CN1407987A - 作为逆转录病毒蛋白酶抑制剂的六氢呋喃并[2,3-b]呋喃-3-基-N-{3-[(1,3-苯并二氧杂环戊-5-基磺酰基)(异丁基)氨基]-1-苄基-2-羟丙基}氨基甲酸酯 - Google Patents
作为逆转录病毒蛋白酶抑制剂的六氢呋喃并[2,3-b]呋喃-3-基-N-{3-[(1,3-苯并二氧杂环戊-5-基磺酰基)(异丁基)氨基]-1-苄基-2-羟丙基}氨基甲酸酯 Download PDFInfo
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- CN1407987A CN1407987A CN00816587A CN00816587A CN1407987A CN 1407987 A CN1407987 A CN 1407987A CN 00816587 A CN00816587 A CN 00816587A CN 00816587 A CN00816587 A CN 00816587A CN 1407987 A CN1407987 A CN 1407987A
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- 239000000395 magnesium oxide Substances 0.000 description 1
- 229960000869 magnesium oxide Drugs 0.000 description 1
- 235000012245 magnesium oxide Nutrition 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
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- 229960000689 nevirapine Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
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- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 1
- XDRYMKDFEDOLFX-UHFFFAOYSA-N pentamidine Chemical compound C1=CC(C(=N)N)=CC=C1OCCCCCOC1=CC=C(C(N)=N)C=C1 XDRYMKDFEDOLFX-UHFFFAOYSA-N 0.000 description 1
- 229960004448 pentamidine Drugs 0.000 description 1
- RLLPVAHGXHCWKJ-UHFFFAOYSA-N permethrin Chemical compound CC1(C)C(C=C(Cl)Cl)C1C(=O)OCC1=CC=CC(OC=2C=CC=CC=2)=C1 RLLPVAHGXHCWKJ-UHFFFAOYSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000010773 plant oil Substances 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- YIQPUIGJQJDJOS-UHFFFAOYSA-N plerixafor Chemical compound C=1C=C(CN2CCNCCCNCCNCCC2)C=CC=1CN1CCCNCCNCCCNCC1 YIQPUIGJQJDJOS-UHFFFAOYSA-N 0.000 description 1
- 229960002169 plerixafor Drugs 0.000 description 1
- 229920000447 polyanionic polymer Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229940093916 potassium phosphate Drugs 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- TVDSBUOJIPERQY-UHFFFAOYSA-N prop-2-yn-1-ol Chemical compound OCC#C TVDSBUOJIPERQY-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000019419 proteases Nutrition 0.000 description 1
- 229940121649 protein inhibitor Drugs 0.000 description 1
- 239000012268 protein inhibitor Substances 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 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 description 1
- 238000007154 radical cyclization reaction Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 102200042996 rs1057521927 Human genes 0.000 description 1
- 102200156953 rs121964883 Human genes 0.000 description 1
- 102220246449 rs143520192 Human genes 0.000 description 1
- 102220018603 rs397517057 Human genes 0.000 description 1
- 102200002453 rs55758736 Human genes 0.000 description 1
- 102220053718 rs573489857 Human genes 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000010956 selective crystallization Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000002600 sunflower oil Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- FIAFUQMPZJWCLV-UHFFFAOYSA-N suramin Chemical compound OS(=O)(=O)C1=CC(S(O)(=O)=O)=C2C(NC(=O)C3=CC=C(C(=C3)NC(=O)C=3C=C(NC(=O)NC=4C=C(C=CC=4)C(=O)NC=4C(=CC=C(C=4)C(=O)NC=4C5=C(C=C(C=C5C(=CC=4)S(O)(=O)=O)S(O)(=O)=O)S(O)(=O)=O)C)C=CC=3)C)=CC=C(S(O)(=O)=O)C2=C1 FIAFUQMPZJWCLV-UHFFFAOYSA-N 0.000 description 1
- 229960005314 suramin Drugs 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 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 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229960000838 tipranavir Drugs 0.000 description 1
