IL139793A - Apavirench in a crystalline form - Google Patents

Apavirench in a crystalline form

Info

Publication number: IL139793A
Authority: IL; Israel
Prior art keywords: compound; medicament; efavirenz; reverse transcriptase; crystalline
Prior art date: 1998-06-11

Application number

IL139793A

Other languages

English (en)

Hebrew (he)

Other versions

IL139793A0 (en

Original Assignee

Bristol Myers Squibb Pharma Co

Priority date (The priority date 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 date listed.)

1998-06-11

Filing date

1999-06-10

Publication date

2006-10-31

Family has litigation

First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=22214647&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=IL139793(A) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.

1999-06-10 Application filed by Bristol Myers Squibb Pharma Co filed Critical Bristol Myers Squibb Pharma Co

2002-02-10 Publication of IL139793A0 publication Critical patent/IL139793A0/xx

2006-10-31 Publication of IL139793A publication Critical patent/IL139793A/en

Links

XPOQHMRABVBWPR-ZDUSSCGKSA-N efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 title claims description 219
XPOQHMRABVBWPR-UHFFFAOYSA-N Efavirenz Natural products O1C(=O)NC2=CC=C(Cl)C=C2C1(C(F)(F)F)C#CC1CC1 XPOQHMRABVBWPR-UHFFFAOYSA-N 0.000 title claims description 218
229960003804 efavirenz Drugs 0.000 title claims description 216
IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 169
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 148
150000001875 compounds Chemical class 0.000 claims description 109
239000000243 solution Substances 0.000 claims description 95
238000000034 method Methods 0.000 claims description 68
239000000203 mixture Substances 0.000 claims description 68
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 58
238000000634 powder X-ray diffraction Methods 0.000 claims description 51
239000002904 solvent Substances 0.000 claims description 51
238000000113 differential scanning calorimetry Methods 0.000 claims description 44
238000001757 thermogravimetry curve Methods 0.000 claims description 44
239000003814 drug Substances 0.000 claims description 43
230000008569 process Effects 0.000 claims description 32
238000002425 crystallisation Methods 0.000 claims description 27
230000008025 crystallization Effects 0.000 claims description 27
239000012047 saturated solution Substances 0.000 claims description 27
241000725303 Human immunodeficiency virus Species 0.000 claims description 26
108010078851 HIV Reverse Transcriptase Proteins 0.000 claims description 25
102100034343 Integrase Human genes 0.000 claims description 25
108010092799 RNA-directed DNA polymerase Proteins 0.000 claims description 25
230000002401 inhibitory effect Effects 0.000 claims description 25
238000002360 preparation method Methods 0.000 claims description 22
238000001914 filtration Methods 0.000 claims description 20
239000013078 crystal Substances 0.000 claims description 19
230000029812 viral genome replication Effects 0.000 claims description 18
230000002829 reductive effect Effects 0.000 claims description 16
230000009385 viral infection Effects 0.000 claims description 16
238000010438 heat treatment Methods 0.000 claims description 15
238000001816 cooling Methods 0.000 claims description 14
238000004519 manufacturing process Methods 0.000 claims description 13
239000003419 rna directed dna polymerase inhibitor Substances 0.000 claims description 13
239000008186 active pharmaceutical agent Substances 0.000 claims description 12
229940088679 drug related substance Drugs 0.000 claims description 12
208000031886 HIV Infections Diseases 0.000 claims description 10
208000037357 HIV infectious disease Diseases 0.000 claims description 10
208000033519 human immunodeficiency virus infectious disease Diseases 0.000 claims description 10
238000001953 recrystallisation Methods 0.000 claims description 10
239000004030 hiv protease inhibitor Substances 0.000 claims description 9
239000012046 mixed solvent Substances 0.000 claims description 8
229920006395 saturated elastomer Polymers 0.000 claims description 7
150000001335 aliphatic alkanes Chemical class 0.000 claims description 6
238000002441 X-ray diffraction Methods 0.000 claims description 2
238000000338 in vitro Methods 0.000 claims 3
