CN114957332A - Avanafil phosphate compound and preparation method and application thereof - Google Patents
Avanafil phosphate compound and preparation method and application thereof Download PDFInfo
- Publication number
- CN114957332A CN114957332A CN202210595665.6A CN202210595665A CN114957332A CN 114957332 A CN114957332 A CN 114957332A CN 202210595665 A CN202210595665 A CN 202210595665A CN 114957332 A CN114957332 A CN 114957332A
- Authority
- CN
- China
- Prior art keywords
- avanafil
- formula
- reaction
- phosphate compound
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229960000307 avanafil Drugs 0.000 title claims abstract description 106
- -1 Avanafil phosphate compound Chemical class 0.000 title claims abstract description 65
- 229910019142 PO4 Inorganic materials 0.000 title claims abstract description 56
- 239000010452 phosphate Substances 0.000 title claims abstract description 55
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 60
- 150000001875 compounds Chemical class 0.000 claims abstract description 49
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 33
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 20
- 125000000547 substituted alkyl group Chemical group 0.000 claims abstract description 19
- 239000003814 drug Substances 0.000 claims abstract description 14
- 201000010099 disease Diseases 0.000 claims abstract description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 12
- 102000011016 Type 5 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 claims abstract description 9
- 108010037581 Type 5 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 claims abstract description 9
- 239000001257 hydrogen Substances 0.000 claims abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 5
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 5
- WEAJZXNPAWBCOA-INIZCTEOSA-N avanafil Chemical compound C1=C(Cl)C(OC)=CC=C1CNC1=NC(N2[C@@H](CCC2)CO)=NC=C1C(=O)NCC1=NC=CC=N1 WEAJZXNPAWBCOA-INIZCTEOSA-N 0.000 claims description 50
- 238000006243 chemical reaction Methods 0.000 claims description 37
- 239000002904 solvent Substances 0.000 claims description 29
- 238000006482 condensation reaction Methods 0.000 claims description 16
- 238000002156 mixing Methods 0.000 claims description 16
- 239000003513 alkali Substances 0.000 claims description 13
- 208000010228 Erectile Dysfunction Diseases 0.000 claims description 12
- 201000001881 impotence Diseases 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- 239000000047 product Substances 0.000 claims description 10
- 238000007254 oxidation reaction Methods 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 9
- 238000006264 debenzylation reaction Methods 0.000 claims description 8
- 230000035484 reaction time Effects 0.000 claims description 8
- 239000012295 chemical reaction liquid Substances 0.000 claims description 7
- 239000002585 base Substances 0.000 claims description 6
- 238000005886 esterification reaction Methods 0.000 claims description 6
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 5
- 239000003880 polar aprotic solvent Substances 0.000 claims description 5
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 claims description 4
- 206010020772 Hypertension Diseases 0.000 claims description 4
- 208000004403 Prostatic Hyperplasia Diseases 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 208000029078 coronary artery disease Diseases 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- 239000013067 intermediate product Substances 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 235000021317 phosphate Nutrition 0.000 claims 12
- 238000004519 manufacturing process Methods 0.000 claims 2
- 239000002671 adjuvant Substances 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 15
- 230000000694 effects Effects 0.000 abstract description 12
- 229940079593 drug Drugs 0.000 abstract description 11
- 230000009471 action Effects 0.000 abstract description 7
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 69
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 58
- 239000000243 solution Substances 0.000 description 28
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 238000010828 elution Methods 0.000 description 11
- 238000000746 purification Methods 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 239000007789 gas Substances 0.000 description 8
- 239000012046 mixed solvent Substances 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 description 6
- 229940123333 Phosphodiesterase 5 inhibitor Drugs 0.000 description 5
- 238000002835 absorbance Methods 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000002590 phosphodiesterase V inhibitor Substances 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 229910000318 alkali metal phosphate Inorganic materials 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 238000001819 mass spectrum Methods 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- SECKRCOLJRRGGV-UHFFFAOYSA-N Vardenafil Chemical compound CCCC1=NC(C)=C(C(N=2)=O)N1NC=2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(CC)CC1 SECKRCOLJRRGGV-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 3
- 150000008041 alkali metal carbonates Chemical class 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- YACKEPLHDIMKIO-UHFFFAOYSA-N methylphosphonic acid Chemical compound CP(O)(O)=O YACKEPLHDIMKIO-UHFFFAOYSA-N 0.000 description 3
- 229960003310 sildenafil Drugs 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 238000013268 sustained release Methods 0.000 description 3
- 239000012730 sustained-release form Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 150000003536 tetrazoles Chemical class 0.000 description 3
- 229960002381 vardenafil Drugs 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000005034 decoration Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 239000006199 nebulizer Substances 0.000 description 2
- 239000012454 non-polar solvent Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 description 2
- 235000011009 potassium phosphates Nutrition 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000001488 sodium phosphate Substances 0.000 description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 description 2
- 229960000835 tadalafil Drugs 0.000 description 2
- IEHKWSGCTWLXFU-IIBYNOLFSA-N tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C([C]4C=CC=CC4=N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 IEHKWSGCTWLXFU-IIBYNOLFSA-N 0.000 description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 2
- QWUWMCYKGHVNAV-UHFFFAOYSA-N 1,2-dihydrostilbene Chemical group C=1C=CC=CC=1CCC1=CC=CC=C1 QWUWMCYKGHVNAV-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 101100189582 Dictyostelium discoideum pdeD gene Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 101150098694 PDE5A gene Proteins 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- BPYBCKBGKAIOBH-UHFFFAOYSA-N [methyl(phenylmethoxy)phosphoryl]oxymethylbenzene Chemical compound C=1C=CC=CC=1COP(=O)(C)OCC1=CC=CC=C1 BPYBCKBGKAIOBH-UHFFFAOYSA-N 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 125000006267 biphenyl group Chemical group 0.000 description 1
- 102100029175 cGMP-specific 3',5'-cyclic phosphodiesterase Human genes 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- VONWDASPFIQPDY-UHFFFAOYSA-N dimethyl methylphosphonate Chemical compound COP(C)(=O)OC VONWDASPFIQPDY-UHFFFAOYSA-N 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 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
- 239000007791 liquid phase Substances 0.000 description 1
- 238000000622 liquid--liquid extraction Methods 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- CAAULPUQFIIOTL-UHFFFAOYSA-N methyl dihydrogen phosphate Chemical compound COP(O)(O)=O CAAULPUQFIIOTL-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000001050 pharmacotherapy Methods 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 229960000438 udenafil Drugs 0.000 description 1
- IYFNEFQTYQPVOC-UHFFFAOYSA-N udenafil Chemical compound C1=C(C=2NC=3C(CCC)=NN(C)C=3C(=O)N=2)C(OCCC)=CC=C1S(=O)(=O)NCCC1CCCN1C IYFNEFQTYQPVOC-UHFFFAOYSA-N 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Urology & Nephrology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Gynecology & Obstetrics (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the technical field of pharmaceutical compounds, and provides an avanafil phosphate compound, which has a structural formula shown in a formula I, wherein R in the formula I is hydrogen, phenyl, substituted phenyl, alkyl or substituted alkyl. The avanafil phosphate compound provided by the invention has good water solubility, long drug action time and good slow release effect, and has wide application prospect in preparing drugs for treating diseases related to phosphodiesterase 5. The invention also provides a preparation method of the avanafil phosphate compound in the scheme, and the preparation method provided by the invention is simple in steps and easy to operateTherefore, the method is suitable for large-scale production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical compounds, and particularly relates to an avanafil phosphate compound, and a preparation method and application thereof.
