DE69430385T2 - Hiv-proteaseinhibitoren - Google Patents
Hiv-proteaseinhibitorenInfo
- Publication number
- DE69430385T2 DE69430385T2 DE69430385T DE69430385T DE69430385T2 DE 69430385 T2 DE69430385 T2 DE 69430385T2 DE 69430385 T DE69430385 T DE 69430385T DE 69430385 T DE69430385 T DE 69430385T DE 69430385 T2 DE69430385 T2 DE 69430385T2
- Authority
- DE
- Germany
- Prior art keywords
- compound
- pharmaceutically acceptable
- hiv
- acceptable salt
- compounds
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 239000004030 hiv protease inhibitor Substances 0.000 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 76
- 238000000034 method Methods 0.000 claims abstract description 30
- 150000003839 salts Chemical class 0.000 claims abstract description 30
- 208000030507 AIDS Diseases 0.000 claims abstract description 23
- 238000011282 treatment Methods 0.000 claims abstract description 22
- 208000015181 infectious disease Diseases 0.000 claims abstract description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- 230000002265 prevention Effects 0.000 claims abstract description 6
- 208000031886 HIV Infections Diseases 0.000 claims description 14
- 208000037357 HIV infectious disease Diseases 0.000 claims description 14
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 claims description 14
- 230000005764 inhibitory process Effects 0.000 claims description 13
- 125000004193 piperazinyl group Chemical group 0.000 claims description 11
- 108010010369 HIV Protease Proteins 0.000 claims description 10
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 claims description 10
- 239000003112 inhibitor Substances 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 108010078851 HIV Reverse Transcriptase Proteins 0.000 claims description 5
- 230000002401 inhibitory effect Effects 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 4
- 229960000689 nevirapine Drugs 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- 229940127073 nucleoside analogue Drugs 0.000 claims 1
- IPWFJLQDVFKJDU-UHFFFAOYSA-N pentanamide Chemical compound CCCCC(N)=O IPWFJLQDVFKJDU-UHFFFAOYSA-N 0.000 claims 1
- 239000003443 antiviral agent Substances 0.000 abstract description 6
- 239000002955 immunomodulating agent Substances 0.000 abstract description 5
- 229940121354 immunomodulator Drugs 0.000 abstract description 5
- 229960005486 vaccine Drugs 0.000 abstract description 4
- 239000003242 anti bacterial agent Substances 0.000 abstract description 2
- 229940088710 antibiotic agent Drugs 0.000 abstract description 2
- 239000004615 ingredient Substances 0.000 abstract 1
- 229940042443 other antivirals in atc Drugs 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 109
- 235000019439 ethyl acetate Nutrition 0.000 description 47
- 239000000243 solution Substances 0.000 description 46
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 39
- 238000006243 chemical reaction Methods 0.000 description 38
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- 239000000203 mixture Substances 0.000 description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 29
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 29
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- 238000002360 preparation method Methods 0.000 description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- 239000002904 solvent Substances 0.000 description 21
- 239000007787 solid Substances 0.000 description 20
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 15
- 238000004128 high performance liquid chromatography Methods 0.000 description 15
- 238000005160 1H NMR spectroscopy Methods 0.000 description 14
- 241000725303 Human immunodeficiency virus Species 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 14
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 13
- 230000014759 maintenance of location Effects 0.000 description 13
- -1 t-butyloxycarbonyl Chemical group 0.000 description 13
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 239000012267 brine Substances 0.000 description 11
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 239000002585 base Substances 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 10
- HLEKYJVHEBHTMR-UHFFFAOYSA-N pentanamide Chemical compound CCCCC(N)=O.CCCCC(N)=O HLEKYJVHEBHTMR-UHFFFAOYSA-N 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 9
- 238000001514 detection method Methods 0.000 description 9
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 9
- 235000019341 magnesium sulphate Nutrition 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 7
- 241000700605 Viruses Species 0.000 description 7
- 150000002924 oxiranes Chemical class 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 239000002002 slurry Substances 0.000 description 7