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 45
239000002002 slurry Substances 0.000 description 37
239000008194 pharmaceutical composition Substances 0.000 description 29
239000002775 capsule Substances 0.000 description 25
238000006243 chemical reaction Methods 0.000 description 24
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239000007788 liquid Substances 0.000 description 23
239000002552 dosage form Substances 0.000 description 19
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 19
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
239000003826 tablet Substances 0.000 description 18
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
239000003795 chemical substances by application Substances 0.000 description 16
-1 polyol esters Chemical class 0.000 description 16
239000007787 solid Substances 0.000 description 16
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
239000000047 product Substances 0.000 description 15
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 14
229930195733 hydrocarbon Natural products 0.000 description 14
150000002430 hydrocarbons Chemical class 0.000 description 14
239000004215 Carbon black (E152) Substances 0.000 description 13
239000007891 compressed tablet Substances 0.000 description 13
239000007884 disintegrant Substances 0.000 description 13
238000009472 formulation Methods 0.000 description 12
239000003937 drug carrier Substances 0.000 description 10
239000003765 sweetening agent Substances 0.000 description 10
DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
238000001035 drying Methods 0.000 description 9
GUBGYTABKSRVRQ-QKKXKWKRSA-N lactose group Chemical group OC1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](O2)CO)[C@H](O1)CO GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 9
239000000843 powder Substances 0.000 description 9
239000000523 sample Substances 0.000 description 9
239000003981 vehicle Substances 0.000 description 9
235000003599 food sweetener Nutrition 0.000 description 8
239000003112 inhibitor Substances 0.000 description 8
239000008101 lactose Substances 0.000 description 8
239000010410 layer Substances 0.000 description 8
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
239000000463 material Substances 0.000 description 8
235000015112 vegetable and seed oil Nutrition 0.000 description 8
239000008158 vegetable oil Substances 0.000 description 8
GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound 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 GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 7
229940079593 drug Drugs 0.000 description 7
239000000314 lubricant Substances 0.000 description 7
239000002777 nucleoside Substances 0.000 description 7
150000003833 nucleoside derivatives Chemical class 0.000 description 7
230000002265 prevention Effects 0.000 description 7
239000000126 substance Substances 0.000 description 7
208000030507 AIDS Diseases 0.000 description 6
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
229920002472 Starch Polymers 0.000 description 6
239000011230 binding agent Substances 0.000 description 6
239000007903 gelatin capsule Substances 0.000 description 6
150000004667 medium chain fatty acids Chemical class 0.000 description 6
235000019698 starch Nutrition 0.000 description 6
235000000346 sugar Nutrition 0.000 description 6
238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
238000004293 19F NMR spectroscopy Methods 0.000 description 5
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
238000005481 NMR spectroscopy Methods 0.000 description 5
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 5
229930006000 Sucrose Natural products 0.000 description 5
238000004458 analytical method Methods 0.000 description 5
238000007707 calorimetry Methods 0.000 description 5
235000010980 cellulose Nutrition 0.000 description 5
229920002678 cellulose Polymers 0.000 description 5
235000014113 dietary fatty acids Nutrition 0.000 description 5
239000003085 diluting agent Substances 0.000 description 5
239000000194 fatty acid Substances 0.000 description 5
229930195729 fatty acid Natural products 0.000 description 5
238000002844 melting Methods 0.000 description 5
230000008018 melting Effects 0.000 description 5
229920000642 polymer Polymers 0.000 description 5