Background
Phosphodiesterase 5(PDE5) belongs to a superfamily of enzymes that catalyze the conversion of cGMP to GMP by a second messenger. PDE5 inhibitors are recommended as first-line drugs for the treatment of Erectile Dysfunction (ED) and, in addition, PDE5 inhibitors are also useful for the treatment of diseases such as hypertension, coronary heart disease and prostatic hyperplasia [ Chinese journal of pharmaceutical chemistry 2017.27.400-07 ]. According to survey statistics, about 15% of men aged 40 to 59 have ED, and 70% of men aged 60 and over 70 have ED, and the incidence of ED increases with age, as well as many other chronic diseases [ Am J Med.2021.134.310-16 ].
Avanafil is a selective PDE5 inhibitor approved by the U.S. FDA for the treatment of ED at month 4 of 2012. Currently, PDE5 inhibitors are also marketed as sildenafil, vardenafil, tadalafil, udenafil and milonafil. Clinical study data indicate that many ED patients can successfully perform sexual life within 30min after taking avanafil, sildenafil and vardenafil, the onset time after taking sildenafil and vardenafil is about 90min, and tadalafil is 2h [ pharmaceutical progress. 2012.36.135-36 ]. Therefore, avanafil's rapid-acting advantage is more favored by ED patients, has The same action mechanism as other PDE5 inhibitors on The market, but has unique pharmacokinetic and pharmacodynamic properties, faster oral absorption, higher selectivity, fewer side effects, and a lower rate of withdrawal of subjects of The product due to adverse reactions in long-term clinical trials [ The Annals of pharmacotherapy.2013.47.1312-20 ]. The accumulated data show that avanafil has better pharmacological action on ED and has good market response.
However, avanafil has the disadvantages of poor water solubility and short action time. Therefore, the development of water-soluble avanafil and avanafil prodrugs to prolong the duration of action of the drugs is of great value.
Disclosure of Invention
In view of the above, the invention provides an avanafil phosphate compound, and a preparation method and application thereof. The avanafil phosphate compound provided by the invention has good water solubility and long action time.
In order to achieve the above object, the present invention provides the following technical solutions:
an avanafil phosphate compound or a pharmaceutically acceptable salt thereof, wherein the avanafil phosphate compound has a structural formula shown in formula I:
in formula I: r is hydrogen, phenyl, substituted phenyl, alkyl or substituted alkyl;
the substituted phenyl is phenyl which is mono-substituted or polysubstituted at the ortho, meta and para positions;
the substituent on the substituted phenyl is halogen, nitro or alkyl;
the substituent on the substituted alkyl is halogen or cyano.
Preferably, R in formula I is any one of the following groups:
H、
preferably, the avanafil phosphate compound is any one of formula II to formula IV:
the invention also provides a preparation method of the avanafil phosphate compound in the scheme, which comprises a first method, a second method, a third method or a fourth method;
the first method comprises the following steps:
mixing avanafil, alkali, a solvent and a compound with a structure shown in a formula a for condensation reaction to obtain an avanafil phosphate compound with a structure shown in a formula I;
in the formula a, R is phenyl, substituted phenyl, alkyl or substituted alkyl;
the second method comprises the following steps:
mixing avanafil, alkali, a solvent and a compound with a structure shown in a formula b for condensation reaction to obtain an intermediate reaction solution; the intermediate product in the intermediate reaction liquid has a structure shown in a formula c;
mixing the intermediate reaction solution and the m-CPBA solution for oxidation reaction to obtain an avanafil phosphate compound with a structure shown in a formula I;
in formulae b and c: r is benzyl, phenyl, alkyl or substituted alkyl.
The third method comprises the following steps:
will (CH) 3 O) 3 PO、POCl 3 Mixing the compound with avanafil for esterification reaction to obtain an avanafil phosphate compound with a structure shown in a formula IV;
the fourth method comprises the following steps:
a compound with a structure shown in a formula III and BCl 3 And mixing the obtained product with a solvent for debenzylation reaction to obtain the avanafil phosphate compound with the structure shown in the formula IV.
Preferably, the solvent in the first and second methods is independently an apolar solvent or a polar aprotic solvent; the base in the first and second methods is independently an organic base or an inorganic base.
Preferably, in the first method, the condensation reaction is carried out at room temperature for 12-24 hours; in the second method, the condensation reaction is carried out at room temperature for 12-24 h; in the second method, the temperature of the oxidation reaction is room temperature, and the time is 4-12 h.
Preferably, in the third method, the esterification reaction is carried out at the temperature of 0-25 ℃ for 1-8 h; in the fourth method, the temperature of the debenzylation reaction is room temperature, and the reaction time is 12-48 h.
The invention also provides application of the avanafil phosphate compound or the pharmaceutically acceptable salt thereof in preparation of a medicament for treating diseases related to phosphodiesterase 5.
Preferably, the phosphodiesterase 5-related disease includes erectile dysfunction-related disease, hypertension, coronary heart disease or prostatic hyperplasia.
Preferably, when the compound is used, the avanafil phosphate compound or the pharmaceutically acceptable salt thereof is used alone or mixed with pharmaceutically acceptable auxiliary materials.
