CN101914100B - Benzenesulfonyl lupetazin derivative and preparation method thereof - Google Patents
Benzenesulfonyl lupetazin derivative and preparation method thereof Download PDFInfo
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- CN101914100B CN101914100B CN 201010145986 CN201010145986A CN101914100B CN 101914100 B CN101914100 B CN 101914100B CN 201010145986 CN201010145986 CN 201010145986 CN 201010145986 A CN201010145986 A CN 201010145986A CN 101914100 B CN101914100 B CN 101914100B
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- Prior art keywords
- lupetazin
- benzenesulfonyl
- add
- polar solvent
- sodium
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- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 title claims abstract description 194
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 150000003839 salts Chemical class 0.000 claims abstract description 80
- 239000002253 acid Substances 0.000 claims abstract description 39
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims abstract description 14
- 229910019142 PO4 Inorganic materials 0.000 claims abstract description 9
- 239000010452 phosphate Substances 0.000 claims abstract description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims abstract description 8
- 239000007787 solid Substances 0.000 claims description 74
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 45
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 38
- 238000001035 drying Methods 0.000 claims description 38
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 35
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 31
- 239000002798 polar solvent Substances 0.000 claims description 30
- 238000001914 filtration Methods 0.000 claims description 28
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 22
- 229910052792 caesium Inorganic materials 0.000 claims description 18
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 claims description 18
- JXAZAUKOWVKTLO-UHFFFAOYSA-L sodium pyrosulfate Chemical compound [Na+].[Na+].[O-]S(=O)(=O)OS([O-])(=O)=O JXAZAUKOWVKTLO-UHFFFAOYSA-L 0.000 claims description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 16
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 claims description 16
- 238000002425 crystallisation Methods 0.000 claims description 15
- 230000008025 crystallization Effects 0.000 claims description 15
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 14
- 229910052700 potassium Inorganic materials 0.000 claims description 14
- 239000011591 potassium Substances 0.000 claims description 14
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 13
- 239000011734 sodium Substances 0.000 claims description 10
- 229940045641 monobasic sodium phosphate Drugs 0.000 claims description 9
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 9
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 8
- 229910052708 sodium Inorganic materials 0.000 claims description 8
- 150000003868 ammonium compounds Chemical class 0.000 claims description 7
- QPTUMKXXAAHOOE-UHFFFAOYSA-M cesium;hydron;phosphate Chemical compound [Cs+].OP(O)([O-])=O QPTUMKXXAAHOOE-UHFFFAOYSA-M 0.000 claims description 7
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- BIGPRXCJEDHCLP-UHFFFAOYSA-N ammonium bisulfate Chemical compound [NH4+].OS([O-])(=O)=O BIGPRXCJEDHCLP-UHFFFAOYSA-N 0.000 claims description 6
- LFVGISIMTYGQHF-UHFFFAOYSA-N ammonium dihydrogen phosphate Chemical compound [NH4+].OP(O)([O-])=O LFVGISIMTYGQHF-UHFFFAOYSA-N 0.000 claims description 6
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 150000001339 alkali metal compounds Chemical class 0.000 claims description 5
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 5
- MEAHOQPOZNHISZ-UHFFFAOYSA-M cesium;hydrogen sulfate Chemical compound [Cs+].OS([O-])(=O)=O MEAHOQPOZNHISZ-UHFFFAOYSA-M 0.000 claims description 5
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 229910052728 basic metal Inorganic materials 0.000 claims description 4
- 150000003818 basic metals Chemical class 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 3
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 3
- 239000005695 Ammonium acetate Substances 0.000 claims description 3
- GHVZOJONCUEWAV-UHFFFAOYSA-N [K].CCO Chemical compound [K].CCO GHVZOJONCUEWAV-UHFFFAOYSA-N 0.000 claims description 3
- 235000019257 ammonium acetate Nutrition 0.000 claims description 3
- 229940043376 ammonium acetate Drugs 0.000 claims description 3
- XJMWHXZUIGHOBA-UHFFFAOYSA-N azane;propanoic acid Chemical compound N.CCC(O)=O XJMWHXZUIGHOBA-UHFFFAOYSA-N 0.000 claims description 3
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- YNTQKXBRXYIAHM-UHFFFAOYSA-N azanium;butanoate Chemical compound [NH4+].CCCC([O-])=O YNTQKXBRXYIAHM-UHFFFAOYSA-N 0.000 claims description 2
- ZOAIGCHJWKDIPJ-UHFFFAOYSA-M caesium acetate Chemical compound [Cs+].CC([O-])=O ZOAIGCHJWKDIPJ-UHFFFAOYSA-M 0.000 claims description 2
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 2
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 2
- BWILYWWHXDGKQA-UHFFFAOYSA-M potassium propanoate Chemical compound [K+].CCC([O-])=O BWILYWWHXDGKQA-UHFFFAOYSA-M 0.000 claims description 2
- 239000004331 potassium propionate Substances 0.000 claims description 2
- 235000010332 potassium propionate Nutrition 0.000 claims description 2
- RWMKSKOZLCXHOK-UHFFFAOYSA-M potassium;butanoate Chemical compound [K+].CCCC([O-])=O RWMKSKOZLCXHOK-UHFFFAOYSA-M 0.000 claims description 2
- WQKGAJDYBZOFSR-UHFFFAOYSA-N potassium;propan-2-olate Chemical compound [K+].CC(C)[O-] WQKGAJDYBZOFSR-UHFFFAOYSA-N 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- LMHHRCOWPQNFTF-UHFFFAOYSA-N s-propan-2-yl azepane-1-carbothioate Chemical compound CC(C)SC(=O)N1CCCCCC1 LMHHRCOWPQNFTF-UHFFFAOYSA-N 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 229960004249 sodium acetate Drugs 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- MFBOGIVSZKQAPD-UHFFFAOYSA-M sodium butyrate Chemical compound [Na+].CCCC([O-])=O MFBOGIVSZKQAPD-UHFFFAOYSA-M 0.000 claims description 2