- NZPXPXAGXYTROM-FYBSXPHGSA-N tipranavir Chemical compound C([C@@]1(CCC)OC(O)=C([C@H](CC)C=2C=C(NS(=O)(=O)C=3N=CC(=CC=3)C(F)(F)F)C=CC=2)C(=O)C1)CC1=CC=CC=C1 NZPXPXAGXYTROM-FYBSXPHGSA-N 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 229950011282 tivirapine Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
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
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Virology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- AIDS & HIV (AREA)
- Tropical Medicine & Parasitology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
Description
化合物 | *1 | *2 | *3 | *4 | *5 | 化合物 | *1 | *2 | *3 | *4 | *5 |
a | R | R | R | R | R | q | R | R | S | S | S |
b | R | R | R | R | S | r | R | S | R | S | S |
c | R | R | R | S | R | s | S | R | R | S | S |
d | R | R | S | R | R | t | R | S | S | R | S |
e | R | S | R | R | R | u | S | R | S | R | S |
f | S | R | R | R | R | v | R | S | S | S | R |
g | R | R | R | S | S | w | S | R | S | S | R |
h | R | R | S | R | S | x | S | S | S | R | R |
i | R | S | R | R | S | y | S | S | R | S | R |
j | S | R | R | R | S | z | S | S | R | R | S |
化合物 | *1 | *2 | *3 | *4 | *5 | 化合物 | *1 | *2 | *3 | *4 | *5 |
k | R | R | S | S | R | aa | S | S | S | S | R |
l | R | S | R | S | R | bb | S | S | S | R | S |
m | S | R | R | S | R | cc | S | S | R | S | S |
n | R | S | S | R | R | dd | S | R | S | S | S |
o | S | R | S | R | R | ee | R | S | S | S | S |
p | S | S | R | R | R | ff | S | S | S | S | S |
病毒株 | 与突变有关的抗性 | SAQ | RIT | IND | NEL | AMP | 化合物14 | 化合物13 |
LAI | 0.0079 | 0.0304 | 0.0276 | 0.0331 | 0.0359 | 0.0008 | 0.0014 | |
r13020 | L10I,K20R,M36I,154V,A71V,V82T,184V | 3.51 | 9.28 | 1.38 | 3.75 | 0.107 | 0.0008 | 0.0014 |
r13021 | L10I,K20R,L24I,M36I,I54V,L63P,A71V,V82T,I84V | 1.45 | >10 | 1.75 | 4.10 | 0.212 | 0.0015 | 0.0055 |
r13022 | K20R,M36I,M46I/M,154V,L63P,A71V/I,V82T,L90M | 0.665 | >10 | 1.70 | 4.03 | 0.181 | 0.0011 | 0.0017 |
r13023 | L10I,M36I/M,I54V/I,L63P,A71V,G73S,I84V,L90M | 0.783 | 3.82 | 0.680 | 1.02 | 0.217 | 0.0028 | 0.0068 |
r13024 | L10I,M36I,L63P,A71V,G73S,I84V,L90M | 2.09 | 2.85 | 1.07 | 3.26 | 0.180 | 0.0055 | 0.0081 |
r13025 | L10I,M46I,L63P,A71V,I84V | 0.157 | 2.24 | 1.25 | 9.13 | 0.661 | 0.0328 | 0.0454 |
r13026 | L10I,M46I,I54V,L63P,A71V,V82T,I84V | 1.99 | >10 | 2.72 | 1.22 | 0.136 | 0.0008 | 0.0014 |
r13027 | L10M/I,K20R,M36I,L63P,A71V,G73S,V77I,I84V,L90M | 2.92 | 3.14 | 0.714 | 3.20 | 0.645 | 0.0073 | 0.0074 |
r13029 | L10I/L,M36I,M46L,L63P,A71V,I84V,N88D,L90M | 2.61 | 3.60 | 0.922 | 3.79 | 0.214 | 0.0052 | 0.0070 |
r13030 | L10V/I,M36I,I54V,L63P,A71V,V82T,L90M | 0.173 | 2.99 | 0.574 | 0.995 | 0.0491 | 0.0002 | 0.0004 |
r13031 | G48V,I54V,V77I,V82A,L90M/L | 0.673 | 0.856 | 0.1542 | 0.497 | 0.0341 | 0.0003 | 0.0005 |
病毒株 | 与突变有关的抗性 | SAQ | IRIT | IND | NEL | AMP | 化合物14 | 化合物13 |
r13033 | L10I,M46L,I54V,L63P,A71V,V82A,L90M | 0.0521 | 3.47 | 0.848 | 1.19 | 0.194 | 0.0011 | 0.0017 |
r13034 | L10I,M36I,I54V,L63P,A71V,I84V | 1.01 | >10 | 0.638 | 1.99 | 0.677 | 0.0055 | 0.0080 |
r13035 | D30N,L63P,V77I,N88D | 0.0053 | 0.0311 | 0.0074 | 0.361 | 0.0105 | 0.0002 | 0.0003 |
r13036 | L10I,L63P,A71V,G73S,L90M | 0.514 | 2.83 | 0.638 | 3.25 | 0.445 | 0.0029 | 0.0054 |
