TWI235152B - Crystalline Efavirenz - Google Patents

Crystalline Efavirenz Download PDF

Info

Publication number: TWI235152B
Authority: TW; Taiwan
Prior art keywords: type; crystalline form; diffraction pattern; ephedrine; powder diffraction
Prior art date: 1998-06-11

Application number

TW088109817A

Other languages

English (en)

Chinese (zh)

Inventor

Lilian A Radesca

Michael B Maurin

Shelley R Rabel

James R Moore

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

1999-07-03

Publication date

2005-07-01

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=TWI235152(B) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.

1999-07-03 Application filed by Bristol Myers Squibb Pharma Co filed Critical Bristol Myers Squibb Pharma Co

2005-07-01 Application granted granted Critical

2005-07-01 Publication of TWI235152B publication Critical patent/TWI235152B/zh

Links

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 abstract 3
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 abstract 3
229960003804 efavirenz Drugs 0.000 title abstract 3
238000000034 method Methods 0.000 claims abstract description 45
238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 24
239000008194 pharmaceutical composition Substances 0.000 claims abstract description 23
KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 claims description 142
IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical group CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 85
KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 claims description 71
229960002179 ephedrine Drugs 0.000 claims description 71
239000000243 solution Substances 0.000 claims description 59
239000000203 mixture Substances 0.000 claims description 53
239000013078 crystal Substances 0.000 claims description 32
239000002904 solvent Substances 0.000 claims description 30
239000002775 capsule Substances 0.000 claims description 28
239000002002 slurry Substances 0.000 claims description 28
239000000843 powder Substances 0.000 claims description 22
238000002425 crystallisation Methods 0.000 claims description 19
239000002689 soil Substances 0.000 claims description 19
230000008025 crystallization Effects 0.000 claims description 18
102100034343 Integrase Human genes 0.000 claims description 12
108010092799 RNA-directed DNA polymerase Proteins 0.000 claims description 12
239000002552 dosage form Substances 0.000 claims description 12
239000012047 saturated solution Substances 0.000 claims description 12
238000001914 filtration Methods 0.000 claims description 11
150000002430 hydrocarbons Chemical class 0.000 claims description 11
229930195733 hydrocarbon Natural products 0.000 claims description 10
239000004215 Carbon black (E152) Substances 0.000 claims description 9
238000003756 stirring Methods 0.000 claims description 9
239000007891 compressed tablet Substances 0.000 claims description 8
230000029812 viral genome replication Effects 0.000 claims description 8
238000010438 heat treatment Methods 0.000 claims description 7
241000700605 Viruses Species 0.000 claims description 6
239000003937 drug carrier Substances 0.000 claims description 6
150000001335 aliphatic alkanes Chemical class 0.000 claims description 5
230000002829 reductive effect Effects 0.000 claims description 5
238000001816 cooling Methods 0.000 claims description 4
102000004163 DNA-directed RNA polymerases Human genes 0.000 claims description 2
108090000626 DNA-directed RNA polymerases Proteins 0.000 claims description 2
241000218671 Ephedra Species 0.000 claims description 2
241001465754 Metazoa Species 0.000 claims description 2
238000001727 in vivo Methods 0.000 claims description 2
238000002156 mixing Methods 0.000 claims description 2
229920006395 saturated elastomer Polymers 0.000 claims description 2
238000011282 treatment Methods 0.000 abstract description 22
241000725303 Human immunodeficiency virus Species 0.000 abstract description 12
239000003419 rna directed dna polymerase inhibitor Substances 0.000 abstract description 8
238000000113 differential scanning calorimetry Methods 0.000 abstract description 5
230000003389 potentiating effect Effects 0.000 abstract description 2
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 50
150000001875 compounds Chemical class 0.000 description 39
239000004615 ingredient Substances 0.000 description 39
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 25
-1 ephedrines Chemical class 0.000 description 22
239000007788 liquid Substances 0.000 description 22
239000003826 tablet Substances 0.000 description 21
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
239000003814 drug Substances 0.000 description 18
239000000126 substance Substances 0.000 description 18
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 17
239000004480 active ingredient Substances 0.000 description 16
239000000047 product Substances 0.000 description 16
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
239000007787 solid Substances 0.000 description 14
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
239000010410 layer Substances 0.000 description 12
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 11
239000003795 chemical substances by application Substances 0.000 description 11
239000003112 inhibitor Substances 0.000 description 11
238000002360 preparation method Methods 0.000 description 11
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 10
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
238000006243 chemical reaction Methods 0.000 description 10
DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
235000014113 dietary fatty acids Nutrition 0.000 description 9
239000000194 fatty acid Substances 0.000 description 9
229930195729 fatty acid Natural products 0.000 description 9
239000000546 pharmaceutical excipient Substances 0.000 description 9
101150041968 CDC13 gene Proteins 0.000 description 8
229940079593 drug Drugs 0.000 description 8
150000004665 fatty acids Chemical class 0.000 description 8
208000015181 infectious disease Diseases 0.000 description 8
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 8
239000003765 sweetening agent Substances 0.000 description 8
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
201000010099 disease Diseases 0.000 description 7
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
239000007884 disintegrant Substances 0.000 description 7
235000003599 food sweetener Nutrition 0.000 description 7
239000000499 gel Substances 0.000 description 7
239000008187 granular material Substances 0.000 description 7
239000008101 lactose Substances 0.000 description 7
238000002844 melting Methods 0.000 description 7
230000008018 melting Effects 0.000 description 7
239000000523 sample Substances 0.000 description 7
235000015112 vegetable and seed oil Nutrition 0.000 description 7
239000008158 vegetable oil Substances 0.000 description 7
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 6
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
108010078851 HIV Reverse Transcriptase Proteins 0.000 description 6
239000008186 active pharmaceutical agent Substances 0.000 description 6
239000000314 lubricant Substances 0.000 description 6
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
229920000642 polymer Polymers 0.000 description 6
235000000346 sugar Nutrition 0.000 description 6
WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 5
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 5
238000005481 NMR spectroscopy Methods 0.000 description 5
239000011230 binding agent Substances 0.000 description 5
239000001913 cellulose Substances 0.000 description 5
229920002678 cellulose Polymers 0.000 description 5
238000000576 coating method Methods 0.000 description 5
229940088679 drug related substance Drugs 0.000 description 5
238000001035 drying Methods 0.000 description 5
230000000694 effects Effects 0.000 description 5
230000002401 inhibitory effect Effects 0.000 description 5
230000000968 intestinal effect Effects 0.000 description 5
229910052757 nitrogen Inorganic materials 0.000 description 5
239000011734 sodium Substances 0.000 description 5
229910052708 sodium Inorganic materials 0.000 description 5
229940124597 therapeutic agent Drugs 0.000 description 5
238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
238000004293 19F NMR spectroscopy Methods 0.000 description 4
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
241001674048 Phthiraptera Species 0.000 description 4
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 4
229930006000 Sucrose Natural products 0.000 description 4
239000002253 acid Substances 0.000 description 4
238000004458 analytical method Methods 0.000 description 4
230000008901 benefit Effects 0.000 description 4
230000015572 biosynthetic process Effects 0.000 description 4
239000000969 carrier Substances 0.000 description 4
235000010980 cellulose Nutrition 0.000 description 4
230000008859 change Effects 0.000 description 4
239000011248 coating agent Substances 0.000 description 4
239000003085 diluting agent Substances 0.000 description 4
238000004519 manufacturing process Methods 0.000 description 4
239000000463 material Substances 0.000 description 4
239000012046 mixed solvent Substances 0.000 description 4
239000002773 nucleotide Substances 0.000 description 4
238000010992 reflux Methods 0.000 description 4
239000005720 sucrose Substances 0.000 description 4
230000002195 synergetic effect Effects 0.000 description 4
208000030507 AIDS Diseases 0.000 description 3
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
229920002472 Starch Polymers 0.000 description 3
239000003242 anti bacterial agent Substances 0.000 description 3
229940088710 antibiotic agent Drugs 0.000 description 3
239000003443 antiviral agent Substances 0.000 description 3
238000007906 compression Methods 0.000 description 3
230000006835 compression Effects 0.000 description 3
239000012141 concentrate Substances 0.000 description 3
235000008504 concentrate Nutrition 0.000 description 3
229920001577 copolymer Polymers 0.000 description 3
229920001887 crystalline plastic Polymers 0.000 description 3
238000002050 diffraction method Methods 0.000 description 3
238000004821 distillation Methods 0.000 description 3
238000009472 formulation Methods 0.000 description 3
210000001035 gastrointestinal tract Anatomy 0.000 description 3
239000002955 immunomodulating agent Substances 0.000 description 3
229940121354 immunomodulator Drugs 0.000 description 3
238000002347 injection Methods 0.000 description 3
239000007924 injection Substances 0.000 description 3
150000002576 ketones Chemical class 0.000 description 3
235000019359 magnesium stearate Nutrition 0.000 description 3
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
231100000252 nontoxic Toxicity 0.000 description 3
230000003000 nontoxic effect Effects 0.000 description 3
125000003729 nucleotide group Chemical group 0.000 description 3
239000003921 oil Substances 0.000 description 3
235000019198 oils Nutrition 0.000 description 3
239000000137 peptide hydrolase inhibitor Substances 0.000 description 3
