CN110818720A - Melatonin (MT1/MT2) receptor agonist, preparation method and application thereof - Google Patents
Melatonin (MT1/MT2) receptor agonist, preparation method and application thereof Download PDFInfo
- Publication number
- CN110818720A CN110818720A CN201911135165.9A CN201911135165A CN110818720A CN 110818720 A CN110818720 A CN 110818720A CN 201911135165 A CN201911135165 A CN 201911135165A CN 110818720 A CN110818720 A CN 110818720A
- Authority
- CN
- China
- Prior art keywords
- formula
- compound
- reaction
- compound shown
- solvent
- 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
- YJPIGAIKUZMOQA-UHFFFAOYSA-N Melatonin Natural products COC1=CC=C2N(C(C)=O)C=C(CCN)C2=C1 YJPIGAIKUZMOQA-UHFFFAOYSA-N 0.000 title claims abstract description 45
- 229960003987 melatonin Drugs 0.000 title claims abstract description 45
- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 title claims abstract description 45
- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- 239000000018 receptor agonist Substances 0.000 title abstract description 20
- 229940044601 receptor agonist Drugs 0.000 title abstract description 20
- 239000003814 drug Substances 0.000 claims abstract description 27
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims description 529
- 238000006243 chemical reaction Methods 0.000 claims description 155
- -1 hydroxy, amino Chemical group 0.000 claims description 92
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 claims description 26
- 206010022437 insomnia Diseases 0.000 claims description 25
- 239000001257 hydrogen Substances 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 22
- 230000003287 optical effect Effects 0.000 claims description 20
- 150000002431 hydrogen Chemical class 0.000 claims description 16
- 239000007800 oxidant agent Substances 0.000 claims description 16
- 239000000126 substance Substances 0.000 claims description 16
- 239000003513 alkali Substances 0.000 claims description 14
- 230000001590 oxidative effect Effects 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- 230000008569 process Effects 0.000 claims description 10
- 239000004480 active ingredient Substances 0.000 claims description 9
- 238000005886 esterification reaction Methods 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
- 238000011282 treatment Methods 0.000 claims description 9
- 208000019901 Anxiety disease Diseases 0.000 claims description 8
- 230000036506 anxiety Effects 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 238000009833 condensation Methods 0.000 claims description 6
- 230000005494 condensation Effects 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 230000032050 esterification Effects 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 208000035475 disorder Diseases 0.000 claims description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 3
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 201000010099 disease Diseases 0.000 abstract description 10
- 208000024891 symptom Diseases 0.000 abstract description 5
- 230000004071 biological effect Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 228
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 196
- 239000002904 solvent Substances 0.000 description 85
- 238000004809 thin layer chromatography Methods 0.000 description 84
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 82
- 230000015572 biosynthetic process Effects 0.000 description 80
- 238000003786 synthesis reaction Methods 0.000 description 80
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 75
- 238000005406 washing Methods 0.000 description 63
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 62
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 62
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 59
- 238000001914 filtration Methods 0.000 description 59
- 238000001704 evaporation Methods 0.000 description 58
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 56
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 55
- 238000001035 drying Methods 0.000 description 52
- 238000003756 stirring Methods 0.000 description 48
- 239000000243 solution Substances 0.000 description 47
- 239000007787 solid Substances 0.000 description 46
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 45
- 239000012074 organic phase Substances 0.000 description 42
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 41
- 239000003208 petroleum Substances 0.000 description 41
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 40
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 39
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 38
- 239000003960 organic solvent Substances 0.000 description 38
- 238000004440 column chromatography Methods 0.000 description 36
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 33
- 238000005160 1H NMR spectroscopy Methods 0.000 description 30
- 230000007958 sleep Effects 0.000 description 30
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 29
- 102100029698 Metallothionein-1A Human genes 0.000 description 28
- YLXDSYKOBKBWJQ-LBPRGKRZSA-N N-[2-[(8S)-2,6,7,8-tetrahydro-1H-cyclopenta[e]benzofuran-8-yl]ethyl]propanamide Chemical compound C1=C2OCCC2=C2[C@H](CCNC(=O)CC)CCC2=C1 YLXDSYKOBKBWJQ-LBPRGKRZSA-N 0.000 description 28
- 230000000694 effects Effects 0.000 description 28
- 229960001150 ramelteon Drugs 0.000 description 28
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- 235000019441 ethanol Nutrition 0.000 description 23
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 22
- 239000007788 liquid Substances 0.000 description 22
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 21
- 230000035484 reaction time Effects 0.000 description 20
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 18
- 239000000010 aprotic solvent Substances 0.000 description 18
- 229940079593 drug Drugs 0.000 description 18
- 239000011734 sodium Substances 0.000 description 17
- 230000037053 non-rapid eye movement Effects 0.000 description 16
- 238000010791 quenching Methods 0.000 description 16
- 238000002474 experimental method Methods 0.000 description 15
- 239000000203 mixture Substances 0.000 description 15
- 239000012043 crude product Substances 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 13
- 239000002585 base Substances 0.000 description 13
- 238000001816 cooling Methods 0.000 description 13
- 238000001727 in vivo Methods 0.000 description 13
- 102000005962 receptors Human genes 0.000 description 13
- 108020003175 receptors Proteins 0.000 description 13
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 12
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
- 229940125797 compound 12 Drugs 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- 239000003153 chemical reaction reagent Substances 0.000 description 11
- 238000010438 heat treatment Methods 0.000 description 11
- 239000012046 mixed solvent Substances 0.000 description 11
- 239000003586 protic polar solvent Substances 0.000 description 11
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 10
- XWSCOGPKWVNQSV-UHFFFAOYSA-N 5-bromo-2,3-dichloropyridine Chemical compound ClC1=CC(Br)=CN=C1Cl XWSCOGPKWVNQSV-UHFFFAOYSA-N 0.000 description 9
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 241000700159 Rattus Species 0.000 description 9
- 239000011575 calcium Substances 0.000 description 9
- 229910052791 calcium Inorganic materials 0.000 description 9
- 229960005111 zolpidem tartrate Drugs 0.000 description 9
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 8
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 8
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- 238000004904 shortening Methods 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 7
- 239000007853 buffer solution Substances 0.000 description 7
- 238000001514 detection method Methods 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 230000028327 secretion Effects 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 229910052786 argon Inorganic materials 0.000 description 6
- 238000004296 chiral HPLC Methods 0.000 description 6
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical group CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 239000005457 ice water Substances 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 150000007529 inorganic bases Chemical group 0.000 description 6
- 239000012280 lithium aluminium hydride Substances 0.000 description 6
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical group O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 6
- 150000007530 organic bases Chemical class 0.000 description 6
- 230000004620 sleep latency Effects 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- 210000000221 suprachiasmatic nucleus Anatomy 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 239000007821 HATU Substances 0.000 description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 230000001270 agonistic effect Effects 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 210000004556 brain Anatomy 0.000 description 5
- 210000005013 brain tissue Anatomy 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 238000009826 distribution Methods 0.000 description 5
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 5
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 5
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 5
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical group Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- OUVXYXNWSVIOSJ-UHFFFAOYSA-N Fluo-4 Chemical compound CC1=CC=C(N(CC(O)=O)CC(O)=O)C(OCCOC=2C(=CC=C(C=2)C2=C3C=C(F)C(=O)C=C3OC3=CC(O)=C(F)C=C32)N(CC(O)=O)CC(O)=O)=C1 OUVXYXNWSVIOSJ-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 102000001419 Melatonin receptor Human genes 0.000 description 4
- 108050009605 Melatonin receptor Proteins 0.000 description 4
- 102100024930 Melatonin receptor type 1A Human genes 0.000 description 4
- 101710098568 Melatonin receptor type 1A Proteins 0.000 description 4
- 102100024970 Melatonin receptor type 1B Human genes 0.000 description 4
- 101710098567 Melatonin receptor type 1B Proteins 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 230000000147 hypnotic effect Effects 0.000 description 4
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical group [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 4
- 230000001737 promoting effect Effects 0.000 description 4
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 4
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000002639 sodium chloride Nutrition 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical group [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 3
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 3
- 239000000556 agonist Substances 0.000 description 3
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 230000037007 arousal Effects 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 239000003326 hypnotic agent Substances 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 239000008297 liquid dosage form Substances 0.000 description 3
- 150000002825 nitriles Chemical class 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 210000001525 retina Anatomy 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- 125000004778 2,2-difluoroethyl group Chemical group [H]C([H])(*)C([H])(F)F 0.000 description 2
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical compound CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 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
- 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 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- PLUBXMRUUVWRLT-UHFFFAOYSA-N Ethyl methanesulfonate Chemical compound CCOS(C)(=O)=O PLUBXMRUUVWRLT-UHFFFAOYSA-N 0.000 description 2
- 241000400611 Eucalyptus deanei Species 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- 102000004300 GABA-A Receptors Human genes 0.000 description 2
- 108090000839 GABA-A Receptors Proteins 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 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
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 235000008331 Pinus X rigitaeda Nutrition 0.000 description 2
- 235000011613 Pinus brutia Nutrition 0.000 description 2
- 241000018646 Pinus brutia Species 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-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
- 102000014384 Type C Phospholipases Human genes 0.000 description 2
- 108010079194 Type C Phospholipases Proteins 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000012752 auxiliary agent Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 description 2
- KQIADDMXRMTWHZ-UHFFFAOYSA-N chloro-tri(propan-2-yl)silane Chemical compound CC(C)[Si](Cl)(C(C)C)C(C)C KQIADDMXRMTWHZ-UHFFFAOYSA-N 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical group C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 230000027288 circadian rhythm Effects 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 description 2
- HQWPLXHWEZZGKY-UHFFFAOYSA-N diethylzinc Chemical compound CC[Zn]CC HQWPLXHWEZZGKY-UHFFFAOYSA-N 0.000 description 2
- NZZFYRREKKOMAT-UHFFFAOYSA-N diiodomethane Chemical compound ICI NZZFYRREKKOMAT-UHFFFAOYSA-N 0.000 description 2
- JMVOCSLPMGHXPG-UHFFFAOYSA-N dipotassium;dioxido(dioxo)osmium Chemical group [K+].[K+].[O-][Os]([O-])(=O)=O JMVOCSLPMGHXPG-UHFFFAOYSA-N 0.000 description 2
- 206010013663 drug dependence Diseases 0.000 description 2
- 230000036267 drug metabolism Effects 0.000 description 2
- 239000000975 dye Substances 0.000 description 2
- 230000000517 effect on sleep Effects 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 2
- FKBSHNBSEUWDAC-UHFFFAOYSA-L lithium sodium dihydroxide Chemical compound [Li+].[OH-].[OH-].[Na+] FKBSHNBSEUWDAC-UHFFFAOYSA-L 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 2
- 210000004560 pineal gland Anatomy 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- 239000012286 potassium permanganate Substances 0.000 description 2
- 229940080818 propionamide Drugs 0.000 description 2
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 2
- 229960004063 propylene glycol Drugs 0.000 description 2
- 235000013772 propylene glycol Nutrition 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 230000004461 rapid eye movement Effects 0.000 description 2
- 230000036385 rapid eye movement (rem) sleep Effects 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinol Chemical compound OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 description 2
- 230000033764 rhythmic process Effects 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000008159 sesame oil Substances 0.000 description 2
- 235000011803 sesame oil Nutrition 0.000 description 2
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical group [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 description 2
- 229960002218 sodium chlorite Drugs 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 description 2
- 239000007909 solid dosage form Substances 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 208000011117 substance-related disease Diseases 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- VEPTXBCIDSFGBF-UHFFFAOYSA-M tetrabutylazanium;fluoride;trihydrate Chemical compound O.O.O.[F-].CCCC[N+](CCCC)(CCCC)CCCC VEPTXBCIDSFGBF-UHFFFAOYSA-M 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical class OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
- OOSZCNKVJAVHJI-UHFFFAOYSA-N 1-[(4-fluorophenyl)methyl]piperazine Chemical compound C1=CC(F)=CC=C1CN1CCNCC1 OOSZCNKVJAVHJI-UHFFFAOYSA-N 0.000 description 1
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 1
- XGDRLCRGKUCBQL-UHFFFAOYSA-N 1h-imidazole-4,5-dicarbonitrile Chemical compound N#CC=1N=CNC=1C#N XGDRLCRGKUCBQL-UHFFFAOYSA-N 0.000 description 1
- OVRWUZYZECPJOB-UHFFFAOYSA-N 2,2-difluoroethanamine Chemical compound NCC(F)F OVRWUZYZECPJOB-UHFFFAOYSA-N 0.000 description 1
- STJFPPKIYLSEKU-UHFFFAOYSA-N 2-(2,6,7,8-tetrahydro-1h-cyclopenta[e][1]benzofuran-8-yl)acetic acid Chemical compound C1=C2OCCC2=C2C(CC(=O)O)CCC2=C1 STJFPPKIYLSEKU-UHFFFAOYSA-N 0.000 description 1
- LAZMLZWHPBPTMK-JTQLQIEISA-N 2-[(8S)-2,6,7,8-tetrahydro-1H-cyclopenta[e][1]benzofuran-8-yl]ethanol Chemical compound C1C2=C(OC1)C=CC=1CC[C@H](C=12)CCO LAZMLZWHPBPTMK-JTQLQIEISA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- FXXUEMLOXFREQD-UHFFFAOYSA-N 6,7-difluoro-2,3-dihydro-1-benzofuran Chemical compound FC1=C(C2=C(CCO2)C=C1)F FXXUEMLOXFREQD-UHFFFAOYSA-N 0.000 description 1
- XBZLTCXFWSZLHA-UHFFFAOYSA-N 6,7-difluoro-2,3-dihydro-1-benzofuran-5-ol Chemical compound FC1=C(F)C(O)=CC2=C1OCC2 XBZLTCXFWSZLHA-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 235000003276 Apios tuberosa Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 235000010744 Arachis villosulicarpa Nutrition 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- 208000017164 Chronobiology disease Diseases 0.000 description 1
- 241000195493 Cryptophyta Species 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 244000166102 Eucalyptus leucoxylon Species 0.000 description 1
- 235000004694 Eucalyptus leucoxylon Nutrition 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 108091006027 G proteins Proteins 0.000 description 1
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
- 102000030782 GTP binding Human genes 0.000 description 1
- 108091000058 GTP-Binding Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 206010021033 Hypomenorrhoea Diseases 0.000 description 1
- 108091008585 IP3 receptors Proteins 0.000 description 1
- 102000007640 Inositol 1,4,5-Trisphosphate Receptors Human genes 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 239000000232 Lipid Bilayer Substances 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 240000007817 Olea europaea Species 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 235000004443 Ricinus communis Nutrition 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- 239000012317 TBTU Substances 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000008272 agar Substances 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
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000011609 ammonium molybdate Substances 0.000 description 1
- 235000018660 ammonium molybdate Nutrition 0.000 description 1
- APUPEJJSWDHEBO-UHFFFAOYSA-P ammonium molybdate Chemical compound [NH4+].[NH4+].[O-][Mo]([O-])(=O)=O APUPEJJSWDHEBO-UHFFFAOYSA-P 0.000 description 1
- 229940010552 ammonium molybdate Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 229940125717 barbiturate Drugs 0.000 description 1
- 210000004227 basal ganglia Anatomy 0.000 description 1
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 1
- 239000012965 benzophenone Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 230000003185 calcium uptake Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 210000003855 cell nucleus Anatomy 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 210000003198 cerebellar cortex Anatomy 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000002060 circadian Effects 0.000 description 1
- 230000007012 clinical effect Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000010835 comparative analysis Methods 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- LDHQCZJRKDOVOX-NSCUHMNNSA-M crotonate Chemical compound C\C=C\C([O-])=O LDHQCZJRKDOVOX-NSCUHMNNSA-M 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- VDCSGNNYCFPWFK-UHFFFAOYSA-N diphenylsilane Chemical compound C=1C=CC=CC=1[SiH2]C1=CC=CC=C1 VDCSGNNYCFPWFK-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- YHGVZVYRHWZVKI-HYXAFXHYSA-N ethyl (z)-2-bromobut-2-enoate Chemical compound CCOC(=O)C(\Br)=C\C YHGVZVYRHWZVKI-HYXAFXHYSA-N 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- PAVZHTXVORCEHP-UHFFFAOYSA-N ethylboronic acid Chemical compound CCB(O)O PAVZHTXVORCEHP-UHFFFAOYSA-N 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 210000001508 eye Anatomy 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 239000012025 fluorinating agent Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000000499 gel 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
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 210000002149 gonad Anatomy 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000001320 hippocampus Anatomy 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- ZTUJDPKOHPKRMO-UHFFFAOYSA-N hydron;2,2,2-trifluoroethanamine;chloride Chemical compound Cl.NCC(F)(F)F ZTUJDPKOHPKRMO-UHFFFAOYSA-N 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000001939 inductive effect Effects 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
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 239000008274 jelly Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000003041 laboratory chemical Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 230000002366 lipolytic effect Effects 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000005228 liver tissue Anatomy 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 210000005075 mammary gland Anatomy 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000012528 membrane Substances 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
- 229920000609 methyl cellulose Polymers 0.000 description 1
- LSEFCHWGJNHZNT-UHFFFAOYSA-M methyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 LSEFCHWGJNHZNT-UHFFFAOYSA-M 0.000 description 1
- KTMKRRPZPWUYKK-UHFFFAOYSA-N methylboronic acid Chemical compound CB(O)O KTMKRRPZPWUYKK-UHFFFAOYSA-N 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 210000004940 nucleus Anatomy 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- DHRLEVQXOMLTIM-UHFFFAOYSA-N phosphoric acid;trioxomolybdenum Chemical compound O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.OP(O)(O)=O DHRLEVQXOMLTIM-UHFFFAOYSA-N 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- HDMGAZBPFLDBCX-UHFFFAOYSA-M potassium;sulfooxy sulfate Chemical compound [K+].OS(=O)(=O)OOS([O-])(=O)=O HDMGAZBPFLDBCX-UHFFFAOYSA-M 0.000 description 1
- 230000002360 prefrontal effect Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 229940059364 ramelteon 8 mg Drugs 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 229940074545 sodium dihydrogen phosphate dihydrate Drugs 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 210000003523 substantia nigra Anatomy 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid group Chemical group S(N)(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 210000001103 thalamus Anatomy 0.000 description 1
- 229940126680 traditional chinese medicines Drugs 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 1
- UAEJRRZPRZCUBE-UHFFFAOYSA-N trimethoxyalumane Chemical compound [Al+3].[O-]C.[O-]C.[O-]C UAEJRRZPRZCUBE-UHFFFAOYSA-N 0.000 description 1
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 1
- HYWCXWRMUZYRPH-UHFFFAOYSA-N trimethyl(prop-2-enyl)silane Chemical compound C[Si](C)(C)CC=C HYWCXWRMUZYRPH-UHFFFAOYSA-N 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 210000004515 ventral tegmental area Anatomy 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 230000002618 waking effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-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
- A61P25/20—Hypnotics; Sedatives
-
- 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
- A61P25/22—Anxiolytics
-
- 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
- A61P25/24—Antidepressants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
-
- 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
- C07B2200/07—Optical isomers
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Neurology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Anesthesiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to melatonin (MT1/MT2) receptor agonists, a preparation method and application thereof. Specifically, the invention provides a novel melatonin (MT1/MT2) receptor agonist, a preparation method and application thereof in preparing medicaments for treating diseases or symptoms related to melatonin (MT1/MT2) receptors. The melatonin (MT1/MT2) receptor agonist has good biological activity.
