CN101798301A - Pyrrolidyl pyrimidine methanesulfonamide derivatives and preparation method thereof - Google Patents
Pyrrolidyl pyrimidine methanesulfonamide derivatives and preparation method thereof Download PDFInfo
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- CN101798301A CN101798301A CN 201010145979 CN201010145979A CN101798301A CN 101798301 A CN101798301 A CN 101798301A CN 201010145979 CN201010145979 CN 201010145979 CN 201010145979 A CN201010145979 A CN 201010145979A CN 101798301 A CN101798301 A CN 101798301A
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- China
- Prior art keywords
- toluidrin
- pyrrolidyl pyrimidine
- pyrrolidyl
- pyrimidine
- sodium
- Prior art date
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- AVKWRGNRHMYCLT-UHFFFAOYSA-N methanesulfonamide 2-pyrrolidin-1-ylpyrimidine Chemical class CS(=O)(=O)N.N1(CCCC1)C1=NC=CC=N1 AVKWRGNRHMYCLT-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 55
- 239000002253 acid Substances 0.000 claims abstract description 13
- 150000001413 amino acids Chemical class 0.000 claims abstract description 11
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229910019142 PO4 Inorganic materials 0.000 claims abstract description 7
- 239000010452 phosphate Substances 0.000 claims abstract description 7
- 229910021529 ammonia Inorganic materials 0.000 claims abstract description 5
- RCFKEIREOSXLET-UHFFFAOYSA-N disulfamide Chemical compound CC1=CC(Cl)=C(S(N)(=O)=O)C=C1S(N)(=O)=O RCFKEIREOSXLET-UHFFFAOYSA-N 0.000 claims description 146
- PCXCZMYBFGWKKH-UHFFFAOYSA-N 2-pyrrolidin-1-ylpyrimidine Chemical compound C1CCCN1C1=NC=CC=N1 PCXCZMYBFGWKKH-UHFFFAOYSA-N 0.000 claims description 145
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 60
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 46
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 36
- 239000007787 solid Substances 0.000 claims description 36
- 238000001035 drying Methods 0.000 claims description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 28
- 238000001914 filtration Methods 0.000 claims description 20
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 20
- 239000002798 polar solvent Substances 0.000 claims description 19
- 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
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 14
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims description 14
- 239000012141 concentrate Substances 0.000 claims description 13
- 238000002425 crystallisation Methods 0.000 claims description 13
- 230000008025 crystallization Effects 0.000 claims description 13
- JXAZAUKOWVKTLO-UHFFFAOYSA-L sodium pyrosulfate Chemical compound [Na+].[Na+].[O-]S(=O)(=O)OS([O-])(=O)=O JXAZAUKOWVKTLO-UHFFFAOYSA-L 0.000 claims description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 12
- 229910052700 potassium Inorganic materials 0.000 claims description 12
- 239000011591 potassium Substances 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 235000001014 amino acid Nutrition 0.000 claims description 10
- 150000001414 amino alcohols Chemical class 0.000 claims description 10
- 229940045641 monobasic sodium phosphate Drugs 0.000 claims description 10
- 239000011734 sodium Substances 0.000 claims description 10
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 10
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 9
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 8
- 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-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 claims description 8
- QPTUMKXXAAHOOE-UHFFFAOYSA-M cesium;hydron;phosphate Chemical compound [Cs+].OP(O)([O-])=O QPTUMKXXAAHOOE-UHFFFAOYSA-M 0.000 claims description 8
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 claims description 8
- 229910052708 sodium Inorganic materials 0.000 claims description 8
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 8
- 239000004475 Arginine Substances 0.000 claims description 7
- 150000003868 ammonium compounds Chemical class 0.000 claims description 7
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 7
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 6
- 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
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-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
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 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
- BIGPRXCJEDHCLP-UHFFFAOYSA-N ammonium bisulfate Chemical compound [NH4+].OS([O-])(=O)=O BIGPRXCJEDHCLP-UHFFFAOYSA-N 0.000 claims description 5
- 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 claims description 4
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 claims description 4
- RHGKLRLOHDJJDR-BYPYZUCNSA-N L-citrulline Chemical compound NC(=O)NCCC[C@H]([NH3+])C([O-])=O RHGKLRLOHDJJDR-BYPYZUCNSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- RHGKLRLOHDJJDR-UHFFFAOYSA-N Ndelta-carbamoyl-DL-ornithine Natural products OC(=O)C(N)CCCNC(N)=O RHGKLRLOHDJJDR-UHFFFAOYSA-N 0.000 claims description 4
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 claims description 4
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-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
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 claims description 4
- 229960002173 citrulline Drugs 0.000 claims description 4
- 235000013477 citrulline Nutrition 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- 229960002442 glucosamine Drugs 0.000 claims description 4
- 229960003104 ornithine Drugs 0.000 claims description 4
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 4
- ZGCHLAJIRWDGFE-UHFFFAOYSA-N 1-aminopropane-1,1-diol Chemical compound CCC(N)(O)O ZGCHLAJIRWDGFE-UHFFFAOYSA-N 0.000 claims description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 3