230000002265 prevention Effects 0.000 description 3
238000010839 reverse transcription Methods 0.000 description 3
229920003109 sodium starch glycolate Polymers 0.000 description 3
239000008109 sodium starch glycolate Substances 0.000 description 3
229940079832 sodium starch glycolate Drugs 0.000 description 3
239000007909 solid dosage form Substances 0.000 description 3
239000008107 starch Substances 0.000 description 3
229940032147 starch Drugs 0.000 description 3
235000019698 starch Nutrition 0.000 description 3
239000004094 surface-active agent Substances 0.000 description 3
208000024891 symptom Diseases 0.000 description 3
231100000331 toxic Toxicity 0.000 description 3
230000002588 toxic effect Effects 0.000 description 3
239000000052 vinegar Substances 0.000 description 3
235000021419 vinegar Nutrition 0.000 description 3
230000009385 viral infection Effects 0.000 description 3
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
208000012124 AIDS-related disease Diseases 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
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 2
FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical group OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
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 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
102000004190 Enzymes Human genes 0.000 description 2
108090000790 Enzymes Proteins 0.000 description 2
LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
208000031886 HIV Infections Diseases 0.000 description 2
208000037357 HIV infectious disease Diseases 0.000 description 2
206010061598 Immunodeficiency Diseases 0.000 description 2
208000029462 Immunodeficiency disease Diseases 0.000 description 2
229930195725 Mannitol Natural products 0.000 description 2
BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
229920000881 Modified starch Polymers 0.000 description 2
239000004368 Modified starch Substances 0.000 description 2
LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-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
102100040678 Programmed cell death protein 1 Human genes 0.000 description 2
101710089372 Programmed cell death protein 1 Proteins 0.000 description 2
229940124158 Protease/peptidase inhibitor Drugs 0.000 description 2
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
235000021355 Stearic acid Nutrition 0.000 description 2
YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 2
206010052428 Wound Diseases 0.000 description 2
208000027418 Wounds and injury Diseases 0.000 description 2
238000010521 absorption reaction Methods 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
150000001412 amines Chemical class 0.000 description 2
239000000538 analytical sample Substances 0.000 description 2
239000007864 aqueous solution Substances 0.000 description 2
235000019445 benzyl alcohol Nutrition 0.000 description 2
239000008280 blood Substances 0.000 description 2
210000004369 blood Anatomy 0.000 description 2
OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
229920006037 cross link polymer Polymers 0.000 description 2
230000002354 daily effect Effects 0.000 description 2
230000007123 defense Effects 0.000 description 2
210000005069 ears Anatomy 0.000 description 2
238000009505 enteric coating Methods 0.000 description 2
239000002702 enteric coating Substances 0.000 description 2
NPTDXPDGUHAFKC-UHFFFAOYSA-N ethynylcyclopropane Chemical group C#CC1CC1 NPTDXPDGUHAFKC-UHFFFAOYSA-N 0.000 description 2
235000019197 fats Nutrition 0.000 description 2
239000000835 fiber Substances 0.000 description 2
238000004128 high performance liquid chromatography Methods 0.000 description 2
208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 2
230000007813 immunodeficiency Effects 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
210000000936 intestine Anatomy 0.000 description 2
239000008297 liquid dosage form Substances 0.000 description 2
230000005923 long-lasting effect Effects 0.000 description 2
239000000594 mannitol Substances 0.000 description 2
235000010355 mannitol Nutrition 0.000 description 2
150000004667 medium chain fatty acids Chemical class 0.000 description 2
UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 2
235000019426 modified starch Nutrition 0.000 description 2
239000012452 mother liquor Substances 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
QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 2
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
239000002245 particle Substances 0.000 description 2
239000000312 peanut oil Substances 0.000 description 2
YNPNZTXNASCQKK-UHFFFAOYSA-N phenanthrene Chemical compound C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 2
239000006187 pill Substances 0.000 description 2
229940068196 placebo Drugs 0.000 description 2
239000000902 placebo Substances 0.000 description 2
229920001223 polyethylene glycol Polymers 0.000 description 2
229920005862 polyol Polymers 0.000 description 2
229920001296 polysiloxane Polymers 0.000 description 2
239000003755 preservative agent Substances 0.000 description 2
230000008569 process Effects 0.000 description 2
QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
238000000746 purification Methods 0.000 description 2
238000001953 recrystallisation Methods 0.000 description 2
229960000311 ritonavir Drugs 0.000 description 2
NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 description 2
238000000926 separation method Methods 0.000 description 2