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 6
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 229940126062 Compound A Drugs 0.000 description 6
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 6
- 150000001408 amides Chemical class 0.000 description 6
- 230000008878 coupling Effects 0.000 description 6
- 238000010168 coupling process Methods 0.000 description 6
- 238000005859 coupling reaction Methods 0.000 description 6
- 238000010828 elution Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 108091005804 Peptidases Proteins 0.000 description 5
- 239000004365 Protease Substances 0.000 description 5
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 5
- 239000002024 ethyl acetate extract Substances 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 238000003818 flash chromatography Methods 0.000 description 5
- 239000006260 foam Substances 0.000 description 5
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 5
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Inorganic materials [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
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- 235000011007 phosphoric acid Nutrition 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 4
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
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- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 4
- 239000002777 nucleoside Substances 0.000 description 4
- 150000003833 nucleoside derivatives Chemical class 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 4
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- 238000004809 thin layer chromatography Methods 0.000 description 4
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 4
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
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- 101710205625 Capsid protein p24 Proteins 0.000 description 3
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- 101710149279 Small delta antigen Proteins 0.000 description 3
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
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- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 2
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- 238000013207 serial dilution Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
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- 229940005550 sodium alginate Drugs 0.000 description 1
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- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
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- NFYVBEJDCCRVLW-ZETCQYMHSA-N tert-butyl n-[(3s)-3-carbamoylpiperazin-1-yl]carbamate Chemical compound CC(C)(C)OC(=O)NN1CCN[C@H](C(N)=O)C1 NFYVBEJDCCRVLW-ZETCQYMHSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
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- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pyrrole Compounds (AREA)
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Claims (15)
1. Eine Verbindung der Formel:
oder ein pharmazeutisch annehmbares Salz davon,
wobei:
ein stabiler 8- bis 10gliedriger bicyclischer
Heterocyclus ist, ausgewählt aus
wobei der Heterocyclus unsubstituiert oder mit OH, Halogen,
Niedrig-C&sub1;&submin;&sub4;-alkyl, Oxo substituiert ist.
2. Eine Verbindung nach Anspruch 1, wobei:
ist
und X O oder S ist,
oder ein pharmazeutisch annehmbares Salz davon.
3. Eine Verbindung nach Anspruch 1, die
genannt N-(2(R)-Hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4(S)-
hydroxy-5-(1-(4-(3-furo[2,3-b]pyridylmethyl)-2(S)-N'-(t-butylcarboxamido)piperazinyl))pentanamid, ist,
oder ein pharmazeutisch annehmbares Salz davon.
4. Eine Verbindung nach Anspruch 1, die ist:
oder ein pharmazeutisch annehmbares Salz davon.
5. Eine pharmazeutische Zusammensetzung, die eine Verbindung
nach irgendeinem der Ansprüche 1-4 oder ein pharmazeutisch
annehmbares Salz davon und einen pharmazeutisch annehmbaren Träger
enthält.
6. Eine wie in irgendeinem der Ansprüche 1-4 beanspruchte
Verbindung oder ein pharmazeutisch annehmbares Salz davon zur
Verwendung bei der Behandlung von AIDS, zur Prävention einer
Infektion durch HIV, zur Behandlung einer HIV-Infektion oder zur
Inhibierung von HIV-Protease.
7. Die Verwendung einer wie in irgendeinem der Ansprüche 1-4
beanspruchten Verbindung oder eines pharmazeutisch annehmbaren
Salzes davon zur Herstellung eines Medikaments zur Verwendung bei
einem Verfahren zur Behandlung von AIDS.
8. Die Verwendung einer wie in irgendeinem der Ansprüche 1-4
beanspruchten Verbindung oder eines pharmazeutisch annehmbaren
Salzes davon zur Herstellung eines Medikaments zur Verwendung bei
einem Verfahren zur Prävention einer Infektion durch HIV.