229920005862 polyol Polymers 0.000 description 5
229940032147 starch Drugs 0.000 description 5
239000008107 starch Substances 0.000 description 5
238000003756 stirring Methods 0.000 description 5
239000005720 sucrose Substances 0.000 description 5
239000002253 acid Substances 0.000 description 4
239000000538 analytical sample Substances 0.000 description 4
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239000013066 combination product Substances 0.000 description 4
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238000007906 compression Methods 0.000 description 4
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208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
238000004090 dissolution Methods 0.000 description 4
230000000694 effects Effects 0.000 description 4
NPTDXPDGUHAFKC-UHFFFAOYSA-N ethynylcyclopropane Chemical group C#CC1CC1 NPTDXPDGUHAFKC-UHFFFAOYSA-N 0.000 description 4
238000005469 granulation Methods 0.000 description 4
230000003179 granulation Effects 0.000 description 4
238000004128 high performance liquid chromatography Methods 0.000 description 4
230000005764 inhibitory process Effects 0.000 description 4
235000019359 magnesium stearate Nutrition 0.000 description 4
239000002245 particle Substances 0.000 description 4
QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 4
238000010992 reflux Methods 0.000 description 4
229920003109 sodium starch glycolate Polymers 0.000 description 4
239000008109 sodium starch glycolate Substances 0.000 description 4
229940079832 sodium starch glycolate Drugs 0.000 description 4
239000007909 solid dosage form Substances 0.000 description 4
238000013268 sustained release Methods 0.000 description 4
239000012730 sustained-release form Substances 0.000 description 4
238000005160 1H NMR spectroscopy Methods 0.000 description 3
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
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 3
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 3
229920000881 Modified starch Polymers 0.000 description 3
WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 3
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
239000008346 aqueous phase Substances 0.000 description 3
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
230000015572 biosynthetic process Effects 0.000 description 3
229910052799 carbon Inorganic materials 0.000 description 3
239000000969 carrier Substances 0.000 description 3
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
238000000576 coating method Methods 0.000 description 3
229940075614 colloidal silicon dioxide Drugs 0.000 description 3
229960000913 crospovidone Drugs 0.000 description 3
DLNKOYKMWOXYQA-UHFFFAOYSA-N dl-pseudophenylpropanolamine Natural products CC(N)C(O)C1=CC=CC=C1 DLNKOYKMWOXYQA-UHFFFAOYSA-N 0.000 description 3
150000004665 fatty acids Chemical class 0.000 description 3
239000008187 granular material Substances 0.000 description 3
CETVQRFGPOGIQJ-UHFFFAOYSA-N lithium;hexane Chemical compound [Li+].CCCCC[CH2-] CETVQRFGPOGIQJ-UHFFFAOYSA-N 0.000 description 3
235000019426 modified starch Nutrition 0.000 description 3
229910052757 nitrogen Inorganic materials 0.000 description 3
231100000252 nontoxic Toxicity 0.000 description 3
230000003000 nontoxic effect Effects 0.000 description 3
239000003182 parenteral nutrition solution Substances 0.000 description 3
239000000546 pharmaceutical excipient Substances 0.000 description 3
229960000395 phenylpropanolamine Drugs 0.000 description 3
235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 3
229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 3
238000010926 purge Methods 0.000 description 3
239000000600 sorbitol Substances 0.000 description 3
235000010356 sorbitol Nutrition 0.000 description 3
239000003549 soybean oil Substances 0.000 description 3
235000012424 soybean oil Nutrition 0.000 description 3
150000008163 sugars Chemical class 0.000 description 3
239000004094 surface-active agent Substances 0.000 description 3
230000003612 virological effect Effects 0.000 description 3
FUYMYLYDBVWEHG-UHFFFAOYSA-N 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone;hydrate;hydrochloride Chemical compound O.Cl.NC1=CC=C(Cl)C=C1C(=O)C(F)(F)F FUYMYLYDBVWEHG-UHFFFAOYSA-N 0.000 description 2
JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 2
