JPH0236183A - ヘテロ環式スピロ化合物及びその製法 - Google Patents
ヘテロ環式スピロ化合物及びその製法Info
- Publication number
- JPH0236183A JPH0236183A JP63251489A JP25148988A JPH0236183A JP H0236183 A JPH0236183 A JP H0236183A JP 63251489 A JP63251489 A JP 63251489A JP 25148988 A JP25148988 A JP 25148988A JP H0236183 A JPH0236183 A JP H0236183A
- Authority
- JP
- Japan
- Prior art keywords
- group
- atom
- formula
- formulas
- piperidine ring
- 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.)
- Granted
Links
- -1 Heterocyclic spirocompound Chemical class 0.000 title claims abstract description 63
- 238000004519 manufacturing process Methods 0.000 title claims description 38
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 33
- 125000003386 piperidinyl group Chemical group 0.000 claims abstract description 27
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 26
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 17
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 17
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 17
- 125000002252 acyl group Chemical group 0.000 claims abstract description 16
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 14
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 11
- 150000002148 esters Chemical class 0.000 claims abstract description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 7
- 150000003566 thiocarboxylic acids Chemical class 0.000 claims abstract description 4
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 claims abstract description 3
- 229910052760 oxygen Inorganic materials 0.000 claims abstract 3
- 239000000126 substance Substances 0.000 claims description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 29
- 125000006239 protecting group Chemical group 0.000 claims description 27
- 229910052757 nitrogen Inorganic materials 0.000 claims description 25
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 12
- 125000004434 sulfur atom Chemical group 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 7
- 125000003277 amino group Chemical group 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- 125000004423 acyloxy group Chemical group 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 239000011630 iodine Substances 0.000 claims description 3
- 125000003003 spiro group Chemical group 0.000 claims 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- 150000001735 carboxylic acids Chemical class 0.000 claims 1
- 230000008030 elimination Effects 0.000 claims 1
- 238000003379 elimination reaction Methods 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 88
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract description 11
- 201000010099 disease Diseases 0.000 abstract description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 abstract description 6
- 238000002360 preparation method Methods 0.000 abstract description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 abstract description 2
- 230000007850 degeneration Effects 0.000 abstract description 2
- 150000002168 ethanoic acid esters Chemical class 0.000 abstract 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 230000000069 prophylactic effect Effects 0.000 abstract 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 61
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 48
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 40
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 33
- 238000004949 mass spectrometry Methods 0.000 description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
- 239000000243 solution Substances 0.000 description 28
- 238000000862 absorption spectrum Methods 0.000 description 26
- 238000003756 stirring Methods 0.000 description 26
- 238000002844 melting Methods 0.000 description 24
- 230000008018 melting Effects 0.000 description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 23
- 238000006243 chemical reaction Methods 0.000 description 23
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 238000000921 elemental analysis Methods 0.000 description 20
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 19
- 238000000034 method Methods 0.000 description 19
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 239000000203 mixture Substances 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 14
- 239000002585 base Substances 0.000 description 14
- 239000003960 organic solvent Substances 0.000 description 14
- 238000010898 silica gel chromatography Methods 0.000 description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 13
- 239000002253 acid Substances 0.000 description 12
- 238000001816 cooling Methods 0.000 description 12
- 239000005457 ice water Substances 0.000 description 12
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 11
- 239000000284 extract Substances 0.000 description 11
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 11