Description
Technical Field
The invention belongs to the fields of pharmacology, medicinal chemistry and pharmacology, and particularly relates to a novel melatonin (MT1/MT2) receptor agonist, a preparation method thereof, and application of the compound in medicines for treating diseases or symptoms such as insomnia, anxiety, depression and the like related to melatonin (MT1/MT2) receptors.
Background
Insomnia is a common clinical condition, and the incidence rate is very high. It has been reported that the prevalence of insomnia in the united states over the last 20 years is about 30-35%, with 10-15% reaching severity; results from british and australian surveys are similar. At present, the number of adult patients with insomnia symptoms of difficult sleep onset, dreaminess and easy awakening, difficult sleep onset after awakening, early awakening in the early morning and the like is about 3 hundred million in China. And this situation tends to rise. Sleep researchers call insomnia "a silently spreading epidemic". Therefore, the development of the medicine for treating insomnia is of great significance.
The Chinese and foreign clinical medicine for treating insomnia mainly comprises traditional Chinese medicines and chemical medicines. The chemical drugs mainly include barbiturates, benzodiazepine receptor agonists, non-benzodiazepine receptor agonists, melatonin (MT1/MT2) receptor agonists, and the like.
Melatonin (MT1/MT2) receptor agonists are novel anti-insomnia drugs. Melatonin (Melatonin) is an important hormone present in many organisms ranging from lower algae to humans, and its content levels in the organism vary with time each day. In higher animals, melatonin is produced by the retina, the lens of the eye, the gastrointestinal tract and the pineal cells in the pineal body (located in the brain). The pine cone determines the amount of melatonin secretion according to the amount and intensity of light received by the eyeball, and the pine cone acts as a clock in the human body and controls the time of waking and sleeping every day. During sleep at night, a large amount of melatonin is secreted by a human body, and the secretion amount drops rapidly after early morning.
Melatonin can systematically regulate sleep mechanisms, and light information (circadian rhythm) of ambient light cycle is transmitted to the pacing point of the biological clock in vivo, namely the suprachiasmatic nucleus (SCN), through retina, and the SCN regulates melatonin secretion of the pineal body. SCN is known as the "biological clock" [ Exp gerntol.2003; 38: 199- & 206] which regulates the body's periodic biorhythm over a 24-hour period, including the period of sleep-wake. The secretion of melatonin is low in daytime and high at night (the night is 1-2 times higher than that in daytime), and is consistent with the brightness cycle and the sleep biorhythmicity. Melatonin is known as a physiological hypnotic agent because it has sedative and sleep-inducing effects. Melatonin is required to exert its biological effects by activating melatonin receptors.
Melatonin receptors belong to members of the G protein-coupled receptor superfamily and are widely found in the SCN, hippocampus, cerebellar cortex, prefrontal lobe, basal ganglia, substantia nigra ventral tegmental area, and in cell membranes and nuclei of other systems of the retina, blood vessels, mammary glands, liver, kidney, gastrointestinal tract, and gonads of the nervous system. The human melatonin receptors have three subtypes of MT1, MT2 and MT 3. Wherein MT1 is highly concentrated in SCN, thalamus nucleus, etc. for regulating sleep, MT2 is related to circadian rhythm, and MT3 has unknown effect. [ Richardson G.the human circadian system in normal and discrete sleep.J. ClinPsychiatry.2005 ]
Reduced melatonin secretion is associated with sleep disorders. The melatonin secretion of the elderly is only 1/l0 of the peak. Abnormal melatonin secretion exists in diseases such as primary insomnia, circadian rhythm disorder, Alzheimer disease and depression. Therefore, the development of melatonin (MT1/MT2) receptor agonists is of great significance for the treatment of insomnia, anxiety, depression and other diseases. The development of new melatonin (MT1/MT2) receptor agonist drugs has also become a hot spot for the development of new anti-insomnia drugs internationally. Many large companies and academic research institutes are actively conducting relevant research and have had great success, and the drugs are powerful competitors of new drugs for treating insomnia. [ Sleep Med.2007; 8:623-636.]
The MT1/MT2 receptor agonist drug Ramelteon (Ramelteon), developed by Wuta pharmaceutical corporation of Japan, was approved by the FDA to be marketed in 7 months of 2005 and can be used for the long-term treatment of insomnia, especially patients with delayed sleep onset. The research result shows that adverse reactions such as overuse, drug withdrawal reaction, drug dependence, sequela on the next day and the like can not occur after the medicine is used. [ Drugs Today 42(4): 255-63 ]
Structures of Melatonin (Melatonin) and Ramelteon
Ramelteon is the first and only prescription hypnotic that does not cause drug dependence in patients, and therefore it is not classified as a control drug by the U.S. drug administration. Except ramelteon, other prescription hypnotics are listed as IV control products, which can indicate that the product has high safety and no addiction. The ramelteon does not influence the sleep structure, only shortens the sleep latency, effectively avoids sequelae caused by other hypnotics, and provides a safe medication opportunity for vast insomnia patients.
Ramelteon MT1/MT2 receptor in vitro has high agonistic activity (EC50<1nM), but has little distribution amount in brain due to short half-life [ JClin Sleep Med 3(5): 495-504 ], thus influencing the full play of the pharmacodynamic action. The weak in vivo metabolic property of the ramelteon causes the ramelteon to show the effect of shortening the time to fall asleep only in a low-dose group in animal experiments, and has no effect in a high-dose group. Therefore, the clinical anti-insomnia effect is not very strong, and the traditional Chinese medicine is only suitable for treating patients with mild and moderate insomnia.
After martian corporation filed a request for marketing to the european medicines agency (EMEA) in 2007, EMEA officially denied a request for release of ramelteon in europe 10 months in 2008. According to various suggestions provided by EMEA, for example, the clinical effect of the ramelteon 16mg group is weaker than that of the ramelteon 8mg group, the hypnotic activity of the ramelteon is insufficient in long-term experiments, the effect of the placebo group is uniform, and the like, and the problems point to the main contradiction that the experimental activity of the ramelteon in vivo is not strong.
In view of the above, there is an urgent need in the art to develop a new class of MT1/MT2 receptor agonists that will overcome the above-mentioned deficiencies of ramelteon and improve on the problems of inadequate distribution, short half-life, insufficient in vivo exposure, etc. in ramelteon brain tissue.
Disclosure of Invention
The invention aims to provide a novel melatonin (MT1/MT2) receptor agonist shown as a structural general formula (I), or an optical isomer thereof;
in a second aspect of the invention, there is provided a process for the preparation of a compound of formula (I), or various optical isomers thereof.
In a third aspect of the present invention, there is provided the use of the above-mentioned compounds of the present invention, or their respective optical isomers, as active ingredients in the manufacture of medicaments for the treatment of insomnia, dysrhythmia, anxiety, depression and other diseases associated with the action of melatonin (MT1/MT2) receptors, particularly insomnia. The present invention contains a pharmacologically acceptable excipient or carrier together with the compound of formula (I) of the present invention, or each optical isomer thereof, as an active ingredient.
In a first aspect of the present invention, there is provided a compound represented by formula (I), or each optical isomer thereof:
wherein n represents an integer of 1 to 5;
a is selected from methylene, oxygen or imino;
R1represents hydrogen, C1-6Alkyl or C3-6Cycloalkyl, said alkyl or cycloalkyl being unsubstituted or substituted with one to three groups independently selected from: halogen, hydroxy, amino or cyano;
R2and R3Each independently selected from: hydrogen, hydroxy, mercapto, amino, halogen, C1-6Alkyl, or R2And R3Are connected by chemical bonds to form a ring;
x and Y are each independently selected from: hydrogen, halogen, nitro, cyano, OR4、SR4Or R4But X and Y are not both hydrogen;
R4represents hydrogen, C1-6Alkyl or C3-6A cycloalkyl group.
In another preferred embodiment, a is selected from methylene, oxygen.
In another preferred embodiment, R is2And R3Each independently selected from: hydrogen, halogen, or R2And R3Are connected into a ring through chemical bonds.
In another preferred embodiment, X and Y are independently selected from: hydrogen, halogen, cyano or R4However, X and Y are not both hydrogen.
The compound provided by the invention, or each optical isomer thereof, is selected from:
in another preferred embodiment, the optical isomer of the compound is in the S configuration.
In a second aspect of the present invention, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier, and as an active ingredient, a compound provided by the present invention as described above, or each optical isomer thereof.
In a third aspect of the invention, there is provided a use of a compound provided by the invention, or individual optical isomers thereof, as described above, for the manufacture of a medicament for the treatment of a condition associated with melatonin (MT1/MT2) receptors.
In another preferred example, the disorder includes insomnia, anxiety, depression.
In a fourth aspect of the invention, there is provided a process for the preparation of a compound of formula i, said process comprising the steps of:
(1) reacting the compound shown as the formula A-4 with alkali to obtain a racemate A-5, and then carrying out manual resolution to obtain a compound shown as a formula A-5; and
(2) carrying out amine ester exchange reaction on a compound shown as a formula A-5 after condensation or esterification to obtain a compound shown as a formula I-1;
in the formulae, R1X, Y, A, n are as defined for formula (I).
The present invention also provides a process for preparing a compound of formula i, said process comprising the steps of:
(1) the compound shown as the formula B-8 and an oxidant react through Pinnick to obtain racemate B-9, and the racemate B-9 is resolved manually to obtain the compound shown as the formula B-9; and
(2) carrying out amine ester exchange reaction on a compound shown as a formula B-9 after condensation or esterification to obtain a compound shown as a formula I-2;
in the formulae, R1X, Y, A, n are as defined for formula (I).
The present invention further provides a process for the preparation of a compound of formula i, said process comprising the steps of:
(1) reacting the compound shown as the formula C-4 with alkali to obtain a racemate C-5, and then carrying out manual resolution to obtain a compound shown as a formula C-5; and
(2) carrying out amine ester exchange reaction on a compound shown as a formula C-5 after condensation or esterification to obtain a compound shown as a formula I-3;
in the formulae, R1X, Y, A, n are as defined for formula (I).
Accordingly, the present invention provides a novel class of MT1/MT2 receptor agonists that can be distributed in brain tissue with sufficient in vivo exposure.
It is to be understood that within the scope of the present invention, the above-described technical features of the present invention and the technical features specifically described below (e.g., examples) may be combined with each other to constitute a new or preferred technical solution. Not to be reiterated herein, but to the extent of space.
Drawings
FIG. 1 shows the effect of Zolpidem tartrate (Zolpidem tartrate) on sleep architecture; wherein,
a shows the effect on sleep latency;
b shows the effect on delta activity;
c shows the effect on the number of arousals (Wake), non-rapid eye movements (NREM), Rapid Eye Movements (REM);
d shows the effect on depth of sleep, length of wake.
Figure 2 shows the effect of compound 12 on NREM sleep latency.
Figure 3 shows the effect of Ramelteon on NREM sleep latency.
Detailed Description
After extensive research, the inventors synthesize and screen a large number of compounds, and find for the first time that the compound of formula (I) has better in vivo metabolic parameters and shows more obvious activity of shortening the time to fall asleep in vivo experiments. The present invention has been completed based on this finding.
Representative compound names and structural formulas of the compounds represented by formula (I) of the present invention are shown in the following table:
unless otherwise indicated, the following terms used in the specification and claims have the following meanings:
"alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 6 carbon atoms. Lower alkyl groups having 1 to 4 carbon atoms are preferred, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl.
"cycloalkyl" refers to a 3 to 6 membered all carbon monocyclic aliphatic hydrocarbon group, a 4 to 6 membered aliphatic fused ring group, wherein one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexane, cyclohexadiene and the like; the cycloalkyl backbone may have 1 to 3 carbon atoms replaced by the following heteroatoms or groups: -O-, -S-, -NR-, -5- (the R)5May be hydrogen, C1-6Alkyl or C3-6Cycloalkyl groups).
"hetero" refers to a non-carbon atom or group: comprising-O-, -S-, -NR-5- (the R)5May be hydrogen, C1-6Alkyl or C3-6Cycloalkyl), -SO-, -SO2-, ═ O, and any combination thereof (e.g., -CONR-, -SO)2NR-, -COO-, -NHCOO-, -NHCONH, and the like); the number of heteroatoms or groups may be 1-6.
"halogen" means fluorine, chlorine, bromine or iodine.
"an integer between 1 and 5" means 1,2, 3,4, 5.
The compounds of the present invention contain at least asymmetric carbon atoms (optical centers), and thus racemates, diastereomers and individual isomers are included within the scope of the present invention. According to the nomenclature of the R, S system (the Kane-Engell-Prerogue rule), the configuration of an asymmetric carbon atom is related to the size of the substituent attached to it, and the difference in the size of the substituent may result in the possibility that the R or S of the same asymmetric carbon atom in the same series of compounds may be different, but the orientation of the substituent space of the asymmetric carbon atom is not changed. The reaction after the chiral resolution step of the invention does not affect the R and S configuration of the compound, the obtained final product keeps consistent configuration, and the S configuration is preferable after comparative analysis of target action modes and feedback verification of in vitro activity test results.
Process for the preparation of the compounds of the invention
The compounds of the present invention and their various intermediates may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combinations thereof with other chemical synthetic methods, and equivalents thereof known to those skilled in the art, with preferred embodiments including, but not limited to, the examples of the present invention.
The following specifically describes the preparation of the compounds of formula (I) according to the invention, but these specific methods do not limit the invention in any way.
The compound having the structure of the general formula (I) of the present invention can be produced by the following method, however, the conditions of the method, such as reactants, solvent, base, amount of the compound used, reaction temperature, time required for the reaction, etc., are not limited to the following explanation. The compounds of the present invention may also be conveniently prepared by optionally combining various synthetic methods described in the present specification or known in the art, and such combinations may be readily carried out by those skilled in the art to which the present invention pertains.
Scheme 1:
X,Y,A,R1and n is as defined for formula (I).
1) The compound of formula A-1 is reduced to obtain the compound of formula A-2.
Dissolving the compound of the formula A-1 in an organic solvent, adding a reducing agent, and reacting to obtain the compound of the formula A-2.
The organic solvent is selected from aprotic solvents, preferably ethyl acetate, tetrahydrofuran, toluene and N, N-dimethylformamide; the reducing agent is sodium borohydride-Lewis acid system, sodium borohydride-organic acid system, lithium aluminum hydride, diisobutyl aluminum hydride, red aluminum, K-select, preferably lithium aluminum hydride; the feeding equivalent ratio of the reducing agent and the compound of the formula A-1 is 1.0-20.0, preferably 2-3 equivalents, and the reaction temperature is 0-60 ℃, preferably 20-40 ℃; the reaction time is 0.5 to 24 hours, preferably 5 to 20 hours.
2) The compound of formula A-2 is converted to give the compound of formula A-3.
Dissolving the compound of the formula A-2 in an organic solvent, adding alkali, dropwise adding methylsulfonyl chloride, and reacting at room temperature to obtain the compound of the formula A-3.
The organic solvent is selected from aprotic solvents, preferably dichloromethane, ethyl acetate, tetrahydrofuran, toluene and N, N-dimethylformamide; the base is inorganic base or organic base, preferably triethylamine, potassium carbonate, sodium carbonate, potassium tert-butoxide and cesium carbonate; the base and the compound of formula A-2 are fed in an equivalent ratio of 1.0 to 20.0, preferably 2 to 3 equivalents; the reaction temperature is 0-60 ℃, and the preferable temperature is 20-30 ℃; the reaction time is from 1 to 48 hours, preferably from 5 to 18 hours.
3) The compound of formula A-3 is converted to give the compound of formula A-4.
Dissolving the compound shown in the formula A-3 in an organic solvent, adding cyanide salt, and reacting to obtain the compound shown in the formula A-4.
The organic solvent is selected from aprotic solvents, preferably ethyl acetate, tetrahydrofuran, toluene and N, N-dimethylformamide; the cyanide salt is preferably potassium cyanide salt or sodium cyanide salt, and the charging equivalent ratio of the cyanide salt and the compound of the formula A-3 is 1.0-20.0, preferably 2-3 equivalents; the reaction temperature is 0-160 ℃, and the optimal temperature is 70-90 ℃; the reaction time is from 1 to 24 hours, preferably from 8 to 20 hours.
4) The compound of formula A-4 is converted to give the compound of formula A-5.
Dissolving the compound of the formula A-4 in an organic solvent, adding alkali, reacting to obtain a racemate A-5, and then carrying out chiral HPLC resolution on the racemate to obtain the required A-5 structure.
The types of chiral columns used were: CHIRALPAK AY-H ((AYH0CD-NB024), chiral column size: 0.46cm I.D.. times.15 cm L, mobile phase: EtOH/MeCN ═ 80/20(V/V), flow rate: 0.7mL/min, wavelength: UV210nM, temperature: 35 ℃, HPLC equipment: Shimadzu LC-20AD CP-HPLC-08.
The organic solvent is selected from protic or aprotic solvent, preferably one or mixture of ethanol, methanol and water; the alkali is inorganic alkali, preferably potassium hydroxide and sodium hydroxide; the charging equivalent ratio of the base to the compound of formula A-4 is 1.0 to 10.0, preferably 1 to 5 equivalents; the reaction temperature is 0-160 ℃, and preferably 60-100 ℃; the reaction time is from 1 to 24 hours, preferably from 2 to 18 hours.
5) The compound of formula A-5 is converted to give the compound of formula I-1.
At a proper temperature, adding an organic solvent to dissolve the compound of the formula A-5, the amine compound, the coupling reagent and the alkali, and reacting to obtain the compound of the formula I-1.
Or dissolving the compound of the formula A-5 in an organic solvent, adding acid, carrying out esterification reaction at a proper temperature, and carrying out amine ester exchange reaction on the obtained intermediate ester to obtain the compound I-1.
The organic solvent is selected from aprotic solvents, preferably dichloromethane, N-dimethylformamide (dimethylformamide), acetonitrile and toluene. The amine compound is a simple amine of C1-C6, preferably methylamine, isopropylamine, propylamine and cyclopropylamine; the coupling reagent is EDCI (N- (3-dimethylaminopropyl) -N ' -ethylcarbodiimide hydrochloride), DCC (dicyclohexylcarbodiimide), DIC (N, N ' -diisopropylcarbodiimide), DCI (4, 5-dicyanoimidazole), CDI (N, N ' -carbonyldiimidazole), HOBt (1-hydroxybenzotriazole), HOAT (1-hydroxy-7-azobenzotriazol), HATU (O- (7-azobenzotriazol) -N, N, N ', N ' -tetramethyluronium hexafluorophosphate), TBTU (O-benzotriazol-N, N, N ', N ' -tetramethyluronium tetrafluoroborate), HBTU (benzotriazol-N, N, N ', N ' -tetramethyluronium hexafluorophosphate), HTCU (6-chlorobenzotriazole-1, 1,3, 3-tetramethyluronium hexafluorophosphate); the base is organic base or inorganic base, the inorganic base is preferably potassium carbonate, cesium carbonate or sodium carbonate, the organic base is preferably DMAP (4-dimethylaminopyridine), triethylamine or DIPEA (diisopropylethylamine); the feeding equivalent ratio of the amine compound and the compound of the formula A-5 is 1.1-2, preferably 1.1-1.5 equivalents; the equivalent ratio of the coupling agent to the compound of formula C-1 is from 1.1 to 2, preferably from 1.1 to 1.5 equivalents; the base and the compound of formula A-5 are fed in an equivalent ratio of 1.0 to 10.0, preferably 1.5 to 3 equivalents; the reaction temperature is 0-100 ℃, and preferably 20-50 ℃; the reaction time is from 1 to 48 hours, preferably from 2 to 20 hours.
