WO2024120555A2 - Prodrugs of benzodiazepine compound and uses thereof - Google Patents
Prodrugs of benzodiazepine compound and uses thereof Download PDFInfo
- Publication number
- WO2024120555A2 WO2024120555A2 PCT/CN2024/087531 CN2024087531W WO2024120555A2 WO 2024120555 A2 WO2024120555 A2 WO 2024120555A2 CN 2024087531 W CN2024087531 W CN 2024087531W WO 2024120555 A2 WO2024120555 A2 WO 2024120555A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- alkyl
- mmol
- added
- aryl
- Prior art date
Links
- -1 benzodiazepine compound Chemical class 0.000 title claims abstract description 12
- 229940002612 prodrug Drugs 0.000 title abstract description 11
- 239000000651 prodrug Substances 0.000 title abstract description 11
- 229940049706 benzodiazepine Drugs 0.000 title abstract description 4
- 210000003169 central nervous system Anatomy 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims description 144
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 38
- 125000003118 aryl group Chemical group 0.000 claims description 27
- 125000001072 heteroaryl group Chemical group 0.000 claims description 25
- 150000003839 salts Chemical class 0.000 claims description 18
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 16
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 6
- 208000026106 cerebrovascular disease Diseases 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 5
- 229910003827 NRaRb Inorganic materials 0.000 claims description 4
- 125000004429 atom Chemical group 0.000 claims description 4
- 208000026005 Central nervous system vascular disease Diseases 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 20
- 201000010099 disease Diseases 0.000 abstract description 15
- 239000003814 drug Substances 0.000 abstract description 13
- 229940079593 drug Drugs 0.000 abstract description 12
- 230000002265 prevention Effects 0.000 abstract description 7
- 238000010521 absorption reaction Methods 0.000 abstract description 4
- 238000001727 in vivo Methods 0.000 abstract description 2
- 230000002490 cerebral effect Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 145
- 239000000203 mixture Substances 0.000 description 65
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 57
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 51
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- 238000006243 chemical reaction Methods 0.000 description 48
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 36
- 239000012074 organic phase Substances 0.000 description 34
- 239000012043 crude product Substances 0.000 description 30
- 238000005160 1H NMR spectroscopy Methods 0.000 description 24
- 230000015572 biosynthetic process Effects 0.000 description 23
- 238000003786 synthesis reaction Methods 0.000 description 23
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 22
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 22
- 230000002829 reductive effect Effects 0.000 description 22
- 239000007832 Na2SO4 Substances 0.000 description 21
- 238000004440 column chromatography Methods 0.000 description 21
- 229910052938 sodium sulfate Inorganic materials 0.000 description 21
- 239000000243 solution Substances 0.000 description 21
- 210000005013 brain tissue Anatomy 0.000 description 20
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 19
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 125000000217 alkyl group Chemical group 0.000 description 15
- 241000699670 Mus sp. Species 0.000 description 14
- 239000008280 blood Substances 0.000 description 14
- 210000004369 blood Anatomy 0.000 description 14
- 125000005842 heteroatom Chemical group 0.000 description 14
- 125000004432 carbon atom Chemical group C* 0.000 description 13
- 238000002360 preparation method Methods 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 11
- 108020003175 receptors Proteins 0.000 description 11
- 102000005962 receptors Human genes 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 10
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 9
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 7
- 238000010253 intravenous injection Methods 0.000 description 7
- 230000009885 systemic effect Effects 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- 229940125773 compound 10 Drugs 0.000 description 6
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 6
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 6
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 6
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 208000015114 central nervous system disease Diseases 0.000 description 5
- 229940125758 compound 15 Drugs 0.000 description 5
- 208000035475 disorder Diseases 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 229910052717 sulfur Inorganic materials 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 4
- 208000024827 Alzheimer disease Diseases 0.000 description 4
- 238000011740 C57BL/6 mouse Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 4
- 125000002619 bicyclic group Chemical group 0.000 description 4
- 229940125810 compound 20 Drugs 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- 230000001575 pathological effect Effects 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 208000020016 psychiatric disease Diseases 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 3
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 208000023105 Huntington disease Diseases 0.000 description 3
- 208000019695 Migraine disease Diseases 0.000 description 3
- 208000018737 Parkinson disease Diseases 0.000 description 3
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 3
- 102100028656 Sigma non-opioid intracellular receptor 1 Human genes 0.000 description 3
- 101710104750 Sigma non-opioid intracellular receptor 1 Proteins 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 230000003281 allosteric effect Effects 0.000 description 3
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 3
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 125000002837 carbocyclic group Chemical group 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 229940126208 compound 22 Drugs 0.000 description 3
- 229940125833 compound 23 Drugs 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 229960003638 dopamine Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 206010015037 epilepsy Diseases 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 206010027599 migraine Diseases 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- 125000004430 oxygen atom Chemical group O* 0.000 description 3
- 230000035790 physiological processes and functions Effects 0.000 description 3
- 238000002953 preparative HPLC Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 108010085082 sigma receptors Proteins 0.000 description 3
- 125000004434 sulfur atom Chemical group 0.000 description 3
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 2
- 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 2
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 2
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- CUYKNJBYIJFRCU-UHFFFAOYSA-N 3-aminopyridine Chemical compound NC1=CC=CN=C1 CUYKNJBYIJFRCU-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 2
- 208000019901 Anxiety disease Diseases 0.000 description 2
- 206010003805 Autism Diseases 0.000 description 2
- 208000020706 Autistic disease Diseases 0.000 description 2
- 229940126657 Compound 17 Drugs 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 208000010886 Peripheral nerve injury Diseases 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 2
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 2
- DZBUGLKDJFMEHC-UHFFFAOYSA-N acridine Chemical compound C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 2
- 230000032683 aging Effects 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 230000036506 anxiety Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
- 229940126543 compound 14 Drugs 0.000 description 2
- 229940126142 compound 16 Drugs 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 230000003412 degenerative effect Effects 0.000 description 2
- 229910052805 deuterium Inorganic materials 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 206010013663 drug dependence Diseases 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 208000015122 neurodegenerative disease Diseases 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- RDOWQLZANAYVLL-UHFFFAOYSA-N phenanthridine Chemical compound C1=CC=C2C3=CC=CC=C3C=NC2=C1 RDOWQLZANAYVLL-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 201000000980 schizophrenia Diseases 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 208000011117 substance-related disease Diseases 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 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
- 150000003536 tetrazoles Chemical class 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 229930192474 thiophene Natural products 0.000 description 2
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
- NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- UVNPEUJXKZFWSJ-LMTQTHQJSA-N (R)-N-[(4S)-8-[6-amino-5-[(3,3-difluoro-2-oxo-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyl]pyrazin-2-yl]-2-oxa-8-azaspiro[4.5]decan-4-yl]-2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@@](=O)N[C@@H]1COCC11CCN(CC1)c1cnc(Sc2ccnc3NC(=O)C(F)(F)c23)c(N)n1 UVNPEUJXKZFWSJ-LMTQTHQJSA-N 0.000 description 1
- RTHCYVBBDHJXIQ-MRXNPFEDSA-N (R)-fluoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-MRXNPFEDSA-N 0.000 description 1
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- QDVBKXJMLILLLB-UHFFFAOYSA-N 1,4'-bipiperidine Chemical compound C1CCCCN1C1CCNCC1 QDVBKXJMLILLLB-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- FLBAYUMRQUHISI-UHFFFAOYSA-N 1,8-naphthyridine Chemical compound N1=CC=CC2=CC=CN=C21 FLBAYUMRQUHISI-UHFFFAOYSA-N 0.000 description 1
- JNKDVJKGFYTHJZ-UHFFFAOYSA-N 1-benzofuran;2h-benzotriazole Chemical compound C1=CC=C2OC=CC2=C1.C1=CC=C2NN=NC2=C1 JNKDVJKGFYTHJZ-UHFFFAOYSA-N 0.000 description 1
- DSVGFKBFFICWLZ-UHFFFAOYSA-N 1-fluoro-4-isocyanatobenzene Chemical compound FC1=CC=C(N=C=O)C=C1 DSVGFKBFFICWLZ-UHFFFAOYSA-N 0.000 description 1
- FMDGXCSMDZMDHZ-UHFFFAOYSA-N 1-isocyanato-4-methoxybenzene Chemical compound COC1=CC=C(N=C=O)C=C1 FMDGXCSMDZMDHZ-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
- MFJCPDOGFAYSTF-UHFFFAOYSA-N 1H-isochromene Chemical compound C1=CC=C2COC=CC2=C1 MFJCPDOGFAYSTF-UHFFFAOYSA-N 0.000 description 1
- AAQTWLBJPNLKHT-UHFFFAOYSA-N 1H-perimidine Chemical compound N1C=NC2=CC=CC3=CC=CC1=C32 AAQTWLBJPNLKHT-UHFFFAOYSA-N 0.000 description 1
- ODMMNALOCMNQJZ-UHFFFAOYSA-N 1H-pyrrolizine Chemical compound C1=CC=C2CC=CN21 ODMMNALOCMNQJZ-UHFFFAOYSA-N 0.000 description 1
- DPQNQLKPUVWGHE-UHFFFAOYSA-N 2,2,3,3,3-pentafluoropropan-1-amine Chemical compound NCC(F)(F)C(F)(F)F DPQNQLKPUVWGHE-UHFFFAOYSA-N 0.000 description 1
- VEPOHXYIFQMVHW-XOZOLZJESA-N 2,3-dihydroxybutanedioic acid (2S,3S)-3,4-dimethyl-2-phenylmorpholine Chemical compound OC(C(O)C(O)=O)C(O)=O.C[C@H]1[C@@H](OCCN1C)c1ccccc1 VEPOHXYIFQMVHW-XOZOLZJESA-N 0.000 description 1
- UKRQMDIFLKHCRO-UHFFFAOYSA-N 2,4,6-trimethylbenzoyl chloride Chemical compound CC1=CC(C)=C(C(Cl)=O)C(C)=C1 UKRQMDIFLKHCRO-UHFFFAOYSA-N 0.000 description 1
- YNZFUWZUGRBMHL-UHFFFAOYSA-N 2-[4-[3-(11-benzo[b][1]benzazepinyl)propyl]-1-piperazinyl]ethanol Chemical compound C1CN(CCO)CCN1CCCN1C2=CC=CC=C2C=CC2=CC=CC=C21 YNZFUWZUGRBMHL-UHFFFAOYSA-N 0.000 description 1
- UXGVMFHEKMGWMA-UHFFFAOYSA-N 2-benzofuran Chemical compound C1=CC=CC2=COC=C21 UXGVMFHEKMGWMA-UHFFFAOYSA-N 0.000 description 1
- OHXPHMPERMIICA-UHFFFAOYSA-N 2-bromo-3-hydroxybenzaldehyde Chemical compound OC1=CC=CC(C=O)=C1Br OHXPHMPERMIICA-UHFFFAOYSA-N 0.000 description 1
- VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical compound C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 0.000 description 1
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 1
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 1
- NQUVCRCCRXRJCK-UHFFFAOYSA-N 4-methylbenzoyl chloride Chemical compound CC1=CC=C(C(Cl)=O)C=C1 NQUVCRCCRXRJCK-UHFFFAOYSA-N 0.000 description 1
- MGYGFNQQGAQEON-UHFFFAOYSA-N 4-tolyl isocyanate Chemical compound CC1=CC=C(N=C=O)C=C1 MGYGFNQQGAQEON-UHFFFAOYSA-N 0.000 description 1
- GDRVFDDBLLKWRI-UHFFFAOYSA-N 4H-quinolizine Chemical compound C1=CC=CN2CC=CC=C21 GDRVFDDBLLKWRI-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 206010001497 Agitation Diseases 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- YIIMEMSDCNDGTB-UHFFFAOYSA-N Dimethylcarbamoyl chloride Chemical compound CN(C)C(Cl)=O YIIMEMSDCNDGTB-UHFFFAOYSA-N 0.000 description 1
- 229940123603 Dopamine D2 receptor antagonist Drugs 0.000 description 1
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 229940124056 Histamine H1 receptor antagonist Drugs 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- 108010006519 Molecular Chaperones Proteins 0.000 description 1
- NUGPIZCTELGDOS-QHCPKHFHSA-N N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclopentanecarboxamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CC[C@@H](C=1C=NC=CC=1)NC(=O)C1CCCC1)C NUGPIZCTELGDOS-QHCPKHFHSA-N 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- AWMVMTVKBNGEAK-UHFFFAOYSA-N Styrene oxide Chemical compound C1OC1C1=CC=CC=C1 AWMVMTVKBNGEAK-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 108091008324 binding proteins Proteins 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 1
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- WCZVZNOTHYJIEI-UHFFFAOYSA-N cinnoline Chemical compound N1=NC=CC2=CC=CC=C21 WCZVZNOTHYJIEI-UHFFFAOYSA-N 0.000 description 1
- 229940121657 clinical drug Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 108010041382 compound 20 Proteins 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- KQWGXHWJMSMDJJ-UHFFFAOYSA-N cyclohexyl isocyanate Chemical compound O=C=NC1CCCCC1 KQWGXHWJMSMDJJ-UHFFFAOYSA-N 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- UZUODNWWWUQRIR-UHFFFAOYSA-L disodium;3-aminonaphthalene-1,5-disulfonate Chemical compound [Na+].[Na+].C1=CC=C(S([O-])(=O)=O)C2=CC(N)=CC(S([O-])(=O)=O)=C21 UZUODNWWWUQRIR-UHFFFAOYSA-L 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000000442 dopamine 2 receptor blocking agent Substances 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- WUDNUHPRLBTKOJ-UHFFFAOYSA-N ethyl isocyanate Chemical compound CCN=C=O WUDNUHPRLBTKOJ-UHFFFAOYSA-N 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 229960002464 fluoxetine Drugs 0.000 description 1
- 229960004038 fluvoxamine Drugs 0.000 description 1
- CJOFXWAVKWHTFT-XSFVSMFZSA-N fluvoxamine Chemical compound COCCCC\C(=N/OCCN)C1=CC=C(C(F)(F)F)C=C1 CJOFXWAVKWHTFT-XSFVSMFZSA-N 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229960003878 haloperidol Drugs 0.000 description 1
- 239000000938 histamine H1 antagonist Substances 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- HOBCFUWDNJPFHB-UHFFFAOYSA-N indolizine Chemical compound C1=CC=CN2C=CC=C21 HOBCFUWDNJPFHB-UHFFFAOYSA-N 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 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
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- YDNLNVZZTACNJX-UHFFFAOYSA-N isocyanatomethylbenzene Chemical compound O=C=NCC1=CC=CC=C1 YDNLNVZZTACNJX-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 210000005228 liver tissue Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000013227 male C57BL/6J mice Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012067 mathematical method Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000004898 mitochondrial function Effects 0.000 description 1
- 210000001700 mitochondrial membrane Anatomy 0.000 description 1
- JFCHSQDLLFJHOA-UHFFFAOYSA-N n,n-dimethylsulfamoyl chloride Chemical compound CN(C)S(Cl)(=O)=O JFCHSQDLLFJHOA-UHFFFAOYSA-N 0.000 description 1
- DAKZISABEDGGSV-UHFFFAOYSA-N n-(2-aminoethyl)acetamide Chemical compound CC(=O)NCCN DAKZISABEDGGSV-UHFFFAOYSA-N 0.000 description 1
- WYLQARGYFXBZMD-UHFFFAOYSA-N n-[chloro(dimethylamino)phosphoryl]-n-methylmethanamine Chemical compound CN(C)P(Cl)(=O)N(C)C WYLQARGYFXBZMD-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
- XHFGWHUWQXTGAT-UHFFFAOYSA-N n-methylpropan-2-amine Chemical compound CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000007512 neuronal protection Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 229960005290 opipramol Drugs 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- VOKSWYLNZZRQPF-GDIGMMSISA-N pentazocine Chemical compound C1C2=CC=C(O)C=C2[C@@]2(C)[C@@H](C)[C@@H]1N(CC=C(C)C)CC2 VOKSWYLNZZRQPF-GDIGMMSISA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 229940124811 psychiatric drug Drugs 0.000 description 1
- CPNGPNLZQNNVQM-UHFFFAOYSA-N pteridine Chemical compound N1=CN=CC2=NC=CN=C21 CPNGPNLZQNNVQM-UHFFFAOYSA-N 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- QAHVHSLSRLSVGS-UHFFFAOYSA-N sulfamoyl chloride Chemical compound NS(Cl)(=O)=O QAHVHSLSRLSVGS-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000008337 systemic blood flow Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Definitions
- the present invention relates to the field of medicine, in particular to the prodrugs of one type of a benzodiazepine compound, which can be used for the prevention or treatment of central nervous related diseases, including Alzheimer's disease (AD) , Parkinson's disease (PD) , epilepsy, pain, central and peripheral nerve injuries, migraine, amyotrophic lateral sclerosis (ALS) , Huntington's disease (HD) and other degenerative and inflammation-related diseases, as well as anxiety, depression, schizophrenia, autism, addiction, drug dependence and other psychiatric disorders. Additionally, it can be used for the prevention or treatment of cerebrovascular diseases, including stroke.
