3.35 (m, 4H, CH2); 3.28-3.07 (m, 8H, CH2); 2.38-2.28 (m, 1H, CH2); 2.00-1.77 (m, 3H, CH2); 1.40 (d, J = 7.2 Hz, 3H, CH3); 1.14 (t, J = 6.8 Hz, 3H, CH3)。
NMR-1H (CD3OD, 400 MHz, δ): 7.22-7.18 (m, 1H, ArH); 7.16-7.10 (m, 1H, ArH); 7.07-7.00 (m, 1H, ArH); 4.22 (q, 1H, J = 6.8 Hz, CH); 3.74-3.71 (m, 1H, CH2); 3.53-3.34 (m, 6H, CH2); 3.29-3.05 (m, 4H, CH2); 2.32-2.27 (m, 1H, CH2); 2.18-2.11 (m, 1H, CH2); 2.05-1.97 (m, 1H, CH2); 1.89-1.83 (m, 2H, CH2); 1.40 (d, J = 6.8 Hz, 3H, CH3); 1.15 (t, J = 7.2 Hz, 3H, CH3)。
NMR-1H (CD3OD, 400 MHz,δ): 7.20-7.13 (m, 2H, ArH); 7.10-7.04 (m, 1H, ArH); 4.23 (q, 1H, J = 6.8 Hz, CH); 3.60-3.34 (m, 8H, CH2); 3.27-3.14 (m, 4H, CH2); 2.42-2.38 (m, 1H, CH2); 2.09-2.01 (m, 1H, CH2); 1.95-1.84 (m, 2H, CH2); 1.41 (d, J = 6.8 Hz, 3H, CH3); 1.15 (t, J = 7.2 Hz, 3H, CH3)。
NMR-1H (CD3OD, 400 MHz, δ): 7.12-7.07 (m, 2H, ArH); 7.02-7.00 (m, 1H, ArH); 4.19 (q, 1H, J = 6.8 Hz, CH); 3.53-3.44 (m, 2H, CH2); 3.40-3.32 (m, 1H, CH2); 3.23-3.20 (m, 1H, CH2); 3.12-2.85 (m, 7H, CH2); 2.77-2.68 (m, 1H, CH2); 2.54 (2, 4H, CH2); 2.21-2.15 (m, 1H, CH2); 1.90-1.83 (m, 1H, CH2); 1.80-1.70 (m, 2H, CH2); 1.38 (d, J = 6.8 Hz, 3H, CH3); 1.13 (t, J = 7.2 Hz, 3H, CH3)。
NMR-1H (CD3OD, 400 MHz, δ): 7.18-7.12 (m, 2H, ArH); 7.09-7.03 (m, 1H, ArH); 4.23 (q, 1H, J = 6.8 Hz, CH); 3.56-3.33 (m, 8H, CH2); 3.28-3.11 (m, 4H, CH2); 2.38-2.33 (m, 1H, CH2); 2.08-2.00 (m, 1H, CH2); 1.93-1.84 (m, 2H, CH2); 1.41 (d, J = 7.2 Hz, 3H, CH3); 1.14 (t, J = 6.8 Hz, 3H, CH3)。
NMR-1H (CD3OD, 400 MHz, δ): 7.18-7.12 (m, 2H, ArH); 7.09-7.03 (m, 1H, ArH); 4.23 (q, 1H, J = 6.8 Hz, CH); 3.56-3.33 (m, 8H, CH2); 3.28-3.11 (m, 4H, CH2); 2.38-2.33 (m, 1H, CH2); 2.08-2.00 (m, 1H, CH2); 1.93-1.84 (m, 2H, CH2); 1.41 (d, J = 7.2 Hz, 3H, CH3); 1.14 (t, J = 6.8 Hz, 3H, CH3)。
NMR-1H (CDCl3, 400 MHz, δ): 7.06-6.93 (m, 3H, ArH); 4.12 (q, 1H, J = 6.8 Hz, CH); 3.53-3.35 (m, 5H, CH2); 3.21 (s, 2H, CH2); 3.20-3.07 (m, 6H, CH2); 2.96-2.90 (m, 1H, CH2); 2.31-2.24 (m, 1H, CH2); 2.23-2.14 (m, 1H, CH2); 2.07-1.99 (m, 1H, CH2); 1.88-1.83 (m, 1H, CH2); 1.45 (d, J = 6.8 Hz, 3H, CH3); 1.14 (t, J = 7.2 Hz, 3H, CH3)。
NMR-1H (CD3OD, 400 MHz, δ): 7.19-7.14 (m, 2H, ArH); 7.10-7.03 (m, 1H, ArH); 4.23 (q, 1H, J = 6.8 Hz, CH); 3.60-3.33 (m, 8H, CH2); 3.27-3.13 (m, 4H, CH2); 2.81 (q, 2H, J = 7.2 Hz, CH2); 2.38-2.33 (m, 1H, CH2); 2.08-1.82 (m, 3H, CH2); 1.41 (d, J = 7.2 Hz, 3H, CH3); 1.31 (t, 3H, J = 7.2 Hz, CH); 1.15 (t, J = 6.8 Hz, 3H, CH3)。