239000000600 sorbitol Substances 0.000 description 2
239000003549 soybean oil Substances 0.000 description 2
235000012424 soybean oil Nutrition 0.000 description 2
239000008117 stearic acid Substances 0.000 description 2
210000002784 stomach Anatomy 0.000 description 2
238000013268 sustained release Methods 0.000 description 2
239000012730 sustained-release form Substances 0.000 description 2
238000003786 synthesis reaction Methods 0.000 description 2
230000007704 transition Effects 0.000 description 2
UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 2
229910052722 tritium Inorganic materials 0.000 description 2
229960005486 vaccine Drugs 0.000 description 2
LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
102000040650 (ribonucleotides)n+m Human genes 0.000 description 1
GWKIPRVERALPRD-ZDUSSCGKSA-N (s)-4-isopropoxycarbonyl-6-methoxy-3-methylthiomethyl-3,4-dihydroquinoxalin-2(1h)-thione Chemical compound N1C(=S)[C@H](CSC)N(C(=O)OC(C)C)C2=CC(OC)=CC=C21 GWKIPRVERALPRD-ZDUSSCGKSA-N 0.000 description 1
LDRPULCXZDDSGE-UHFFFAOYSA-N 1,1,1-trifluorobutane Chemical compound CCCC(F)(F)F LDRPULCXZDDSGE-UHFFFAOYSA-N 0.000 description 1
ULTHEAFYOOPTTB-UHFFFAOYSA-N 1,4-dibromobutane Chemical compound BrCCCCBr ULTHEAFYOOPTTB-UHFFFAOYSA-N 0.000 description 1
HOCFDYZWQYGULA-UHFFFAOYSA-N 1-(5-bromopyridin-2-yl)-3-(2-pyridin-2-ylethyl)thiourea Chemical compound N1=CC(Br)=CC=C1NC(=S)NCCC1=CC=CC=N1 HOCFDYZWQYGULA-UHFFFAOYSA-N 0.000 description 1
JEKYMVBQWWZVHO-UHFFFAOYSA-N 1-chloro-2,2-dimethylpropane Chemical compound CC(C)(C)CCl JEKYMVBQWWZVHO-UHFFFAOYSA-N 0.000 description 1
IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
FNHMJTUQUPQWJN-UHFFFAOYSA-N 2,2-dimethylpropanimidamide Chemical compound CC(C)(C)C(N)=N FNHMJTUQUPQWJN-UHFFFAOYSA-N 0.000 description 1
GLDQAMYCGOIJDV-UHFFFAOYSA-N 2,3-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC=CC(O)=C1O GLDQAMYCGOIJDV-UHFFFAOYSA-N 0.000 description 1
VIBQRYBYKVEMJI-YSIASYRMSA-N 4-[[(2s,3s)-4-[(4r)-4-(tert-butylcarbamoyl)-5,5-dimethyl-1,3-thiazolidin-3-yl]-3-hydroxy-4-oxo-1-phenylbutan-2-yl]amino]-2,2-dimethyl-4-oxobutanoic acid Chemical compound C1SC(C)(C)[C@@H](C(=O)NC(C)(C)C)N1C(=O)[C@@H](O)[C@@H](NC(=O)CC(C)(C)C(O)=O)CC1=CC=CC=C1 VIBQRYBYKVEMJI-YSIASYRMSA-N 0.000 description 1
QSNSCYSYFYORTR-UHFFFAOYSA-N 4-chloroaniline Chemical compound NC1=CC=C(Cl)C=C1 QSNSCYSYFYORTR-UHFFFAOYSA-N 0.000 description 1
FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
241000208140 Acer Species 0.000 description 1
PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 1
235000003911 Arachis Nutrition 0.000 description 1
244000105624 Arachis hypogaea Species 0.000 description 1
FMMWHPNWAFZXNH-UHFFFAOYSA-N Benz[a]pyrene Chemical compound C1=C2C3=CC=CC=C3C=C(C=C3)C2=C2C3=CC=CC2=C1 FMMWHPNWAFZXNH-UHFFFAOYSA-N 0.000 description 1
ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical compound N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 1
KQHKVTAYUYYPDO-UHFFFAOYSA-N C(=O)(O)C1=CC=CC=2C3=CC=CC=C3CC12.[Na] Chemical compound C(=O)(O)C1=CC=CC=2C3=CC=CC=C3CC12.[Na] KQHKVTAYUYYPDO-UHFFFAOYSA-N 0.000 description 1
QAGYKUNXZHXKMR-UHFFFAOYSA-N CPD000469186 Natural products CC1=C(O)C=CC=C1C(=O)NC(C(O)CN1C(CC2CCCCC2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 QAGYKUNXZHXKMR-UHFFFAOYSA-N 0.000 description 1
OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
239000005635 Caprylic acid (CAS 124-07-2) Substances 0.000 description 1
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
241001125840 Coryphaenidae Species 0.000 description 1
229920000742 Cotton Polymers 0.000 description 1
OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
229940126656 GS-4224 Drugs 0.000 description 1
244000068988 Glycine max Species 0.000 description 1
235000010469 Glycine max Nutrition 0.000 description 1
241000578422 Graphosoma lineatum Species 0.000 description 1
229910004373 HOAc Inorganic materials 0.000 description 1
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
240000007049 Juglans regia Species 0.000 description 1
235000009496 Juglans regia Nutrition 0.000 description 1
NJBBLOIWMSYVCQ-VZTVMPNDSA-N Kynostatin 272 Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)COC=1C2=CC=NC=C2C=CC=1)CSC)[C@H](O)C(=O)N1[C@@H](CSC1)C(=O)NC(C)(C)C)C1=CC=CC=C1 NJBBLOIWMSYVCQ-VZTVMPNDSA-N 0.000 description 1
LKDRXBCSQODPBY-AMVSKUEXSA-N L-(-)-Sorbose Chemical compound OCC1(O)OC[C@H](O)[C@@H](O)[C@@H]1O LKDRXBCSQODPBY-AMVSKUEXSA-N 0.000 description 1
WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
239000004594 Masterbatch (MB) Substances 0.000 description 1
CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 description 1
229920000168 Microcrystalline cellulose Polymers 0.000 description 1
KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 1
MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 1
244000170916 Paeonia officinalis Species 0.000 description 1
235000006484 Paeonia officinalis Nutrition 0.000 description 1
108091005804 Peptidases Proteins 0.000 description 1
239000001888 Peptone Substances 0.000 description 1
108010080698 Peptones Proteins 0.000 description 1
229930182556 Polyacetal Natural products 0.000 description 1
239000004698 Polyethylene Substances 0.000 description 1
239000002202 Polyethylene glycol Substances 0.000 description 1
229920000954 Polyglycolide Polymers 0.000 description 1
239000004365 Protease Substances 0.000 description 1
235000014443 Pyrus communis Nutrition 0.000 description 1
206010038997 Retroviral infections Diseases 0.000 description 1
102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 description 1