- central nervous related diseases including Alzheimer's disease (AD) , Parkinson's disease (PD) , epilepsy, pain, central and peripheral nerve injuries, migraine, amyotrophic lateral sclerosis (ALS) , Huntington's disease (HD) and other degenerative and inflammation-related diseases, as well as anxiety, depression, schizophrenia, autism, addiction, drug dependence and other psychiatric disorders. Additionally
- CNS central nervous system
- cerebrovascular diseases cause the second largest morbidity following the tumor diseases globally.
- CNS diseases are the leading cause of disability adjusted life years (DALYs) , with stroke accounting for 42.2% (38.6-46.1) , migraine 16.3% (11.7-20.8) , AD and other dementia 10.4% (11.7-20.8) , and meningitis 7.9% (6.6-10.4) ; in addition, the stroke causes the second mortality, accounting for 11.6%of total deaths.
- depression induces an increasing attention in the society, due to lacking effective, rapid onset of clinical drugs with few side effects.
- Sigma receptor ( ⁇ receptor) was proposed in 1976 for the first time and it has been found it is widely expressed in various tissues, but particularly high in the CNS and liver tissues.
- ⁇ receptor is mainly expressed on the surface of endoplasmic reticulum and mitochondrial membrane and participates in maintenance and regulation of the normal survival and physiological function of cells, tissue microenvironment stability, nerve cell excitability, and of normal physiological function of central nervous and cardiovascular system. Further research on the biology and function of ⁇ receptor has confirmed that drugs targeting ligands of ⁇ receptor can be used to prevent or treat psychiatric disorders and degenerative diseases of the CNS. Additionally, it also has potential therapeutic value in neuronal protection against stroke and neurotrauma (Aishwarya R et al. 2021 review) .
- the Sigma-1 receptor ( ⁇ 1 receptor) has been verified as a novel drug target in recent years, and served as a binding protein for a variety of specific psychiatric drugs.
- the ⁇ 1 receptor is a ligand-regulated protein chaperone that provides its functions by interacting with other receptors such as N-methyl-D-aspartate (NMDA) , 5-hydroxytryptamine (5-HT) , and dopamine (DA) ; it also functions by regulating other ion channels such as Na + , K + , and Ca ++ , as well as downstream receptors, thereby regulating mitochondrial function and the release of neurotransmitters such as 5-HT and DA.
- NMDA N-methyl-D-aspartate
- 5-HT 5-hydroxytryptamine
- DA dopamine
- the Chinese patent (CN102895233A) disclosed a class of benzodiazepine compound and its pharmaceutically acceptable salts as a modulator of sigma-1 receptor, which can be used in the preparation of drugs for epilepsy prevention or treatment.
- the patent also published that the Compound S1 was able to raise the convulsion threshold in mice, demonstrating its anti-epileptic property.
- the inventors of the present disclosure discovered certain defects of this compound during their research. Firstly, its solubility is poor, likely resulting in very low oral bioavailability and plasma concentration due to its unstable absorption in human patients, which hinders its efficacy in the clinical applications.
- the compound relies on the intravenous injection, leading to poor patient compliance and inconvenient administration. Therefore, it is still necessary to modify the structure of the compound to overcome these defections.
- the present disclosure discovered that when a protective group is introduced into the phenolic hydroxyl group of the molecular structure to form a prodrug molecule to the Compound S1, the solubility and stability are greatly improved. Therefore, the prodrug significantly improves the oral administration bioavailability of the Compound S1 and greatly potentially improves its pharmaceutical value.
- the present disclosure provides compounds with the structure of formula (I) or a pharmaceutically acceptable salt,
- each R 1 and R 2 independently represent hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halogenated C 1 -C 6 alkyl, -CH 2 - (C 6 -C 10 aryl) , - (C 6 -C 10 aryl) , - (5-10 membered heteroaryl) , or-CH 2 - (5-10 membered heteroaryl) ; or R 1 and R 2 together with the atoms to which they are attached to form a 5-6 membered ring;
- aryl or heteroaryl group (s) can be substituted with 0, 1, or 2 substituents selected from the following groups: deuterium, halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, cyano, -OR a , hydroxy (C 1 -C 6 alkyl) , -NR a R b , nitro, -C (O) R a , -OC (O) R a , -C (O) NR a R b ;
- R 1 represents hydrogen or C 1 -C 6 alkyl
- R 2 represents C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halogenated C 1 -C 6 alkyl, -CH 2 - (C 6 -C 10 aryl) , or- (C 6 -C 10 aryl) ; wherein the aryl or heteroaryl group can be optionally substituted with 0, 1, or 2 substituents selected from the following groups: deuterium, halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl or cyano.
- R 1 represents hydrogen
- R 2 represents C 1 -C 6 alkyl or- (C 6 -C 10 aryl) ; wherein the aryl or heteroaryl group can be substituted with 0, 1, or 2 substituents selected from the following groups: halogen, C 1 -C 6 alkyl, halogenated C1-C 6 alkyl or cyano.
- R 1 represents hydrogen
- R 2 represents- (C 6 -C 10 aryl) , wherein the aryl group can be substituted with 0, 1, or 2 substituents selected from the following groups: halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl or cyano.
- R 1 represents hydrogen
- R 2 represents phenyl, wherein the phenyl group can be substituted with 0, 1, or 2 substituents selected from the following groups: halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl or cyano.
- compositions comprising of the compounds with the structure of Formula (I) or their pharmaceutically acceptable salt.
- the present disclosure provides novel methods of treating or preventing central nervous system and cerebrovascular diseases, including the applications of their effective doses to the patient with the compound of claim 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition with the structure of Formula (I) or its pharmaceutically acceptable salt to a patient in need.
- alkyl refers to a saturated branched or straight chain monovalent hydrocarbon group derived from a parent alkane by removing one hydrogen atom.
- Typical alkyl groups include, but not limited to, methyl, ethyl, propyl (e.g., prop-1-yl and prop-2-yl) , butyl (e.g., but-1-yl, but-2-yl, 2-methylprop-1-yl, 2-methylprop-2-yl, tert-butyl) , and so on.
- alkyl groups comprise 1 to 20 carbon atoms.
- alkyl groups comprise 1 to 10 carbon atoms or 1 to 6 carbon atoms, while in other embodiments, alkyl groups comprise 1 to 4 carbon atoms. In other embodiments, alkyl groups comprise 1 or 2 carbon atoms. In some embodiments, branched alkyl groups comprise at least 3 carbon atoms and typically contain 3 to 7 carbon atoms. In other embodiments, branched alkyl groups comprise 3 to 6 carbon atoms. Alkyl groups with 1 to 6 carbon atoms can be referred to as (C 1 -C 6 ) alkyl groups, and alkyl groups with 1 to 4 carbon atoms can be referred to as (C 1 -C 4 ) alkyl groups. These nomenclature rules can also be used for alkyl groups with various numbers of carbon atoms.
- aryl refers to a monovalent aromatic hydrocarbon group obtained by removing one hydrogen atom form a single carbon atom of the parent aromatic ring system.
- Aryl groups encompass single-ring carbon aromatic rings, such as benzene.
- Aryl groups also encompass fused carbon aromatic ring systems where each ring is aromatic, such as naphthalene.
- aryl groups can encompass fused ring systems where each ring is a carbon aromatic ring.
- aryl groups may contain 6 to 10 carbon atoms. Such groups can be referred to as C 6 -C 10 aryl groups.
- aryl groups do not in any way cover or overlap with the separately defined heteroaryl groups as defined herein.
- the obtained ring system can be a heteroaryl group, not an aryl group as defined herein.
- heteroaryl refers to a monovalent heteroaromatic group derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system.
- Heteroaryl groups typically include 5-to 14-membered, but more typically include 5-to 10-membered aromatic, monocyclic, bicyclic, and tricyclic rings containing one or more, for example, 1, 2, 3, or 4, or in certain embodiments, 1, 2, or 3, heteroatoms chosen from O, S, or N, with the remaining ring atoms being carbon.
- the single ring is aromatic and includes at least one heteroatom.
- a monocyclic heteroaryl group may include 5 or 6 ring members and may include 1, 2, 3, or 4 heteroatoms, 1, 2, or 3 heteroatoms, 1 or 2 heteroatoms, or 1 heteroatom where the heteroatom (s) are independently selected from O, S, or N.
- bicyclic aromatic rings both rings are aromatic.
- bicyclic heteroaryl groups at least one of the rings must include a heteroatom, but it is not necessary that both rings include a heteroatom although it is permitted for them to do so.
- heteroaryl includes a 5-to 7-membered heteroaromatic ring fused to a carbocyclic aromatic ring or fused to another heteroaromatic ring.
- the rings are aromatic and at least one of the rings includes at least one heteroatom.
- the point of attachment may be at the ring including at least one heteroatom or at a carbocyclic ring.
- the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another.
- the total number of S and O atoms in the heteroaryl group is not more than 2.
- the total number of S and O atoms in the aromatic heterocycle is not more than 1.
- Heteroaryl does not encompass or overlap with aryl as defined above.
- heteroaryl groups include, but are not limited to, groups derived from acridine, carbazole, cinnoline, furan, imidazole, indazole, indole, indolizine, isobenzofuran, isochromene, isoindole, isoquinoline, isothiazole, 2H-benzo [d] [1, 2, 3] triazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazo
- the heteroaryl group can be between 5 to 20 membered heteroaryl, such as, for example, a5 to 14 membered or 5 to 10 membered heteroaryl.
- heteroaryl groups can be those derived from thiophene, pyrrole, benzothiophene, 2H-benzo [d] [1, 2, 3] triazole benzofuran, indole, pyridine, quinoline, imidazole, benzimidazole, oxazole, tetrazole, and pyrazine.
- halogen and “halogenated” refer to atoms selected from fluorine, chlorine, bromine, and iodine.
- mono-, di-or tri-halo-Cn-m alkyl refers to an alkyl group that is substituted by one, two or three halo, wherein the alkyl group has n to m carbon atoms and the halo as substituent may be same or different.
- Examples of mono-, di-or tri-halo-Cn-m alkyl include without limitation, trichloromethyl, chloromethyl, bischloromethyl, chlorobromomethyl.
- cyano refers to the group of formula-CN.
- hydroxyl refers to a group of formula-OH.
- salt or “pharmaceutically acceptable salt” includes pharmaceutically acceptable acid make-up salt and pharmaceutically acceptable base make-up salt.
- pharmaceutically acceptable refers to compounds, materials, compositions, and/or formulations, which should be within the range of reliable medical judgment and suitable for use in contact with tissues of humans and animals without excessive toxicity, irritancy, allergic reactions, or other problems or complications, in accordance with a reasonable benefit/risk ratio.
- “pharmaceutical composition” refers to a formulation of the present invention compound in a medium that is commonly accepted for delivering biologically active compounds to mammals (e.g., humans) .
- the medium includes pharmaceutically acceptable carrier.
- the purpose of the pharmaceutical composition is to facilitate administration to a biological organism, to enhance the absorption of the active ingredient, and to exert its biological activity.
- “pharmaceutically acceptable carrier” includes, but not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier, which should be approved by the relevant regulatory authorities for use in humans or animals.
- excipient refers to a pharmaceutically acceptable inert ingredient.
- excipients include, but not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents. Excipient can enhance the operational characteristic of a drug formulation, making it more suitable for direct compression by increasing flowability and/or adhesiveness.