NMR-1H (CD3OD, 400 MHz, δ): 7.19-7.13 (m, 2H, ArH); 7.10-7.03 (m, 1H, ArH); 4.23 (q, 1H, J = 6.8 Hz, CH); 3.55-3.33 (m, 8H, CH2); 3.28-3.24 (m, 2H, CH2); 3.14-3.10 (m, 2H, CH2); 2.40-2.28 (m, 1H, CH2); 2.08-1.74 (m, 3H, CH2); 1.41 (d, J = 6.8 Hz, 3H, CH3); 1.14 (t, J = 7.2 Hz, 3H, CH3)。
NMR-1H (CD3OD, 400 MHz,δ): 7.49-7.46 (m, 2H, ArH); 7.33-7.23 (m, 3H, ArH); 7.15-7.00 (m, 3H, ArH); 4.98 (s, 1H, CH); 4.19 (q, 1H, J = 6.8 Hz, CH); 3.51-3.43 (m, 2H, CH2); 3.40-3.33 (m, 2H, CH2); 3.18-2.94 (m, 7H, CH2); 2.26.-2.20 (m, 1H, CH2); 1.95-1.88 (m, 1H, CH2); 1.83-1.74 (m, 2H, CH2); 1.39 (d, J = 6.8 Hz, 3H, CH3); 1.13 (t, J = 7.2 Hz, 3H, CH3)。
ACN:アセトニトリル
AcOH:酢酸
AcOiBu:酢酸イソブチル
aq.:水性
DCM:ジクロロメタン
DMSO:ジメチルスルホキシド
Eq:等量
EtOAc:酢酸エチル
EtOH:エタノール
EX:例
h:時間/秒
MeOH:メタノール
MIK:メチルイソブチルケトン
Min:分
MTBE:メチルtert−ブチルエーテル
IPA:イソプロパノール
rt:室温
Sat:飽和
Sol:溶液
THF:テトラヒドロフラン
本発明では、(R)−9−(2,5−ジフルオロフェネチル)−4−エチル−2−メチル−1−オキサ−4,9−ジアザスピロ[5.5]ウンデカン−3−オン又はその異なる塩のいずれかを特徴付けかつ同定するために、以下の技術を使用した:
XRPD分析は、ブラッグ−ブレンターノジオメトリでCuKα放射線を使用するPANalytical X‘Pert回折計を使用して実施された。このシステムには、1次元のリアルタイム複数ストリップ検出器が装備されている。毎分17.6°のスキャン速度で3°から40°(2θ)までの回折図を記録した。
DSC分析はMettler Toledo DSC2で記録された。試料をピンホール蓋付きの40μLアルミニウムるつぼに量り入れ、窒素下(50mL/in)で25°Cから300°Cまで10°C/minの速度で加熱した。
1H−NMR分析は、5mmの広帯域プローブATB 1H/19F/Xを備えたVarian Mercury 400分光計で重水素化メタノール(d4−CH3OH)又はクロロホルム(d−CHCl3)で記録した。5〜10mgの試料を0.7mLの重水素化溶媒に溶解してスペクトルを取得した。
使用する最も適切な溶媒を決定するために、(R)−9−(2,5−ジフルオロフェネチル)−4−エチル−2−メチル−1−オキサ−4,9−ジアザスピロ[5.5]ウンデカン−3−オン遊離塩基の混和性が、選択した溶媒で検討された(表2を参照)。オイルを室温で対応する溶媒に「溶解」するのに必要な容量の数を表に示す。一般的に、オイルはテストしたすべての溶媒と自由に混和する。
化学合成によって得られた遊離塩基はオイルとして得られ、1H核磁気共鳴によって特徴付けられた(図1)。
(R)−9−(2,5−ジフルオロフェネチル)−4−エチル−2−メチル−1−オキサ−4,9−ジアザスピロ[5.5]ウンデカン−3−オンの塩を検討するために使用された酸は、次の基準である:
−遊離塩基をプロトン化するのに十分な酸性度の酸
−薬学的に許容される化合物である酸
粉砕実験:2mLのマイクロチューブに、遊離塩基及び約1eq.の対応する酸性対イオンを加えた。1滴の溶媒と2つのステンレス鋼のボールを加え、得られた混合物をボールミルで粉砕した(3x15分、30Hz)。回収された固体は、XRPD分析の前に乾燥された。
スラリー、沈殿及び蒸発実験:2Lのマイクロチューブで、遊離塩基及び約1eq.の対応する酸性対イオンを混合した。 溶媒を加えて、透明な溶液又は懸濁液を得た。
−懸濁液が得られた場合、混合物を室温又は40℃で一晩撹拌した。
−透明な溶液が準備できたら、溶液を0〜5℃又は−20℃に冷却して、固体を沈殿(沈殿)させるか、周囲環境条件下又はロタリーエバポレーター(蒸発)で蒸発乾固させた。
・無機酸:HCl、HBr、H3PO4、H2SO4及び硝酸
・スルホン酸:ベンゼンスルホン酸、メタンスルホン酸、エタンスルホン酸
・非置換C1−C4二カルボン酸−マレイン酸、フマル酸、シュウ酸、マロン酸、コハク酸
・(S)−(+)−マンデル酸。
Claims (13)
- (R)−9−(2,5−ジフルオロフェネチル)−4−エチル−2−メチル−1−オキサ−4,9−ジアザスピロ[5.5]ウンデカン−3−オンの塩。
- 固体形態であることを特徴とする、請求項1に記載の塩。
- 非晶質形態であることを特徴とする、請求項1又は2のいずれか一項に記載の塩。
- 結晶形態であることを特徴とする、請求項1又は2のいずれか一項に記載の塩。