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
PJANXHGTPQOBST-VAWYXSNFSA-N Stilbene Natural products C=1C=CC=CC=1/C=C/C1=CC=CC=C1 PJANXHGTPQOBST-VAWYXSNFSA-N 0.000 description 1
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
239000005864 Sulphur Substances 0.000 description 1
STSCVKRWJPWALQ-UHFFFAOYSA-N TRIFLUOROACETIC ACID ETHYL ESTER Chemical compound CCOC(=O)C(F)(F)F STSCVKRWJPWALQ-UHFFFAOYSA-N 0.000 description 1
AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
239000004473 Threonine Substances 0.000 description 1
235000009499 Vanilla fragrans Nutrition 0.000 description 1
244000263375 Vanilla tahitensis Species 0.000 description 1
235000012036 Vanilla tahitensis Nutrition 0.000 description 1
108020000999 Viral RNA Proteins 0.000 description 1
238000002441 X-ray diffraction Methods 0.000 description 1
238000009825 accumulation Methods 0.000 description 1
239000013543 active substance Substances 0.000 description 1
230000001154 acute effect Effects 0.000 description 1
230000032683 aging Effects 0.000 description 1
229940024606 amino acid Drugs 0.000 description 1
150000001413 amino acids Chemical group 0.000 description 1
239000000728 ammonium alginate Substances 0.000 description 1
235000010407 ammonium alginate Nutrition 0.000 description 1
KPGABFJTMYCRHJ-YZOKENDUSA-N ammonium alginate Chemical compound [NH4+].[NH4+].O1[C@@H](C([O-])=O)[C@@H](OC)[C@H](O)[C@H](O)[C@@H]1O[C@@H]1[C@@H](C([O-])=O)O[C@@H](O)[C@@H](O)[C@H]1O KPGABFJTMYCRHJ-YZOKENDUSA-N 0.000 description 1
229960001830 amprenavir Drugs 0.000 description 1
YMARZQAQMVYCKC-OEMFJLHTSA-N amprenavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 YMARZQAQMVYCKC-OEMFJLHTSA-N 0.000 description 1
229940035674 anesthetics Drugs 0.000 description 1
230000000844 anti-bacterial effect Effects 0.000 description 1
230000002924 anti-infective effect Effects 0.000 description 1
230000000840 anti-viral effect Effects 0.000 description 1
239000003963 antioxidant agent Substances 0.000 description 1
235000006708 antioxidants Nutrition 0.000 description 1
239000008346 aqueous phase Substances 0.000 description 1
235000010323 ascorbic acid Nutrition 0.000 description 1
229960005070 ascorbic acid Drugs 0.000 description 1
239000011668 ascorbic acid Substances 0.000 description 1
229960001230 asparagine Drugs 0.000 description 1
239000012298 atmosphere Substances 0.000 description 1
150000001540 azides Chemical class 0.000 description 1
230000004888 barrier function Effects 0.000 description 1
230000009286 beneficial effect Effects 0.000 description 1
239000012965 benzophenone Substances 0.000 description 1
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
210000000941 bile Anatomy 0.000 description 1
229920002988 biodegradable polymer Polymers 0.000 description 1
239000004621 biodegradable polymer Substances 0.000 description 1
230000033228 biological regulation Effects 0.000 description 1
229910052797 bismuth Inorganic materials 0.000 description 1
JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 description 1
230000000903 blocking effect Effects 0.000 description 1
239000012928 buffer substance Substances 0.000 description 1
239000011575 calcium Substances 0.000 description 1
229910052791 calcium Inorganic materials 0.000 description 1
239000007963 capsule composition Substances 0.000 description 1
125000004432 carbon atom Chemical group C* 0.000 description 1
BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
239000001768 carboxy methyl cellulose Substances 0.000 description 1
235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
239000008112 carboxymethyl-cellulose Substances 0.000 description 1
235000013339 cereals Nutrition 0.000 description 1
238000002512 chemotherapy Methods 0.000 description 1
229960004926 chlorobutanol Drugs 0.000 description 1
239000004927 clay Substances 0.000 description 1
239000003240 coconut oil Substances 0.000 description 1
235000019864 coconut oil Nutrition 0.000 description 1
239000010635 coffee oil Substances 0.000 description 1
239000003086 colorant Substances 0.000 description 1
238000011284 combination treatment Methods 0.000 description 1
229940125904 compound 1 Drugs 0.000 description 1
238000013270 controlled release Methods 0.000 description 1
235000012343 cottonseed oil Nutrition 0.000 description 1
239000002385 cottonseed oil Substances 0.000 description 1
229960000913 crospovidone Drugs 0.000 description 1
239000012043 crude product Substances 0.000 description 1
150000004292 cyclic ethers Chemical class 0.000 description 1
125000004122 cyclic group Chemical group 0.000 description 1
231100000135 cytotoxicity Toxicity 0.000 description 1
230000003013 cytotoxicity Effects 0.000 description 1
230000006378 damage Effects 0.000 description 1
DIOQZVSQGTUSAI-NJFSPNSNSA-N decane Chemical compound CCCCCCCCC[14CH3] DIOQZVSQGTUSAI-NJFSPNSNSA-N 0.000 description 1
230000007812 deficiency Effects 0.000 description 1
238000006477 desulfuration reaction Methods 0.000 description 1
229940071221 dihydroxybenzoate Drugs 0.000 description 1
125000005442 diisocyanate group Chemical group 0.000 description 1
238000010790 dilution Methods 0.000 description 1
239000012895 dilution Substances 0.000 description 1
XPPKVPWEQAFLFU-UHFFFAOYSA-N diphosphoric acid Chemical compound OP(O)(=O)OP(O)(O)=O XPPKVPWEQAFLFU-UHFFFAOYSA-N 0.000 description 1
229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
238000006073 displacement reaction Methods 0.000 description 1
238000010494 dissociation reaction Methods 0.000 description 1