- prodrug refers to a compound that can be converted to a biologically active parent compound/composition under physiological conditions or through conversion by a solvent.
- the prodrugs of the present disclosure are prepared by modifying functional groups in the parent compound. These modifications can be removed by conventional methods or in vivo ways to obtain the parent compound.
- Prodrugs include compounds formed by linking a hydroxyl group or an amino group of the compounds in the present disclosure to any other groups. When the prodrugs of the present disclosure are administered to single mammal, the prodrug are cleaved to form free hydroxyl and free amino groups.
- Comprising means infinitely open, i.e., all-encompassing and non-limiting. It may be used herein synonymously with “having” or “including” . Comprising means including each indicated or recited component or element (s) while not excluding any other components or elements.
- treatment and other similar synonyms used in this disclosure include the following meanings:
- therapeutically effective amount refers to the amount of a compound that, when administered to a subject for treating a disease, or at least one of the clinical symptoms of a disease or disorder, is sufficient to affect such treatment for the disease, disorder, or symptom. As realized by those skilled researchers in the field, this amount is not limited to a single dose but also can be multiple doses within a key period necessary to produce a therapeutic or preventative response in the subject. Thus, “therapeutically effective amount” is not limited to the amount in a single capsule or tablet but also can comprise more than one capsule or tablet as prescribed by a qualified physician or healthcare provider.
- the “therapeutically effective amount” can vary in terms of the compound, the disease, disorder, and/or symptoms of the disease or disorder, and/or the severity of the symptoms of the disease or disorder, the age of the subject to be treated, and/or the weight of the subject to be treated. An appropriate amount in any given instance can be apparent to those skilled in the art or can be determined by routine experiments.
- AUC area under the curve
- AUC refers to a total amount of drug absorbed or exposed to a human or animal subject. Generally, AUC may be obtained from a mathematical method in a plot of drug concentration in the human or animal subject over time until the concentration is negligible.
- AUC area under the curve
- AUC 0-inf refers to the area under the concentration-time curve from time 0 to infinity.
- T max refers to the time at which the drug reaches it maximum concentration in the blood, serum, designated compartment, or test area of the subject between the administration of the current dose and the next dose.
- C max refers to the maximum concentration of the drug in the blood, serum, designated compartment, or test area of the subject between the administration of the current dose and the next dose. If specified, the term C max may also refer to the dose-normalized ratio.
- FIG. 1 Plasma concentration-time profiles of Compound S1 after single intragastric administration of different compounds in mice
- reaction flask was added in order with intermediate S1 (200 mg, 0.79 mmol) and DCM (15 mL) were added in order into the reaction flask. Under nitrogen atmosphere, DIPEA (306 mg, 2.36 mmol) and dimethyl carbamoyl chloride (170 mg, 1.58 mmol) were added. The mixture was stirred for 15 hours. After being diluted with water, the mixture was extracted with dichloromethane (15 mL ⁇ 2) .
- the intermediate S1 (150 mg, 0.592 mmol) was added into the reaction flask, and dissolved in DCM (10 mL) , then 2, 4, 6-Trimethylbenzoyl chloride (216 mg, 1.18 mmol) and Et 3 N (239 mg, 2.37 mmol) was added on ice bath under nitrogen condition. The mixture was slowly raised to room temperature and stirred for 14 hours. The mixture was diluted with water, extracted with dichloromethane (15 mL*2) .
- the intermediate S1 (150 mg, 0.592 mmol) was added into the reaction flask, and dissolved in DCM (10 mL) , then Triethylamine (239 mg, 2.368mmol) was added. Triphosgene (117 mg, 0.395 mmol) was added under nitrogen at ice bath and stirred for 1 hours, and then 3-aminopyridine (111 mg, 1.184 mmol) was added, stirred for 15 hours. After the reaction was completed, the mixture was diluted with water, extracted with dichloromethane (15 mL*2) .
- the intermediate S1 (200 mg, 0.79 mmol) was added into the reaction flask, and dissolved in DMAc (4 mL) .
- Aminosulfonyl chloride (137 mg, 1.18 mmol) was added at ice bath (0-5°C) and stirred for 12 hours under nitrogen. After the reaction was completed, the mixture was purified directly by prep-HPLC and lyophilized to obtain the Compound 18 (74 mg, yield: 28%) .
- mice In order to verify the low oral absorption of Compound S1 published in CN102895233A, aPK study of mice was conducted to determine plasma and brain exposure by different routes of administration.
- the experimental procedures were as follows: Male C57BL/6J mice weighing 20 ⁇ 25 g were administered with 10 mg/kg Compound S1 by intragastric administration and 5 mg/kg Compound S1 by intravenous injection at concentration of 1 mg/mL. Blood samples were collected at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, and 6 h post-dose and placed in tubes containing EDTA-2Na as the anticoagulant. Plasma samples were obtained by centrifugation at 5000 rpm and 4°Cfor 10 min.
- mice Male C57BL/6 mice were administrated with 10 mg/kg Compound S1 of the published patent application (CN102895233A) and Compounds 2, 3, 9, 10, 11, 15, 17, 18, 20, 21, and 23 by single intragastric administration.
- Whole blood samples were collected at pre-dose and 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h post-dose, and placed on an ice box containing wet ice and centrifuged within 2 hours.
- the concentration of Compound S1 in plasma was measured using LC-MS/MS. The results are shown in Table 2 and Figure 1.
- the plasma C max of S1 level after intragastric administration of Compounds 2, 3, 9, 10, 11, 15, 17, 18, 20, 21, and 23 were about 0.50, 0.94, 0.02, 7.70, 0.21, 0.81, 1.92, 0.19, 0.20, 0.17, and 0.23 times to that of Compound S1, respectively.
- the plasma AUC 0-inf of S1 were about 1.40, 2.43, 0.08, 10.72, 0.21, 2.09, 2.97, 0.34, 1.35, 0.81, and 0.34 times to that of Compound S1, respectively.
- mice Male C57BL/6 mice were administrated with Compound S1 of the published patent application (CN102895233A) and Compounds 3, 9, 10, 15, and 23 by single intragastric administration (IG) at dose of 10 mg/kg and intravenous injection (IV) at dose of 5 mg/kg.
- Whole blood samples were collected at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, and 6 h post-dose for the intragastric administration group and 2 min, 5 min, 0.25h, 0.5h, 1 h, 2 h, 4 h, and 6 h post-dose for the intravenous injection group. Blood samples were placed on an ice box containing wet ice and centrifuged within 2 hours. The concentration of Compound S1 in plasma was measured using LC-MS/MS, and the bioavailability was calculated. The results are shown in Table 3, Figure 2, and Figure 3.
- the determination of S1 concentration of some of the above-mentioned compounds in the brain was conducted at different time points post-dose to verify whether the exposure of S1 in the brain was increased compared with that of Compound S1 in the published patent application (CN102895233A) .
- mice Male C57BL/6 mice were administrated with 10 mg/kg Compound S1 of the published patent application (CN102895233A) and Compounds 3, 10, 11, 15, 18, 20, and 21 by single intragastric administration.
- Whole blood and brain tissue samples were collected at 1 h post-dose. Blood samples were placed on an ice box containing wet ice and centrifuged within 2 hours. After brain tissue collection, the blood and water on the surface was cleaned, and then the brain tissue was weighed and homogenized by adding 4 times the volume of PBS. The concentrations of Compound S1 in plasma and brain tissue were measured using LC-MS/MS. The results are shown in Table 4.
- the concentrations of S1 in brain tissue were 12.70, 16.46, 3.87, 8.99, 1.88, 3.49, and 4.73 times to that of Compound S1, respectively.
- the concentrations of Compound S1 in plasma and brain tissue were significantly increased after intragastric administration of the above compounds, especially the Compounds 3 and 10, which increase by more than 10 times.
- the concentrations of Compound S1 in plasma and brain tissue of Compound 10 were higher than those of Compound 3 and Compound 15.
- mice Male C57BL/6 mice were administrated with 10 mg/kg Compounds 3, 10, and 11 by single intragastric administration.
- Whole blood and brain tissue samples were collected at 0.25 h, 0.5 h, 1 h, and 2h post-dose. Blood samples were placed on an ice box containing wet ice and centrifuged within 2 hours. After brain tissue collection, the blood and water on the tissue surface was cleaned, and then the brain tissue was weighed and homogenized by adding 4 times to the volume of PBS. The concentrations of Compound S1 in plasma and brain tissue were measured using LC-MS/MS. The results are shown in Table 5, Figure 4 and Figure 5.
- the systemic exposure (AUC 0-inf ) of S1 were 31.82, 730.45, 3393.41, and 241.08 h*ng/mL, respectively.
- the AUC 0-inf of S1 were 22.96, 106.64, and 7.58 times, respectively.
- the plasma exposure of Compound S1 after intragastric administration of Compounds 3, 10 and 15 was significantly increased compared with Compound S1.
- the systemic exposure of Compound S1 after intragastric administration of Compound 10 was significantly higher than that of Compound 3 and 15.
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a pro-drug of a benzodiazepine compound, which has improved significantly the in vivo bioavailability and oral absorption compared with its parent drug, and can be used for the prevention or treatment of diseases related to the central nervous system and cerebral vessels.
Description
Field of Technology
The present invention relates to the field of medicine, in particular to the prodrugs of one type of a benzodiazepine compound, which can be used for the prevention or treatment of central nervous related diseases, including Alzheimer's disease (AD) , Parkinson's disease (PD) , epilepsy, pain, central and peripheral nerve injuries, migraine, amyotrophic lateral sclerosis (ALS) , Huntington's disease (HD) and other degenerative and inflammation-related diseases, as well as anxiety, depression, schizophrenia, autism, addiction, drug dependence and other psychiatric disorders. Additionally, it can be used for the prevention or treatment of cerebrovascular diseases, including stroke.
Background Technology
Currently central nervous system (CNS) and cerebrovascular diseases cause the second largest morbidity following the tumor diseases globally. With the further extension of human life span, the increases of aging population and social pressure, the development of CNS drugs has become an important concern in today's aging society, and CNS diseases even become a greater social and economic burden than those on tumors. Globally, CNS diseases are the leading cause of disability adjusted life years (DALYs) , with stroke accounting for 42.2% (38.6-46.1) , migraine 16.3% (11.7-20.8) , AD and other dementia 10.4% (11.7-20.8) , and meningitis 7.9% (6.6-10.4) ; in addition, the stroke causes the second mortality, accounting for 11.6%of total deaths. Meanwhile, depression induces an increasing attention in the society, due to lacking effective, rapid onset of clinical drugs with few side effects.
Sigma receptor (σreceptor) was proposed in 1976 for the first time and it has been found it is widely expressed in various tissues, but particularly high in the CNS and liver tissues. σreceptor is mainly expressed on the surface of endoplasmic reticulum and mitochondrial membrane and participates in maintenance and regulation of the normal survival and physiological function of cells, tissue microenvironment stability, nerve cell excitability, and of normal physiological function of central nervous and cardiovascular system. Further research on the biology and function ofσreceptor has confirmed that drugs targeting ligands ofσreceptor can be used to prevent or treat psychiatric disorders and degenerative diseases of the CNS. Additionally, it also has potential therapeutic value in neuronal protection against stroke and neurotrauma (Aishwarya R et al. 2021 review) .
At least two subtypes ofσreceptors have been identified, among which the Sigma-1 receptor (σ1 receptor) has been verified as a novel drug target in recent years, and served as a binding protein for a variety of specific psychiatric drugs. Theσ1 receptor is a ligand-regulated protein chaperone that provides its functions by interacting with other receptors such as N-methyl-D-aspartate (NMDA) , 5-hydroxytryptamine (5-HT) , and dopamine (DA) ; it also functions by regulating other ion channels such as Na+, K+, and Ca++, as well as downstream receptors, thereby regulating mitochondrial function and the release of neurotransmitters such as 5-HT and DA. Although there have been some researches on theσ1 receptor for degenerative CNS diseases, the traditional agonists toσ1 receptor are limited by their significant side effects. Conversely, allosteric modulators of theσ1 receptor have greater advantages in terms of safety and selectivity than the traditional orthosteric ligands because the allosteric modulators provide more effective time and spatial selectivity without influencing the normal physiological function of theσ1
receptor. Therefore, the studies onσ1 receptor and its allosteric modulators have potential development value in the prevention or treatment of psychiatric and CNS diseases.
So far, many marketed drugs targetingσ1 receptors for the prevention or treatment of central nervous system and cerebrovascular diseases have been reported as non-selective, among which SA4503, (+) -Pentazocine, (+) -SKD-10047, PER-084, Fluvoxamine, Fluoxetine etc., can be used asσ1 receptor agonists. BD-1047, BD-1063, Haloperidol, E-52862, NE-100, etc., can be used asσ1 receptor antagonists. The marketed drug Opipramol targetsσ1 receptor, but also partially functions as a dopamine D2 receptor antagonist and a histamine H1 receptor antagonist, which muti-target mechanisms also generate some side effects.
Therefore, there is an urgent need to develop small molecular ligands that selectively acts onσ1 receptor. These drugs will provide very important treatment options on degenerative diseases and psychiatric diseases including AD, PD, epilepsy, pain, migraine, ALS, HD, central and peripheral nerve injuries, depression, anxiety, schizophrenia, autism, and drug addiction. Additionally, it is also of great significance for the treatment of major cerebrovascular diseases, including stroke.
The Chinese patent (CN102895233A) disclosed a class of benzodiazepine compound and its pharmaceutically acceptable salts as a modulator of sigma-1 receptor, which can be used in the preparation of drugs for epilepsy prevention or treatment. The patent also published that the Compound S1was able to raise the convulsion threshold in mice, demonstrating its anti-epileptic property. However, the inventors of the present disclosure discovered certain defects of this compound during their research. Firstly, its solubility is poor, likely resulting in very low oral bioavailability and plasma concentration due to its unstable absorption in human patients, which hinders its efficacy in the clinical applications. Secondly, the compound relies on the intravenous injection, leading to poor patient compliance and inconvenient administration. Therefore, it is still necessary to modify the structure of the compound to overcome these defections.