The invention provides an avanafil phosphate compound, and the structural formula is shown as a formula I. The avanafil phosphate compound provided by the invention has good water solubility due to the structure and polarity increase of phosphate, has long drug action time through the sustained release effect of the phosphate, and has wide application prospect in drugs for treating diseases related to phosphodiesterase 5.
The invention also provides a preparation method of the avanafil phosphate compound in the scheme, and the preparation method provided by the invention is simple in steps, easy to operate and suitable for large-scale production.
Drawings
FIG. 1 is a graph comparing the release effect of avanafil and the compound of the structure shown in formula II and formula III;
FIG. 2 is a graph comparing the effect of the release of avanafil from the gavage drug with a compound of formula IV.
Detailed Description
The invention provides an avanafil phosphate compound or a pharmaceutically acceptable salt thereof, wherein the structural formula of the avanafil phosphate compound is shown as a formula I:
in formula I: r is hydrogen, phenyl, substituted phenyl, alkyl or substituted alkyl;
the substituted phenyl is phenyl which is mono-substituted or polysubstituted at the ortho, meta and para positions;
the substituent on the substituted phenyl is halogen, nitro or alkyl;
the substituent on the substituted alkyl is halogen or cyano.
In the present invention, the substituted phenyl group is specifically preferably a mono-substituted phenyl group, a di-substituted phenyl group, or a tri-substituted phenyl group, and when the substituent on the substituted phenyl group is a halogen, the halogen is preferably fluorine, chlorine, or bromine, and when the substituent on the substituted phenyl group is an alkyl group, the number of carbon atoms of the alkyl group is preferably 1 to 18, more preferably 1 to 5, and specifically, the alkyl group is preferably a methyl group or an isobutyl group.
In the invention, when R is alkyl or substituted alkyl, the number of carbon atoms of the alkyl or substituted alkyl is preferably 1-18, and more preferably 1-10; the substituent on the substituted alkyl group is preferably halogen or cyano, and the halogen is preferably fluorine, chlorine or bromine.
In the present invention, R in the formula I is preferably any one of the following groups:
H、
in the present invention, the avanafil phosphate compound is preferably any one of the formulae II to IV:
in the invention, the chemical name of the compound with the structure shown in the formula II is as follows: (S) - (1- (4- ((3-chloro-4-methoxybenzyl) amino) 5- ((pyrimidin-2-methylidene) carbamoyl) -2-pyrimidinyl) -2-pyrrolidinyl) methylphosphonic acid dimethyl ester; the chemical name of the compound with the structure shown in the formula III is as follows: (S) - (1- (4- ((3-chloro-4-methoxybenzyl) amino) 5- ((pyrimidin-2-methylene) carbamoyl) -2-pyrimidinyl) -2-pyrrolidinyl) methylphosphonic acid dibenzyl ester; the chemical name of the compound with the structure shown in the formula IV is as follows: (S) - (1- (4- ((3-chloro-4-methoxybenzyl) amino) 5- ((pyrimidin-2-methylidene) carbamoyl) -2-pyrimidinyl) -2-pyrrolidinyl) methylphosphonic acid. In a specific embodiment of the present invention, the avanafil phosphate compound is most preferably a compound having a structure represented by formula IV.
The invention also provides a preparation method of the avanafil phosphate compound in the scheme, which comprises a first method, a second method, a third method and a fourth method, wherein the first method is used for preparing the avanafil phosphate compound when R is phenyl, substituted phenyl, alkyl or substituted alkyl, the second method is used for preparing the avanafil phosphate compound when R is benzyl, phenyl, alkyl or substituted alkyl, and the third method and the fourth method are used for preparing the avanafil phosphate compound when R is hydrogen (namely the avanafil phosphate compound shown in the formula IV). The following are detailed below:
in the present invention, the first method comprises the following steps:
mixing avanafil, alkali, a solvent and a compound with a structure shown in a formula a for condensation reaction to obtain an avanafil phosphate compound with a structure shown in a formula I;
in the formula a, R is phenyl, substituted phenyl, alkyl or substituted alkyl, and the kinds of the substituted phenyl and the substituted alkyl are consistent with the scheme, so the description is omitted.
In the present invention, the synthetic route of the first method is shown as the following formula:
in the present invention, the solvent used in the first method is preferably an apolar solvent or a polar aprotic solvent, and more preferably includes one or more of dichloromethane, 1, 2-dichloroethane, dioxane, tetrahydrofuran, N-dimethylacetamide, and dimethylsulfoxide; the alkali is preferably an inorganic alkali or an organic alkali, the inorganic alkali preferably comprises an alkali metal carbonate or an alkali metal phosphate, the alkali builder carbonate preferably comprises one or more of potassium carbonate, cesium carbonate and sodium carbonate, and the alkali metal phosphate preferably comprises one or two of potassium phosphate and sodium phosphate; the organic base preferably comprises one or more of pyridine, 4-dimethylaminopyridine, triethylamine, trimethylamine and tetrazole.
In the invention, in the first method, the molar ratio of avanafil to the base is preferably 1 (1.1-1.3), and more preferably 1: 1.2; the molar ratio of the avanafil to the compound with the structure shown in the formula a is preferably 1 (1.1-1.3), and more preferably 1: 1.2; the source of the compound having the structure shown in formula a is not particularly required in the present invention, and the compound can be synthesized by using the above-mentioned compounds which are commercially available or by using methods well known to those skilled in the art. The invention has no special requirements on the dosage of the solvent, and can ensure that the reaction is carried out smoothly.
In the invention, the condensation reaction in the first method is preferably carried out at room temperature, and the reaction time is preferably 12-24 h; the condensation reaction is preferably carried out under the protection of nitrogen; in the specific embodiment of the present invention, avanafil is preferably dissolved in a solvent, then an alkali is added, then an ice water bath is performed for cooling for 15min under the protection of nitrogen, a compound having a structure represented by formula a is added into a reaction solution by using a syringe, and then the temperature is naturally raised to room temperature for reaction. According to the invention, the TLC is preferably adopted to monitor the reaction, and the reaction is stopped after the raw materials are completely reacted; the TLC monitoring used a reagent that was a mixture of methanol and dichloromethane, preferably with a methanol volume fraction of 5%, reported as 5% MeOH/DCM.