9. Die Verwendung einer wie in irgendeinem der Ansprüche 1-4
beanspruchten Verbindung oder eines pharmazeutisch annehmbaren
Salzes davon zur Herstellung eines Medikaments zur Verwendung bei
einem Verfahren zur Behandlung einer Infektion durch HIV.
10. Die Verwendung einer wie in irgendeinem der Ansprüche 1-4
beanspruchten Verbindung oder eines pharmazeutisch annehmbaren
Salzes davon zur Herstellung eines Medikaments zur Verwendung bei
einem Verfahren zur Inhibierung von HIV-Protease.
11. Eine Kombination aus Verbindungen, die die Verbindung nach
Anspruch 3 oder 4 oder ein pharmazeutisch annehmbares Salz davon
und ein Nichtnukleosid-Analoga-Inhibitor von reverser
HIV-Transkriptase, ausgewählt aus Verbindung B und Verbindung C und
Nevirapin und gegebenenfalls irgendeinem von AZT oder ddI oder ddC, ist.
12. Eine Kombination aus Verbindungen, die die Verbindung nach
Anspruch 3 oder 4 oder ein pharmazeutisch annehmbares Salz davon
und irgendeines von AZT oder ddI oder ddC ist.
13. Eine pharmazeutische Zusammensetzung, die die Verbindung
nach Anspruch 4 und einen pharmazeutisch annehmbaren Träger
enthält.
14. Die Verbindung nach Anspruch 4 zur Verwendung bei einem
Verfahren zur Behandlung des menschlichen Körpers durch Therapie.
15. Die Verwendung der Verbindung nach Anspruch 4 zur
Herstellung eines Medikaments zur Verwendung bei einem Verfahren zur
Behandlung von AIDS, zur Prävention einer Infektion durch HIV, zur
Behandlung einer Infektion durch HIV oder zur Inhibierung von HIV-
Protease.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US16801393A | 1993-12-15 | 1993-12-15 | |
| US17047593A | 1993-12-20 | 1993-12-20 | |
| PCT/US1994/014187 WO1995016688A1 (en) | 1993-12-15 | 1994-12-12 | Hiv protease inhibitors |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE69430385D1 DE69430385D1 (de) | 2002-05-16 |
| DE69430385T2 true DE69430385T2 (de) | 2002-11-07 |
Family
ID=26863718
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE69430385T Expired - Fee Related DE69430385T2 (de) | 1993-12-15 | 1994-12-12 | Hiv-proteaseinhibitoren |
Country Status (19)
| Country | Link |
|---|---|
| US (2) | US5646148A (de) |
| EP (1) | EP0734387B1 (de) |
| JP (1) | JP3000564B2 (de) |
| KR (1) | KR100234863B1 (de) |
| CN (1) | CN1046727C (de) |
| AT (1) | ATE215952T1 (de) |
| AU (1) | AU692509B2 (de) |
| BG (1) | BG62093B1 (de) |
| BR (1) | BR9408305A (de) |
| CA (1) | CA2178760C (de) |
| CZ (1) | CZ288312B6 (de) |
| DE (1) | DE69430385T2 (de) |
| ES (1) | ES2174921T3 (de) |
| FI (1) | FI962488A0 (de) |
| HU (1) | HUT74681A (de) |
| NZ (1) | NZ278201A (de) |
| PL (1) | PL314984A1 (de) |
| SK (1) | SK75796A3 (de) |
| WO (1) | WO1995016688A1 (de) |
Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2246498T3 (es) | 1995-11-13 | 2006-02-16 | Vitaleech Bioscience N.V. | Aislados antivirales obtenidos de sanguijuelas. |