MSHFRERJPWKJFX-UHFFFAOYSA-N 4-Methoxybenzyl alcohol Chemical compound COC1=CC=C(CO)C=C1 MSHFRERJPWKJFX-UHFFFAOYSA-N 0.000 description 2
QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
QSNSCYSYFYORTR-UHFFFAOYSA-N 4-chloroaniline Chemical compound NC1=CC=C(Cl)C=C1 QSNSCYSYFYORTR-UHFFFAOYSA-N 0.000 description 2
125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 2
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NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 2
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 2
IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
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 2
229930195725 Mannitol Natural products 0.000 description 2
241001465754 Metazoa Species 0.000 description 2
BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 2
LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
235000019483 Peanut oil Nutrition 0.000 description 2
OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
229920000954 Polyglycolide Polymers 0.000 description 2
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
STSCVKRWJPWALQ-UHFFFAOYSA-N TRIFLUOROACETIC ACID ETHYL ESTER Chemical compound CCOC(=O)C(F)(F)F STSCVKRWJPWALQ-UHFFFAOYSA-N 0.000 description 2
238000010521 absorption reaction Methods 0.000 description 2
239000013543 active substance Substances 0.000 description 2
230000032683 aging Effects 0.000 description 2
229910052782 aluminium Inorganic materials 0.000 description 2
XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
239000003242 anti bacterial agent Substances 0.000 description 2
229940088710 antibiotic agent Drugs 0.000 description 2
239000003443 antiviral agent Substances 0.000 description 2
WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
239000008280 blood Substances 0.000 description 2
210000004369 blood Anatomy 0.000 description 2
OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
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WHBIGIKBNXZKFE-UHFFFAOYSA-N delavirdine Chemical compound CC(C)NC1=CC=CN=C1N1CCN(C(=O)C=2NC3=CC=C(NS(C)(=O)=O)C=C3C=2)CC1 WHBIGIKBNXZKFE-UHFFFAOYSA-N 0.000 description 2
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239000012535 impurity Substances 0.000 description 2
CBVCZFGXHXORBI-PXQQMZJSSA-N indinavir Chemical compound C([C@H](N(CC1)C[C@@H](O)C[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H]2C3=CC=CC=C3C[C@H]2O)C(=O)NC(C)(C)C)N1CC1=CC=CN=C1 CBVCZFGXHXORBI-PXQQMZJSSA-N 0.000 description 2
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150000002711 medium chain fatty acid esters Chemical class 0.000 description 2
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 2
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QAGYKUNXZHXKMR-HKWSIXNMSA-N nelfinavir Chemical compound CC1=C(O)C=CC=C1C(=O)N[C@H]([C@H](O)CN1[C@@H](C[C@@H]2CCCC[C@@H]2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 QAGYKUNXZHXKMR-HKWSIXNMSA-N 0.000 description 2
NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 description 2
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LXCFILQKKLGQFO-UHFFFAOYSA-N p-hydroxybenzoic acid methyl ester Natural products COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
239000000312 peanut oil Substances 0.000 description 2
239000000137 peptide hydrolase inhibitor Substances 0.000 description 2
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239000000902 placebo Substances 0.000 description 2
229920000747 poly(lactic acid) Polymers 0.000 description 2
229920001223 polyethylene glycol Polymers 0.000 description 2
239000004633 polyglycolic acid Substances 0.000 description 2
239000004626 polylactic acid Substances 0.000 description 2
239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
229940068968 polysorbate 80 Drugs 0.000 description 2
229920000053 polysorbate 80 Polymers 0.000 description 2
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
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238000012545 processing Methods 0.000 description 1
230000000750 progressive effect Effects 0.000 description 1
230000000069 prophylactic effect Effects 0.000 description 1
230000005855 radiation Effects 0.000 description 1
239000011541 reaction mixture Substances 0.000 description 1
238000011084 recovery Methods 0.000 description 1