- 前記塩が無機酸から選択される、請求項1〜4のいずれか一項に記載の塩。
- 前記塩が有機酸から選択される、請求項1〜4のいずれか一項に記載の塩。
- 前記塩が、塩酸塩、フマル酸塩、臭化水素酸塩、マレイン酸塩、リン酸塩、硫酸塩、コハク酸塩、シュウ酸塩、マロン酸塩、メシル酸塩、エシル酸塩、ベシル酸塩、硝酸塩及び(S)−(+)−マンデル酸塩からなる群から選択される、請求項1〜6のいずれか一項に記載の塩。
- 塩酸塩の多形体P1、P2又はP3、フマル酸塩の多形体P1、臭化水素酸塩の多形体P1、マレイン酸塩の多形体P1、P2又はP3、リン酸塩の多形体P1、硫酸塩の多形体P1、コハク酸塩の多形体P1、シュウ酸塩の多形体P1、P2又はP3、マロン酸塩の多形体P1、メシル酸塩の多形体P1、エシル酸塩の多形体P1、ベシル酸塩の多形体P1、硝酸塩の多形体P1及び(S)−(+)−マンデル酸塩の多形体P1からなる群から選択される、請求項4に記載の塩。
- 請求項1〜8のいずれか一項に記載の少なくとも塩を含む医薬組成物。
- 医薬として使用するための、請求項1〜8のいずれか一項に記載の塩、又は請求項9に記載の医薬組成物。
- σ1受容体及び/又はμ−オピオイド受容体が介在する疾患又は状態の治療及び/又は予防に使用するための、請求項1〜8のいずれか一項に記載の塩、又は請求項9に記載の医薬組成物。
- 疼痛の治療及び/又は予防に使用するための、請求項1〜8のいずれか一項に記載の塩又は請求項9に記載の医薬組成物。
- 疾患が中等度から重度の疼痛、内臓痛、慢性疼痛、癌性疼痛、片頭痛、炎症性疼痛、急性疼痛若しくは神経因性疼痛、異痛症又は痛覚過敏である疾患の治療及び/又は予防に使用するための、請求項1〜8のいずれか一項に記載の塩又は請求項9に記載の医薬組成物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP17382695 | 2017-10-17 | ||
EP17382695.9 | 2017-10-17 | ||
PCT/EP2018/000470 WO2019076475A1 (en) | 2017-10-17 | 2018-10-16 | (R) -9- (2,5-DIFLUOROPHENETHYL) -4-ETHYL-2-METHYL-1-OXA-4,9-DIAZASPIRO SALTS [5.5] UNDECAN-3-ONE |
Publications (1)
Publication Number | Publication Date |
---|---|
JP2020537648A true JP2020537648A (ja) | 2020-12-24 |
Family
ID=60201976
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2020520801A Pending JP2020537648A (ja) | 2017-10-17 | 2018-10-16 | (r)−9−(2,5−ジフルオロフェネチル)−4−エチル−2−メチル−1−オキサ−4,9−ジアザスピロ[5.5]ウンデカン−3−オンの塩 |
Country Status (21)
Country | Link |
---|---|
US (1) | US11236110B2 (ja) |
EP (1) | EP3697795B1 (ja) |
JP (1) | JP2020537648A (ja) |
KR (1) | KR20200071107A (ja) |
CN (1) | CN111263764A (ja) |
AR (1) | AR113770A1 (ja) |
AU (1) | AU2018353107B2 (ja) |
BR (1) | BR112020007359A2 (ja) |
CA (1) | CA3076765A1 (ja) |
CO (1) | CO2020005710A2 (ja) |
DK (1) | DK3697795T3 (ja) |
FI (1) | FI3697795T3 (ja) |
IL (1) | IL273751B2 (ja) |
LT (1) | LT3697795T (ja) |
MA (1) | MA50395A (ja) |
MX (1) | MX2020004214A (ja) |
PH (1) | PH12020550104A1 (ja) |
PT (1) | PT3697795T (ja) |
RU (1) | RU2020115274A (ja) |
SG (1) | SG11202002731YA (ja) |
WO (1) | WO2019076475A1 (ja) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2021018824A1 (en) * | 2019-07-31 | 2021-02-04 | Esteve Pharmaceuticals, S.A. | Use of (r)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one for the treatment of nociceptive pain, neuropathic pain, osteoarthritis pain and cancer pain, while having reduced side effects compared to opioids |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2017516818A (ja) * | 2014-06-02 | 2017-06-22 | ラボラトリオス・デル・デエレ・エステベ・エセ・ア | 疼痛に対する多様な活性を有する1−オキサ−4,9−ジアザスピロウンデカン化合物のアルキル誘導体 |