After the reaction is finished, the solvent in the obtained reaction liquid is preferably evaporated to dryness to obtain a crude product, and then the crude product is subjected to silica gel column chromatography purification to obtain an avanafil phosphate compound with the structure shown in the formula I; in the invention, an elution reagent adopted by the silica gel column chromatography purification is a mixed solvent of methanol and dichloromethane, and the volume ratio of the methanol to the dichloromethane in the mixed solvent is preferably 1 (20-30).
In the present invention, the second method comprises the following steps:
mixing avanafil, alkali, a solvent and a compound with a structure shown in a formula b for condensation reaction to obtain an intermediate reaction solution; the intermediate product in the intermediate reaction liquid has a structure shown in a formula c;
mixing the intermediate reaction solution and the m-CPBA solution for oxidation reaction to obtain an avanafil phosphate compound with a structure shown in a formula I;
in formulae b and c: r is benzyl, phenyl, alkyl or substituted alkyl.
In the invention, the synthetic route of the second method is shown as the following formula:
the method comprises the steps of mixing avanafil, alkali, a solvent and a compound with a structure shown in a formula b for condensation reaction to obtain an intermediate reaction liquid. In the invention, the solvent used in the second method is preferably a non-polar solvent or a polar aprotic solvent, and more preferably comprises one or more of dichloromethane, 1, 2-dichloroethane, dioxane, tetrahydrofuran, N-dimethylacetamide and dimethyl sulfoxide; the base is preferably an inorganic base or an organic base, the inorganic base preferably comprises an alkali metal carbonate or an alkali metal phosphate, the alkali metal carbonate preferably comprises one or more of potassium carbonate, cesium carbonate and sodium carbonate, and the alkali metal phosphate preferably comprises one or two of potassium phosphate and sodium phosphate; the organic base preferably comprises one or more of pyridine, 4-dimethylamino pyridine, triethylamine, trimethylamine and tetrazole.
In the second method, the molar ratio of avanafil to the base is preferably 1 (1.1-1.3), and more preferably 1: 1.2; the molar ratio of the avanafil to the compound with the structure shown in the formula b is preferably 1 (1.1-1.3), and more preferably 1: 1.2; the compound having the structure shown in formula b is not particularly required to be sourced in the invention, and can be synthesized by using the above-mentioned compounds which are commercially available or by methods well known to those skilled in the art. The invention has no special requirements on the dosage of the solvent, and can ensure that the reaction is smoothly carried out.
In the invention, the temperature of the condensation reaction in the second method is preferably room temperature, the reaction time is preferably 12-24 h, and the condensation reaction is preferably carried out under the protection of nitrogen. In the embodiment of the present invention, avanafil is preferably dissolved in a solvent, then a base is added, and then the mixture is stirred for 5min under the protection of nitrogen, and a compound having a structure shown in formula b is added into the reaction solution by using a syringe and reacted under the stirring condition. After the reaction is finished, the reaction of the next step is directly carried out without any treatment.
After the intermediate reaction liquid is obtained, the intermediate reaction liquid and m-CPBA (m-chloroperoxybenzoic acid) solution are mixed for oxidation reaction, and the avanafil phosphate compound with the structure shown in the formula I is obtained. In the invention, the preference of the solvent adopted by the m-CPBA solution is consistent with that of the solvent adopted in the condensation reaction step, and the details are not repeated; the concentration of the m-CPBA solution is preferably 0.143 g/mL; the mass ratio of the m-CPBA to the avanafil is preferably (0.7-0.8): 1, and more preferably 0.715: 1.
In the invention, the temperature of the oxidation reaction is preferably room temperature, and the reaction time is preferably 4-12 h; in the specific embodiment of the invention, preferably, the intermediate reaction solution is transferred to a-78 ℃ cold trap to be cooled and stirred for 15min, then a constant pressure dropping funnel is adopted to add the m-CPBA solution, and after the dropping is finished, the temperature is naturally raised to the room temperature to carry out the oxidation reaction; according to the invention, the TLC is preferably adopted to monitor the reaction, and the reaction is stopped after the raw materials are completely reacted; the TLC monitoring used a reagent that was a mixture of methanol and dichloromethane, preferably with a methanol volume fraction of 5%, reported as 5% MeOH/DCM.
After the oxidation reaction is finished, preferably, the obtained product feed liquid and water are mixed and then layered, an aqueous layer is extracted by an organic solvent, the obtained organic layer is washed by saturated sodium chloride, dried by anhydrous sodium sulfate and evaporated to dryness in sequence to obtain a crude product, and the obtained crude product is subjected to silica gel column chromatography purification to obtain the avanafil phosphate compound with the structure shown in the formula I. In the present invention, the organic solvent for extraction is preferably dichloromethane, and the number of times of extraction is preferably 2; an elution reagent adopted by the silica gel column chromatography purification is a mixed solvent of methanol and dichloromethane, and the volume ratio of the methanol to the dichloromethane in the mixed solvent is preferably 1 (20-30).
In the present invention, the third method comprises the following steps:
will (CH) 3 O) 3 PO、POCl 3 Mixing with avanafil for esterification reaction to obtain an avanafil phosphate compound with a structure shown in a formula IV.
In the invention, the synthetic route of the third method is shown as the following formula:
in the present invention, the (CH) 3 O) 3 PO、POCl 3 And avanafil are preferably used in a ratio of 6mL:6mL:1 mol; the temperature of the esterification reaction is preferably 0-25 ℃, and the reaction time is preferably 1-8 h; in a particular embodiment of the invention, avanafil is added to (CH), preferably at 5 ℃ 3 O) 3 PO and POCl 3 Then, the mixture is rapidly stirred until the reaction is completed. After the reaction is completed, the present invention preferably quenches the reaction with ice water, and the obtained productAdjusting the pH value of the aqueous solution to 4-6 by NaOH, and then using C 18 Purifying the column to obtain an avanafil phosphate compound; said C is 18 The eluent used for column purification is preferably a mixed solvent of methanol and water, the volume ratio of the methanol to the water in the mixed solvent is preferably 1 (1-10), in the specific embodiment of the invention, the elution mode used for the C18 column purification is preferably gradient elution, and preferably the gradient elution is performed according to the volume ratio of the methanol to the water of 1:10, 2: 8: 3:7, 4: 6: gradient elution is carried out according to the ratio of 5:5 to 6:4, and components eluted when the volume ratio is 6:4 are collected.