230000005593 dissociations Effects 0.000 description 1
DLNKOYKMWOXYQA-UHFFFAOYSA-N dl-pseudophenylpropanolamine Natural products CC(N)C(O)C1=CC=CC=C1 DLNKOYKMWOXYQA-UHFFFAOYSA-N 0.000 description 1
239000000428 dust Substances 0.000 description 1
235000013601 eggs Nutrition 0.000 description 1
MLILORUFDVLTSP-UHFFFAOYSA-N emivirine Chemical compound O=C1NC(=O)N(COCC)C(CC=2C=CC=CC=2)=C1C(C)C MLILORUFDVLTSP-UHFFFAOYSA-N 0.000 description 1
239000003974 emollient agent Substances 0.000 description 1
239000003995 emulsifying agent Substances 0.000 description 1
239000000839 emulsion Substances 0.000 description 1
238000005538 encapsulation Methods 0.000 description 1
238000005516 engineering process Methods 0.000 description 1
239000002532 enzyme inhibitor Substances 0.000 description 1
150000002148 esters Chemical class 0.000 description 1
230000003203 everyday effect Effects 0.000 description 1
239000000284 extract Substances 0.000 description 1
239000000706 filtrate Substances 0.000 description 1
239000000796 flavoring agent Substances 0.000 description 1
238000007667 floating Methods 0.000 description 1
239000012530 fluid Substances 0.000 description 1
125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
235000013355 food flavoring agent Nutrition 0.000 description 1
230000006870 function Effects 0.000 description 1
239000007789 gas Substances 0.000 description 1
239000003193 general anesthetic agent Substances 0.000 description 1
239000011521 glass Substances 0.000 description 1
239000003292 glue Substances 0.000 description 1
229930195712 glutamate Natural products 0.000 description 1
239000010439 graphite Substances 0.000 description 1
229910002804 graphite Inorganic materials 0.000 description 1
JEGUKCSWCFPDGT-UHFFFAOYSA-N h2o hydrate Chemical compound O.O JEGUKCSWCFPDGT-UHFFFAOYSA-N 0.000 description 1
230000036541 health Effects 0.000 description 1
241000411851 herbal medicine Species 0.000 description 1
IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
239000008240 homogeneous mixture Substances 0.000 description 1
150000007857 hydrazones Chemical class 0.000 description 1
239000000017 hydrogel Substances 0.000 description 1
230000002209 hydrophobic effect Effects 0.000 description 1
150000004679 hydroxides Chemical class 0.000 description 1
WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
210000000987 immune system Anatomy 0.000 description 1
230000036039 immunity Effects 0.000 description 1
230000006872 improvement Effects 0.000 description 1
239000012535 impurity Substances 0.000 description 1
229960001936 indinavir Drugs 0.000 description 1
229910052738 indium Inorganic materials 0.000 description 1
APFVFJFRJDLVQX-UHFFFAOYSA-N indium atom Chemical compound [In] APFVFJFRJDLVQX-UHFFFAOYSA-N 0.000 description 1
230000002458 infectious effect Effects 0.000 description 1
230000005764 inhibitory process Effects 0.000 description 1
229910052500 inorganic mineral Inorganic materials 0.000 description 1
238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
238000001990 intravenous administration Methods 0.000 description 1
108010075606 kynostatin 272 Proteins 0.000 description 1
150000002596 lactones Chemical class 0.000 description 1
239000000787 lecithin Substances 0.000 description 1
235000010445 lecithin Nutrition 0.000 description 1
229940067606 lecithin Drugs 0.000 description 1
239000012669 liquid formulation Substances 0.000 description 1
239000006194 liquid suspension Substances 0.000 description 1
CETVQRFGPOGIQJ-UHFFFAOYSA-N lithium;hexane Chemical compound [Li+].CCCCC[CH2-] CETVQRFGPOGIQJ-UHFFFAOYSA-N 0.000 description 1
210000004072 lung Anatomy 0.000 description 1
239000011777 magnesium Substances 0.000 description 1
229910052749 magnesium Inorganic materials 0.000 description 1
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
229920000609 methyl cellulose Polymers 0.000 description 1
235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 1
239000001923 methylcellulose Substances 0.000 description 1
229960002216 methylparaben Drugs 0.000 description 1
229940016286 microcrystalline cellulose Drugs 0.000 description 1
235000019813 microcrystalline cellulose Nutrition 0.000 description 1
239000008108 microcrystalline cellulose Substances 0.000 description 1
239000011707 mineral Substances 0.000 description 1
235000010755 mineral Nutrition 0.000 description 1
239000003595 mist Substances 0.000 description 1
238000000465 moulding Methods 0.000 description 1
210000003205 muscle Anatomy 0.000 description 1
DIOQZVSQGTUSAI-UHFFFAOYSA-N n-butylhexane Natural products CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 1
229960000884 nelfinavir Drugs 0.000 description 1
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 1
229960000689 nevirapine Drugs 0.000 description 1
ZCYXXKJEDCHMGH-UHFFFAOYSA-N nonane Chemical compound CCCC[CH]CCCC ZCYXXKJEDCHMGH-UHFFFAOYSA-N 0.000 description 1
BKIMMITUMNQMOS-UHFFFAOYSA-N normal nonane Natural products CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 1
239000002777 nucleoside Substances 0.000 description 1
150000003833 nucleoside derivatives Chemical class 0.000 description 1
TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
229960002446 octanoic acid Drugs 0.000 description 1
239000012044 organic layer Substances 0.000 description 1
239000012074 organic phase Substances 0.000 description 1
125000001979 organolithium group Chemical group 0.000 description 1
229940042443 other antivirals in atc Drugs 0.000 description 1