- 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
- XUYPXLNMDZIRQH-LURJTMIESA-N N-acetyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC(C)=O XUYPXLNMDZIRQH-LURJTMIESA-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
- MEAHOQPOZNHISZ-UHFFFAOYSA-M cesium;hydrogen sulfate Chemical compound [Cs+].OS([O-])(=O)=O MEAHOQPOZNHISZ-UHFFFAOYSA-M 0.000 claims description 3
- 229930182817 methionine Natural products 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-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
- 101100283604 Caenorhabditis elegans pigk-1 gene Proteins 0.000 claims description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- GHVZOJONCUEWAV-UHFFFAOYSA-N [K].CCO Chemical compound [K].CCO GHVZOJONCUEWAV-UHFFFAOYSA-N 0.000 claims description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 2
- 229960003121 arginine Drugs 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
- 239000000203 mixture Substances 0.000 claims description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 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
- -1 ammonia compound Chemical class 0.000 abstract description 13
- 229910052783 alkali metal Inorganic materials 0.000 abstract description 4
- 150000001340 alkali metals Chemical class 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 4
- 238000000034 method Methods 0.000 abstract description 4
- 239000008280 blood Substances 0.000 abstract description 3
- 210000004369 blood Anatomy 0.000 abstract description 3
- 238000013461 design Methods 0.000 abstract description 2
- 208000010228 Erectile Dysfunction Diseases 0.000 abstract 1
- WZKFMLQJQDSTMD-UHFFFAOYSA-N S(=O)(=O)(O)O.CS(=O)(=O)N.N1(CCCC1)C1=NC=CC=N1 Chemical compound S(=O)(=O)(O)O.CS(=O)(=O)N.N1(CCCC1)C1=NC=CC=N1 WZKFMLQJQDSTMD-UHFFFAOYSA-N 0.000 abstract 1
- 238000010521 absorption reaction Methods 0.000 abstract 1
- 201000001881 impotence Diseases 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- IFJSXDRFYWADMW-UHFFFAOYSA-N methanesulfonamide phosphoric acid 2-pyrrolidin-1-ylpyrimidine Chemical compound P(=O)(O)(O)O.CS(=O)(=O)N.N1(CCCC1)C1=NC=CC=N1 IFJSXDRFYWADMW-UHFFFAOYSA-N 0.000 abstract 1
- 238000011084 recovery Methods 0.000 description 23
- 238000003756 stirring Methods 0.000 description 23
- 238000002156 mixing Methods 0.000 description 18
- 238000005406 washing Methods 0.000 description 14
- 150000001875 compounds Chemical class 0.000 description 13
- 241000405119 Virga Species 0.000 description 10
- 239000003814 drug Substances 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 5
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 5
- 229940079593 drug Drugs 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 3
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 3
- 239000000902 placebo Substances 0.000 description 3
- 229940068196 placebo Drugs 0.000 description 3
- 210000002784 stomach Anatomy 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 229940099471 Phosphodiesterase inhibitor Drugs 0.000 description 2
- 201000001880 Sexual dysfunction Diseases 0.000 description 2
- 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 description 2
- 229960000307 avanafil Drugs 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- VQTGUFBGYOIUFS-UHFFFAOYSA-N nitrosylsulfuric acid Chemical compound OS(=O)(=O)ON=O VQTGUFBGYOIUFS-UHFFFAOYSA-N 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 231100000872 sexual dysfunction Toxicity 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
- MCSJGXLZPITMIH-UHFFFAOYSA-N 2-aminobutane-1,1,1-triol Chemical compound CCC(N)C(O)(O)O MCSJGXLZPITMIH-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
- 102000009346 Adenosine receptors Human genes 0.000 description 1
- 108050000203 Adenosine receptors Proteins 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010016825 Flushing Diseases 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
- 230000036772 blood pressure Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229940082638 cardiac stimulant phosphodiesterase inhibitors Drugs 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 208000012201 sexual and gender identity disease Diseases 0.000 description 1
- 208000015891 sexual disease Diseases 0.000 description 1
- 230000036299 sexual function Effects 0.000 description 1
- 208000029257 vision disease Diseases 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides pyrrolidyl pyrimidine methanesulfonamide derivatives which are obtained by reacting pyrrolidyl pyrimidine methanesulfonamide with acid and alkali metal or ammonia compound or amino acid or alkamine or directly reacting the pyrrolidyl pyrimidine methanesulfonamide with acid salt. When the acid or acid salt is sulfate radical, a pyrrolidyl pyrimidine methanesulfonamide hydrogensulfate double salt is obtained; and when the acid or acid salt is phosphate radical, a pyrrolidyl pyrimidine methanesulfonamide di-hydrogen phosphate double salt is obtained. The method has reasonable design, stable process and good production feasibility. The pyrrolidyl pyrimidine methanesulfonamide derivatives have the remarkable advantages of good dissolubility, high bioavailability and the like, can be prepared into preparations, and has rapid absorption and quick effect taking by delivering the pyrrolidyl pyrimidine methanesulfonamide into blood after a patient takes the preparations orally, thereby playing a role of better treating male erectile dysfunction. The invention has the following general formula described in the specification.
Description
Technical field
The invention belongs to compound, relate to Pyrrolidyl pyrimidine methanesulfonamide derivatives and preparation method and purposes.