238000011160 research Methods 0.000 description 1
230000002441 reversible effect Effects 0.000 description 1
235000019204 saccharin Nutrition 0.000 description 1
CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
229940081974 saccharin Drugs 0.000 description 1
239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
235000005713 safflower oil Nutrition 0.000 description 1
239000003813 safflower oil Substances 0.000 description 1
229960001852 saquinavir Drugs 0.000 description 1
QWAXKHKRTORLEM-UGJKXSETSA-N saquinavir Chemical compound C([C@@H]([C@H](O)CN1C[C@H]2CCCC[C@H]2C[C@H]1C(=O)NC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)C=1N=C2C=CC=CC2=CC=1)C1=CC=CC=C1 QWAXKHKRTORLEM-UGJKXSETSA-N 0.000 description 1
238000000646 scanning calorimetry Methods 0.000 description 1
238000000926 separation method Methods 0.000 description 1
238000004904 shortening Methods 0.000 description 1
URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
235000010234 sodium benzoate Nutrition 0.000 description 1
239000004299 sodium benzoate Substances 0.000 description 1
235000017557 sodium bicarbonate Nutrition 0.000 description 1
229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
239000012279 sodium borohydride Substances 0.000 description 1
229910000033 sodium borohydride Inorganic materials 0.000 description 1
235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
239000011780 sodium chloride Substances 0.000 description 1
235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
235000019333 sodium laurylsulphate Nutrition 0.000 description 1
235000010265 sodium sulphite Nutrition 0.000 description 1
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
239000008247 solid mixture Substances 0.000 description 1
239000007921 spray Substances 0.000 description 1
239000003381 stabilizer Substances 0.000 description 1
239000008117 stearic acid Substances 0.000 description 1
239000010959 steel Substances 0.000 description 1
210000002784 stomach Anatomy 0.000 description 1
239000007929 subcutaneous injection Substances 0.000 description 1
238000010254 subcutaneous injection Methods 0.000 description 1
239000002600 sunflower oil Substances 0.000 description 1
238000001356 surgical procedure Methods 0.000 description 1
239000000375 suspending agent Substances 0.000 description 1
230000002459 sustained effect Effects 0.000 description 1
208000024891 symptom Diseases 0.000 description 1
239000011885 synergistic combination Substances 0.000 description 1
239000006188 syrup Substances 0.000 description 1
235000020357 syrup Nutrition 0.000 description 1
239000000454 talc Substances 0.000 description 1
229910052623 talc Inorganic materials 0.000 description 1
BEUUJDAEPJZWHM-COROXYKFSA-N tert-butyl n-[(2s,3s,5r)-3-hydroxy-6-[[(2s)-1-(2-methoxyethylamino)-3-methyl-1-oxobutan-2-yl]amino]-6-oxo-1-phenyl-5-[(2,3,4-trimethoxyphenyl)methyl]hexan-2-yl]carbamate Chemical compound C([C@@H]([C@@H](O)C[C@H](C(=O)N[C@H](C(=O)NCCOC)C(C)C)CC=1C(=C(OC)C(OC)=CC=1)OC)NC(=O)OC(C)(C)C)C1=CC=CC=C1 BEUUJDAEPJZWHM-COROXYKFSA-N 0.000 description 1
UGNWTBMOAKPKBL-UHFFFAOYSA-N tetrachloro-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(Cl)=C(Cl)C1=O UGNWTBMOAKPKBL-UHFFFAOYSA-N 0.000 description 1
UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
230000001225 therapeutic effect Effects 0.000 description 1
230000000699 topical effect Effects 0.000 description 1
150000003626 triacylglycerols Chemical class 0.000 description 1
238000001665 trituration Methods 0.000 description 1
229950000977 trovirdine Drugs 0.000 description 1
MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 1
235000012141 vanillin Nutrition 0.000 description 1
239000008170 walnut oil Substances 0.000 description 1
210000002268 wool Anatomy 0.000 description 1
239000000811 xylitol Substances 0.000 description 1
235000010447 xylitol Nutrition 0.000 description 1
HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
229960002675 xylitol Drugs 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
- C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
- C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D265/18—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in position 2
- 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
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants

Landscapes

Health & Medical Sciences (AREA)
Organic Chemistry (AREA)
Chemical & Material Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
Immunology (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Chemical Kinetics & Catalysis (AREA)
Pharmacology & Pharmacy (AREA)
Virology (AREA)
Animal Behavior & Ethology (AREA)
General Health & Medical Sciences (AREA)
General Chemical & Material Sciences (AREA)
AIDS & HIV (AREA)
Engineering & Computer Science (AREA)
Tropical Medicine & Parasitology (AREA)
Molecular Biology (AREA)
Bioinformatics & Cheminformatics (AREA)
Communicable Diseases (AREA)
Oncology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

IL139793A 1998-06-11 1999-06-10 Apavirench in a crystalline form IL139793A (en)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
US8898198P	1998-06-11	1998-06-11
PCT/US1999/013199 WO1999064405A1 (en)	1998-06-11	1999-06-10	Crystalline efavirenz

Publications (2)

Publication Number	Publication Date
IL139793A0 IL139793A0 (en)	2002-02-10
IL139793A true IL139793A (en)	2006-10-31

Family

ID=22214647

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
IL139793A IL139793A (en)	1998-06-11	1999-06-10	Apavirench in a crystalline form

Country Status (21)

Country	Link
EP (1)	EP1086087A1 (pl)
JP (1)	JP2002517487A (pl)
CN (1)	CN1307568A (pl)
AR (3)	AR018670A1 (pl)
AU (1)	AU758114C (pl)
BR (1)	BR9911523A (pl)
CA (1)	CA2333550A1 (pl)
EE (1)	EE05547B1 (pl)
HR (1)	HRP990182A2 (pl)
HU (1)	HUP0103819A3 (pl)
IL (1)	IL139793A (pl)
MY (1)	MY126450A (pl)
NO (1)	NO20006255L (pl)
NZ (1)	NZ507713A (pl)
PL (1)	PL198504B1 (pl)
SG (3)	SG111980A1 (pl)
SK (1)	SK18182000A3 (pl)
TW (1)	TWI235152B (pl)
UA (1)	UA74324C2 (pl)
WO (1)	WO1999064405A1 (pl)
ZA (1)	ZA200006173B (pl)

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US5965729A (en)	1997-02-05	1999-10-12	Merck & Co., Inc.	Process for the crystallization of a reverse transcriptase inhibitor using an anti-solvent
WO2006018853A2 (en)	2004-08-19	2006-02-23	Hetero Drugs Limited	Novel polymorphs of efavirenz
US7205402B2 (en) *	2004-09-02	2007-04-17	Bristol-Myers Squibb Company	Synthesis of a benzoxazinone
WO2008108630A1 (en) *	2007-03-02	2008-09-12	Ultimorphix Technologies B.V.	Polymorphic forms of efavirenz
WO2009011567A1 (en) *	2007-07-16	2009-01-22	Ultimorphix Technologies B.V.	Crystalline forms of efavirenz
CA2712574C (en)	2008-02-04	2014-01-07	Pfizer Limited	Polymorphic form of a [1,2,4]triazolo[4,3-a]pyridine derivative for treating inflammatory diseases
US8383811B2 (en)	2008-12-22	2013-02-26	Hetero Research Foundation	Process for preparing efavirenz polymorph
DE102009041443A1 (de)	2009-09-16	2011-03-31	Archimica Gmbh	Salze des 6-Chlor-4-(cyclopropylethinyl)-1,4-dihydro-4-(trifluormethyl)-2H-3,1-benzoxazin-2-ons und deren Synthese, Aufreinigung und Anwendung als Vorstufen für Efavirenz
EP2471783A1 (en)	2010-12-23	2012-07-04	Esteve Química, S.A.	Novel polymorphic form of efavirenz
CN103508973B (zh) *	2012-06-25	2016-04-27	上海迪赛诺药业有限公司	制备依非韦伦i型结晶的方法
CN102924398B (zh) *	2012-11-22	2015-11-18	安徽贝克生物制药有限公司	用于除去依非韦伦对应异构体的方法
US9468646B2 (en)	2013-01-23	2016-10-18	Alienor Farma	Increased dosage of efavirenz for the treatment of cancer
CN105037175B (zh) *	2014-07-18	2017-02-22	盐城迪赛诺制药有限公司	一种用于提高依非韦伦中间体光学纯度的方法
CN105001101B (zh) *	2015-05-28	2017-11-28	乐平市瑞盛制药有限公司	一种4‑氯‑2‑三氟乙酰基苯胺水合物盐酸盐的合成方法
CN108947855B (zh) *	2018-08-10	2021-10-22	江苏沙星化工有限公司	一种依非韦伦关键中间体的合成方法

