EP0415981A1 - Inhibiteurs de protease retrovirale - Google Patents
Inhibiteurs de protease retroviraleInfo
- Publication number
- EP0415981A1 EP0415981A1 EP89905856A EP89905856A EP0415981A1 EP 0415981 A1 EP0415981 A1 EP 0415981A1 EP 89905856 A EP89905856 A EP 89905856A EP 89905856 A EP89905856 A EP 89905856A EP 0415981 A1 EP0415981 A1 EP 0415981A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- loweralkyl
- amino
- alkyl
- mmol
- substituted
- 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.)
- Ceased
Links
- 230000001177 retroviral effect Effects 0.000 title claims abstract description 18
- 239000000137 peptide hydrolase inhibitor Substances 0.000 title abstract description 5
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 605
- 150000002148 esters Chemical class 0.000 claims abstract description 21
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 239000000651 prodrug Substances 0.000 claims abstract description 9
- 229940002612 prodrug Drugs 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims description 347
- 125000000217 alkyl group Chemical group 0.000 claims description 157
- -1 (naphthyl)methyl Chemical group 0.000 claims description 150
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 134
- 125000001624 naphthyl group Chemical group 0.000 claims description 133
- 239000001257 hydrogen Substances 0.000 claims description 85
- 229910052739 hydrogen Inorganic materials 0.000 claims description 85
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 82
- 125000003545 alkoxy group Chemical group 0.000 claims description 70
- 125000000623 heterocyclic group Chemical group 0.000 claims description 59
- 125000003282 alkyl amino group Chemical group 0.000 claims description 57
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 37
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 36
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 36
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 35
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 30
- 150000002431 hydrogen Chemical class 0.000 claims description 30
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 29
- 238000005859 coupling reaction Methods 0.000 claims description 23
- 230000008878 coupling Effects 0.000 claims description 22
- 238000010168 coupling process Methods 0.000 claims description 22
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 21
- 125000005309 thioalkoxy group Chemical group 0.000 claims description 21
- 239000002253 acid Substances 0.000 claims description 19
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 19
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 18
- 108091005804 Peptidases Proteins 0.000 claims description 17
- 239000004365 Protease Substances 0.000 claims description 17
- 125000001424 substituent group Chemical group 0.000 claims description 15
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
- 238000011282 treatment Methods 0.000 claims description 13
- MBVFRSJFKMJRHA-UHFFFAOYSA-N 4-fluoro-1-benzofuran-7-carbaldehyde Chemical compound FC1=CC=C(C=O)C2=C1C=CO2 MBVFRSJFKMJRHA-UHFFFAOYSA-N 0.000 claims description 12
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
- 125000005343 heterocyclic alkyl group Chemical group 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 7
- 150000004820 halides Chemical class 0.000 claims description 7
- 125000001326 naphthylalkyl group Chemical group 0.000 claims description 7
- 125000000266 alpha-aminoacyl group Chemical group 0.000 claims description 6
- 230000002401 inhibitory effect Effects 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 208000031886 HIV Infections Diseases 0.000 claims description 5
- 150000001371 alpha-amino acids Chemical class 0.000 claims description 5
- 235000008206 alpha-amino acids Nutrition 0.000 claims description 5
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 5
- 206010038997 Retroviral infections Diseases 0.000 claims description 4
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 4
- 108010016183 Human immunodeficiency virus 1 p16 protease Proteins 0.000 claims description 3
- 235000001014 amino acid Nutrition 0.000 claims description 3
- 150000001735 carboxylic acids Chemical class 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 241000713772 Human immunodeficiency virus 1 Species 0.000 claims description 2
- 241000713340 Human immunodeficiency virus 2 Species 0.000 claims description 2
- 108010016191 Human immunodeficiency virus 2 p16 protease Proteins 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 257
- 239000000243 solution Substances 0.000 description 248
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 219
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 192
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 173
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 146
- 239000000203 mixture Substances 0.000 description 144
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 120
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 107
- 239000000047 product Substances 0.000 description 91
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 89
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 88
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 84
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 84
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 78
- 235000019439 ethyl acetate Nutrition 0.000 description 73
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 73
- 238000001819 mass spectrum Methods 0.000 description 69
- 238000005160 1H NMR spectroscopy Methods 0.000 description 63
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 63
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 60
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 59
- 239000012267 brine Substances 0.000 description 59
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 57
- 150000003254 radicals Chemical class 0.000 description 48
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 47
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 44
- 230000002829 reductive effect Effects 0.000 description 42
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 40
- 239000007832 Na2SO4 Substances 0.000 description 39
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
- 239000000741 silica gel Substances 0.000 description 39
- 229910002027 silica gel Inorganic materials 0.000 description 39
- 229910052938 sodium sulfate Inorganic materials 0.000 description 39
- 238000003756 stirring Methods 0.000 description 38
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 37
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 35
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 33
- 150000008064 anhydrides Chemical class 0.000 description 33
- 239000003921 oil Substances 0.000 description 32
- 239000011541 reaction mixture Substances 0.000 description 32
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 30
- 238000000746 purification Methods 0.000 description 29
- 239000012074 organic phase Substances 0.000 description 28
- 229910052760 oxygen Inorganic materials 0.000 description 28
- 239000007787 solid Substances 0.000 description 28
- 238000006243 chemical reaction Methods 0.000 description 27
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 26
- 229910052717 sulfur Inorganic materials 0.000 description 26
- 239000000706 filtrate Substances 0.000 description 25
- FUCKRCGERFLLHP-VIFPVBQESA-N (2s)-4-amino-4-oxo-2-(phenylmethoxycarbonylamino)butanoic acid Chemical compound NC(=O)C[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 FUCKRCGERFLLHP-VIFPVBQESA-N 0.000 description 23
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 22
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 description 22
- 238000004587 chromatography analysis Methods 0.000 description 22
- 239000002904 solvent Substances 0.000 description 21