| MY126358A (en) * | 1996-03-22 | 2006-09-29 | Glaxo Group Ltd | Compositions comprising vx478 and a water soluble tocopherol derivative such as vitamin e-tpgs |
| TW438799B (en) * | 1997-05-29 | 2001-06-07 | Merck & Co Inc | HIV protease inhibitor |
| CO4940492A1 (es) * | 1997-05-29 | 2000-07-24 | Merck & Co Inc | Inhibidor de proteasa de vih |
| CO4970782A1 (es) * | 1997-11-13 | 2000-11-07 | Merck & Co Inc | Terapia combinada para el tratamiento del sida |
| US6180634B1 (en) | 1997-11-13 | 2001-01-30 | Merck & Co., Inc. | Combination therapy for the treatment of AIDS |
| US6251906B1 (en) | 1998-05-15 | 2001-06-26 | Abbott Laboratories | Retroviral protease inhibiting compounds |
| FR2780649B1 (fr) * | 1998-07-06 | 2001-03-09 | Univ Paris Vii Denis Diderot | Derives de la piperazine pour l'inhibition de la replication du virus de l'immunodeficience humaine |
| GB2341385A (en) | 1998-09-14 | 2000-03-15 | Merck & Co Inc | Recovery of iodide from chemical process waste water |
| US6440946B1 (en) * | 1999-02-25 | 2002-08-27 | Takeda Chemical Industries, Ltd. | Multiple-agents-binding compound, production and use thereof |
| US6589962B1 (en) | 1999-07-20 | 2003-07-08 | Merck & Co., Inc. | Alpha-hydroxy-gamma-[[(carbocyclic-or heterocyclic-substituted)amino]carbonyl]alkanamide derivatives and uses thereof |
| JP2003514910A (ja) * | 1999-11-24 | 2003-04-22 | メルク エンド カムパニー インコーポレーテッド | Ｈｉｖプロテアーゼ阻害剤としてのガンマ−ヒドロキシ−２−（フルオロアルキルアミノカルボニル）−１−ピペラジンペンタンアミド類 |
| US6482952B2 (en) | 2000-06-20 | 2002-11-19 | Merck & Co., Inc. | Process for preparing acetonides |
| US7049146B2 (en) | 2000-11-14 | 2006-05-23 | Facet Analytical Services And Technology, Llc | Calibration standards, methods, and kits for water determination |
| US7122376B2 (en) * | 2001-11-01 | 2006-10-17 | Facet Analytical Services And Technology, Llc | Calibration standards, methods, and kits for water determination |
| WO2004027361A1 (en) * | 2002-09-17 | 2004-04-01 | University Of Virginia Patent Foundation | Remote temperature sensing of small volume and related apparatus thereof |
| GB0720503D0 (en) * | 2007-10-22 | 2007-11-28 | Angeletti P Ist Richerche Bio | New compound |
| WO2011156594A2 (en) | 2010-06-09 | 2011-12-15 | Vaccine Technologies, Incorporated | Therapeutic immunization in hiv infected subjects receiving stable antiretroviral treatment |
| CN108178764A (zh) * | 2018-01-09 | 2018-06-19 | 天津科技大学 | 呋喃并[2,3-b]吡啶类化合物及无金属催化的合成方法 |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL89900A0 (en) * | 1988-04-12 | 1989-12-15 | Merck & Co Inc | Hiv protease inhibitors useful for the treatment of aids and pharmaceutical compositions containing them |
| WO1993008184A1 (en) * | 1991-10-23 | 1993-04-29 | Merck & Co., Inc. | Hiv protease inhibitors |
| US5413999A (en) * | 1991-11-08 | 1995-05-09 | Merck & Co., Inc. | HIV protease inhibitors useful for the treatment of AIDS |
| IL103613A (en) * | 1991-11-08 | 1999-05-09 | Merck & Co Inc | VIH protease inhibitors, and the process of preparing intermediates and pharmaceutical preparations containing them. |