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* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
IL106507A (en) *	1992-08-07	1997-11-20	Merck & Co Inc	Pharmaceutical compositions containing benzoxazinones and some novel compounds of this type
WO1995020389A1 (en) *	1994-01-28	1995-08-03	Merck & Co., Inc.	Benzoxazinones as inhibitors of hiv reverse transcriptase
US5633405A (en) *	1995-05-25	1997-05-27	Merck & Co., Inc.	Asymmetric synthesis of (-)-6-chloro-4-cyclopropyl-ethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxanzin-2-one
CA2260922A1 (en) *	1996-07-26	1998-02-05	Du Pont Pharmaceuticals Company	A practical synthesis of benzoxazinones useful as hiv reverse transcriptase inhibitors
ES2203790T3 (es) *	1996-10-02	2004-04-16	Bristol-Myers Squibb Pharma Company	1,4-dihidro-2h-3,1-benzoxacin-2-onas 4,4-disustituidas utiles como inhibidores de la transcriptasa reversa del hiv e intermedios y procedimientos para su preparacion.
HU229087B1 (en) *	1997-02-05	2013-07-29	Merck Sharp & Dohme	Process for the crystallization of a reverse transcriptase inhibitor using an anti-solvent

1999
- 1999-06-08 HR HR60/088,981A patent/HRP990182A2/hr not_active Application Discontinuation
- 1999-06-10 SG SG200207220A patent/SG111980A1/en unknown
- 1999-06-10 SG SG200207221A patent/SG111981A1/en unknown
- 1999-06-10 AU AU44364/99A patent/AU758114C/en not_active Expired
- 1999-06-10 MY MYPI99002384A patent/MY126450A/en unknown
- 1999-06-10 SG SG200207226-2A patent/SG134977A1/en unknown
- 1999-06-10 IL IL139793A patent/IL139793A/en not_active IP Right Cessation
- 1999-06-10 HU HU0103819A patent/HUP0103819A3/hu unknown
- 1999-06-10 PL PL345221A patent/PL198504B1/pl unknown
- 1999-06-10 SK SK1818-2000A patent/SK18182000A3/sk unknown
- 1999-06-10 NZ NZ507713A patent/NZ507713A/en not_active IP Right Cessation
- 1999-06-10 EE EEP200000743A patent/EE05547B1/xx unknown
- 1999-06-10 WO PCT/US1999/013199 patent/WO1999064405A1/en not_active Ceased
- 1999-06-10 UA UA2000127048A patent/UA74324C2/uk unknown
- 1999-06-10 CN CN99807219A patent/CN1307568A/zh active Pending
- 1999-06-10 CA CA002333550A patent/CA2333550A1/en not_active Abandoned
- 1999-06-10 EP EP99927468A patent/EP1086087A1/en not_active Withdrawn
- 1999-06-10 JP JP2000553414A patent/JP2002517487A/ja active Pending
- 1999-06-10 BR BR9911523-9A patent/BR9911523A/pt not_active Application Discontinuation
- 1999-06-11 AR ARP990102809A patent/AR018670A1/es not_active Application Discontinuation
- 1999-07-03 TW TW088109817A patent/TWI235152B/zh not_active IP Right Cessation
2000
- 2000-10-31 ZA ZA200006173A patent/ZA200006173B/xx unknown
- 2000-12-08 NO NO20006255A patent/NO20006255L/no not_active Application Discontinuation
2010
- 2010-07-08 AR ARP100102491A patent/AR077469A2/es not_active Application Discontinuation
- 2010-07-08 AR ARP100102490A patent/AR077407A2/es not_active Application Discontinuation

Also Published As

Publication number	Publication date
AU758114C (en)	2003-10-30
AR018670A1 (es)	2001-11-28
EE200000743A (et)	2002-10-15
SG111980A1 (en)	2005-06-29
PL198504B1 (pl)	2008-06-30
TWI235152B (en)	2005-07-01
CA2333550A1 (en)	1999-12-16
NO20006255D0 (no)	2000-12-08
AU4436499A (en)	1999-12-30
PL345221A1 (en)	2001-12-03
EP1086087A1 (en)	2001-03-28
HUP0103819A2 (hu)	2002-02-28
SK18182000A3 (sk)	2001-08-06
MY126450A (en)	2006-10-31
NZ507713A (en)	2003-08-29
SG111981A1 (en)	2005-06-29
ZA200006173B (en)	2001-10-31
IL139793A0 (en)	2002-02-10
HRP990182A2 (en)	2000-02-29
NO20006255L (no)	2001-02-12
BR9911523A (pt)	2001-09-18
SG134977A1 (en)	2007-09-28
UA74324C2 (uk)	2005-12-15
WO1999064405A1 (en)	1999-12-16
CN1307568A (zh)	2001-08-08
JP2002517487A (ja)	2002-06-18
HUP0103819A3 (en)	2003-05-28
AR077469A2 (es)	2011-08-31
EE05547B1 (et)	2012-06-15
AU758114B2 (en)	2003-03-13
AR077407A2 (es)	2011-08-24