- 238000004440 column chromatography Methods 0.000 description 20
- 238000003818 flash chromatography Methods 0.000 description 20
- 238000010898 silica gel chromatography Methods 0.000 description 20
- 239000000725 suspension Substances 0.000 description 20
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- 238000001704 evaporation Methods 0.000 description 19
- 239000012299 nitrogen atmosphere Substances 0.000 description 19
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 18
- 229920006395 saturated elastomer Polymers 0.000 description 18
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 16
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 15
- 150000001718 carbodiimides Chemical class 0.000 description 15
- 239000012043 crude product Substances 0.000 description 15
- 230000008020 evaporation Effects 0.000 description 15
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 15
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 14
- 239000012044 organic layer Substances 0.000 description 14
- 125000000278 alkyl amino alkyl group Chemical group 0.000 description 13
- 239000012298 atmosphere Substances 0.000 description 13
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 description 13
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 12
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 12
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 12
- 125000004963 sulfonylalkyl group Chemical group 0.000 description 12
- ZJTYRNPLVNMVPQ-LBPRGKRZSA-N tert-butyl n-[(2s)-1-oxo-3-phenylpropan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H](C=O)CC1=CC=CC=C1 ZJTYRNPLVNMVPQ-LBPRGKRZSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- 239000000284 extract Substances 0.000 description 11
- 238000001914 filtration Methods 0.000 description 11
- 238000010992 reflux Methods 0.000 description 11
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 10
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 10
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 10
- 150000001299 aldehydes Chemical class 0.000 description 10
- 239000008346 aqueous phase Substances 0.000 description 10
- 150000003857 carboxamides Chemical class 0.000 description 10
- 125000001188 haloalkyl group Chemical group 0.000 description 10
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- 238000001816 cooling Methods 0.000 description 9
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 235000019270 ammonium chloride Nutrition 0.000 description 8
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 8
- 125000002843 carboxylic acid group Chemical group 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- GOLHZPOXCLTFRB-UHFFFAOYSA-N furan-3-carboxamide Chemical compound NC(=O)C=1C=COC=1 GOLHZPOXCLTFRB-UHFFFAOYSA-N 0.000 description 8
- 150000004702 methyl esters Chemical class 0.000 description 8
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 8
- LBMYHNBGDFONCB-UHFFFAOYSA-N 2-amino-1-(oxolan-2-yl)-3-phenylpropan-1-ol Chemical compound C1CCOC1C(O)C(N)CC1=CC=CC=C1 LBMYHNBGDFONCB-UHFFFAOYSA-N 0.000 description 7
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 7
- 208000030507 AIDS Diseases 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical class CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 7
- 102000035195 Peptidases Human genes 0.000 description 7
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 7
- 150000001412 amines Chemical class 0.000 description 7
- 125000005335 azido alkyl group Chemical group 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 7
- 239000003112 inhibitor Substances 0.000 description 7
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 7
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 7
- QVDXUKJJGUSGLS-LURJTMIESA-N methyl L-leucinate Chemical compound COC(=O)[C@@H](N)CC(C)C QVDXUKJJGUSGLS-LURJTMIESA-N 0.000 description 7
- 239000008363 phosphate buffer Substances 0.000 description 7
- 241001430294 unidentified retrovirus Species 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
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 244000309464 bull Species 0.000 description 6
- 239000006185 dispersion Substances 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- BMFVGAAISNGQNM-UHFFFAOYSA-N isopentylamine Chemical compound CC(C)CCN BMFVGAAISNGQNM-UHFFFAOYSA-N 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- JYIYTPHWOKLCEB-UHFFFAOYSA-N 2-amino-1-cyclopentyl-3-phenylpropan-1-ol Chemical compound C1CCCC1C(O)C(N)CC1=CC=CC=C1 JYIYTPHWOKLCEB-UHFFFAOYSA-N 0.000 description 5
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 5
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 5
- 241000282414 Homo sapiens Species 0.000 description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
- 125000002947 alkylene group Chemical group 0.000 description 5
- 239000012300 argon atmosphere Substances 0.000 description 5
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 5
- 229910052681 coesite Inorganic materials 0.000 description 5
- 229910052906 cristobalite Inorganic materials 0.000 description 5
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 5
- 125000004990 dihydroxyalkyl group Chemical group 0.000 description 5
- 239000006260 foam Substances 0.000 description 5
- 230000007062 hydrolysis Effects 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- 239000002461 renin inhibitor Substances 0.000 description 5
- 229940086526 renin-inhibitors Drugs 0.000 description 5
- 239000000377 silicon dioxide Substances 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 229910052682 stishovite Inorganic materials 0.000 description 5
- 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 5
- 125000005296 thioaryloxy group Chemical group 0.000 description 5
- 229910052905 tridymite Inorganic materials 0.000 description 5
- 238000001665 trituration Methods 0.000 description 5
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 4
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 4
- XRXMNWGCKISMOH-UHFFFAOYSA-N 2-bromobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Br XRXMNWGCKISMOH-UHFFFAOYSA-N 0.000 description 4
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 4
- FEJUGLKDZJDVFY-UHFFFAOYSA-N 9-borabicyclo(3.3.1)nonane Chemical compound C1CCC2CCCC1B2 FEJUGLKDZJDVFY-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- 241000725303 Human immunodeficiency virus Species 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 4
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 4
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 4
- 239000012359 Methanesulfonyl chloride Substances 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
- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 125000003302 alkenyloxy group Chemical group 0.000 description 4
- 125000004688 alkyl sulfonyl alkyl group Chemical group 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 125000004966 cyanoalkyl group Chemical group 0.000 description 4
- PYRZPBDTPRQYKG-UHFFFAOYSA-N cyclopentene-1-carboxylic acid Chemical compound OC(=O)C1=CCCC1 PYRZPBDTPRQYKG-UHFFFAOYSA-N 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 125000005113 hydroxyalkoxy group Chemical group 0.000 description 4
- 229960003136 leucine Drugs 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- CTMQWXHGILXONZ-NSHDSACASA-N methyl (2s)-2-[cyclohexyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoate Chemical compound COC(=O)[C@H](C)N(C(=O)OC(C)(C)C)C1CCCCC1 CTMQWXHGILXONZ-NSHDSACASA-N 0.000 description 4
- OWNNQFMHLFDOKY-UHFFFAOYSA-N methyl 2-formylcyclopentane-1-carboxylate Chemical compound COC(=O)C1CCCC1C=O OWNNQFMHLFDOKY-UHFFFAOYSA-N 0.000 description 4
- ZWUTWTZOUNJUJA-UHFFFAOYSA-N n-methylcyclohexene-1-carboxamide Chemical compound CNC(=O)C1=CCCCC1 ZWUTWTZOUNJUJA-UHFFFAOYSA-N 0.000 description 4
