JP5398662B2 - ヌクレオチドアナログ組成物および合成方法 - Google Patents
ヌクレオチドアナログ組成物および合成方法 Download PDFInfo
- Publication number
- JP5398662B2 JP5398662B2 JP2010175808A JP2010175808A JP5398662B2 JP 5398662 B2 JP5398662 B2 JP 5398662B2 JP 2010175808 A JP2010175808 A JP 2010175808A JP 2010175808 A JP2010175808 A JP 2010175808A JP 5398662 B2 JP5398662 B2 JP 5398662B2
- Authority
- JP
- Japan
- Prior art keywords
- pmpa
- typically
- bppf
- adenine
- composition
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 239000000203 mixture Substances 0.000 title abstract description 111
- 125000003729 nucleotide group Chemical group 0.000 title 1
- 238000001308 synthesis method Methods 0.000 title 1
- -1 diethyl PMPA Chemical compound 0.000 claims abstract description 47
- 238000000034 method Methods 0.000 claims abstract description 47
- 229930024421 Adenine Natural products 0.000 claims description 9
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims description 9
- 229960000643 adenine Drugs 0.000 claims description 9
- SGOIRFVFHAKUTI-ZCFIWIBFSA-N tenofovir (anhydrous) Chemical compound N1=CN=C2N(C[C@@H](C)OCP(O)(O)=O)C=NC2=C1N SGOIRFVFHAKUTI-ZCFIWIBFSA-N 0.000 claims description 4
- 230000001376 precipitating effect Effects 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- SGOIRFVFHAKUTI-UHFFFAOYSA-N 1-(6-aminopurin-9-yl)propan-2-yloxymethylphosphonic acid Chemical compound N1=CN=C2N(CC(C)OCP(O)(O)=O)C=NC2=C1N SGOIRFVFHAKUTI-UHFFFAOYSA-N 0.000 claims 1
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 abstract description 42
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 abstract description 31
- 238000006243 chemical reaction Methods 0.000 abstract description 31
- 150000001875 compounds Chemical class 0.000 abstract description 23
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 abstract description 18
- MJZYTEBKXLVLMY-UHFFFAOYSA-N 1-(6-aminopurin-9-yl)propan-2-ol Chemical compound N1=CN=C2N(CC(O)C)C=NC2=C1N MJZYTEBKXLVLMY-UHFFFAOYSA-N 0.000 abstract description 11
- 230000015572 biosynthetic process Effects 0.000 abstract description 11
- 239000001530 fumaric acid Substances 0.000 abstract description 11
- 238000002360 preparation method Methods 0.000 abstract description 11
- 238000003786 synthesis reaction Methods 0.000 abstract description 9
- 230000000840 anti-viral effect Effects 0.000 abstract description 7
- 239000000543 intermediate Substances 0.000 abstract description 7
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 abstract description 6
- 239000003960 organic solvent Substances 0.000 abstract description 6
- 239000006227 byproduct Substances 0.000 abstract description 3
- JFVZFKDSXNQEJW-CQSZACIVSA-N tenofovir disoproxil Chemical compound N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N JFVZFKDSXNQEJW-CQSZACIVSA-N 0.000 abstract description 3
- 238000002560 therapeutic procedure Methods 0.000 abstract description 2
- ZRGHYSBYGWGKOY-UHFFFAOYSA-N diethyl (4-methylphenyl)sulfonylmethyl phosphate Chemical compound CCOP(=O)(OCC)OCS(=O)(=O)C1=CC=C(C)C=C1 ZRGHYSBYGWGKOY-UHFFFAOYSA-N 0.000 abstract 1
- 238000011321 prophylaxis Methods 0.000 abstract 1
- WHLKCPQPGTUZBU-UHFFFAOYSA-N 1-[4-[9-(4-pyren-1-ylphenyl)fluoren-9-yl]phenyl]pyrene Chemical compound C1=C2C(C3=CC=C(C=C3)C3(C=4C=CC(=CC=4)C=4C5=CC=C6C=CC=C7C=CC(C5=C76)=CC=4)C4=CC=CC=C4C=4C3=CC=CC=4)=CC=C(C=C3)C2=C2C3=CC=CC2=C1 WHLKCPQPGTUZBU-UHFFFAOYSA-N 0.000 description 73
- 239000013078 crystal Substances 0.000 description 43
- 239000000243 solution Substances 0.000 description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 41
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 33
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- 238000009472 formulation Methods 0.000 description 31
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- 239000003826 tablet Substances 0.000 description 26
- 239000007787 solid Substances 0.000 description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- JFVZFKDSXNQEJW-UHFFFAOYSA-N [1-(6-aminopurin-9-yl)propan-2-yloxymethyl-(propan-2-yloxycarbonyloxymethoxy)phosphoryl]oxymethyl propan-2-yl carbonate Chemical compound N1=CN=C2N(CC(C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N JFVZFKDSXNQEJW-UHFFFAOYSA-N 0.000 description 22
- 239000004480 active ingredient Substances 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- 239000000047 product Substances 0.000 description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 19