Legal Events

Date	Code	Title
2008-12-29	NP	Permission for amending the patent specification granted (section 66, patents law 1967)
2010-10-31	FF	Patent granted
2013-06-27	KB	Patent renewed
2017-05-29	KB	Patent renewed
2020-01-30	EXP	Patent expired

Publication	Publication Date	Title
KR100612795B1 (ko)	2006-08-17	결정성 에파비렌즈
AU758114C (en)	2003-10-30	Crystalline efavirenz
AU734928B2 (en)	2001-06-28	4,4-disubstituted-3,4-dihydro-2(1H)-quinazolinones useful as HIV reverse transcriptase inhibitors
EA004146B1 (ru)	2004-02-26	Сульфонамиды и их производные, модулирующие активность эндотелина
JP2001505873A (ja)	2001-05-08	Ｈｉｖ逆転写酵素阻害剤として有用な４，４―二置換―１，４―ジヒドロ―２ｈ―３，１―ベンゾオキサジン―２―オン類、およびそれらを製造するための中間体および方法
KR910007968B1 (ko)	1991-10-05	축합 7원 고리 화합물의 제조방법
ZA200303789B (en)	2004-08-16	Lactam compound to inhibit beta-amyloid peptide release or synthesis.
WO2002006292A1 (en)	2002-01-24	Phosphate esters of bis-amino acid sulfonamides containing substituted benzyl amines
US6423718B1 (en)	2002-07-23	4,4-disubstituted-3,4-dihydro-2(1H)-quinazolinones useful as HIV reverse transcriptase inhibitors
US6673372B1 (en)	2004-01-06	Crystalline Efavirenz
US6225317B1 (en)	2001-05-01	Crystalline (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone
WO1999050253A1 (en)	1999-10-07	4,4-disubstituted-3,4-dihydro-2(1h)-quinazolinthione derivatives, their preparation and their use as hiv reverse transcriptase inhibitors
MXPA00012228A (en)	2001-09-07	Crystalline efavirenz
CZ20004417A3 (cs)	2001-05-16	Krystalický Efavirenz
ZA200406027B (en)	2006-06-28	Novel amino acid derivatives method for productionthereof and pharmaceutical compositions comprisin g said derivative
US6946469B2 (en)	2005-09-20	Cyanamide, alkoxyamino, and urea derivatives of 4,4-disubstituted-3,4-dihydro-2(1H)-quinazolinones as HIV reverse transcriptase inhibitors
AU722489B2 (en)	2000-08-03	(4r,5s,6s,7r)-hexahydro-1- {5-(3-aminoinazole)methyl} -3-butyl-5,6-dihydr oxy-4,7-bis {phaenylmethyl} -2h-1,3-diazepin-2-one, its preparation and its use as HIV protease inhibitor
US20040116420A1 (en)	2004-06-17	Remedial agent for viral infectious disease
US20020022659A1 (en)	2002-02-21	Crystalline and salt forms of an HIV protease inhibitor
MXPA99008909A (en)	2000-01-01	4,4-disubstituted-3,4-dihydro-2(1h)-quinazolinones useful as hiv reverse transcriptase inhibitors
AU7371301A (en)	2002-02-07	4,4-disubstituted-3,4-dihydro-2-)1H)- quinazolinones useful as HIV reverse transcriptase inhibitors
MXPA99004294A (en)	2000-01-01	(4r,5s,6s,7r)-hexahydro-1- [5-(3-aminoinazole)methyl]-3-butyl-5,6-dihydroxy-4,7-bis [phaenylmethyl]-2h-1,3-diazepin-2-one, its preparation and its use as hiv protease inhibitor
CZ352499A3 (cs)	2000-02-16	4,4-Disubstituované-3,4-dihydro-2 (1H)- chinazolinony vhodné jako inhibitory HIV reverzní transkriptázy