- 229910000489 osmium tetroxide Inorganic materials 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000002243 precursor Substances 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 239000012279 sodium borohydride Substances 0.000 description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- VCGRFBXVSFAGGA-UHFFFAOYSA-N (1,1-dioxo-1,4-thiazinan-4-yl)-[6-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]pyridin-3-yl]methanone Chemical compound CC=1ON=C(C=2C=CC(F)=CC=2)C=1COC(N=C1)=CC=C1C(=O)N1CCS(=O)(=O)CC1 VCGRFBXVSFAGGA-UHFFFAOYSA-N 0.000 description 3
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 3
- HAFSPQFRFQTNHC-MHZLTWQESA-N (2s)-3-phenyl-2-(tritylamino)propanal Chemical compound C([C@@H](C=O)NC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 HAFSPQFRFQTNHC-MHZLTWQESA-N 0.000 description 3
- YBUPWRYTXGAWJX-RXMQYKEDSA-N (4s)-4-propan-2-yl-1,3-oxazolidin-2-one Chemical compound CC(C)[C@H]1COC(=O)N1 YBUPWRYTXGAWJX-RXMQYKEDSA-N 0.000 description 3
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 3
- PHRABVHYUHIYGY-UHFFFAOYSA-N 1-methylnaphthalene Chemical group C1=CC=C2C([CH2])=CC=CC2=C1 PHRABVHYUHIYGY-UHFFFAOYSA-N 0.000 description 3
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 3
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 3
- HCDMJFOHIXMBOV-UHFFFAOYSA-N 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-4,7-dihydropyrrolo[4,5]pyrido[1,2-d]pyrimidin-2-one Chemical compound C=1C2=C3N(CC)C(=O)N(C=4C(=C(OC)C=C(OC)C=4F)F)CC3=CN=C2NC=1CN1CCOCC1 HCDMJFOHIXMBOV-UHFFFAOYSA-N 0.000 description 3
- KVCQTKNUUQOELD-UHFFFAOYSA-N 4-amino-n-[1-(3-chloro-2-fluoroanilino)-6-methylisoquinolin-5-yl]thieno[3,2-d]pyrimidine-7-carboxamide Chemical compound N=1C=CC2=C(NC(=O)C=3C4=NC=NC(N)=C4SC=3)C(C)=CC=C2C=1NC1=CC=CC(Cl)=C1F KVCQTKNUUQOELD-UHFFFAOYSA-N 0.000 description 3
- KCBWAFJCKVKYHO-UHFFFAOYSA-N 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-[[4-[1-propan-2-yl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]pyrazolo[3,4-d]pyrimidine Chemical compound C1(CC1)C1=NC=NC(=C1C1=NC=C2C(=N1)N(N=C2)CC1=CC=C(C=C1)C=1N(C=C(N=1)C(F)(F)F)C(C)C)OC KCBWAFJCKVKYHO-UHFFFAOYSA-N 0.000 description 3
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- 208000037357 HIV infectious disease Diseases 0.000 description 3
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 3
- 108090000783 Renin Proteins 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 241000700605 Viruses Species 0.000 description 3
- 125000005122 aminoalkylamino group Chemical group 0.000 description 3
- 229960001230 asparagine Drugs 0.000 description 3
- 235000009582 asparagine Nutrition 0.000 description 3
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 3
- 125000006277 halobenzyl group Chemical group 0.000 description 3
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000003701 inert diluent Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- DODCBMODXGJOKD-RGMNGODLSA-N methyl (2s)-2-amino-4-methylpentanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CC(C)C DODCBMODXGJOKD-RGMNGODLSA-N 0.000 description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
- 125000004043 oxo group Chemical group O=* 0.000 description 3
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 229920002477 rna polymer Polymers 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000012265 solid product Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- 239000003039 volatile agent Substances 0.000 description 3
- 238000010626 work up procedure Methods 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- CQIUZHAQYHXKRY-VIFPVBQESA-N (2s)-2-amino-3-phenylpropanal Chemical compound O=C[C@@H](N)CC1=CC=CC=C1 CQIUZHAQYHXKRY-VIFPVBQESA-N 0.000 description 2
- VVNYDCGZZSTUBC-LURJTMIESA-N (2s)-5-amino-2-[(2-methylpropan-2-yl)oxycarbonylamino]-5-oxopentanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CCC(N)=O VVNYDCGZZSTUBC-LURJTMIESA-N 0.000 description 2
- MAYZWDRUFKUGGP-VIFPVBQESA-N (3s)-1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol Chemical compound CN1N=NN=C1CN1C2=NC(C(C)(C)C)=NC(N3C[C@@H](O)CC3)=C2N=N1 MAYZWDRUFKUGGP-VIFPVBQESA-N 0.000 description 2
- JLOAXHVHCCBEOL-HOTGVXAUSA-N (3s,4s)-4-amino-6-methyl-1-(2-phenylethylsulfanyl)heptan-3-ol Chemical compound CC(C)C[C@H](N)[C@@H](O)CCSCCC1=CC=CC=C1 JLOAXHVHCCBEOL-HOTGVXAUSA-N 0.000 description 2
- ZGYIXVSQHOKQRZ-COIATFDQSA-N (e)-n-[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-3-cyano-7-[(3s)-oxolan-3-yl]oxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide Chemical compound N#CC1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 ZGYIXVSQHOKQRZ-COIATFDQSA-N 0.000 description 2
- MOWXJLUYGFNTAL-DEOSSOPVSA-N (s)-[2-chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(6-methoxypyridazin-3-yl)methanol Chemical compound N1=NC(OC)=CC=C1[C@@H](O)C1=CC(C=2C3=CC=C(C=C3N=CN=2)N2CCOCC2)=C(F)C=C1Cl MOWXJLUYGFNTAL-DEOSSOPVSA-N 0.000 description 2
- HNMNMMVBTHCENE-HJWRWDBZSA-N (z)-5-amino-4-hydroxy-n-(3-methylbutyl)-6-phenylhex-2-enamide Chemical compound CC(C)CCNC(=O)\C=C/C(O)C(N)CC1=CC=CC=C1 HNMNMMVBTHCENE-HJWRWDBZSA-N 0.000 description 2
- APWRZPQBPCAXFP-UHFFFAOYSA-N 1-(1-oxo-2H-isoquinolin-5-yl)-5-(trifluoromethyl)-N-[2-(trifluoromethyl)pyridin-4-yl]pyrazole-4-carboxamide Chemical compound O=C1NC=CC2=C(C=CC=C12)N1N=CC(=C1C(F)(F)F)C(=O)NC1=CC(=NC=C1)C(F)(F)F APWRZPQBPCAXFP-UHFFFAOYSA-N 0.000 description 2
- BIAAQBNMRITRDV-UHFFFAOYSA-N 1-(chloromethoxy)-2-methoxyethane Chemical compound COCCOCCl BIAAQBNMRITRDV-UHFFFAOYSA-N 0.000 description 2
- ABDDQTDRAHXHOC-QMMMGPOBSA-N 1-[(7s)-5,7-dihydro-4h-thieno[2,3-c]pyran-7-yl]-n-methylmethanamine Chemical compound CNC[C@@H]1OCCC2=C1SC=C2 ABDDQTDRAHXHOC-QMMMGPOBSA-N 0.000 description 2
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- VJROPLWGFCORRM-UHFFFAOYSA-N 2-methylbutan-1-amine Chemical compound CCC(C)CN VJROPLWGFCORRM-UHFFFAOYSA-N 0.000 description 2
- BYHQTRFJOGIQAO-GOSISDBHSA-N 3-(4-bromophenyl)-8-[(2R)-2-hydroxypropyl]-1-[(3-methoxyphenyl)methyl]-1,3,8-triazaspiro[4.5]decan-2-one Chemical compound C[C@H](CN1CCC2(CC1)CN(C(=O)N2CC3=CC(=CC=C3)OC)C4=CC=C(C=C4)Br)O BYHQTRFJOGIQAO-GOSISDBHSA-N 0.000 description 2
- WNEODWDFDXWOLU-QHCPKHFHSA-N 3-[3-(hydroxymethyl)-4-[1-methyl-5-[[5-[(2s)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl]amino]-6-oxopyridin-3-yl]pyridin-2-yl]-7,7-dimethyl-1,2,6,8-tetrahydrocyclopenta[3,4]pyrrolo[3,5-b]pyrazin-4-one Chemical compound C([C@@H](N(CC1)C=2C=NC(NC=3C(N(C)C=C(C=3)C=3C(=C(N4C(C5=CC=6CC(C)(C)CC=6N5CC4)=O)N=CC=3)CO)=O)=CC=2)C)N1C1COC1 WNEODWDFDXWOLU-QHCPKHFHSA-N 0.000 description 2
- SRVXSISGYBMIHR-UHFFFAOYSA-N 3-[3-[3-(2-amino-2-oxoethyl)phenyl]-5-chlorophenyl]-3-(5-methyl-1,3-thiazol-2-yl)propanoic acid Chemical compound S1C(C)=CN=C1C(CC(O)=O)C1=CC(Cl)=CC(C=2C=C(CC(N)=O)C=CC=2)=C1 SRVXSISGYBMIHR-UHFFFAOYSA-N 0.000 description 2
- KLDLRDSRCMJKGM-UHFFFAOYSA-N 3-[chloro-(2-oxo-1,3-oxazolidin-3-yl)phosphoryl]-1,3-oxazolidin-2-one Chemical compound C1COC(=O)N1P(=O)(Cl)N1CCOC1=O KLDLRDSRCMJKGM-UHFFFAOYSA-N 0.000 description 2
- IHCCAYCGZOLTEU-UHFFFAOYSA-N 3-furoic acid Chemical compound OC(=O)C=1C=COC=1 IHCCAYCGZOLTEU-UHFFFAOYSA-N 0.000 description 2
- LVFPDQUAUOUBPO-UHFFFAOYSA-N 3-methyl-3-(phenylmethoxycarbonylamino)butanoic acid Chemical compound OC(=O)CC(C)(C)NC(=O)OCC1=CC=CC=C1 LVFPDQUAUOUBPO-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- VJPPLCNBDLZIFG-ZDUSSCGKSA-N 4-[(3S)-3-(but-2-ynoylamino)piperidin-1-yl]-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide Chemical compound C(C#CC)(=O)N[C@@H]1CN(CCC1)C1=C2C(=C(NC2=C(C=C1F)C(=O)N)C)C VJPPLCNBDLZIFG-ZDUSSCGKSA-N 0.000 description 2
- XYWIPYBIIRTJMM-IBGZPJMESA-N 4-[[(2S)-2-[4-[5-chloro-2-[4-(trifluoromethyl)triazol-1-yl]phenyl]-5-methoxy-2-oxopyridin-1-yl]butanoyl]amino]-2-fluorobenzamide Chemical compound CC[C@H](N1C=C(OC)C(=CC1=O)C1=C(C=CC(Cl)=C1)N1C=C(N=N1)C(F)(F)F)C(=O)NC1=CC(F)=C(C=C1)C(N)=O XYWIPYBIIRTJMM-IBGZPJMESA-N 0.000 description 2
- 125000003143 4-hydroxybenzyl group Chemical group [H]C([*])([H])C1=C([H])C([H])=C(O[H])C([H])=C1[H] 0.000 description 2