In the esterification reaction, a protic or aprotic solvent is selected, and methanol is preferred; the acid is sulfuric acid, hydrochloric acid, phosphoric acid, preferably sulfuric acid; the feed equivalent ratio of acid to compound of formula a-5 is 1.0-20.0, preferably 8-10 equivalents; the reaction temperature is 0-160 ℃, and preferably 60-100 ℃; the reaction time is from 1 to 24 hours, preferably from 8 to 18 hours.
The amine transesterification reaction is carried out using an aprotic solvent, preferably tetrahydrofuran (tetrahydrofuran), dichloromethane (dichloromethane), acetonitrile and toluene. The feeding equivalent ratio of the methylamine alcohol solution and the compound of the formula B-1 is 10-40, preferably 20-30; the reaction temperature is 0-100 ℃, and preferably 20-80 ℃; the reaction time is 1 to 24 hours, preferably 2 to 6 hours.
And (2) a flow scheme:
X,Y,A,R1and n is as defined for formula (I).
l) converting the compound of formula B-1 to give the compound of formula B-2.
Dissolving the compound shown in the formula B-1 in an organic solvent, adding an oxidation reagent, a catalyst and alkali, and reacting to obtain the compound shown in the formula B-2.
The organic solvent is selected from protic solvent, preferably tert-butanol and water. The oxidizing agent is preferably potassium ferricyanide, the catalyst is preferably potassium osmate, and the base is an inorganic or organic base, preferably potassium carbonate. The feed equivalent ratio of oxidant and compound of formula C-3 is 1.1 to 5, preferably 2 to 3 equivalents; the catalyst and the compound of formula B-1 are fed in an equivalent ratio of 0.01 to 2, preferably 0.02 to 0.05; the base and the compound of formula B-1 are fed in an equivalent ratio of 1.0 to 10.0, preferably 1.5 to 5 equivalents; the reaction temperature is 0-100 ℃, and preferably 20-40 ℃; the reaction time is 5 to 48 hours, preferably 10 to 30 hours.
2) The compound of formula B-2 is converted to give the compound of formula B-3.
Dissolving the compound shown in the formula B-2 in an organic solvent, adding a protective reagent and alkali, and reacting to obtain the compound shown in the formula B-3.
The organic solvent is selected from protic or aprotic solvent, preferably dichloromethane. The protective reagent is trimethyl chlorosilane, triethyl chlorosilane, triisopropyl chlorosilane, tert-butyl dimethyl chlorosilane, tert-butyl diphenyl chlorosilane, preferably tert-butyl diphenyl chlorosilane. The base is an inorganic base or an organic base, preferably imidazole. The feeding equivalent ratio of the protective agent to the compound of formula B-2 is 1.1 to 5, preferably 1.1 to 1.5 equivalents, and the feeding equivalent ratio of the base to the compound of formula B-2 is 1.1 to 20, preferably 1.2 to 2 equivalents; the reaction temperature is 0-100 ℃, and preferably 20-40 ℃; the reaction time is 0.5 to 5 hours, preferably 1 to 3 hours.
3) The compound of formula B-3 is converted to give the compound of formula B-4.
Dissolving the compound shown in the formula B-3 in an organic solvent, adding an oxidant, and reacting to obtain the compound shown in the formula B-4.
The organic solvent is selected from protic or aprotic solvent, preferably dichloromethane. The oxidant is manganese dioxide, DMP (1,1, 1-triacetoxy-1, 1-dihydro-1, 2-phenyliodoxy-3- (1H) -one), DCC (dicyclohexylcarbodiimide), DMSO (dimethyl sulfoxide), and preferably DMP (1,1, 1-triacetoxy-1, 1-dihydro-1, 2-phenyliodoxy-3- (1H) -one). The feeding equivalent ratio of the oxidant and the compound of the formula B-3 is 1.0-3.0, preferably 1.0-2.0 equivalents; the reaction temperature is 0-50 ℃, and the preferable temperature is 20-30 ℃; the reaction time is 5 to 48 hours, preferably 2 to 10 hours.
4) The compound of formula B-4 is converted to give the compound of formula B-5.
Dissolving the compound shown in the formula B-4 in an organic solvent, and carrying out Witting reaction to obtain the compound shown in the formula B-5.
The organic solvent is selected from aprotic solvents, preferably tetrahydrofuran. The base is an inorganic base or an organic base, and is preferably potassium tert-butoxide. The base and the compound of formula B-4 are fed in an equivalent ratio of 1.0 to 10.0, preferably 2 to 5 equivalents; the reaction temperature is 0-80 ℃, and preferably 20-30 ℃; the reaction time is 5 to 48 hours, preferably 5 to 18 hours.
5) The compound of formula B-5 is converted to give the compound of formula B-6.
Dissolving the compound shown in the formula B-5 in an organic solvent, adding a deprotection reagent, and reacting to obtain the compound shown in the formula B-6.
The organic solvent is selected from aprotic solvents, preferably dichloromethane, tetrahydrofuran, N, N-dimethylformamide; the deprotection reagent is tetra-n-butyl ammonium fluoride, hydrofluoric acid, pyridinium hydrogen fluoride, preferably tetra-n-butyl ammonium fluoride. The feeding equivalent ratio of the deprotection agent reagent and the compound shown as the formula B-5 is 1.0-10.0, preferably 2-5 equivalents; the reaction temperature is 0-80 ℃, and preferably 20-30 ℃; the reaction time is 1 to 10 hours, preferably 3 to 6 hours.
6) The compound of formula B-6 is converted to give the compound of formula B-7.
Dissolving the compound shown in the formula B-6 in an organic solvent, and carrying out addition reaction on carbene-like and double bonds to obtain the compound shown in the formula B-7.
The organic solvent is selected from aprotic solvents, preferably dichloromethane, tetrahydrofuran, and N, N-dimethylformamide. The carbene-like compound is preferably diiodomethane, diethyl zinc. The feeding equivalent ratio of the carbene-like compound to the compound shown in the formula B-6 is 1.0-20.0, preferably 2-10 equivalents; the reaction temperature is 0-80 ℃, preferably 10-30 ℃; the reaction time is 1 to 8 hours, preferably 1.5 to 3 hours.
7) The compound of formula B-7 is converted to give the compound of formula B-8.
Dissolving the compound shown in the formula B-7 in an organic solvent, adding an oxidant, and reacting to obtain the compound shown in the formula B-8.
The organic solvent is selected from aprotic solvents, preferably dichloromethane, tetrahydrofuran, and N, N-dimethylformamide. The oxidant is manganese dioxide, DMP (1,1, 1-triacetoxy-1, 1-dihydro-1, 2-phenyliodoxy-3- (1H) -one), DCC (dicyclohexylcarbodiimide), DMSO (dimethyl sulfoxide), and preferably DMP (1,1, 1-triacetoxy-1, 1-dihydro-1, 2-phenyliodoxy-3- (1H) -one). The feeding equivalent ratio of the oxidant and the compound of the formula B-7 is 1.0-3.0, preferably 1.0-2.0 equivalents; the reaction temperature is 0-50 ℃, and the preferable temperature is 20-30 ℃; the reaction time is 1 to 10 hours, preferably 2 to 5 hours.
10) The compound of formula B-8 is converted to give the compound of formula B-9.
Dissolving the compound shown in the formula B-8 in an organic solvent, adding an oxidant, carrying out Pinnick reaction to obtain a racemate B-9, and carrying out chiral HPLC separation on the racemate to obtain the required B-9 structure.
The chiral HPLC resolution conditions used were as described above.
The organic solvent is selected from one or more of protic solvent or aprotic solvent, preferably tert-butanol, and water. The oxidizing agent is preferably sodium chlorite. The reaction auxiliary agent is sulfamic acid, resorcinol, 2-methyl-2-butylene and hydrogen peroxide, preferably 2-methyl-2-butylene. The buffer solution is preferably sodium dihydrogen phosphate. The feeding equivalent ratio of the oxidant and the compound of the formula B-8 is 5.0-20.0, preferably 10.0-15.0 equivalents; the feeding equivalent ratio of the reaction auxiliary agent and the compound shown in the formula B-8 is 10.0-50.0, preferably 10.0-15.0 equivalent; the feeding equivalent ratio of the buffer solution to the compound of the formula B-8 is 7.0-10.0, preferably 8.0-9.0, the reaction temperature is 0-50 ℃, preferably 20-30 ℃; the reaction time is 5 to 24 hours, preferably 10 to 20 hours.
11) The compound of formula B-9 is converted to give the compound of formula I-2.
The procedure is the same as for the conversion of the compound of formula A-5 in scheme 1 to the compound of formula I-1.
And (3) a flow path:
X,Y,A,R1and n is as defined for formula (I).
l) converting the compound of formula A-2 to give the compound of formula C-1.
Dissolving the compound shown in the formula A-2 in an organic solvent, adding an oxidant, and reacting to obtain the compound shown in the formula C-1.
The organic solvent is selected from protic or aprotic solvent, preferably dichloromethane. The oxidant is manganese dioxide, DMP (1,1, 1-triacetoxy-1, 1-dihydro-1, 2-phenyliodoxy-3- (1H) -one), DCC (dicyclohexylcarbodiimide), DMSO (dimethyl sulfoxide), and preferably DMP (1,1, 1-triacetoxy-1, 1-dihydro-1, 2-phenyliodoxy-3- (1H) -one). The feeding equivalent ratio of the oxidant and the compound of formula A-2 is 1.0-3.0, preferably 1.0-2.0 equivalents; the reaction temperature is 0-50 ℃, and the preferable temperature is 20-30 ℃; the reaction time is 5 to 48 hours, preferably 2 to 20 hours.
2) The compound of formula C-1 is converted to give the compound of formula C-2.
Dissolving the compound shown in the formula C-1 in an organic solvent, adding sodium bisulfite, carrying out nucleophilic addition reaction to obtain α -sodium hydroxysulfonate, and then reacting with potassium cyanide to obtain the compound shown in the formula C-1.
The organic solvent is selected from protic or aprotic solvent, preferably one or more of dichloromethane, ethyl acetate, tetrahydrofuran, N, N-dimethylformamide, methanol, ethanol, and water. The equivalent ratio of sodium bisulfite to C-1 compound is 1 to 5, preferably 1 to 2 equivalents; the equivalent ratio of potassium cyanide to C-1 compound is 1-5, preferably 2-3 equivalents; the reaction temperature is 0-50 ℃, and the preferable temperature is 20-30 ℃; the reaction time is 2 to 10 hours, preferably 1 to 3 hours.
3) The compound of formula C-2 is converted to give the compound of formula C-3.
Dissolving the compound shown in the formula C-2 in an organic solvent, and carrying out hydrolysis esterification reaction to obtain the compound shown in the formula C-3.
The organic solvent is selected from protic solvent, preferably one or more of methanol, ethanol, and water. The acid is preferably hydrochloric acid, sulfuric acid. The equivalent ratio of acid to C-2 compound is 5-100, preferably 5-10 equivalents; the reaction temperature is 0-160 ℃, and preferably 60-100 ℃; the reaction time is 10 to 80 hours, preferably 24 to 48 hours.
4) The compound of formula C-3 is converted to give the compound of formula C-4.
Dissolving the compound shown in the formula C-3 in an organic solvent, adding a fluoro reagent, and reacting to obtain the compound shown in the formula C-4.
The organic solvent is selected from protic or aprotic solvents, preferably one or a mixture of any more of dichloromethane, tetrahydrofuran and toluene; the fluorinating agent is preferably DAST (diethylaminosulfur trifluoride); the feed equivalent ratio of the fluoro reagent to the compound of formula C-3 is from 1 to 50.0, preferably from 1 to 5 equivalents; the reaction temperature is-10-50 ℃, and preferably 20-30 ℃; the reaction time is from 1 to 72 hours, preferably from 1 to 5 hours.
5) The compound of formula C-4 is converted to give the compound of formula C-5.
Dissolving the compound shown in the formula C-4 in a mixed solvent of an organic solvent and water, adding alkali, reacting to obtain a racemate C-5, and then carrying out chiral HPLC separation on the racemate to obtain the required C-5 structure.
The chiral HPLC resolution conditions used were as described above. The organic solvent is selected from protic or aprotic solvent, preferably one or mixture of ethanol, methanol and water; the alkali is inorganic alkali, preferably lithium hydroxide, potassium hydroxide and sodium hydroxide; the charging equivalent ratio of the base to the compound of formula C-4 is 0.01 to 10.0, preferably 0.1 to 3 equivalents; the reaction temperature is 0-80 ℃, and preferably 20-30 ℃; the reaction time is 18 to 120 hours, preferably 24 to 80 hours.
6) The compound of formula C-5 is converted to give the compound of formula I-3.
The procedure is the same as for the conversion of the compound of formula A-5 in scheme 1 to give the compound of formula I-3.
Pharmaceutical compositions and methods of administration
The compound has excellent melatonin (MT1/MT2) agonizing activity, so that the compound, each optical isomer thereof and a pharmaceutical composition containing the compound as a main active ingredient can be used for treating diseases or symptoms such as insomnia, rhythm disorder, anxiety, depression and the like related to the action of melatonin (MT1/MT2) receptors, particularly the insomnia.
The pharmaceutical composition of the present invention may use a pharmaceutically acceptable excipient or carrier, and the compound of formula (i) of the present invention, or each optical isomer thereof, as an active ingredient.
The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the present invention in an acceptable excipient or carrier. Wherein "safe, effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. The safe and effective amount of the compound is determined according to the age, condition, course of treatment and other specific conditions of a treated subject. Generally, from about 0.1 to 99.5% by weight of a compound of formula (i) of the present invention, or each optical isomer thereof, as the active ingredient, based on the total weight of each unit dose, together with one or more suitable pharmaceutically acceptable excipients or carriers as a balance; preferably, the active ingredient is present in a proportion of about 0.5-95 wt%.
"pharmaceutically acceptable excipient or carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of being blended with the compounds of the present invention and with each other without significantly diminishing the efficacy of the compounds. Pharmaceutically acceptableExamples of excipients or carrier moieties are diluents, excipients (e.g., water), fillers (e.g., starch), binders (e.g., gelatin), disintegrants (calcium carbonate), absorption enhancers (e.g., quaternary ammonium compounds), surfactants (e.g., cetyl alcohol), cellulose and its derivatives (e.g., sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), lubricants (e.g., talc), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (e.g., tween), and the like
) Colorants, flavors, stabilizers, antioxidants, preservatives, and the like.
In the present invention, the "active ingredient" means a compound represented by the general formula (I) or each optical isomer thereof.
Administration of the compounds of the invention may be oral, systemic (e.g., transdermal, nasal or by suppository).
Dosage forms for oral administration include solid dosage forms, liquid dosage forms, and gaseous dosage forms. Solid dosage forms include pharmaceutically acceptable tablets, pills, capsules, semisolids, powders, sustained release dosage forms, and the like.
Liquid dosage forms include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.
In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
The gaseous dosage form includes pharmaceutically acceptable aerosols and the like.
The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
When using pharmaceutical compositions, a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment at a dosage which is pharmaceutically acceptable for effective administration, e.g., a daily dosage of about 0.01 to about 50mg/kg of body weight of the subject; preferably about 0.1-10 mg/kg/day, and may be administered in one or more administrations. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
The main advantages of the invention include:
1. the melatonin (MT1/MT2) receptor agonist shown in the general formula (I) or an optical isomer thereof is a melatonin (MT1/MT2) receptor agonist with a novel molecular structure, and has strong agonistic activity on melatonin (MT1/MT2) receptors.
2. The compound has excellent drug metabolism property, longer half-life period and better brain tissue distribution.
3. The compound has good sleep promoting effect, and has better effect of shortening the time of falling asleep in vivo experiments. Is particularly suitable to be used as melatonin (MT1/MT2) receptor agonist for treating insomnia, anxiety, depression and other diseases or symptoms related to melatonin (MT1/MT2) receptors.
The various specific aspects, features and advantages of the compounds, methods and pharmaceutical compositions described above are set forth in detail in the following description, which makes the present invention clear. It should be understood herein that the detailed description and examples, while indicating specific embodiments, are given by way of illustration only. After reading the description of the present invention, those skilled in the art can make various changes or modifications to the present invention, which also fall within the scope defined by the present application.
The present invention is more specifically explained in the following examples. It should be understood, however, that these examples are for the purpose of illustrating the present invention and are not intended to limit the scope of the present invention in any way. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Parts and percentages are parts and percentages by weight unless otherwise indicated. Examples the organic solvents used in the reactions were all subjected to drying methods known in the art.
Thin Layer Chromatography (TLC) was performed on pre-fabricated 0.5mm thick HF254 silica gel plates; the silica gel of column chromatography is not indicated to be 200-300 meshes, and the proportions of the eluents are volume ratios; 1H-NMR was recorded using a Varian Mercury 300 or 400 NMR spectrometer with chemical shifts expressed in delta (ppm); mass Spectrometry MS was measured using Shimadzu LC-MS-2020 Mass spectrometer.
Tetrahydrofuran is pressed into sodium filaments, benzophenone is added to flow back to blue, and the sodium filaments are evaporated out under the protection of nitrogen.
Dichloromethane is added, calcium and hydrogen are added for reflux, and the mixture is distilled out under the protection of nitrogen.
N, N-Dimethylformamide (DMF) was used directly after drying overnight with freshly dried molecular sieves.
Triethylamine (TEA) plus solid KOH was stirred at room temperature overnight.
Other solvents and reagents were dried, purified and worked up according to standard methods except where specifically indicated. The detailed purification steps can be referred to as: purification of Laboratory Chemicals,4th Ed., Armarego, W.L.F.; perrin, d.d. butterworth-heineman, 1998.
The formulation method and the range of use of the color developer used in the examples are as follows:
ammonium molybdate-sulfuric acid color developing agent: 20mL of concentrated sulfuric acid was slowly added to 100mL of an aqueous solution of 20g of ammonium molybdate, and then diluted to 300mL with water.
Phosphomolybdic acid-ethanol solution: 3 to 15 mass percent of phosphomolybdic acid in ethanol.
Diluted potassium permanganate solution: 1g of potassium permanganate and 1g of sodium bicarbonate are dissolved in 100mL of water to prepare the water-soluble potassium permanganate-sodium bicarbonate-potassium permanganate-sodium bicarbonate water.
Iodine vapor: 0.5g of solid iodine and a proper amount of crude silica gel are mixed for preparation.
In the examples, other starting materials required for the preparation of each compound, unless otherwise specified, are known in the art or are available commercially.
Example 1
Preparation of (S) -3- (4, 5-difluoro-1, 2,7, 8-tetrahydrobenzo [1,2-b:4,3-b' ] difuran-1-yl) -N-methylpropanamide (compound of formula 1)
Step (1) synthesis of 2, 3-difluorophenyl-2-chloroacetate (compound of formula 1-2).