- 239000012044 organic layer Substances 0.000 description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 9
- 239000010410 layer Substances 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- XJLDYKIEURAVBW-UHFFFAOYSA-N 3-decanone Chemical compound CCCCCCCC(=O)CC XJLDYKIEURAVBW-UHFFFAOYSA-N 0.000 description 8
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 8
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 8
- 235000011114 ammonium hydroxide Nutrition 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 8
- 239000012312 sodium hydride Substances 0.000 description 8
- 229910000104 sodium hydride Inorganic materials 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 8
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 229960004373 acetylcholine Drugs 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 7
- 238000007796 conventional method Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000002994 raw material Substances 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- 208000024827 Alzheimer disease Diseases 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 6
- 150000001721 carbon Chemical group 0.000 description 6
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000010828 elution Methods 0.000 description 6
- 239000001530 fumaric acid Substances 0.000 description 6
- 150000002688 maleic acid derivatives Chemical class 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 5
- UUFQTNFCRMXOAE-UHFFFAOYSA-N 1-methylmethylene Chemical compound C[CH] UUFQTNFCRMXOAE-UHFFFAOYSA-N 0.000 description 5
- 101100167062 Caenorhabditis elegans chch-3 gene Proteins 0.000 description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical class [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 5
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- 230000002378 acidificating effect Effects 0.000 description 5
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 5
- 239000011976 maleic acid Substances 0.000 description 5
- 206010027175 memory impairment Diseases 0.000 description 5
- 239000012046 mixed solvent Substances 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 239000008096 xylene Substances 0.000 description 5
- 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 compound 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 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 101150041968 CDC13 gene Proteins 0.000 description 4
- 101150065749 Churc1 gene Proteins 0.000 description 4
- 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 4
- 102100038239 Protein Churchill Human genes 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 206010044565 Tremor Diseases 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- HJJPJSXJAXAIPN-UHFFFAOYSA-N arecoline Chemical compound COC(=O)C1=CCCN(C)C1 HJJPJSXJAXAIPN-UHFFFAOYSA-N 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000003638 chemical reducing agent Substances 0.000 description 4
- 230000007423 decrease Effects 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 239000012280 lithium aluminium hydride Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 239000004593 Epoxy Substances 0.000 description 3
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 description 3
- 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 206010039966 Senile dementia Diseases 0.000 description 3
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 3
- 150000001447 alkali salts Chemical class 0.000 description 3
- 150000001350 alkyl halides Chemical class 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 239000001110 calcium chloride Substances 0.000 description 3
- 229910001628 calcium chloride Inorganic materials 0.000 description 3
- 210000003710 cerebral cortex Anatomy 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 description 3
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- 210000005036 nerve Anatomy 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 3
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 2
- 125000004813 2-ethylethylene group Chemical group [H]C([H])([H])C([H])([H])C([H])([*:2])C([H])([H])[*:1] 0.000 description 2
- 229930000680 A04AD01 - Scopolamine Natural products 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 229910015900 BF3 Inorganic materials 0.000 description 2