- IRPVABHDSJVBNZ-RTHVDDQRSA-N 5-[1-(cyclopropylmethyl)-5-[(1R,5S)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrazol-3-yl]-3-(trifluoromethyl)pyridin-2-amine Chemical compound C1=C(C(F)(F)F)C(N)=NC=C1C1=NN(CC2CC2)C(C2[C@@H]3CN(C[C@@H]32)C2COC2)=C1 IRPVABHDSJVBNZ-RTHVDDQRSA-N 0.000 description 2
- CYJRNFFLTBEQSQ-UHFFFAOYSA-N 8-(3-methyl-1-benzothiophen-5-yl)-N-(4-methylsulfonylpyridin-3-yl)quinoxalin-6-amine Chemical compound CS(=O)(=O)C1=C(C=NC=C1)NC=1C=C2N=CC=NC2=C(C=1)C=1C=CC2=C(C(=CS2)C)C=1 CYJRNFFLTBEQSQ-UHFFFAOYSA-N 0.000 description 2
- AMKGKYQBASDDJB-UHFFFAOYSA-N 9$l^{2}-borabicyclo[3.3.1]nonane Chemical compound C1CCC2CCCC1[B]2 AMKGKYQBASDDJB-UHFFFAOYSA-N 0.000 description 2
- ZRPZPNYZFSJUPA-UHFFFAOYSA-N ARS-1620 Chemical compound Oc1cccc(F)c1-c1c(Cl)cc2c(ncnc2c1F)N1CCN(CC1)C(=O)C=C ZRPZPNYZFSJUPA-UHFFFAOYSA-N 0.000 description 2
- 101800000734 Angiotensin-1 Proteins 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 2
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- 102000053602 DNA Human genes 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 108010010369 HIV Protease Proteins 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
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 2
- STVVMTBJNDTZBF-VIFPVBQESA-N L-phenylalaninol Chemical compound OC[C@@H](N)CC1=CC=CC=C1 STVVMTBJNDTZBF-VIFPVBQESA-N 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- AYCPARAPKDAOEN-LJQANCHMSA-N N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-[(2-methyl-4-thieno[3,2-d]pyrimidinyl)amino]-1,4-dihydropyrrolo[3,4-c]pyrazole-5-carboxamide Chemical compound C1([C@H](NC(=O)N2C(C=3NN=C(NC=4C=5SC=CC=5N=C(C)N=4)C=3C2)(C)C)CN(C)C)=CC=CC=C1 AYCPARAPKDAOEN-LJQANCHMSA-N 0.000 description 2
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 2
- IDRGFNPZDVBSSE-UHFFFAOYSA-N OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F Chemical compound OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F IDRGFNPZDVBSSE-UHFFFAOYSA-N 0.000 description 2
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 description 2
- 108010076039 Polyproteins Proteins 0.000 description 2
- 239000007868 Raney catalyst Substances 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- 102100028255 Renin Human genes 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 2
- 108700022715 Viral Proteases Proteins 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical class [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- LXRZVMYMQHNYJB-UNXOBOICSA-N [(1R,2S,4R)-4-[[5-[4-[(1R)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methylthiophene-2-carbonyl]pyrimidin-4-yl]amino]-2-hydroxycyclopentyl]methyl sulfamate Chemical compound CC1=C(C=C(S1)C(=O)C1=C(N[C@H]2C[C@H](O)[C@@H](COS(N)(=O)=O)C2)N=CN=C1)[C@@H]1NCCC2=C1C=C(Cl)C=C2 LXRZVMYMQHNYJB-UNXOBOICSA-N 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 125000000539 amino acid group Chemical group 0.000 description 2
- 150000001414 amino alcohols Chemical class 0.000 description 2
- 125000005124 aminocycloalkyl group Chemical group 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 239000003443 antiviral agent Substances 0.000 description 2
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 2
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 2
- AYJRCSIUFZENHW-UHFFFAOYSA-L barium carbonate Chemical compound [Ba+2].[O-]C([O-])=O AYJRCSIUFZENHW-UHFFFAOYSA-L 0.000 description 2
- ZUDYPQRUOYEARG-UHFFFAOYSA-L barium(2+);dihydroxide;octahydrate Chemical compound O.O.O.O.O.O.O.O.[OH-].[OH-].[Ba+2] ZUDYPQRUOYEARG-UHFFFAOYSA-L 0.000 description 2
- MJSHDCCLFGOEIK-UHFFFAOYSA-N benzyl (2,5-dioxopyrrolidin-1-yl) carbonate Chemical compound O=C1CCC(=O)N1OC(=O)OCC1=CC=CC=C1 MJSHDCCLFGOEIK-UHFFFAOYSA-N 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 2
- RBGLVWCAGPITBS-UHFFFAOYSA-L bis(trifluoromethylsulfonyloxy)tin Chemical compound [Sn+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F RBGLVWCAGPITBS-UHFFFAOYSA-L 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 125000000707 boryl group Chemical group B* 0.000 description 2
- 150000001649 bromium compounds Chemical class 0.000 description 2
- 230000005587 bubbling Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 2
- 125000005708 carbonyloxy group Chemical group [*:2]OC([*:1])=O 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- DGLFSNZWRYADFC-UHFFFAOYSA-N chembl2334586 Chemical compound C1CCC2=CN=C(N)N=C2C2=C1NC1=CC=C(C#CC(C)(O)C)C=C12 DGLFSNZWRYADFC-UHFFFAOYSA-N 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 125000004981 cycloalkylmethyl group Chemical group 0.000 description 2
- XRLDSWLMHUQECH-UHFFFAOYSA-N cyclopentanecarboxamide Chemical compound NC(=O)C1CCCC1 XRLDSWLMHUQECH-UHFFFAOYSA-N 0.000 description 2
- FAVAVMFXAKZTMV-UHFFFAOYSA-N dibutylboranyl trifluoromethanesulfonate Chemical compound CCCCB(CCCC)OS(=O)(=O)C(F)(F)F FAVAVMFXAKZTMV-UHFFFAOYSA-N 0.000 description 2
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 2
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 239000012259 ether extract Substances 0.000 description 2
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 238000007327 hydrogenolysis reaction Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 150000004694 iodide salts Chemical class 0.000 description 2
- 239000012948 isocyanate Substances 0.000 description 2
- 150000002513 isocyanates Chemical class 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- GUWHRJQTTVADPB-UHFFFAOYSA-N lithium azide Chemical compound [Li+].[N-]=[N+]=[N-] GUWHRJQTTVADPB-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- RMGJCSHZTFKPNO-UHFFFAOYSA-M magnesium;ethene;bromide Chemical compound [Mg+2].[Br-].[CH-]=C RMGJCSHZTFKPNO-UHFFFAOYSA-M 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- MJGFBOZCAJSGQW-UHFFFAOYSA-N mercury sodium Chemical compound [Na].[Hg] MJGFBOZCAJSGQW-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- CGYVFCHCRBGGJG-UHFFFAOYSA-N n-(1,3-dihydroxypropan-2-yl)-2-hexyl-3-oxodecanamide Chemical compound CCCCCCCC(=O)C(C(=O)NC(CO)CO)CCCCCC CGYVFCHCRBGGJG-UHFFFAOYSA-N 0.000 description 2
- FMASTMURQSHELY-UHFFFAOYSA-N n-(4-fluoro-2-methylphenyl)-3-methyl-n-[(2-methyl-1h-indol-4-yl)methyl]pyridine-4-carboxamide Chemical compound C1=CC=C2NC(C)=CC2=C1CN(C=1C(=CC(F)=CC=1)C)C(=O)C1=CC=NC=C1C FMASTMURQSHELY-UHFFFAOYSA-N 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- DTUQWGWMVIHBKE-UHFFFAOYSA-N phenylacetaldehyde Chemical compound O=CCC1=CC=CC=C1 DTUQWGWMVIHBKE-UHFFFAOYSA-N 0.000 description 2
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical class [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- KJRCEJOSASVSRA-UHFFFAOYSA-N propane-2-thiol Chemical compound CC(C)S KJRCEJOSASVSRA-UHFFFAOYSA-N 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine Chemical compound C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 description 2
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 229910001023 sodium amalgam Inorganic materials 0.000 description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 2
- 235000010265 sodium sulphite Nutrition 0.000 description 2
- 239000007909 solid dosage form Substances 0.000 description 2
- 239000012258 stirred mixture Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 239000011593 sulfur Chemical group 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- RQSBRFZHUKLKNO-VIFPVBQESA-N tert-butyl n-[(2s)-4-methyl-1-oxopentan-2-yl]carbamate Chemical compound CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C RQSBRFZHUKLKNO-VIFPVBQESA-N 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 230000007442 viral DNA synthesis Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- LSPHULWDVZXLIL-UHFFFAOYSA-N (+/-)-Camphoric acid Chemical compound CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- IWLPVZQFUJSAKT-JTQLQIEISA-N (1r)-1-(4-methoxyphenyl)-2-(methylamino)ethanol Chemical compound CNC[C@H](O)C1=CC=C(OC)C=C1 IWLPVZQFUJSAKT-JTQLQIEISA-N 0.000 description 1