Dissolving a compound (2.6g, 0.02mol) of a formula 1-1 in dried dichloromethane, carrying out ice bath, adding triethylamine (2.63g, 0.026mol), slowly dropwise adding chloroacetyl chloride (2.94g, 0.026mol, 1.3eq), naturally heating to room temperature overnight after finishing dropping, carrying out thin layer chromatography detection, pouring into ice water to quench after the reaction is finished, extracting dichloromethane, washing an organic phase with saturated saline solution, drying with anhydrous sodium sulfate, filtering, and distilling under reduced pressure to remove a solvent to obtain brown liquid (4.13g, 100 percent), namely the compound of the formula 1-2, and directly putting the brown liquid into the next step for reaction.
Step (2) synthesis of 2-chloro-1- (3, 4-difluoro-2-hydroxyphenyl) ethane-1-one (compound of formula 1-3).
Adding aluminum trichloride (4g, 0.03mol) directly into a compound (4.13g, 0.02mol) of formula 1-2, reacting at 150 ℃ for 3 hours, detecting by thin layer chromatography, slowly adding the product into ice water to quench after the reaction is finished, adding a certain amount of concentrated hydrochloric acid to prevent emulsification, extracting with dichloromethane, washing with organic phase saturated saline solution, drying with anhydrous sodium sulfate, filtering, evaporating under reduced pressure to remove a solvent, and eluting by column chromatography (petroleum ether/ethyl acetate: 10/1) to obtain a pure yellow solid (3.7g, 60%) which is the compound of formula 1-3.
Compounds of formulae 1-3:1H NMR(400MHz,Chloroform-d)δ11.91(d,J＝1.5Hz,1H),7.52(ddd,J＝9.1,5.4,2.3Hz,1H),6.78(m,1H),4.65(s,2H).
and (3) synthesizing 6, 7-difluoro-2, 3-dihydrobenzofuran (compound shown in formula 1-4). .
Dissolving the compound of formula 1-3 (3.7g, 0.018mol) in trifluoroacetic acid, adding triethylsilylhydride (4.37g, 0.038mol, 2.1eq) dropwise, reacting at 60 ℃ for 18h, detecting by thin layer chromatography, removing the solvent by evaporation under reduced pressure after the reaction is finished, and eluting by silica gel column chromatography (petroleum ether/ethyl acetate: 20/1) to obtain a light yellow liquid (2.1g, 75%) which is the compound of formula 1-4.
Compounds of formulae 1-4:1H NMR(400MHz，Chloroform-d)δ6.84–6.78(m，1H)，6.59(ddd，J＝10.7，8.2，6.7Hz，1H)，4.69(t，J＝8.7Hz，2H)，3.20(t，J＝8.7Hz，2H).
and (4) synthesizing 5-bromo-6, 7-difluoro-2, 3-dihydrobenzofuran (compound shown in formula 1-5). .
Dissolving the compound of formula 1-4 (2.1g, 0.013mol) in glacial acetic acid, carrying out ice bath, dropwise adding an acetic acid solution of liquid bromine (2.26g, 0.014mol), naturally heating to room temperature, stirring overnight, detecting by thin layer chromatography, after the reaction is finished, evaporating the solvent under reduced pressure, adding a small amount of petroleum ether, pulping, filtering to obtain a white solid, and recovering and carrying out column chromatography elution on the filtrate (petroleum ether/ethyl acetate: 50/1) to obtain a white solid (2.9g, 96%), namely the compound of formula 1-5.
Compounds of formulae 1-5:1H NMR(400MHz,Chloroform-d)δ7.12(ddt，J＝5.9,2.0,1.1Hz,1H),4.76(t，J＝8.8Hz,2H),3.40–3.04(m,2H).
step (5) Synthesis of (6, 7-difluoro-2, 3-dihydrobenzofuran-5-yl) boronic acid (compound of formula 1-6). .
Dissolving the compound of formula 1-5 (5g, 0.0213mol) in dry tetrahydrofuran (100mL) under argon, cooling to-78 ℃, adding N-butyllithium (15mL, 0.0383mol), reacting for 30min, adding trimethyl borate (5.3mL, 0.0469mol), reacting for 2h at room temperature, detecting by thin layer chromatography, adding 2N hydrochloric acid (30mL) after the reaction is finished, stirring for 30min, adding water, extracting with ethyl acetate, washing with organic phase saturated saline, drying with anhydrous sodium sulfate, filtering, and evaporating the solvent under reduced pressure to obtain a white solid (4.66g, 100%), namely the compound of formula 1-6.
And (6) synthesizing 6, 7-difluoro-2, 3-dihydrobenzofuran-5-ol (a compound shown in a formula 1-7). .
Dissolving the compound of formula 1-6 (4.66g, 0.023mol) in acetone (150mL), adding an aqueous solution of potassium hydrogen persulfate complex salt (15.7g, 0.093mol), reacting for 5h at room temperature, detecting by thin-layer chromatography, adding sodium thiosulfate to quench the reaction after the reaction is finished, spin-drying, adding water, extracting by ethyl acetate, washing by organic phase saturated saline, drying by anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure, and then carrying out column chromatography (petroleum ether: ethyl acetate: 5:1) to obtain a white solid (3g, 75%) which is the compound of formula 1-7.
Step (7) Synthesis of 4-bromo-6, 7-difluoro-2, 3-dihydrobenzofuran-5-ol (compound of formula 1-8). .
The compound of formula 1-7 (1.96g, 0.014mol) was dissolved in ethanol (20mL), NBS (2.8g, 0.016mol) was added under ice bath, reacted at room temperature overnight, detected by thin layer chromatography, the reaction was completed, the solvent was distilled off under reduced pressure, and column chromatography (petroleum ether: ethyl acetate 10:1) was performed to obtain a yellow solid (848mg, 28%), i.e., the compound of formula 1-8.
Compounds of formulae 1-8:1H NMR(400MHz,Chloroform-d)δ4.66(t,J＝8.7Hz,2H),3.21(td,J＝8.7,2.0Hz,2H).
step (8) Synthesis of Ethyl (E) -4- ((4-bromo-6, 7-difluoro-2, 3-dihydrobenzofuran-5-yl) oxo) but-2-enoate (Compound of formula 1-9). .
Dissolving the compound of formula 1-8 (1.82g, 7.25mmol) in acetone (40mL), adding sodium iodide (5% mol/mol), potassium carbonate (3g,0.022mol), bromocrotonic acid ethyl ester (1.7g,8.7mmol), reacting at 60 ℃ for 3h, detecting by thin layer chromatography, adding water, extracting with ethyl acetate, washing the organic phase with saturated saline, drying with anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure, and performing column chromatography (petroleum ether: ethyl acetate ═ 30:1) to obtain a yellow oily substance (1.88g, 71%) which is the compound of formula 1-9.
Compounds of formulae 1-9:1H NMR(400MHz,Chloroform-d)δ7.05(dt,J＝15.7,4.7Hz,1H),6.26(dt,J＝15.7,1.9Hz,1H),4.77–4.61(m,4H),4.22(q,J＝7.2Hz,2H),3.23(td,J＝8.8,1.9Hz,2H),1.30(t,J＝7.1Hz,3H).
step (9) Synthesis of Ethyl 2- (4, 5-difluoro-7, 8-dihydrobenzo [1,2-b:4,3-b' ] difuran-1-yl) acetate (compound of formula 1-10). .
Dissolving the compound of formula 1-9 (1.88g, 5.2mmol) in DMF (350mL) under argon, adding palladium acetate (55mg,0.21mmol), sodium acetate (640mg,7.8mmol), triphenylphosphine (120mg,0.42mmol), reacting at 80 ℃ for 5h, detecting by thin layer chromatography, cooling the reaction solution, adding water, extracting with ethyl acetate, washing with saturated saline, drying over anhydrous sodium sulfate, filtering, evaporating off the solvent under reduced pressure, and performing column chromatography (petroleum ether: ethyl acetate: 10:1) to obtain a yellow solid (450mg, 31%), namely the compound of formula 1-10.
Compounds of formulae 1-10:1H NMR(400MHz,Chloroform-d)δ7.60(d,J＝1.1Hz,1H),4.75(t,J＝8.8Hz,2H),4.17(q,J＝7.1Hz,2H),3.63(d,J＝1.0Hz,2H),3.41(td,J＝8.8,2.0Hz,2H),1.28–1.22(m,3H).
step (10) Synthesis of Ethyl 2- (4, 5-difluoro-1, 2,7, 8-tetrahydrobenzo [1,2-b:4,3-b' ] difuran-1-yl) acetate (compound of formula 1-11). .
Dissolving the compound of formula 1-10 (455mg, 1.6mmol) in ethanol (40mL), adding acetic acid 4mL and 10% palladium carbon (45mg), introducing hydrogen, reacting at 60 ℃ for 5h, detecting by thin layer chromatography, after the reaction is finished, filtering off the palladium carbon, evaporating the solvent under reduced pressure, adding saturated sodium bicarbonate solution, extracting with ethyl acetate, washing with organic phase saturated saline, drying with anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure, and performing column chromatography (petroleum ether: ethyl acetate ═ 10:1) to obtain a yellow oily substance (366mg, 80%) which is the compound of formula 1-11.
Compounds of formulae 1-11:1H NMR(400MHz,Chloroform-d)δ4.78(t,J＝9.0Hz,1H),4.69–4.59(m,2H),4.38(dd,J＝9.3,5.8Hz,1H),4.18–4.12(m,2H),3.82(dt,J＝9.6,4.8Hz,1H),3.17–3.05(m,2H),2.73(dd,J＝16.5,4.2Hz,1H),2.52(dd,J＝16.5,10.2Hz,1H),1.28–1.22(m,3H).
step (11) Synthesis of 2- (4, 5-difluoro-1, 2,7, 8-tetrahydrobenzo [1,2-b:4,3-b' ] difuran-1-yl) ethan-1-ol (compound of formula 1-12). .
Dissolving the compound of formula 1-11 (245mg, 0.86mmol) in dry tetrahydrofuran (15mL), adding lithium aluminum hydride (65mg,1.72mmol) under ice bath, reacting overnight at room temperature, detecting by thin layer chromatography, adding 0.065mL of water under ice bath after reaction, stirring for 15min, adding 15% sodium hydroxide (0.065mL), stirring for 15min, adding 0.2mL of water, stirring for 15min, adding magnesium sulfate, stirring for 30min, filtering, and evaporating the solvent under reduced pressure to obtain yellow oily substance (190mg, 91%), namely the compound of formula 1-12.
Compounds of formulae 1-12: LC-MS 243.08[ M + H ]]+.
Step (12) Synthesis of 2- (4, 5-difluoro-1, 2,7, 8-tetrahydrobenzo [1,2-b:4,3-b' ] difuran-1-yl) ethyl methanesulfonate (compound of formula 1-13). .
Dissolving the compound of formula 1-12 (190mg, 0.78mmol) in dichloromethane (10mL), adding DIPEA (305mg,2.34mmol), MsCl (180mg,1.57mmol), reacting overnight at room temperature, detecting by thin layer chromatography, adding water, extracting with dichloromethane, washing the organic phase with saturated saline, drying over anhydrous sodium sulfate, filtering, and evaporating the solvent under reduced pressure to obtain a yellow oil (315mg, 100%) which is the compound of formula 1-13.
Compounds of formulae 1-13: LC-MS 321.05[ M + H ]]+.
Step (13) Synthesis of 2- (4, 5-difluoro-1, 2,7, 8-tetrahydrobenzo [1,2-b:4,3-b' ] difuran-1-yl) ethyl methanesulfonate (compound of formula 1-14). .
Dissolving the compound of formula 1-13 (315mg, 0.98mmol) in N, N-dimethylformamide (15mL), adding sodium cyanide (145mg,2.95mmol), reacting overnight at 80 ℃, detecting by thin layer chromatography, cooling after the reaction is finished, adding water, extracting with ethyl acetate, washing with saturated organic phase sodium chloride, drying with anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure, and performing column chromatography (petroleum ether: ethyl acetate ═ 2:1) to obtain a white solid (170mg, 86%), namely the compound of formula 1-14.
Compounds of formulae 1-14: LC-MS 252.08[ M + H ]]+.
Step (14) Synthesis of (S) -3- (4, 5-difluoro-1, 2,7, 8-tetrahydrobenzo [1,2-b:4,3-b' ] difuran-1-yl) propanoic acid (compound of formula 1-15).
Dissolving the compound of formula 1-14 (170mg, 6.8mmol) in ethanol (20mL) water 1:1, adding 30% sodium hydroxide (5mL) to adjust pH to 12, reacting at 80 ℃ for 5h, detecting by thin layer chromatography, adjusting to acidity with 6N hydrochloric acid after reaction, extracting with dichloromethane, washing with organic phase saturated saline, drying with anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure to obtain a white solid (165mg, 90%), and resolving by manual HPLC to obtain a white solid (50mg), namely the compound of formula 1-15.
Compounds of formulae 1-15:1H NMR(400MHz,Chloroform-d)δ4.80–4.51(m,3H),4.36(dd,J＝9.1,5.1Hz,1H),3.63–3.41(m,1H),3.17(dtd,J＝32.1,16.0,8.5Hz,2H),2.47–2.26(m,2H),2.09(dtd,J＝15.3,7.6,4.0Hz,1H),2.01–1.82(m,1H).
step (15) Synthesis of (S) -3- (4, 5-difluoro-1, 2,7, 8-tetrahydrobenzo [1,2-b:4,3-b' ] difuran-1-yl) -N-methylpropanamide (Compound of formula 1).
Dissolving the compound of formula 1-15 (33mg, 0.12mmol)12mmol) in dry dichloromethane (5mL), adding HOBT (25mg,0.18mmol), HATU (70mg,0.18 mmol), diisopropylethylamine (21mg,0.3mmol), methylamine hydrochloride (12mg,0.18mmol), reacting overnight at room temperature, detecting by thin layer chromatography, evaporating the solvent under reduced pressure, and performing column chromatography (EA) to obtain a white solid (13mg, 38%), i.e. the compound of formula 1.
A compound of formula 1:1H NMR(400MHz,Chloroform-d)δ5.41(s,1H),4.70–4.56(m,3H),4.32(dd,J＝9.0,5.2Hz,1H),3.56–3.47(m,1H),3.29–3.17(m,1H),3.14–3.04(m,1H),2.75(d,J＝4.8Hz,3H),2.19–2.04(m,3H),1.90(td,J＝8.4,7.9,5.6Hz,1H).
example 2
Preparation of (S) -3- (4, 5-difluoro-1, 2,7, 8-tetrahydrobenzo [1,2-b:4,3-b' ] difuran-1-yl) -N-propylpropanamide (Compound of formula 2)
Synthesis of (S) -3- (4, 5-difluoro-1, 2,7, 8-tetrahydrobenzo [1,2-b:4,3-b' ] difuran-1-yl) -N-propylpropanamide (Compound of formula 2). .
The compound of formula 1-15 (55mg,0.2 mmol) was dissolved in dry dichloromethane (5mL), HOBT (42mg, 0.3mmol), HATU (117mg, 0.3mmol), diisopropylethylamine (35mg, 0.5mmol), n-propylamine (18mg, 0.3mmol) were added, the reaction was carried out overnight at room temperature, detection was carried out by thin layer chromatography, after completion of the reaction, the solvent was distilled off under reduced pressure, and column chromatography (EA) was carried out to give a white solid (28mg, 45%) of the compound of formula 2.
A compound of formula 2:1H NMR(400MHz,Chloroform-d)δ5.38(s,1H),4.73–4.55(m,3H),4.33(dd,J＝9.0,5.2Hz,1H),3.59–3.46(m,1H),3.15(dddtd,J＝18.0,15.3,12.9,7.7,5.7Hz,4H),2.20–2.02(m,3H),1.98–1.84(m,1H),1.47(d,J＝7.3Hz,2H),0.88(t,J＝7.4Hz,3H).
example 3
Preparation of (S) -3- (4, 5-difluoro-1, 2,7, 8-tetrahydrobenzo [1,2-b:4,3-b' ] difuran-1-yl) -N-isopropylpropanamide (Compound of formula 3)
Synthesis of (S) -3- (4, 5-difluoro-1, 2,7, 8-tetrahydrobenzo [1,2-b:4,3-b' ] difuran-1-yl) -N-isopropylpropanamide (Compound of formula 3). .
The compound of formula 1-15 (41mg, 0.15mmol) was dissolved in dry dichloromethane (5mL), HOBT (32mg, 0.225mmol), HATU (88mg, 0.225mmol), diisopropylethylamine (26mg, 0.375mmol), isopropylamine (14mg, 0.225mmol) were added, the reaction was overnight at room temperature, detection was performed by thin layer chromatography, the reaction was completed, the solvent was distilled off under reduced pressure, and column chromatography (EA) was performed to obtain a white solid (20mg, 42%), which is the compound of formula 3.
A compound of formula 3:1H NMR(400MHz,Chloroform-d)δ5.21(s,1H),4.72–4.52(m,3H),4.32(dd,J＝9.0,5.2Hz,1H),3.99(dp,J＝7.7,6.5Hz,1H),3.50(dd,J＝8.6,4.5Hz,1H),3.29–3.16(m,1H),3.09(dddd,J＝15.3,9.2,6.9,1.8Hz,1H),2.16–1.99(m,3H),1.96–1.80(m,1H),1.10(dd,J＝8.9,6.5Hz,6H).
example 4
Preparation of (S) -N-cyclopropyl-3- (4, 5-difluoro-1, 2,7, 8-tetrahydrobenzo [1,2-b:4,3-b' ] difuran-1-yl) propanamide (Compound of formula 4)
Synthesis of (S) -N-cyclopropyl-3- (4, 5-difluoro-1, 2,7, 8-tetrahydrobenzo [1,2-b:4,3-b' ] difuran-1-yl) propanamide (Compound of formula 4). .
The compound of formula 1-15 (51mg, 0.188mmol) was dissolved in dry dichloromethane (5mL), HOBT (40mg, 0.282mmol), HATU (110mg, 0.282mmol), diisopropylethylamine (33mg, 0.47mmol), cyclopropylamine (16mg, 0.282mmol) were added, the reaction was carried out overnight at room temperature, detection was carried out by thin layer chromatography, after completion of the reaction, the solvent was distilled off under reduced pressure, and column chromatography (EA) was carried out to give a white solid (30mg, 52%), which is the compound of formula 4.
A compound of formula 4:1H NMR(400MHz,Chloroform-d)δ5.53(s,1H),4.72–4.58(m,3H),4.33(dd,J＝9.1,5.1Hz,1H),3.53(s,1H),3.32–3.17(m,1H),3.18–3.05(m,1H),2.64(tq,J＝7.1,3.7Hz,1H),2.15–2.00(m,3H),1.91(td,J＝7.3,6.5,4.8Hz,1H),0.80–0.70(m,2H),0.49–0.38(m,2H).
example 5
Preparation of (S) -3- (4, 5-difluoro-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) -N- (2, 2-difluoroethyl) propionamide (compound of formula 5)
Step (1) Synthesis of Ethyl (E) -3- (6, 7-difluoro-2, 3-dihydrobenzofuran-5-yl) acryloyl ester (compound of formula 5-1). .
The compound of formula 1-5 (53.8g, 0.23mol), ethyl acrylate (124mL, 1.14mol), triethylamine (160mL, 1.14mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (5g, 6.8mmol) were mixed in N, N-dimethylformamide (200mL), stirred overnight at 110 ℃, detected by thin layer chromatography, after the reaction was completed, 37% hydrochloric acid (80mL) was added dropwise in an ice-salt bath, diluted with ethyl acetate (200mL), washed with saturated brine 3 times, the solvent was evaporated under reduced pressure, petroleum ether/ethyl acetate (30/1 mL) (150mL) was added, stirred for 5 minutes, and filtered to obtain a brown solid powder (35.4g, 60%), i.e., the compound of formula 5-1.