- 208000028698 Cognitive impairment Diseases 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- 208000023105 Huntington disease Diseases 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- STECJAGHUSJQJN-GAUPFVANSA-N Hyoscine Natural products C1([C@H](CO)C(=O)OC2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-GAUPFVANSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000002841 Lewis acid Substances 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 208000016285 Movement disease Diseases 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- STECJAGHUSJQJN-UHFFFAOYSA-N N-Methyl-scopolamin Natural products C1C(C2C3O2)N(C)C3CC1OC(=O)C(CO)C1=CC=CC=C1 STECJAGHUSJQJN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 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 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 239000003377 acid catalyst Substances 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid group Chemical group C(CCCCC(=O)O)(=O)O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 230000003496 anti-amnesic effect Effects 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 210000001638 cerebellum Anatomy 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 208000010877 cognitive disease Diseases 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 210000001320 hippocampus Anatomy 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000002198 insoluble material Substances 0.000 description 2
- CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 description 2
- 150000007517 lewis acids Chemical class 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 230000004770 neurodegeneration Effects 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 2
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 2
- 229960002646 scopolamine Drugs 0.000 description 2
- STECJAGHUSJQJN-FWXGHANASA-N scopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-FWXGHANASA-N 0.000 description 2
- 229960004499 scopolamine hydrobromide Drugs 0.000 description 2
- WTGQALLALWYDJH-MOUKNHLCSA-N scopolamine hydrobromide (anhydrous) Chemical compound Br.C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 WTGQALLALWYDJH-MOUKNHLCSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- BGHCVCJVXZWKCC-UHFFFAOYSA-N tetradecane Chemical compound CCCCCCCCCCCCCC BGHCVCJVXZWKCC-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 1
- 125000004815 1,2-dimethylethylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([*:2])C([H])([H])[H] 0.000 description 1
- 125000005923 1,2-dimethylpropyloxy group Chemical group 0.000 description 1
- 125000004720 1,2-dimethylpropylthio group Chemical group CC(C(C)C)S* 0.000 description 1
- VYMPLPIFKRHAAC-UHFFFAOYSA-N 1,2-ethanedithiol Chemical compound SCCS VYMPLPIFKRHAAC-UHFFFAOYSA-N 0.000 description 1
- FKHYEYLREYXOLX-UHFFFAOYSA-N 1-(3-hydroxy-4-methyl-1-oxa-8-azaspiro[4.5]decan-8-yl)ethanone Chemical compound CC1C(O)COC11CCN(C(C)=O)CC1 FKHYEYLREYXOLX-UHFFFAOYSA-N 0.000 description 1
- POLOOTGROZHXJT-UHFFFAOYSA-N 1-(4-but-3-en-2-yl-4-hydroxypiperidin-1-yl)ethanone Chemical compound C=CC(C)C1(O)CCN(C(C)=O)CC1 POLOOTGROZHXJT-UHFFFAOYSA-N 0.000 description 1
- XDHJBIYJRNFDKS-IBGZPJMESA-N 1-[(4-methoxyphenyl)methyl]-5-[(2s)-2-(pyridin-3-yloxymethyl)pyrrolidin-1-yl]sulfonylindole-2,3-dione Chemical compound C1=CC(OC)=CC=C1CN1C2=CC=C(S(=O)(=O)N3[C@@H](CCC3)COC=3C=NC=CC=3)C=C2C(=O)C1=O XDHJBIYJRNFDKS-IBGZPJMESA-N 0.000 description 1
- 125000004831 1-ethyl-2-methylethylene group Chemical group [H]C([H])([H])C([H])([H])C([H])([*:1])C([H])([*:2])C([H])([H])[H] 0.000 description 1
- 125000006218 1-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004812 1-ethylethylene group Chemical group [H]C([H])([H])C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- LIKMAJRDDDTEIG-UHFFFAOYSA-N 1-hexene Chemical group CCCCC=C LIKMAJRDDDTEIG-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- RMHMFHUVIITRHF-RLXJOQACSA-N 11-[2-[4-(tritritiomethyl)piperazin-1-yl]acetyl]-5h-pyrido[2,3-b][1,4]benzodiazepin-6-one Chemical compound C1CN(C([3H])([3H])[3H])CCN1CC(=O)N1C2=NC=CC=C2NC(=O)C2=CC=CC=C21 RMHMFHUVIITRHF-RLXJOQACSA-N 0.000 description 1
- DEMBDVIMYBYOEO-UHFFFAOYSA-N 2,8-dimethyl-1-thia-8-azaspiro[4.5]decan-3-ol Chemical compound C1C(O)C(C)SC21CCN(C)CC2 DEMBDVIMYBYOEO-UHFFFAOYSA-N 0.000 description 1
- HKJRQPFPEMYXCW-UHFFFAOYSA-N 2,8-dimethyl-3-methylidene-1-thia-8-azaspiro[4.5]decane Chemical compound C1C(=C)C(C)SC21CCN(C)CC2 HKJRQPFPEMYXCW-UHFFFAOYSA-N 0.000 description 1
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 1
- 125000004832 2-ethyl-1-methylethylene group Chemical group [H]C([H])([H])C([H])([H])C([H])([*:2])C([H])([*:1])C([H])([H])[H] 0.000 description 1
- UNYWJQCJOSOOBE-UHFFFAOYSA-N 2-ethyl-8-methyl-1-oxa-8-azaspiro[4.5]decan-3-one Chemical compound C1C(=O)C(CC)OC21CCN(C)CC2 UNYWJQCJOSOOBE-UHFFFAOYSA-N 0.000 description 1
- AVDJPQACQFGXMJ-UHFFFAOYSA-N 2-ethyl-8-methyl-3-methylidene-1-oxa-8-azaspiro[4.5]decane Chemical compound C1C(=C)C(CC)OC21CCN(C)CC2 AVDJPQACQFGXMJ-UHFFFAOYSA-N 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000004714 2-methylbutylthio group Chemical group CC(CS*)CC 0.000 description 1