Background technology
The Pyrrolidyl pyrimidine Toluidrin is that non-(Avanafil of name Ah cutting down also, TA 1790), chemistry 4-[(3-chloro-4-methoxy-benzyl by name) amino]-2-[2-(methylol)-1-pyrrolidyl]-N-(2-Pyrimidylmethyl)-5-pyrimidine Toluidrin, can help erective dysfunction (ED) male sex generation effect in 30 minutes, have onset speed characteristics faster.
The Pyrrolidyl pyrimidine Toluidrin is a kind of novel phosphodiesterase inhibitor, is used for the treatment of male sexual disorder, has finished the II clinical trial phase in the U.S., European Union and Japan at present, and the III clinical trial phase will start.This product is by day Honda limit drugmaker and VIVUS company exploitation.The Pyrrolidyl pyrimidine Toluidrin is a kind of phosphodiesterase inhibitor of potent, high selectivity, and experiment in vitro finds than Virga phosphodiesterase is had stronger selectivity.This compound to other phosphodiesterase affinitys a little less than, and the effect of Adenosine Receptors reduced, show that the cardiovascular effect of Pyrrolidyl pyrimidine Toluidrin should be than a little less than the Virga.Preclinical study confirm the Pyrrolidyl pyrimidine Toluidrin and organic nitrose is medication combined when taking its reduction to blood pressure will be significantly smaller than Virga and nitrose medicine with clothes.And the Pyrrolidyl pyrimidine Toluidrin is very weak to the restraining effect of phosphodiesterase, and the inhibition of this enzyme may be relevant with the visual disorder that other phosphodiesterase inhibitors cause.
Disclosed clinical trial shows, 83 sexual dysfunction patients have participated in an II phase intersects clinical trial.Patient at first accepts the treatment of Pyrrolidyl pyrimidine Toluidrin 50mg (27 people), Pyrrolidyl pyrimidine Toluidrin 100mg (28 people) or Pyrrolidyl pyrimidine Toluidrin 200mg (28 people).Accept Virga 50mg and placebo treatment afterwards more successively.Patient gives sense of vision to be stimulated the back to use Rigiscan to estimate, and evaluation time is respectively take medicine back 20-40 minute, 60-80 minute and 100-120 minute.Primary terminal point is the time length of hardness greater than baseline value 60%.Patient's the basic condition of participating in test is similar, age 49-53 year, the time length 3.9-5.6 of sexual dysfunction.Most of patient (78.6-88.9) is a moderate for severity extent, and the international index of average baselining sexual function (IIEF) must be divided into 17.9-19.4.
The patient takes Pyrrolidyl pyrimidine Toluidrin or Virga, and 60% hardness time length all significantly was longer than placebo.The peak value of Pyrrolidyl pyrimidine Toluidrin 50mg or 100mg is reflected at takes medicine back 20-40 minute, and the peak value reaction duration is similar with Virga, but the peak value reaction times of 200mg then significantly is longer than Virga.The onset of Pyrrolidyl pyrimidine Toluidrin is faster than Virga, and the peak is reflected at the back of taking medicine and occurred in 20-40 minute, and the peak reaction times of Virga occurred after 60-120 minute.The tolerance of Pyrrolidyl pyrimidine Toluidrin is relatively good, does not have patient to withdraw from test because of untoward reaction.The untoward reaction of normal appearance is a flushed face, and the occurrence rate of Pyrrolidyl pyrimidine Toluidrin treatment group is 7-11%; The occurrence rate of Virga group is 4-8%; The occurrence rate of placebo is 0-7%.
Summary of the invention
The object of the invention is to provide a kind of quality height, good stability, solubleness is good, bioavailability is high Pyrrolidyl pyrimidine methanesulfonamide derivatives.
Pyrrolidyl pyrimidine methanesulfonamide derivatives 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 Pyrrolidyl pyrimidine methanesulfonamide derivatives:
First kind of preparation method realizes by following steps: Pyrrolidyl pyrimidine Toluidrin and equimolar H
2After Y mixes in polar solvent, make Pyrrolidyl pyrimidine Toluidrin acid salt, after the compound of adding and the equimolar alkali metal containing of Pyrrolidyl pyrimidine Toluidrin or ammonium compound or amino acid or amino alcohol react completely again, concentrate, add the weak polar solvent crystallization, filter,, promptly get Pyrrolidyl pyrimidine methanesulfonamide derivatives solid drying.
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 compound is selected a kind of in ammonia, ammoniacal liquor, ammonium acetate, propionic acid ammonium or the butyric acid ammonium for use.
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.
Second kind of preparation method realizes by following steps: with the Pyrrolidyl pyrimidine Toluidrin with after acid salt MHY mixes in polar solvent, reacts completely with 1: 1 mol ratio, concentrate, add the weak polar solvent crystallization, filter, with solid drying, promptly get Pyrrolidyl pyrimidine methanesulfonamide derivatives.
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 for use.
Described polar solvent is selected a kind of among water, ethanol, methyl alcohol, Virahol, acetone, DMF (N, dinethylformamide) or the DMSO (dimethyl sulfoxide (DMSO)) for use.