- JXKPEJDQGNYQSM-UHFFFAOYSA-M sodium propionate Chemical compound [Na+].CCC([O-])=O JXKPEJDQGNYQSM-UHFFFAOYSA-M 0.000 claims description 2
- 239000004324 sodium propionate Substances 0.000 claims description 2
- 235000010334 sodium propionate Nutrition 0.000 claims description 2
- 229960003212 sodium propionate Drugs 0.000 claims description 2
- SYXYWTXQFUUWLP-UHFFFAOYSA-N sodium;butan-1-olate Chemical compound [Na+].CCCC[O-] SYXYWTXQFUUWLP-UHFFFAOYSA-N 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 7
- 150000001413 amino acids Chemical class 0.000 abstract description 6
- 150000001414 amino alcohols Chemical class 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 6
- 229910052783 alkali metal Inorganic materials 0.000 abstract description 4
- -1 ammonia (ammonium) compound Chemical class 0.000 abstract description 4
- 239000008280 blood Substances 0.000 abstract description 3
- 210000004369 blood Anatomy 0.000 abstract description 3
- 208000010228 Erectile Dysfunction Diseases 0.000 abstract 1
- 201000001881 impotence Diseases 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 238000011084 recovery Methods 0.000 description 34
- 238000003756 stirring Methods 0.000 description 34
- 238000002156 mixing Methods 0.000 description 26
- 238000005406 washing Methods 0.000 description 19
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 13
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 13
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 13
- 150000003016 phosphoric acids Chemical class 0.000 description 13
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 12
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 8
- 239000003208 petroleum Substances 0.000 description 7
- 229910021529 ammonia Inorganic materials 0.000 description 6
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 5
- RHGKLRLOHDJJDR-BYPYZUCNSA-N L-citrulline Chemical compound NC(=O)NCCC[C@H]([NH3+])C([O-])=O RHGKLRLOHDJJDR-BYPYZUCNSA-N 0.000 description 5
- RHGKLRLOHDJJDR-UHFFFAOYSA-N Ndelta-carbamoyl-DL-ornithine Natural products OC(=O)C(N)CCCNC(N)=O RHGKLRLOHDJJDR-UHFFFAOYSA-N 0.000 description 5
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 5
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 5
- 235000001014 amino acid Nutrition 0.000 description 5
- 229960002173 citrulline Drugs 0.000 description 5
- 235000013477 citrulline Nutrition 0.000 description 5
- 229960003104 ornithine Drugs 0.000 description 5
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 4
- XUYPXLNMDZIRQH-LURJTMIESA-N N-acetyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC(C)=O XUYPXLNMDZIRQH-LURJTMIESA-N 0.000 description 4
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 229960002442 glucosamine Drugs 0.000 description 4
- 229930182817 methionine Natural products 0.000 description 4
- ZGCHLAJIRWDGFE-UHFFFAOYSA-N 1-aminopropane-1,1-diol Chemical compound CCC(N)(O)O ZGCHLAJIRWDGFE-UHFFFAOYSA-N 0.000 description 3
- 150000001340 alkali metals Chemical class 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000003304 gavage Methods 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- MCSJGXLZPITMIH-UHFFFAOYSA-N 2-aminobutane-1,1,1-triol Chemical compound CCC(N)C(O)(O)O MCSJGXLZPITMIH-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 0 CCOc(c(C(NC1=O)=NC(C(*)=N)=C1[N+]C)c1)ccc1S(N1CC(C)NC(C)C1)(=O)=O Chemical compound CCOc(c(C(NC1=O)=NC(C(*)=N)=C1[N+]C)c1)ccc1S(N1CC(C)NC(C)C1)(=O)=O 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- ZATDRGTYIJCRBA-WCCKRBBISA-N (2s)-2-amino-4-methylsulfanylbutanoic acid;sulfuric acid Chemical compound OS(O)(=O)=O.CSCC[C@H](N)C(O)=O ZATDRGTYIJCRBA-WCCKRBBISA-N 0.000 description 1
- UZUMQQZPGOFJBQ-UHFFFAOYSA-N 1-aminopropane-1,2-diol Chemical compound CC(O)C(N)O UZUMQQZPGOFJBQ-UHFFFAOYSA-N 0.000 description 1
- IQGWPPQNIZBTBM-UHFFFAOYSA-N 2-aminoethanol;sulfuric acid Chemical compound NCCO.OS(O)(=O)=O IQGWPPQNIZBTBM-UHFFFAOYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 101100283604 Caenorhabditis elegans pigk-1 gene Proteins 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 206010016825 Flushing Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- WFVXRFBTYRMVEP-UHFFFAOYSA-N NC(CC)(O)O.S(=O)(=O)(O)O Chemical compound NC(CC)(O)O.S(=O)(=O)(O)O WFVXRFBTYRMVEP-UHFFFAOYSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229960003121 arginine Drugs 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000001856 erectile effect Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 229960002639 sildenafil citrate Drugs 0.000 description 1
- DEIYFTQMQPDXOT-UHFFFAOYSA-N sildenafil citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 DEIYFTQMQPDXOT-UHFFFAOYSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a benzenesulfonyl lupetazin derivative, which is obtained by reacting benzenesulfonyl lupetazin with acid and alkali metal elements or an ammonia (ammonium) compound or amino acid or amino alcohol in turn or directly reacting the benzenesulfonyl lupetazin with acid salt. When acid or the acid salt is a sulfate radical, benzenesulfonyl lupetazin complex bisulfate is obtained; and when acid or the acid salt is a phosphate radical, benzenesulfonyl lupetazin complex dihydric phosphate is obtained. A method of the invention has the advantages of reasonable design, stable process and high production practicability. The benzenesulfonyl lupetazin derivative provided by the invention has the remarkable advantages of high solubility, high bioavailability and the like and can be prepared into a preparation. After the preparation is taken orally, benzenesulfonyl lupetazin goes into blood, so that a better effect for treating male erectile dysfunction is achieved. The derivative has the structural formula shown in the specifications.