- PZKNEFTZCZBTND-ROUUACIJSA-N (2,5-dioxopyrrolidin-1-yl) (2S)-4-methyl-2-[[(2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoyl]amino]pentanoate Chemical compound C(=O)(OC(C)(C)C)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)C(=O)ON1C(CCC1=O)=O PZKNEFTZCZBTND-ROUUACIJSA-N 0.000 description 1
- DOMQFIFVDIAOOT-ROUUACIJSA-N (2S,3R)-N-[4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-1,2,4-triazol-3-yl]-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide Chemical compound COC1=C(C(=CC=C1)OC)N1C(=NN=C1C=1C=NC=C(C=1)C)NS(=O)(=O)[C@@H](C)[C@H](C)C1=NC=C(C=N1)C DOMQFIFVDIAOOT-ROUUACIJSA-N 0.000 description 1
- XOYXESIZZFUVRD-YGGZJJQXSA-N (2S,3S,4R,5S,6R)-6-[(2R,3R,4R,5S,6S)-6-[(2R,3S,4S,5S,6S)-5-acetamido-6-[(2R,3R,4R,5S,6S)-4-acetyloxy-6-[(2R,3R,4R,5S,6S)-4-acetyloxy-6-[(2R,3R,4R,5S,6R)-4-acetyloxy-5-hydroxy-2-(hydroxymethyl)-6-methoxyoxan-3-yl]oxy-5-hydroxy-2-(hydroxymethyl)oxan-3-yl]oxy-5-hydroxy-2-(hydroxymethyl)oxan-3-yl]oxy-4-hydroxy-2-(hydroxymethyl)oxan-3-yl]oxy-4-acetyloxy-5-hydroxy-2-(hydroxymethyl)oxan-3-yl]oxy-4-acetyloxy-3-[(2S,3S,4R,5R,6R)-4-acetyloxy-5-[(2S,3S,4R,5R,6R)-4-acetyloxy-3-hydroxy-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxy-3-hydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-5-hydroxyoxane-2-carboxylic acid Polymers CO[C@@H]1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@@H](O[C@@H]3O[C@H](CO)[C@@H](O[C@@H]4O[C@H](CO)[C@@H](O[C@@H]5O[C@H](CO)[C@@H](O[C@@H]6O[C@@H]([C@@H](O[C@@H]7O[C@H](CO)[C@@H](O[C@@H]8O[C@H](CO)[C@@H](OC)[C@H](OC(C)=O)[C@@H]8O)[C@H](OC(C)=O)[C@@H]7O)[C@H](OC(C)=O)[C@@H]6O)C(O)=O)[C@H](OC(C)=O)[C@@H]5O)[C@@H](O)[C@@H]4NC(C)=O)[C@H](OC(C)=O)[C@@H]3O)[C@H](OC(C)=O)[C@@H]2O)[C@H](OC(C)=O)[C@@H]1O XOYXESIZZFUVRD-YGGZJJQXSA-N 0.000 description 1
- PWQSBXROKKCTET-MRVPVSSYSA-N (2r)-2-[(ethoxycarbonylamino)methyl]-4-methylpentanoic acid Chemical compound CCOC(=O)NC[C@H](C(O)=O)CC(C)C PWQSBXROKKCTET-MRVPVSSYSA-N 0.000 description 1
- LWYSDIXSLYXZRG-CYBMUJFWSA-N (2r)-2-[2-[2-(2-methoxyethoxymethoxy)ethyl-methylamino]-2-oxoethyl]-4-methylpentanoic acid Chemical compound COCCOCOCCN(C)C(=O)C[C@H](C(O)=O)CC(C)C LWYSDIXSLYXZRG-CYBMUJFWSA-N 0.000 description 1
- POSVYQQTVOINRC-SNVBAGLBSA-N (2r)-4-methyl-2-(2-morpholin-4-yl-2-oxoethyl)pentanoic acid Chemical compound CC(C)C[C@@H](C(O)=O)CC(=O)N1CCOCC1 POSVYQQTVOINRC-SNVBAGLBSA-N 0.000 description 1
- KPPXMTDZWRHTTO-SNVBAGLBSA-N (2r)-4-methyl-2-[(morpholine-4-carbonylamino)methyl]pentanoic acid Chemical compound CC(C)C[C@@H](C(O)=O)CNC(=O)N1CCOCC1 KPPXMTDZWRHTTO-SNVBAGLBSA-N 0.000 description 1
- CQIJXMZPAKGHBP-YQQAZPJKSA-N (2r,4s,5s)-5-amino-2-(azidomethyl)-6-cyclohexyl-2,4-dihydroxy-n-(2-methylpropyl)hexanamide Chemical compound CC(C)CNC(=O)[C@](O)(CN=[N+]=[N-])C[C@H](O)[C@@H](N)CC1CCCCC1 CQIJXMZPAKGHBP-YQQAZPJKSA-N 0.000 description 1
- LHRPBKHHWKOSHL-MQWKRIRWSA-N (2s)-2-(2,3-dihydroxypropoxycarbonylamino)-4-methylpentanoic acid Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)OCC(O)CO LHRPBKHHWKOSHL-MQWKRIRWSA-N 0.000 description 1
- LLPLJUYJCMTKLH-QMMMGPOBSA-N (2s)-2-(3-hydroxypropoxycarbonylamino)-4-methylpentanoic acid Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)OCCCO LLPLJUYJCMTKLH-QMMMGPOBSA-N 0.000 description 1
- UQNLLXYSUXPMFS-JTQLQIEISA-N (2s)-2-[(6-methoxy-6-oxohexanoyl)amino]-4-methylpentanoic acid Chemical compound COC(=O)CCCCC(=O)N[C@H](C(O)=O)CC(C)C UQNLLXYSUXPMFS-JTQLQIEISA-N 0.000 description 1
- KZBPNZXPUDBBDM-UWVGGRQHSA-N (2s)-2-[[(2s)-2-acetamido-3-methylbutanoyl]amino]-3-methylbutanoic acid Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(C)=O KZBPNZXPUDBBDM-UWVGGRQHSA-N 0.000 description 1
- PHXXVROYZWJYHY-GKAPJAKFSA-N (2s)-2-[[2,3-dihydroxypropyl(methyl)carbamoyl]amino]-4-methylpentanoic acid Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)N(C)CC(O)CO PHXXVROYZWJYHY-GKAPJAKFSA-N 0.000 description 1
- YDLOTVUORAYIOP-FHWLQOOXSA-N (2s)-2-acetamido-3-methyl-n-[(2s)-3-methyl-1-oxo-1-[[(2s)-1-oxo-3-phenylpropan-2-yl]amino]butan-2-yl]butanamide Chemical compound CC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C=O)CC1=CC=CC=C1 YDLOTVUORAYIOP-FHWLQOOXSA-N 0.000 description 1
- GVFCCIDALKIGMK-DCYPJBMNSA-N (2s)-2-acetamido-n-[(2s)-1-(1,5-diphenylpent-3-en-2-ylamino)-3-methyl-1-oxobutan-2-yl]-3-methylbutanamide Chemical compound C=1C=CC=CC=1CC=CC(NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(C)=O)C(C)C)CC1=CC=CC=C1 GVFCCIDALKIGMK-DCYPJBMNSA-N 0.000 description 1
- QZJXRPDQIKVHQU-WTMZWYFGSA-N (2s)-2-acetamido-n-[(2s)-1-[(3,4-dihydroxy-1,5-diphenylpentan-2-yl)amino]-3-methyl-1-oxobutan-2-yl]-3-methylbutanamide Chemical compound C=1C=CC=CC=1CC(O)C(O)C(NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(C)=O)C(C)C)CC1=CC=CC=C1 QZJXRPDQIKVHQU-WTMZWYFGSA-N 0.000 description 1
- RGZIDUHCRREKNN-FHWLQOOXSA-N (2s)-2-acetamido-n-[(2s)-1-[[(2s)-1-hydroxy-3-phenylpropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]-3-methylbutanamide Chemical compound CC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](CO)CC1=CC=CC=C1 RGZIDUHCRREKNN-FHWLQOOXSA-N 0.000 description 1
- RRONHWAVOYADJL-HNNXBMFYSA-N (2s)-3-phenyl-2-(phenylmethoxycarbonylamino)propanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC=1C=CC=CC=1)C1=CC=CC=C1 RRONHWAVOYADJL-HNNXBMFYSA-N 0.000 description 1
- WLAHZBUXAUZITA-AWEZNQCLSA-N (2s)-4-methyl-2-(3-phenylmethoxypropanoylamino)pentanoic acid Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CCOCC1=CC=CC=C1 WLAHZBUXAUZITA-AWEZNQCLSA-N 0.000 description 1
- KGLCCBGHIBQHDI-DOERSZECSA-N (2s,3r,4s,6s)-2,7-diamino-1-cyclohexyl-6-methylheptane-3,4-diol Chemical compound NC[C@@H](C)C[C@H](O)[C@H](O)[C@@H](N)CC1CCCCC1 KGLCCBGHIBQHDI-DOERSZECSA-N 0.000 description 1
- WBYVPHAUXSMTEC-LRGNLBRXSA-N (2s,3r,4s,6s)-2-amino-7-(benzylamino)-1-cyclohexyl-6-methylheptane-3,4-diol Chemical compound C([C@@H](C)C[C@H](O)[C@H](O)[C@@H](N)CC1CCCCC1)NCC1=CC=CC=C1 WBYVPHAUXSMTEC-LRGNLBRXSA-N 0.000 description 1
- VTQHAQXFSHDMHT-NTSWFWBYSA-N (2s,3s)-2-amino-3-methylpentan-1-ol Chemical compound CC[C@H](C)[C@H](N)CO VTQHAQXFSHDMHT-NTSWFWBYSA-N 0.000 description 1
- QJCNLJWUIOIMMF-YUMQZZPRSA-N (2s,3s)-3-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]pentanoic acid Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)OC(C)(C)C QJCNLJWUIOIMMF-YUMQZZPRSA-N 0.000 description 1
- GOSQQKSTRCGTQP-YQQAZPJKSA-N (2s,4s,5s)-5-amino-2-(chloromethyl)-6-cyclohexyl-2,4-dihydroxy-n-(2-methylpropyl)hexanamide Chemical compound CC(C)CNC(=O)[C@](O)(CCl)C[C@H](O)[C@@H](N)CC1CCCCC1 GOSQQKSTRCGTQP-YQQAZPJKSA-N 0.000 description 1
- CIXCPBHBQQGBRW-BQFCYCMXSA-N (2s,4s,5s)-5-amino-6-cyclohexyl-2,4-dihydroxy-2-methyl-n-(3-methylbutyl)hexanamide Chemical compound CC(C)CCNC(=O)[C@@](C)(O)C[C@H](O)[C@@H](N)CC1CCCCC1 CIXCPBHBQQGBRW-BQFCYCMXSA-N 0.000 description 1
- CFMRKUYJARYXBX-CYBMUJFWSA-N (3r)-5-methyl-3-phenylmethoxycarbonylhexanoic acid Chemical compound CC(C)C[C@H](CC(O)=O)C(=O)OCC1=CC=CC=C1 CFMRKUYJARYXBX-CYBMUJFWSA-N 0.000 description 1
- ZOEIDLHSPUJXOJ-QWRGUYRKSA-N (3s,4s)-4-amino-5-cyclohexylpent-1-en-3-ol Chemical compound C=C[C@H](O)[C@@H](N)CC1CCCCC1 ZOEIDLHSPUJXOJ-QWRGUYRKSA-N 0.000 description 1
- QBXLKIUNMXOEEC-HOTGVXAUSA-N (3s,4s)-4-amino-6-methyl-1-(2-phenylethylsulfonyl)heptan-3-ol Chemical compound CC(C)C[C@H](N)[C@@H](O)CCS(=O)(=O)CCC1=CC=CC=C1 QBXLKIUNMXOEEC-HOTGVXAUSA-N 0.000 description 1
- VGMWZVMXAAKMKC-JTQLQIEISA-N (4r)-3-(4-methylpentanoyl)-4-propan-2-yl-1,3-oxazolidin-2-one Chemical compound CC(C)CCC(=O)N1[C@H](C(C)C)COC1=O VGMWZVMXAAKMKC-JTQLQIEISA-N 0.000 description 1
- OBCDZJOBILYTMH-ZCFIWIBFSA-N (4s)-3-(2-bromoacetyl)-4-propan-2-yl-1,3-oxazolidin-2-one Chemical compound CC(C)[C@H]1COC(=O)N1C(=O)CBr OBCDZJOBILYTMH-ZCFIWIBFSA-N 0.000 description 1
- GXVWYKHLLARYNC-CYBMUJFWSA-N (4s)-3-(2-phenylmethoxyacetyl)-4-propan-2-yl-1,3-oxazolidin-2-one Chemical compound CC(C)[C@H]1COC(=O)N1C(=O)COCC1=CC=CC=C1 GXVWYKHLLARYNC-CYBMUJFWSA-N 0.000 description 1