A compound of formula 5-1: LC-MS 255.00[ M + H ]]+.
Step (2) Synthesis of Ethyl 3- (6, 7-difluoro-2, 3-dihydrobenzofuran-5-yl) propionate (compound of formula 5-2).
Dissolving the compound of formula 5-1 (35.4g,0.14mol) in ethanol (300mL), adding 10% palladium/carbon (36g,35mmol), introducing hydrogen, stirring at room temperature for 4 days, detecting by thin layer chromatography, after the reaction is finished, filtering, washing with ethyl acetate, and evaporating under reduced pressure to remove the solvent to obtain a dark brown liquid (30.4g, 85%), namely the compound of formula 5-2.
A compound of formula 5-2: LC-MS 256.95[ M + H ]]+；278.9[M+Na]+.
Step (3) Synthesis of 3- (6, 7-difluoro-2, 3-dihydrobenzofuran-5-yl) propionic acid (compound of formula 5-3).
The compound of formula 5-2 (30.4g,0.12mol) was dissolved in ethanol (150mL), sodium hydroxide (7.1g,0.18mol) in water (100mL) was added, the mixture was stirred at 90 ℃ for 2 hours, the thin layer chromatography was performed, the reaction was completed, the solvent was evaporated under reduced pressure, water (200mL) was added for dilution, dichloromethane was washed (70mL × 2), 37% hydrochloric acid (15mL) was added under ice bath to adjust pH to 1, a white solid was precipitated, and the mixture was filtered, washed with water, and dried under vacuum to obtain a solid powder (23.4g, 85%), i.e., the compound of formula 5-3.
Step (4) Synthesis of 3- (6, 7-difluoro-2, 3-dihydrobenzofuran-5-yl) propionylchloride (compound of formula 5-4).
Dissolving the compound of formula 5-3 (23.4g, 0.1mol) in thionyl chloride (75mL), stirring at 80 ℃ for 3 hours, evaporating under reduced pressure to remove thionyl chloride to obtain the compound of formula 5-4, and directly putting into the next reaction.
Step (5) Synthesis of 4, 5-difluoro-1, 2,6, 7-tetrahydro-8H-indeno [5,4-b ] furan-8-one (Compound of formula 5-5).
Dissolving the compound of formula 5-4 (25.3g, 0.1mol) in 1, 2-dichloroethane (200mL), adding anhydrous aluminum chloride (18g, 0.13mol) under ice bath, slowly raising to room temperature and stirring for 2 hours, detecting by thin layer chromatography, after the reaction is finished, adding sodium hydroxide solution under ice bath to adjust the pH to 3, filtering, extracting the filtrate with dichloromethane (100mL × 3), washing once with 4% sodium hydroxide solution (100mL), washing once with saturated saline (50mL), drying with anhydrous sodium sulfate, filtering, and evaporating the solvent under reduced pressure to obtain brown solid (21.6g, 93%), namely the compound of formula 5-5.
Compounds of formulae 5-5: LC-MS 211.00[ M + H ]]+.
Step (6) Synthesis of Ethyl 2- (4, 5-difluoro-1, 2,6, 7-tetrahydro-8H-indeno [5,4-b ] furan-8-ylidene) acetate (Compound of formula 5-6).
Suspending 60% sodium hydride (8g, 0.2mol) in toluene (50mL), dropwise adding triethyl phosphonoacetate (38mL, 0.2mol) under ice bath, stirring at room temperature for 30 minutes, dropwise adding a compound of formula 5-5 (10g, 0.048mol) dissolved in toluene (50mL) under ice bath, replacing with argon three times, stirring at 90 ℃ for 2 hours, detecting by thin layer chromatography, after the reaction is finished, adding water (100mL), separating a toluene layer, extracting an aqueous phase once with petroleum ether/ethyl acetate (10/1 mL), combining organic phases, washing with saturated common salt water, drying with anhydrous sodium sulfate, filtering, and evaporating the solvent under reduced pressure to obtain a yellow liquid (23.2g, directly putting the yellow liquid into the next reaction without purification), namely the compound of formula 5-6.
Compounds of formulae 5-6: LC-MS 280.90[ M + H ]]+.
Step (7) Synthesis of Ethyl 2- (4, 5-difluoro-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) acetate (Compound of formula 5-7). .
The compound of formula 5-6 (23.2g,0.048mol) was dissolved in ethanol (150mL), 10% palladium on carbon (5g,4.76mmol) was added, hydrogen was introduced, the mixture was stirred overnight at room temperature, detected by thin layer chromatography, the reaction was completed, filtered through celite, washed with petroleum ether/ethyl acetate (10/1), and the solvent was evaporated under reduced pressure to give a brown liquid (15.6g, which was not purified and directly used in the next reaction), i.e., the compound of formula 5-7.
Compounds of formulae 5-7: LC-MS 283.00[ M + H ]]+.
Step (8) Synthesis of 2- (4, 5-difluoro-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) ethan-1-ol (Compound of formula 5-8).
Lithium aluminum hydride (3.6g, 0.095mol) was suspended in tetrahydrofuran (100mL), the compound of formula 5-7 (15.6g,0.048mol) dissolved in tetrahydrofuran (50mL) was added dropwise in an ice bath, and the mixture was slowly warmed to room temperature and stirred for 1 hour, followed by detection by thin layer chromatography, after completion of the reaction, water (3.6mL) and a 15% sodium hydroxide solution (3.6mL) were added in an ice bath, water (11mL) was added, stirring was carried out at room temperature for 15 minutes, magnesium sulfate was added, stirring was carried out at room temperature for 15 minutes, filtration was carried out with celite, washing was carried out with petroleum ether/ethyl acetate 2/1(125mL), and the filtrate was evaporated under reduced pressure to remove the solvent to give a yellow viscous liquid (10.6g, three steps 93%), i.e., the compound of formula 5.
Compounds of formulae 5-8: LC-MS 240.95[ M + H ]]+.
Step (9) Synthesis of 2- (4, 5-difluoro-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) ethyl methanesulfonate (Compound of formula 5-9).
Dissolving the compound of formula 5-8 (3g, 13mmol) in dry tetrahydrofuran (20mL), adding methanesulfonyl chloride (1.3mL, 16mmol) and triethylamine (2.6mL, 18mmol) under ice bath, stirring overnight at room temperature, detecting by thin layer chromatography, after the reaction is completed, adding water (20mL) and 37% hydrochloric acid (0.5mL), extracting with ethyl acetate (40 mL. times.2), washing once with saturated sodium bicarbonate solution (20mL), washing 1 time with saturated saline (20mL), drying with anhydrous sodium sulfate, filtering, and evaporating the solvent under reduced pressure to obtain yellow viscous liquid (4g, 96%), i.e., the compound of formula 5-9.
Compounds of formulae 5-9: LC-MS 318.90[ M + H ]]+；340.90[M+Na]+；356.8[M+K]+.
Step (10) Synthesis of 3- (4, 5-difluoro-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) propionitrile (Compound of formula 5-10).
Dissolving the compound of formula 5-9 (4g, 12.4mmol) in N, N-dimethylformamide (20mL), adding sodium cyanide (1.22g, 25mmol), stirring overnight at 80 ℃, detecting by thin layer chromatography, after the reaction is completed, adding ice water (50mL), extracting with petroleum ether/ethyl acetate (4/1) (30mL × 5), washing twice with water, washing with saturated saline for 1 time, drying with anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure, and then performing column chromatography, eluting with petroleum ether/ethyl acetate (10/1) to obtain colorless viscous liquid (1.867g, 60%), namely the compound of formula 5-10.
Compounds of formulae 5-10: LC-MS 249.90[ M + H ] +; 271.90[ M + Na ] +.
Compounds of formulae 5-10:1H NMR(400MHz,Chloroform-d)δ4.78–4.63(m,2H),3.32–3.10(m,3H),2.97–2.80(m,2H),2.43–2.29(m,3H),2.17–2.08(m,1H),1.85–1.69(m,2H).
step (11) Synthesis of (S) -3- (4, 5-difluoro-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) propanoic acid (Compound of formula 5-11).
Dissolving the compound of formula 5-10 (0.4g,1.6mmol) in ethanol (1.5mL), adding sodium hydroxide (257mg,6.4mmol) dissolved in water (1.5mL), stirring at 80 ℃ for 4 hours, detecting by thin layer chromatography, after the reaction is finished, adding 37% hydrochloric acid (0.5mL) under ice bath to adjust to acidity, extracting with ethyl acetate for three times, washing with saturated salt water once, drying with anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure to obtain a white solid (415mg, 97%), and performing manual HPLC to obtain a white solid (185mg), namely the compound of formula 5-11.
Compounds of formulae 5-11: LC-MS 268.90[ M + H ] +.
Compounds of formulae 5-11：1H NMR(400MHz,Chloroform-d)δ4.76–4.61(m,2H),3.31–3.21(m,1H),3.20–3.07(m,2H),2.96–2.86(m,1H),2.85–2.76(m,1H),2.40(t,J＝7.7Hz,2H),2.29(m,1H),2.16–2.06(m,1H),1.85–1.76(m,1H),1.76–1.67(m,1H).
Step (12) Synthesis of (S) -3- (4, 5-difluoro-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) -N- (2, 2-difluoroethyl) propionamide (Compound of formula 5).
The compound of formula 5-11 (51mg,0.2mmol) was dissolved in dichloromethane (1.5mL), 2-difluoroethylamine (20mg,0.25mmol), diisopropylethylamine (0.083mL,0.5mmol), 1-hydroxybenzotriazole (34mg,0.25mmol) and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (48mg,0.25mmol) were added, stirred at room temperature overnight, checked by thin layer chromatography, water and 6 drops of 37% hydrochloric acid were added after completion of the reaction, dichloromethane was extracted twice, the organic phase was washed once with a saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, column chromatography was performed, and petroleum ether/ethyl acetate 2/1 was eluted to give a white solid (51mg, 77%), i.e. the compound of formula 5.
A compound of formula 5: LC-MS 331.90[ M + H ]]+.
A compound of formula 5:1H NMR(400MHz,Chloroform-d)δ5.79(s,1H),4.75–4.55(m,2H),3.61(m,2H),3.32–3.20(m,1H),3.18–3.02(m,2H),2.92–2.84(m,1H),2.82–2.73(m,1H),2.30–2.18(m,3H),2.17–2.05(m,1H),1.73(m,2H),1.42–1.31(m,1H).
example 6
Preparation of (S) -1- ((4, 5-difluoro-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) methyl) -N-methylcyclopropane-1-carboxamide (Compound of formula 6)
Step (1) synthesis of 4, 5-difluoro-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-ol (compound of formula 6-1).
Dissolving the compound of formula 5-5 (200mg,0.95mmol) in methanol (5mL), adding sodium borohydride (36mg,0.95mmol) at 0 ℃, stirring overnight at room temperature, detecting by thin layer chromatography, after the reaction is finished, evaporating the solvent under reduced pressure, adding water, extracting with ethyl acetate, washing the organic phase with saturated saline, drying with anhydrous sodium sulfate, filtering, and evaporating the solvent under reduced pressure to obtain a white solid (159mg, 79%), namely the compound of formula 6-1.
Step (2) Synthesis of 8-allyl-4, 5-difluoro-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan (Compound of formula 6-2).
The compound of formula 6-1 (100mg,0.47mmol) was dissolved in dichloromethane (10mL), allyltrimethylsilane (162mg,1.4mmol), boron trifluoride etherate (74mg,0.52mmol) were added, stirred at room temperature overnight, detected by thin layer chromatography, the reaction was completed, and the reaction was quenched by addition of saturated sodium bicarbonate, extracted with dichloromethane, washed with saturated brine of the organic phase, dried over anhydrous sodium sulfate, filtered, evaporated under reduced pressure to remove the solvent, and subjected to column chromatography (petroleum ether/ethyl acetate: 8/1) to give a white solid (106mg, 95%) which is the compound of formula 6-2.
Step (3) Synthesis of 3- (4, 5-difluoro-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) propane-1, 2-diol (Compound of formula 6-3).
The compound of formula 6-2 (100mg,0.42mmol) was dissolved in t-butanol: adding potassium ferricyanide (493mg,1.27mmol), potassium carbonate (58mg,1.48mmol) and potassium osmate (6mg,0.0168mmol) into water ═ 1:1(2mL), stirring at room temperature for reaction, detecting by thin layer chromatography, adding saturated sodium sulfite solution to quench the reaction after the reaction is finished, extracting with ethyl acetate three times, washing with organic phase saturated brine, drying with anhydrous sodium sulfate, filtering, and evaporating the solvent under reduced pressure to obtain the compound of formula 6-3.
Step (4) Synthesis of 1- ((tert-butyldiphenylsilyl) oxo) -3- (4, 5-difluoro-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) propan-2-ol (Compound of formula 6-4).
Dissolving the compound of formula 6-3 (42.8g,0.16mol) in dichloromethane (500mL), adding imidazole (12.9g,0.19mol) and tert-butyldiphenylchlorosilane (44g,0.16mol) under ice bath, stirring at room temperature for reaction, detecting by thin layer chromatography, adding water to quench the reaction after the reaction is finished, extracting by dichloromethane, washing by organic phase saturated saline, drying by anhydrous sodium sulfate, filtering, and evaporating the solvent under reduced pressure to obtain a white solid (25g, 31%), namely the compound of formula 6-4.
Step (5) Synthesis of 1- ((tert-butyldiphenylsilyl) oxo) -3- (4, 5-difluoro-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) propan-2-one (Compound of formula 6-5).
Dissolving the compound of formula 6-4 (17.0g,0.033mmol) in dichloromethane (200mL), adding (1,1, 1-triacetoxy) -1, 1-dihydro-1, 2-phenyliodoyl-3 (1H) -ketone (21.2g,0.05mol), reacting overnight at room temperature, detecting by thin layer chromatography, adding saturated sodium thiosulfate solution to quench the reaction after the reaction is finished, extracting with dichloromethane three times, washing the organic phase with saturated sodium bicarbonate solution, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, and evaporating the solvent under reduced pressure to obtain the compound of formula 6-5.
Step (6) Synthesis of tert-butyl ((2- ((4, 5-difluoro-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) methyl) allyl) oxo) diphenylsilane (Compound of formula 6-6).
Adding methyl triphenyl phosphonium bromide (11.6g,0.032mol) into tetrahydrofuran (200mL), adding potassium tert-butoxide (3.6g,0.032mol), stirring for 30 minutes, dropwise adding a tetrahydrofuran solution of a compound of formula 6-5 (6.6g,0.013mol), stirring overnight at room temperature, detecting by thin layer chromatography, adding water to quench the reaction after the reaction is finished, adding diluted hydrochloric acid to adjust the pH to be neutral, extracting by ethyl acetate, washing by organic phase saturated saline, drying by anhydrous sodium sulfate, filtering, and evaporating the solvent under reduced pressure to obtain the compound of formula 6-6 (4g, 61%).
Step (7) Synthesis of 2- ((4, 5-difluoro-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) methyl) prop-2-en-1-ol (Compound of formula 6-7).
Dissolving the compound of formula 6-6 (4g,8mmol) in tetrahydrofuran (30mL), adding tetrabutylammonium fluoride trihydrate (3.2g,12mmol), stirring at room temperature for 5 hours, detecting by thin layer chromatography, after the reaction is finished, adding water to quench the reaction, extracting with ethyl acetate, washing with saturated common salt water once, drying with anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure, performing silica gel column chromatography, and eluting with petroleum ether/ethyl acetate (4/1) to obtain yellow viscous liquid (2g, 93%), namely the compound of formula 6-7.
Compounds of formulae 6-7: LC-MS 267.00[ M + H ]]+；284.05[M+NH4]+；289.0[M+Na]+.
Step (8) Synthesis of (1- ((4, 5-difluoro-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) methyl) cyclopropyl) methanol (compound of formula 6-8).
Dissolving ethylene glycol dimethyl ether (1.2mL,11.3mmol) in anhydrous dichloromethane (15mL), adding diethyl zinc (5.65mL,11.3mmol) and diiodomethane (1.82mL,22.6mmol) at-10 ℃ under the protection of argon, stirring for 10 minutes, adding a compound of formula 6-7 (1.5g,5.65mmol) dissolved in anhydrous dichloromethane (4mL), stirring for 3 hours at room temperature, detecting by thin layer chromatography, adding saturated ammonium chloride solution and 10% hydrochloric acid (8mL), stirring for several minutes, extracting with dichloromethane three times, washing the organic phase once with saturated sodium bicarbonate solution, drying with anhydrous sodium sulfate, filtering, and evaporating the solvent under reduced pressure to obtain yellow liquid (2.16 g). I.e., compounds of formulas 6-8.
Compounds of formulae 6-8: LC-MS 263.00[ M-OH]+.
Step (9) Synthesis of 1- ((4, 5-difluoro-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) methyl) cyclopropane-1-carbaldehyde (compound of formula 6-9).
Dissolving the compound of formula 6-8 (0.2g, theory 0.56mmol) in dichloromethane (2mL), adding (1,1, 1-triacetoxy) -1, 1-dihydro-1, 2-phenyliodoacyl-3 (1H) -ketone (355mg,0.84mmol), stirring at room temperature for 4 hours, detecting by thin layer chromatography, adding saturated sodium thiosulfate solution to quench the reaction after the reaction is finished, extracting with dichloromethane, washing the organic phase once with saturated sodium bicarbonate solution, washing once with saturated salt solution, drying with anhydrous sodium sulfate, filtering, and evaporating the solvent under reduced pressure to obtain yellow liquid (245mg), namely the compound of formula 6-9.
Compounds of formulae 6-9: LC-MS 279.00[ M + H ]]+；295.95[M+NH4]+；300.9[M+Na]+.
Step (10) Synthesis of (S) -1- ((4, 5-difluoro-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) methyl) cyclopropane-1-carboxylic acid (Compound of formula 6-10).
Dissolving the compound of formula 6-9 (245mg, theory 0.56mmol) and 2-methyl-2-butene (0.65mL,6.16mmol) in tert-butanol (5mL), adding sodium dihydrogen phosphate dihydrate (0.743g,4.76mmol) and sodium chlorite (0.658g,7.28mmol) dissolved in water (2.5mL), stirring overnight at room temperature, detecting by thin layer chromatography, adding saturated sodium thiosulfate solution to quench the reaction, extracting with ethyl acetate three times, washing the organic phase with sodium bicarbonate solution, washing with water, drying over anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure to obtain a yellow viscous liquid (0.247g), and performing manual HPLC to obtain a white solid (90mg), namely the compound of formula 6-10.
Compounds of formulae 6-10: LC-MS 295.00[ M + H ]]+；317.00[M+Na]+.
Step (11) Synthesis of (S) -1- ((4, 5-difluoro-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) methyl) -N-methylcyclopropane-1-carboxamide (Compound of formula 6).