The weak polar solvent that described its crystallization is used is a kind of in ether, sherwood oil, normal hexane or the hexanaphthene.
Pyrrolidyl pyrimidine methanesulfonamide derivatives of the present invention comprises Pyrrolidyl pyrimidine Toluidrin hydrogen sulfate double salt and Pyrrolidyl pyrimidine Toluidrin biphosphate double salt.
Pyrrolidyl pyrimidine Toluidrin hydrogen sulfate double salt of the present invention prepares by following steps respectively:
1. the Pyrrolidyl pyrimidine Toluidrin is with after equimolar sulfuric acid mixes in polar solvent, add compound or ammonium compound or amino acid or amino alcohol again with the equimolar alkali metal containing of Pyrrolidyl pyrimidine Toluidrin, after reacting completely, concentrate, add diethyl ether or sherwood oil or normal hexane crystallization, filter,, promptly get Pyrrolidyl pyrimidine Toluidrin hydrogen sulfate double salt solid drying;
2. Pyrrolidyl pyrimidine Toluidrin and equimolar sodium pyrosulfate or sal enixum or cesium dihydrogen phosphate or monoammonium sulfate are mixed in polar solvent, after reacting completely, concentrate, add diethyl ether or sherwood oil or normal hexane crystallization, filter, with solid drying, promptly get Pyrrolidyl pyrimidine Toluidrin hydrogen sulfate double salt.
Pyrrolidyl pyrimidine Toluidrin biphosphate double salt of the present invention prepares by following steps respectively:
1. the Pyrrolidyl pyrimidine Toluidrin is with after equimolar phosphoric acid mixes in polarity, add compound or ammonium compound or amino acid or amino alcohol again with the equimolar alkali metal containing of Pyrrolidyl pyrimidine Toluidrin, after reacting completely, concentrate, add diethyl ether or sherwood oil or normal hexane crystallization, filter,, promptly get Pyrrolidyl pyrimidine Toluidrin biphosphate double salt solid drying;
2. Pyrrolidyl pyrimidine Toluidrin and equimolar SODIUM PHOSPHATE, MONOBASIC or potassium primary phosphate or cesium dihydrogen phosphate or primary ammonium phosphate mix in polar solvent, after reacting completely, concentrate, add diethyl ether or sherwood oil or normal hexane crystallization, separate out solid filtering, with solid drying, promptly get Pyrrolidyl pyrimidine Toluidrin biphosphate double salt.
Preparation method of the present invention is reasonable in design, and technology is simple.By Pyrrolidyl pyrimidine methanesulfonamide derivatives purity, the content height of the inventive method preparation, have good stability, characteristics that quality is high.Described Pyrrolidyl pyrimidine methanesulfonamide derivatives bioavailability height is converted into the Pyrrolidyl pyrimidine Toluidrin in the body of oral back, and goes into blood with the Pyrrolidyl pyrimidine Toluidrin, 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 for explanation.
Embodiment 1
In the 100ml reaction flask, add Pyrrolidyl pyrimidine Toluidrin 483.95mg, use the 50ml anhydrous alcohol solution, stir, add sulfuric acid 98mg, after reaction was finished, recovery concentrated, and obtains Pyrrolidyl pyrimidine Toluidrin vitriol 523mg, Pyrrolidyl pyrimidine Toluidrin vitriol is mixing in acetone again, add 54mg sodium methylate reaction 2 hours, concentrating under reduced pressure adds an amount of ether, separate out solid, filtration, with ether washing, drying, obtain Pyrrolidyl pyrimidine Toluidrin sodium pyrosulfate double salt 502mg, yield 92%.
Embodiment 2
In the 100ml reaction flask, add Pyrrolidyl pyrimidine Toluidrin 483.95, dissolve with the 50ml anhydrous methanol, stir, add sulfuric acid 98mg, after reaction was finished, recovery concentrated, and obtains Pyrrolidyl pyrimidine Toluidrin vitriol 525mg, Pyrrolidyl pyrimidine Toluidrin vitriol is mixing in acetone again, add 70mg potassium methylate reaction 2.5 hours, concentrating under reduced pressure adds an amount of sherwood oil, separate out solid, filtration, with petroleum ether, drying, obtain Pyrrolidyl pyrimidine Toluidrin sal enixum double salt 495mg, yield 88%.
Embodiment 3
In the 100ml reaction flask, add Pyrrolidyl pyrimidine Toluidrin 483.95mg, dissolve with the 50ml dry DMF, stir, add sulfuric acid 98mg, after reaction was finished, recovery concentrated, and obtains Pyrrolidyl pyrimidine Toluidrin vitriol 524mg, Pyrrolidyl pyrimidine Toluidrin vitriol 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 Pyrrolidyl pyrimidine Toluidrin monoammonium sulfate double salt 357mg, yield 66%.
Embodiment 4
In the 100ml reaction flask, add Pyrrolidyl pyrimidine Toluidrin 483.95mg, dissolve with the 50ml anhydrous propanone, stir, add sulfuric acid 98mg, after reaction was finished, recovery concentrated, and obtains Pyrrolidyl pyrimidine Toluidrin vitriol 520mg, Pyrrolidyl pyrimidine Toluidrin vitriol is mixing in acetone again, add 217mg butyric acid caesium reaction 1 hour, concentrating under reduced pressure adds an amount of normal hexane, separate out solid, filtration, with normal hexane washing, drying, obtain Pyrrolidyl pyrimidine Toluidrin cesium hydrogen sulfate double salt 377mg, yield 58%.