- 125000004807 2-methylethylene group Chemical group [H]C([H])([H])C([H])([*:2])C([H])([H])[*:1] 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- SBOXIRRKTOEDTN-UHFFFAOYSA-N 3-ethylidene-2,8-dimethyl-1-oxa-8-azaspiro[4.5]decane Chemical compound O1C(C)C(=CC)CC11CCN(C)CC1 SBOXIRRKTOEDTN-UHFFFAOYSA-N 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- MGGVALXERJRIRO-UHFFFAOYSA-N 4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-2-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-1H-pyrazol-5-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C(=NN(C=1)CC(=O)N1CC2=C(CC1)NN=N2)O MGGVALXERJRIRO-UHFFFAOYSA-N 0.000 description 1
- OVTWFMGZHFOWHX-UHFFFAOYSA-N 8-ethyl-4-methyl-1-oxa-8-azaspiro[4.5]decan-3-ol Chemical compound C1CN(CC)CCC21C(C)C(O)CO2 OVTWFMGZHFOWHX-UHFFFAOYSA-N 0.000 description 1
- 102000012440 Acetylcholinesterase Human genes 0.000 description 1
- 108010022752 Acetylcholinesterase Proteins 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 1
- 125000006519 CCH3 Chemical group 0.000 description 1
- 102000017926 CHRM2 Human genes 0.000 description 1
- 108010058699 Choline O-acetyltransferase Proteins 0.000 description 1
- 102100023460 Choline O-acetyltransferase Human genes 0.000 description 1
- 108010009685 Cholinergic Receptors Proteins 0.000 description 1
- 101150012960 Chrm2 gene Proteins 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 108010015720 Dopamine beta-Hydroxylase Proteins 0.000 description 1
- 102100033156 Dopamine beta-hydroxylase Human genes 0.000 description 1
- 201000011240 Frontotemporal dementia Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 102000008214 Glutamate decarboxylase Human genes 0.000 description 1
- 108091022930 Glutamate decarboxylase Proteins 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 101100468997 Homo sapiens RIOK2 gene Proteins 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 102000010909 Monoamine Oxidase Human genes 0.000 description 1
- 108010062431 Monoamine oxidase Proteins 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- 238000007126 N-alkylation reaction Methods 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- RSDOPYMFZBJHRL-UHFFFAOYSA-N Oxotremorine Chemical compound O=C1CCCN1CC#CCN1CCCC1 RSDOPYMFZBJHRL-UHFFFAOYSA-N 0.000 description 1
- PIJVFDBKTWXHHD-UHFFFAOYSA-N Physostigmine Natural products C12=CC(OC(=O)NC)=CC=C2N(C)C2C1(C)CCN2C PIJVFDBKTWXHHD-UHFFFAOYSA-N 0.000 description 1
- 208000000609 Pick Disease of the Brain Diseases 0.000 description 1
- 102100022090 Serine/threonine-protein kinase RIO2 Human genes 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- 108091000117 Tyrosine 3-Monooxygenase Proteins 0.000 description 1
- 102000048218 Tyrosine 3-monooxygenases Human genes 0.000 description 1
- MNZMECMQTYGSOI-UHFFFAOYSA-N acetic acid;hydron;bromide Chemical compound Br.CC(O)=O MNZMECMQTYGSOI-UHFFFAOYSA-N 0.000 description 1
- 102000034337 acetylcholine receptors Human genes 0.000 description 1
- 229940022698 acetylcholinesterase Drugs 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- 229910000086 alane Inorganic materials 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000001118 alkylidene group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 210000004727 amygdala Anatomy 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 210000003192 autonomic ganglia Anatomy 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000001743 benzylic group Chemical group 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 230000003684 cardiac depression Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- UXTMROKLAAOEQO-UHFFFAOYSA-N chloroform;ethanol Chemical compound CCO.ClC(Cl)Cl UXTMROKLAAOEQO-UHFFFAOYSA-N 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 230000006949 cholinergic function Effects 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- GKIRPKYJQBWNGO-OCEACIFDSA-N clomifene Chemical compound C1=CC(OCCN(CC)CC)=CC=C1C(\C=1C=CC=CC=1)=C(\Cl)C1=CC=CC=C1 GKIRPKYJQBWNGO-OCEACIFDSA-N 0.000 description 1
- 230000019771 cognition Effects 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- YTKRILODNOEEPX-NSCUHMNNSA-N crotyl chloride Chemical compound C\C=C\CCl YTKRILODNOEEPX-NSCUHMNNSA-N 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000000911 decarboxylating effect Effects 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- NPOMSUOUAZCMBL-UHFFFAOYSA-N dichloromethane;ethoxyethane Chemical compound ClCCl.CCOCC NPOMSUOUAZCMBL-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
- AFLBAXPZSPPPIW-UHFFFAOYSA-N disodium;dioxidoboranylformonitrile Chemical compound [Na+].[Na+].[O-]B([O-])C#N AFLBAXPZSPPPIW-UHFFFAOYSA-N 0.000 description 1
- HFCSXCKLARAMIQ-UHFFFAOYSA-L disodium;sulfate;hydrate Chemical compound O.[Na+].[Na+].[O-]S([O-])(=O)=O HFCSXCKLARAMIQ-UHFFFAOYSA-L 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000012156 elution solvent Substances 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- LBAQSKZHMLAFHH-UHFFFAOYSA-N ethoxyethane;hydron;chloride Chemical compound Cl.CCOCC LBAQSKZHMLAFHH-UHFFFAOYSA-N 0.000 description 1
- LZCLXQDLBQLTDK-UHFFFAOYSA-N ethyl 2-hydroxypropanoate Chemical compound CCOC(=O)C(C)O LZCLXQDLBQLTDK-UHFFFAOYSA-N 0.000 description 1