The compound of formula 6-10 (247mg, theoretical 0.56mmol) was dissolved in dichloromethane (1.5mL), methylamine hydrochloride (49mg,0.73mmol), diisopropylethylamine (0.23mL,1.4mmol), 1-hydroxybenzotriazole (99mg,0.73mmol) and 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (140mg,0.73mmol) were added, stirred at room temperature for 3 hours, detected by thin layer chromatography, water and 37% hydrochloric acid (0.13mL) were added, dichloromethane was extracted twice, the organic phase was washed once with a saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and the dichloromethane/methanol ═ 200/1 was eluted to give a white solid (44mg, four steps 26%), i.e. the compound of formula 6.
A compound of formula 6:1H NMR(400MHz,Chloroform-d)δ5.49(s,1H),4.74–4.58(m,2H),3.32–3.21(m,2H),3.17–3.07(m,1H),2.92–2.74(m,2H),2.79(d,J＝4.8Hz,3H),2.32–2.16(m,2H),1.90(ddt,J＝12.4,7.8,4.7Hz,1H),1.40(dd,J＝14.6,9.5Hz,1H),1.15–1.08(m,1H),1.04–0.97(m,1H),0.71(ddd,J＝9.4,6.2,4.5Hz,1H),0.56–0.49(m,1H).
example 7
Preparation of (S) -1- ((4, 5-difluoro-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) methyl) -N- (2,2, 2-trifluoroethyl) cyclopropane-1-carboxamide (the compound of formula 7)
Synthesis of (S) -1- ((4, 5-difluoro-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) methyl) -N- (2,2, 2-trifluoroethyl) cyclopropane-1-carboxamide (Compound of formula 7).
The compound of formula 6-10 (47mg,0.16mmol) was dissolved in dichloromethane (1.5mL), trifluoroethylamine hydrochloride (28mg,0.2mmol), diisopropylethylamine (0.07mL,0.4mmol), 1-hydroxybenzotriazole (27mg,0.2mmol) and 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (38mg,0.2mmol) were added, stirred at room temperature overnight, checked by thin layer chromatography, the reaction was completed, diluted with dichloromethane, washed once with dilute hydrochloric acid, washed once with dilute sodium hydroxide solution, dried over anhydrous sodium sulfate, filtered, evaporated under reduced pressure to remove the solvent, column chromatography, and eluted with petroleum ether/ethyl acetate 2/1 to give a white solid (19mg, 32%), i.e. the compound of formula 7.
A compound of formula 7:1H NMR(400MHz,Chloroform-d)δ5.80(s,1H),4.72–4.57(m,2H),4.02–3.81(m,2H),3.29–3.17(m,2H),3.13–3.03(m,1H),2.90–2.72(m,2H),2.25(m,1H),2.14(dd,J＝14.7,5.4Hz,1H),1.91(m,1H),1.46(dd,J＝14.7,9.6Hz,1H),1.21–1.13(m,1H),1.10–1.02(m,1H),0.79–0.71(m,1H),0.62–0.54(m,1H).
example 8
Preparation of (S) -N- (2, 2-difluoroethyl) -3- (4-fluoro-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) propionamide (compound of formula 8)
Step (1) Synthesis of Ethyl (Z) -2- (1,2,6, 7-tetrahydro-8H-indeno [5,4-b ] furan-8-ylidene) acetate (Compound of formula 8-2).
Sodium hydride (77mg,1.9mmol) was added to dry toluene (20mL) under ice-cooling, stirring was carried out for 10 minutes, triethyl phosphonoacetate (426mg,1.9mmol) was added dropwise, the reaction was carried out at room temperature for 2 hours, a toluene solution (5mL) of the compound of formula 8-1 (280mg,1.6mmol) was added dropwise, and after completion of the addition, the temperature was raised to 90 ℃ and the reaction was refluxed overnight. LC-MS showed the reaction of the starting materials to be complete, evaporated under reduced pressure to remove the solvent, diluted with ethyl acetate, quenched with water, separated, the aqueous phase extracted three times with ethyl acetate, the organic phases combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to remove the solvent to give a colorless oil (290mg, 74%), which is the compound of formula 8-2.
Step (2) Synthesis of 2- (1,6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) acetic acid (Compound of formula 8-3).
The compound of formula 8-2 (190mg,0.77mmol) was added to a mixed solvent of methanol and water (5:1) (12mL), palladium on carbon was added thereto, hydrogen was introduced, and the reaction was allowed to proceed overnight at room temperature. After the raw materials are completely reacted by LC-MS, filtering and washing by methanol, directly adding sodium hydroxide solid (155mg,3.88mmol) into the filtrate, stirring at room temperature, detecting by thin layer chromatography, after the reaction is finished, evaporating the solvent under reduced pressure, pouring into ice water, acidifying to pH 1, stirring for crystallization, filtering, washing to neutrality by water, and drying to obtain white solid (150mg, 90%), namely the compound of formula 8-3.
Step (3) Synthesis of 2- (1,6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) ethan-1-ol (Compound of formula 8-4).
Dissolving lithium aluminum hydride (134mg,3.54mmol) in tetrahydrofuran (10mL) under the protection of Ar, cooling to 0 ℃ in ice bath, slowly adding a tetrahydrofuran solution (5mL) of a compound (290mg,1.18mmol) of formula 8-3, reacting at room temperature for 1-2h, detecting by thin layer chromatography, after the reaction is finished, adding 5mL of tetrahydrofuran for dilution, sequentially adding 0.2mL of water and 0.2mL of a sodium hydroxide (15%) aqueous solution into the ice bath, stirring for 10min, adding 0.6mL of water, and stirring at room temperature for 15 min. Dried over anhydrous sodium sulfate, filtered, and the solvent evaporated under reduced pressure to give a brown gum (200mg, 83%), which is a compound of formula 8-4.
A compound of formula 8-4:1H NMR(400MHz,Chloroform-d)δ6.93(t,J＝15.9Hz,1H),6.62(d,J＝7.9Hz,1H),4.66–4.42(m,2H),3.90–3.65(m,2H),3.26(dt,J＝15.0,9.7Hz,2H),3.19–3.05(m,1H),2.99–2.82(m,1H),2.83–2.67(m,1H),2.27(dtd,J＝12.6,8.3,6.4Hz,1H),2.11(dtd,J＝13.5,7.5,4.1Hz,1H),1.92–1.74(m,1H),1.68(dddd,J＝13.4,10.1,6.8,5.4Hz,1H).
step (4) Synthesis of 2- (2,6,7, 8-tetrahydro-1H-indeno [5,4-b ] furan-8-yl) ethyl methanesulfonate (Compound of formula 8-5).
Under the protection of Ar, dissolving a compound (155mg, 0.76mmol) of formula 8-4 in dry tetrahydrofuran (10mL), cooling to 0 ℃ in an ice bath, adding triethylamine (123mg,1.22mmol), dropwise adding methanesulfonyl chloride (105mg,0.91mmol), reacting at room temperature for 1h after dropwise adding, detecting by thin layer chromatography, completely reacting, adding a saturated sodium bicarbonate solution to quench the reaction, extracting with ethyl acetate, washing with organic phase saturated common salt water, drying with anhydrous sodium sulfate, filtering, and evaporating the solvent under reduced pressure to obtain a jelly (180mg, 72%), namely the compound of formula 8-5.
A compound of formula 8-5: LC-MS 283.20[ M + H ] +,284.20[ M +2H ] +,305.20[ M + Na ] +.
Step (5) Synthesis of 3- (2,6,7, 8-tetrahydro-1H-inden [5,4-b ] furan-8-yl) propionitrile (Compound of formula 8-6).
Dissolving the compound of formula 8-5 (8g,28mmol) in N, N-dimethylformamide (50mL), adding sodium cyanide (4.9g,100mmol), reacting overnight at 85 ℃, detecting by thin layer chromatography that the reaction is almost complete, pouring the reaction solution into crushed ice, extracting with ethyl acetate, washing the organic phase with saturated sodium chloride, drying over anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure to obtain crude product, separating by column chromatography (petroleum ether/ethyl acetate: 3/1) to obtain colorless gum (5.1g, 83%), i.e. the compound of formula 8-6.
Compounds of formulae 8-6:1H NMR(400MHz,Chloroform-d)δ6.97(d,J＝8.0Hz,1H),6.64(d,J＝8.0Hz,1H),4.74–4.37(m,2H),3.30(ddd,J＝16.3,8.6,3.8Hz,1H),3.25–3.05(m,2H),2.95–2.73(m,2H),2.48–2.36(m,2H),2.36–2.24(m,1H),2.24–2.11(m,1H),1.86–1.71(m,2H).
step (6) Synthesis of 3- (2,6,7, 8-tetrahydro-1H-indeno [5,4-b ] furan-8-yl) propanoic acid (Compound of formula 8-7).
Dissolving the compound of formula 8-6 (100mg,0.47mmol) in 10mL of a mixed solvent of ethanol and water (1:1), adding 30% sodium hydroxide solution (2mL), reacting overnight at 80 ℃, detecting the substantial reaction completion by thin layer chromatography, pouring the reaction solution into crushed ice, extracting with dichloromethane, washing the organic phase with saturated saline, drying over anhydrous sodium sulfate, filtering, and evaporating the solvent under reduced pressure to obtain a yellow colloidal crude product (201mg, 100%), namely the compound of formula 8-7.
Compounds of formulae 8-7: LC-MS 232.15[ M + H ] +
Step (7) Synthesis of methyl 3- (2,6,7, 8-tetrahydro-1H-indeno [5,4-b ] furan-8-yl) propionate (Compound of formula 8-8).
Dissolving the compound of the formula 8-7 (860mg,3.64mmol) in methanol, dropwise adding 3-4 drops of concentrated sulfuric acid, heating the reaction solution to 70 ℃, refluxing for reaction overnight, detecting basic reaction by thin-layer chromatography, evaporating the solvent under reduced pressure, and separating by column chromatography (petroleum ether/ethyl acetate: 4/1) to obtain a colorless oily substance (862mg, 96%), namely the compound of the formula 8-8.
Compounds of formulae 8-8: LC-MS 247.10[ M + H ] +.
Step (8) Synthesis of methyl 3- (4-nitro-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) propionate (Compound of formula 8-9).
Dissolving the compound of formula 8-8 (0.247g,1mmol,1eq.) in acetic acid (8mL), adding 0.2mL of 60% nitric acid dropwise, reacting at room temperature for 4-6h, detecting the substantial reaction completion by thin layer chromatography (PE: EA ═ 3:1), pouring into crushed ice, extracting with ethyl acetate, washing the organic phase with saturated sodium bicarbonate and saturated sodium chloride, drying over anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure to obtain the crude product, and separating by column chromatography (petroleum ether/ethyl acetate ═ 3/1) to obtain a colorless gum (193mg, 78%), i.e., the compound of formula 8-9.
Step (9) Synthesis of methyl-3- (4-amino-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) propanoate (Compound of formula 8-10).
Dissolving the compound of formula 8-9 (1.1g,3.78mmol) in ethanol (10mL), adding Raney Ni (cat. amount) and hydrazine hydrate in sequence, reacting at room temperature for 12h, detecting by thin layer chromatography that the reaction is almost complete, filtering, distilling off the solvent under reduced pressure, adding water and mixed solvent (DCM: CH3OH ═ 10:1), separating out the organic phase, adding mixed solvent (DCM: CH3OH ═ 10:1) to the aqueous phase, extracting, washing the organic phase with water three times, washing with saturated sodium chloride, drying with anhydrous sodium sulfate, concentrating to obtain the crude product, and separating by column chromatography (dichloromethane: methanol ═ 25:1) to obtain a colorless gum (730mg, 81%), i.e. the compound of formula 8-10.
Step (10) Synthesis of methyl 3- (4-fluoro-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) propanoate (Compound of formula 8-11).
Dissolving nitroso tetrafluoroborate (70mg,0.28mmol) in dry dichloromethane (10mL), cooling to 0 ℃, dropwise adding the solution into a dichloromethane solution of a compound (65mg,0.25mmol) of formula 8-10, keeping the temperature for reaction for 1-2h, evaporating the solvent under reduced pressure, adding xylene, heating to 130 ℃, and reacting for 1 h. The reaction was essentially complete by thin layer chromatography, concentrated to give the crude product which was separated by column chromatography (petroleum ether/ethyl acetate 2/1) to give a colourless gum (20mg, 30%), i.e. the compound of formula 8-11.
Step (11) Synthesis of (S) -3- (4-fluoro-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) propanoic acid (Compound of formula 8-12).
Dissolving the compound of formula 8-11 (26mg,0.1mmol) in 10mL of mixed solvent of methanol and water (1:1), adding lithium hydroxide (10mg,0.15mmol), heating to 80 ℃ for reaction overnight, detecting by thin layer chromatography that the reaction is almost complete, distilling off the solvent under reduced pressure, pouring into crushed ice, extracting with dichloromethane, washing the organic phase with saturated saline, drying over anhydrous sodium sulfate, filtering, concentrating to obtain a yellow colloidal crude product (20mg, 78%), and resolving by manual HPLC to obtain a white solid (8mg), namely the compound of formula 8-12.
Step (12) Synthesis of (S) -N- (2, 2-difluoroethyl) -3- (4-fluoro-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) propionamide (Compound of formula 8).
The compound of formula 8-12 (53mg,0.21mmol) was dissolved in anhydrous dichloromethane (10mL), 2-difluoroethylamine (15mg,0.25mmol), 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (48mg,0.25mmol) and 1-hydroxybenzotriazole (35mg,0.25mmol) were added, stirred at room temperature for 2 hours, the reaction was substantially completed by thin layer chromatography, the solvent was evaporated under reduced pressure and column chromatography (petroleum ether/ethyl acetate: 2/1) was performed to obtain a white solid (30mg, 68%), which is the compound of formula 8.
A compound of formula 8:1H NMR(400MHz,Chloroform-d)δ6.75(d,J＝10.5Hz,1H),6.08–5.68(m,1H),5.66(s,1H),4.76–4.54(m,2H),3.63(tdd,J＝15.0,6.2,4.0Hz,2H),3.41–3.24(m,1H),3.16(dt,J＝15.5,8.2Hz,2H),2.96–2.80(m,1H),2.81–2.68(m,1H),2.31–2.20(m,4H),2.21(d,J＝4.1Hz,1H),1.83–1.66(m,3H).
example 9
Preparation of (S) -3- (4, 5-difluoro-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) -2-fluoro-N-methylpropanamide (compound of formula 9)
Step (1) Synthesis of 2- (4, 5-difluoro-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) acetaldehyde (Compound of formula 9-1).
Dissolving the compound of formula 5-8 (3.973g,16.54mmol) in dichloromethane (30mL), adding (1,1, 1-triacetoxy) -1, 1-dihydro-1, 2-phenyliodoyl-3 (1H) -one (14g,33mmol), stirring overnight at room temperature, detecting the substantial reaction completion by thin layer chromatography, adding sodium thiosulfate solution to quench the reaction, extracting with dichloromethane, washing the organic phase once with saturated sodium bicarbonate solution, washing once with saturated saline, drying with anhydrous sodium sulfate, filtering, evaporating off the solvent under reduced pressure, performing column chromatography, and eluting with petroleum ether/ethyl acetate 5/1 to obtain a yellow liquid (2.88g, 73%), namely the compound of formula 9-1.
A compound of formula 9-1: LC-MS 238.90[ M + H ]]+.
Step (2) Synthesis of 3- (4, 5-difluoro-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) -2-hydroxypropionitrile (Compound of formula 9-2).
Suspending the compound of formula 9-1 (2.83g,11.87mmol) in tetrahydrofuran (7mL) and water (14mL), adding sodium bisulfite (1.6g,15mmol), stirring at room temperature for half an hour, adding potassium cyanide (1.55g,24mmol), stirring at room temperature for 2.5 hours, detecting the completion of the basic reaction by thin layer chromatography, adding water to quench the reaction, extracting with ethyl acetate, washing the organic phase with saturated saline solution once, drying over anhydrous sodium sulfate, filtering, and evaporating the solvent under reduced pressure to obtain a yellow liquid (2.2g, 70%), namely the compound of formula 9-2.
Step (3) Synthesis of methyl 3- (4, 5-difluoro-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) -2-hydroxypropionate (Compound of formula 9-3).
Dissolving the compound of formula 9-2 (1.844g,7mmol) in methanol (20mL), adding 37% hydrochloric acid (6mL), stirring at 80 ℃ for 2 days, detecting the basic reaction by thin layer chromatography, adding water to quench the reaction, extracting with ethyl acetate for 3 times, washing the organic phase with sodium bicarbonate solution once, washing with saturated saline solution once, drying with anhydrous sodium sulfate, filtering, and evaporating the solvent under reduced pressure to obtain brown viscous liquid (1.57g, 75%) which is the compound of formula 9-3.
A compound of formula 9-3: LC-MS 298.90[ M + H ]]+；320.90[M+Na]+.
Step (4) Synthesis of methyl 3- (4, 5-difluoro-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) -2-fluoropropionate (Compound of formula 9-4).
Dissolving the compound (1g,3.5mmol) of the formula 9-3 in dichloromethane (15mL), adding diethylaminosulfur trifluoride (1.84mL,14mmol) under ice bath, stirring at room temperature for 4 hours, detecting the basic reaction by thin layer chromatography, adding water to quench the reaction, extracting with dichloromethane for 3 times, drying with anhydrous sodium sulfate, filtering, and evaporating the solvent under reduced pressure to obtain a brown viscous liquid (1.3 g). I.e., a compound of formula 9-4.
Compounds of formulae 9-4: LC-MS 300.90[ M + H ]]+.
Step (5) Synthesis of (S) -3- (4, 5-difluoro-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) -2-fluoropropionic acid (Compound of formula 9-5).
Dissolving a compound of formula 9-4 (900mg,2.6mmol) in ethanol (1.5mL), adding lithium hydroxide (0.11g,2.6mmol) dissolved in water (5mL), stirring at room temperature for 3 days, detecting the basic completion of the reaction by thin layer chromatography, adding water and 8 drops of 37% hydrochloric acid to adjust the pH to 3-4, extracting with ethyl acetate three times, washing with saturated saline once, drying with anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure to obtain brown viscous liquid (0.86g), and performing chiral HPLC to obtain a white solid (320mg), namely the compound of formula 9-5.
Compounds of formulae 9-5: LC-MS 286.90[ M + H ]]+.
Step (6) Synthesis of (S) -3- (4, 5-difluoro-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) -2-fluoropropionic acid (Compound of formula 9).
Dissolving a compound of formula 9-5 (155mg,0.46mmol) in dichloromethane (2.5mL), adding methylamine hydrochloride (41mg,0.6mmol), diisopropylethylamine (0.2mL,1.15mmol), 1-hydroxybenzotriazole (81mg,0.6mmol) and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (115mg,0.6mmol), stirring overnight at room temperature, detecting substantial reaction completion by thin layer chromatography, adding water and 5 drops of 37% hydrochloric acid, extracting twice with dichloromethane, washing with a saturated sodium bicarbonate solution, drying over anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure, and then performing column chromatography with 200-300 mesh silica gel column chromatography, eluting petroleum ether/ethyl acetate ═ 2/1 to obtain a brown solid (100mg, 62%), namely the compound of formula 9.
A compound of formula 9: LC-MS 299.95[ M + H ]]+；321.90[M+Na]+.
A compound of formula 9:1H NMR(400MHz,Chloroform-d)δ6.35(s,1H),4.90(m,1H),4.62(m,2H),3.34–3.17(m,2H),3.11(m,1H),3.02–2.72(m,5H),2.46–1.85(m,4H).
example 10
Preparation of (S) -3- (4-chloro-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) -N-cyclopropylpropionamide (compound of formula 10)
Step (1) Synthesis of (S) -2- (1,6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) ethan-1-ol (Compound of formula 10-2).