Based on the above technical issues, based on the above Compound S1, the present disclosure discovered that when a protective group is introduced into the phenolic hydroxyl group of the molecular structure to form a prodrug molecule to the Compound S1, the solubility and stability are greatly improved. Therefore, the prodrug significantly improves the oral administration bioavailability of the Compound S1 and greatly potentially improves its pharmaceutical value.
Invention content
To address the above technical problems, the present disclosure provides the following technical solutions:
On the one hand, the present disclosure provides compounds with the structure of formula (I) or a pharmaceutically acceptable salt,
wherein R represents one or more groups from the followings: -OC (=O) R1, -OC (=O) NR1R2, -OC (=O) NR1 (C1-C6alkyl) NHC (=O) R2, -OC (=O) OR1, -OS (=O) 2NR1R2, -OP (=O) (OR1) 2, or-B (OR1) 2or
wherein each R1 and R2 independently represent hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, -CH2- (C6-C10 aryl) , - (C6-C10 aryl) , - (5-10 membered heteroaryl) , or-CH2- (5-10 membered heteroaryl) ; or R1 and R2together with the atoms to which they are attached to form a 5-6 membered ring;
wherein the aryl or heteroaryl group (s) can be substituted with 0, 1, or 2 substituents selected from the following groups: deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, cyano, -ORa, hydroxy (C1-C6 alkyl) , -NRaRb, nitro, -C (O) Ra, -OC (O) Ra, -C (O) NRaRb;
wherein Ra and Rb separately represent hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl. Further, R represents the following group: -OC (=O) NR1R2;
wherein R1 represents hydrogen or C1-C6 alkyl; R2 represents C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, -CH2- (C6-C10 aryl) , or- (C6-C10 aryl) ; wherein the aryl or heteroaryl group can be optionally substituted with 0, 1, or 2 substituents selected from the following groups: deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl or cyano.
Furthermore, R1 represents hydrogen; R2 represents C1-C6 alkyl or- (C6-C10 aryl) ; wherein the aryl or heteroaryl group can be substituted with 0, 1, or 2 substituents selected from the following groups: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl or cyano.
Furthermore, R1 represents hydrogen; R2 represents- (C6-C10 aryl) , wherein the aryl group can be substituted with 0, 1, or 2 substituents selected from the following groups: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl or cyano.
Furthermore, R1 represents hydrogen; R2 represents phenyl, wherein the phenyl group can be substituted with 0, 1, or 2 substituents selected from the following groups: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl or cyano.
On the other hand, the present disclosure provides compounds with the structure of Formula (I) optionally selected from compounds with the following structure or their pharmaceutically acceptable salt:
Furthermore, the present disclosure also provides pharmaceutical compositions comprising of the compounds with the structure of Formula (I) or their pharmaceutically acceptable salt.
Furthermore, the present disclosure provides novel methods of treating or preventing central nervous system and cerebrovascular diseases, including the applications of their effective doses to the patient with the compound of claim 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition with the structure of Formula (I) or its pharmaceutically acceptable salt to a patient in need.
Definition
In the present disclosure, “alkyl” refers to a saturated branched or straight chain monovalent hydrocarbon group derived from a parent alkane by removing one hydrogen atom. Typical alkyl groups include, but not limited to, methyl, ethyl, propyl (e.g., prop-1-yl and prop-2-yl) , butyl (e.g., but-1-yl, but-2-yl, 2-methylprop-1-yl, 2-methylprop-2-yl, tert-butyl) , and so on. In some embodiments, alkyl groups comprise 1 to 20 carbon atoms. In some embodiments, alkyl groups comprise 1 to 10 carbon atoms or 1 to 6 carbon atoms, while in other embodiments, alkyl groups comprise 1 to 4 carbon atoms. In other embodiments, alkyl groups comprise 1 or 2 carbon atoms. In some embodiments, branched alkyl groups comprise at least 3 carbon atoms and typically contain 3 to 7 carbon atoms. In other embodiments, branched alkyl groups comprise 3 to 6 carbon atoms. Alkyl groups with 1 to 6 carbon atoms can be referred to as (C1-C6) alkyl groups, and alkyl groups with 1 to 4 carbon atoms can be referred to as (C1-C4) alkyl groups. These nomenclature rules can also be used for alkyl groups with various numbers of carbon atoms.
In the present disclosure, the term “aryl” or “aryl group” refers to a monovalent aromatic hydrocarbon group obtained by removing one hydrogen atom form a single carbon atom of the parent aromatic ring system. Aryl groups encompass single-ring carbon aromatic rings, such as benzene. Aryl groups also encompass fused carbon aromatic ring systems where each ring is aromatic, such as naphthalene. Thus, aryl groups can encompass fused ring systems where each ring is a carbon aromatic ring. In some embodiments, aryl groups may contain 6 to 10 carbon atoms. Such groups can be referred to as C6-C10 aryl groups. However, aryl groups do not in any way cover or overlap with the separately defined heteroaryl groups as defined herein. Thus, if one or more carbocyclic aromatic rings are fused with a heteroaromatic ring containing at least one heteroatom, the obtained ring system can be a heteroaryl group, not an aryl group as defined herein.
In the present disclosure, “heteroaryl” refers to a monovalent heteroaromatic group derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system. Heteroaryl groups typically include 5-to 14-membered, but more typically include 5-to 10-membered aromatic, monocyclic, bicyclic, and tricyclic rings containing one or more, for example, 1, 2, 3, or 4, or in certain embodiments, 1, 2, or 3, heteroatoms chosen from O, S, or N, with the remaining ring atoms being carbon. In monocyclic heteroaryl groups, the single ring is aromatic and includes at least one heteroatom. In some embodiments, a monocyclic heteroaryl group may include 5 or 6 ring members and may include 1, 2, 3, or 4 heteroatoms, 1, 2, or 3 heteroatoms, 1 or
2 heteroatoms, or 1 heteroatom where the heteroatom (s) are independently selected from O, S, or N. In bicyclic aromatic rings, both rings are aromatic. In bicyclic heteroaryl groups, at least one of the rings must include a heteroatom, but it is not necessary that both rings include a heteroatom although it is permitted for them to do so. For example, the term “heteroaryl” includes a 5-to 7-membered heteroaromatic ring fused to a carbocyclic aromatic ring or fused to another heteroaromatic ring. In tricyclic aromatic rings, all three of the rings are aromatic and at least one of the rings includes at least one heteroatom. For fused, bicyclic and tricyclic heteroaryl ring systems where only one of the rings contains one or more heteroatoms, the point of attachment may be at the ring including at least one heteroatom or at a carbocyclic ring. When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another. In certain embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2. In certain embodiments, the total number of S and O atoms in the aromatic heterocycle is not more than 1. Heteroaryl does not encompass or overlap with aryl as defined above. Examples of heteroaryl groups include, but are not limited to, groups derived from acridine, carbazole, cinnoline, furan, imidazole, indazole, indole, indolizine, isobenzofuran, isochromene, isoindole, isoquinoline, isothiazole, 2H-benzo [d] [1, 2, 3] triazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, and the like. In certain embodiments, the heteroaryl group can be between 5 to 20 membered heteroaryl, such as, for example, a5 to 14 membered or 5 to 10 membered heteroaryl. In certain embodiments, heteroaryl groups can be those derived from thiophene, pyrrole, benzothiophene, 2H-benzo [d] [1, 2, 3] triazole benzofuran, indole, pyridine, quinoline, imidazole, benzimidazole, oxazole, tetrazole, and pyrazine.
As used herein, the terms “halogen” and “halogenated” refer to atoms selected from fluorine, chlorine, bromine, and iodine.
As used herein, “mono-, di-or tri-halo-Cn-m alkyl” refers to an alkyl group that is substituted by one, two or three halo, wherein the alkyl group has n to m carbon atoms and the halo as substituent may be same or different. Examples of mono-, di-or tri-halo-Cn-m alkyl include without limitation, trichloromethyl, chloromethyl, bischloromethyl, chlorobromomethyl. As used herein, the term “cyano” refers to the group of formula-CN.
As used herein, the term “hydroxyl” refers to a group of formula-OH.
In the present disclosure, the terms “salt” or “pharmaceutically acceptable salt” includes pharmaceutically acceptable acid make-up salt and pharmaceutically acceptable base make-up salt. The term “pharmaceutically acceptable” refers to compounds, materials, compositions, and/or formulations, which should be within the range of reliable medical judgment and suitable for use in contact with tissues of humans and animals without excessive toxicity, irritancy, allergic reactions, or other problems or complications, in accordance with a reasonable benefit/risk ratio.
In the present disclosure, “pharmaceutical composition” refers to a formulation of the present invention compound in a medium that is commonly accepted for delivering biologically active compounds to mammals (e.g., humans) . The medium includes pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate administration to a biological organism, to enhance the absorption of the active ingredient, and to exert its biological activity.
In the present disclosure, “pharmaceutically acceptable carrier” includes, but not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier, which should be approved by the relevant regulatory authorities for use in humans or animals.
The term “excipient” refers to a pharmaceutically acceptable inert ingredient. Examples of types of “excipients” include, but not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents. Excipient can enhance the operational characteristic of a drug formulation, making it more suitable for direct compression by increasing flowability and/or adhesiveness.
The term “prodrug” refers to a compound that can be converted to a biologically active parent compound/composition under physiological conditions or through conversion by a solvent. The prodrugs of the present disclosure are prepared by modifying functional groups in the parent compound. These modifications can be removed by conventional methods or in vivo ways to obtain the parent compound. Prodrugs include compounds formed by linking a hydroxyl group or an amino group of the compounds in the present disclosure to any other groups. When the prodrugs of the present disclosure are administered to single mammal, the prodrug are cleaved to form free hydroxyl and free amino groups.
The term “comprising” means infinitely open, i.e., all-encompassing and non-limiting. It may be used herein synonymously with “having” or “including” . Comprising means including each indicated or recited component or element (s) while not excluding any other components or elements.
The terms “treatment” and other similar synonyms used in this disclosure include the following meanings:
(i) Preventing the occurrence of a disease or pathological condition in mammals, especially when such mammals are susceptible to the disease or condition but have not yet been diagnosed with it;
(ii) Alleviating a disease or pathological condition, i.e., inhibiting its progress;
(iii) Alleviating a disease or pathological condition, i.e., causing the state of the disease or condition to recede; or
(iv) Alleviating the symptoms caused by the disease or pathological condition.
The term “therapeutically effective amount” as herein used, refers to the amount of a compound that, when administered to a subject for treating a disease, or at least one of the clinical symptoms of a disease or disorder, is sufficient to affect such treatment for the disease, disorder, or symptom. As realized by those skilled researchers in the field, this amount is not limited to a single dose but also can be multiple doses within a key period necessary to produce a therapeutic or preventative response in the subject. Thus, “therapeutically effective amount” is not limited to the amount in a single capsule or tablet but also can comprise more than one capsule or tablet as prescribed by a qualified physician or healthcare provider. The “therapeutically effective amount” can vary in terms of the compound, the disease, disorder, and/or symptoms of the disease or disorder, and/or the severity of the symptoms of the disease or disorder, the age of the subject to be treated, and/or the weight of the subject to be treated. An appropriate amount in any given instance can be apparent to those skilled in the art or can be determined by routine experiments.
The term “AUC” (area under the curve) refers to a total amount of drug absorbed or exposed to a human or animal subject. Generally, AUC may be obtained from a mathematical
method in a plot of drug concentration in the human or animal subject over time until the concentration is negligible. The term “AUC” (area under the curve) could also refer to partial AUC at specified time intervals. “AUC0-inf” refers to the area under the concentration-time curve from time 0 to infinity.
The term “bioavailability” (F%) refers to the relative amount of a compound absorbed into the systemic blood circulation after administration via extravascular routes to a human or animal subject. The calculation is usually given by F%= (AUCT·Div) / (AUCiv·DT) ×100%, where the subscripts T and iv represent the test formulation and intravenous reference formulation, respectively, and D represents the administered dose (assuming the drug exhibits linear pharmacokinetic characteristic) .
The term “Tmax” refers to the time at which the drug reaches it maximum concentration in the blood, serum, designated compartment, or test area of the subject between the administration of the current dose and the next dose.
The term “Cmax” refers to the maximum concentration of the drug in the blood, serum, designated compartment, or test area of the subject between the administration of the current dose and the next dose. If specified, the term Cmax may also refer to the dose-normalized ratio.
Figure 1 Plasma concentration-time profiles of Compound S1 after single intragastric administration of different compounds in mice
Figure 2 Plasma concentration-time profiles of Compound S1 after single intragastric administration of different compounds in mice
Figure 3 Plasma concentration-time profiles of Compound S1 after intravenous injection of different compounds in mice
Figure 4 Plasma concentration-time profiles of Compound S1 after single intragastric administration of different compounds in mice
Figure 5 Brain tissue concentration-time profiles of Compound S1 after single intragastric administration of different compounds in mice
Figure 4 Plasma concentration-time profiles of Compound S1 after single intragastric administration of different compounds in rats
The following preparation methods and examples are used to illustrate the present disclosure, but these illustrations should not limit this invention in any way.
The aims of the detailed description of the selected examples are to support better understanding of the features and advantages of all the related disclosed subjects. The subjects to be disclosed and claimed for their protection in this disclosure can be modified in various aspects, and all such modifications should be within the scope of the claims. Therefore, the following example description should be considered as illustrative rather than prescriptive to the disclosure. The entire scope of the subjects of this disclosure is inclusive in the claims.
The present disclosure can be more easily understood by referring to the following examples, which are provided only to illustrate the present disclosure but not to limit the scope of the present disclosure.
Intermediate
Preparation of intermediate S1
Step 1: Preparation of intermediate 1
2-Bromo-3-hydroxybenzaldehyde (25 g) was added to a 500 mL pear-shaped flask at room temperature. DMF (250 mL) , potassium carbonate (52 g) , and iodomethane (53 g) were added, and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction mixture was filtered, and the filter cake was washed twice with ethyl acetate (100 mL*2) . The filtrate was concentrated to two-thirds of its volume, half-saturated brine (300 mL) was added, and extract three times with ethyl acetate (100 mL*3) . The organic phase was combined, washed twice with water (100 mL*2) and then washed with saturated brine (150 mL) . Then the organic phase was dried and concentrated to obtain intermediate 1 (25.8 g) , yield: 97%.