Embodiment 5
In the 100ml reaction flask, add Pyrrolidyl pyrimidine Toluidrin 483.95mg, dissolve with the 50ml anhydrous propanone, stir, add phosphatase 79 8mg, after reaction was finished, recovery concentrated, and obtains Pyrrolidyl pyrimidine Toluidrin phosphoric acid salt 528mg, Pyrrolidyl pyrimidine Toluidrin phosphoric acid salt is mixing in acetone again, add 94mg butyl alcohol-tert sodium reaction 1 hour, concentrating under reduced pressure adds an amount of ether, separate out solid, filtration, with ether washing, drying, obtain Pyrrolidyl pyrimidine Toluidrin SODIUM PHOSPHATE, MONOBASIC double salt 492mg, yield 90%.
Embodiment 6
In the 100ml reaction flask, add Pyrrolidyl pyrimidine Toluidrin 483.95mg, dissolve with the 50ml anhydrous propanone, stir, add phosphatase 79 8mg, after reaction was finished, recovery concentrated, and obtains Pyrrolidyl pyrimidine Toluidrin phosphoric acid salt 526mg, Pyrrolidyl pyrimidine Toluidrin phosphoric acid salt is mixing in acetone again, add 70mg potassium methylate reaction 1 hour, concentrating under reduced pressure adds an amount of ether, separate out solid, filtration, with ether washing, drying, obtain Pyrrolidyl pyrimidine Toluidrin potassium primary phosphate double salt 502mg, yield 89%.
Embodiment 7
In the 100ml reaction flask, add Pyrrolidyl pyrimidine Toluidrin 483.95mg, dissolve with the 50ml dry DMF, stir, add phosphatase 79 8mg, after reaction was finished, recovery concentrated, and obtains Pyrrolidyl pyrimidine Toluidrin phosphoric acid salt 522mg, Pyrrolidyl pyrimidine Toluidrin phosphoric acid salt is mixing in acetone 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 Pyrrolidyl pyrimidine Toluidrin primary ammonium phosphate double salt 366mg, yield 68%.
Embodiment 8
In the 100ml reaction flask, add Pyrrolidyl pyrimidine Toluidrin 483.95mg, with the anhydrous DMSO dissolving of 50ml, stir, add phosphatase 79 8mg, after reaction was finished, recovery concentrated, and obtains Pyrrolidyl pyrimidine Toluidrin phosphoric acid salt 524mg, Pyrrolidyl pyrimidine Toluidrin phosphoric acid salt is mixing in acetone again, add 164mg methyl alcohol caesium reaction 2 hours, concentrating under reduced pressure adds an amount of hexanaphthene, separate out solid, filtration, with hexanaphthene washing, drying, obtain Pyrrolidyl pyrimidine Toluidrin cesium dihydrogen phosphate double salt 353mg, yield 54%.
Embodiment 9
In the 100ml reaction flask, add 50ml water, sodium pyrosulfate 120mg stirs, and adds Pyrrolidyl pyrimidine Toluidrin 483.95mg again, and after reaction was finished, recovery concentrated, and obtains white solid Pyrrolidyl pyrimidine Toluidrin sodium pyrosulfate double salt 598mg, yield 99%.。
Embodiment 10
In the 100ml reaction flask, add 50ml water, sal enixum 136mg stirs, and adds Pyrrolidyl pyrimidine Toluidrin 483.95mg again, and after reaction was finished, recovery concentrated, and obtains white solid Pyrrolidyl pyrimidine Toluidrin sal enixum double salt 508mg, yield 82%.
Embodiment 11
In the 100ml reaction flask, add Pyrrolidyl pyrimidine Toluidrin 483.95mg, use the 50ml water dissolution, stir, add SODIUM PHOSPHATE, MONOBASIC 120mg, after reaction was finished, recovery concentrated, and obtains Pyrrolidyl pyrimidine Toluidrin SODIUM PHOSPHATE, MONOBASIC double salt 592mg, yield 98%.
Embodiment 12
In the 100ml reaction flask, add 50ml water, primary ammonium phosphate 115mg, stir, add Pyrrolidyl pyrimidine Toluidrin 483.95mg again, after reaction is finished, recovery concentrates, and obtains white solid Pyrrolidyl pyrimidine Toluidrin sodium pyrosulfate double salt 389mg, yield 65%.
Embodiment 13
In the 100ml reaction flask, add 50ml water, cesium dihydrogen phosphate 230mg, stir, add Pyrrolidyl pyrimidine Toluidrin 483.95mg again, after reaction is finished, recovery concentrates, and obtains white solid Pyrrolidyl pyrimidine Toluidrin sodium pyrosulfate double salt 406mg, yield 57%.