- CTHMOVCPUUIPBN-VUWPPUDQSA-N (4s)-4-(cyclohexylmethyl)-5-ethenyl-1,3-oxazolidin-2-one Chemical compound C=CC1OC(=O)N[C@H]1CC1CCCCC1 CTHMOVCPUUIPBN-VUWPPUDQSA-N 0.000 description 1
- XWBZDZMNVYVVNL-MELADBBJSA-N (4s,5r,6s)-6-amino-7-cyclohexyl-2,2-dimethylheptane-1,4,5-triol Chemical compound OCC(C)(C)C[C@H](O)[C@H](O)[C@@H](N)CC1CCCCC1 XWBZDZMNVYVVNL-MELADBBJSA-N 0.000 description 1
- VYQMDRFCXFENQH-SPOOISQMSA-N (4s,5s)-5-amino-4-hydroxy-2-(hydroxymethyl)-n-methyl-6-phenylhexanamide Chemical compound CNC(=O)C(CO)C[C@H](O)[C@@H](N)CC1=CC=CC=C1 VYQMDRFCXFENQH-SPOOISQMSA-N 0.000 description 1
- XWCPLZSIBMODGZ-STQMWFEESA-N (4s,5s)-5-amino-4-hydroxy-n-methyl-2-methylidene-6-phenylhexanamide Chemical compound CNC(=O)C(=C)C[C@H](O)[C@@H](N)CC1=CC=CC=C1 XWCPLZSIBMODGZ-STQMWFEESA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- UKGJZDSUJSPAJL-YPUOHESYSA-N (e)-n-[(1r)-1-[3,5-difluoro-4-(methanesulfonamido)phenyl]ethyl]-3-[2-propyl-6-(trifluoromethyl)pyridin-3-yl]prop-2-enamide Chemical compound CCCC1=NC(C(F)(F)F)=CC=C1\C=C\C(=O)N[C@H](C)C1=CC(F)=C(NS(C)(=O)=O)C(F)=C1 UKGJZDSUJSPAJL-YPUOHESYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- OZAYQHFUDXSAIE-UHFFFAOYSA-N 1-(ethoxymethoxy)-2-methoxy-n-methylethanamine Chemical compound CCOCOC(NC)COC OZAYQHFUDXSAIE-UHFFFAOYSA-N 0.000 description 1
- IOAQMGSIMAGQEA-UHFFFAOYSA-N 1-amino-2-benzyl-1-(furan-2-yl)-3,3,3-triphenylpropan-1-ol Chemical compound O1C(=CC=C1)C(C(CC1=CC=CC=C1)C(C1=CC=CC=C1)(C1=CC=CC=C1)C1=CC=CC=C1)(O)N IOAQMGSIMAGQEA-UHFFFAOYSA-N 0.000 description 1
- VFWCMGCRMGJXDK-UHFFFAOYSA-N 1-chlorobutane Chemical compound CCCCCl VFWCMGCRMGJXDK-UHFFFAOYSA-N 0.000 description 1
- VUQPJRPDRDVQMN-UHFFFAOYSA-N 1-chlorooctadecane Chemical class CCCCCCCCCCCCCCCCCCCl VUQPJRPDRDVQMN-UHFFFAOYSA-N 0.000 description 1
- IJHOLMCJRXVNJP-MRXNPFEDSA-N 1-o-benzyl 4-o-tert-butyl (2r)-2-(2-methylpropyl)butanedioate Chemical compound CC(C)(C)OC(=O)C[C@@H](CC(C)C)C(=O)OCC1=CC=CC=C1 IJHOLMCJRXVNJP-MRXNPFEDSA-N 0.000 description 1
- URTPNQRAHXRPMP-UHFFFAOYSA-N 1-phenylmethoxycarbonylpiperidine-4-carboxylic acid Chemical compound C1CC(C(=O)O)CCN1C(=O)OCC1=CC=CC=C1 URTPNQRAHXRPMP-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 description 1
- LHJGJYXLEPZJPM-UHFFFAOYSA-N 2,4,5-trichlorophenol Chemical compound OC1=CC(Cl)=C(Cl)C=C1Cl LHJGJYXLEPZJPM-UHFFFAOYSA-N 0.000 description 1
- XTGFJELPBRGIHZ-UHFFFAOYSA-N 2-(2-amino-1-hydroxy-3-phenylpropyl)benzoic acid Chemical compound C=1C=CC=C(C(O)=O)C=1C(O)C(N)CC1=CC=CC=C1 XTGFJELPBRGIHZ-UHFFFAOYSA-N 0.000 description 1
- NZNCTFNQOFRTAH-UHFFFAOYSA-N 2-(2-amino-1-hydroxy-3-phenylpropyl)cyclohexane-1-carboxylic acid Chemical compound C1CCCC(C(O)=O)C1C(O)C(N)CC1=CC=CC=C1 NZNCTFNQOFRTAH-UHFFFAOYSA-N 0.000 description 1
- RAKZLKFNKMCIRF-UHFFFAOYSA-N 2-(2-amino-1-hydroxy-3-phenylpropyl)cyclopropane-1-carboxylic acid Chemical compound C1C(C(O)=O)C1C(O)C(N)CC1=CC=CC=C1 RAKZLKFNKMCIRF-UHFFFAOYSA-N 0.000 description 1
- YFDIPVXHXBJTLY-UHFFFAOYSA-N 2-(3-benzyloxiran-2-yl)cyclopentane-1-carboxylic acid Chemical compound OC(=O)C1CCCC1C1C(CC=2C=CC=CC=2)O1 YFDIPVXHXBJTLY-UHFFFAOYSA-N 0.000 description 1
- BMZJORGYEOQMFR-UHFFFAOYSA-N 2-(iodomethyl)oxolane Chemical compound ICC1CCCO1 BMZJORGYEOQMFR-UHFFFAOYSA-N 0.000 description 1
- DGJMFCAWGKNEAZ-UHFFFAOYSA-N 2-(methoxymethoxy)ethanamine Chemical compound COCOCCN DGJMFCAWGKNEAZ-UHFFFAOYSA-N 0.000 description 1
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 1
- VRPJIFMKZZEXLR-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid Chemical compound CC(C)(C)OC(=O)NCC(O)=O VRPJIFMKZZEXLR-UHFFFAOYSA-N 0.000 description 1
- QVHJQCGUWFKTSE-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound OC(=O)C(C)NC(=O)OC(C)(C)C QVHJQCGUWFKTSE-UHFFFAOYSA-N 0.000 description 1
- LOYUNHURLPICNF-UHFFFAOYSA-N 2-[1-[tert-butyl(dimethyl)silyl]oxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropyl]benzoic acid Chemical compound C=1C=CC=C(C(O)=O)C=1C(O[Si](C)(C)C(C)(C)C)C(NC(=O)OC(C)(C)C)CC1=CC=CC=C1 LOYUNHURLPICNF-UHFFFAOYSA-N 0.000 description 1
- IHMCZUGUQKUQMJ-UHFFFAOYSA-N 2-[1-[tert-butyl(dimethyl)silyl]oxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropyl]cyclopentene-1-carboxylic acid Chemical compound OC(=O)C=1CCCC=1C(O[Si](C)(C)C(C)(C)C)C(NC(=O)OC(C)(C)C)CC1=CC=CC=C1 IHMCZUGUQKUQMJ-UHFFFAOYSA-N 0.000 description 1
- 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 1
- CBWFTZNMONHKNZ-UHFFFAOYSA-N 2-[methyl(phenylmethoxycarbonyl)amino]acetic acid Chemical compound OC(=O)CN(C)C(=O)OCC1=CC=CC=C1 CBWFTZNMONHKNZ-UHFFFAOYSA-N 0.000 description 1
- SYTZETCSOIKOQM-UHFFFAOYSA-N 2-amino-1-(1,3-benzothiazol-2-yl)-4-methylpentan-1-ol Chemical compound C1=CC=C2SC(C(O)C(N)CC(C)C)=NC2=C1 SYTZETCSOIKOQM-UHFFFAOYSA-N 0.000 description 1
- YRNBJWIYJPKNNW-UHFFFAOYSA-N 2-amino-1-(1-methylimidazol-2-yl)-3-phenylpropan-1-ol Chemical compound CN1C=CN=C1C(O)C(N)CC1=CC=CC=C1 YRNBJWIYJPKNNW-UHFFFAOYSA-N 0.000 description 1
- VNQMUFAPSITPCU-UHFFFAOYSA-N 2-amino-1-(1-methyltetrazol-5-yl)-3-phenylpropan-1-ol Chemical compound CN1N=NN=C1C(O)C(N)CC1=CC=CC=C1 VNQMUFAPSITPCU-UHFFFAOYSA-N 0.000 description 1
- VNNKVQCRTDBLQW-UHFFFAOYSA-N 2-amino-1-(2,3-dihydrofuran-5-yl)-3-phenylpropan-1-ol Chemical compound C=1CCOC=1C(O)C(N)CC1=CC=CC=C1 VNNKVQCRTDBLQW-UHFFFAOYSA-N 0.000 description 1
- OUZXSTHKHYRYPY-UHFFFAOYSA-N 2-amino-1-(3,4-dihydro-2h-pyran-6-yl)-3-phenylpropan-1-ol Chemical compound C=1CCCOC=1C(O)C(N)CC1=CC=CC=C1 OUZXSTHKHYRYPY-UHFFFAOYSA-N 0.000 description 1
- AKXITTLHIWYNIY-UHFFFAOYSA-N 2-amino-1-(4,4-dimethyl-5h-1,3-oxazol-2-yl)-3-phenylpropan-1-ol Chemical compound CC1(C)COC(C(O)C(N)CC=2C=CC=CC=2)=N1 AKXITTLHIWYNIY-UHFFFAOYSA-N 0.000 description 1
- FIZWGYUYHNTUMZ-UHFFFAOYSA-N 2-amino-1-(oxan-2-yl)-3-phenylpropan-1-ol Chemical compound C1CCCOC1C(O)C(N)CC1=CC=CC=C1 FIZWGYUYHNTUMZ-UHFFFAOYSA-N 0.000 description 1
- KGYZGGUJJIVOQX-UHFFFAOYSA-N 2-amino-1-cyclohexyl-6-methylheptane-3,4-diol Chemical compound CC(C)CC(O)C(O)C(N)CC1CCCCC1 KGYZGGUJJIVOQX-UHFFFAOYSA-N 0.000 description 1
- BSHIIXDRPYWZRV-UHFFFAOYSA-N 2-amino-3-phenyl-1-(1,3-thiazol-2-yl)propan-1-ol Chemical compound N=1C=CSC=1C(O)C(N)CC1=CC=CC=C1 BSHIIXDRPYWZRV-UHFFFAOYSA-N 0.000 description 1
- YDPMTQLDOFBYRX-UHFFFAOYSA-N 2-amino-3-phenyl-1-(1h-pyrrol-2-yl)propan-1-ol Chemical compound C=1C=CNC=1C(O)C(N)CC1=CC=CC=C1 YDPMTQLDOFBYRX-UHFFFAOYSA-N 0.000 description 1
- YVGZXTQJQNXIAU-UHFFFAOYSA-N 2-amino-5-(hydroxyamino)-5-oxopentanoic acid Chemical compound OC(=O)C(N)CCC(=O)NO YVGZXTQJQNXIAU-UHFFFAOYSA-N 0.000 description 1
- LSTRKXWIZZZYAS-UHFFFAOYSA-N 2-bromoacetyl bromide Chemical compound BrCC(Br)=O LSTRKXWIZZZYAS-UHFFFAOYSA-N 0.000 description 1
- ZLXLAGQLWBJSSF-UHFFFAOYSA-N 2-bromocyclohexene-1-carboxylic acid Chemical group OC(=O)C1=C(Br)CCCC1 ZLXLAGQLWBJSSF-UHFFFAOYSA-N 0.000 description 1
- FBXSCLJLRKVMCV-UHFFFAOYSA-N 2-bromocyclopentene-1-carboxylic acid Chemical group OC(=O)C1=C(Br)CCC1 FBXSCLJLRKVMCV-UHFFFAOYSA-N 0.000 description 1
- CFMZSMGAMPBRBE-UHFFFAOYSA-N 2-hydroxyisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(O)C(=O)C2=C1 CFMZSMGAMPBRBE-UHFFFAOYSA-N 0.000 description 1
- SJRNDWRNVLNHKC-UHFFFAOYSA-N 2-isocyanato-3-methylbutanoic acid Chemical compound CC(C)C(C(O)=O)N=C=O SJRNDWRNVLNHKC-UHFFFAOYSA-N 0.000 description 1
- YOWQWFMSQCOSBA-UHFFFAOYSA-N 2-methoxypropene Chemical compound COC(C)=C YOWQWFMSQCOSBA-UHFFFAOYSA-N 0.000 description 1
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- 229940080296 2-naphthalenesulfonate Drugs 0.000 description 1
- ZMRFRBHYXOQLDK-UHFFFAOYSA-N 2-phenylethanethiol Chemical compound SCCC1=CC=CC=C1 ZMRFRBHYXOQLDK-UHFFFAOYSA-N 0.000 description 1
- WMPPDTMATNBGJN-UHFFFAOYSA-N 2-phenylethylbromide Chemical class BrCCC1=CC=CC=C1 WMPPDTMATNBGJN-UHFFFAOYSA-N 0.000 description 1