LCMS: [M+H] +=213.96
Step 2: Preparation of intermediate 2
Intermediate 1 (10 g) was added to a 250 mL three-neck flask, followed by the addition of 100 mL of acetic acid. Then, 7.2 g of ammonium acetate was added, and the mixture was stirred at room temperature for 15 minutes. Nitromethane (8.5 g) was slowly added dropwise, and the mixture was refluxed and stirred for 4.5 hours. After the reaction was completed, water (200 mL) was added, and the mixture was extracted with ethyl acetate (200 mL) . The organic phase was separated, and the aqueous phase was washed three times with saturated brine solution (100 mL) . The organic phase was dried and concentrated to obtain the crude product which was purified by silica gel column chromatography (eluting solvent: petroleum ether: ethyl acetate=30: 1-20: 1) to obtain intermediate 2 (10 g) , yield: 84%.
LCMS: [M+H] +=256.97
Step 3: Preparation of intermediate 3
Intermediate 2 (7 g) was added to a 1 L three-neck flask and dissolved in tetrahydrofuran (140 mL) . Borane-tetrahydrofuran complex (136 mL) was slowly added dropwise under ice-salt bath conditions. After the addition was completed, the mixture was moved to room temperature. Sodium borohydride (1 g) was added, and the temperature was raised to 65℃. After being stirred for 4.5 hours at 65℃, the mixture was cooled down to 0℃. Then, 2N hydrochloric acid (100 mL) was slowly added dropwise, and the mixture was stirred at room temperature for 1.5 hours. After being cooled down to room temperature, the pH was adjusted to 9-10 using 4N sodium hydroxide solution. The mixture was extracted for three times with ethyl acetate (100 mL) , the organic phase
was combined, and then washed with saturated brine solution (100 mL) , dried and concentrated to obtain the crude product which was purified by silica gel column chromatography (eluting solvent: dichloromethane: methanol=30: 1-30: 1+1%NH3. H2O) to obtain yellow liquid intermediate 3 (5 g) , yield: 80%.
LCMS: [M+H] +=229.01
Step 4: Preparation of intermediate 4
Intermediate 3 (35 g) was added to a 250 mL pear-shaped flask, followed by the addition of THF(50 mL) and water (50 mL) . Sodium bicarbonate (4.6 g) was added to the mixture. Under ice-water bath, Boc anhydride (7.1 g) was slowly added, and the mixture was stirred at room temperature for 1 hour. Then, 50 mL H2O was added to the reaction mixture, extracted with ethyl acetate twice (100 mL) . The organic phase was combined and washed with saturated brine solution (50 mL) , and then dried and concentrated to obtain the crude product which was purified by silica gel column chromatography (eluting solvent: petroleum ether: ethyl acetate=20: 1) to obtain intermediate 4 (6.4 g) , yield: 89%.
LCMS: [M+H] +=329.06
Step 5: Synthesis of intermediate 5
Intermediate 4 (6.4 g) was added to a 1 L pear-shaped flask and dissolved in THF (70 mL) . Sodium hydride (1.6 g) was added under ice bath conditions, and the mixture was stirred for 30 minutes at room temperature. Iodomethane (5.5 g) was slowly added dropwise to the reaction mixture, and the temperature was raised to 35℃and stirred overnight. After the reaction was completed, water (50 mL) was slowly added under ice bath conditions, and the mixture was extracted twice times with ethyl acetate (50 mL) . The organic phase was combined, washed twice with saturated brine solution (50 mL) , and then dried and concentrated to obtain the crude product which was purified by silica gel column chromatography (eluting solvent: petroleum ether: ethyl acetate=30: 1) to obtain yellow liquid intermediate 5 (6.4 g) , yield: 96%.
Step 6: Synthesis of intermediate 6
Intermediate 5 (6.4 g) was added to a 250 mL pear-shaped flask and dissolved in DCM (64 mL) . The mixture was cooled down to 0℃, and trifluoroacetic acid (6.4 mL) was slowly added dropwise. After the addition was completed, the temperature was raised to room temperature and stirred for 16 hours. After the reaction was completed, the pH was adjusted to 9-10 using 2N sodium hydroxide solution under ice bath conditions. The mixture was extracted with dichloromethane, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (50 mL) twice. The organic phase was combined, washed with saturated brine solution (100 mL) , and then dried and concentrated to obtain the crude product which was purified by silica gel column chromatography (eluting solvent: dichloromethane: methanol=10: 1+1%ammonia water) to obtain yellow liquid intermediate 6 (4 g) , yield: 89%.
LCMS: [M+H] +=243.03
Step 7: Synthesis of intermediate 7
Intermediate 6 (4 g) and styrene oxide (2 g) were added to a 100 mL pear-shaped flask and stirred at 120℃for 3 hours. After the reaction was completed, the mixture was cooled down to room temperature, and water (100 mL) and ethyl acetate (50 mL) were added. The organic phase was separated, and the aqueous phase was extracted twice with ethyl acetate (50 mL) . The organic phase was combined, and then washed with saturated brine solution, dried, and concentrated to obtain the crude product which was purified by silica gel column chromatography (eluting solvent:
petroleum ether: ethyl acetate=5: 1) to obtain intermediate 7 (5.2 g) , yield: 87%.
LCMS: [M+H] +=363.08
Step 8: Synthesis of intermediate 8
Intermediate 7 (5.2 g) was added to a 250 mL pear-shaped flask, followed by the addition of trifluoroacetic acid (20 mL) , and slowly add concentrated sulfuric acid (1.6 mL) dropwise, raised the temperature to 100℃and stirred for 4 hours. After the reaction was completed, most of the trifluoroacetic acid was removed by concentration. The mixture was cooled down to 0℃under ice bath, and the pH was adjusted to 9-10 using 4N sodium hydroxide solution. The mixture was extracted twice with ethyl acetate (50 mL) , the organic phase was combined, and then washed with saturated brine solution, dried, and concentrated to obtain the crude product which was then purified by silica gel column chromatography (eluting solvent: petroleum ether: ethyl acetate=2: 1) to obtain intermediate 8 (4.5 g) , yield: 92%.
LCMS: [M+H] +=345.07
Step 9: Synthesis of intermediate 9
Intermediate 8 (4.5 g) was added to a 500 mL pear-shaped flask and dissolved in methanol (200 mL) . Then, it was added with Pd-C (0.9 g) . The mixture was replaced with hydrogen three times and stirred at 45℃overnight. After the reaction was completed, the Pd-C was filtered, and the filter cake was washed with methanol (30 mL) . The filtrate was concentrated to obtain intermediate 9 (3.8 g) .
LCMS: [M+H] +=267.16
Step 10: Preparation of S1
Intermediate 9 (3.8 g) was added to a 250 mL pear-shaped flask, followed by the addition of hydrobromic acid (40 mL) . The mixture was stirred for 3 hours at 120℃. After the reaction was completed, the solvent was partially concentrated, and the mixture was cooled down to 0℃under ice bath. The pH was adjusted to 7-8 using 4N sodium hydroxide solution. The mixture was extracted five times with 20%dichloromethane in methanol, the organic phase was combined, and then washed with saturated brine solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product which was then purified by silica gel column chromatography (eluting solvent: dichloromethane: methanol=10: 1) to obtain Compound S1 (2.4 g) , yield: 67%.
LCMS: 253.15
Preparation of Intermediate S2
The above intermediate S1 (500 mg, 1.97 mmol) , trifluoromethanesulfonic anhydride (1.1 g, 3.94 mmol) , pyridine (468 mg, 5.92 mmol) and dichloromethane (15 mL) were added into the reaction bottle, and stirred at 25℃ for 2 hours. After the reaction was completed, the reaction mixture was diluted with dichloromethane (15 mL) and washed with 1 M hydrochloric acid (12
mL) , saturated sodium bicarbonate (15 mL) , and then the organic phase was concentrated to give intermediate S2 (600 mg, yield: 79%) .
Examples
Example 1: Synthesis of Compound 1
Compound 1
Intermediate S1 (200 mg, 0.79 mmol) was added into the reaction flask, and dissolved in DCM(20 mL) . Isocyanate (68 mg, 1.58 mmol) and DMAP (19.2 mg, 0.157 mmol) were added under ice bath, and then slowly raise to room temperature, and stirred for 6 hours. The mixture was diluted with water, extracted with dichloromethane (20 mL*2) . The organic phase was combined, and then washed with saturated NaCl (10 mL) , dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain the crude product which was purified by column chromatography (DCM: MeOH=25: 1) to obtain Compound 1 (95 mg, yield: 40%) .
1H NMR (400 MHz, CDCl3) δ7.31–7.19 (m, 5H) , 7.16–7.10 (m, 1H) , 7.06 (dd, J=8.6, 1.9 Hz, 1H) , 6.91 (dt, J=2.0, 1.0 Hz, 1H) , 5.64 (d, J=8.0 Hz, 1H) , 5.57 (d, J=8.2 Hz, 1H) , 4.29 (ddt, J=6.6, 5.8, 0.6 Hz, 1H) , 3.16 (d, J=5.8 Hz, 1H) , 3.02 (d, J=5.8 Hz, 1H) , 2.92 (q, J=6.4 Hz,1H) , 2.92–2.85 (m, 1H) , 2.88–2.83 (m, 1H) , 2.80 (ddd, J=7.0, 6.1, 1.0 Hz, 1H) , 2.33 (s, 3H) .
Example 2: Synthesis of Compound 2
The reaction flask was added in order with intermediate S1 (200 mg, 0.79 mmol) and DCM (15 mL) were added in order into the reaction flask. Under nitrogen atmosphere, DIPEA (306 mg, 2.36 mmol) and dimethyl carbamoyl chloride (170 mg, 1.58 mmol) were added. The mixture was stirred for 15 hours. After being diluted with water, the mixture was extracted with dichloromethane (15 mL×2) . The organic phase was combined, and then washed with saturated NaCl (10 mL) , dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product which was purified by column chromatography (DCM: MeOH=50: 1) to obtain Compound 2 (84 mg, 32%yield) .
1H NMR (400 MHz, CDCl3) δ7.35 (dd, J=8.1, 6.7 Hz, 2H) , 7.29–7.26 (m, 1H) , 7.20–7.16 (m,2H) , 6.91 (d, J=2.5 Hz, 1H) , 6.77 (dd, J=8.4, 2.5 Hz, 1H) , 6.61 (d, J=8.4 Hz, 1H) , 4.39 (d, J=8.6 Hz, 1H) , 3.25–3.16 (m, 1H) , 3.12 (d, J=12.2 Hz, 1H) , 3.07 (s, 3H) , 2.99 (s, 3H) , 2.91 (dd, J=10.2, 7.3 Hz, 2H) , 2.87–2.81 (m, 1H) , 2.46 (d, J=11.0 Hz, 1H) , 2.42 (s, 3H) .
Example 3: Synthesis of Compound 3
Intermediate S1 (400 mg, 1.58 mmol) was added into the reaction flask, and dissolved in DCM(25 mL) and then p-nitrophenylchloroformic acid (357 mg, 1.74 mmol) was added followed by Et3N (399 mg, 3.95 mmol) . Under nitrogen condition, the mixture was slowly raised to room temperature and stirred for 1 h and then isopropylamine (140 mg, 2.37 mmol) was added. The reaction was stirred for 7 hours. After the reaction was completed, water was added to dilute the mixture, and the reaction mixture was extracted with dichloromethane (30 mL*2) . The organic phase was combined, and then washed with saturated NaCl (15 mL) , dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product which was purified by column chromatography (DCM: MeOH=50: 1) to obtain Compound 3 (240 mg, yield: 45%) .
1H NMR (300 MHz, CDCl3) δ7.62 (d, J=7.7 Hz, 1H) , 7.35 (t, J=7.4 Hz, 2H) , 7.25 (d, J=7.0 Hz, 1H) , 7.19 (d, J=7.6 Hz, 2H) , 6.91 (s, 1H) , 6.77 (dd, J=8.3, 2.5 Hz, 1H) , 6.61 (d, J=8.4 Hz,1H) , 4.34 (d, J=7.5 Hz, 1H) , 3.68-3.57 (m, 1H) , 3.08–2.83 (m, 2H) , 2.82-2.62 (m, 1H) , 2.48-2.36 (m, 1H) , 2.32 (s, 3H) , 1.10 (d, J=6.6 Hz, 6H) .
Example 4: Synthesis of Compound 4
Intermediate S1 (200 mg, 0.79 mmol) , DCM (25 mL) and pyridine (312 mg, 317μL, 3.95 mmol) were added into the flask in order. Triphosgene (281 mg, 0.95 mmol) was added under nitrogen condition, stirred for 2 hours, and then N-isopropylmethylamine (87 mg, 1.18 mmol) was added. The reaction was continued for 15 hours. After the reaction was completed, the mixture was diluted with water, and extracted with dichloromethane (15 mL*2) . The organic phase was combined, and then washed with saturated NaCl solution (10 mL) , dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product which was purified with column chromatography (DCM: MeOH=50: 1) to obtain Compound 4 (62 mg, yield: 22%) .
1H NMR (400 MHz, CDCl3) δ7.31–7.19 (m, 5H) , 7.13 (dd, J=8.6, 0.7 Hz, 1H) , 7.02 (dd, J =8.6, 1.9 Hz, 1H) , 6.90 (dt, J=2.0, 1.0 Hz, 1H) , 4.29 (ddt, J=6.4, 5.7, 0.6 Hz, 1H) , 3.98 (p, J=7.3 Hz, 1H) , 3.16 (d, J=5.8 Hz, 1H) , 3.02 (d, J=5.9 Hz, 1H) , 2.98 (s, 3H) , 2.92 (q, J=6.4 Hz, 1H) , 2.92–2.85 (m, 1H) , 2.88–2.83 (m, 1H) , 2.80 (ddd, J=7.0, 6.2, 1.0 Hz, 1H) , 2.33 (s, 3H) , 1.21 (dd, J=20.0, 7.2 Hz, 6H) .