r13037 | L10I,M46I,I54VL63P,A71T,V77IV82A,L90M | 0.0274 | 2.72 | 0.196 | 0.656 | 0.165 | 0.0005 | 0.0003 |
给药后时间(分钟) | 血清中化合物13的浓度(μM) |
060180300 | 0.00000.98580.68690.2159 |
Claims (18)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US15785099P | 1999-10-06 | 1999-10-06 | |
US60/157,850 | 1999-10-06 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1407987A true CN1407987A (zh) | 2003-04-02 |
CN1191256C CN1191256C (zh) | 2005-03-02 |
Family
ID=22565540
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB008165874A Expired - Lifetime CN1191256C (zh) | 1999-10-06 | 2000-10-06 | 作为逆转录病毒蛋白酶抑制剂的六氢呋喃并[2,3-b]呋喃-3-基-N-{3-[(1,3-苯并二氧杂环戊-5-基磺酰基)(异丁基)氨基)-1苄基-2-羟丙基}氨基甲酸酯 |
Country Status (26)
Country | Link |
---|---|
US (2) | US6649651B1 (zh) |
EP (1) | EP1222192B8 (zh) |
JP (1) | JP4951179B2 (zh) |
KR (1) | KR100792391B1 (zh) |
CN (1) | CN1191256C (zh) |
AP (1) | AP1459A (zh) |
AT (1) | ATE398623T1 (zh) |
AU (1) | AU781656B2 (zh) |
BR (1) | BR0014602A (zh) |
CA (1) | CA2386850C (zh) |
CZ (1) | CZ300031B6 (zh) |
DE (1) | DE60039244D1 (zh) |
DK (1) | DK1222192T3 (zh) |
ES (1) | ES2307533T3 (zh) |
HK (1) | HK1054746A1 (zh) |
HU (1) | HU228938B1 (zh) |
IL (2) | IL149005A0 (zh) |
MX (1) | MXPA02003607A (zh) |
NO (1) | NO327996B1 (zh) |
NZ (1) | NZ518580A (zh) |
OA (1) | OA12053A (zh) |
PL (1) | PL204924B1 (zh) |
RU (1) | RU2247123C2 (zh) |
SK (1) | SK287153B6 (zh) |
WO (1) | WO2001025240A1 (zh) |
ZA (1) | ZA200202655B (zh) |
Families Citing this family (28)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NZ518580A (en) * | 1999-10-06 | 2004-01-30 | Us Gov Health & Human Serv | Hexahydrofuro[2,3-B]furan-3-YL-N- {3-[1,3-benzodioxol-5-ylsulfonyl) (isobutyl) amino]-1-benzyl-2-hydroxypropyl} carbamate as retroviral protease inhibitor |
CN100491360C (zh) * | 2001-04-09 | 2009-05-27 | 泰博特克药品有限公司 | 广谱2-(取代的-氨基)-苯并唑磺酰胺hiv蛋白酶抑制剂 |
DE60234952D1 (de) * | 2001-09-10 | 2010-02-11 | Tibotec Pharm Ltd | VERFAHREN ZUR HERSTELLUNG VON HEXAHYDROFUROc2,3-BÜFURAN-3-OL |
US7285566B2 (en) * | 2002-01-07 | 2007-10-23 | Erickson John W | Resistance-repellent retroviral protease inhibitors |
EP1483254A4 (en) * | 2002-01-07 | 2005-06-08 | Sequoia Pharmaceuticals | INHIBITORS OF ANTI-RESISTANCE RETROVIRAL PROTEASE |
US7157489B2 (en) * | 2002-03-12 | 2007-01-02 | The Board Of Trustees Of The University Of Illinois | HIV protease inhibitors |
IL165043A0 (en) | 2002-05-17 | 2005-12-18 | Tibotec Pharm Ltd | broadspectrum substituted benzisoxazole sulfonamide hiv protease inhibitors |
KR101327772B1 (ko) * | 2002-08-02 | 2013-11-11 | 얀센 알 앤드 디 아일랜드 | 광범위 2-아미노-벤조티아졸 설폰아미드 hiv 프로테아제 저해제 |
EP1589018A4 (en) | 2002-12-27 | 2007-03-14 | Sumitomo Chemical Co | PROCESS FOR PRODUCING A DERIVATIVE OF HEXAHYDROFURANOL, INTERMEDIATE THEREOF AND PROCESS FOR PRODUCING THE SAME |
MXPA06010365A (es) * | 2004-03-11 | 2007-05-04 | Sequoia Pharmaceuticals Inc | Inhibidores de proteasa retrovirales repelentes a la resistencia. |
TWI383975B (zh) | 2004-03-31 | 2013-02-01 | Tibotec Pharm Ltd | 製備(3R,3aS,6aR)六氫-呋喃并〔2,3-b〕呋喃-3-醇之方法 |
KR100698291B1 (ko) * | 2004-12-29 | 2007-03-22 | 엘지전자 주식회사 | 조명계 |
JP5260965B2 (ja) | 2005-02-25 | 2013-08-14 | テイボテク・フアーマシユーチカルズ | プロテアーゼ阻害剤前駆体合成 |
EP3696171A1 (en) | 2006-07-07 | 2020-08-19 | Gilead Sciences, Inc. | Modulators of pharmacokinetic properties of therapeutics |