In the present invention, the method four comprises the following steps:
a compound with a structure shown in a formula III and BCl 3 And mixing the obtained product with a solvent for debenzylation reaction to obtain the avanafil phosphate compound with the structure shown in the formula IV.
In the invention, the synthetic route of the method four is as follows:
in the invention, the solvent adopted by the method IV is preferably a non-polar solvent or a polar aprotic solvent, and more preferably comprises one or more of dichloromethane, 1, 2-dichloroethane, dioxane, tetrahydrofuran, N-dimethylacetamide and dimethyl sulfoxide; the compound with the structure shown in formula II and BCl 3 Is preferably 1: 12.5; the temperature of the debenzylation reaction is preferably room temperature, and the reaction time is preferably 12-48 h. In a specific embodiment of the present invention, it is preferable to first dissolve the compound having the structure represented by formula II in a solvent, and then add BCl at 0 deg.C 3 Heating the solution to room temperature for reaction, and monitoring by LC-MS until the reaction is finished; the BCl 3 The concentration of the solution is preferably 1mol/L, and the BCl 3 The solvent used for the solution is preferably the same as the solvent used for the debenzylation reaction, and will not be described in detail herein.
After the debenzylation reaction is completed, the invention preferably adds saturated carbonic acid into the obtained product feed liquidNeutralizing with sodium hydrogen solution, freeze drying to obtain crude product, and adding C to the crude product 18 Purifying the column to obtain an avanafil phosphate compound; said C is 18 The eluent adopted for column purification is preferably a mixed solvent of methanol and water, and the volume ratio of the methanol to the water in the mixed solvent is preferably 1 (1-10).
The invention also provides application of the avanafil phosphate compound or the pharmaceutically acceptable salt thereof in preparing a medicament for treating diseases related to phosphodiesterase 5; in the present invention, the phosphodiesterase 5-related disease preferably includes erectile dysfunction-related disease, hypertension, coronary heart disease or prostatic hyperplasia; in the application, the avanafil phosphate compound or the pharmaceutically acceptable salt thereof is preferably used alone or mixed with pharmaceutically acceptable auxiliary materials; the invention has no special requirement on the specific type of the auxiliary materials, and the auxiliary materials known by the technical personnel in the field can be adopted, such as excipient, diluent and the like, in the specific embodiment of the invention, the auxiliary materials are preferably adopted, and the avanafil phosphate compound or the pharmaceutically acceptable salt thereof is prepared into tablets, capsules, granules or syrup for oral administration.
The technical solutions in the present invention will be clearly and completely described below with reference to the embodiments of the present invention, but they should not be construed as limiting the scope of the present invention.
In the following examples, it is preferred that, 1 H-NMR was recorded using a JEOL JNM-ECZS 400 nuclear magnetic resonance apparatus, chemical shifts are expressed in delta (ppm); the silica gel for separation and purification is 200-300 mesh, the ratio of the eluent is volume ratio, and the used reagents are all commercial analytical purifiers if not specified.
Example 1
Preparation of dimethyl (S) - (1- (4- ((3-chloro-4-methoxybenzyl) amino) 5- ((pyrimidine-2-methylene) carbamoyl) -2-pyrimidinyl) -2-pyrrolidinyl) methyl phosphate (formula II)
Avanafil (2.0g,4.13mmol) was dissolved in DCM (50mL), Py (400mg,4.96mmol) was added under nitrogen, cooled in an ice water bath for 15min, O-dimethylphosphoryl chloride (720mg,4.96mmol) was added via syringe, allowed to warm to room temperature naturally, and stirred overnight. The reaction was monitored by TLC (5% MeOH/DCM) and stopped after the starting material had reacted completely, the solvent was evaporated directly to dryness and column chromatography was performed with 4-5% MeOH/DCM to give 1.64g of a yellow oil in 67.2% yield.
1 H NMR(400MHz,Chloroform-d)δ9.02(t,J＝5.9Hz,1H),8.69(d,J＝4.9Hz,2H),8.39(d,J＝11.5Hz,1H),7.44–7.28(m,2H),7.23–7.12(m,2H),6.83(d,J＝7.8Hz,1H),4.75(d,J＝4.5Hz,2H),4.66–4.45(m,2H),4.38–4.22(m,2H),3.83(s,3H),3.76–3.44(m,9H),2.16–1.87(m,4H).HPLC-MS(ESI + ):[M+H] + :593.0
Example 2
Preparation of dibenzyl (S) - (1- (4- ((3-chloro-4-methoxybenzyl) amino) 5- ((pyrimidin-2-methylene) carbamoyl) -2-pyrimidinyl) -2-pyrrolidinyl) methylphosphonate (formula III) the reaction scheme is as follows:
avanafil (2.0g,4.13mmol) was dissolved in DCM (50mL), tetrazole (350mg,4.96mmol) was added under nitrogen, stirring was carried out at room temperature for 5min, diphenyl N, N' -diisopropylphosphoramidite (1.72g,4.96mmol) was added via syringe, and stirring was carried out overnight. Transferring the reaction solution to a cold trap at-78 ℃, cooling and stirring for 15min, adding a dichloromethane solution (1.43g,10mL DCM) of m-CPBA into a constant-pressure dropping funnel, dropwise adding the m-CPBA into the reaction solution, and naturally heating to room temperature after dropwise adding. The reaction was monitored by TLC (5% MeOH/DCM) and stopped after 6h at RT. 100mL of water is added for liquid separation, 50mL of DCM is used as an aqueous layer for extraction, dichloromethane layers are combined, 50mL of saturated sodium chloride is used for washing by 1, anhydrous sodium sulfate is dried and evaporated to dryness, and the yellow oily product is obtained by 3% MeOH/DCM column chromatography purification, wherein the yield is 55.4%.