Description
Technical field
The invention belongs to the compound preparation, relate to benzenesulfonyl lupetazin derivative and preparation method and effect.
Background technology
The benzenesulfonyl lupetazin clinical application is its Citrate trianion, and also name citric acid edenaphy is the synthetic new drug of Oral Chemical of China's autonomous design development.
Experimentation on animals shows; the benzenesulfonyl lupetazin Citrate trianion can obviously promote rat erection activity; show: the first response latency obviously shortens; the erectile response number of times obviously increases; the erection time length obviously prolongs; area obviously increases under intracavernous pressure-time curve, and its effect and intensity are similar to sildenafil citrate.The mechanism of action of benzenesulfonyl lupetazin Citrate trianion is the PDE that selectivity suppresses to decompose cGMP
5, improve the cGMP level, strengthen the effect of NO.One, the second stage of clinical study confirms that all it has obvious therapeutic action to ED.
Erection function scoring score was obviously greater than placebo after clinical experimental study showed benzenesulfonyl lupetazin Citrate trianion 60mg treatment; treatment group relatively has utmost point significant difference before and after taking medicine, and illustrates that benzenesulfonyl lupetazin Citrate trianion 60mg treatment ED is effective.The untoward reaction that single is taken the benzenesulfonyl lupetazin Citrate trianion is visual abnormality, flushed face, headache or dizziness etc.The incidence of untoward reaction increases with dosage.Structure and the preparation method of benzenesulfonyl lupetazin are disclosed among the CN1393444.
Summary of the invention
The object of the present invention is to provide a kind of quality height, good stability, solubleness is good, bioavailability is high benzenesulfonyl lupetazin derivative.
Benzenesulfonyl lupetazin derivative of the present invention has formula (I) general structure:
Wherein:
M is a kind of in basic metal, ammonia (or ammonium), amino acid, the amino alcohol, and described basic metal is Na
+, K
+Or Cs
+, amino acid is arginine, ornithine, citrulline or Methionin, amino alcohol is tromethane, amino-propanediol, monoethanolamine or glucosamine.
Y is SO4
2-(sulfate radical) or HPO4
2-(phosphoric acid one hydrogen root).
The present invention also provides two kinds of preparation methods of described benzenesulfonyl lupetazin derivative:
The first preparation method realizes by following steps: benzenesulfonyl lupetazin and equimolar acid (H
2Y) in polar solvent, mix after; make benzenesulfonyl lupetazin acid salt; after the compound of adding and the equimolar alkali metal containing of benzenesulfonyl lupetazin or ammonium compound or amino acid or amino alcohol react completely again; concentrated; add the weak polar solvent crystallization; filter, with solid drying, namely get benzenesulfonyl lupetazin derivative.
Reaction formula is
Wherein M, Y in the compound (I) definition.
Alkali metal compound comprises in the method for making: a kind of in sodium methylate, potassium methylate, methyl alcohol caesium, sodium ethylate, potassium ethylate, ethanol caesium, sodium propylate, potassium propylate, propyl alcohol caesium, sodium butylate, butanols potassium, butanols caesium, sodium isopropylate, potassium isopropoxide, Virahol caesium, butyl alcohol-tert sodium, butyl alcohol-tert potassium, butyl alcohol-tert caesium, sodium-acetate, Potassium ethanoate, cesium acetate, Sodium Propionate, potassium propionate, propionic acid caesium, Sodium propanecarboxylate, potassium butyrate, butyric acid caesium, sodium hydroxide, potassium hydroxide or the cesium hydroxide.Ammonium or ammoniate are selected a kind of in ammonia, ammoniacal liquor, ammonium acetate, propionic acid ammonium or the butyric acid ammonium.
R is CH
3-, CH
3CH
2-, CH
3CH
2CH
2-, CH
3CH
2CH
2CH
2-, (CH
3)
2CH-, (CH
3)
3C-, CH
3CO-, CH
3CH
2CO-, CH
3CH
2CH
2A kind of among CO-, the H.
The second is the preparation method realize by following steps: with benzenesulfonyl lupetazin with after acid salt MHY mixes in polar solvent, reacts completely with 1: 1 mol ratio; concentrated, add the weak polar solvent crystallization, filter; with solid drying, namely get benzenesulfonyl lupetazin derivative.
Reaction formula is
Wherein M, Y in the compound (I) definition.
Acid salt described in the preparation method (MHY) is selected a kind of in sodium pyrosulfate, sal enixum, monoammonium sulfate, cesium hydrogen sulfate, SODIUM PHOSPHATE, MONOBASIC, potassium primary phosphate, primary ammonium phosphate or the cesium dihydrogen phosphate.
Described polar solvent is selected a kind of among water, ethanol, methyl alcohol, Virahol, acetone, DMF (DMF) or the DMSO (dimethyl sulfoxide (DMSO)) during reaction.