- QISAUDWTBBNJIR-UHFFFAOYSA-N 2-phenylmethoxyacetyl chloride Chemical compound ClC(=O)COCC1=CC=CC=C1 QISAUDWTBBNJIR-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- IMLWTPYJNIEPII-JKSUJKDBSA-N 3-[(4S,5R)-4-benzyl-2,2-dimethyl-3-[(2-methylpropan-2-yl)oxycarbonyl]-1,3-oxazolidin-5-yl]prop-2-enoic acid Chemical compound C(C1=CC=CC=C1)[C@@H]1N(C(O[C@@H]1C=CC(=O)O)(C)C)C(=O)OC(C)(C)C IMLWTPYJNIEPII-JKSUJKDBSA-N 0.000 description 1
- YGYGASJNJTYNOL-CQSZACIVSA-N 3-[(4r)-2,2-dimethyl-1,1-dioxothian-4-yl]-5-(4-fluorophenyl)-1h-indole-7-carboxamide Chemical compound C1CS(=O)(=O)C(C)(C)C[C@@H]1C1=CNC2=C(C(N)=O)C=C(C=3C=CC(F)=CC=3)C=C12 YGYGASJNJTYNOL-CQSZACIVSA-N 0.000 description 1
- PUQDAKFKACUGKE-UHFFFAOYSA-N 3-amino-4-cyclohexyl-1-propan-2-ylsulfanylbutan-2-ol Chemical compound CC(C)SCC(O)C(N)CC1CCCCC1 PUQDAKFKACUGKE-UHFFFAOYSA-N 0.000 description 1
- MINNLZMVGCNAHJ-UHFFFAOYSA-N 3-amino-4-cyclohexyl-1-propan-2-ylsulfonylbutan-2-ol Chemical compound CC(C)S(=O)(=O)CC(O)C(N)CC1CCCCC1 MINNLZMVGCNAHJ-UHFFFAOYSA-N 0.000 description 1
- YXQDBEZPBMCYAI-UHFFFAOYSA-N 3-amino-4-phenylbutane-1,2-diol Chemical compound OCC(O)C(N)CC1=CC=CC=C1 YXQDBEZPBMCYAI-UHFFFAOYSA-N 0.000 description 1
- KQIGMPWTAHJUMN-UHFFFAOYSA-N 3-aminopropane-1,2-diol Chemical compound NCC(O)CO KQIGMPWTAHJUMN-UHFFFAOYSA-N 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 description 1
- WOMTYMDHLQTCHY-UHFFFAOYSA-N 3-methylamino-1,2-propanediol Chemical compound CNCC(O)CO WOMTYMDHLQTCHY-UHFFFAOYSA-N 0.000 description 1
- GZLGTVRDLCJQTO-UHFFFAOYSA-M 3-methylbutyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CCC(C)C)C1=CC=CC=C1 GZLGTVRDLCJQTO-UHFFFAOYSA-M 0.000 description 1
- QGXQKGLWWDUOEY-UHFFFAOYSA-N 3-n-hydroxybicyclo[2.2.1]hept-5-ene-2,3-dicarboxamide Chemical compound C1C2C=CC1C(C(=O)N)C2C(=O)NO QGXQKGLWWDUOEY-UHFFFAOYSA-N 0.000 description 1
- OZGUGVRKYBSDBN-UHFFFAOYSA-N 3-phenylmethoxypropanoic acid Chemical compound OC(=O)CCOCC1=CC=CC=C1 OZGUGVRKYBSDBN-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-M 3-phenylpropionate Chemical compound [O-]C(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-M 0.000 description 1
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- JVQIKJMSUIMUDI-UHFFFAOYSA-N 3-pyrroline Chemical compound C1NCC=C1 JVQIKJMSUIMUDI-UHFFFAOYSA-N 0.000 description 1
- YFCIFWOJYYFDQP-PTWZRHHISA-N 4-[3-amino-6-[(1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl]pyrazin-2-yl]-N-[(1S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl]-2-fluorobenzamide Chemical compound CNC[C@@H](NC(=O)c1ccc(cc1F)-c1nc(cnc1N)[C@H]1CC[C@H](O)[C@@H](F)C1)c1cc(F)cc(Br)c1 YFCIFWOJYYFDQP-PTWZRHHISA-N 0.000 description 1
- UHLVRGQVUJQHGC-UHFFFAOYSA-N 4-[tert-butyl(dimethyl)silyl]oxy-5-[(2-methylpropan-2-yl)oxycarbonylamino]-6-phenylhex-2-enoic acid Chemical compound CC(C)(C)OC(=O)NC(C(O[Si](C)(C)C(C)(C)C)C=CC(O)=O)CC1=CC=CC=C1 UHLVRGQVUJQHGC-UHFFFAOYSA-N 0.000 description 1
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 1
- MUXJXSWYXDORJN-UHFFFAOYSA-N 4-methoxy-2,2-dimethyl-4-oxobutanoic acid Chemical compound COC(=O)CC(C)(C)C(O)=O MUXJXSWYXDORJN-UHFFFAOYSA-N 0.000 description 1
- SVWCVXFHTHCJJB-UHFFFAOYSA-N 4-methylpentanoyl chloride Chemical compound CC(C)CCC(Cl)=O SVWCVXFHTHCJJB-UHFFFAOYSA-N 0.000 description 1
- YBUPWRYTXGAWJX-UHFFFAOYSA-N 4-propan-2-yl-1,3-oxazolidin-2-one Chemical compound CC(C)C1COC(=O)N1 YBUPWRYTXGAWJX-UHFFFAOYSA-N 0.000 description 1
- HPHMNSPJTLYSAI-UHFFFAOYSA-N 5-(2-amino-1-hydroxy-3-phenylpropyl)-1,2-thiazole-4-carboxylic acid Chemical compound S1N=CC(C(O)=O)=C1C(O)C(N)CC1=CC=CC=C1 HPHMNSPJTLYSAI-UHFFFAOYSA-N 0.000 description 1
- SHNFHXXTISOWTG-UHFFFAOYSA-N 5-(5-oxo-3-phenylmethoxycarbonyl-1,3-oxazolidin-4-yl)pentanoic acid Chemical compound C1OC(=O)C(CCCCC(=O)O)N1C(=O)OCC1=CC=CC=C1 SHNFHXXTISOWTG-UHFFFAOYSA-N 0.000 description 1
- YSIKMVBJYGKCCW-UHFFFAOYSA-N 5-[1-hydroxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropyl]-1,2-thiazole-4-carboxylic acid Chemical compound S1N=CC(C(O)=O)=C1C(O)C(NC(=O)OC(C)(C)C)CC1=CC=CC=C1 YSIKMVBJYGKCCW-UHFFFAOYSA-N 0.000 description 1
- DZRJNQFWWIUBDI-UHFFFAOYSA-N 5-amino-4-hydroxy-6-phenylhex-2-enoic acid Chemical compound OC(=O)C=CC(O)C(N)CC1=CC=CC=C1 DZRJNQFWWIUBDI-UHFFFAOYSA-N 0.000 description 1
- ULRZEUXHKLNBBA-UHFFFAOYSA-N 6-(2-amino-1-hydroxy-3-phenylpropyl)-n-methylcyclohexene-1-carboxamide;hydrochloride Chemical compound Cl.CNC(=O)C1=CCCCC1C(O)C(N)CC1=CC=CC=C1 ULRZEUXHKLNBBA-UHFFFAOYSA-N 0.000 description 1
- RUFDYIJGNPVTAY-UHFFFAOYSA-N 6-[(2-methylpropan-2-yl)oxycarbonylamino]hexanoic acid Chemical compound CC(C)(C)OC(=O)NCCCCCC(O)=O RUFDYIJGNPVTAY-UHFFFAOYSA-N 0.000 description 1
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 1
- ILDXDBSWYJDHAL-UHFFFAOYSA-N 6-o-(2,5-dioxopyrrolidin-1-yl) 1-o-methyl hexanedioate Chemical compound COC(=O)CCCCC(=O)ON1C(=O)CCC1=O ILDXDBSWYJDHAL-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- NQDOMBRQXKSSNQ-UHFFFAOYSA-N 7-benzylsulfonyl-3,3,5-trimethyl-7-azabicyclo[3.2.1]octane Chemical compound C1C(C)(C)CC(C)(C2)CC1N2S(=O)(=O)CC1=CC=CC=C1 NQDOMBRQXKSSNQ-UHFFFAOYSA-N 0.000 description 1
- KBMOUSRPXRITFH-UHFFFAOYSA-N 7-methoxy-7-oxo-6-(phenylmethoxycarbonylamino)heptanoic acid Chemical compound OC(=O)CCCCC(C(=O)OC)NC(=O)OCC1=CC=CC=C1 KBMOUSRPXRITFH-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 102400000344 Angiotensin-1 Human genes 0.000 description 1
- 101800000733 Angiotensin-2 Proteins 0.000 description 1
- 108090001067 Angiotensinogen Proteins 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- IHQYPVSEADAIKK-QBYKZECYSA-N C(C)(C)(C)OC(=O)N1C(O[C@H]([C@@H]1CC1=C(C=CC=C1)O)[C@@H]1OC(C[C@H]1C(=O)O)C)(C)C Chemical compound C(C)(C)(C)OC(=O)N1C(O[C@H]([C@@H]1CC1=C(C=CC=C1)O)[C@@H]1OC(C[C@H]1C(=O)O)C)(C)C IHQYPVSEADAIKK-QBYKZECYSA-N 0.000 description 1
- WSPLPZPGMIKLCY-MSEHENTLSA-N C(C)(C)(C)OC(=O)N1C(O[C@H]([C@@H]1CC1CCCCC1)[C@@H]1OC(C[C@H]1C(=O)O)C)(C)C Chemical compound C(C)(C)(C)OC(=O)N1C(O[C@H]([C@@H]1CC1CCCCC1)[C@@H]1OC(C[C@H]1C(=O)O)C)(C)C WSPLPZPGMIKLCY-MSEHENTLSA-N 0.000 description 1
- ZQRCPUIDNDXAAN-QWXVGGSQSA-N C(C1=CC=CC=C1)OC(=O)NC([C@@H]([C@@H]([C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)OCOCCOC)O)NC Chemical compound C(C1=CC=CC=C1)OC(=O)NC([C@@H]([C@@H]([C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)OCOCCOC)O)NC ZQRCPUIDNDXAAN-QWXVGGSQSA-N 0.000 description 1
- UCCAUFVSFWGQRY-UHFFFAOYSA-N C(CC)C1=C(CCCC1)C(=O)N Chemical compound C(CC)C1=C(CCCC1)C(=O)N UCCAUFVSFWGQRY-UHFFFAOYSA-N 0.000 description 1
- OJCOFFFEROYRGC-UHFFFAOYSA-N C1=CC=C2SC([Li])=NC2=C1 Chemical compound C1=CC=C2SC([Li])=NC2=C1 OJCOFFFEROYRGC-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 101710132601 Capsid protein Proteins 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 241000701459 Caulimovirus Species 0.000 description 1
- XJUZRXYOEPSWMB-UHFFFAOYSA-N Chloromethyl methyl ether Chemical compound COCCl XJUZRXYOEPSWMB-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- NMEZJSDUZQOPFE-UHFFFAOYSA-N Cyclohex-1-enecarboxylic acid Chemical compound OC(=O)C1=CCCCC1 NMEZJSDUZQOPFE-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 241000450599 DNA viruses Species 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- KMTRUDSVKNLOMY-UHFFFAOYSA-N Ethylene carbonate Chemical compound O=C1OCCO1 KMTRUDSVKNLOMY-UHFFFAOYSA-N 0.000 description 1
- 108010091443 Exopeptidases Proteins 0.000 description 1
- 102000018389 Exopeptidases Human genes 0.000 description 1
- GISRWBROCYNDME-PELMWDNLSA-N F[C@H]1[C@H]([C@H](NC1=O)COC1=NC=CC2=CC(=C(C=C12)OC)C(=O)N)C Chemical compound F[C@H]1[C@H]([C@H](NC1=O)COC1=NC=CC2=CC(=C(C=C12)OC)C(=O)N)C GISRWBROCYNDME-PELMWDNLSA-N 0.000 description 1
- 241000714165 Feline leukemia virus Species 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 102100034343 Integrase Human genes 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 238000005684 Liebig rearrangement reaction Methods 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- JOSNYUDSMPILKL-UHFFFAOYSA-N Methyl DL-Leucate Chemical compound COC(=O)C(O)CC(C)C JOSNYUDSMPILKL-UHFFFAOYSA-N 0.000 description 1