In the 100ml reaction flask, add Pyrrolidyl pyrimidine Toluidrin 483.95mg, use the 50ml anhydrous alcohol solution, stir, add sulfuric acid 98mg, after reaction was finished, recovery concentrated, and obtains Pyrrolidyl pyrimidine Toluidrin vitriol 525mg, Pyrrolidyl pyrimidine Toluidrin vitriol 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 Pyrrolidyl pyrimidine Toluidrin hydrogen sulfate tromethane 606mg, yield 94%.
Embodiment 15
In the 100ml reaction flask, add Pyrrolidyl pyrimidine Toluidrin 483.95mg, dissolve with the 50ml anhydrous methanol, stir, add sulfuric acid 98mg, after reaction was finished, recovery concentrated, and obtains Pyrrolidyl pyrimidine Toluidrin vitriol 522mg, Pyrrolidyl pyrimidine Toluidrin vitriol is mixing in DMF again, add 91.11mg amino-propanediol reaction 2 hours, concentrating under reduced pressure adds an amount of sherwood oil, separate out solid, filtration, with petroleum ether, drying, obtain Pyrrolidyl pyrimidine Toluidrin hydrogen sulfate amino-propanediol 441mg, yield 72%.
Embodiment 16
In the 100ml reaction flask, add Pyrrolidyl pyrimidine Toluidrin 483.95mg, dissolve with the 50ml anhydrous isopropyl alcohol, stir, add sulfuric acid 98mg, after reaction was finished, recovery concentrated, and obtains Pyrrolidyl pyrimidine Toluidrin vitriol 526mg, Pyrrolidyl pyrimidine Toluidrin vitriol is mixing in methyl alcohol again, add 61.08mg monoethanolamine reaction 2 hours, concentrating under reduced pressure adds an amount of normal hexane, separate out solid, filtration, with normal hexane washing, drying, obtain Pyrrolidyl pyrimidine Toluidrin hydrogen sulfate monoethanolamine 411mg, yield 70%.
Embodiment 17
In the 100ml reaction flask, add Pyrrolidyl pyrimidine Toluidrin 483.95mg, dissolve with the 50ml dry DMF, stir, add sulfuric acid 98mg, after reaction was finished, recovery concentrated, and obtains Pyrrolidyl pyrimidine Toluidrin vitriol 525mg, Pyrrolidyl pyrimidine Toluidrin vitriol is mixing in DMSO 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 Pyrrolidyl pyrimidine Toluidrin hydrogen sulfate glucosamine 458mg, yield 65%.
Embodiment 18
In the 100ml reaction flask, add Pyrrolidyl pyrimidine Toluidrin 483.95mg, use the 50ml anhydrous alcohol solution, stir, add sulfuric acid 98mg, after reaction was finished, recovery concentrated, and obtains Pyrrolidyl pyrimidine Toluidrin vitriol 523mg, Pyrrolidyl pyrimidine Toluidrin vitriol is mixing in acetone again, add 174.2mg arginine reaction 2 hours, concentrating under reduced pressure adds an amount of ether, separate out solid, filtration, with ether washing, drying, obtain Pyrrolidyl pyrimidine Toluidrin hydrogen sulfate arginine 662mg, yield 95%.
In the 100ml reaction flask, add Pyrrolidyl pyrimidine Toluidrin 483.95mg, dissolve with the 50ml anhydrous methanol, stir, add sulfuric acid 98mg, after reaction was finished, recovery concentrated, and obtains Pyrrolidyl pyrimidine Toluidrin vitriol 520mg, Pyrrolidyl pyrimidine Toluidrin vitriol is mixing in acetone again, add 132.16mg ornithine reaction 2 hours, concentrating under reduced pressure adds an amount of sherwood oil, separate out solid, filtration, with petroleum ether, drying, obtain Pyrrolidyl pyrimidine Toluidrin hydrogen sulfate ornithine 539mg, yield 83%.
Embodiment 20
In the 100ml reaction flask, add Pyrrolidyl pyrimidine Toluidrin 483.95mg, dissolve with the 50ml anhydrous isopropyl alcohol, stir, add sulfuric acid 98mg, after reaction was finished, recovery concentrated, and obtains Pyrrolidyl pyrimidine Toluidrin vitriol 526mg, Pyrrolidyl pyrimidine Toluidrin vitriol is mixing in DMF 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 Pyrrolidyl pyrimidine Toluidrin hydrogen sulfate citrulline 505mg, yield 72%.
Embodiment 21
In the 100ml reaction flask, add Pyrrolidyl pyrimidine Toluidrin 483.95mg, dissolve with the 50ml anhydrous propanone, stir, add sulfuric acid 98mg, after reaction was finished, recovery concentrated, and obtains Pyrrolidyl pyrimidine Toluidrin vitriol 522mg, Pyrrolidyl pyrimidine Toluidrin vitriol is mixing in Virahol 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 Pyrrolidyl pyrimidine Toluidrin hydrogen sulfate Methionin 414mg, yield 62%.
Embodiment 22
In the 100ml reaction flask, add Pyrrolidyl pyrimidine Toluidrin 483.95mg, use the 50ml water dissolution, stir, add sulfuric acid 98mg, after reaction was finished, recovery concentrated, and obtains Pyrrolidyl pyrimidine Toluidrin vitriol 576mg, Pyrrolidyl pyrimidine Toluidrin vitriol 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 Pyrrolidyl pyrimidine Toluidrin sodium pyrosulfate double salt 631mg, yield 98%.