The weak polar solvent that described its crystallization is used is a kind of in ether, sherwood oil, normal hexane or the hexanaphthene.
Benzenesulfonyl lupetazin derivative of the present invention comprises benzenesulfonyl lupetazin hydrogen sulfate double salt and benzenesulfonyl lupetazin biphosphate double salt.
The method for making of benzenesulfonyl lupetazin hydrogen sulfate double salt of the present invention is:
1. benzenesulfonyl lupetazin is with after equimolar sulfuric acid mixes in polar solvent, add and the equimolar alkali metal-containing compound of benzenesulfonyl lupetazin or ammonium compound or amino acid or amino alcohol again, after reacting completely, concentrated, add the weak polar solvent crystallization, filter, with solid drying, namely get benzenesulfonyl lupetazin hydrogen sulfate double salt;
2. benzenesulfonyl lupetazin and equimolar sodium pyrosulfate or sal enixum or cesium dihydrogen phosphate or monoammonium sulfate mix, and be concentrated after reacting completely, and adds the weak polar solvent crystallization, filters, and with solid drying, namely gets benzenesulfonyl lupetazin hydrogen sulfate double salt.
The method for making of benzenesulfonyl lupetazin biphosphate double salt of the present invention is:
1. benzenesulfonyl lupetazin is with after equimolar phosphoric acid mixes in polar solvent, add and the equimolar alkali metal-containing compound of benzenesulfonyl lupetazin or ammonium compound or amino acid or amino alcohol again, after reacting completely, concentrated, add the weak polar solvent crystallization, filter, with solid drying, namely get benzenesulfonyl lupetazin biphosphate double salt;
2. benzenesulfonyl lupetazin and equimolar SODIUM PHOSPHATE, MONOBASIC or potassium primary phosphate or cesium dihydrogen phosphate or primary ammonium phosphate mix, and be after reacting completely, concentrated; add the weak polar solvent crystallization; separate out solid filtering, with solid drying, namely get benzenesulfonyl lupetazin biphosphate double salt.
Preparation method of the present invention is reasonable, and technique is simple.Benzenesulfonyl lupetazin double salt purity, content by the inventive method preparation are high, have good stability, characteristics that quality is high.Described benzenesulfonyl lupetazin derivative bioavailability is high, is converted into benzenesulfonyl lupetazin in the oral rear body, and enters blood with benzenesulfonyl lupetazin, absorbs fast, rapid-action, thereby bring into play better curative effect.
Embodiment
The present invention is further described in conjunction with the embodiments.Present invention is described for following examples, and these examples only are can not be interpreted as limitation of the scope of the invention in order to illustrate.
Embodiment 1
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; dissolve with the 50ml anhydrous methanol; stir; add sulfuric acid 98mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin vitriol 556mg; benzenesulfonyl lupetazin acid salt is mixing in acetone again; add 68mg sodium ethylate reaction 2 hours, concentrating under reduced pressure adds an amount of ether; separate out solid, filtration; with ether washing, drying, obtain white solid benzenesulfonyl lupetazin sodium pyrosulfate double salt 526mg, yield 91%.
Embodiment 2
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; use the 50ml anhydrous alcohol solution; stir; add sulfuric acid 98mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin vitriol 572mg; benzenesulfonyl lupetazin acid salt is mixing in DMF again; add 84mg potassium ethylate reaction 2 hours, concentrating under reduced pressure adds an amount of sherwood oil; separate out solid, filtration; with petroleum ether, drying, obtain white solid benzenesulfonyl lupetazin sal enixum double salt 458mg, yield 75%.
Embodiment 3
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; dissolve with the 50ml dry DMF; stir; add sulfuric acid 98mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin vitriol 559mg; benzenesulfonyl lupetazin acid salt is mixing in ethanol again; add 92mg propionic acid ammonium reaction 3 hours, concentrating under reduced pressure adds an amount of normal hexane; separate out solid, filtration; with normal hexane washing, drying, obtain white solid benzenesulfonyl lupetazin monoammonium sulfate double salt 403mg, yield 70%.
Embodiment 4
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; with the anhydrous DMSO dissolving of 50ml; stir; add sulfuric acid 98mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin vitriol 579mg; benzenesulfonyl lupetazin acid salt is mixing in methyl alcohol again; add 164mg methyl alcohol caesium reaction 3 hours, concentrating under reduced pressure adds an amount of hexanaphthene; separate out solid, filtration; with hexanaphthene washing, drying, obtain white solid benzenesulfonyl lupetazin cesium hydrogen sulfate double salt 248mg, yield 35%.
Embodiment 5
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; use the 50ml anhydrous alcohol solution; stir; add phosphatase 79 8mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin phosphoric acid salt 577mg; benzenesulfonyl lupetazin acid salt is mixing in methyl alcohol again; add 82mg sodium propylate reaction 2 hours, concentrating under reduced pressure adds an amount of ether; separate out solid, filtration; with ether washing, drying, obtain white solid benzenesulfonyl lupetazin SODIUM PHOSPHATE, MONOBASIC double salt 540mg, yield 82%.
Embodiment 6
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; dissolve with the 50ml anhydrous methanol; stir; add phosphatase 79 8mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin phosphoric acid salt 580mg; benzenesulfonyl lupetazin acid salt is mixing in acetone again; add 98mg potassium propylate reaction 2 hours, concentrating under reduced pressure adds an amount of sherwood oil; separate out solid, filtration; with petroleum ether, drying, obtain white solid benzenesulfonyl lupetazin potassium primary phosphate double salt 445mg, yield 72%.