Example 5: Synthesis of Compound 5
The intermediate S1 (200 mg, 0.79 mmol) , DCM (20 mL) and pyridine (312 mg, 317μL, 3.95 mmol) were added in order into the reaction flask and triphosgene (281 mg, 0.95 mmol) was added under nitrogen. The mixture was stirred for 2 hours and then added 2, 2, 3, 3, 3-pentafluoropropylamine (176 mg, 1.18 mmol) . The reaction continues for 14 hours. After the reaction was completed, the mixture was diluted with water, extracted with dichloromethane (15 mL*2) . The organic phase was combined, and then washed with saturated NaCl solution (10 mL) , dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product which was then purified by column chromatography (EA: PE=3: 1) to obtain Compound 5 (81 mg, yield: 24%) .
1H NMR (400 MHz, CDCl3) δ7.32–7.18 (m, 5H) , 7.17–7.09 (m, 1H) , 7.05–6.90 (m, 2H) , 6.87 (dt, J=2.0, 1.0 Hz, 1H) , 4.29 (ddt, J=6.5, 5.8, 0.6 Hz, 1H) , 4.10–3.92 (m, 2H) , 3.16 (d, J=5.8 Hz, 1H) , 3.02 (d, J=5.8 Hz, 1H) , 2.97–2.75 (m, 4H) , 2.33 (s, 3H) .
Example 6: Synthesis of Compound 6
The intermediate S1 (200 mg, 0.79 mmol) , DCM (20 mL) and pyridine (312 mg, 317μL, 3.95 mmol) were added into the flask in order, and triphosgene (281 mg, 0.95 mmol) was added under nitrogen condition. The mixture was stirred for 2 hours and then added with N-Acetylethylenediamine (121 mg, 1.18 mmol) . The mixture was stirred for 15 hours. After the reaction was completed, the mixture was diluted with water, extracted with dichloromethane (15 mL*2) . The organic phase was combined, and then washed with saturated NaCl solution (10 mL) , dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product which was then purified by column chromatography (DCM: MeOH=50: 1) to obtain Compound 6 (90 mg, yield: 30%) .
1H NMR (400 MHz, CDCl3) δ7.32–7.18 (m, 5H) , 7.17–7.09 (m, 1H) , 7.00 (dd, J=8.6, 2.1 Hz, 1H) , 6.97–6.90 (m, 1H) , 6.87 (dt, J=1.9, 1.0 Hz, 1H) , 5.93–5.85 (m, 1H) , 4.29 (ddt, J=6.6, 5.8, 0.7 Hz, 1H) , 3.40–3.27 (m, 4H) , 3.16 (d, J=5.8 Hz, 1H) , 3.02 (d, J=5.8 Hz, 1H) , 2.97 –2.75 (m, 4H) , 2.33 (s, 3H) , 1.93 (s, 3H) .
Example 7: Synthesis of Compound 7
The intermediate S1 (200 mg, 0.79 mmol) , DCM (20 mL) and pyridine (312 mg, 317μL, 3.95 mmol) were added into the flask in order, and triphosgene (281 mg, 0.95 mmol) was added under nitrogen condition. The mixture was stirred for 2 hours and then added with piperidine (101 mg,1.18 mmol) . The mixture was stirred for 15 hours. After the reaction was completed, the mixture was diluted with water, extracted with dichloromethane (15 mL*2) . The organic phase was combined, and then washed with saturated NaCl solution (10 mL) , dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product which was then purified with column chromatography (EA: PE=3: 1) to obtain Compound 7 (170 mg, yield: 59%) .
1H NMR (400 MHz, CDCl3) δ7.31–7.19 (m, 5H) , 7.13 (dd, J=8.5, 0.6 Hz, 1H) , 7.02 (dd, J=8.6, 1.9 Hz, 1H) , 6.91 (dt, J=2.0, 1.0 Hz, 1H) , 4.29 (td, J=5.8, 0.7 Hz, 1H) , 3.48 (dd, J=6.2, 3.5 Hz,2H) , 3.42 (dd, J=6.2, 3.5 Hz, 2H) , 3.16 (d, J=5.8 Hz, 1H) , 3.02 (d, J=5.8 Hz, 1H) , 2.92 (q, J=6.4 Hz, 1H) , 2.92–2.83 (m, 2H) , 2.80 (ddd, J=7.0, 6.2, 1.0 Hz, 1H) , 2.33 (s, 3H) , 1.72 (tdt, J=7.0, 6.2, 3.4 Hz, 4H) , 1.65–1.54 (m, 2H) .
Example 8: Synthesis of Compound 8
The intermediate S1 (200 mg, 0.79 mmol) was added into the reaction flask, and dissolved in DCM (20 mL) , then cyclohexyl isocyanate (197 mg, 1.58 mmol) and DMAP (19.2 mg, 0.157 mmol) were added and then stirred for 15 hours. The mixture was diluted with water, extracted with dichloromethane (20 mL*2) . The organic phase was combined, and then washed with saturated NaCl (10 mL) , dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product which was purified by column chromatography (EA: PE=3: 1) to obtain Compound 8 (121 mg, yield: 42%) .
1H NMR (400 MHz, CDCl3) δ7.32-7.18 (m, 5H) , 7.17-7.09 (m, 1H) , 7.00 (dd, J=8.6, 2.1 Hz,1H) , 6.87 (dt, J=1.9, 1.0 Hz, 1H) , 5.86 (d, J=8.1 Hz, 1H) , 4.29 (ddt, J=6.5, 5.8, 0.6 Hz, 1H) , 3.44 (dp, J=7.9, 4.8 Hz, 1H) , 3.16 (d, J=5.8 Hz, 1H) , 3.02 (d, J=5.8 Hz, 1H) , 2.92 (q, J=6.4 Hz,1H) , 2.92-2.85 (m, 1H) , 2.88-2.83 (m, 1H) , 2.80 (ddd, J=7.0, 6.2, 1.0 Hz, 1H) , 2.33 (s, 3H) , 1.89-1.76 (m, 2H) , 1.74-1.49 (m, 3H) , 1.48-1.28 (m, 5H) .
Example 9: Synthesis of Compound 9
The intermediate S1 (200 mg, 0.79 mmol) , DCM (20 mL) and pyridine (312 mg, 317μL, 3.95 mmol) were added into the flask in order, and triphosgene (281 mg, 0.95 mmol) was added under nitrogen condition. The mixture was stirred for 2 hours and then added with 1, 4'-bipiperidine (200 mg, 1.18 mmol) . The mixture was stirred for 12 hours. After the reaction was completed, the mixture was diluted with water, extracted with dichloromethane (15 mL*2) . The organic phase was combined, and then washed with saturated NaCl solution (10 mL) , dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product which was purified with column chromatography (EA: PE=3: 1) to obtain Compound 9 (150 mg, yield: 36%) .
1H NMR (300 MHz, CDCl3) δ7.72 (t, J=7.3 Hz, 2H) , 7.64 (d, J=7.7 Hz, 2H) , 7.54 (d, J=7.4 Hz, 2H) , 7.11 (d, J=8.4 Hz, 1H) , 6.97 (d, J=8.4Hz, 1H) , 4.73 (d, J=9.9 Hz, 3H) , 3.52 (dd, J =27.0, 12.9 Hz, 2H) , 3.40–3.03 (m, 10H) , 2.77 (s, 4H) , 2.44 (s, 2H) , 2.19 (s, 4H) , 2.01 (d, J=12.0 Hz, 2H) , 1.91 (s, 2H) .
Example 10: Synthesis of Compound 10
The intermediate S1 (200 mg, 0.79 mmol) was added into the reaction flask, and dissolved in DCM (20 mL) , p-toluene isocyanate (115 mg, 0.87 mmol) and DMAP (19.2 mg, 0.157 mmol) were added and stirred for 14 hours. The mixture was diluted with water, extracted with dichloromethane (20 mL*2) . The organic phase was combined, and then washed with saturated NaCl (10 mL) , dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain the crude product which was purified by column chromatography (EA: PE=3: 1) to obtain Compound 10 (110 mg, yield: 36%) .
1H NMR (300 MHz, CDCl3) δ7.41–7.29 (m, 4H) , 7.19 (d, J=7.5 Hz, 2H) , 7.13 (d, J=8.0 Hz, 2H) , 6.98 (d, J=2.5 Hz, 1H) , 6.84 (dd, J=8.3, 2.7 Hz, 2H) , 6.64 (d, J=8.3 Hz, 1H) , 4.35 (d, J=8.5 Hz, 1H) , 3.13 (dd, J=25.9, 12.2 Hz, 2H) , 2.98–2.76 (m, 3H) , 2.39 (s, 4H) , 2.31 (s, 3H) .
Example 11: Synthesis of Compound 11
The intermediate S1 (200 mg, 0.79 mmol) was added into the reaction flask, and dissolved in DCM (10 mL) , then p-Toluoyl chloride (244 mg, 1.58 mmol) and Et3N (399 mg, 3.95 mmol) were added, stirred under nitrogen condition for 6 hours. The mixture was diluted with water, extracted with dichloromethane (15 mL*2) . The organic phase was combined, and then washed with saturated NaCl (10 mL) , dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain the crude product which was purified by column chromatography (EA: PE=3: 1) to obtain Compound 11 (70 mg, yield: 24%) .
1H NMR (400 MHz, DMSO-d6) δ8.00 (d, J=8.2 Hz, 2H) , 7.40 (d, J=8.0 Hz, 2H) , 7.36 (t, J=7.5 Hz, 2H) , 7.26 (d, J=7.4 Hz, 1H) , 7.23–7.19 (m, 2H) , 7.09 (d, J=2.5 Hz, 1H) , 6.96 (dd, J =8.3, 2.6 Hz, 1H) , 6.73 (d, J=8.3 Hz, 1H) , 4.38 (d, J=7.7 Hz, 1H) , 3.00 (dd, J=14.0, 8.8 Hz, 2H) , 2.89–2.74 (m, 2H) , 2.66 (t, J=10.0 Hz, 1H) , 2.42 (s, 3H) , 2.38 (d, J=10.6 Hz, 1H) , 2.30 (s, 3H) .
Example 12: Synthesis of Compound 12
The intermediate S1 (200 mg, 0.79 mmol) was added into the reaction flask, and dissolved in DCM (20 mL) . 4-methoxyphenyl isocyanate (235 mg, 1.58 mmol) and DMAP (19.2 mg, 0.157 mmol) were added and stirred for 15 hours. The mixture was diluted with water, extracted with dichloromethane (20 mL*2) . The organic phase was combined, and then washed with saturated NaCl (10 mL) , dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product which was purified by column chromatography (EA: PE=4: 1) to obtain Compound 12 (35 mg, yield: 11%) .
1H NMR (300 MHz, CDCl3) δ7.72 (dd, J=19.5, 7.3 Hz, 4H) , 7.66 (s, 1H) , 7.59 (d, J=7.4 Hz,2H) , 7.42–7.26 (m, 3H) , 7.23–7.16 (m, 1H) , 7.02 (d, J=8.3 Hz, 1H) , 4.89–4.76 (m, 1H) , 4.19 (s, 3H) , 3.75–3.51 (m, 2H) , 3.46–3.18 (m, 3H) , 2.85 (s, 4H) .
Example 13: Synthesis of Compound 13
The intermediate S1 (200 mg, 0.79 mmol) was added into the reaction flask, and dissolved in DCM (20 mL) , then p-fluorophenyl isocyanate (216 mg, 1.58 mmol) and DMAP (19.2 mg, 0.157 mmol) were added and stirred for 15 hours. The mixture was diluted with water, extracted with dichloromethane (20 mL*2) . The organic phase was combined, and then washed with saturated NaCl (10 mL) , dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product which was purified by column chromatography (EA: PE=4: 1) to obtain Compound 13 (75 mg, yield: 24%) .
1H NMR (400 MHz, CDCl3) δ8.83 (s, 1H) , 7.55–7.48 (m, 2H) , 7.27 (qd, J=3.2, 2.8, 1.3 Hz,3H) , 7.28–7.19 (m, 1H) , 7.13 (dd, J=8.7, 0.6 Hz, 1H) , 7.10–7.00 (m, 3H) , 6.89 (dt, J=2.1, 1.0 Hz, 1H) , 4.29 (ddd, J=5.8, 5.4, 0.7 Hz, 1H) , 3.16 (d, J=5.8 Hz, 1H) , 3.02 (d, J=5.8 Hz, 1H) , 2.97–2.76 (m, 4H) , 2.33 (s, 3H) .
Example 14: Synthesis of Compound 14
The intermediate S1 (200 mg, 0.79 mmol) was added into the reaction flask, and dissolved in DCM (20 mL) , then benzyl isocyanate (210 mg, 1.58 mmol) and DMAP (19.2 mg, 0.157 mmol) were added and stirred for 15 hours. The mixture was diluted with water, extracted with dichloromethane (20 mL*2) . The organic phase was combined, and then washed with saturated NaCl (10 mL) , dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product which was purified by column chromatography (DCM: MeOH=50: 1) to obtain Compound 14 (125 mg, yield: 41%) .
1H NMR (400 MHz, CDCl3) δ7.37–7.27 (m, 2H) , 7.31 (s, 3H) , 7.32–7.18 (m, 6H) , 7.13 (dd, J=8.6, 0.6 Hz, 1H) , 7.00 (dd, J=8.6, 2.0 Hz, 1H) , 6.87 (dt, J=1.9, 1.0 Hz, 1H) , 6.11 (t, J=5.9 Hz, 1H) , 4.45 (dd, J=5.9, 0.9 Hz, 2H) , 4.29 (td, J=5.8, 0.8 Hz, 1H) , 3.16 (d, J=5.8 Hz, 1H) , 3.02 (d, J=5.8 Hz, 1H) , 2.97–2.75 (m, 4H) , 2.33 (s, 3H) .
Example 15: Synthesis of Compound 15
The intermediate S1 (200 mg, 0.79 mmol) was added into the reaction flask, and dissolved in DCM (20 mL) , then ethyl isocyanate (112 mg, 1.58 mmol) and DMAP (19.2 mg, 0.157 mmol) were added and stirred for 6 hours. The mixture was diluted with water, extracted with dichloromethane (20 mL*2) . The organic phase was combined, and then washed with saturated NaCl (10 mL) , dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product which was purified by column chromatography (DCM: MeOH=40: 1) to obtain Compound 15 (75 mg, yield: 29%) .