- FAGRQKLLMXVQML-UHFFFAOYSA-N ethyl 3-hydroxy-2-methyl-1-oxa-8-azaspiro[4.5]decane-8-carboxylate Chemical compound C1CN(C(=O)OCC)CCC11OC(C)C(O)C1 FAGRQKLLMXVQML-UHFFFAOYSA-N 0.000 description 1
- GELSOTNVVKOYAW-UHFFFAOYSA-N ethyl(triphenyl)phosphanium Chemical compound C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CC)C1=CC=CC=C1 GELSOTNVVKOYAW-UHFFFAOYSA-N 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 125000004705 ethylthio group Chemical group C(C)S* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 230000008717 functional decline Effects 0.000 description 1
- 210000001156 gastric mucosa Anatomy 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
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 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 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000005935 hexyloxycarbonyl group Chemical group 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 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
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000005921 isopentoxy group Chemical group 0.000 description 1
- 125000005932 isopentyloxycarbonyl group Chemical group 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
- 210000003734 kidney Anatomy 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 229910052751 metal Chemical class 0.000 description 1
- 239000002184 metal Chemical class 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 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
- PAUXODZHHDWEKV-UHFFFAOYSA-N methyl(triphenyl)phosphanium;phosphane Chemical compound P.C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 PAUXODZHHDWEKV-UHFFFAOYSA-N 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 239000000472 muscarinic agonist Substances 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- AFFLGGQVNFXPEV-UHFFFAOYSA-N n-decene Natural products CCCCCCCCC=C AFFLGGQVNFXPEV-UHFFFAOYSA-N 0.000 description 1
- 125000005484 neopentoxy group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005933 neopentyloxycarbonyl group Chemical group 0.000 description 1
- 210000001577 neostriatum Anatomy 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- HVZWVEKIQMJYIK-UHFFFAOYSA-N nitryl chloride Chemical compound [O-][N+](Cl)=O HVZWVEKIQMJYIK-UHFFFAOYSA-N 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical group CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 238000011302 passive avoidance test Methods 0.000 description 1
- YWAKXRMUMFPDSH-UHFFFAOYSA-N pentene Chemical group CCCC=C YWAKXRMUMFPDSH-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000001148 pentyloxycarbonyl group Chemical group 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 239000010451 perlite Substances 0.000 description 1
- 235000019362 perlite Nutrition 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229960001697 physostigmine Drugs 0.000 description 1
- PIJVFDBKTWXHHD-HIFRSBDPSA-N physostigmine Chemical compound C12=CC(OC(=O)NC)=CC=C2N(C)[C@@H]2[C@@]1(C)CCN2C PIJVFDBKTWXHHD-HIFRSBDPSA-N 0.000 description 1
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- KOUKXHPPRFNWPP-UHFFFAOYSA-N pyrazine-2,5-dicarboxylic acid;hydrate Chemical compound O.OC(=O)C1=CN=C(C(O)=O)C=N1 KOUKXHPPRFNWPP-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 101150107611 rio2 gene Proteins 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
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 150000003413 spiro compounds Chemical class 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 235000013616 tea 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
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005922 tert-pentoxy group Chemical group 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005934 tert-pentyloxycarbonyl group Chemical group 0.000 description 1
- HWCKGOZZJDHMNC-UHFFFAOYSA-M tetraethylammonium bromide Chemical compound [Br-].CC[N+](CC)(CC)CC HWCKGOZZJDHMNC-UHFFFAOYSA-M 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 1
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 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
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/48—Oxygen atoms attached in position 4 having an acyclic carbon atom attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/10—Spiro-condensed systems
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Hydrogenated Pyridines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63251489A JPH0236183A (ja) | 1987-10-05 | 1988-10-04 | ヘテロ環式スピロ化合物及びその製法 |
| MX9203593A MX9203593A (es) | 1987-10-05 | 1992-06-26 | Compuestos espiro heterociclicos y metodos para prepararlos. |
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62-252104 | 1987-10-05 | ||
| JP25210487 | 1987-10-05 | ||
| JP62-286297 | 1987-11-12 | ||
| JP28629787 | 1987-11-12 | ||