Embodiment 7
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; dissolve with the 50ml dry DMF; stir; add phosphatase 79 8mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin phosphoric acid salt 580mg; benzenesulfonyl lupetazin acid salt is mixing in acetone again; add 77mg ammonium acetate reaction 1 hour, concentrating under reduced pressure adds an amount of normal hexane; separate out solid, filtration; with normal hexane washing, drying, obtain white solid benzenesulfonyl lupetazin primary ammonium phosphate double salt 340mg, yield 57%.
Embodiment 8
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; use the 50ml anhydrous alcohol solution; stir; add phosphatase 79 8mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin phosphoric acid salt 575mg; benzenesulfonyl lupetazin acid salt is mixing in acetone again; add 192mg propyl alcohol caesium reaction 2 hours, concentrating under reduced pressure adds an amount of ether; separate out solid, filtration; with ether washing, drying, obtain white solid benzenesulfonyl lupetazin cesium dihydrogen phosphate double salt 282mg, yield 40%.
Embodiment 9
In the 100ml reaction flask, add 50ml water, sodium pyrosulfate 120mg stirs, and adds benzene sulfonyl again
Base lupetazin 488.6mg, after reaction was finished, recovery was concentrated, obtains white solid benzenesulfonyl lupetazin sodium pyrosulfate double salt 603mg, yield 99%.
Embodiment 10
In the 100ml reaction flask, add 50ml water, sal enixum 136mg stirs, and adds benzenesulfonyl lupetazin 488.6mg again, and after reaction was finished, recovery was concentrated, obtains white solid benzenesulfonyl lupetazin sodium pyrosulfate double salt 425mg, yield 68%.
Embodiment 11
In the 100ml reaction flask, add 50ml water, monoammonium sulfate 115mg stirs, and adds benzenesulfonyl lupetazin 488.6mg again, and after reaction was finished, recovery was concentrated, obtains white solid benzenesulfonyl lupetazin sodium pyrosulfate double salt 392mg, yield 65%.
Embodiment 12
In the 100ml reaction flask, add 50ml water, cesium hydrogen sulfate 230mg stirs, and adds benzenesulfonyl lupetazin 488.6mg again, and after reaction was finished, recovery was concentrated, obtains white solid benzenesulfonyl lupetazin sodium pyrosulfate double salt 273mg, yield 38%.
Embodiment 13
In the 100ml reaction flask, add 50ml water, SODIUM PHOSPHATE, MONOBASIC 120mg stirs, and adds benzenesulfonyl lupetazin 488.6mg again, and after reaction was finished, recovery was concentrated, obtains white solid benzenesulfonyl lupetazin sodium pyrosulfate double salt 596mg, yield 98%.
Embodiment 14
In the 100ml reaction flask, add 50ml water, potassium primary phosphate 136mg stirs, and adds benzenesulfonyl lupetazin 488.6mg again, and after reaction was finished, recovery was concentrated, obtains white solid benzenesulfonyl lupetazin sodium pyrosulfate double salt 443mg, yield 71%.
Embodiment 15
In the 100ml reaction flask, add 50ml water, primary ammonium phosphate 115mg stirs, and adds benzenesulfonyl lupetazin 488.6mg again, and after reaction was finished, recovery was concentrated, obtains white solid benzenesulfonyl lupetazin sodium pyrosulfate double salt 320mg, yield 53%.
Embodiment 16
In the 100ml reaction flask, add 50ml water, cesium dihydrogen phosphate 230mg stirs, and adds benzenesulfonyl lupetazin 488.6mg again, and after reaction was finished, recovery was concentrated, obtains white solid benzenesulfonyl lupetazin sodium pyrosulfate double salt 302mg, yield 42%.
Embodiment 17
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; use the 50ml anhydrous alcohol solution; stir; add sulfuric acid 98mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin vitriol 556mg; benzenesulfonyl lupetazin acid salt is mixing in acetone again; add 121.14mg tromethane reaction 2 hours, concentrating under reduced pressure adds an amount of ether; separate out solid, filtration; with ether washing, drying, obtain white solid benzenesulfonyl lupetazin hydrogen sulfate tromethane 623mg, yield 92%.
Embodiment 18
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; dissolve with the 50ml anhydrous methanol; stir; add phosphatase 79 8mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin phosphoric acid salt 556mg; benzenesulfonyl lupetazin acid salt is mixing in DMF again; add 121.14mg tromethane reaction 2 hours, concentrating under reduced pressure adds an amount of sherwood oil; separate out solid, filtration; with petroleum ether, drying, obtain the amino trihydroxybutane 609mg of white solid benzenesulfonyl lupetazin biphosphate, yield 90%.
Embodiment 19
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; dissolve with the 50ml anhydrous isopropyl alcohol; stir; add sulfuric acid 98mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin vitriol 556mg; benzenesulfonyl lupetazin acid salt is mixing in acetone again; add 91.11mg amino-propanediol reaction 2 hours, concentrating under reduced pressure adds an amount of normal hexane; separate out solid, filtration; with normal hexane washing, drying, obtain white solid benzenesulfonyl lupetazin hydrogen sulfate amino-propanediol 466mg, yield 72%.
Embodiment 20
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; dissolve with the 50ml dry DMF; stir; add phosphatase 79 8mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin phosphoric acid salt 550mg; benzenesulfonyl lupetazin acid salt is mixing in methyl alcohol again; add 91.11mg amino-propanediol reaction 2 hours, concentrating under reduced pressure adds an amount of hexanaphthene; separate out solid, filtration; with hexanaphthene washing, drying, obtain the amino propylene glycol 449mg of white solid benzenesulfonyl lupetazin biphosphate, yield 70%.