1H NMR (300 MHz, CDCl3) δ7.51–7.21 (m, 5H) , 7.00 (s, 1H) , 6.87 (d, J=9.1 Hz, 1H) , 6.68 (t, J=6.9 Hz, 1H) , 5.05 (s, 1H) , 4.43 (d, J=8.7 Hz, 1H) , 3.38 (q, J=6.8 Hz, 2H) , 3.16 (d, J =13.3 Hz, 2H) , 2.96 (d, J=13.4 Hz, 3H) , 2.48 (s, 4H) , 1.28 (q, J=6.9 Hz, 3H) .
Example 16: Synthesis of Compound 16
The intermediate S1 (150 mg, 0.592 mmol) was added into the reaction flask, and dissolved in DCM (10 mL) , then 2, 4, 6-Trimethylbenzoyl chloride (216 mg, 1.18 mmol) and Et3N (239 mg, 2.37 mmol) was added on ice bath under nitrogen condition. The mixture was slowly raised to room temperature and stirred for 14 hours. The mixture was diluted with water, extracted with dichloromethane (15 mL*2) . The organic phase was combined, and then washed with saturated NaCl (10 mL) , dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product which was purified by column chromatography (EA: PE=3: 1) to obtain Compound 16 (70 mg, yield: 29%) .
1H NMR (300 MHz, CDCl3) δ7.37 (t, J=7.3 Hz, 2H) , 7.29 (d, J=7.8 Hz, 1H) , 7.20 (d, J=7.5 Hz, 2H) , 7.02 (d, J=2.5 Hz, 1H) , 6.90 (d, J=8.4 Hz, 3H) , 6.69 (d, J=8.3 Hz, 1H) , 4.39 (d, J =8.5 Hz, 1H) , 3.29–3.07 (m, 2H) , 2.90 (q, J=9.0, 8.1 Hz, 3H) , 2.49 (s, 1H) , 2.43 (s, 9H) , 2.31 (s, 3H) .
Example 17: Synthesis of Compound 17
The intermediate S1 (150 mg, 0.592 mmol) was added into the reaction flask, and dissolved in DCM (10 mL) , then Triethylamine (239 mg, 2.368mmol) was added. Triphosgene (117 mg, 0.395 mmol) was added under nitrogen at ice bath and stirred for 1 hours, and then 3-aminopyridine (111 mg, 1.184 mmol) was added, stirred for 15 hours. After the reaction was completed, the mixture was diluted with water, extracted with dichloromethane (15 mL*2) . The organic phase was combined, and then washed with saturated NaCl solution (10 mL) , dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product which was purified by column chromatography (DCM: MeOH=50: 1) to obtain Compound 17 (18 mg, yield: 8.1%) .
1H NMR (300 MHz, CDCl3) δ8.59 (s, 1H) , 8.36 (d, J=4.8 Hz, 1H) , 8.04 (d, J=8.2 Hz, 1H) , 7.36 (dd, J=16.7, 9.6 Hz, 4H) , 7.19 (d, J=7.5 Hz, 2H) , 7.01–6.93 (m, 1H) , 6.90–6.81 (m, 1H) , 6.65 (d, J=8.5 Hz, 1H) , 4.45 (d, J=8.6 Hz, 1H) , 3.36–3.12 (m, 2H) , 3.08–2.79 (m, 3H) , 2.46 (s, 4H) .
Example 18: Synthesis of Compound 18
The intermediate S1 (200 mg, 0.79 mmol) was added into the reaction flask, and dissolved in DMAc (4 mL) . Aminosulfonyl chloride (137 mg, 1.18 mmol) was added at ice bath (0-5℃) and stirred for 12 hours under nitrogen. After the reaction was completed, the mixture was purified directly by prep-HPLC and lyophilized to obtain the Compound 18 (74 mg, yield: 28%) .
1H NMR (400 MHz, DMSO-d6) δ8.16 (s, 1H) , 7.94 (br, 1H) , 7.35 (t, J=7.5 Hz, 2H) , 7.25 (t, J=7.3 Hz, 1H) , 7.19 (d, J=7.6 Hz, 2H) , 7.10 (d, J=2.6 Hz, 1H) , 6.98 (dd, J=8.4, 2.6 Hz, 1H) , 6.71 (d, J=8.4 Hz, 1H) , 4.38 (d, J=7.8 Hz, 1H) , 3.01 (dd, J=13.9, 8.9 Hz, 2H) , 2.88 (d, J=12.4 Hz, 1H) , 2.79 (dd, J=14.5, 8.0 Hz, 1H) , 2.70 (t, J=10.3 Hz, 1H) , 2.43 (t, J=10.4 Hz, 1H) , 2.32 (s, 3H) .
Example 19: Synthesis of Compound 19
The intermediate S1 (200 mg, 0.79 mmol) was added into the reaction flask, and dissolved in DMAc (4 mL) . Dimethylaminosulfonyl chloride (170 mg, 1.18 mmol) was added at ice bath (0-5℃) and stirred for 12 hours under nitrogen condition. After the reaction was completed, the mixture was purified directly by prep-HPLC and lyophilized to obtain Compound 19 (85 mg, yield: 30%) .
1H NMR (400 MHz, CDCl3) δ7.31–7.19 (m, 5H) , 7.05 (dd, J=8.6, 0.7 Hz, 1H) , 6.98 (dd, J=8.5, 1.9 Hz, 1H) , 6.85 (dt, J=2.0, 1.0 Hz, 1H) , 4.29 (tq, J=5.7, 0.6 Hz, 1H) , 3.16 (d, J=5.8 Hz,1H) , 3.02 (d, J=5.8 Hz, 1H) , 2.98–2.77 (m, 4H) , 2.85 (s, 6H) , 2.33 (s, 3H) .
Example 20: Synthesis of Compound20
The intermediate S2 (400 mg, 1.58 mmol) , Bis (pinacolato) diboron (801 mg, 3.16 mmol) , Pd (dppf) Cl2 (110 mg, 0.16 mmol) , cesium carbonate (1.03 g, 3.16 mmol) and 1, 4-dioxane (10 mL) were mixed and stirred for 6 hours at 100℃. After the reaction was completed, the mixture was diluted with ethyl acetate (50 mL) , washed with water (50 mL) , dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product which was purified
by column chromatography (methanol/dichloromethane: 7-10%) to obtain Compound 20 (400 mg, yield: 71%) .
MS m/z [M+H] +: 364.2
1H NMR (400 MHz, DMSO-d6) δ7.49 (d, J=1.3 Hz, 1H) , 7.41 (dd, J=7.5, 1.3 Hz, 1H) , 7.36 (t, J=7.6 Hz, 2H) , 7.29–7.22 (m, 1H) , 7.21–7.13 (m, 2H) , 6.77 (d, J=7.5 Hz, 1H) , 4.39 (d, J=7.6 Hz, 1H) , 3.08–2.94 (m, 2H) , 2.80 (t, J=12.3 Hz, 2H) , 2.72–2.58 (m, 1H) , 2.47–2.35 (m, 1H) , 2.30 (s, 3H) , 1.30 (s, 12H) .
Example 21: Synthesis of Compound21
The above Compound 20 (200 mg, 0.55 mmol) , sodium periodate (471 mg, 2.20 mmol) , tetrahydrofuran (6 mL) and water (1mL) were added into the reaction flask and stirred for 16 hours at 25℃. After the reaction was completed, the mixture was neutralized with 1 M hydrochloric acid (2 mL) , and then concentrated. The crude product was purified by prep-HPLC and then lyophilized to obtain Compound 20 (400 mg, yield: 71%) .
MS m/z [M+H] +: 282.1
1H NMR (400 MHz, DMSO-d6) δ8.01 (s, 2H) , 7.60 (d, J=1.3 Hz, 1H) , 7.52 (dd, J=7.6, 1.3 Hz, 1H) , 7.39 (t, J=7.5 Hz, 2H) , 7.33–7.26 (m, 1H) , 7.25–7.18 (m, 2H) , 6.64 (d, J=7.7 Hz, 1H) , 4.45 (d, J=8.1 Hz, 1H) , 3.18 (d, J=9.5 Hz, 1H) , 3.08 (s, 1H) , 2.84 (d, J=13.8 Hz, 2H) , 2.59 (t, J =10.1 Hz, 2H) , 2.45 (s, 3H) .
Example 22: Synthesis of Compound22
Step 1: Preparation of Intermediate 1
The intermediate S1 (1 g, 3.95 mmol) was added into the reaction flask, and dissolved in acetonitrile (20 mL) . Then Potassium carbonate (1.09 g, 7.89 mmol) and CD3I (560 mg, 3.95 mmol) were added and reaction for 2 hours at the room temperature. When no raw material and new spots were found using TLC methods, the mixture was concentrated under reduced pressure, diluted with water, extracted with dichloromethane (20 mL*2) . The organic phase was combined, and then washed with saturated NaCl (15 mL) , dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product which was then purified by column chromatography (DCM: MeOH=50: 1) to obtain intermediate 1 (100 mg, yield: 9.4%) .
Step 2: Preparation of Compound 22
The above intermediate 1 (100 mg, 0.358 mmol) , 48%Hydrobromic acid (3 mL) were added into the reaction flask. The mixture was heated to 120℃, stirred for 2 hours. After the reaction was completed, the mixture was concentrated and cooled down to 0℃with ice bath, adjusted to PH=7-8 by 4N Sodium hydroxide solution, extracted with dichloromethane (20 mL*2) . The organic phase was combined, and then washed with saturated NaCl (15 mL) , dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain the crude product which was purified by column chromatography (DCM: MeOH=40: 1-20: 1) to obtain Compound 22 (50 mg, yield 52.7%) .
1H NMR (600 MHz, DMSO-d6) δ9.14 (s, 1H) , 7.31 (t, J=7.6 Hz, 2H) , 7.20 (t, J=7.3 Hz, 1H) , 7.15 (d, J=7.6 Hz, 2H) , 6.56 (d, J=2.3 Hz, 1H) , 6.49–6.41 (m, 2H) , 4.19 (d, J=7.7 Hz, 1H) , 2.96 (s, 1H) , 2.83 (dd, J=14.1, 9.1 Hz, 1H) , 2.76 (d, J=12.1 Hz, 1H) , 2.64 (t, J=7.2 Hz, 1H) , 2.58 (s, 1H) , 2.41–2.34 (m, 1H) .
Example 23: Synthesis of Compound23
Step 1: Preparation of Intermediate 1
The intermediate S1 (200 mg, 0.789 mmol) in DCM (15 mL) was added with DBU (240 mg, 1.578 mmol) , Bis (dimethylamino) phosphoryl Chloride (202 mg, 1.184 mmol) and DMAP (10 mg,0.0789 mmol) at 0℃. The mixture was stirred at room temperature for 12 hours. After the reaction was completed, the mixture was extracted with dichloromethane (10 mL*2) . The organic phase was combined and washed with NH4Cl (aqueous solution) (10 mL*2) , dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product which was then purified by column chromatography (ethyl acetate/methanol=10: 1) to obtain intermediate 1 (104 mg, 34%) .
MS: [MH] +388.25
1HNMR (400 MHz, CDCl3) : δ7.35 (t, J=7.4 Hz, 2H) , 7.28-7.25 (m, 1H) , 7.17 (d, J=7.2 Hz, 2H) , 6.98 (d, J=2 Hz, 1H) , 6.81-6.79 (m, 1H) , 6.54 (d, J=8.4 Hz, 1H) , 4.41 (d, J=8.8 Hz, 1H) , 3.28-3.15 (m, 2H) , 3.01-2.98 (m, 1H) , 2.93-2.79 (m, 3H) , 2.71 (s, 6H) , 2.69 (s, 6H) .
Step 2: Preparation of Compound 23
TFA (0.5 mL) was added into the solution of intermediate 1 (94 mg, 0.24 mmol) in acetonitrile/H2O (5/5 mL) . The mixture was stirred at room temperature for 12 hours. After the reaction was completed, the mixture was concentrated to remove acetonitrile and then lyophilized to obtain Compound 23 (37 mg, 13%) as a white solid product.
MS: [MH] +334.0
1HNMR (400 MHz, CD3OD) : δ7.40-7.35 (m, 3H) , 7.16-7.14 (m, 3H) , 6.98 (d, J=8 Hz, 1H) , 6.54 (s, 1H) , 4.42 (s, 1H) , 3.64-3.49 (m, 3H) , 3.05-3.03 (m, 2H) , 2.89 (m, 4H) .
Example 24: Pharmacokinetic (PK) Study of Compound S1
In order to verify the low oral absorption of Compound S1 published in CN102895233A, aPK study of mice was conducted to determine plasma and brain exposure by different routes of administration. The experimental procedures were as follows: Male C57BL/6J mice weighing 20~25 g were administered with 10 mg/kg Compound S1 by intragastric administration and 5 mg/kg Compound S1 by intravenous injection at concentration of 1 mg/mL. Blood samples were collected at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, and 6 h post-dose and placed in tubes containing EDTA-2Na as the anticoagulant. Plasma samples were obtained by centrifugation at 5000 rpm and 4℃for 10 min. 20μL plasma was mixed with 20μL methanol and 100μL acetonitrile containing internal standard, the samples were vortexed and centrifugated at 13, 500 rpm for 15 min, and 10 μL of the supernatant was applied into the LC-MS/MS to analyze the concentration of Compound S1.The experimental data showed that the oral bioavailability of Compound S1 was 1.56%, and the AUC of Compound S1 in plasma was about 40 ng/ml*hr. The extremely low exposure and low bioavailability by oral administration indicated that Compound S1 was not suitable for clinical development. The results are shown in Table 1.
Table 1
Summary of key pharmacokinetic data of Compound S1 in mice administrated by different routes
Example 25 Pharmacokinetic Data of Mice
(1) Pharmacokinetic study after single intragastric administration
In order to investigate whether the compounds in the examples of the present disclosure can improve the systemic exposure of Compound S1 in the published patent application (CN102895233A) , the plasma exposure of Compound S1 in mice was determined after single intragastric administration of several example compounds in this disclosure.
Male C57BL/6 mice were administrated with 10 mg/kg Compound S1 of the published patent application (CN102895233A) and Compounds 2, 3, 9, 10, 11, 15, 17, 18, 20, 21, and 23 by single intragastric administration. Whole blood samples were collected at pre-dose and 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h post-dose, and placed on an ice box containing wet ice and centrifuged within 2 hours. The concentration of Compound S1 in plasma was measured using LC-MS/MS. The results are shown in Table 2 and Figure 1.