RXBWRFDZXRAEJT-SZNOJMITSA-N palinavir Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)C=1N=C2C=CC=CC2=CC=1)C(C)C)[C@H](O)CN1[C@@H](C[C@@H](CC1)OCC=1C=CN=CC=1)C(=O)NC(C)(C)C)C1=CC=CC=C1 RXBWRFDZXRAEJT-SZNOJMITSA-N 0.000 description 1
229950006460 palinavir Drugs 0.000 description 1
239000013618 particulate matter Substances 0.000 description 1
230000001575 pathological effect Effects 0.000 description 1
125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
235000019319 peptone Nutrition 0.000 description 1
230000010412 perfusion Effects 0.000 description 1
239000012071 phase Substances 0.000 description 1
229960000395 phenylpropanolamine Drugs 0.000 description 1
239000004033 plastic Substances 0.000 description 1
229920000747 poly(lactic acid) Polymers 0.000 description 1
229920002721 polycyanoacrylate Polymers 0.000 description 1
229920000573 polyethylene Polymers 0.000 description 1
229920000223 polyglycerol Polymers 0.000 description 1
239000004633 polyglycolic acid Substances 0.000 description 1
239000004626 polylactic acid Substances 0.000 description 1
229920006324 polyoxymethylene Polymers 0.000 description 1
235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
230000003449 preventive effect Effects 0.000 description 1
YWAKXRMUMFPDSH-UHFFFAOYSA-N propyl ethylene Natural products CCCC=C YWAKXRMUMFPDSH-UHFFFAOYSA-N 0.000 description 1
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
229960003415 propylparaben Drugs 0.000 description 1
102000004169 proteins and genes Human genes 0.000 description 1
108090000623 proteins and genes Proteins 0.000 description 1
235000011962 puddings Nutrition 0.000 description 1
150000003254 radicals Chemical class 0.000 description 1
238000011084 recovery Methods 0.000 description 1
210000000664 rectum Anatomy 0.000 description 1
238000007670 refining Methods 0.000 description 1
230000003716 rejuvenation Effects 0.000 description 1
230000010076 replication Effects 0.000 description 1
238000011160 research Methods 0.000 description 1
230000002441 reversible effect Effects 0.000 description 1
238000007363 ring formation reaction Methods 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
235000019204 saccharin Nutrition 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
150000003839 salts Chemical class 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
230000001568 sexual effect Effects 0.000 description 1
210000000813 small intestine Anatomy 0.000 description 1
235000017557 sodium bicarbonate Nutrition 0.000 description 1
229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
229910000033 sodium borohydride Inorganic materials 0.000 description 1
239000012279 sodium borohydride Substances 0.000 description 1
235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
229910052938 sodium sulfate Inorganic materials 0.000 description 1
235000011152 sodium sulphate Nutrition 0.000 description 1
235000010265 sodium sulphite Nutrition 0.000 description 1
239000008247 solid mixture Substances 0.000 description 1
235000014347 soups Nutrition 0.000 description 1
210000005070 sphincter Anatomy 0.000 description 1
239000007921 spray Substances 0.000 description 1
239000003381 stabilizer Substances 0.000 description 1
238000010025 steaming Methods 0.000 description 1
238000004659 sterilization and disinfection Methods 0.000 description 1
PJANXHGTPQOBST-UHFFFAOYSA-N stilbene Chemical compound C=1C=CC=CC=1C=CC1=CC=CC=C1 PJANXHGTPQOBST-UHFFFAOYSA-N 0.000 description 1
235000021286 stilbenes Nutrition 0.000 description 1
150000005846 sugar alcohols Polymers 0.000 description 1
238000009495 sugar coating Methods 0.000 description 1
235000021092 sugar substitutes Nutrition 0.000 description 1
150000008163 sugars Chemical class 0.000 description 1
238000001356 surgical procedure Methods 0.000 description 1
239000000375 suspending agent Substances 0.000 description 1
239000000725 suspension Substances 0.000 description 1
208000011580 syndromic disease 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
238000012360 testing method Methods 0.000 description 1
RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
230000001225 therapeutic effect Effects 0.000 description 1
238000002560 therapeutic procedure Methods 0.000 description 1
238000002076 thermal analysis method Methods 0.000 description 1
210000001541 thymus gland Anatomy 0.000 description 1
229940098465 tincture Drugs 0.000 description 1
238000013518 transcription Methods 0.000 description 1
230000035897 transcription Effects 0.000 description 1
230000002103 transcriptional effect Effects 0.000 description 1
238000012546 transfer Methods 0.000 description 1
230000009466 transformation Effects 0.000 description 1
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
239000013638 trimer Substances 0.000 description 1
AAAQKTZKLRYKHR-UHFFFAOYSA-N triphenylmethane Chemical compound C1=CC=CC=C1C(C=1C=CC=CC=1)C1=CC=CC=C1 AAAQKTZKLRYKHR-UHFFFAOYSA-N 0.000 description 1
229950000977 trovirdine Drugs 0.000 description 1
229960003986 tuaminoheptane Drugs 0.000 description 1
VSRBKQFNFZQRBM-UHFFFAOYSA-N tuaminoheptane Chemical compound CCCCCC(C)N VSRBKQFNFZQRBM-UHFFFAOYSA-N 0.000 description 1
241001430294 unidentified retrovirus Species 0.000 description 1
150000003673 urethanes Chemical class 0.000 description 1
229920002554 vinyl polymer Polymers 0.000 description 1
230000003612 virological effect Effects 0.000 description 1
235000020234 walnut Nutrition 0.000 description 1
238000009736 wetting Methods 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)