1 H NMR(400MHz,Chloroform-d)δ9.28–9.11(m,1H),8.69(d,J＝5.0Hz,2H),8.59(s,1H),7.95(t,J＝1.9Hz,1H),7.87(dd,J＝7.7,1.5Hz,1H),7.84–7.74(m,1H),7.45–7.39(m,1H),7.31(d,J＝11.4Hz,2H),7.25(d,J＝7.7Hz,3H),7.19(t,J＝5.0Hz,2H),7.07(td,J＝9.1,3.5Hz,1H),6.76(d,J＝8.8Hz,1H),5.25(s,1H),4.98(td,J＝9.0,3.2Hz,4H),4.79(d,J＝4.9Hz,2H),4.52(p,J＝7.4,6.6Hz,1H),4.32–4.18(m,2H),4.07–3.89(m,1H),3.79(d,J＝13.2Hz,3H),3.72–3.41(m,2H),2.03–1.82(m,4H).HPLC-MS(ESI + ):[M+H] + :745.1
Example 3
Preparation of (S) - (1- (4- ((3-chloro-4-methoxybenzyl) amino) 5- ((pyrimidin-2-methylidene) carbamoyl) -2-pyrimidinyl) -2-pyrrolidinyl) methylphosphonic acid (compound III). Prepared using scheme 1 and scheme 2, respectively, the reaction of scheme 1 is as follows:
at 5 deg.C of (CH) 3 O) 3 PO (6mL) and POCl 3 To a solution (6mL, 40mmol) was added avanafil (1.0g, 2.0mmol) and stirred rapidly. After the reaction is completed, quenching the reaction by ice water, adjusting the pH of the obtained aqueous solution to 4-6(pH test paper is yellow) by NaOH, and directly loading the sample C 18 Column, water 400mL elution, methanol 200mL elution to get the product, methanol rotary evaporation to 50mL, standing crystallization to get 1.4g product, yield 62%.
The reaction of scheme 2 is as follows:
compound II (1.0g, 1.3mmol) was dissolved in DCM (20mL) and 1mol/L BCl was added at 0 deg.C 3 The solution (16.25mL) was stirred at room temperature for 2 days. Monitoring the reaction by LC-MS, adding saturated sodium bicarbonate to adjust pH to 7 after the reaction is completed, freeze-drying the reaction solution, and using C 18 Column MeOH: h 2 Gradient elution purification with 1: 10-3: 2O gave 300mg of white solid product with a yield of 40.8%.
1 H NMR(400MHz,DMSO-d 6 )δ9.14(dt,J＝11.6,6.0Hz,1H),8.82(dt,J＝11.8,5.8Hz,1H),8.75(d,J＝4.9Hz,2H),8.54(d,J＝4.2Hz,1H),7.37(dd,J＝8.6,3.7Hz,2H),7.34–7.23(m,1H),7.07(t,J＝7.5Hz,1H),4.57(d,J＝5.9Hz,3H),4.29–3.89(m,5H),3.80(s,3H),3.65–3.37(m,3H),2.11–1.71(m,4H).HPLC-MS(ESI+):[M+H] + :564.1.
Test example 1 Water solubility test
1. Provision of standard curves
Weighing 500mg of the sample, grinding the sample in a mortar for 5min, weighing 24.57mg in a 50mL volumetric flask, diluting the sample to the scale with methanol, and dissolving the sample by ultrasound for 5 min. The mother liquor solubility obtained was 0.4914mg/mL, and the mother liquor was diluted according to the proportions in Table 1 to give a linear solution.
TABLE 1 dilution ratio of mother liquors
2. The standard curve is measured by a UV instrument
UV model: SHIMADZU UV-2550UV-visible spectrophotometer
Detection wavelength: 260nm
The standard curve obtained by the test is: y 0.0248x +0.0185, R 2 0.9984, r 0.9992, wherein y is solubility and x is absorbance;
3. precisely weighing a sample to be tested (about 20 mg), adding pure water to fix the volume to 2mL, carrying out vortex dissolution for 20 seconds, filtering the sample by using a 0.22-micron filter membrane, diluting the filtrate by 100 times with water to be tested (pipetting a 100-10 mL volumetric flask to fix the volume), testing absorbance at a wavelength of 260nm, substituting the test result into a standard curve, and calculating the solubility.
The test results were as follows:
a compound of formula II: absorbance: 0.476, solubility: 18.44. mu.g/mL multiplied by the dilution factor 100, solubility 1.872 mg/mL. A compound of formula III: absorbance 0.481, solubility: 18.65. mu.g/mL, multiplied by the dilution factor 100, solubility: 1.840 mg/mL. A compound of formula IV: absorbance of 0.869, solubility: 34.29. mu.g/mL multiplied by the dilution factor 100, solubility 3.392 mg/mL.
Test example 2 biological Activity test
The activity of the compounds of the invention was assessed by testing the rate of release of avanafil in rats.
The experimental principle and method are as follows: plasma concentrations of avanafil and avanafil phosphate derivative compounds were compared in rats after intraperitoneal administration based on ultra performance liquid-mass spectrometry (LC-MS).
The experimental method comprises the following steps:
(1) liquid sample preparation: after consulting the avanafil pharmacokinetic literature, it is difficult to detect avanafil proto-drug after 6h, so this experiment chose to detect blood samples within 1h of intraperitoneal administration. By liquid-liquid extraction, 300 μ L of serum and 300 μ L of ethyl acetate were placed in a clean EP tube, vortexed, the supernatant was aspirated, repeated three times, and the supernatants were combined. After the supernatant was vacuum dried, the residue was redissolved in 200. mu.L of 75% acetonitrile, centrifuged at high speed (18000g, 4 ℃) for 20min at low temperature, 150. mu.L of the resulting solution was aspirated, and the resulting solution was placed in a sample vial for analysis.
(2) Liquid phase analysis conditions:
chromatographic conditions are as follows: the chromatographic column is AgilentZORBAX Eclipse Plus C 18 Column (2.1X 100mm,1.8 μm), mobile phase A0.1% aqueous formic acid, mobile phase B acetonitrile, gradient elution according to the following Table 1, flow rate of 0.4mL/min, column temperature of 25 ℃, sample volume: 2 μ L.
TABLE 1 gradient elution procedure (volume fraction)
(3) Mass spectrum conditions: application of ESI + For positive mode detection, the Gas temperature (Gas temp.) was 325 ℃, the Drying Gas (Drying Gas) was 8L/min, the Nebulizer (Nebulizer) was 35psi, the Sheath Gas temperature (shear Gas temp.) was 350 ℃, the Sheath Gas Flow rate (Aux Gas Flow) was 11L/min, the capillary voltage (VCap) was 4000V, the fragmentation voltage (Fragment) was 150V, the separator (Skimmer) was 65V, and the Oct 1RF Vpp was 750V. Using ESI-L Low Concentration tuning Mix (G1969-8500) corrects the exact mass number. Primary mass spectrum scanning range: m/z is 50-1100; and (3) selecting the first 3 intensities on the basis of primary scanning to perform induced collision dissociation (CID) to obtain secondary mass spectrum data.