The results showed that the Cmax of Compound S1 in plasma after intragastric administration of Compound S1 and Compounds 2, 3, 9, 10, 11, 15, 17, 18, 20, 21, and 23 were 98.12, 48.80, 92.37, 1.83, 755.41, 20.12, 79.19, 188.30, 18.93, 19.50, 16.23, and 22.38 ng/mL, respectively. The systemic exposure (AUC0-inf) of S1 were 70.70, 98.77, 171.87, 5.69, 758.26, 15.06, 147.82, 209.67, 24.19, 95.41, 57.55, and 24.38 h*ng/mL, respectively. The plasma Cmax of
S1 level after intragastric administration of Compounds 2, 3, 9, 10, 11, 15, 17, 18, 20, 21, and 23 were about 0.50, 0.94, 0.02, 7.70, 0.21, 0.81, 1.92, 0.19, 0.20, 0.17, and 0.23 times to that of Compound S1, respectively. The plasma AUC0-inf of S1 were about 1.40, 2.43, 0.08, 10.72, 0.21, 2.09, 2.97, 0.34, 1.35, 0.81, and 0.34 times to that of Compound S1, respectively.
Table 2
Summary of plasma exposure data of Compound S1 after single intragastric administration of different compounds in mice
Therefore, the systemic exposure of Compound S1 was significantly increased after intragastric administration of Compounds 3, 10, 15, and 17 compared with that of Compound S1. Meanwhile, the systemic exposure of Compound S1 level after intragastric administration of Compound 10 was significantly higher than that of Compounds 3, 15, and 17.
(2) Bioavailability study after single intragastric administration
In order to verify whether the Compounds in the invention can improve the bioavailability of Compound S1 in the published patent application (CN102895233A) after intragastric administration, the following experiment in mice was conducted.
Male C57BL/6 mice were administrated with Compound S1 of the published patent application (CN102895233A) and Compounds 3, 9, 10, 15, and 23 by single intragastric administration (IG) at dose of 10 mg/kg and intravenous injection (IV) at dose of 5 mg/kg. Whole blood samples were collected at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, and 6 h post-dose for the intragastric administration group and 2 min, 5 min, 0.25h, 0.5h, 1 h, 2 h, 4 h, and 6 h post-dose for the intravenous injection group. Blood samples were placed on an ice box containing wet ice and centrifuged within 2 hours. The concentration of Compound S1 in plasma was measured using LC-MS/MS, and the bioavailability was calculated. The results are shown in Table 3, Figure 2, and Figure 3.
The results showed that the system exposure (AUC0-inf) of S1 after intragastric administration of Compound S1 and Compounds 3, 9, 10, 15, and 23 were 40.38, 195.69, 5.69, 860.07, 147.82, and 24.38 h*ng/mL, respectively. The system exposure (AUC0-inf) of S1 after intravenous injection of each compound were 1171.99, 160.70, 35.49, 567.61, 129.25, and 663.30
h*ng/mL, respectively. The bioavailability (F) of S1 after intragastric administration of each compound were 1.56%, 60.32%, 7.86%, 75.72%, 56.68%, and 1.82%, respectively. Compared with Compound S1, the bioavailability of S1 level was significantly increased after intragastric administration of Compounds 3, 10, and 15. The bioavailability of S1 level after intragastric administration of Compound 10 was higher than that of Compound 3 and Compound 15.
Table 3
(3) Determination of plasma and brain tissue concentrations after single intragastric administration
Considering that the compounds of the present invention are aimed at the prevention or treatment of CNS diseases, the determination of S1 concentration of some of the above-mentioned compounds in the brain was conducted at different time points post-dose to verify whether the exposure of S1 in the brain was increased compared with that of Compound S1 in the published patent application (CN102895233A) .
Experiment 1: Male C57BL/6 mice were administrated with 10 mg/kg Compound S1 of the published patent application (CN102895233A) and Compounds 3, 10, 11, 15, 18, 20, and 21 by single intragastric administration. Whole blood and brain tissue samples were collected at 1 h post-dose. Blood samples were placed on an ice box containing wet ice and centrifuged within 2 hours. After brain tissue collection, the blood and water on the surface was cleaned, and then the brain tissue was weighed and homogenized by adding 4 times the volume of PBS. The concentrations of Compound S1 in plasma and brain tissue were measured using LC-MS/MS. The results are shown in Table 4.
The results showed that the concentrations of Compound S1 in plasma after intragastric administration of Compound S1 and Compounds 3, 10, 11, 15, 18, 20, and 21 were 1.8, 138.6, 582.8, 7.7, 125.4, 3.5, 13.2, and 25.2 ng/mL, respectively. The concentrations of S1 in brain tissue were 35.9, 455.3, 590.0, 138.9, 322.9, 67.3, 125.0, and 169.4 ng/g, respectively. The concentrations of Compound S1 in plasma after intragastric administration of Compounds 3, 10, 11, 15, 18, 20 and 21 were 75.75, 318.44, 4.21, 69.67, 1.91, 7.23, and 13.75 times to that of Compound S1, respectively. The concentrations of S1 in brain tissue were 12.70, 16.46, 3.87, 8.99, 1.88, 3.49, and 4.73 times to that of Compound S1, respectively. Compared with Compound S1, the concentrations of Compound S1 in plasma and brain tissue were significantly increased after intragastric administration of the above compounds, especially the Compounds 3 and 10, which increase by more than 10 times. The concentrations of Compound S1 in plasma and brain tissue of Compound 10 were higher than those of Compound 3 and Compound 15.
Table 4
Data summary of Compound S1 level in plasma and brain tissue after single intragastric
administration of different compounds in mice (1h post-dose)
Experiment 2: Male C57BL/6 mice were administrated with 10 mg/kg Compounds 3, 10, and 11 by single intragastric administration. Whole blood and brain tissue samples were collected at 0.25 h, 0.5 h, 1 h, and 2h post-dose. Blood samples were placed on an ice box containing wet ice and centrifuged within 2 hours. After brain tissue collection, the blood and water on the tissue surface was cleaned, and then the brain tissue was weighed and homogenized by adding 4 times to the volume of PBS. The concentrations of Compound S1 in plasma and brain tissue were measured using LC-MS/MS. The results are shown in Table 5, Figure 4 and Figure 5.
The results showed that the Cmax of Compound S1 level in plasma after intragastric administration of Compounds 3, 10, and 11 were 138.6, 582.8, and 13.4 ng/mL, respectively. The Cmax of Compound S1 level in brain tissue were 574.1, 590, and 40.4 ng/g, respectively. The systemic exposure (AUC0-2h) of Compound S1 in plasma were 175.4, 687.1, and 8.8 h*ng/mL, respectively. The exposure (AUC0-2h) of Compound S1 in brain tissue were 700.1, 808.8, and 57.6 h*ng/g, respectively. The Cmax and exposure of Compound S1 in plasma and brain tissue of Compounds 3 and 10 were significantly higher than those of Compound 11. The exposure of Compound S1 in plasma and brain tissue of Compound 10 was the highest among the tested compounds.
Table 5
Data summary of Compound S1 in plasma and brain tissue after single intragastric administration of different compounds in mice
Example 26 Pharmacokinetic Test in Rats
In order to verify whether the compounds in the present invention can also significantly
increase the plasma exposure of Compound S1 in rats after intragastric administration, the following experiment of rats was conducted.
Male SD rats were administrated with 10 mg/kg Compound S1 of the published patent application (CN102895233A) and Compounds 3, 10, and 15 by single intragastric administration. Whole blood samples were collected at 0.25 h, 0.5 h, 1 h, 2 h, 4h, 6 h, 8 h, and 24h post-dose. Blood samples were placed on an ice box containing wet ice and centrifuged within 2 hours. The concentration of Compound S1 in plasma was measured by LC-MS/MS, and the results are shown in Table 6 and Figure 6.
The results showed that the Cmax of Compound S1 after single intragastric administration of Compound S1 and Compounds 3, 10, and 15 were 6.58, 259.94, 1701.18, and 65.86 ng/mL, respectively. The systemic exposure (AUC0-inf) of S1 were 31.82, 730.45, 3393.41, and 241.08 h*ng/mL, respectively. The Cmax of Compound S1 in plasma after intragastric administration of Compounds 3, 10, and 15 were about 39.50, 258.54, and 10.01 times to that of Compound S1, respectively. The AUC0-inf of S1 were 22.96, 106.64, and 7.58 times, respectively. The plasma exposure of Compound S1 after intragastric administration of Compounds 3, 10 and 15 was significantly increased compared with Compound S1. The systemic exposure of Compound S1 after intragastric administration of Compound 10 was significantly higher than that of Compound 3 and 15.
Table 6
Data summary of Compound S1 in plasma after single intragastric administration of different compounds in rats
Claims (8)
- Compound with the following structure or a pharmaceutically acceptable salt:
wherein R is selected from the following groups: -OC (=O) R1, -OC (=O) NR1R2, -OC (=O) NR1 (C1-C6 alkyl) NHC (=O) R2, -OC (=O) OR1, -OS (=O) 2NR1R2, -OP (=O) (OR1) 2, -B (OR1) 2 orwherein each R1 and R2 independently represent hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, Halogenated C1-C6 alkyl, -CH2- (C6-C10 aryl) , - (C6-C10 aryl) , - (5-10 membered heteroaryl) or-CH2- (5-10 membered heteroaryl) ; or R1 and R2 together with the atoms to which they are attached, form a 5-6 membered ring;wherein the aryl or heteroaryl group can be substituted with 0, 1, or 2 substituents selected from the following group: deuterated, halogen, C1-C6 alkyl, haloC1-C6 alkyl, cyano, -ORa, hydroxy (C1-C6 alkyl) , -NRaRb, nitro, -C (O) Ra, -OC (O) Ra, -C (O) NRaRb;wherein either of Ra or Rb can independently represent hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl. - The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R represents the following groups: -OC (=O) NR1R2;wherein R1 represents hydrogen or C1-C6 alkyl; R2 represents C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, -CH2- (C6-C10 aryl) or- (C6-C10 aryl) ; wherein the aryl or heteroaryl group may be optionally substituted with 0, 1, or 2 substituents selected from the following group: deuterated, halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl or cyano.
- The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 represents hydrogen; R2 represents C1-C6 alkyl, - (C6-C10 aryl) ; wherein the aryl or heteroaryl group may be optionally substituted with 0, 1, or 2 substituents selected from the group: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl or cyano.
- The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 represents hydrogen; R2 represents- (C6-C10 aryl) ; wherein the aryl group (s) may be optionally substituted with 0, 1, and 2 substituents selected from the group: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl or cyano.
- The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 represents hydrogen; R2 represents phenyl, which may be optionally substituted with 0, 1, or 2 substituents selected from the group: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl or cyano.
- Compound with the following structure or their pharmaceutically acceptable salts:
- A pharmaceutical composition comprising the compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof.
- The methods of treating or preventing central nervous system and cerebrovascular diseases comprising of administering an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 7 to a subject in need thereof.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202311540897 | 2023-11-17 | ||
CN202311540897.2 | 2023-11-17 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2024120555A2 true WO2024120555A2 (en) | 2024-06-13 |
Family
ID=91375976
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2024/087531 WO2024120555A2 (en) | 2023-11-17 | 2024-04-12 | Prodrugs of benzodiazepine compound and uses thereof |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2024120555A2 (en) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102895233A (en) | 2012-09-04 | 2013-01-30 | 苏州大学 | Application of benzoazepine compounds in preparation of drugs for prevention or treatment of epilepsy |
-
2024
- 2024-04-12 WO PCT/CN2024/087531 patent/WO2024120555A2/en unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102895233A (en) | 2012-09-04 | 2013-01-30 | 苏州大学 | Application of benzoazepine compounds in preparation of drugs for prevention or treatment of epilepsy |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US9688654B2 (en) | Compounds inhibiting leucine-rich repeat kinase enzyme activity | |
WO2021088945A1 (en) | Compound as shp2 inhibitor and use thereof | |
EP4293027A1 (en) | Pyrimidine aromatic ring compounds | |
WO2022135432A1 (en) | Macrocyclic heterocyclic compounds as egfr inhibitors, and use thereof | |
EP3684772B1 (en) | Cyclic iminopyrimidine derivatives as kinase inhibitors | |
KR20210031727A (en) | Tri-cyclic compounds fused as PDE3/PDE4 double inhibitors | |
WO2021238827A1 (en) | Egfr inhibitor and preparation method and use thereof | |
WO2018005801A2 (en) | Novel non-systemic tgr5 agonists | |
JP2010505747A (en) | Selective antagonist of A2A adenosine receptor | |
EP4332102A1 (en) | Isoquinolone compound and use thereof | |
EP3418277B1 (en) | Substituted amino six-membered nitric heterocyclic ring compound and preparation and use thereof | |
EP4273139A1 (en) | 2-pyridone derivative, and preparation method therefor and pharmaceutical application thereof | |
JP2021513549A (en) | Spiro compound as an indole-2,3-dioxygenase inhibitor | |
CN108884099B (en) | Crystal form of free base of imidazo isoindole derivative and preparation method thereof | |
WO2024120555A2 (en) | Prodrugs of benzodiazepine compound and uses thereof | |
WO2020135454A1 (en) | Class of steroid compounds and use thereof | |
CN111349077B (en) | Pyridazine derivative and preparation method and medical application thereof | |
WO2019001307A1 (en) | Amide compound, composition containing same, and use thereof | |
EP4067349A1 (en) | Fused pyridine ring derivative, preparation method therefor, and pharmaceutical use thereof | |
US20240083844A1 (en) | Kinase inhibitors and uses thereof | |
CN115433207A (en) | Macrocyclic heterocyclic compound as EGFR inhibitor and application thereof | |
EP4155304A1 (en) | Compound used as ret kinase inhibitor and application thereof | |
WO2021249324A1 (en) | Alkenyl pyrimidine compound, preparation method therefor, and application thereof | |
TW201400470A (en) | 4-alkanoylamino-3-pyrazolone derivatives | |
WO2024056091A1 (en) | Pyridonopyrimidine derivative as rsk inhibitor and use thereof |