- 229910052744 lithium Inorganic materials 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 14
- 238000003756 stirring Methods 0.000 description 13
- 239000002585 base Substances 0.000 description 11
- 239000007788 liquid Substances 0.000 description 11
- 239000000843 powder Substances 0.000 description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- 239000000546 pharmaceutical excipient Substances 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 9
- 229940011051 isopropyl acetate Drugs 0.000 description 9
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 238000000113 differential scanning calorimetry Methods 0.000 description 8
- 239000008187 granular material Substances 0.000 description 8
- 238000000634 powder X-ray diffraction Methods 0.000 description 8
- 235000019441 ethanol Nutrition 0.000 description 7
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 6
- GCOFRXOOFANVPB-SNVBAGLBSA-N 9-[(2r)-2-(diethoxyphosphorylmethoxy)propyl]purin-6-amine Chemical compound N1=CN=C2N(C[C@@H](C)OCP(=O)(OCC)OCC)C=NC2=C1N GCOFRXOOFANVPB-SNVBAGLBSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 238000004566 IR spectroscopy Methods 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 6
- 238000013019 agitation Methods 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000006071 cream Substances 0.000 description 6
- UOEFFQWLRUBDME-UHFFFAOYSA-N diethoxyphosphorylmethyl 4-methylbenzenesulfonate Chemical compound CCOP(=O)(OCC)COS(=O)(=O)C1=CC=C(C)C=C1 UOEFFQWLRUBDME-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000004615 ingredient Substances 0.000 description 6
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 6
- 239000000376 reactant Substances 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- CTKINSOISVBQLD-VKHMYHEASA-N (S)-Glycidol Chemical compound OC[C@H]1CO1 CTKINSOISVBQLD-VKHMYHEASA-N 0.000 description 5
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 5
- 229920002785 Croscarmellose sodium Polymers 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 229920000881 Modified starch Polymers 0.000 description 5
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 5
- 150000004703 alkoxides Chemical class 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 5
- 239000012298 atmosphere Substances 0.000 description 5
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 5
- 239000003995 emulsifying agent Substances 0.000 description 5
- 239000000839 emulsion Substances 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 229960001021 lactose monohydrate Drugs 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- SDTMFDGELKWGFT-UHFFFAOYSA-N 2-methylpropan-2-olate Chemical compound CC(C)(C)[O-] SDTMFDGELKWGFT-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- 239000004775 Tyvek Substances 0.000 description 4
- 229920000690 Tyvek Polymers 0.000 description 4
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 239000011230 binding agent Substances 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 238000007906 compression Methods 0.000 description 4
- 229960001681 croscarmellose sodium Drugs 0.000 description 4
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 235000019197 fats Nutrition 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 239000000314 lubricant Substances 0.000 description 4
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 239000002002 slurry Substances 0.000 description 4
- 238000001757 thermogravimetry curve Methods 0.000 description 4
- 239000008096 xylene Substances 0.000 description 4
- RUOJZAUFBMNUDX-GSVOUGTGSA-N (4r)-4-methyl-1,3-dioxolan-2-one Chemical compound C[C@@H]1COC(=O)O1 RUOJZAUFBMNUDX-GSVOUGTGSA-N 0.000 description 3
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 3
- 208000036142 Viral infection Diseases 0.000 description 3
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 230000006835 compression Effects 0.000 description 3
- 238000013270 controlled release Methods 0.000 description 3
- 239000007884 disintegrant Substances 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 description 3
- 229940093499 ethyl acetate Drugs 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- NBTOZLQBSIZIKS-UHFFFAOYSA-N methoxide Chemical group [O-]C NBTOZLQBSIZIKS-UHFFFAOYSA-N 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 125000005270 trialkylamine group Chemical group 0.000 description 3
- 230000009385 viral infection Effects 0.000 description 3