Embodiment 21
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; use the 50ml anhydrous alcohol solution; stir; add sulfuric acid 98mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin vitriol 553mg; benzenesulfonyl lupetazin acid salt is mixing in acetone again; add 61.08mg monoethanolamine reaction 2 hours, concentrating under reduced pressure adds an amount of ether; separate out solid, filtration; with ether washing, drying, obtain white solid benzenesulfonyl lupetazin hydrogen sulfate monoethanolamine 430mg, yield 70%.
Embodiment 22
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; with the anhydrous DMSO dissolving of 50ml; stir; add phosphatase 79 8mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin phosphoric acid salt 550mg; benzenesulfonyl lupetazin acid salt is mixing in methyl alcohol again; add 61.08mg monoethanolamine reaction 2 hours, concentrating under reduced pressure adds an amount of sherwood oil; separate out solid, filtration; with petroleum ether, drying, obtain the amino ethanol 446mg of white solid benzenesulfonyl lupetazin biphosphate, yield 73%.
Embodiment 23
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; dissolve with the 50ml anhydrous propanone; stir; add sulfuric acid 98mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin vitriol 550mg; benzenesulfonyl lupetazin acid salt is mixing in acetone again; add 179.17mg glucosamine reaction 2 hours, concentrating under reduced pressure adds an amount of hexanaphthene; separate out solid, filtration; with hexanaphthene washing, drying, obtain white solid benzenesulfonyl lupetazin hydrogen sulfate glucosamine 481mg, yield 66%.
Embodiment 24
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; dissolve with the 50ml anhydrous isopropyl alcohol; stir; add phosphatase 79 8mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin phosphoric acid salt 549mg; benzenesulfonyl lupetazin acid salt is mixing in ethanol again; add 179.17mg glucosamine reaction 2 hours, concentrating under reduced pressure adds an amount of normal hexane; separate out solid, filtration; with normal hexane washing, drying, obtain the amino glucose 473mg of white solid benzenesulfonyl lupetazin biphosphate, yield 65%.
Embodiment 25
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; dissolve with the 50ml dry DMF; stir; add sulfuric acid 98mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin vitriol 553mg; benzenesulfonyl lupetazin acid salt is mixing in Virahol again; add the smart sour ammonia react of 174.2mg 2 hours, concentrating under reduced pressure adds an amount of ether; separate out solid, filtration; with ether washing, drying, obtain the smart sour ammonia 676mg of white solid benzenesulfonyl lupetazin hydrogen sulfate, yield 93%.
Embodiment 26
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; with the anhydrous DMSO dissolving of 50ml; stir; add phosphatase 79 8mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin phosphoric acid salt 554mg; benzenesulfonyl lupetazin acid salt is mixing in ethanol again; add the smart sour ammonia react of 174.2mg 2 hours, concentrating under reduced pressure adds an amount of sherwood oil; separate out solid, filtration; with petroleum ether, drying, obtain the smart sour ammonia 685mg of white solid benzenesulfonyl lupetazin biphosphate, yield 94%.
Embodiment 27
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; dissolve with the 50ml anhydrous methanol; stir; add sulfuric acid 98mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin vitriol 564mg; benzenesulfonyl lupetazin acid salt is mixing in DMF again; add 132.16mg ornithine reaction 2 hours, concentrating under reduced pressure adds an amount of normal hexane; separate out solid, filtration; with normal hexane washing, drying, obtain white solid benzenesulfonyl lupetazin hydrogen sulfate ornithine 404mg, yield 58%.
Embodiment 28
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; dissolve with the 50ml anhydrous propanone; stir; add phosphatase 79 8mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin phosphoric acid salt 564mg; benzenesulfonyl lupetazin acid salt is mixing in DMSO again; add 132.16mg ornithine reaction 2 hours, concentrating under reduced pressure adds an amount of hexanaphthene; separate out solid, filtration; with hexanaphthene washing, drying, obtain white solid benzenesulfonyl lupetazin biphosphate ornithine 348mg, yield 50%.
Embodiment 29
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; dissolve with the 50ml dry DMF; stir; add sulfuric acid 98mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin vitriol 560mg; benzenesulfonyl lupetazin acid salt is mixing in acetone again; add 175.19mg citrulline reaction 2 hours, concentrating under reduced pressure adds an amount of sherwood oil; separate out solid, filtration; with petroleum ether, drying, obtain white solid benzenesulfonyl lupetazin hydrogen sulfate citrulline 441mg, yield 60%.
Embodiment 30
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; use the 50ml anhydrous alcohol solution; stir; add phosphatase 79 8mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin phosphoric acid salt 563mg; benzenesulfonyl lupetazin acid salt is mixing in methyl alcohol again; add 175.19mg citrulline reaction 2 hours, concentrating under reduced pressure adds an amount of normal hexane; separate out solid, filtration; with normal hexane washing, drying, obtain white solid benzenesulfonyl lupetazin biphosphate citrulline 480mg, yield 65%.
Embodiment 31
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; with the anhydrous DMSO dissolving of 50ml; stir; add sulfuric acid 98mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin vitriol 549mg; benzenesulfonyl lupetazin acid salt is mixing in DMF again; add 146.19mg Methionin reaction 2 hours, concentrating under reduced pressure adds an amount of normal hexane; separate out solid, filtration; with normal hexane washing, drying, obtain white solid benzenesulfonyl lupetazin hydrogen sulfate Methionin 431mg, yield 62%.
Embodiment 32
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; use the 50ml anhydrous alcohol solution; stir; add phosphatase 79 8mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin phosphoric acid salt 550mg; benzenesulfonyl lupetazin acid salt is mixing in DMF again; add 146.19mg Methionin reaction 2 hours, concentrating under reduced pressure adds an amount of hexanaphthene; separate out solid, filtration; with hexanaphthene washing, drying, obtain white solid benzenesulfonyl lupetazin biphosphate Methionin 404mg, yield 58%.