TW088109817A 1998-06-11 1999-07-03 Crystalline Efavirenz TWI235152B (en)

Applications Claiming Priority (1)

Application Number	Priority Date	Filing Date	Title
US8898198P	1998-06-11	1998-06-11

Publications (1)

Publication Number	Publication Date
TWI235152B true TWI235152B (en)	2005-07-01

Family

ID=22214647

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
TW088109817A TWI235152B (en)	1998-06-11	1999-07-03	Crystalline Efavirenz

Country Status (21)

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

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

Family Cites Families (6)

* 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
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
IL139793A (en)	2006-10-31
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	Description
2019-08-11	MK4A	Expiration of patent term of an invention patent

Publication	Publication Date	Title
TWI235152B (en)	2005-07-01	Crystalline Efavirenz
KR100612795B1 (ko)	2006-08-17	결정성 에파비렌즈
ES2261234T5 (es)	2010-12-23	Metabolitos de bupropion y metodos de sintesis y uso.
CN105164117B (zh)	2019-02-01	二肽和三肽环氧酮蛋白酶抑制剂
AU2012276114B2 (en)	2016-08-04	Substituted cinnamamide derivative, preparation method and use thereof
TW201043623A (en)	2010-12-16	Crystalline tripeptide epoxy ketone protease inhibitors
JPH08505133A (ja)	1996-06-04	解熱方法および鎮痛方法並びに光学的に純粋なｒ−ケトロラックを含む組成物
CN102898505A (zh)	2013-01-30	Arpak/咪唑啉/rgd三元缀合物及其制备方法和用途
KR102889111B1 (ko)	2025-11-19	니코티닐 알코올 에테르 유도체의 말레에이트, 이의 결정형, 및 이의 응용
US6673372B1 (en)	2004-01-06	Crystalline Efavirenz
JP2019203007A (ja)	2019-11-28	Ｔｒｈアナログ及びアルンド酸を組み合わせてなる組成物、並びにアルンド酸の薬学的に許容される塩
WO2001079263A1 (en)	2001-10-25	Peptide derivatives and medicinal compositions
TWI916846B (zh)	2026-03-01	N-(甲氧羰基)-3-甲基-l-纈胺醯基-(4r)-n-{(1s)-1-氰基-2-[(3s)-2-側氧基吡咯啶-3-基]乙基}-4-(三氟甲基)-l-脯胺醯胺及其溶劑合物之固體形式
BR112021016171A2 (pt)	2021-10-05	Combinações de iadademstat para terapia de câncer
US10647745B2 (en)	2020-05-12	Compound for treating sequelae of ischemic cerebral stroke
WO2007132280A1 (en)	2007-11-22	Isatin and its derivatives for use as a medicament
TWI757573B (zh)	2022-03-11	化合物在製備治療出血性腦中風的藥物中的應用
HK40122848A (zh)	2025-10-10	双取代酰胺卟啉衍生物、其制备方法及其作为光敏剂的用途
HK40122848B (zh)	2025-11-21	双取代酰胺卟啉衍生物、其制备方法及其作为光敏剂的用途
JP2019509321A (ja)	2019-04-04	疼痛を処置するための組み合わせ
WO2005007155A1 (ja)	2005-01-27	医薬組成物
Diamond	1990	Management of headaches: Focus on new strategies
TW200425910A (en)	2004-12-01	Optically active bicyclol, method for producing the same, pharmaceutical composition and use thereof
US20140271604A1 (en)	2014-09-18	HDAC Inhibitor Polymorphic Forms and Methods of Use
NZ618801B2 (en)	2016-03-30	Substituted cinnamamide derivative, preparation method and use thereof