- 238000005550 wet granulation Methods 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- MJZYTEBKXLVLMY-RXMQYKEDSA-N (2r)-1-(6-aminopurin-9-yl)propan-2-ol Chemical compound N1=CN=C2N(C[C@H](O)C)C=NC2=C1N MJZYTEBKXLVLMY-RXMQYKEDSA-N 0.000 description 2
- LVOASXNJWPROPP-UHFFFAOYSA-N (4-methylphenyl)sulfonyloxymethylphosphonic acid Chemical compound CC1=CC=C(S(=O)(=O)OCP(O)(O)=O)C=C1 LVOASXNJWPROPP-UHFFFAOYSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- XFJOUYRJZNKVJV-UHFFFAOYSA-N 4-chlorobutan-2-yl hydrogen carbonate Chemical compound ClCCC(C)OC(O)=O XFJOUYRJZNKVJV-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
- 240000007472 Leucaena leucocephala Species 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 229930040373 Paraformaldehyde Natural products 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000007913 intrathecal administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- 239000003883 ointment base Substances 0.000 description 2
- 229920002866 paraformaldehyde Polymers 0.000 description 2
- 239000006072 paste Substances 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 229940090181 propyl acetate Drugs 0.000 description 2
- 230000002685 pulmonary effect Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 238000007910 systemic administration Methods 0.000 description 2
- HLZKNKRTKFSKGZ-UHFFFAOYSA-N tetradecan-1-ol Chemical compound CCCCCCCCCCCCCCO HLZKNKRTKFSKGZ-UHFFFAOYSA-N 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- 239000001993 wax Substances 0.000 description 2
- XINQFOMFQFGGCQ-UHFFFAOYSA-L (2-dodecoxy-2-oxoethyl)-[6-[(2-dodecoxy-2-oxoethyl)-dimethylazaniumyl]hexyl]-dimethylazanium;dichloride Chemical compound [Cl-].[Cl-].CCCCCCCCCCCCOC(=O)C[N+](C)(C)CCCCCC[N+](C)(C)CC(=O)OCCCCCCCCCCCC XINQFOMFQFGGCQ-UHFFFAOYSA-L 0.000 description 1
- QMMJWQMCMRUYTG-UHFFFAOYSA-N 1,2,4,5-tetrachloro-3-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=C(Cl)C(Cl)=CC(Cl)=C1Cl QMMJWQMCMRUYTG-UHFFFAOYSA-N 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- LGEZTMRIZWCDLW-UHFFFAOYSA-N 14-methylpentadecyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCC(C)C LGEZTMRIZWCDLW-UHFFFAOYSA-N 0.000 description 1
- SFAAOBGYWOUHLU-UHFFFAOYSA-N 2-ethylhexyl hexadecanoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(CC)CCCC SFAAOBGYWOUHLU-UHFFFAOYSA-N 0.000 description 1
- 125000004398 2-methyl-2-butyl group Chemical group CC(C)(CC)* 0.000 description 1
- 125000004918 2-methyl-2-pentyl group Chemical group CC(C)(CCC)* 0.000 description 1
- 125000004922 2-methyl-3-pentyl group Chemical group CC(C)C(CC)* 0.000 description 1
- 125000004917 3-methyl-2-butyl group Chemical group CC(C(C)*)C 0.000 description 1
- 125000004921 3-methyl-3-pentyl group Chemical group CC(CC)(CC)* 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- 125000004920 4-methyl-2-pentyl group Chemical group CC(CC(C)*)C 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 239000004358 Butane-1, 3-diol Substances 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 235000013162 Cocos nucifera Nutrition 0.000 description 1
- 244000060011 Cocos nucifera Species 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 241000713813 Gibbon ape leukemia virus Species 0.000 description 1
- 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 description 1
- 238000003109 Karl Fischer titration Methods 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 206010038997 Retroviral infections Diseases 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 235000015241 bacon Nutrition 0.000 description 1
- 239000013060 biological fluid Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229940082500 cetostearyl alcohol Drugs 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- SASYSVUEVMOWPL-NXVVXOECSA-N decyl oleate Chemical compound CCCCCCCCCCOC(=O)CCCCCCC\C=C/CCCCCCCC SASYSVUEVMOWPL-NXVVXOECSA-N 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000012631 diagnostic technique Methods 0.000 description 1
- 239000002027 dichloromethane extract Substances 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- PQZTVWVYCLIIJY-UHFFFAOYSA-N diethyl(propyl)amine Chemical compound CCCN(CC)CC PQZTVWVYCLIIJY-UHFFFAOYSA-N 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 238000010571 fourier transform-infrared absorption spectrum Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 239000010439 graphite Substances 0.000 description 1