US20090312318A1 (en) * | 2006-07-24 | 2009-12-17 | Desai Manoj C | Therapeutic compounds and methods |
CN102432621B (zh) | 2006-11-09 | 2016-02-17 | 爱尔兰詹森科学公司 | 六氢呋喃并[2,3-b]呋喃-3-醇的制备方法 |
US9808527B2 (en) | 2006-11-21 | 2017-11-07 | Purdue Research Foundation | Methods and compositions for treating HIV infections |
ES2603617T3 (es) | 2007-02-23 | 2017-02-28 | Gilead Sciences, Inc. | Moduladores de propiedades farmacocinéticas de la terapéutica |
US7981929B2 (en) * | 2007-03-16 | 2011-07-19 | Sequoia Pharmaceuticals, Inc. | Benzofuran derived HIV protease inhibitors |
JP5393665B2 (ja) | 2007-07-06 | 2014-01-22 | ギリアード サイエンシーズ, インコーポレイテッド | 治療剤の薬物動態特性の調整剤 |
EP2231628B1 (en) | 2008-01-04 | 2015-10-28 | Gilead Sciences, Inc. | Inhibitors of cytochrome p450 |
US20110046199A1 (en) * | 2008-01-17 | 2011-02-24 | Purdue Research Foundation | Small molecule inhibitors of hiv proteases |
WO2010002994A1 (en) | 2008-07-01 | 2010-01-07 | Purdue Research Foundation | Nonpeptide hiv-1 protease inhibitors |
US8501961B2 (en) | 2008-07-09 | 2013-08-06 | Purdue Research Foundation | HIV protease inhibitors and methods for using |
NZ600156A (en) | 2009-12-21 | 2015-01-30 | Janssen R & D Ireland | Degradable removable implant for the sustained release of an active compound |
EP2643326B1 (en) | 2010-11-23 | 2016-09-14 | Mylan Laboratories, Limited | Process for the preparation of (3R, 3aS, 6aR)-hexahydrofuro[2,3-b]furan-3-ol |
ES2657227T3 (es) | 2012-08-09 | 2018-03-02 | Sumitomo Chemical Company, Limited | Método para producir un derivado de hexahidrofurofuranol |
CN103664976B (zh) * | 2013-12-12 | 2015-11-04 | 惠州市莱佛士制药技术有限公司 | 一种顺式六氢呋喃并[2,3-b]呋喃-3-醇的制备方法 |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995006030A1 (en) * | 1993-08-24 | 1995-03-02 | G.D. Searle & Co. | Hydroxyethylamino sulphonamides useful as retroviral protease inhibitors |
JP3657002B2 (ja) * | 1992-08-25 | 2005-06-08 | ジー.ディー.サール アンド カンパニー | レトロウイルスプロテアーゼ阻害剤として有用なα−およびβ−アミノ酸ヒドロキシエチルアミノスルホンアミド |
IS2334B (is) * | 1992-09-08 | 2008-02-15 | Vertex Pharmaceuticals Inc., (A Massachusetts Corporation) | Aspartyl próteasi hemjari af nýjum flokki súlfonamíða |
US5723490A (en) * | 1992-09-08 | 1998-03-03 | Vertex Pharmaceuticals Incorporated | THF-containing sulfonamide inhibitors of aspartyl protease |
UA49803C2 (uk) * | 1994-06-03 | 2002-10-15 | Дж.Д. Сьорль Енд Ко | Спосіб лікування ретровірусних інфекцій |
US5705500A (en) * | 1995-03-10 | 1998-01-06 | G.D. Searle & Co. | Sulfonylalkanoylamino hydroxyethylamino sulfonamide retroviral protease inhibitors |
US5691372A (en) * | 1995-04-19 | 1997-11-25 | Vertex Pharmaceuticals Incorporated | Oxygenated-Heterocycle containing sulfonamide inhibitors of aspartyl protease |
AU4828199A (en) | 1998-06-23 | 2000-01-10 | Board Of Trustees Of The University Of Illinois, The | Multi-drug resistant retroviral protease inhibitors and associated methods |
CA2336160C (en) * | 1998-06-23 | 2015-02-17 | The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Use of compounds for treating hiv |
GB9815567D0 (en) * | 1998-07-18 | 1998-09-16 | Glaxo Group Ltd | Antiviral compound |
NZ518580A (en) * | 1999-10-06 | 2004-01-30 | Us Gov Health & Human Serv | Hexahydrofuro[2,3-B]furan-3-YL-N- {3-[1,3-benzodioxol-5-ylsulfonyl) (isobutyl) amino]-1-benzyl-2-hydroxypropyl} carbamate as retroviral protease inhibitor |
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