Embodiment 33
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; use the 50ml water dissolution; stir; add sulfuric acid 98mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin vitriol 581mg; benzenesulfonyl lupetazin acid salt is mixing in ethanol again; add 68mg sodium ethylate reaction 2 hours, concentrating under reduced pressure adds an amount of ether; separate out solid, filtration; with ether washing, drying, obtain white solid benzenesulfonyl lupetazin sodium pyrosulfate double salt 643mg, yield 99%.
Embodiment 34
In the 100ml reaction flask; add benzenesulfonyl lupetazin 488.6mg; use the 50ml water dissolution; stir; add phosphatase 79 8mg; after reaction was finished, recovery was concentrated, obtains benzenesulfonyl lupetazin phosphoric acid salt 580mg; benzenesulfonyl lupetazin acid salt is mixing in Virahol again; add 82mg n-propyl alcohol sodium reaction 1 hour, concentrating under reduced pressure adds an amount of sherwood oil; separate out solid, filtration; with petroleum ether, drying, obtain white solid benzenesulfonyl lupetazin SODIUM PHOSPHATE, MONOBASIC double salt 649mg, yield 98%.
Embodiment 35
Pressing 2005 editions solubleness vocabularies of terms of Chinese Pharmacopoeia explains; the solubleness of new compound of the present invention in water sees Table 1; benzenesulfonyl lupetazin is insoluble in water, benzenesulfonyl lupetazin Citrate trianion slightly soluble in water, and compound dissolution degree of the present invention all reaches slightly molten.
Table 1
| Sequence number | New compound | Solubleness |
| 1 | Benzenesulfonyl lupetazin sodium pyrosulfate double salt | Slightly molten |
| 2 | Benzenesulfonyl lupetazin sal enixum double salt | Slightly molten |
| 3 | Benzenesulfonyl lupetazin hydrogen sulfate Arginine Salts | Slightly molten |
| 4 | Benzenesulfonyl lupetazin hydrogen sulfate tromethane double salt | Slightly molten |
| 5 | Benzenesulfonyl lupetazin SODIUM PHOSPHATE, MONOBASIC double salt | Slightly molten |
| 6 | Benzenesulfonyl lupetazin potassium primary phosphate double salt | Slightly molten |
| 7 | The amino trihydroxybutane double salt of benzenesulfonyl lupetazin biphosphate | Slightly molten |
Embodiment 36
The beagle dog is adopted in the bioavailability test, and is complete male, body weight 10kg, and fasting 12h can't help water; Control group benzenesulfonyl lupetazin Citrate trianion capsule.Medicine of the present invention is directly overlapped into capsule (being 20mg in the benzenesulfonyl lupetazin Citrate trianion) gavage; feed in about 3 hours after the gavage; respectively 0h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h and the about 0.5mL of 10h venous blood collection after gavage; measure the benzenesulfonyl lupetazin Plasma Concentration, the results are shown in Table 2.Illustrate that compound of the present invention is significantly improved than benzenesulfonyl lupetazin Citrate trianion bioavailability.Peak time significantly shifts to an earlier date, and the results are shown in Table 3.
Table 2 compares with the benzenesulfonyl lupetazin Citrate trianion, and the relative bioavailability of the compounds of this invention is:
| Medicine | Relative bioavailability |
| Benzenesulfonyl lupetazin sodium pyrosulfate double salt | 130％ |
| Benzenesulfonyl lupetazin sulfuric acid Arginine Salts | 125％ |
| Benzenesulfonyl lupetazin sulfuric acid tromethane double salt | 126％ |
| Benzenesulfonyl lupetazin SODIUM PHOSPHATE, MONOBASIC double salt | 128％ |
| Benzenesulfonyl lupetazin phosphoric acid hydrogen tromethane double salt | 124％ |
| Benzenesulfonyl lupetazin phosphoric acid hydrogen Arginine Salts | 123％ |
The peak time of table 3 the compounds of this invention and benzenesulfonyl lupetazin Citrate trianion compares:
| Medicine | Peak time |
| The benzenesulfonyl lupetazin Citrate trianion | 2 hours |
| Benzenesulfonyl lupetazin sodium pyrosulfate double salt | 0.9 hour |
| Benzenesulfonyl lupetazin sulfuric acid tromethane double salt | 1 o'clock |
Claims (5)
1. a class benzenesulfonyl lupetazin derivative has following general structure:
Wherein:
M is a kind of in basic metal, the ammonium ion,
Described basic metal is Na
+, K
+Or Cs
+
Y is SO
4 2-Or HPO
4 2-
2. the preparation method of benzenesulfonyl lupetazin derivative according to claim 1 is characterized in that realizing by following steps:
1-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl group-1H-pyrazolo ［ 4,3-d ］ pyrimidine-5-yl)-4-phenetole alkylsulfonyl ］-cis-3,5-lupetazin and equimolar H
2After Y mixes in polar solvent; make acid salt, add and 1-［ 3-(6,7-dihydro-1-methyl-7-oxo-3-propyl group-1H-pyrazolo ［ 4 again; 3-d ］ pyrimidine-5-yl)-4-phenetole alkylsulfonyl ］-cis-3; after the equimolar alkali metal compound of 5-lupetazin or ammonium compound react completely, concentrated, add the weak polar solvent crystallization; filter; with solid drying, namely get the purpose derivative
Reaction formula is:
Wherein the definition of M, Y is with claim 1,
Described alkali metal compound is selected: sodium methylate, potassium methylate, the methyl alcohol caesium, sodium ethylate, potassium ethylate, the ethanol caesium, sodium propylate, potassium propylate, the propyl alcohol caesium, sodium butylate, butanols potassium, the butanols caesium, sodium isopropylate, potassium isopropoxide, the Virahol caesium, butyl alcohol-tert sodium, butyl alcohol-tert potassium, the butyl alcohol-tert caesium, sodium-acetate, Potassium ethanoate, cesium acetate, Sodium Propionate, potassium propionate, the propionic acid caesium, Sodium propanecarboxylate, potassium butyrate, the butyric acid caesium, sodium hydroxide, a kind of in potassium hydroxide or the cesium hydroxide, described ammonium compound is selected ammonium acetate, a kind of in propionic acid ammonium or the butyric acid ammonium, described polar solvent is selected water, ethanol, methyl alcohol, Virahol, acetone, a kind of among DMF or the DMSO; The weak polar solvent that crystallization is used is selected a kind of in ether, sherwood oil, normal hexane or the hexanaphthene;
R is CH
3-, CH
3CH
2-, CH
3CH
2CH
2-, CH
3CH
2CH
2CH
2-, (CH
3)
2CH-, (CH
3)
3C-, CH
3CO-, CH
3CH
2CO-, CH
3CH
2CH
2A kind of among CO-or the H.