Family Cites Families (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4332804A (en) | 1981-03-23 | 1982-06-01 | Syntex (U.S.A.) Inc. | 9-[2-(3-Indolyl)ethyl]-1oxa-4,9-diazaspiro[5.5]undecan-3-ones |
US4353900A (en) | 1981-10-19 | 1982-10-12 | Syntex (U.S.A.) Inc. | 9-(Arylalkyl or aroylalkyl)-1-oxa-4,9-diazaspiro(5.5)undecan-3-ones |
US6114541A (en) | 1997-03-10 | 2000-09-05 | Hoffmann-La Roche Inc. | Method for the preparation of α-Bromo-Lactam derivatives |
DE102005030051A1 (de) | 2005-06-27 | 2006-12-28 | Grünenthal GmbH | Substituierte 1-Oxa-3,8-diazaspiro[4,5]-decan-2-on-Verbindungen und deren Verwendung zur Herstellung von Arzneimitteln |
ES2407115T3 (es) | 2005-11-18 | 2013-06-11 | Ono Pharmaceutical Co., Ltd. | Compuesto que contiene un grupo básico y uso del mismo |
CN101622241B (zh) | 2007-03-01 | 2013-05-22 | 田边三菱制药株式会社 | 苯并咪唑化合物及其医药用途 |
EP1982714A1 (en) | 2007-04-16 | 2008-10-22 | Laboratorios del Dr. Esteve S.A. | Pyrano-pyrazole-amines |
EP2020414A1 (en) | 2007-06-20 | 2009-02-04 | Laboratorios del Dr. Esteve S.A. | spiro[piperidine-4,4'-thieno[3,2-c]pyran] derivatives and related compounds as inhibitors of the sigma receptor for the treatment of psychosis |
EP2197876A1 (en) | 2007-08-29 | 2010-06-23 | Glaxosmithkline LLC | Thiazole and oxazole kinase inhibitors |
US8148373B2 (en) | 2008-02-06 | 2012-04-03 | Astrazeneca Ab | Compounds |
CN103517910B (zh) | 2011-03-14 | 2016-12-14 | 沃泰克斯药物股份有限公司 | 作为离子通道调节剂的吗啉-螺环哌啶酰胺 |
GB201107985D0 (en) | 2011-05-13 | 2011-06-29 | Astrazeneca Ab | Process |
CN105263933B (zh) * | 2013-04-23 | 2017-12-22 | 埃斯蒂维实验室股份有限公司 | 一种吡嗪并[1,2‑a]吲哚化合物及其制备方法和在药物中的应用 |
WO2015017305A1 (en) | 2013-07-31 | 2015-02-05 | Merck Sharp & Dohme Corp | Inhibitors of the renal outer medullary potassium channel |
JP2017100951A (ja) * | 2014-04-04 | 2017-06-08 | 大正製薬株式会社 | オキサゾリジノン及びオキサジナノン誘導体 |
TW201615643A (zh) | 2014-06-02 | 2016-05-01 | 伊史帝夫博士實驗室股份有限公司 | 具有多重模式抗疼痛活性之1-氧雜-4,9-二氮雜螺十一烷化合物之烷基與芳基衍生物 |
TW201615642A (zh) | 2014-06-02 | 2016-05-01 | 伊史帝夫博士實驗室股份有限公司 | 具有多重模式抗疼痛活性的1-氧雜-4,9-二氮雜螺十一烷化合物之醯胺衍生物 |
-
2018
- 2018-10-16 CN CN201880069276.1A patent/CN111263764A/zh active Pending
- 2018-10-16 MA MA050395A patent/MA50395A/fr unknown