Embodiment 23
In the 100ml reaction flask, add Pyrrolidyl pyrimidine Toluidrin 483.95mg, use the 50ml water dissolution, stir, add phosphatase 79 8mg, after reaction was finished, recovery concentrated, and obtains Pyrrolidyl pyrimidine Toluidrin phosphoric acid salt 576mg, Pyrrolidyl pyrimidine Toluidrin phosphoric 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 Pyrrolidyl pyrimidine Toluidrin SODIUM PHOSPHATE, MONOBASIC double salt 638mg, yield 97%.
Embodiment 24
Press 2005 editions solubleness vocabularies of terms of Chinese Pharmacopoeia and explain that the solubleness of new compound of the present invention in water sees Table 1, the Pyrrolidyl pyrimidine Toluidrin is water insoluble, and compound of the present invention all can reach dissolving.
Table 1
| Sequence number | New compound | Solubleness |
| ??1 | Pyrrolidyl pyrimidine Toluidrin sodium pyrosulfate double salt | Dissolving |
| ??2 | Pyrrolidyl pyrimidine Toluidrin sal enixum double salt | Dissolving |
| ??3 | Pyrrolidyl pyrimidine Toluidrin hydrogen sulfate arginine double salt | Dissolving |
| ??4 | Pyrrolidyl pyrimidine Toluidrin hydrogen sulfate tromethane double salt | Dissolving |
| ??5 | Pyrrolidyl pyrimidine Toluidrin SODIUM PHOSPHATE, MONOBASIC double salt | Dissolving |
| ??6 | Pyrrolidyl pyrimidine Toluidrin potassium primary phosphate double salt | Dissolving |
| ??7 | The amino trihydroxybutane double salt of Pyrrolidyl pyrimidine Toluidrin biphosphate | Dissolving |
Embodiment 25
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 Pyrrolidyl pyrimidine Toluidrin capsule.Medicine of the present invention is directly overlapped into capsule (being 20mg in the Pyrrolidyl pyrimidine Toluidrin) irritate stomach, feed in about 3 hours behind the filling stomach, 0h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h and the about 0.5ml of 10h venous blood collection after irritating stomach respectively, measure Pyrrolidyl pyrimidine Toluidrin Plasma Concentration, the results are shown in Table 2.Illustrate that compound of the present invention is significantly improved than Pyrrolidyl pyrimidine Toluidrin bioavailability.Peak time shifts to an earlier date significantly, the results are shown in Table 3.
Table 2 compares with the Pyrrolidyl pyrimidine Toluidrin, and the relative bioavailability of The compounds of this invention is:
| Medicine | Relative bioavailability |
| Pyrrolidyl pyrimidine Toluidrin sodium pyrosulfate double salt | ??126％ |
| Pyrrolidyl pyrimidine Toluidrin sulfuric acid arginine double salt | ??123％ |
| Pyrrolidyl pyrimidine Toluidrin sulfuric acid tromethane double salt | ??118％ |
| Pyrrolidyl pyrimidine Toluidrin SODIUM PHOSPHATE, MONOBASIC double salt | ??125％ |
| Pyrrolidyl pyrimidine Toluidrin phosphoric acid hydrogen tromethane double salt | ??116％ |
| Pyrrolidyl pyrimidine Toluidrin phosphoric acid hydrogen arginine double salt | ??121％ |
The peak time of table 3 The compounds of this invention and Pyrrolidyl pyrimidine Toluidrin relatively
| Medicine | Peak time |
| The Pyrrolidyl pyrimidine Toluidrin | 50 minutes |
| Pyrrolidyl pyrimidine Toluidrin sodium pyrosulfate double salt | 20 minutes |
| Pyrrolidyl pyrimidine Toluidrin sulfuric acid tromethane double salt | 30 minutes |
Claims (6)
1. a class Pyrrolidyl pyrimidine methanesulfonamide derivatives has following general structure:
Wherein:
M is a kind of in basic metal, ammonia or ammonium, amino acid, the amino alcohol,
Described basic metal is Na
+, K
+Or Cs
+, described amino acid is arginine, ornithine, citrulline or Methionin, described amino alcohol are tromethane, amino-propanediol, monoethanolamine or glucosamine;
Y is SO4
2-Or HPO4
2-
2. the preparation method of Pyrrolidyl pyrimidine methanesulfonamide derivatives according to claim 1 is characterized in that realizing by following steps:
Pyrrolidyl pyrimidine Toluidrin and equimolar H
2After the acid of Y mixes in polar solvent, make Pyrrolidyl pyrimidine Toluidrin acid salt, after adding and the equimolar alkali metal compound of Pyrrolidyl pyrimidine Toluidrin or ammonium compound or amino acid or amino alcohol react completely again, concentrate, add the weak polar solvent crystallization, filter, solid drying, promptly get Pyrrolidyl pyrimidine methanesulfonamide derivatives
Reaction formula is:
Wherein the definition of M, Y is with claim 1,
Described alkali metal compound is selected sodium methylate for use, 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 or ammoniate are selected ammonia for use, ammoniacal liquor, ammonium acetate, a kind of in 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-or the H.