3. the preparation method of benzenesulfonyl lupetazin derivative according to claim 1 is characterized in that realizing by following steps:
With 1-［ 3-(6; 7-dihydro-1-methyl-7-oxo-3-propyl group-1H-pyrazolo ［ 4; 3-d ］ pyrimidine-5-yl)-4-phenetole alkylsulfonyl ］-cis-3; the 5-lupetazin is with after acid salt MHY mixes in polar solvent, reacts completely with the mol ratio of 1:1, and is concentrated, adds the weak polar solvent crystallization; filter; with solid drying, namely get the purpose derivative
Reaction formula is
Wherein the definition of M, Y is with claim 1,
Described acid salt selects a kind of in sodium pyrosulfate, sal enixum, monoammonium sulfate, cesium hydrogen sulfate, SODIUM PHOSPHATE, MONOBASIC, potassium primary phosphate, primary ammonium phosphate or the cesium dihydrogen phosphate, described polar solvent to select a kind of among water, ethanol, methyl alcohol, Virahol, acetone, DMF or the DMSO; The weak polar solvent that crystallization is used is selected a kind of in ether, sherwood oil, normal hexane or the hexanaphthene.
4. according to claim 2 or the preparation method of 3 described benzenesulfonyl lupetazin derivatives, it is characterized in that the hydrogen sulfate double salt of described derivative is realized by following steps respectively:
1. 1-［ 3-(6,7-dihydro-1-methyl-7-oxo-3-propyl group-1H-pyrazolo ［ 4,3-d ］ pyrimidine-5-yl)-4-phenetole alkylsulfonyl ］-cis-3, the 5-lupetazin is with after equimolar sulfuric acid mixes in polar solvent, add and 1-［ 3-(6 again, 7-dihydro-1-methyl-7-oxo-3-propyl group-1H-pyrazolo ［ 4,3-d ］ pyrimidine-5-yl)-4-phenetole alkylsulfonyl ］-cis-3, the equimolar alkali metal compound of 5-lupetazin or ammonium compound, after reacting completely, concentrated, add the weak polar solvent crystallization, filter, with solid drying, namely get hydrogen sulfate double salt;
2. 1-［ 3-(6,7-dihydro-1-methyl-7-oxo-3-propyl group-1H-pyrazolo ［ 4,3-d ］ pyrimidine-5-yl)-4-phenetole alkylsulfonyl ］-cis-3,5-lupetazin and equimolar sodium pyrosulfate or sal enixum or cesium hydrogen sulfate or monoammonium sulfate mix, and be after reacting completely, concentrated, add the weak polar solvent crystallization, filter, with solid drying, namely get hydrogen sulfate double salt;
Described polar solvent and weak polar solvent are with claim 2 or 3.
5. according to claim 2 or the preparation method of 3 described benzenesulfonyl lupetazin derivatives, it is characterized in that the biphosphate double salt of described derivative is realized by following steps respectively:
1. 1-［ 3-(6,7-dihydro-1-methyl-7-oxo-3-propyl group-1H-pyrazolo ［ 4,3-d ］ pyrimidine-5-yl)-4-phenetole alkylsulfonyl ］-cis-3, the 5-lupetazin is with after equimolar phosphoric acid mixes in polar solvent, add and 1-［ 3-(6 again, 7-dihydro-1-methyl-7-oxo-3-propyl group-1H-pyrazolo ［ 4,3-d ］ pyrimidine-5-yl)-4-phenetole alkylsulfonyl ］-cis-3, the equimolar alkali metal compound of 5-lupetazin or ammonium compound, after reacting completely, concentrated, add the weak polar solvent crystallization, filter, with solid drying, namely get biphosphate double salt;
2. 1-［ 3-(6,7-dihydro-1-methyl-7-oxo-3-propyl group-1H-pyrazolo ［ 4,3-d ］ pyrimidine-5-yl)-4-phenetole alkylsulfonyl ］-cis-3,5-lupetazin and equimolar SODIUM PHOSPHATE, MONOBASIC or potassium primary phosphate or cesium dihydrogen phosphate or primary ammonium phosphate mix, and be after reacting completely, concentrated, add the weak polar solvent crystallization, separate out solid filtering, with solid drying, namely get biphosphate double salt;
Described polar solvent and weak polar solvent are with claim 2 or 3.
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