- 2018-10-16 KR KR1020207013907A patent/KR20200071107A/ko not_active Application Discontinuation
- 2018-10-16 SG SG11202002731YA patent/SG11202002731YA/en unknown
- 2018-10-16 WO PCT/EP2018/000470 patent/WO2019076475A1/en unknown
- 2018-10-16 IL IL273751A patent/IL273751B2/en unknown
- 2018-10-16 FI FIEP18796360.8T patent/FI3697795T3/fi active
- 2018-10-16 AR ARP180102999A patent/AR113770A1/es unknown
- 2018-10-16 BR BR112020007359-8A patent/BR112020007359A2/pt unknown
- 2018-10-16 JP JP2020520801A patent/JP2020537648A/ja active Pending
- 2018-10-16 MX MX2020004214A patent/MX2020004214A/es unknown
- 2018-10-16 CA CA3076765A patent/CA3076765A1/en active Pending
- 2018-10-16 EP EP18796360.8A patent/EP3697795B1/en active Active
- 2018-10-16 DK DK18796360.8T patent/DK3697795T3/da active
- 2018-10-16 AU AU2018353107A patent/AU2018353107B2/en active Active
- 2018-10-16 PT PT187963608T patent/PT3697795T/pt unknown
- 2018-10-16 LT LTEPPCT/EP2018/000470T patent/LT3697795T/lt unknown
- 2018-10-16 US US16/649,824 patent/US11236110B2/en active Active
- 2018-10-16 RU RU2020115274A patent/RU2020115274A/ru unknown
-
2020
- 2020-03-20 PH PH12020550104A patent/PH12020550104A1/en unknown
- 2020-05-09 CO CONC2020/0005710A patent/CO2020005710A2/es unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2017516818A (ja) * | 2014-06-02 | 2017-06-22 | ラボラトリオス・デル・デエレ・エステベ・エセ・ア | 疼痛に対する多様な活性を有する1−オキサ−4,9−ジアザスピロウンデカン化合物のアルキル誘導体 |
Also Published As
Publication number | Publication date |
---|---|
AU2018353107A1 (en) | 2020-04-23 |
KR20200071107A (ko) | 2020-06-18 |
AU2018353107B2 (en) | 2023-07-06 |
MX2020004214A (es) | 2020-08-13 |
EP3697795A1 (en) | 2020-08-26 |
CO2020005710A2 (es) | 2020-05-29 |
LT3697795T (lt) | 2024-04-10 |
BR112020007359A2 (pt) | 2020-09-29 |
US20200331929A1 (en) | 2020-10-22 |
CN111263764A (zh) | 2020-06-09 |
PT3697795T (pt) | 2024-02-29 |
CA3076765A1 (en) | 2019-04-25 |
AR113770A1 (es) | 2020-06-10 |
RU2020115274A3 (ja) | 2022-04-29 |
IL273751B2 (en) | 2024-02-01 |
MA50395A (fr) | 2020-08-26 |
FI3697795T3 (fi) | 2024-02-23 |
TW201922752A (zh) | 2019-06-16 |
PH12020550104A1 (en) | 2021-01-25 |
EP3697795B1 (en) | 2023-11-22 |
RU2020115274A (ru) | 2021-11-01 |
SG11202002731YA (en) | 2020-05-28 |
US11236110B2 (en) | 2022-02-01 |
IL273751A (en) | 2020-05-31 |
WO2019076475A1 (en) | 2019-04-25 |
IL273751B1 (en) | 2023-10-01 |