3. the preparation method of Pyrrolidyl pyrimidine methanesulfonamide derivatives according to claim 1 is characterized in that realizing by following steps:
The Pyrrolidyl pyrimidine Toluidrin with after acid salt MHY mixes in polar solvent, reacts completely with 1: 1 mol ratio, is concentrated, adds the weak polar solvent crystallization, filter,, promptly get Pyrrolidyl pyrimidine methanesulfonamide derivatives solid drying,
Reaction formula is:
Wherein the definition of M, Y is with claim 1,
Described acid salt 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 for use.
4. according to the preparation method of claim 2 or 3 described Pyrrolidyl pyrimidine methanesulfonamide derivatives, it is characterized in that: described polar solvent is selected water, ethanol, methyl alcohol, Virahol, acetone, N for use, a kind of in dinethylformamide or the dimethyl sulfoxide (DMSO), described weak polar solvent is a kind of in ether, sherwood oil, normal hexane or the hexanaphthene.
5. according to the preparation method of claim 2 or 3 described Pyrrolidyl pyrimidine methanesulfonamide derivatives, it is characterized in that Pyrrolidyl pyrimidine Toluidrin hydrogen sulfate double salt obtains by following steps respectively:
1. the Pyrrolidyl pyrimidine Toluidrin is with after equimolar sulfuric acid mixes in polar solvent, add and the equimolar alkali metal compound of Pyrrolidyl pyrimidine Toluidrin or ammonium compound or amino acid or amino alcohol again, after reacting completely, concentrate, add diethyl ether or sherwood oil or normal hexane crystallization, filter,, promptly get Pyrrolidyl pyrimidine Toluidrin hydrogen sulfate double salt solid drying;
2. Pyrrolidyl pyrimidine Toluidrin and equimolar sodium pyrosulfate or sal enixum or cesium dihydrogen phosphate or monoammonium sulfate are mixed in polar solvent, after reacting completely, concentrate, add diethyl ether or sherwood oil or normal hexane crystallization, filter, with solid drying, promptly get Pyrrolidyl pyrimidine Toluidrin hydrogen sulfate double salt.
6. according to the preparation method of claim 2 or 3 described Pyrrolidyl pyrimidine methanesulfonamide derivatives, it is characterized in that Pyrrolidyl pyrimidine Toluidrin biphosphate double salt obtains by following steps respectively:
1. the Pyrrolidyl pyrimidine Toluidrin is with after equimolar phosphoric acid mixes in polar solvent, add and the equimolar alkali metal compound of Pyrrolidyl pyrimidine Toluidrin or ammonium compound or amino acid or amino alcohol again, after reacting completely, concentrate, add diethyl ether or sherwood oil or normal hexane crystallization, filter,, promptly get Pyrrolidyl pyrimidine Toluidrin biphosphate double salt solid drying;
2. Pyrrolidyl pyrimidine Toluidrin and equimolar SODIUM PHOSPHATE, MONOBASIC or potassium primary phosphate or cesium dihydrogen phosphate or primary ammonium phosphate mix in polar solvent, after reacting completely, concentrate, add diethyl ether or sherwood oil or normal hexane crystallization, separate out solid filtering, with solid drying, promptly get Pyrrolidyl pyrimidine Toluidrin biphosphate double salt.
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| CN104151299A (en) * | 2014-08-22 | 2014-11-19 | 北京科莱博医药开发有限责任公司 | Compound, crystal form compound and preparation method thereof |
| CN104628708A (en) * | 2013-11-13 | 2015-05-20 | 北大方正集团有限公司 | Avanaphil crystal form as well as preparation method, application and pharmaceutical composition thereof |
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| CN1374953A (en) * | 1999-09-16 | 2002-10-16 | 田边制药株式会社 | Aromatic nitrogenous six-membered ring compounds |
| JP2002338466A (en) * | 2001-03-15 | 2002-11-27 | Tanabe Seiyaku Co Ltd | Pharmaceutical composition |
| CN101511364A (en) * | 2006-09-07 | 2009-08-19 | 尼科梅德有限责任公司 | Combination treatment for diabetes mellitus |
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| CN1374953A (en) * | 1999-09-16 | 2002-10-16 | 田边制药株式会社 | Aromatic nitrogenous six-membered ring compounds |
| JP2002338466A (en) * | 2001-03-15 | 2002-11-27 | Tanabe Seiyaku Co Ltd | Pharmaceutical composition |
| CN101511364A (en) * | 2006-09-07 | 2009-08-19 | 尼科梅德有限责任公司 | Combination treatment for diabetes mellitus |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104628708A (en) * | 2013-11-13 | 2015-05-20 | 北大方正集团有限公司 | Avanaphil crystal form as well as preparation method, application and pharmaceutical composition thereof |
| CN104151299A (en) * | 2014-08-22 | 2014-11-19 | 北京科莱博医药开发有限责任公司 | Compound, crystal form compound and preparation method thereof |
| CN104151299B (en) * | 2014-08-22 | 2017-03-08 | 北京科莱博医药开发有限责任公司 | Compound, crystal-form compound and preparation method thereof |
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