| JP63-84327 | 1988-04-05 | ||
| JP8432788 | 1988-04-05 | ||
| JP63251489A JPH0236183A (ja) | 1987-10-05 | 1988-10-04 | ヘテロ環式スピロ化合物及びその製法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0236183A true JPH0236183A (ja) | 1990-02-06 |
| JPH0544948B2 JPH0544948B2 (enExample) | 1993-07-07 |
Family
ID=27304516
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63251489A Granted JPH0236183A (ja) | 1987-10-05 | 1988-10-04 | ヘテロ環式スピロ化合物及びその製法 |
Country Status (14)
| Country | Link |
|---|---|
| US (4) | US4940795A (enExample) |
| EP (1) | EP0311313B1 (enExample) |
| JP (1) | JPH0236183A (enExample) |
| KR (1) | KR970007947B1 (enExample) |
| CN (1) | CN1036653C (enExample) |
| AT (1) | ATE122353T1 (enExample) |
| AU (1) | AU621559B2 (enExample) |
| CA (1) | CA1337817C (enExample) |
| DE (1) | DE3853758T2 (enExample) |
| DK (1) | DK554288A (enExample) |
| ES (1) | ES2074441T3 (enExample) |
| GR (1) | GR3016995T3 (enExample) |
| HU (1) | HU211687A9 (enExample) |
| NO (1) | NO171109C (enExample) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992020683A1 (fr) * | 1991-05-15 | 1992-11-26 | Yamanouchi Pharmaceutical Co., Ltd. | L-tartrate de (-)-(s)-2,8-dimethyl-3-methylen-1-oxa-8-azaspiro[4,5]decane |
| EP0647642A1 (en) * | 1993-10-06 | 1995-04-12 | Sanwa Kagaku Kenkyusho Co., Ltd. | 1-Azabicyclo(3.3.0)octane derivatives and their use |
| JP2002534525A (ja) * | 1999-01-15 | 2002-10-15 | アストラゼネカ・アクチエボラーグ | 治療において有用なスピロフロピリジンの新規なアラルキルアミン |
| JP2003063964A (ja) * | 2001-08-28 | 2003-03-05 | Senju Pharmaceut Co Ltd | ドライアイまたはドライアイを伴なう疾病の予防治療剤 |
| JP2009541392A (ja) * | 2006-06-30 | 2009-11-26 | ウニヴェルシタ’ デリ ストゥディ ディ ミラノ | アルファ７受容体サブタイプ選択的なニコチン性アゴニスト、その製造方法およびそれの医薬組成物 |
| JP2015172098A (ja) * | 2009-01-26 | 2015-10-01 | イスラエル インスティトゥート フォー バイオロジカル リサーチ | 複素二環スピロ化合物又はその薬学的に許容される塩、これらの化合物を含む医薬組成物、および哺乳類のアルツハイマー病及びインスリン抵抗性症候群及び２型糖尿病を治療するための薬剤の調整における、これらの化合物の利用 |
Families Citing this family (40)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3853758T2 (de) * | 1987-10-05 | 1995-09-07 | Yamanouchi Pharma Co Ltd | Heterozyklische Spiroverbindungen und ihre Herstellung. |
| US5412096A (en) * | 1987-10-05 | 1995-05-02 | Yamanouchi Pharmaceutical Co., Ltd. | Hydrochloride salts of heterocyclic spiro compounds |
| US5594000A (en) * | 1989-06-21 | 1997-01-14 | Astra Ab | Spirofurane derivatives |
| US5075317A (en) * | 1989-06-21 | 1991-12-24 | Fisons Corporation | Spirofurane derivatives |
| US5407938A (en) * | 1990-04-10 | 1995-04-18 | Israel Institute For Biological Research | Certain 1-methyl-piperidine-4-spiro-4'-(1'-3'-oxazolines) and corresponding -(1',3' thiazolines) |
| US5534520A (en) * | 1990-04-10 | 1996-07-09 | Fisher; Abraham | Spiro compounds containing five-membered rings |
| US5852029A (en) * | 1990-04-10 | 1998-12-22 | Israel Institute For Biological Research | Aza spiro compounds acting on the cholinergic system with muscarinic agonist activity |
| US5073560A (en) * | 1990-07-20 | 1991-12-17 | Fisons Corporation | Spiro-isoxazolidine derivatives as cholinergic agents |
| IE914238A1 (en) * | 1990-12-19 | 1992-07-01 | Fisons Corp | Novel spirofurane derivatives |
| ES2119174T3 (es) * | 1993-01-28 | 1998-10-01 | Merck & Co Inc | Azaciclos espiro-sustituidos como antagonistas de los receptores de las taquiquininas. |
| ATE166650T1 (de) * | 1993-03-04 | 1998-06-15 | Pfizer | Spiroazacyclischderivate als substanz p antagonisten |
| NZ500643A (en) | 1997-05-30 | 2001-12-21 | Neurosearch As | Spiro-quinuclidine derivatives and their use in treating conditions responsive to nicotinic ACh receptor modulators |
| US6528529B1 (en) | 1998-03-31 | 2003-03-04 | Acadia Pharmaceuticals Inc. | Compounds with activity on muscarinic receptors |
| WO2001011968A2 (en) * | 1999-08-13 | 2001-02-22 | Aventis Cropscience Gmbh | Heterocyclic spiro compounds as pesticides |
| EP1328261A2 (en) * | 2000-04-12 | 2003-07-23 | Minerva Biotechnologies Corporation | Treatment of neurodegenerative disease |
| US7780981B2 (en) | 2004-09-13 | 2010-08-24 | Chrono Therapeutics, Inc. | Biosynchronous transdermal drug delivery |
| KR20080031430A (ko) * | 2005-07-26 | 2008-04-08 | 센주 세이야꾸 가부시키가이샤 | 경피적으로 흡수가능한 안과용 제제 |
| US7678363B2 (en) * | 2005-08-26 | 2010-03-16 | Braincells Inc | Methods of treating psychiatric conditions comprising administration of muscarinic agents in combination with SSRIs |
| EP2258358A3 (en) | 2005-08-26 | 2011-09-07 | Braincells, Inc. | Neurogenesis with acetylcholinesterase inhibitor |
| EP2377530A3 (en) | 2005-10-21 | 2012-06-20 | Braincells, Inc. | Modulation of neurogenesis by PDE inhibition |
| EP1942879A1 (en) | 2005-10-31 | 2008-07-16 | Braincells, Inc. | Gaba receptor mediated modulation of neurogenesis |
| US20100216734A1 (en) | 2006-03-08 | 2010-08-26 | Braincells, Inc. | Modulation of neurogenesis by nootropic agents |