| RO118000B1 (ro) * | 1993-03-31 | 2002-12-30 | Merck & Co Inc | Metoda pentru tratamentul sida, prevenirea si tratamentul infectiei cu hiv sau inhibarea proteazei hiv si compozitie farmaceutica pentru aplicarea metodei |
-
1994
- 1994-12-12 NZ NZ278201A patent/NZ278201A/en unknown
- 1994-12-12 BR BR9408305A patent/BR9408305A/pt not_active Application Discontinuation
- 1994-12-12 HU HU9601649A patent/HUT74681A/hu unknown
- 1994-12-12 CZ CZ19961586A patent/CZ288312B6/cs not_active IP Right Cessation
- 1994-12-12 WO PCT/US1994/014187 patent/WO1995016688A1/en active Search and Examination
- 1994-12-12 CN CN94194954A patent/CN1046727C/zh not_active Expired - Fee Related
- 1994-12-12 CA CA002178760A patent/CA2178760C/en not_active Expired - Fee Related
- 1994-12-12 JP JP7516855A patent/JP3000564B2/ja not_active Expired - Fee Related
- 1994-12-12 SK SK757-96A patent/SK75796A3/sk unknown
- 1994-12-12 DE DE69430385T patent/DE69430385T2/de not_active Expired - Fee Related
- 1994-12-12 PL PL94314984A patent/PL314984A1/xx unknown
- 1994-12-12 EP EP95905886A patent/EP0734387B1/de not_active Expired - Lifetime
- 1994-12-12 ES ES95905886T patent/ES2174921T3/es not_active Expired - Lifetime
- 1994-12-12 AU AU14331/95A patent/AU692509B2/en not_active Ceased
- 1994-12-12 AT AT95905886T patent/ATE215952T1/de not_active IP Right Cessation
- 1994-12-12 KR KR1019960703165A patent/KR100234863B1/ko not_active IP Right Cessation
-
1995
- 1995-03-29 US US08/412,509 patent/US5646148A/en not_active Expired - Fee Related
-
1996
- 1996-06-05 BG BG100643A patent/BG62093B1/bg unknown
- 1996-06-14 FI FI962488A patent/FI962488A0/fi unknown
-
1997
- 1997-04-08 US US08/825,787 patent/US5807841A/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| AU692509B2 (en) | 1998-06-11 |
| CZ288312B6 (en) | 2001-05-16 |
| CA2178760C (en) | 2000-08-01 |
| BG100643A (bg) | 1997-02-28 |
| SK75796A3 (en) | 1997-05-07 |
| EP0734387A4 (de) | 1997-03-05 |
| BR9408305A (pt) | 1997-08-26 |
| CN1142827A (zh) | 1997-02-12 |
| EP0734387B1 (de) | 2002-04-10 |
| CN1046727C (zh) | 1999-11-24 |
| BG62093B1 (bg) | 1999-02-26 |
| NZ278201A (en) | 1998-01-26 |
| PL314984A1 (en) | 1996-09-30 |
| AU1433195A (en) | 1995-07-03 |
| FI962488A (fi) | 1996-06-14 |
| ES2174921T3 (es) | 2002-11-16 |
| KR100234863B1 (ko) | 1999-12-15 |
| DE69430385D1 (de) | 2002-05-16 |
| HU9601649D0 (en) | 1996-08-28 |
| ATE215952T1 (de) | 2002-04-15 |
| HUT74681A (en) | 1997-01-28 |
| US5646148A (en) | 1997-07-08 |
| JPH09506619A (ja) | 1997-06-30 |
| WO1995016688A1 (en) | 1995-06-22 |
| US5807841A (en) | 1998-09-15 |
| FI962488A0 (fi) | 1996-06-14 |
| CA2178760A1 (en) | 1995-06-22 |
| EP0734387A1 (de) | 1996-10-02 |
| CZ158696A3 (en) | 1996-11-13 |
| JP3000564B2 (ja) | 2000-01-17 |
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| 8339 | Ceased/non-payment of the annual fee |