The experimental results are as follows:
optimizing the chromatographic mass spectrum: avanafil belongs to heterocyclic compound containing nitrogen heteroatom (structural formula is shown in formula V), and molecular formula is C 23 H 27 ClN 7 O 3 Accurate molecular weight 483.1858Da at ESI + Chromatographic peak response at state superior to ESI - Chromatographic peak at state. Therefore [ M + H ] was chosen to monitor avanafil] + The chromatographic peak of 484.1858 showed a peak at 7.88min in the chromatogram, and no other interference of hetero z9hi around this retention time, indicating good chromatographic specificity.
The results of comparing the release effects of avanafil phosphate compounds and avanafil gastric lavage drugs are shown in fig. 1-fig. 2, fig. 1 is a comparison of the release effects of avanafil gastric lavage drugs with compounds having structures shown in formulas II and III, and fig. 2 is a comparison of the release effects of avanafil gastric lavage drugs with compounds having structures shown in formula IV; in fig. 1 to 2, AV represents an avanafil prodrug, II, III, and IV represent compounds having structures represented by formulae II, III, and IV, and are subsequently represented as compound (II), compound (III), and compound (IV).
As can be seen from fig. 1, avanafil 1h begins to decrease in blood concentration compared to avanafil 0.5h, indicating that avanafil enters the excretory phase. The blood concentration of avanafil started to rise for 1h of compound (II) compared to 0.5h of compound (II), indicating that avanafil is in the absorption phase. Thus indicating that compound (II) may have some sustained release effect; the 1h of compound (III) compared to 0.5h of compound (III) began to decrease in avanafil blood concentration, indicating that compound (III) entered the excretory phase with no sustained release effect. Compared with the compound (IV) for 0.5h, the blood concentration of the avanafil begins to rise in 1h of the compound (IV), which indicates that the avanafil is in an absorption phase, and the blood concentration of 1h reaches 80% of that of the avanafil, so that the derivative compound (IV) has a good slow release effect.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (10)
1. An avanafil phosphate compound or a pharmaceutically acceptable salt thereof, wherein the avanafil phosphate compound has a structural formula shown in formula I:
in formula I: r is hydrogen, phenyl, substituted phenyl, alkyl or substituted alkyl;
the substituted phenyl is phenyl which is mono-substituted or polysubstituted at the ortho, meta and para positions;
the substituent on the substituted phenyl is halogen, nitro or alkyl;
the substituent on the substituted alkyl is halogen or cyano.
2. Avanafil phosphate compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R in formula I is any one of the following groups:
H、
3. the avanafil phosphate compound or the pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the avanafil phosphate compound is any one of formula II to formula IV:
4. a process for preparing avanafil phosphates as claimed in any of claims 1 to 3, which comprises process one, process two, process three or process four;
the first method comprises the following steps:
mixing avanafil, alkali, a solvent and a compound with a structure shown in a formula a for condensation reaction to obtain an avanafil phosphate compound with a structure shown in a formula I;
in the formula a, R is phenyl, substituted phenyl, alkyl or substituted alkyl;
the second method comprises the following steps:
mixing avanafil, alkali, a solvent and a compound with a structure shown in a formula b for condensation reaction to obtain an intermediate reaction solution; the intermediate product in the intermediate reaction liquid has a structure shown in a formula c;
mixing the intermediate reaction solution and the m-CPBA solution for oxidation reaction to obtain an avanafil phosphate compound with a structure shown in a formula I;
in formulae b and c: r is benzyl, phenyl, alkyl or substituted alkyl.
The third method comprises the following steps:
will (CH) 3 O) 3 PO、POCl 3 Mixing the obtained product with avanafil for esterification reaction to obtain an avanafil phosphate compound with a structure shown in a formula IV;
the fourth method comprises the following steps:
a compound with a structure shown in a formula III and BCl 3 And mixing the obtained product with a solvent for debenzylation reaction to obtain the avanafil phosphate compound with the structure shown in the formula IV.
5. The process according to claim 4, wherein the solvent in the first and second processes is independently an apolar solvent or a polar aprotic solvent; the base in the first and second methods is independently an organic base or an inorganic base.
6. The preparation method according to claim 4, wherein the condensation reaction in the first method is performed at room temperature for 12-24 h; in the second method, the condensation reaction is carried out at room temperature for 12-24 h; in the second method, the temperature of the oxidation reaction is room temperature, and the time is 4-12 h.
7. The preparation method according to claim 5, wherein the temperature of the esterification reaction in the third method is 0-25 ℃, and the reaction time is 1-8 h; in the fourth method, the temperature of the debenzylation reaction is room temperature, and the reaction time is 12-48 h.
8. Use of an avanafil phosphate compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3 in the manufacture of a medicament for the treatment of a phosphodiesterase 5 related disease.
9. The use of claim 8, wherein the phosphodiesterase 5-related disease comprises erectile dysfunction-related disease, hypertension, coronary heart disease or prostatic hyperplasia.