DK3697795T3 (da) | 2024-02-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10208018B2 (en) | Indane and indoline derivatives and the use thereof as soluble guanylate cyclase activators | |
US11344510B2 (en) | Arylcyclohexylamine derivatives and their use in the treatment of psychiatric disorders | |
JP6611736B2 (ja) | 疼痛に対する多様な活性を有する1−オキサ−4,9−ジアザスピロウンデカン化合物のアルキル誘導体 | |
US9273026B2 (en) | Carbamate/urea derivatives | |
CA3105161C (en) | Manufacturing process and intermediates for a pyrrolo[2,3- d]pyrimidine compound and use thereof | |
TW201305148A (zh) | 5-甲基-1-(萘-2-基)-1h-吡唑衍生物類 | |
EP0912494A1 (en) | Coumpounds active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases | |
JP2016540793A (ja) | 疼痛に対して多重モードの活性を有するピペリジン化合物 | |
WO2014180327A1 (zh) | 苯酚衍生物及其制备方法和在医药上的应用 | |
JP2020537648A (ja) | (r)−9−(2,5−ジフルオロフェネチル)−4−エチル−2−メチル−1−オキサ−4,9−ジアザスピロ[5.5]ウンデカン−3−オンの塩 | |
TWI835755B (zh) | (r)-9-(2,5-二氟苯乙基)-4-乙基-2-甲基-1-氧雜-4,9-二氮雜螺[5.5]十一烷-3-酮之鹽 | |
WO2014159501A2 (en) | Processes for preparing tetrahydroisoquinolines | |
AU2021282582A1 (en) | Forms and compositions of a beta adrenergic agonist | |
US20190194129A1 (en) | Novel salt of (r)-(1-methylpyrrolidine-3-yl)methyl(3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate and crystal form thereof | |
WO1998056752A1 (en) | Compounds active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases | |
JP2018521090A (ja) | 疼痛に対する多様な活性を有するアミド誘導体 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20200617 |
|
RD01 | Notification of change of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7426 Effective date: 20200617 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20210818 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20220714 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20220823 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20221118 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20230328 |
|
A711 | Notification of change in applicant |
Free format text: JAPANESE INTERMEDIATE CODE: A711 Effective date: 20230606 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20230606 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20230707 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20230711 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20230731 |
|
A912 | Re-examination (zenchi) completed and case transferred to appeal board |
Free format text: JAPANESE INTERMEDIATE CODE: A912 Effective date: 20230929 |