- 229910002804 graphite Inorganic materials 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 239000008241 heterogeneous mixture Substances 0.000 description 1
- 229920001903 high density polyethylene Polymers 0.000 description 1
- 239000004700 high-density polyethylene Substances 0.000 description 1
- 238000009775 high-speed stirring Methods 0.000 description 1
- 239000008309 hydrophilic cream Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000002664 inhalation therapy Methods 0.000 description 1
- 230000000266 injurious effect Effects 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 229940078545 isocetyl stearate Drugs 0.000 description 1
- XUGNVMKQXJXZCD-UHFFFAOYSA-N isopropyl palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC(C)C XUGNVMKQXJXZCD-UHFFFAOYSA-N 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 229940071648 metered dose inhaler Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 239000007932 molded tablet Substances 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 239000002324 mouth wash Substances 0.000 description 1
- 229940043348 myristyl alcohol Drugs 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- GNVRJGIVDSQCOP-UHFFFAOYSA-N n-ethyl-n-methylethanamine Chemical compound CCN(C)CC GNVRJGIVDSQCOP-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- ZPVFWPFBNIEHGJ-UHFFFAOYSA-N n-hexyl methyl ketone Natural products CCCCCCC(C)=O ZPVFWPFBNIEHGJ-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 238000010935 polish filtration Methods 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920006324 polyoxymethylene Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- 238000003918 potentiometric titration Methods 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- RUOJZAUFBMNUDX-UHFFFAOYSA-N propylene carbonate Chemical compound CC1COC(=O)O1 RUOJZAUFBMNUDX-UHFFFAOYSA-N 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 239000013074 reference sample Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 229940100611 topical cream Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229940100615 topical ointment Drugs 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000723 toxicological property Toxicity 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- LGQXXHMEBUOXRP-UHFFFAOYSA-N tributyl borate Chemical compound CCCCOB(OCCCC)OCCCC LGQXXHMEBUOXRP-UHFFFAOYSA-N 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
- C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Virology (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Communicable Diseases (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- AIDS & HIV (AREA)
- Tropical Medicine & Parasitology (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Saccharide Compounds (AREA)
- Medicinal Preparation (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Steroid Compounds (AREA)
Description
本発明は、9−[2−(R)−[[ビス[[(イソプロポキシカルボニル)オキシ]メトキシ]ホスフィノイル]メトキシ]プロピル]アデニン(「ビス(POC)PMPA」)、および抗ウイルス剤として使用するための、(R)−9−[2−(ホスホノメトキシ)プロピル]アデニン(「PMPA」)のヒトまたは動物への経口送達のために適切な組成物に関する。
本発明は、9−[2−(R)−[[ビス[[(イソプロポキシカルボニル)オキシ]メトキシ]ホスフィ
ノイル]メトキシ]プロピル]−アデニン・フマル酸(1:1)(「ビス(POC)PMPAフマレート」または「BPPF」)を含む、式(1)の組成物を提供し、
(項目1)以下の式(1)の組成物であって、
(項目2)両方のRが−CH2−O−C(O)−O−CH(CH3)2である、項目1に記載の組成物。
(項目3)前記組成物が結晶性固体である、項目1に記載の組成物。
(項目4)前記化合物が、炭素原子キラル中心(*)で富化されるかまたは分割される、項目1に記載の組成物。
(項目5)約25.0の2θ(度)で表される、Cu−Kα照射を使用するX−線粉末回折スペクトルピークを有する、項目1に記載の組成物。
(項目6)項目1に記載の組成物および受容可能な賦形剤を含む、組成物。
(項目7)リチウムアルコキシドおよび9−(2−ヒドロキシプロピル)アデニン溶液を含む、組成物。
(項目8)約2.7〜3.5のpHで(R,S)−PMPA溶液を含む組成物であって、ここで、該溶液は、約0.1g/mL未満の(R,S)−PMPAを有し、そしてここで、約90〜94%のPMPAは(R)立体配置である、組成物。
(項目9)ウイルスに感染したかまたはウイルス感染の危険のある患者へ、治療的に有効量の項目1に記載の組成物を、経口投与する工程を含む方法。
(項目10)ビス(POC)PMPAをフマル酸と接触する工程を含む、項目1に記載の組成物を生成するための方法。
(項目11)フマル酸が2−プロパノール中に溶解される、項目10に記載の方法。
(項目12)項目7に記載の組成物を生成するための方法であって、リチウムアルコキシドを9−(2−ヒドロキシプロピル)アデニン溶液と混合する工程を含む、方法。
(項目13)前記リチウムアルコキシドが、メトキシド、エトキシド、n−プロポキシド、i−プロポキシド、n−ブトキシド、i−ブトキシド、t−ブトキシド、ネオペントキシド、n−ペントキシド、i−ペントキシドまたはn−ヘキソキシド、n−ヘプトキシド、2−ヘプトキシド、n−オクトキシド、2−オクトキシド、典型的にはt−ブトキシドまたはi−プロポキシドからなる群より選択されるアルコキシドである、項目12に記載の方法。
(項目14)前記リチウムアルコキシドが、リチウムt−ブトキシドまたはリチウムi−プロポキシドである、項目13に記載の方法。
(項目15)約0.08g/mL未満の(R,S)−PMPAを含む溶液のpHを約2.7〜3.5に調節する工程を含む方法であって、ここで、約90〜94%のPMPAが(R)立体配置である、方法。
(項目16)9−[2−(R)−[[ビス[[(イソプロポキシカルボニル)オキシ]メトキシ]ホスフィノイル]メトキシ]プロピル]アデニン・フマル酸(1:1)、前ゼラチン化デンプン、クロスカルメロースナトリウム、ラクトース一水和物およびステアリン酸マグネシウムを含む錠剤を含有する、組成物。
(項目17)前記9−[2−(R)−[[ビス[[(イソプロポキシカルボニル)オキシ]メトキシ]ホスフィノイル]メトキシ]プロピル]アデニン・フマル酸(1:1)が結晶性である、項目16に記載の組成物。
(項目18)前記錠剤が、75mgの9−[2−(R)−[[ビス[[(イソプロポキシカルボニル)オキシ]メトキシ]ホスフィノイル]メトキシ]プロピル]アデニン・フマル酸(1:1)、11mgの前ゼラチン化デンプン、8.8mgのクロスカルメロースナトリウム、123.6mgのラクトース一水和物および2.2mgのステアリン酸マグネシウムを含む、項目16に記載の組成物。
(項目19)液体および薬学的に受容可能な賦形剤を含む混合物から、湿った顆粒を調製するプロセスによって生成される、9−[2−(R)−[[ビス[[(イソプロポキシカルボニル)オキシ]メトキシ]ホスフィノイル]メトキシ]プロピル]アデニン・フマル酸(1:1)を含む生成物。
(項目20)前記液体が水であり、そして前記プロセスが必要に応じてさらに湿った顆粒を乾燥させる工程を包含する、項目19に記載の生成物。
本明細書中で使用される「アルキル」は、反対の記述が無ければ、1、2、3、4、5、6、7、8、9、10、11または12の第一級、第二級、第三級または環状構造を含む炭化水素である。その例は、−CH3、−CH2CH3、−CH2CH2CH3、−CH(CH3)2、−CH2CH2CH2CH3、−CH2CH(CH3)2、−CH(CH3)CH2CH3、−C(CH3)3、−CH2CH2CH2CH2CH3、−CH(CH3)CH2CH2CH3、−CH(CH2CH3)2、−C(CH3)2CH2CH3、−CH(CH3)CH(CH3)2、−CH2CH2CH(CH3)2、−CH2CH(CH3)CH2CH3、−CH2CH2CH2CH2CH2CH3、−CH(CH3)CH2CH2CH2CH3、−CH(CH2CH3)(CH2CH2CH3)、−C(CH3)2CH2CH2CH3、−CH(CH3)CH(CH3)CH2CH3、−CH(CH3)CH2CH(CH3)2、−C(CH3)(CH2CH3)2、−CH(CH2CH3)CH(CH3)2、−C(CH3)2CH(CH3)2、−CH(CH3)C(CH3)3、シクロプロピル、シクロブチル、シクロプロピルメチル、シクロペンチル、シクロブチルメチル、1−シクロプロピル−1−エチル、2−シクロプロピル−1−エチル、シクロヘキシル、シクロペンチルメチル、1−シクロブチル−1−エチル、2−シクロブチル−1−エチル、1−シクロプロピル−1−プロピル、2−シクロプロピル−1−プロピル、3−シクロプロピル−1−プロピル、2−シクロプロピル−2−プロピル、および1−シクロプロピル−2−プロピル、である。
結晶性BPPFは、遊離の塩基および他の塩と比較して、予想外に優れた物理−化学の特性の組み合わせを有する。結晶性BPPFは、高融点を有し、非吸湿性であり、優れた固体状態安定性を有し、そして良好な水溶性および安定性を有する。これらの特性は、製造あるいはヒトおよび動物における優れた経口バイオアベイラビリティー特性の寄与のために有用である。これらの特性は、生体流体(例えば、血漿または細胞原形質)へのBPPFまたはPMPAの効率的な送達を可能とする。例えば、ヒトにおいて一日一回投与される、75mgの結晶性BPPFの経口バイオアベイラビリティーは、約30〜40%である。
態を得た。研究者は通常、結晶性組成物の特徴づけまたは同定のために、X線粉末回折を使用する(例えば、U.S.Pharmacopoeia, 第23巻, 1995, 方法941, 1843−1845頁, U.S.P. Pharmacopeial Convention,Inc, Rockville, MD; Stoutら, X−Ray Structure Determination; A Practical Guide,MacMillan Co., New York, N.Y. 1968を参照のこと)。結晶性
化合物から得られる回折パターンは、しばしば、与えられた結晶形態の診断用であるが、結晶の連続的なバッチから得られる回折パターンの複製として、弱いまたは非常に弱い回折ピークが必ず表れ得るわけではない。これは、他の結晶性組成物が、感知可能な量のサンプル中に存在する場合に、特定のものである。バンドの相対的な強度、特に、低角のX線入射の値(低2θ)は、好ましい配向効果、結晶成長の方向、粒子サイズおよび測定の他の条件に従って変化し得る。従って、回折ピークの相対強度は、結論的に、問題の結晶形態の診断用とならない。代わりに、BPPF結晶の同一性を決定するために、正確な振幅よりもむしろ、相対的な間隔および一般的なパターンを必要に応じて含む、ピークの位置を見るべきである。さらに、高純度の参照サンプルで観察された全てのバンドを同定に使用する必要は無い;単一のバンドでさえ与えられた結晶形態を診断し得る(例えば、cBPPFについて25.0)。
、物理的情報を提供し得る。
PMPAおよびビス(POC)PMPAは、特にレトロウイルス、HIV、SIVおよびGALV、およびヘパドナウイルス(例えば、HBV)を含む、ヒトまたは動物における1つ以上のウイルス感染の、処置または予防法において有用であることが公知である。PMPAを用いて処理されるべき他の感染は、MSV、RSV、FIV、MuLV、および齧歯類および他の動物の他のレトロウイルス感染を含む。先行技術は、PMPAの抗ウイルス特異性を記述し、そして本発明の化合物はこの特異性を有する。
BPPFは、フマル酸とPMPAとの間に複合体または塩を形成することによって調製される。PMPAは、公知の方法によるかまたは以下の手順によって調製される、公知の化合物である。
PMPA調製方法について:(S)−グリシドール(Glycidol)を、接触水素化によって(R)−1,2−プロパンジオールに還元し、次いでこれをジエチルカーボネートと反応させて(R)−1,2−プロピレンカーボネートとする。このカーボネートを、アデニンおよび触媒量の塩基(例えば、水酸化ナトリウム)と反応させて、(R)−9−[2−(ジエチルホスホノメトキシ)プロピル]アデニンを得、これを、単離することなく、リチウムアルコキシドおよびジエチルp−トルエンスルホニル−オキシメチルホスホネート(ジエチルホスファイトとパラホルムアルデヒドとを反応させ、生成物をインサイチュでトシル化させることによって調製する)と反応させる。得られる(R)−9−[2−ジエチルホスホノメトキシプロピル]アデニンを、ブロモトリメチルシランで脱エステル化して、粗PMPAを得、次いでこれを、pHを調節した水からの沈殿によって精製する。生成物をさらに水からの再結晶によって精製してPMPA一水和物とする。
不活性雰囲気(例えば、窒素)を含む反応器中、トルエン(0.11kg)中のジエチルホスファイト(0.80kg)、パラホルムアルデヒド(0.22kg)、およびトリエチルアミン(0.06kg)の混合物を87℃で約2時間加熱し、次いで、TLCでモニターしたときに検出可能なジエチルホスファイトを微量に示すかまたは示さないように、反応が完了するまで、約1時間還流する。反応の間、不活性雰囲気を維持する。トルエンは、反応を緩和するために使用し、そうでなければ制御不能となり得る。反応の完了を、任意に1HNMR(δ 8.4〜8.6ppmのジエチルホスファイトのピークはもはや検出されない)によって確認する。溶液を約1℃まで(典型的には約−2〜4℃)冷却し、p−トルエンスルホニルクロリド(1.0kg)を添加し、次いで約5℃でトリエチルアミン(0.82kg)をゆっくり添加し(発熱性の添加)、この間温度を約10℃を超えないように維持する(典型的には0〜10℃)。得られる混合物を22℃まで加温し、そして反応の完了がTLCによって示される(p−トルエンスルホニルクロリドが微量に検出されるかまたは検出されない)まで少なくとも約5時間攪拌し(典型的には約4.5〜6.0時間)、そして任意に1HNMR(δ 7.9ppmのp−トルエンスルホニルクロリドの二重線のピークはもはや検出されない)によって確認する。固体を濾過によって除去し、トルエン(0.34kg)で洗浄する。合わせた洗浄液および濾液を、水で2回(洗浄1回あたり1.15kg)、または必要に応じて水(1.15kg)、5%炭酸ナトリウム水溶液(3.38kg)、次いで水で2回(洗浄1回あたり1.15kg)の順序のいずれかで洗浄する。各洗浄の後に、反応器の含有物を短時間攪拌し、固体を沈降させ、下方の水層を廃棄する。反応物が乳濁物になる場合、ブライン(0.08kgのNaClを含む0.23kgの水)を第1の有機/水混合物に添加し得、続いて、反応器含有物を攪拌し、固体を沈降させ、下方の水層を廃棄し、1.15kgの水を添加し、攪拌し、固体を沈降させ、再び下方の水層を廃棄する。50℃を超えない有機相を減圧で蒸留し(110℃で10%を超えないLOD、およびKF滴定により0.3%を超えない含水量まで)、収率約60〜70%の表題化合物を、純度約85〜95%のオイルとして、トルエンを含まずに、得る。
粗(R)−PMPAを、(R)−PMPAジエチルエステルを遊離酸に転換することによって調製する。(R)−PMPA約90〜94%および(S)−PMPA約6〜10%を含む混合物中の(R)−異性体の割合は、(R)−PMPA約97〜99%まで増
加し得る。(R)−異性体の濃縮は、約2.7〜3.5のpHで、(R,S)−PMPAを含む組成物からPMPAを沈殿させることによって達成され、ここで、溶液は約0.1g/mL未満の、一般的には約0.08g/mL未満の、典型的には約0.07g/mL未満の(R,S)−PMPAを有し、ここで、(R,S)−PMPA溶液は約10〜25℃、典型的には約15〜22℃の温度である。このような(R,S)−PMPA溶液中の約40〜55℃での(R)−PMPA異性体の濃縮は、pHを約2.4〜3.5に調節し、必要に応じて続いて溶液温度を約10〜25℃として、次いで必要に応じてpHを約2.7〜3.5に調節することによって達成し得る。
実施例1
ビス(POC)PMPAフマレートの物理特性。cBPPFのX−線粉末回折パターンを、General Electric model XRD−5 X−線回折計およびSiemens SoftwareSystemsインターフェースを使用して、公表された手順(U.S. Pharmacopoeia、第23巻、1995、方法941、U.S.P.Pharmacopeial Convention, Inc, Rockville, MD)に従って、1分あたり2度(degree)の2シータ(2θ)のスキャン速度で決定した。グラファイトモノクロメータ(ESIndustries)およびシンチレーション検出器を有する標準焦点銅X−線管(Varican CA−8)を使用して、40KVおよび−20mAで操作したX−線発生装置に曝することによって、BPPF結晶を、4と35度との間の2θで走査した。計算に使用したX−線波長の重み付き平均値は、CuKα1.541838Åであった。BPPFは、約4.9、10.2、10.5、18.2、20.0、21.9、24.0、25.0、25.5、27.8、30.1および30.4の2θ(度)で表される、特徴的なX−線粉末回折ピークを示す。例示的なX−線粉末回折パターンを以下に示す。
収スペクトルを示した。
(R)−PMPAのキラル濃縮。(R,S)−PMPA・H2O(2.5g、約93% R異性体)を、水(100mL)を含むフラスコ中で懸濁し、必要ならばHClまたはNaOHを使用して、pHを7.12に調節した。溶液を40℃まで加温し、pHを約5.0に調節した。次いで、pHを3.1に調節し、溶液に(R)−PMPAを種播した。溶液を室温にまで冷却し、約2時間置いた。固体を、粗ガラスフリット焼結ガラス漏斗上で収集し、氷冷水(10mL)で洗浄し、次いでアセトン(10mL)で洗浄した。得られるPMPAは、98.3%の(R)異性体からなった。2.5gの(R,S)−PMPA(約93%(R)異性体)および25mLの水を使用して同様の手順を行った場合、(R)異性体のキラル濃縮は観察されなかった。0.766gの(R,S)−PMPA(約93%(R)異性体)および10mLの水を使用して同様の手順を行った場合、99.6%(R)異性体までの(R)異性体のキラル濃縮が観察された。
cBPPFおよびビス(POC)PMPA・クエン酸塩の、固体状態化学安定性を、各化合物を異なった条件下で貯蔵した後の分析によって比較した。その結果、BPPF粉末は予想外に、高温および相対湿度において貯蔵に対してより安定であることを示した。
実施例4
ビス(POC)PMPAフマレートの処方物。結晶性BPPFを、いくつかの以下の賦形剤を用いて
処方した。
Claims (5)
- 9−[2−(ホスホノメトキシ)プロピル]アデニンの(R)異性体を濃縮する方法であって、0.1 g/mL未満の(R,S)−9−[2−(ホスホノメトキシ)プロピル]アデニンを含む溶液のpHを2.7〜3.5のpHに調節することによって(R)−9−[2−(ホスホノメトキシ)プロピル]アデニンを沈殿させる工程を含み、ここで、該(R,S)−9−[2−(ホスホノメトキシ)プロピル]アデニンの90〜94%が(R)立体配置である、方法。
- 前記溶液が0.08 g/mL未満の(R,S)−9−[2−(ホスホノメトキシ)プロピル]アデニンを含む、請求項1に記載の方法。
- 前記溶液が0.07 g/mL未満の(R,S)−9−[2−(ホスホノメトキシ)プロピル]アデニンを含む、請求項1に記載の方法。
- 前記溶液が10〜25℃の温度である、請求項1に記載の方法。
- 前記溶液が15〜22℃の温度である、請求項1に記載の方法。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US5377797P | 1997-07-25 | 1997-07-25 | |
US08/900,752 | 1997-07-25 | ||
US60/053,777 | 1997-07-25 | ||
US08/900,752 US5935946A (en) | 1997-07-25 | 1997-07-25 | Nucleotide analog composition and synthesis method |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2008058798A Division JP4628437B2 (ja) | 1997-07-25 | 2008-03-07 | ヌクレオチドアナログ組成物および合成方法 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2013151752A Division JP2013213071A (ja) | 1997-07-25 | 2013-07-22 | ヌクレオチドアナログ組成物および合成方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2010280694A JP2010280694A (ja) | 2010-12-16 |
JP5398662B2 true JP5398662B2 (ja) | 2014-01-29 |
Family
ID=26732232
Family Applications (7)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP51006799A Expired - Lifetime JP4173202B2 (ja) | 1997-07-25 | 1998-07-23 | ヌクレオチドアナログ組成物および合成方法 |
JP2008058798A Expired - Lifetime JP4628437B2 (ja) | 1997-07-25 | 2008-03-07 | ヌクレオチドアナログ組成物および合成方法 |
JP2010175808A Expired - Lifetime JP5398662B2 (ja) | 1997-07-25 | 2010-08-04 | ヌクレオチドアナログ組成物および合成方法 |
JP2013151752A Withdrawn JP2013213071A (ja) | 1997-07-25 | 2013-07-22 | ヌクレオチドアナログ組成物および合成方法 |
JP2015138309A Withdrawn JP2015199773A (ja) | 1997-07-25 | 2015-07-10 | ヌクレオチドアナログ組成物および合成方法 |
JP2017000870A Withdrawn JP2017057233A (ja) | 1997-07-25 | 2017-01-06 | ヌクレオチドアナログ組成物および合成方法 |
JP2017210439A Withdrawn JP2018016645A (ja) | 1997-07-25 | 2017-10-31 | ヌクレオチドアナログ組成物および合成方法 |
Family Applications Before (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP51006799A Expired - Lifetime JP4173202B2 (ja) | 1997-07-25 | 1998-07-23 | ヌクレオチドアナログ組成物および合成方法 |
JP2008058798A Expired - Lifetime JP4628437B2 (ja) | 1997-07-25 | 2008-03-07 | ヌクレオチドアナログ組成物および合成方法 |
Family Applications After (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2013151752A Withdrawn JP2013213071A (ja) | 1997-07-25 | 2013-07-22 | ヌクレオチドアナログ組成物および合成方法 |
JP2015138309A Withdrawn JP2015199773A (ja) | 1997-07-25 | 2015-07-10 | ヌクレオチドアナログ組成物および合成方法 |
JP2017000870A Withdrawn JP2017057233A (ja) | 1997-07-25 | 2017-01-06 | ヌクレオチドアナログ組成物および合成方法 |
JP2017210439A Withdrawn JP2018016645A (ja) | 1997-07-25 | 2017-10-31 | ヌクレオチドアナログ組成物および合成方法 |
Country Status (19)
Country | Link |
---|---|
EP (1) | EP0998480B1 (ja) |
JP (7) | JP4173202B2 (ja) |
KR (3) | KR100661153B1 (ja) |
CN (2) | CN100383148C (ja) |
AT (3) | ATE305009T1 (ja) |
AU (1) | AU756793B2 (ja) |
BR (1) | BR9811045A (ja) |
CA (1) | CA2298059C (ja) |
DE (3) | DE69829010T2 (ja) |
DK (2) | DK0998480T3 (ja) |
ES (3) | ES2236389T3 (ja) |
HK (3) | HK1029793A1 (ja) |
ID (1) | ID24701A (ja) |
IN (1) | IN190780B (ja) |
NZ (1) | NZ501287A (ja) |
PT (2) | PT1243590E (ja) |
SG (2) | SG106656A1 (ja) |
TW (2) | TWI224103B (ja) |
WO (1) | WO1999005150A1 (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2013213071A (ja) * | 1997-07-25 | 2013-10-17 | Gilead Sciences Inc | ヌクレオチドアナログ組成物および合成方法 |
Families Citing this family (34)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB0013407D0 (en) * | 2000-06-02 | 2000-07-26 | Astrazeneca Ab | Forms of a chemical compound |
ES2627903T3 (es) * | 2000-07-21 | 2017-08-01 | Gilead Sciences, Inc. | Profármacos de análogos de nucleótidos de fosfonato y métodos para seleccionar y preparar los mismos |
UA93354C2 (ru) * | 2004-07-09 | 2011-02-10 | Гилиад Сайенсиз, Инк. | Местный противовирусный препарат |
TWI471145B (zh) | 2005-06-13 | 2015-02-01 | Bristol Myers Squibb & Gilead Sciences Llc | 單一式藥學劑量型 |
CN100352823C (zh) * | 2005-08-19 | 2007-12-05 | 浙江车头制药有限公司 | 一种腺嘌呤衍生物的制备方法 |
CN100396689C (zh) * | 2006-03-07 | 2008-06-25 | 中国医学科学院医药生物技术研究所 | 一组具有抑制hiv-1/hbv病毒复制活性的替诺福韦单酯化合物 |
WO2008007392A2 (en) | 2006-07-12 | 2008-01-17 | Matrix Laboratories Limited | Process for the preparation of tenofovir |
AU2008253803A1 (en) * | 2007-05-22 | 2008-11-27 | Ultimorphix Technolgies B.V. | Tenofovir disoproxil hemi-fumaric acid Co-crystal |
WO2010026603A2 (en) * | 2008-09-05 | 2010-03-11 | Matrix Laboratories Limited | Novel amine salts of tenofovir, process for producing the same and use thereof in production of tenofovir dioproxil |
CN101906119B (zh) * | 2009-06-03 | 2012-12-26 | 中国人民解放军军事医学科学院毒物药物研究所 | 制备替诺福韦的新方法 |
EP2389929A1 (en) | 2010-05-30 | 2011-11-30 | Abdi Ibrahim Ilac Sanayi ve Ticaret Anonim Sirketi | Pharmaceutical formulations of tenofovir |
CN103282369A (zh) | 2011-04-08 | 2013-09-04 | 劳乐斯实验室私营有限公司 | 抗逆转录病毒化合物与抗氧化酸的固体形式、其制备方法以及其药物组合物 |
CN102295660A (zh) * | 2011-07-04 | 2011-12-28 | 常州大学 | 泰诺福韦的合成工艺 |
EP3070088A1 (en) | 2011-08-16 | 2016-09-21 | Gilead Sciences, Inc. | Tenofovir alafenamide hemifumarate |
CN103626803B (zh) * | 2012-08-23 | 2017-12-15 | 四川海思科制药有限公司 | 替诺福韦二吡呋酯的固体及其制备方法和用途 |
CN107312039B (zh) | 2012-08-30 | 2019-06-25 | 江苏豪森药业集团有限公司 | 一种替诺福韦前药的制备方法 |
CN103230404A (zh) * | 2013-05-14 | 2013-08-07 | 福建广生堂药业股份有限公司 | 替诺福韦二吡呋酯或其药用盐的新用途 |
PT2860184T (pt) | 2013-10-09 | 2018-11-20 | Zentiva Ks | Sal de di-hidrogenofosfato de tenofovir disoproxil |
EP2860185A1 (en) | 2013-10-09 | 2015-04-15 | Zentiva, k.s. | An improved process for the preparation of Tenofovir disoproxil and pharmaceutically acceptable salts thereof |
CN103483385B (zh) * | 2013-10-11 | 2015-11-18 | 福建广生堂药业股份有限公司 | 替诺福韦单酯富马酸盐的新晶型及其制备方法 |
CN104688747B (zh) * | 2013-12-04 | 2019-04-12 | 重庆药友制药有限责任公司 | 包含富马酸替诺福韦二吡呋酯的药物组合物 |
CN104725423A (zh) * | 2013-12-18 | 2015-06-24 | 山东新时代药业有限公司 | 一种富马酸替诺福韦二吡呋酯的合成方法 |
CN103705478B (zh) * | 2013-12-23 | 2020-02-07 | 浙江华海药业股份有限公司 | 含有富马酸替诺福韦二吡呋酯的口服片剂 |
CN104744512B (zh) * | 2013-12-26 | 2017-01-11 | 成都伊诺达博医药科技有限公司 | 一种“一锅法”制备泰诺福韦的新工艺 |
KR20160003532A (ko) | 2014-07-01 | 2016-01-11 | 한미약품 주식회사 | 테노포비어 디소프록실 인산염과, 비금속염 붕해제 및 비금속염 활택제를 포함하는 약학 조성물 |
CN104288118A (zh) * | 2014-07-08 | 2015-01-21 | 南京卡文迪许生物工程技术有限公司 | 富马酸替诺福韦二吡呋酯片剂及其制备方法 |
WO2016052930A1 (ko) * | 2014-09-30 | 2016-04-07 | 한미정밀화학주식회사 | 고순도의 (r)-9-[2-(포스포노메톡시)프로필]아데닌의 제조방법 |
CN106046055A (zh) * | 2016-05-27 | 2016-10-26 | 湖北丽益医药科技有限公司 | R‑9‑(2‑膦酰甲氧基丙基)‑腺嘌呤一水合物晶体及制备、富马酸替诺福韦二吡呋酯制备 |
KR101909570B1 (ko) | 2016-12-05 | 2018-10-19 | (주) 성운파마코피아 | 고순도 테노포비어 디소프록실 제조방법 |
CN108358968B (zh) * | 2018-04-03 | 2020-09-15 | 科兴生物制药股份有限公司 | 一种替诺福韦的制备方法 |
CN109942634A (zh) * | 2019-01-24 | 2019-06-28 | 深圳科兴药业有限公司 | 一种富马酸替诺福韦二吡呋酯的晶型i及制备方法和应用 |
CN110507625A (zh) * | 2019-09-19 | 2019-11-29 | 苏州东瑞制药有限公司 | 一种新型富马酸替诺福韦酯片及其制备方法 |
CN111939134B (zh) * | 2020-08-24 | 2023-02-17 | 山东罗欣药业集团股份有限公司 | 一种抗病毒药物组合物 |
KR20220141457A (ko) | 2021-04-13 | 2022-10-20 | 경동제약 주식회사 | 신규 결정형의 테노포비어 알라펜아미드 말레산염 및 이를 포함하는 약제학적 조성물 |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CS263951B1 (en) * | 1985-04-25 | 1989-05-12 | Antonin Holy | 9-(phosponylmethoxyalkyl)adenines and method of their preparation |
US6057305A (en) * | 1992-08-05 | 2000-05-02 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Antiretroviral enantiomeric nucleotide analogs |
EP0632048B1 (en) * | 1993-06-29 | 2001-03-21 | Mitsubishi Chemical Corporation | Phosphonate-nucleotide ester derivatives |
WO1998004569A1 (en) * | 1996-07-26 | 1998-02-05 | Gilead Sciences, Inc. | Nucleotide analogs |
SG106656A1 (en) * | 1997-07-25 | 2004-10-29 | Gilead Sciences Inc | Nucleotide analog composition and synthesis method |
-
1998
- 1998-07-23 SG SG200200438A patent/SG106656A1/en unknown
- 1998-07-23 CN CNB988074354A patent/CN100383148C/zh not_active Ceased
- 1998-07-23 AT AT02010677T patent/ATE305009T1/de active
- 1998-07-23 KR KR1020007000636A patent/KR100661153B1/ko not_active IP Right Cessation
- 1998-07-23 ES ES02010678T patent/ES2236389T3/es not_active Expired - Lifetime
- 1998-07-23 ID IDW991548A patent/ID24701A/id unknown
- 1998-07-23 CA CA002298059A patent/CA2298059C/en not_active Expired - Lifetime
- 1998-07-23 DK DK98937022T patent/DK0998480T3/da active
- 1998-07-23 JP JP51006799A patent/JP4173202B2/ja not_active Expired - Lifetime
- 1998-07-23 KR KR1020067001297A patent/KR100707505B1/ko not_active IP Right Cessation
- 1998-07-23 PT PT02010678T patent/PT1243590E/pt unknown
- 1998-07-23 ES ES02010677T patent/ES2249511T3/es not_active Expired - Lifetime
- 1998-07-23 DE DE69829010T patent/DE69829010T2/de not_active Expired - Lifetime
- 1998-07-23 EP EP98937022A patent/EP0998480B1/en not_active Expired - Lifetime
- 1998-07-23 DE DE69809750T patent/DE69809750T2/de not_active Expired - Lifetime
- 1998-07-23 DK DK02010677T patent/DK1243593T3/da active
- 1998-07-23 WO PCT/US1998/015254 patent/WO1999005150A1/en not_active Application Discontinuation
- 1998-07-23 AT AT98937022T patent/ATE228526T1/de active
- 1998-07-23 ES ES98937022T patent/ES2187989T3/es not_active Expired - Lifetime
- 1998-07-23 CN CNB200410046290XA patent/CN1251679C/zh not_active Expired - Lifetime
- 1998-07-23 DE DE69831694T patent/DE69831694T2/de not_active Expired - Lifetime
- 1998-07-23 PT PT98937022T patent/PT998480E/pt unknown
- 1998-07-23 BR BR9811045-4A patent/BR9811045A/pt not_active Application Discontinuation
- 1998-07-23 KR KR1020067001298A patent/KR100617608B1/ko not_active IP Right Cessation
- 1998-07-23 AT AT02010678T patent/ATE288914T1/de active
- 1998-07-23 NZ NZ501287A patent/NZ501287A/en not_active IP Right Cessation
- 1998-07-23 AU AU85827/98A patent/AU756793B2/en not_active Expired
- 1998-07-23 SG SG200200487A patent/SG106657A1/en unknown
- 1998-07-24 TW TW087112168A patent/TWI224103B/zh not_active IP Right Cessation
- 1998-07-24 TW TW093112403A patent/TWI242561B/zh not_active IP Right Cessation
- 1998-07-24 IN IN2174DE1998 patent/IN190780B/en unknown
-
2000
- 2000-11-10 HK HK00107207A patent/HK1029793A1/xx not_active IP Right Cessation
-
2003
- 2003-03-25 HK HK03102166.1A patent/HK1051373B/zh not_active IP Right Cessation
- 2003-03-25 HK HK03102167.0A patent/HK1051360B/zh not_active IP Right Cessation
-
2008
- 2008-03-07 JP JP2008058798A patent/JP4628437B2/ja not_active Expired - Lifetime
-
2010
- 2010-08-04 JP JP2010175808A patent/JP5398662B2/ja not_active Expired - Lifetime
-
2013
- 2013-07-22 JP JP2013151752A patent/JP2013213071A/ja not_active Withdrawn
-
2015
- 2015-07-10 JP JP2015138309A patent/JP2015199773A/ja not_active Withdrawn
-
2017
- 2017-01-06 JP JP2017000870A patent/JP2017057233A/ja not_active Withdrawn
- 2017-10-31 JP JP2017210439A patent/JP2018016645A/ja not_active Withdrawn
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2013213071A (ja) * | 1997-07-25 | 2013-10-17 | Gilead Sciences Inc | ヌクレオチドアナログ組成物および合成方法 |
JP2015199773A (ja) * | 1997-07-25 | 2015-11-12 | ギリアード サイエンシーズ, インコーポレイテッド | ヌクレオチドアナログ組成物および合成方法 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5398662B2 (ja) | ヌクレオチドアナログ組成物および合成方法 | |
US5935946A (en) | Nucleotide analog composition and synthesis method | |
AU747163B2 (en) | Nucleotide analog compositions | |
US6451340B1 (en) | Nucleotide analog compositions | |
JP2000515866A (ja) | ヌクレオチドアナログ | |
KR20000029705A (ko) | 뉴클레오타이드동족체 | |
EP1256584B1 (en) | Process for preparing Adefovir Dipivoxil | |
EP1243593A2 (en) | Nucleotide analog composition and synthesis method | |
CA2605226C (en) | Nucleotide analog composition and synthesis method | |
MXPA00000808A (en) | Nucleotide analog composition and synthesis method |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20110331 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20121106 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20130205 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20130208 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20130222 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20130322 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20130722 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20130805 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20130905 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20130912 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20131002 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20131022 |
|
R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
EXPY | Cancellation because of completion of term |