| AU2007223036A1 (en) * | 2006-03-08 | 2007-09-13 | Braincells, Inc. | Modulation of neurogenesis by nootropic agents |
| US7678808B2 (en) | 2006-05-09 | 2010-03-16 | Braincells, Inc. | 5 HT receptor mediated neurogenesis |
| US20100009983A1 (en) * | 2006-05-09 | 2010-01-14 | Braincells, Inc. | 5 ht receptor mediated neurogenesis |
| WO2007134136A2 (en) | 2006-05-09 | 2007-11-22 | Braincells, Inc. | Neurogenesis by modulating angiotensin |
| AU2007292848A1 (en) | 2006-09-08 | 2008-03-13 | Braincells, Inc. | Combinations containing a 4-acylaminopyridine derivative |
| US20100184806A1 (en) | 2006-09-19 | 2010-07-22 | Braincells, Inc. | Modulation of neurogenesis by ppar agents |
| US20080103165A1 (en) * | 2006-09-19 | 2008-05-01 | Braincells, Inc. | Ppar mediated modulation of neurogenesis |
| US20080103105A1 (en) * | 2006-09-22 | 2008-05-01 | Braincells, Inc. | HMG CoA REDUCTASE MEDIATED MODULATION OF NEUROGENESIS |
| KR101122469B1 (ko) | 2007-04-02 | 2012-07-12 | 파킨슨즈 인스티튜트 | 처치 치료의 부작용을 감소시키기 위한 방법 및 조성물 |
| US9034891B2 (en) | 2009-01-26 | 2015-05-19 | Israel Institute For Biological Research | Bicyclic heterocyclic spiro compounds |
| US20100216805A1 (en) | 2009-02-25 | 2010-08-26 | Braincells, Inc. | Modulation of neurogenesis using d-cycloserine combinations |
| EP2882428B1 (en) | 2012-07-13 | 2019-01-16 | Pain Therapeutics, Inc. | A method of inhibiting tau phosphorylation |
| US9433604B2 (en) | 2013-10-08 | 2016-09-06 | Pain Therapeutics Inc. | Method for inhibiting growth of cancer cells |
| JP2018511355A (ja) | 2015-01-28 | 2018-04-26 | クロノ セラピューティクス インコーポレイテッドＣｈｒｏｎｏ Ｔｈｅｒａｐｅｕｔｉｃｓ Ｉｎｃ． | 薬剤送達方法及びシステム |
| WO2018129304A1 (en) | 2017-01-06 | 2018-07-12 | Chrono Therapeutics Inc. | Transdermal drug delivery devices and methods |
| CA3101966A1 (en) | 2018-05-29 | 2019-12-05 | Morningside Venture Investments Limited | Drug delivery methods and systems |
| MA54245A (fr) | 2018-11-16 | 2022-02-23 | Morningside Venture Investments Ltd | Système d'administration transdermique de médicaments à régulation thermique |
| CN115124545B (zh) * | 2022-08-31 | 2023-01-03 | 南京远淑医药科技有限公司 | 一种促性腺激素释放激素受体拮抗剂中间体的合成方法 |
Family Cites Families (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3305556A (en) * | 1962-11-23 | 1967-02-21 | Pfizer & Co C | Novel hypoglycemic agents |
| NL124853C (enExample) * | 1963-07-19 | |||
| SU335944A1 (ru) * | 1970-12-15 | 1976-01-25 | Научно-исследовательский институт химии Саратовского государственного университета им.Н.Г.Чернышевского | Способ получени соединений р да 1-окса6-азаспиро(4,4)нонана |
| US3784551A (en) * | 1971-07-08 | 1974-01-08 | Yoshitomi Pharmaceutical | 2-oxo-1,4-dioxa-8-azaspiro (4.5) decanes and related compounds |
| GB1301254A (enExample) * | 1971-07-08 | 1972-12-29 | ||
| US3839273A (en) * | 1971-11-13 | 1974-10-01 | Sankyo Co | N-substituted piperidine derivatives, process for preparing the same and their use as stabilizers |
| SU434735A1 (ru) * | 1972-03-01 | 1975-12-15 | Научно-исследовательский институт химии Саратовского государственного университета им.Н.Г.Чернышевского | Способ получени 7-метил-(или 2,7диметил)-2-метокси- -пропионитрил1-окса-6-азаспиро-(4,4)-нонана |
| SU465399A1 (ru) * | 1973-07-19 | 1975-03-30 | Научно-исследовательский институт химии при Саратовском государственном университете им.Н.Г.Чернышевского | Способ получени натриевых солей 2-метокси- -карбоксиэтил-1-окса6-азаспиро-(4,4)-нонана |
| IL48452A (en) * | 1975-11-11 | 1979-07-25 | Purdue Frederick Co | Spiro (1,3-dioxolane-4,3') quinuclidines,their preparationand pharmaceutical compositions comprising them |
| US4321379A (en) * | 1981-01-28 | 1982-03-23 | American Cyanamid Company | 4-Aryl-1-oxa-8-azaspiro[4,5]dec-3-en-2-ones |
| SU1002294A1 (ru) * | 1981-08-14 | 1983-03-07 | Ордена Трудового Красного Знамени Институт Тонкой Органической Химии Им.А.Л.Мнджояна | 2,2-Диалкил-3-тиа-8-азаспиро/5,5/ундеканы |
| EP0189370A3 (de) * | 1985-01-16 | 1988-01-27 | Sandoz Ag | Spiro-dioxolane, -dithiolane und -oxothiolane |
| US4855290A (en) * | 1985-05-10 | 1989-08-08 | State Of Israel, Represented By Prime Minister's Office, Israel Institute For Biological Research | Derivatives of quinuclidine |
| US4981858A (en) * | 1987-08-13 | 1991-01-01 | State Of Israel, Represented By The Prime Minister's Office, Israel Institute For Biological Research | Optical isomers |
| DE3853758T2 (de) * | 1987-10-05 | 1995-09-07 | Yamanouchi Pharma Co Ltd | Heterozyklische Spiroverbindungen und ihre Herstellung. |
| US5073560A (en) * | 1990-07-20 | 1991-12-17 | Fisons Corporation | Spiro-isoxazolidine derivatives as cholinergic agents |
-
1988
- 1988-09-30 DE DE3853758T patent/DE3853758T2/de not_active Expired - Lifetime
- 1988-09-30 ES ES88309095T patent/ES2074441T3/es not_active Expired - Lifetime
- 1988-09-30 EP EP88309095A patent/EP0311313B1/en not_active Expired - Lifetime
- 1988-09-30 AT AT88309095T patent/ATE122353T1/de not_active IP Right Cessation
- 1988-10-03 CA CA000579193A patent/CA1337817C/en not_active Expired - Fee Related
- 1988-10-04 JP JP63251489A patent/JPH0236183A/ja active Granted
- 1988-10-04 NO NO884406A patent/NO171109C/no unknown
- 1988-10-04 DK DK554288A patent/DK554288A/da not_active Application Discontinuation
- 1988-10-05 AU AU23449/88A patent/AU621559B2/en not_active Ceased
- 1988-10-05 CN CN88109138A patent/CN1036653C/zh not_active Expired - Fee Related
- 1988-10-05 KR KR1019880012963A patent/KR970007947B1/ko not_active Expired - Fee Related
- 1988-10-05 US US07/254,375 patent/US4940795A/en not_active Ceased
-
1990
- 1990-01-25 US US07/470,093 patent/US5041549A/en not_active Expired - Fee Related
- 1990-01-25 US US07/470,091 patent/US4996210A/en not_active Expired - Fee Related
-
1992
- 1992-07-07 US US07/909,639 patent/USRE34653E/en not_active Expired - Lifetime
-
1995
- 1995-06-30 HU HU95P/P00638P patent/HU211687A9/hu unknown
- 1995-08-02 GR GR950402111T patent/GR3016995T3/el unknown
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992020683A1 (fr) * | 1991-05-15 | 1992-11-26 | Yamanouchi Pharmaceutical Co., Ltd. | L-tartrate de (-)-(s)-2,8-dimethyl-3-methylen-1-oxa-8-azaspiro[4,5]decane |
| EP0647642A1 (en) * | 1993-10-06 | 1995-04-12 | Sanwa Kagaku Kenkyusho Co., Ltd. | 1-Azabicyclo(3.3.0)octane derivatives and their use |
| US5530138A (en) * | 1993-10-06 | 1996-06-25 | Sanwa Kagaku Kenkyusho Co., Ltd. | Compounds and use thereof |
| JP2002534525A (ja) * | 1999-01-15 | 2002-10-15 | アストラゼネカ・アクチエボラーグ | 治療において有用なスピロフロピリジンの新規なアラルキルアミン |
| JP2003063964A (ja) * | 2001-08-28 | 2003-03-05 | Senju Pharmaceut Co Ltd | ドライアイまたはドライアイを伴なう疾病の予防治療剤 |
| JP2009541392A (ja) * | 2006-06-30 | 2009-11-26 | ウニヴェルシタ’ デリ ストゥディ ディ ミラノ | アルファ７受容体サブタイプ選択的なニコチン性アゴニスト、その製造方法およびそれの医薬組成物 |
| JP2015172098A (ja) * | 2009-01-26 | 2015-10-01 | イスラエル インスティトゥート フォー バイオロジカル リサーチ | 複素二環スピロ化合物又はその薬学的に許容される塩、これらの化合物を含む医薬組成物、および哺乳類のアルツハイマー病及びインスリン抵抗性症候群及び２型糖尿病を治療するための薬剤の調整における、これらの化合物の利用 |
Also Published As
| Publication number | Publication date |
|---|---|
| USRE34653E (en) | 1994-07-05 |
| AU2344988A (en) | 1989-04-06 |
| EP0311313A3 (en) | 1990-12-05 |
| DK554288D0 (da) | 1988-10-04 |
| NO884406L (no) | 1989-04-06 |
| KR890006649A (ko) | 1989-06-15 |
| HU211687A9 (en) | 1995-12-28 |
| KR970007947B1 (ko) | 1997-05-19 |
| CA1337817C (en) | 1995-12-26 |
| NO884406D0 (no) | 1988-10-04 |
| US4996210A (en) | 1991-02-26 |
| JPH0544948B2 (enExample) | 1993-07-07 |
| DK554288A (da) | 1989-05-26 |
| NO171109C (no) | 1993-01-27 |
| DE3853758T2 (de) | 1995-09-07 |
| AU621559B2 (en) | 1992-03-19 |
| ES2074441T3 (es) | 1995-09-16 |
| DE3853758D1 (de) | 1995-06-14 |
| CN1036653C (zh) | 1997-12-10 |
| CN1033629A (zh) | 1989-07-05 |
| EP0311313B1 (en) | 1995-05-10 |
| US5041549A (en) | 1991-08-20 |
| GR3016995T3 (en) | 1995-11-30 |
| ATE122353T1 (de) | 1995-05-15 |
| US4940795A (en) | 1990-07-10 |
| NO171109B (no) | 1992-10-19 |
| EP0311313A2 (en) | 1989-04-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JPH0236183A (ja) | ヘテロ環式スピロ化合物及びその製法 | |
| JPH05507687A (ja) | キヌクリジン誘導体 | |
| EP1931652A2 (en) | Amido compounds and their use as pharmaceuticals | |
| HU222726B1 (hu) | Piperidinszármazékok, eljárás elżállításukra és az ezeket tartalmazó gyógyszerkészítmények | |
| JPWO1996014297A1 (ja) | 新規なラクタム誘導体 | |
| WO2007049798A1 (ja) | 新規ベンゾオキサチイン誘導体 | |
| KR20080063288A (ko) | 신규 융합 피롤 유도체 | |
| JP2009541251A (ja) | 置換フェニルメタノン誘導体 | |
| US5412096A (en) | Hydrochloride salts of heterocyclic spiro compounds | |
| KR100425953B1 (ko) | 티오피란유도체 | |
| HU201020B (en) | Process for producine new naphthalene derivatives and pharmaceutical compositions comprising same | |
| AT414125B (de) | Neue derivate des 4a,5,9,10,11,12-hexahydro- benzofuro(3a,3,2)(2) benzazepin, verfahren zu deren herstellung sowie deren verwendung zur herstellung von arzneimitteln | |
| US4447434A (en) | Substituted dibenzodiazepinones | |
| CA1337770C (en) | Hydrocarbon substituted pyrrolidinones | |
| JP3308507B2 (ja) | スピロ〔ピペリジン−４，１′−ピロロ〔３，４−ｃ〕ピロール〕 | |
| JPS5959685A (ja) | 新規なピペリジン誘導体 | |
| US5843945A (en) | AMPA antagonists and a method of treatment | |
| KR100392060B1 (ko) | 5-ht2수용체에대한친화성을가진치환된테트라사이클릭아제핀유도체 | |
| EP0001585B1 (de) | Piperazino-pyrrolobenzodiazepine, Verfahren zu ihrer Herstellung sowie pharmazeutische Präparate enthaltend diese Verbindungen | |
| JPH02164882A (ja) | スピロ化合物及びその中間体 | |
| CN1950370B (zh) | 对映体纯的六氢吡咯并环戊吡啶-衍生物 | |
| JPH0288576A (ja) | ラセミ型スピロヒダントインの新規な分割方法 | |
| EP1409490B1 (en) | 2-(aminomethyl)-tetrahydro-9-oxa-1,3-diaza-cyclopenta a|naphthalenyl derivatives with antipsychotic activity | |
| Takahashi et al. | Photochemistry of 5-methylpyrimidin-4-ones in acetic acid solution: thermal rearrangements of Dewar pyrimidinones and 4-acetoxyazetidin-2-ones | |
| JPH0751566B2 (ja) | ２−ピペラジノピリミジン誘導体 |