Under the protection of Ar, dissolving lithium aluminum hydride (134mg,3.54mmol) in tetrahydrofuran (10mL), cooling to 0 ℃ in ice bath, slowly adding 5mL of tetrahydrofuran solution of a compound (290mg,1.18mmol) of formula 10-1, reacting at room temperature for 1-2h, detecting the basic reaction completion by thin layer chromatography, adding tetrahydrofuran (5mL) for dilution, sequentially adding 0.2mL of water and 0.2mL of sodium hydroxide (15%) aqueous solution in ice bath, stirring for 10min, then adding 0.6mL of water, and stirring at room temperature for 15 min. Dried over anhydrous sodium sulfate, filtered, and concentrated to give a brown gum (193mg, 80%), which is the compound of formula 10-2.
A compound of formula 10-2:1H NMR(400MHz,Chloroform-d)δ6.93(t,J＝15.9Hz,1H),6.62(d,J＝7.9Hz,1H),4.66–4.42(m,2H),3.90–3.65(m,2H),3.26(dt,J＝15.0,9.7Hz,2H),3.19–3.05(m,1H),2.99–2.82(m,1H),2.83–2.67(m,1H),2.27(dtd,J＝12.6,8.3,6.4Hz,1H),2.11(dtd,J＝13.5,7.5,4.1Hz,1H),1.92–1.74(m,1H),1.68(dddd,J＝13.4,10.1,6.8,5.4Hz,1H).
step (2) Synthesis of (S) -2- (2,6,7, 8-tetrahydro-1H-indeno [5,4-b ] furan-8-yl) ethyl methanesulfonate (Compound of formula 10-3).
Under the protection of Ar, dissolving a compound of formula 10-2 (155mg, 0.76mmol) in dry tetrahydrofuran (10mL), cooling to 0 ℃ in an ice bath, adding triethylamine (123mg,1.22mmol), dropwise adding methanesulfonyl chloride (105mg,0.91mmol), reacting at room temperature for 1h after dropwise adding, completing the thin layer chromatography reaction, adding an aqueous solution of sodium bicarbonate to quench the reaction, extracting with ethyl acetate, washing with organic phase saturated common salt water, drying with anhydrous sodium sulfate, filtering, concentrating to obtain a gum (185mg, 73%), namely the compound of formula 10-3.
A compound of formula 10-3: LC-MS 283.20[ M + H ] +.
Step (3) Synthesis of (S) -3- (2,6,7, 8-tetrahydro-1H-inden [5,4-b ] furan-8-yl) propionitrile (Compound of formula 10-4).
50mL of crude compound of formula 10-3 (8g,28mmol) dissolved in N, N-dimethylformamide was added with sodium cyanide (4.9g,100mmol), reacted overnight at 85 deg.C, the reaction was checked for substantial completion by thin layer chromatography (petroleum ether: ethyl acetate ═ 2:1), poured into crushed ice, extracted with ethyl acetate, the organic phase was washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated to give crude product, and column chromatography (petroleum ether/ethyl acetate ═ 3/1) separated to give colorless gum (5.5g, 91%), i.e., compound of formula 10-4.
A compound of formula 10-4:1H NMR(400MHz,Chloroform-d)δ6.97(d,J＝8.0Hz,1H),6.64(d,J＝8.0Hz,1H),4.74–4.37(m,2H),3.30(ddd,J＝16.3,8.6,3.8Hz,1H),3.25–3.05(m,2H),2.95–2.73(m,2H),2.48–2.36(m,2H),2.36–2.24(m,1H),2.24–2.11(m,1H),1.86–1.71(m,2H).
step (4) Synthesis of (S) -3- (4-chloro-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) propionitrile (Compound of formula 10-5).
Dissolving the compound of formula 10-4 (1.1g,5mmol.) in 15mL of DMF, cooling to 0 deg.C, adding N-chlorosuccinimide (0.8g,6mmol) slowly in portions, reacting at room temperature for 12h, detecting the basic reaction completion by thin layer chromatography TLC (PE: EA ═ 3:1), pouring into crushed ice, extracting with ethyl acetate, washing with water, washing the organic phase with saturated sodium chloride, drying with anhydrous sodium sulfate, filtering, concentrating to obtain a crude product, and separating by column chromatography (petroleum ether/ethyl acetate ═ 3/1) to obtain a colorless gum (1.12g, 91%), namely the compound of formula 10-5.
Step (5) Synthesis of (S) -3- (4-chloro-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) propanoic acid (Compound of formula 10-6).
Dissolving the compound of formula 10-5 (247mg,1mmol) in 10mL of a mixed solvent of ethanol and water (1:1), adding 30% sodium lithium hydroxide solution (4mL), heating to 80 ℃ for overnight reaction, detecting the substantial completion of the reaction by thin layer chromatography, evaporating the solvent under reduced pressure, pouring into crushed ice, extracting with dichloromethane, washing the organic phase with saturated saline, drying over anhydrous sodium sulfate, filtering, and concentrating to obtain a yellow colloidal crude product (207mg, 78%), which is the compound of formula 10-6.
Step (6) Synthesis of (S) -3- (4-chloro-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) -N-cyclopropylpropionamide (compound of formula 10).
Dissolving the compound of formula 10-6 (53mg,0.21mmol) in anhydrous dichloromethane (2mL), adding cyclopropylamine (14mg,0.25mmol), 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (48mg,0.25mmol) and 1-hydroxybenzotriazole (35mg,0.25mmol), stirring at room temperature for 2 hours, detecting by thin layer chromatography that the reaction is substantially complete, evaporating the solvent under reduced pressure, and performing column chromatography (petroleum ether/ethyl acetate ═ 2/1) to obtain a white solid, namely the compound of formula 10.
Formula 10Compound (a):1H NMR(400MHz,Chloroform-d)δ6.95(s,1H),5.52(s,1H),4.65(dq,J＝18.3,8.8Hz,2H),3.36(dt,J＝17.8,8.9Hz,1H),3.26–3.08(m,2H),2.96–2.79(m,1H),2.72(ddd,J＝11.0,10.4,5.9Hz,3H),2.27–2.16(m,2H),2.17(s,4H),1.82–1.67(m,3H),0.79–0.71(m,3H),0.47(q,J＝6.7Hz,2H).
example 11
Preparation of (S) -3- (4-cyano-2, 6,7, 8-tetrahydro-1H-indeno [5,4-b ] furan-8-yl) -N-2, 2-difluoroethyl) propionamide (compound of formula 11)
Step (1) Synthesis of (S) -3- (4-bromo-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) propionitrile (Compound of formula 11-1).
Dissolving the compound of formula 10-4 (1.1g,5mmol) in N, N-dimethylformamide (15mL), cooling to 0 deg.C, adding NBS (1.1g,6mmol) slowly in portions, reacting at room temperature for 12h, detecting the basic reaction completion by thin layer chromatography (PE: EA ═ 3:1), pouring into crushed ice, extracting with ethyl acetate, washing with water, washing the organic phase with saturated sodium chloride, drying over anhydrous sodium sulfate, filtering, concentrating to obtain a crude product, and separating by column chromatography (petroleum ether/ethyl acetate ═ 3/1) to obtain a colorless gum (1.12g, 91%), namely the compound of formula 11-1.
Step (2) Synthesis of (S) -3- (4-bromo-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) propanoic acid (Compound of formula 11-2).
Dissolving the compound of formula 11-1 (247mg,1mmol) in 10mL of a mixed solvent of ethanol and water (1:1), adding 30% sodium lithium hydroxide (4mL), heating to 80 ℃ for overnight reaction, detecting by thin layer chromatography that the reaction is almost complete, evaporating the solvent under reduced pressure, pouring into crushed ice, extracting with dichloromethane, washing the organic phase with saturated saline, drying over anhydrous sodium sulfate, filtering, and concentrating to obtain a yellow colloidal crude product (207mg, 82%), which is the compound of formula 11-2.
Step (3) Synthesis of methyl (S) -3- (4-bromo-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) propionate (Compound of formula 11-3).
The compound of formula 11-2 (1.23g,3.95mmol) was dissolved in methanol (20mL), 3-4 drops of concentrated sulfuric acid were added dropwise, the reaction solution was warmed to 70 ℃, refluxed overnight, the reaction was checked by thin layer chromatography to be complete, the solvent was evaporated under reduced pressure, and column chromatography (petroleum ether/ethyl acetate: 5/1) was performed to obtain a colorless oil (1.23g, 96%), i.e., the compound of formula 11-3.
Step (4) Synthesis of methyl (S) -3- (4-cyano-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) propionate (Compound of formula 11-4).
Dissolving a compound (1.4g,4.32mmol) shown in formula 11-3 in N, N-dimethylformamide (20mL), sequentially adding palladium acetate (194mg,0.86mmol), potassium ferricyanide (877mg,2.07mmol), sodium carbonate (458mg,4.32mmol) and isopropanol (1mL), heating to 140 ℃, sealing and reacting for 4h, detecting the reaction completion by thin-layer chromatography, filtering, evaporating the solvent under reduced pressure, adding water, extracting with ethyl acetate, washing with water, washing the organic phase with saturated sodium chloride, drying with anhydrous sodium sulfate, filtering, concentrating to obtain a crude product, and separating by column chromatography (petroleum ether/ethyl acetate ═ 5/1) to obtain a colorless gum (0.4g, 25%), namely the compound shown in formula 11-4.
Step (5) Synthesis of (S) -3- (4-cyano-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) propanoic acid (Compound of formula 11-5).
Dissolving the compound of formula 11-4 (26mg,0.1mmol) in 10mL of a mixed solvent of methanol and water (1:1), adding lithium hydroxide (10mg,0.15mmol), heating to 80 ℃ for reaction overnight, detecting by thin layer chromatography that the reaction is almost complete, distilling off the solvent under reduced pressure, pouring into crushed ice, extracting with dichloromethane, washing the organic phase with saturated saline, drying over anhydrous sodium sulfate, filtering, and concentrating to obtain a yellow gum crude product (20mg, 78%), namely the compound of formula 11-5.
Step (6) Synthesis of (S) -3- (4-cyano-2, 6,7, 8-tetrahydro-1H-indeno [5,4-b ] furan-8-yl) -N-2, 2-difluoroethyl) propionamide (Compound of formula 11).
Dissolving the compound of formula 11-5 (53mg,0.21mmol) in anhydrous dichloromethane (2mL), adding 2, 2-difluoroethylamine (20mg,0.25mmol), 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (48mg,0.25mmol) and 1-hydroxybenzotriazole (35mg,0.25mmol), stirring at room temperature for 2 hours, detecting the substantial reaction completion by thin layer chromatography, evaporating the solvent under reduced pressure, and separating by column chromatography (petroleum ether/ethyl acetate ═ 2/1) to obtain a white solid (38mg, 57%), namely the compound of formula 11.
A compound of formula 11:1H NMR(400MHz,Chloroform-d)δ7.11(s,1H),6.09–5.61(m,3H),4.84–4.51(m,2H),3.74–3.54(m,3H),3.38–3.27(m,1H),3.25–3.10(m,2H),2.93–2.82(m,1H),2.82–2.66(m,1H),2.32–2.13(m,4H),1.74(ddd,J＝22.9,13.4,8.7Hz,2H)
example 12
Preparation of (S) -3- (4, 5-difluoro-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) -N-methylpropanamide (compound of formula 12)
Step (1) Synthesis of methyl (S) -3- (4, 5-difluoro-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) propionate (Compound of formula 12-1).
Dissolving the compound of formula 5-11 (83mg,0.31mmol) in methanol (1.1mL), adding 3 drops of concentrated sulfuric acid, stirring at 70 ℃ for 18h, detecting by thin layer chromatography, adding ice water (50mL) after the reaction is finished, extracting with ethyl acetate (5 mL. times.3), washing with saturated sodium bicarbonate solution for 1 time, drying with anhydrous sodium sulfate, filtering, and evaporating the solvent under reduced pressure to obtain brown liquid (96mg, which is directly put into the next reaction without purification), namely the compound of formula 12-1.
A compound of formula 12-1: LC-MS 283.00[ M + H ]]+；305.0[M+Na]+.
Step (2) Synthesis of (S) -3- (4, 5-difluoro-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) -N-methylpropanamide (Compound of formula 12).
The compound of formula 12-1 (96mg,0.31mmol) was dissolved in tetrahydrofuran (2mL), placed in a sealed tube, methylamine alcohol solution (963mg,9.3mmol) was added, heated and stirred at 60 ℃ for 4 hours, detected by thin layer chromatography, the reaction was completed, the solvent was distilled off under reduced pressure, and plate purification was performed (petroleum ether/ethyl acetate ═ 4/1) to obtain a white solid (30mg, 34% in two steps), i.e., the compound of formula 12.
A compound of formula 12: LC-MS 281.95[ M + H ]]+.
A compound of formula 12:1H NMR(400MHz,Chloroform-d)δ5.43(s,1H),4.75–4.60(m,2H),3.34–3.23(m,1H),3.14(m,2H),2.95–2.85(m,1H),2.84–2.74(m,4H),2.31–2.23(m,1H),2.17(m,3H),1.80(m,1H),1.71(m,1H).
example 13
Preparation of (R) -3- (4, 5-difluoro-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) -N-methylpropanamide (compound of formula 13)
Step (1) Synthesis of (R) -3- (4, 5-difluoro-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) propanoic acid (Compound of formula 13-1).
Dissolving the compound of formula 5-10 (0.4g,1.6mmol) in ethanol (1.5mL), adding sodium hydroxide (257mg,6.4mmol) dissolved in water (1.5mL), stirring at 80 ℃ for 4 hours, detecting by thin layer chromatography, after the reaction is finished, adding 37% hydrochloric acid (0.5mL) under ice bath to adjust to acidity, extracting with ethyl acetate for three times, washing with saturated salt water once, drying with anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure to obtain a white solid (415mg, 97%), and performing manual HPLC to obtain a white solid (165mg), namely the compound of formula 13-1.
A compound of formula 13-1: LC-MS 268.90[ M + H ] +.
Step (2) Synthesis of methyl- (R) -3- (4, 5-difluoro-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) propionate (Compound of formula 13-2).
Dissolving the compound of formula 13-1 (96mg,0.36mmol) in methanol (2mL), adding 3 drops of concentrated sulfuric acid, stirring overnight at 70 ℃, detecting by thin layer chromatography, adding ice water (50mL) after the reaction is finished, extracting by ethyl acetate (10 mL. times.3), washing by saturated sodium bicarbonate solution for 1 time, drying by anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure to obtain brown liquid (111mg, which is directly put into the next reaction without purification), namely the compound of formula 13-2.
A compound of formula 13-2: LC-MS 283.00[ M + H ]]+；305.0[M+Na]+.
Step (3) Synthesis of (R) -3- (4, 5-difluoro-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) -N-methylpropanamide (Compound of formula 13).
The compound of formula 13-2 (111mg,0.36mmol) was dissolved in tetrahydrofuran (5mL), placed in a sealed tube, added with a methylamine alcohol solution (1.12g,10.8mmol), heated and stirred at 60 ℃ for 4 hours, detected by thin layer chromatography, after the reaction was completed, the solvent was distilled off under reduced pressure, and plate purification (petroleum ether/ethyl acetate: 4/1) was performed to obtain a white solid (35mg, 40% of two steps), i.e., the compound of formula 13.
A compound of formula 13: LC-MS 281.95[ M + H ]]+.
A compound of formula 13:1H NMR(400MHz,Chloroform-d)δ5.43(s,1H),4.75–4.60(m,2H),3.34–3.23(m,1H),3.14(m,2H),2.95–2.85(m,1H),2.84–2.74(m,4H),2.31–2.23(m,1H),2.17(m,3H),1.80(m,1H),1.71(m,1H).
example 14
Preparation of (S) -N-methyl-3- (4-methyl-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) propionamide (compound of formula 14)
Step (1) Synthesis of methyl- (S) -3- (4-methyl-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) propionate (Compound of formula 14-1).
The compound of formula 11-3 (120mg, 0.37mmol) was dissolved in toluene (20mL), and methylboronic acid (22mg, 0.37mmol), potassium carbonate (102mg, 0.74mmol), and palladium tetrakistriphenylphosphine (85mg, 0.074mmol) were added to replace argon, and the mixture was heated and stirred at 100 ℃ for 18 hours, followed by detection by thin layer chromatography and completion of the reaction. Cooling, filtering off insoluble substances, evaporating the solvent under reduced pressure, and separating by column chromatography (petroleum ether/ethyl acetate: 4/1) to obtain a white solid (50mg, 52%), which is the compound of formula 14-1.
A compound of formula 14-1: LC-MS 261.1[ M + H ]]+
Step (2) Synthesis of (S) -3- (4-methyl-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) propanoic acid (Compound of formula 14-2).
Dissolving the compound of formula 14-1 (126mg,0.48mmol) in 10mL of a mixed solvent of methanol and water (1:1), adding lithium hydroxide (48mg,0.73mmol), heating to 80 ℃ for reaction overnight, detecting by thin layer chromatography that the reaction is substantially complete, evaporating the solvent under reduced pressure, pouring into crushed ice, extracting with dichloromethane, washing the organic phase with saturated saline, drying over anhydrous sodium sulfate, filtering, and concentrating to obtain a crude product (95mg, 80%) as a colorless gum, i.e., the compound of formula 14-2.
Step (3) Synthesis of (S) -N-methyl-3- (4-methyl-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) propionamide (Compound of formula 14).
Dissolving the compound of formula 14-2 (95mg,0.39mmol) in anhydrous dichloromethane (5mL), adding methylamine hydrochloride (31mg,0.46mmol), 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (89mg,0.46mmol) and 1-hydroxybenzotriazole (65mg,0.46mmol), stirring at room temperature for 2 hours, detecting the substantial reaction completion by thin layer chromatography, evaporating the solvent under reduced pressure, and separating by column chromatography (petroleum ether/ethyl acetate ═ 2/1) to obtain a white solid (48mg, 48%), namely the compound of formula 14.
A compound of formula 14: LC-MS 260.1[ M + H ]]+.
A compound of formula 14:1H NMR(500MHz,Chloroform-d)δ6.83(q,J＝1.0Hz,1H),5.89(s,1H),4.62–4.48(m,2H),3.39(dtd,J＝19.0,9.2,2.7Hz,2H),3.10(tdd,J＝12.5,4.3,1.8Hz,1H),2.96–2.82(m,3H),2.80(s,3H),2.78–2.70(m,1H),2.39(td,J＝12.7,1.8Hz,1H),2.22(d,J＝1.1Hz,3H),2.01–1.83(m,2H),1.70(dt,J＝13.3,7.0Hz,1H).
example 15
Preparation of (S) -N-methyl-3- (4-ethyl-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) propionamide (compound of formula 15)
Step (1) Synthesis of methyl (S) -3- (4-ethyl-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) propionate (Compound of formula 15-1).
The compound of formula 11-3 (120mg, 0.37mmol) was dissolved in toluene (20mL), ethylboronic acid (28mg, 0.37mmol), potassium carbonate (102mg, 0.74mmol), palladium tetrakistriphenylphosphine (85mg, 0.074mmol) were added, argon was replaced, the mixture was heated and stirred at 100 ℃ for 18h, and the reaction was completed by thin layer chromatography. Cooling, filtering off insoluble substances, evaporating the solvent under reduced pressure, and separating by column chromatography (petroleum ether/ethyl acetate: 4/1) to obtain a white solid (60mg, 60%), which is the compound of formula 15-1.