10. The use according to claim 8, wherein the avanafil phosphate compound or the pharmaceutically acceptable salt thereof is used alone or in combination with a pharmaceutically acceptable adjuvant.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210595665.6A CN114957332A (en) | 2022-05-30 | 2022-05-30 | Avanafil phosphate compound and preparation method and application thereof |
| PCT/CN2022/122414 WO2023231254A1 (en) | 2022-05-30 | 2022-09-29 | Avanafil phosphate compounds as well as preparation method therefor and use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210595665.6A CN114957332A (en) | 2022-05-30 | 2022-05-30 | Avanafil phosphate compound and preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114957332A true CN114957332A (en) | 2022-08-30 |
Family
ID=82958646
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210595665.6A Pending CN114957332A (en) | 2022-05-30 | 2022-05-30 | Avanafil phosphate compound and preparation method and application thereof |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN114957332A (en) |
| WO (1) | WO2023231254A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023231254A1 (en) * | 2022-05-30 | 2023-12-07 | 苏州正永生物医药有限公司 | Avanafil phosphate compounds as well as preparation method therefor and use thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070099942A1 (en) * | 2004-06-22 | 2007-05-03 | Biocryst Pharmaceuticals, Inc. | AZA nucleosides, preparation thereof and use as inhibitors of RNA viral polymerases |
| WO2008097819A2 (en) * | 2007-02-05 | 2008-08-14 | Smithkline Beecham Corporation | Chemical compounds |
| WO2011030351A2 (en) * | 2009-09-03 | 2011-03-17 | Rubicon Research Private Limited | Taste - masked pharmaceutical compositions |
| US20160075693A1 (en) * | 2013-05-23 | 2016-03-17 | Suzhou Miracpharma Technology Co., Ltd. | Avanafil preparation method |
| WO2021226584A1 (en) * | 2020-05-08 | 2021-11-11 | University Of Southern California | Site-specific antibody-drug conjugates by adp-ribosyl cyclases |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101100474B (en) * | 2006-07-03 | 2011-06-08 | 上海阳帆医药科技有限公司 | Fluoroquinolone compound containing phosphate ester group and its preparation method and use |
| CN102229608B (en) * | 2011-08-10 | 2013-02-27 | 上海清松制药有限公司 | Improved method for preparing entecavir |
| CN104710411B (en) * | 2015-03-13 | 2017-04-26 | 安润医药科技（苏州）有限公司 | Synthesis method of avanafil |
| CN112521421A (en) * | 2020-12-07 | 2021-03-19 | 商河探荣新技术开发中心 | Preparation method of pharmaceutical compound |
| CN114249788B (en) * | 2021-12-17 | 2023-08-08 | 河南师范大学 | Non-natural base nucleotide phosphate monoester prodrug molecule and preparation method and application thereof |
| CN114957332A (en) * | 2022-05-30 | 2022-08-30 | 苏州正永生物医药有限公司 | Avanafil phosphate compound and preparation method and application thereof |
-
2022
- 2022-05-30 CN CN202210595665.6A patent/CN114957332A/en active Pending
- 2022-09-29 WO PCT/CN2022/122414 patent/WO2023231254A1/en unknown
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070099942A1 (en) * | 2004-06-22 | 2007-05-03 | Biocryst Pharmaceuticals, Inc. | AZA nucleosides, preparation thereof and use as inhibitors of RNA viral polymerases |
| WO2008097819A2 (en) * | 2007-02-05 | 2008-08-14 | Smithkline Beecham Corporation | Chemical compounds |
| WO2011030351A2 (en) * | 2009-09-03 | 2011-03-17 | Rubicon Research Private Limited | Taste - masked pharmaceutical compositions |
| US20160075693A1 (en) * | 2013-05-23 | 2016-03-17 | Suzhou Miracpharma Technology Co., Ltd. | Avanafil preparation method |
| WO2021226584A1 (en) * | 2020-05-08 | 2021-11-11 | University Of Southern California | Site-specific antibody-drug conjugates by adp-ribosyl cyclases |
Non-Patent Citations (3)
| Title |
|---|
| 姬勋等: "磷酸酯前药在药物研究中的应用", 《药学学报》, vol. 48, no. 5, pages 621 - 634 * |
| 段艳冰等: "磷酸酯化在新药开发中的应用", 《医药导报》, vol. 30, no. 8, pages 1056 - 1057 * |
| 龚智华等: "磷酸酯类前药的合成方法与应用", 《化学进展》, vol. 34, no. 9, pages 1972 - 1981 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023231254A1 (en) * | 2022-05-30 | 2023-12-07 | 苏州正永生物医药有限公司 | Avanafil phosphate compounds as well as preparation method therefor and use thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2023231254A1 (en) | 2023-12-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110092745B (en) | Compound containing aromatic ring and application thereof | |
| CN112424185B (en) | Benzene ring-containing compound, preparation method and application thereof | |
| CN111362967B (en) | Benzoxadiazatetetradecene derivatives and use thereof | |
| JPH07508028A (en) | 6-amino-substituted imidazo[4,5-b]pyridine as angiotensin 2 antagonist | |
| TWI721104B (en) | 6-aryl or 6-heteroaryl 4-morpholin-4-yl-pyridine-2-one compounds | |
| JP7491896B2 (en) | Fused tricyclic compounds as dual PDE3/PDE4 inhibitors | |
| CN112920201A (en) | Macrocyclic compound and composition containing same | |
| CN110759908A (en) | N-benzenesulfonyl benzamide compound for inhibiting Bcl-2 protein and composition and application thereof | |
| CN113365631A (en) | Bruton's tyrosine kinase inhibitors | |
| WO2023231254A1 (en) | Avanafil phosphate compounds as well as preparation method therefor and use thereof | |
| Zhao et al. | Pyrrolo [2, 3-b] pyridine derivatives as potent Bruton’s tyrosine kinase inhibitors | |
| EP1922319A2 (en) | Pure paliperidone and processes for preparing thereof | |
| EP3560928B1 (en) | Fused imidazole compound having indoleamine 2,3-dioxygenase inhibitory activity | |
| CN110857300B (en) | Condensed ring triazole compounds, preparation method and application | |
| EP3567028A1 (en) | Biphenyl compound as ccr2/ccr5 receptor antagonist | |
| EP4092022A1 (en) | Crystal of pde3/pde4 dual inhibitor and use thereof | |
| CN108350007B (en) | Substituted adenine compound and pharmaceutical composition thereof | |
| CN111087408B (en) | Macrocyclic IDH2 mutant inhibitor and medical application thereof | |
| CN114621256A (en) | Pyrazolo [1,5-a ] pyridine compound and preparation method and application thereof | |
| CN112028880A (en) | Oxitinib dimer, preparation method and application thereof | |
| CN109734716B (en) | Doxofylline impurity and preparation method thereof | |
| WO2022089604A1 (en) | New crystalline forms of a kras g12c inhibitor compound | |
| CN108794448A (en) | The preparation method of one koji Ge Lieting and its salt | |
| CN117460726A (en) | Novel solid forms of (3R) -N- [ 2-cyano-4-fluoro-3- (3-methyl-4-oxo-quinazolin-6-yl) oxy-phenyl ] -3-fluoro-pyrrolidine-1-sulfonamide | |
| EP3666767B1 (en) | Phthalazinone derivatives, method for their preparation thereof, pharmaceutical composition comprising them, and their use |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |