CN100475819C - 一种拟多晶型hiv蛋白酶抑制剂 - Google Patents
一种拟多晶型hiv蛋白酶抑制剂 Download PDFInfo
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- CN100475819C CN100475819C CNB038164590A CN03816459A CN100475819C CN 100475819 C CN100475819 C CN 100475819C CN B038164590 A CNB038164590 A CN B038164590A CN 03816459 A CN03816459 A CN 03816459A CN 100475819 C CN100475819 C CN 100475819C
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- 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
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Abstract
Description
观察数 | 3467[F<sup>2</sup>>2σ(F<sup>2</sup>)] |
剩余(R) | 0.0446 |
x | y | z | U(eq) | |
C16C17C18C19O20C21N22C23C24C25C26S27O28O29C30C31C32C33C34C35N36C37C38O39 | 5494(5)4975(6)3926(5)1423(3)494(2)1829(3)699(3)521(4)-61(4)-1453(5)-47(7)510(1)572(3)-693(2)1854(3)1803(3)2871(4)4033(4)4063(4)2998(4)5076(3)1920(10)1310(10)1768(4) | -581(3)-413(3)126(2)2464(2)2112(1)3307(2)3880(1)4312(2)3785(2)3497(3)4247(3)4414(1)3860(1)4873(1)5080(2)5825(2)6341(2)6133(2)5385(2)4869(2)6667(2)2231(7)1590(6)1393(2) | 8530(3)7881(3)7810(2)7976(2)7502(1)7740(2)7721(1)7048(2)6473(2)6654(2)5779(2)8440(1)9015(1)8345(1)8509(2)8159(2)8195(2)8564(2)8909(2)8883(2)8596(2)5258(4)5564(4)6249(2) | 96(2)98(2)78(1)45(1)61(1)48(1)49(1)58(1)67(1)86(2)102(2)50(1)61(1)65(1)50(1)54(1)56(1)55(1)59(1)56(1)72(1)232(6)191(5)94(1) |
U<sub>11</sub> | U<sub>22</sub> | U<sub>33</sub> | U<sub>23</sub> | U<sub>13</sub> | U<sub>12</sub> | |
C6AO7O8C9N10C11C12C13C14C15C16C17C18C19O20C21N22C23C24C25C26S27O28O29C30C31C32C33C34C35N36C37C38O39 | 47(2)34(1)42(1)35(2)31(1)32(2)44(2)50(2)64(2)68(3)77(3)114(4)89(3)30(2)44(1)36(2)42(1)59(2)79(3)75(3)143(5)44(1)64(2)46(1)50(2)50(2)59(2)57(2)56(2)63(2)67(2)290(10)280(10)99(2) | 80(2)69(1)68(1)41(1)50(1)41(1)42(1)39(1)56(2)72(2)68(2)72(2)60(2)44(1)56(1)42(1)47(1)50(1)59(2)83(2)99(3)47(1)58(1)58(1)46(1)48(1)45(1)55(2)63(2)52(1)70(2)260(10)187(7)91(2) | 59(2)50(1)50(1)49(1)49(1)57(1)87(2)78(2)80(2)100(3)143(4)109(3)85(2)61(1)83(1)64(2)57(1)64(2)62(2)101(3)65(2)61(1)61(1)92(2)54(1)64(2)65(2)52(1)59(2)53(1)80(2)145(7)104(4)93(2) | 5(2)0(1)3(1)1(1)-1(1)-4(1)2(1)0(1)0(2)18(2)26(3)-6(2)-4(2)-3(1)-6(1)2(1)1(1)7(1)1(1)6(2)14(2)2(1)9(1)-4(1)2(1)6(1)4(1)-4(1)6(1)5(1)4(2)68(7)1(5)1(2) | -6(2)-1(1)2(1)-3(1)1(1)0(1)2(2)8(2)5(2)7(2)34(3)32(3)10(2)-5(1)-18(1)-4(1)0(1)-8(2)-11(2)-30(3)-15(3)2(1)3(1)6(1)1(1)-4(2)2(2)1(1)-13(2)-8(2)-5(2)67(8)-53(6)-13(2) | -7(2)-9(1)-12(1)3(1)-2(1)-2(1)-4(1)0(1)9(2)12(2)28(2)38(3)10(2)-5(1)-6(1)-1(1)3(1)1(2)6(2)-5(2)-6(3)1(1)-7(1)10(1)1(1)6(1)1(1)-3(1)-3(2)-2(2)-19(2)120(10)-80(10)-28(2) |
波数(cm<sup>-1</sup>)和吸收带的相对强度(<sup>1</sup>) |
3454w,3429w,3354w,3301w,3255w,3089w,3060w,3041w,3028w |
2964w,2905w,2875w,2856w,2722vw,2684vw,2644vw,2603vw,2234vw |
1704s,1646w,1595s,1550m,1503m,1466w,1453w,1444w,1413w |
1373w,1367w,1340w,1324m,1314m,1306m,1290w,1266m,1244m,1229m |
1187w,1146s,1124m,1104m,1090m,1076m,1052m,1042s,1038m,1024s |
987s,971m,944m,909w,890w,876w,841m,792w,768s,742s,732w,697m,674s,645w,630m |
598w,593w,574m,564s,553vs,538m,533m,531m,526m,508m,501m,491m,471m,458w,445w,442w,436w,428w,418w |
波数(cm<sup>-1</sup>)和吸收带的相对强度(<sup>1</sup>) |
3614w,3361m,3291m,3088w,3061w,3043w,3028w |
2967w,2905w,2872w,2222vw |
1703s,1631w,1595s,1553m,1502w,1467w,1453w,1444w,1436w |
1388vw,1374vw,1366w,1355vw,1340w,1308m,1291w,1267m,1245m |
1187w,1148s,1125m,1105m,1091m,1077m,1052m,1044m,1025s |
990m,972w,944m,912w,891w,876vw,862w,843w,836w,792w,769m,757w,743m,717w,699m,672m |
598w,591w,585w,576m,566m,553vs,536m,509w,502m,484w,471w,432vw,425w,418w |
溶剂 | A型(1∶1)的近似溶解度(mg/ml) |
丙酮 | 106-211 |
二氯甲烷 | 105-209 |
1-甲氧基-2-丙醇 | 160-213 |
甲基乙基甲酮 | 102-204 |
乙酸乙酯 | 71-107 |
无水乙醇 | <3.4 |
庚烷 | <3.4 |
水 | <3.5 |
异丙醚 | <3.4 |
氰酸甲酯(methacyanate) | >200 |
甲醇 | <3.4 |
2-丙醇 | <3.4 |
四氢呋喃 | 102-203 |
甲苯 | <3.5 |
溶剂 | 溶解度(mg/100ml溶液) |
水 | 16(pH 5.9) |
pH 2缓冲液(柠檬酸/HCl) | 18(pH 2.0) |
pH 3缓冲液(柠檬酸/HCl) | 10(pH 3.0) |
pH 4缓冲液(柠檬酸/HCl) | 9(pH 4.0) |
0.01N HCl | 18(pH 2.1) |
0.1N HCl | 83(pH 1.1) |
1.0N HCl | 620(pH 0.2) |
溶剂 | 溶解度(mg/ml溶液) |
水 | 0.16(pH=5.9) |
5%HPβCD水溶液 | 2.4(pH=5.8) |
10%HPβCD水溶液 | 6.5(pH=6.0) |
20%HPβCD水溶液 | 17(pH=6.0) |
40%HPβCD水溶液 | 40(pH=5.9) |
拟多晶型物 | BP[℃] | 半溶剂合物 | 单溶剂合物 | 二溶剂合物 | 三溶剂合物 |
D型 | 56 | 5.0 | 9.6 | 17.5 | 24.1 |
H型 | 152 | 9.0 | 16.5 | 28.3 | 37.2 |
E型 | 40 | 7.2 | 13.4 | 23.7 | 31.8 |
G型 | 119 | 7.6 | 14.1 | 24.8 | 33.1 |
F型 | 76 | 7.4 | 13.9 | 24.3 | 32.6 |
A型 | 78 | 4.0 | 7.8 | 14.4 | 20.2 |
B型 | 100 | 1.6 | 3.2 | 6.2 | 9.0 |
C型 | 65 | 2.8 | 5.5 | 10.5 | 14.9 |
I型 | 66 | 6.2 | 11.6 | 20.8 | 28.3 |
测试 | 出厂数据 | 0月 | 1月 | 3月 |
残存溶剂:%(w/w)乙醇 | 7.5 | 7.6 | 7.6 | 7.1 |
%(w/w)水份 | 0.10 | 0.27 | 0.26 | 0.55 |
测试 | 备注 | 标准 | 出厂数据 | 0月 | 1月 | 3月 | 6月 |
多晶型性DSC | ℃(开始时)最高℃ | 仅供参考仅供参考 | 97.3104 | 97.3104.2 | 95.5103.5 | 97.9104.2 | 97.5104 |
残存溶剂 | %(w/w)乙醇%(w/w)异丙醇%(w/w)THF%(w/w)丙酮%(w/w)CH<sub>2</sub>C1<sub>2</sub> | <=10.0%<=0.5%<=0.5%<=0.5%<=0.06% | 6.710.04<0.01<0.01<0.01 | 6.310.04<0.01<0.01<0.01 | 6.330.05<0.01<0.01<0.01 | 6.400.05<0.01<0.01<0.01 | 6.330.05<0.01<0.01<0.01 |
水分(KF) | %(w/w) | <=7.0% | 0.63 | 0.23 | 0.34 | 0.32 | 0.46 |
X射线粉末衍射 | 仅供参考 | C | C | - | - | - |
测试 | 备注 | 标准 | 出厂数据 | 0月 | 1月 | 3月 | 6月 |
多晶型性DSC | ℃(开始时)最高℃ | 仅供参考仅供参考 | 97.3104 | 97.3104.2 | 97.5103.4 | 98.01039 | 97.8104.3 |
残存溶剂 | %(w/w)乙醇%(w/w)异丙醇%(w/w)THF%(w/w)丙酮%(w/w)CH<sub>2</sub>Cl<sub>2</sub> | <=10.0%<=0.5%<=0.5%<=0.5%<=0.06% | 6.710.04<0.01<0.01<0.01 | 6.310.04<0.01<0.01<0.01 | 6.730.05<0.01<0.01<0.01 | 6.320.05<0.01<0.01<0.01 | 6.500.05<0.01<0.01<0.01 |
水分(KF) | %(w/w) | <=7.0% | 0.63 | 0.23 | 0.37 | 0.34 | 0.42 |
X射线粉末衍射 | 仅供参考 | C | C | - | - | - |
测试 | 备注 | 标准 | 出厂数据 | 0月 | 1月 | 3月 | 6月 |
多晶型性DSC | ℃(开始时)最高℃ | 仅供参考仅供参考 | 97.3104 | 97.3104.2 | 96.3103.1 | 96.2103.8 | 98.5103.9 |
残存溶剂 | %(w/w)乙醇%(w/w)异丙醇%(w/w)THF%(w/w)丙酮%(w/w)CH<sub>2</sub>Cl<sub>2</sub> | <=10.0%<=0.5%<=0.5%<=0.5%<=0.06% | 6.710.04<0.01<0.01<0.01 | 6.310.04<0.01<0.01<0.01 | 6.420.06<0.01<0.01<0.01 | 6.350.05<0.01<0.01<0.01 | 6.520.05<0.01<0.01<0.01 |
水分(KF) | %(w/w) | <=7.0% | 0.63 | 0.23 | 0.32 | 0.38 | 0.49 |
X射线粉末衍射 | 仅供参考 | C | C | - | - | - |
测试 | 备注 | 标准 | 出厂数据 | 0月 | 1月 | 3月 | 6月 |
多晶型性DSC | ℃(开始时)最高℃ | 仅供参考仅供参考 | 97.3104 | 97.3104.2 | 97.8103.4 | 97.5103.7 | 97.9104.0 |
残存溶剂 | %(w/w)乙醇%(w/w)异丙醇%(w/w)THF%(w/w)丙酮%(w/w)CH<sub>2</sub>Cl<sub>2</sub> | <=10.0%<=0.5%<=0.5%<=0.5%<=0.06% | 6.710.04<0.01<0.01<0.01 | 6.310.04<0.01<0.01<0.01 | 6.350.06<0.01<0.01<0.01 | 6.310.05<0.01<0.01<0.01 | 6.300.05<0.01<0.01<0.01 |
水分(KF) | %(w/w) | <=7.0% | 0.63 | 0.23 | 0.31 | 0.36 | 0.51 |
X射线粉末衍射 | 仅供参考 | C | C | - | - | - |
溶剂 | 溶解度(mg/100ml溶液) |
水 | 10(pH 5.1) |
pH 2缓冲液(柠檬酸/HCl) | 23(pH 2.0) |
pH 3缓冲液(柠檬酸/HCl) | 13(pH 3.0) |
pH 4缓冲液(柠檬酸/HCl) | 12(pH 4.0) |
0.01N HCl | 18(pH 2.1) |
0.1N HCl | 150(pH 1.1) |
1.0N HCl | 510(pH 0.14) |
波数(cm<sup>-1</sup>)和吸收带的相对强度(<sup>1</sup>) |
3362m,3064w |
2985m,2964m,2906m,2873m,2632w,2585w |
1687s,1627w,1601w |
1554m,1495m,1480w,1470w,1452w,1443w,1421w |
1383w,1373w,1369w,1345m,1324m,1314m,1299w,1268m,1245m,1221m,1202s |
1190s,1166vs,1122m,1091m,1077m,1051s,1043s,1023m,1002m |
992m,969w,943w,912w,888w,867vw,836w,813vw |
773m,754w,743m,711w,700m,658m,634w |
581w,556m,505w,472vw,452vw,435vw,417vw |
波数(cm<sup>-1</sup>)和吸收带的相对强度(<sup>1</sup>) |
3080m,3068m,3059m,3043w,3022w,3006m |
2989s,2978s,2962s,2933vs,2906m,2871m |
1685vw,1628w,1603s,1585w,1495w,1479w,1466w,1450m,1423w |
1381w,1346w,1336w,1313w,1290w,1271w,1244w,1230w,1209m |
1190w,1182m,1163vs,1122w,1105w,1090m,1049vs,1032w,1003s |
968w,955w,941w,914w,897w,877w,866w,845w,823m,814m |
783m,771m,742w,658w,634m,621w |
577w,561m,534w,524w,497w,451w,436w |
337w,308w,287m,247w,206w,162m,129m |
溶剂 | 溶解度(mg/100ml溶液) |
水 | 19(pH 3.3) |
pH 2缓冲液(柠檬酸/HCl) | 21(pH 2.0) |
pH 3缓冲液(柠檬酸/HCl) | 12(pH 3.0) |
pH 4缓冲液(柠檬酸/HCl) | 11(pH 4.0) |
0.01N HCl | 24(pH 2.0) |
20%HPβCD水溶液 | 2100(pH 1.6) |
Claims (18)
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PT1088098E (pt) | 1998-06-23 | 2011-05-25 | Univ Illinois | Medicamento para tratar mam?feros infectados com hiv |
EA007120B8 (ru) | 2002-05-16 | 2012-03-30 | Тиботек Фармасьютикалз Лтд. | Псевдополиморфные формы ингибитора вич-протеазы |
HRP20020614A2 (en) * | 2002-07-22 | 2004-06-30 | PLIVA-ISTRAŽIVAČKI INSTITUT d.o.o. | Rhombic pseudopolymorph of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin a |
JP4818124B2 (ja) | 2003-12-23 | 2011-11-16 | テイボテク・フアーマシユーチカルズ・リミテツド | (3R,3aS,6aR)−ヘキサヒドロフロ〔2,3−b〕フラン−3−イル(1S,1R)−3−〔〔(4−アミノフェニル)スルホニル〕(イソブチル)アミノ〕−1−ベンジル−2−ヒドロキシプロピルカルバマートの製造方法 |
KR101333627B1 (ko) | 2005-02-25 | 2013-11-27 | 얀센 알 앤드 디 아일랜드 | 프로테아제 저해제 전구체 합성 |
WO2008055970A2 (en) * | 2006-11-09 | 2008-05-15 | Tibotec Pharmaceuticals Ltd. | Methods for the preparation of hexahydrofuro[2,3-b]furan-3-ol |
AR073248A1 (es) | 2008-09-01 | 2010-10-20 | Tibotec Pharm Ltd | Proceso para la preparacion de (1s, 2r)-3- ((4-aminofenil) sulfonil) ( isobutil) amino)-1- bencil-2- hidroxipropilcarbamato de (3r, 3as,6ar)- hexahidrofuro-(2,3-b) furan-3- ilo (darunavir) y compuestos intermediarios utiles en dicho proceso. |
US8921415B2 (en) | 2009-01-29 | 2014-12-30 | Mapi Pharma Ltd. | Polymorphs of darunavir |
MX2011007790A (es) * | 2009-01-29 | 2011-11-18 | Mapi Pharma Ltd | Polimorfos de darunavir. |
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