A compound of formula 15-1: LC-MS of 274.2[ M + H ]]+
Step (2) Synthesis of (S) -3- (4-ethyl-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) propanoic acid (Compound of formula 15-2).
Dissolving the compound of formula 15-1 (148mg,0.54mmol) in 10mL of a mixed solvent of methanol and water (1:1), adding lithium hydroxide (53mg,0.81mmol), heating to 80 ℃ for reaction overnight, detecting by thin layer chromatography that the reaction is substantially complete, evaporating the solvent under reduced pressure, pouring into crushed ice, extracting with dichloromethane, washing the organic phase with saturated saline, drying over anhydrous sodium sulfate, filtering, and concentrating to obtain a crude colorless gum (98mg, 70%) which is the compound of formula 15-2.
Step (3) Synthesis of (S) -N-methyl-3- (4-ethyl-1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) propionamide (Compound of formula 15).
Dissolving the compound of formula 15-2 (98mg,0.37mmol) in anhydrous dichloromethane (5mL), adding methylamine hydrochloride (30mg,0.44mmol), 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (85mg,0.44mmol) and 1-hydroxybenzotriazole (62mg,0.44mmol), stirring at room temperature for 2 hours, detecting the substantial reaction completion by thin layer chromatography, evaporating the solvent under reduced pressure, and separating by column chromatography (petroleum ether/ethyl acetate ═ 2/1) to obtain a white solid (60mg, 60%), namely the compound of formula 15.
A compound of formula 15: LC-MS 273.2[ M + H ]]+.
A compound of formula 15:1H NMR(500MHz,Chloroform-d)δ6.95–6.81(m,1H),5.89(s,1H),4.61–4.38(m,2H),3.31–3.20(m,1H),3.10(ddt,J＝18.5,6.1,1.9Hz,1H),3.00–2.85(m,2H),2.80(s,4H),2.70–2.58(m,2H),2.43(dtd,J＝9.2,8.0,1.2Hz,3H),2.18–2.07(m,1H),1.83–1.66(m,2H),1.18(t,J＝8.0Hz,3H).
example 16
The above compounds of the present invention have an agonistic activity on melatonin (MT1/MT2) receptors
For experimental methods, please refer to the literature: genomics.27(2): 355-7, endocrinology.139(7): 3064-71.
Through transient G α 16 transfer of CHO/MT1 cell line, the receptor can be activated to activate G α 16 protein, and then activate phospholipase C (PLC) to generate IP3 and DAG, IP3 can be combined with IP3 receptor on endoplasmic reticulum and mitochondria in cells, thereby causing the release of intracellular calcium, therefore, the change of intracellular calcium can be used as a method for detecting the activation state of MT 1. Fluo-4/AM is a calcium fluorescent probe indicator for measuring calcium ion, which is a non-polar lipid soluble compound, after entering cells, under the action of cell lipolytic enzyme, AM group is dissociated to release Fluo-4, because Fluo-4 is a polar molecule, it can not easily pass through lipid bilayer membrane, so that Fluo-4 can be kept in cells for a long time, finally, the activated level of G protein can be reflected by measuring the intensity of excited fluorescence, if the screened compound can activate MT1 receptor, the calcium flux reaction can be caused.
The CHO/MT1 cells instantly transformed to G α 16 are planted in a 96-well plate, cultured overnight, culture solution in the holes planted with the cells is sucked off, 401 holes of freshly prepared dye are added, incubation is carried out for 40 minutes at constant temperature in an incubator at 37 ℃, the medicine to be detected is diluted and uniformly mixed by using calcium buffer solution, the dye is sucked off and discarded, the calcium buffer solution is washed once by using the freshly prepared calcium buffer solution, 50L of calcium buffer solution is added, detection is carried out by using a FlexStation II instrument, 25L of calcium buffer solution dissolved with the agonist to be detected of MT1 receptor is automatically added by the instrument from the 15 th second, and finally the fluorescence value at 525nm and the 50% agonist concentration (EC) are read (the fluorescence value is measured at 525nm50) Values were calculated from dose-response curves using the least squares method. The results of the bioactivity tests of representative compounds of the invention are shown in table 2.
Table 2: the compounds of the invention have agonist activity on melatonin (MT1/MT2) receptors
As can be seen from Table 2, the compounds of the present invention have strong in vitro agonistic activity to melatonin (MT1/MT2) receptors, and most of the compounds have in vitro activity close to or better than that of a control drug Ramelteon, which indicates that the compounds of the present invention have good in vitro melatonin receptor agonistic activity. While the activity data for compounds 12 and 13 also indicate that the S configuration is the preferred structure, the activity of the compound of the R structure is very weak.
Example 17
In vivo metabolism test of normal rat with the compound of the invention
The experimental method comprises the following steps:
healthy SD rats, male, with the weight of 200-; fasted for 12h before the test, water was freely available. The diets were uniformly fed 2h after dosing. Blood sampling time points and sample treatment:
after administration, 5min,10min,20min,30min,45min,1h,2h,3h,4h,5h,6h, 0.1ml of venous blood was taken from the retrobulbar venous plexus of rats, placed on ice, and plasma was centrifuged within 30 minutes (centrifugation conditions: 5000 rpm, 10min, 4 ℃), and the collected plasma was stored at-80 ℃ before analysis. Plasma concentrations at each sampling point were determined using LC/MS and pharmacokinetic parameters were calculated.
After the administration, blood is collected for 30min and then dissected, after liver and brain tissue samples are taken, the surface is cleaned by physiological saline, and after medical gauze is wiped dry, the samples are placed in a marked small self-sealing bag and stored at the temperature of minus 80 ℃ to be detected. The drug concentration in the tissue is determined by LC-MS/MS method, and the plasma concentration corresponding to the corresponding time point is divided to obtain the Kp value of the tissue distribution. The results are shown in Table 3.
Table 3 metabolism of Ramelteon and compound 12 in normal rats and Kp data table
It can be seen from table 3 that compound 12 of the present invention has good pharmacokinetic parameters in rats, a longer half-life in vivo (1.33h) and ideal in vivo drug exposure (127ng x h/mL), superior to the control drug Ramelteon. The compound has obvious drug-like property, and is suitable for treating or preventing diseases related to melatonin (MT1/MT2) receptors, such as insomnia, rhythm disorder and depression.
Compound 12 acts on sleep and, most importantly, needs to pass through the blood-brain barrier and enter the brain to exert its pharmacological effect. As can be seen from the table, the targeting of the compound 12 in the brain is obviously better than Ramelteon, so that the concentration of the compound 12 in the brain is determined to be better than Ramelteon.
In conclusion, compound 12 exhibited better values of drug metabolism and better brain tissue distribution in animals, and would be more advantageous for the prevention and treatment of diseases associated with melatonin (MT1/MT2) receptors.
Example 18
Experiment for promoting sleep of normal rats by using compound of the invention
The experimental method comprises the following steps: SPF male SD rats (280-320g, 11-13 weeks) were raised in an environment of room temperature 22 + -0.5 deg.C, relative humidity 60 + -2%, automatic light control 12h light period/12 h dark period (lamp-on time: 07:00, light intensity ≈ 100 lux). The animals had free access to food and water. Before the experiment, the multi-lead electroencephalogram recording electrode is embedded in the cranium of a rat, and then the rat is transferred to a recovery cage to be independently raised for 10 days for recovery.
Test compound 12 and positive control drugs Ramelteon and zolpidem tartrate were prepared to the desired concentrations in 0.5% methylcellulose solution prior to administration. The administration time is 21:00, and the administration volume is 0.15ml/100g by intragastric administration.
The experiment is carried out by a double-blind method, the animal is accessed into an electroencephalogram recording system and adapted for 3 days, then the recording is started at 19:00, and the recording lasts for 72 hours. The first day of intragastric administration of 21:00 vehicle control was recorded, the next day of 21:00 vehicle, compound 12, Ramelteon and zolpidem tartrate were administered separately in groups, and no treatment was done on the third day. The experiment is totally provided with 9 groups which are respectively a solvent group, 6 groups of 1mg/kg,3mg/kg and 10mg/kg are respectively provided for the compound 12 and Ramelteon, and two groups of 1m/kg and 3mg/kg are respectively provided for zolpidem tartrate. After the animal recordings were completed, brainwaves were examined by offline automatic analysis using SleepSign software (Biotex Kyoto, Japan) to derive data analysis, as shown in fig. 1-3.
The results show that Ramelteon in the literature promotes NREM sleep by reducing the latency of NREM, but has little influence on the sleep structure. Also, high dose Ramelteon has a tendency to increase arousal by reducing the onset of REM sleep. Zolpidem tartrate (Zolpidem tartrate) can promote the amount of NREM sleep by shortening NREM sleep latency, reducing the number of transitions from NREM sleep to REM sleep; and meanwhile, the delta activity of the NREM sleep period is increased, and the sleep depth is deepened. FIG. 1 shows the reliability of experimental models, zolpidem tartrate reduces the sleep latency of mice, has a significant effect on sleep architecture (see FIG. 1A), increases delta activity during NREM sleep, and increases sleep depth (see FIG. 1B); reduce the number of segments of arousal and NREM sleep, and increase the duration of NREM sleep (fig. 1C, 1D). Zolpidem tartrate plays a role in promoting NREM sleep by shortening the sleep-onset latency and promoting NREM sleep maintenance. Figure 2 shows that each experimental dose of compound 12, capable of shortening NREM sleep latency, exhibits good in vivo activity and stable reproducibility. Fig. 3 is a result of a mouse experiment by Ramelteon, and it can be seen from the experiment result that no tendency of shortening the time for falling asleep of the mouse is reflected, and no difference is reflected in the sleeping structure and the time for falling asleep between the mouse without vehicle and the mouse with the vehicle.
Compared with the doses of the test drugs, the compound 12 shows the effect of stably and effectively shortening the time for the mice to fall asleep, has good sleep-promoting effect compared with Ramelteon, shows more stable sleep-promoting activity in vivo experiments, and is suitable to be used as the melatonin (MT1/MT2) receptor agonist for treating insomnia, anxiety, depression and other diseases related to melatonin (MT1/MT2) receptors.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (12)
1. A compound of formula (I), or each optical isomer thereof:
wherein n represents an integer of 1 to 5;
a is selected from methylene, oxygen or imino;
R1represents hydrogen, C1-6Alkyl or C3-6Cycloalkyl, said alkyl or cycloalkyl being unsubstituted or substituted with one to three groups independently selected from: halogen, hydroxy, amino or cyano;
R2and R3Each independently selected from: hydrogen, hydroxy, mercapto, amino, halogen, C1-6Alkyl, or R2And R3Are connected by chemical bonds to form a ring;
x and Y are each independently selected from: hydrogen, halogen, nitro, cyano, OR4、SR4Or R4But X and Y are not both hydrogen;
R4represents hydrogen, C1-6Alkyl or C3-6A cycloalkyl group.
2. The compound of claim 1, wherein a is selected from methylene and oxygen.
3. A compound of claim 1 wherein R is2And R3Each independently selected from: hydrogen, halogen, or R2And R3Are connected into a ring through chemical bonds.
4. The compound of claim 1, wherein X and Y are each independently selected from the group consisting of: hydrogen, halogen, cyano or R4However, X and Y are not both hydrogen.
5. A compound, or optical isomers thereof, selected from the group consisting of:
6. the compound of any one of claims 1-5, wherein the optical isomer of the compound is in the S configuration.
7. A pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier and, as active ingredient, a compound according to claim 1, or each of its optical isomers.
8. Use of a compound according to claim 1, or optical isomers thereof, for the preparation of a medicament for the treatment of a condition associated with melatonin (MT1/MT2) receptors.
9. The use of claim 8, wherein said disorders include insomnia, anxiety, depression.
10. A process for preparing a compound of formula i, said process comprising the steps of:
(1) reacting the compound shown as the formula A-4 with alkali to obtain a racemate A-5, and then carrying out manual resolution to obtain a compound shown as a formula A-5;
(2) carrying out amine ester exchange reaction on a compound shown as a formula A-5 after condensation or esterification to obtain a compound shown as a formula I-1;
in the formulae, R1X, Y, A, n are as defined for formula (I).
11. A process for preparing a compound of formula i, said process comprising the steps of:
(1) the compound shown as the formula B-8 and an oxidant react through Pinnick to obtain racemate B-9, and the racemate B-9 is resolved manually to obtain the compound shown as the formula B-9;
(2) carrying out amine ester exchange reaction on a compound shown as a formula B-9 after condensation or esterification to obtain a compound shown as a formula I-2;
in the formulae, R1X, Y, A, n and the formula (I)Are the same as above.
12. A process for preparing a compound of formula i, said process comprising the steps of:
(1) reacting the compound shown as the formula C-4 with alkali to obtain a racemate C-5, and then carrying out manual resolution to obtain a compound shown as a formula C-5;
(2) carrying out amine ester exchange reaction on a compound shown as a formula C-5 after condensation or esterification to obtain a compound shown as a formula I-3;
in the formulae, R1X, Y, A, n are as defined for formula (I).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911135165.9A CN110818720A (en) | 2019-11-19 | 2019-11-19 | Melatonin (MT1/MT2) receptor agonist, preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911135165.9A CN110818720A (en) | 2019-11-19 | 2019-11-19 | Melatonin (MT1/MT2) receptor agonist, preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN110818720A true CN110818720A (en) | 2020-02-21 |
Family
ID=69556897
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201911135165.9A Pending CN110818720A (en) | 2019-11-19 | 2019-11-19 | Melatonin (MT1/MT2) receptor agonist, preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110818720A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021210920A1 (en) * | 2020-04-16 | 2021-10-21 | 제이투에이치바이오텍 주식회사 | Method for producing ramelteon, and intermediate compound used for same |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2005256625A1 (en) * | 2004-06-23 | 2006-01-05 | Janssen Pharmaceutica N.V. | Novel unsaturated tetracyclic tetrahydrofuran derivatives |
| US20120136050A1 (en) * | 2009-07-16 | 2012-05-31 | Vanda Pharmaceuticals Inc. | Use of a melatonin agonist for the treatment of sleep disorders including primary insomnia |
| CN103664849A (en) * | 2012-08-31 | 2014-03-26 | 上海阳帆医药科技有限公司 | Method for preparing 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-idenethamine |
| CN104109143A (en) * | 2013-04-22 | 2014-10-22 | 上海阳帆医药科技有限公司 | Melatonin (MT1-MT2) receptor stimulant, and preparation method and use thereof |
-
2019
- 2019-11-19 CN CN201911135165.9A patent/CN110818720A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2005256625A1 (en) * | 2004-06-23 | 2006-01-05 | Janssen Pharmaceutica N.V. | Novel unsaturated tetracyclic tetrahydrofuran derivatives |
| US20120136050A1 (en) * | 2009-07-16 | 2012-05-31 | Vanda Pharmaceuticals Inc. | Use of a melatonin agonist for the treatment of sleep disorders including primary insomnia |
| CN103664849A (en) * | 2012-08-31 | 2014-03-26 | 上海阳帆医药科技有限公司 | Method for preparing 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-idenethamine |
| CN104109143A (en) * | 2013-04-22 | 2014-10-22 | 上海阳帆医药科技有限公司 | Melatonin (MT1-MT2) receptor stimulant, and preparation method and use thereof |
Non-Patent Citations (2)
| Title |
|---|
| TORU YAMANO ET AL.: "Approach to the stereoselective synthesis of melatonin receptor agonist Ramelteon via asymmetric hydrogenation", 《TETRAHEDRON: ASYMMETRY》 * |
| 杨建武 等: "褪黑激素的合成与表征", 《化学研究》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021210920A1 (en) * | 2020-04-16 | 2021-10-21 | 제이투에이치바이오텍 주식회사 | Method for producing ramelteon, and intermediate compound used for same |
| KR20210128263A (en) * | 2020-04-16 | 2021-10-26 | 제이투에이치바이오텍 (주) | A method for manufacturing ramelteon and intermediate compounds used therein |
| KR102359229B1 (en) | 2020-04-16 | 2022-02-07 | 제이투에이치바이오텍 (주) | A method for manufacturing ramelteon and intermediate compounds used therein |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI794190B (en) | Substituted pyridinone-containing tricyclic compounds, and methods using same | |
| KR102042112B1 (en) | Drug composition comprising deuterated kenodeoxycholic acid derivatives and compounds thereof | |
| JP5711813B2 (en) | 5,6-Dihydro-2H- [1,4] oxazin-3-yl-amine derivatives useful as inhibitors of β-secretase (BACE) | |
| KR20200029509A (en) | FXR agonists | |
| JP2023524493A (en) | heterocyclic GLP-1 agonists | |
| US11203597B2 (en) | Crystalline spirocyclic compound, a dosage form containing, a method for using in treatment of disease, and a method for recrystallizing | |
| CN1128789C (en) | Benzocycloheptathiophene compounds | |
| CN103370315A (en) | Compositions and methods for modulating farnesoid x receptors | |
| TW200533343A (en) | Aminoalcohol compounds | |
| TWI810550B (en) | 3-azabicycloalkyl derivatives and pharmaceutical composition comprising the same | |
| CN104583201B (en) | Difluoro lactam compound as the EP4 receptor selective agonists for using in the disease for the treatment of EP4 mediation and condition of illness | |
| CN112739696B (en) | [1,2,4] triazolo [1,5-a ] pyridines as JAK inhibitors and application thereof | |
| WO2012175049A1 (en) | Amide compound, preparation method and uses thereof | |
| CN101657453A (en) | Purine class as the PKC-theta inhibitors | |
| TW202045499A (en) | Amide derivatives useful in the treatment of hbv infection or hbv-induced diseases | |
| CN103622954A (en) | Applications of sesquiterpene lactone compound and derivative of sesquiterpene lactone compound in treatment of diabetes | |
| CN105263924A (en) | Cxcr7 receptor modulators | |
| CN114149423A (en) | Tetrahydropyridopyrimidine diketone derivative, preparation method and medical application thereof | |
| CN101341150A (en) | Nitroimidazole compounds | |
| CN104109143A (en) | Melatonin (MT1-MT2) receptor stimulant, and preparation method and use thereof | |
| CN110818720A (en) | Melatonin (MT1/MT2) receptor agonist, preparation method and application thereof | |
| JP5645823B2 (en) | Thienoxazepine derivatives | |
| CN115066425A (en) | Application of JAK inhibitor in preparation of medicine for treating JAK kinase related diseases | |
| CN105693520B (en) | Compound with higher protein kinase G inhibitory activity and preparation method thereof | |
| WO2018039641A1 (en) | Methods and compounds for treating alcohol use disorders and associated diseases |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20210817 Address after: No. 1, Hengfei Road, Xingang economic and Technological Development Zone, Nanjing, Jiangsu 210038 Applicant after: Nanjing Changao Pharmaceutical Science & Technology Co.,Ltd. Address before: 201203 4 / 5F, building 7, Lane 1690, Cailun Road, Zhangjiang hi tech park, Pudong New Area, Shanghai Applicant before: Shanghai Sun-Sail Pharmaceutical Science & Technology Co.,Ltd. |
|
| TA01 | Transfer of patent application right | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20200221 |
|
| RJ01 | Rejection of invention patent application after publication |