- MDXGYYOJGPFFJL-QMMMGPOBSA-N N(alpha)-t-butoxycarbonyl-L-leucine Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)OC(C)(C)C MDXGYYOJGPFFJL-QMMMGPOBSA-N 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- FEYNFHSRETUBEM-UHFFFAOYSA-N N-[3-(1,1-difluoroethyl)phenyl]-1-(4-methoxyphenyl)-3-methyl-5-oxo-4H-pyrazole-4-carboxamide Chemical compound COc1ccc(cc1)N1N=C(C)C(C(=O)Nc2cccc(c2)C(C)(F)F)C1=O FEYNFHSRETUBEM-UHFFFAOYSA-N 0.000 description 1
- USPFMEKVPDBMCG-LBPRGKRZSA-N N-benzyloxycarbonyl-L-leucine Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 USPFMEKVPDBMCG-LBPRGKRZSA-N 0.000 description 1
- OPKOKAMJFNKNAS-UHFFFAOYSA-N N-methylethanolamine Chemical compound CNCCO OPKOKAMJFNKNAS-UHFFFAOYSA-N 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- XWZIYPPMXRCTDI-UHFFFAOYSA-N O1C(=CCC1)C(C(CC1=CC=CC=C1)C(C1=CC=CC=C1)(C1=CC=CC=C1)C1=CC=CC=C1)(O)N Chemical compound O1C(=CCC1)C(C(CC1=CC=CC=C1)C(C1=CC=CC=C1)(C1=CC=CC=C1)C1=CC=CC=C1)(O)N XWZIYPPMXRCTDI-UHFFFAOYSA-N 0.000 description 1
- AGJYORKWIWZSER-UHFFFAOYSA-N OC(=O)C1CCCC1C=CCC1=CC=CC=C1 Chemical compound OC(=O)C1CCCC1C=CCC1=CC=CC=C1 AGJYORKWIWZSER-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 208000001388 Opportunistic Infections Diseases 0.000 description 1
- 229910003870 O—Li Inorganic materials 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010033661 Pancytopenia Diseases 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 1
- 241000712907 Retroviridae Species 0.000 description 1
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 1
- 108010077895 Sarcosine Proteins 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 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 1
- FHNINJWBTRXEBC-UHFFFAOYSA-N Sudan III Chemical compound OC1=CC=C2C=CC=CC2=C1N=NC(C=C1)=CC=C1N=NC1=CC=CC=C1 FHNINJWBTRXEBC-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- WREGKURFCTUGRC-POYBYMJQSA-N Zalcitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)CC1 WREGKURFCTUGRC-POYBYMJQSA-N 0.000 description 1
- ZMHHHKVQBZIPIG-UTONKHPSSA-M [Li+].CN([C@@](CC(C)C)(C(=O)[O-])C(N)=O)CCN(C)C Chemical compound [Li+].CN([C@@](CC(C)C)(C(=O)[O-])C(N)=O)CCN(C)C ZMHHHKVQBZIPIG-UTONKHPSSA-M 0.000 description 1
- WIXHMRBONDKINO-UHFFFAOYSA-M [Li]C1=C(C=NS1)C(=O)[O-].[Li+] Chemical compound [Li]C1=C(C=NS1)C(=O)[O-].[Li+] WIXHMRBONDKINO-UHFFFAOYSA-M 0.000 description 1
- ZKKKLOYIQKWIJX-UHFFFAOYSA-N [Li]C1=CC=CN1C(=O)OC(C)(C)C Chemical compound [Li]C1=CC=CN1C(=O)OC(C)(C)C ZKKKLOYIQKWIJX-UHFFFAOYSA-N 0.000 description 1
- FKEAMUMDYQLHSA-UHFFFAOYSA-N [Li]C1=CCCCO1 Chemical compound [Li]C1=CCCCO1 FKEAMUMDYQLHSA-UHFFFAOYSA-N 0.000 description 1
- GLHZCEPUMVSODI-UHFFFAOYSA-N [Li]C1=CCCO1 Chemical compound [Li]C1=CCCO1 GLHZCEPUMVSODI-UHFFFAOYSA-N 0.000 description 1
- PGGUIZNCKIWWBO-UHFFFAOYSA-N [Li]C1=NC=CN1C Chemical compound [Li]C1=NC=CN1C PGGUIZNCKIWWBO-UHFFFAOYSA-N 0.000 description 1
- JXFVYUVMDQYFEQ-UHFFFAOYSA-N [Li]C1=NN=NN1C Chemical compound [Li]C1=NN=NN1C JXFVYUVMDQYFEQ-UHFFFAOYSA-N 0.000 description 1
- RBMMFCZYNOLLBF-UHFFFAOYSA-N [Li]C=1OCC(N1)(C)C Chemical compound [Li]C=1OCC(N1)(C)C RBMMFCZYNOLLBF-UHFFFAOYSA-N 0.000 description 1
- WLLIXJBWWFGEHT-UHFFFAOYSA-N [tert-butyl(dimethyl)silyl] trifluoromethanesulfonate Chemical compound CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F WLLIXJBWWFGEHT-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000005036 alkoxyphenyl group Chemical group 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229960002684 aminocaproic acid Drugs 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- ORWYRWWVDCYOMK-HBZPZAIKSA-N angiotensin I Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 ORWYRWWVDCYOMK-HBZPZAIKSA-N 0.000 description 1
- 229960005475 antiinfective agent Drugs 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- UPSAAXBMQQAFQQ-QGZVFWFLSA-N benzyl (2r)-4-methyl-2-(2-morpholin-4-yl-2-oxoethyl)pentanoate Chemical compound C([C@@H](CC(C)C)C(=O)OCC=1C=CC=CC=1)C(=O)N1CCOCC1 UPSAAXBMQQAFQQ-QGZVFWFLSA-N 0.000 description 1
- WOMLRLAVFCMIPT-QGZVFWFLSA-N benzyl (2r)-4-methyl-2-[(morpholine-4-carbonylamino)methyl]pentanoate Chemical compound C([C@@H](CC(C)C)C(=O)OCC=1C=CC=CC=1)NC(=O)N1CCOCC1 WOMLRLAVFCMIPT-QGZVFWFLSA-N 0.000 description 1
- MBRRYUQWSOODEO-LBPRGKRZSA-N benzyl (2s)-2-amino-4-methylpentanoate Chemical compound CC(C)C[C@H](N)C(=O)OCC1=CC=CC=C1 MBRRYUQWSOODEO-LBPRGKRZSA-N 0.000 description 1
- QTQGHKVYLQBJLO-YDALLXLXSA-N benzyl (2s)-2-amino-4-methylpentanoate;4-methylbenzenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1.CC(C)C[C@H](N)C(=O)OCC1=CC=CC=C1 QTQGHKVYLQBJLO-YDALLXLXSA-N 0.000 description 1
- DAMJAHUBTRVKPI-UHFFFAOYSA-N benzyl n-(2,3-dihydroxypropyl)carbamate Chemical compound OCC(O)CNC(=O)OCC1=CC=CC=C1 DAMJAHUBTRVKPI-UHFFFAOYSA-N 0.000 description 1
- GMIQMQBHYROSKY-UHFFFAOYSA-N benzyl n-(2-hydroxyethyl)-n-methylcarbamate Chemical compound OCCN(C)C(=O)OCC1=CC=CC=C1 GMIQMQBHYROSKY-UHFFFAOYSA-N 0.000 description 1
- SAGINAGERRNGGV-UHFFFAOYSA-N benzyl n-(2-hydroxyethyl)carbamate Chemical compound OCCNC(=O)OCC1=CC=CC=C1 SAGINAGERRNGGV-UHFFFAOYSA-N 0.000 description 1
- PRIYUSMWEKKHHT-UHFFFAOYSA-N benzyl n-(methylamino)carbamate Chemical compound CNNC(=O)OCC1=CC=CC=C1 PRIYUSMWEKKHHT-UHFFFAOYSA-N 0.000 description 1
- JMLWKNDDJMUXOO-UHFFFAOYSA-N benzyl n-[2-(1-methoxyethoxymethoxy)ethyl]-n-methylcarbamate Chemical compound COC(C)OCOCCN(C)C(=O)OCC1=CC=CC=C1 JMLWKNDDJMUXOO-UHFFFAOYSA-N 0.000 description 1
- VTEZVUHFLIJPQP-UHFFFAOYSA-N benzyl n-[2-(methoxymethoxy)ethyl]carbamate Chemical compound COCOCCNC(=O)OCC1=CC=CC=C1 VTEZVUHFLIJPQP-UHFFFAOYSA-N 0.000 description 1
- DHBHFHDKOHJROV-UHFFFAOYSA-N benzyl n-amino-n-methylcarbamate Chemical compound CN(N)C(=O)OCC1=CC=CC=C1 DHBHFHDKOHJROV-UHFFFAOYSA-N 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N beta-phenylpropanoic acid Natural products OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 125000005997 bromomethyl group Chemical group 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- RBHJBMIOOPYDBQ-UHFFFAOYSA-N carbon dioxide;propan-2-one Chemical compound O=C=O.CC(C)=O RBHJBMIOOPYDBQ-UHFFFAOYSA-N 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 229940061627 chloromethyl methyl ether Drugs 0.000 description 1
- IFMWVBVPVXRZHE-UHFFFAOYSA-M chlorotitanium(3+);propan-2-olate Chemical compound [Cl-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-] IFMWVBVPVXRZHE-UHFFFAOYSA-M 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 208000024389 cytopenia Diseases 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- XUWHAWMETYGRKB-UHFFFAOYSA-N delta-valerolactam Natural products O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 150000008050 dialkyl sulfates Chemical class 0.000 description 1
- MVLMPMUGCWJDLE-UHFFFAOYSA-M dibutylboron trifluoromethanesulfonate Chemical compound [O-]S(=O)(=O)C(F)(F)F.CCCC[B+]CCCC MVLMPMUGCWJDLE-UHFFFAOYSA-M 0.000 description 1
- 239000002027 dichloromethane extract Substances 0.000 description 1
- WBKFWQBXFREOFH-UHFFFAOYSA-N dichloromethane;ethyl acetate Chemical compound ClCCl.CCOC(C)=O WBKFWQBXFREOFH-UHFFFAOYSA-N 0.000 description 1
- XNYOSXARXANYPB-UHFFFAOYSA-N dicyclohexylborane Chemical compound C1CCCCC1BC1CCCCC1 XNYOSXARXANYPB-UHFFFAOYSA-N 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 1
- 229960004132 diethyl ether Drugs 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- GAFRWLVTHPVQGK-UHFFFAOYSA-N dipentyl sulfate Chemical class CCCCCOS(=O)(=O)OCCCCC GAFRWLVTHPVQGK-UHFFFAOYSA-N 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 241001493065 dsRNA viruses Species 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- BBWMASBANDIFMV-UHFFFAOYSA-N ethyl 4-phenylpiperidine-4-carboxylate;hydrochloride Chemical compound [Cl-].C=1C=CC=CC=1C1(C(=O)OCC)CC[NH2+]CC1 BBWMASBANDIFMV-UHFFFAOYSA-N 0.000 description 1
- WUDNUHPRLBTKOJ-UHFFFAOYSA-N ethyl isocyanate Chemical compound CCN=C=O WUDNUHPRLBTKOJ-UHFFFAOYSA-N 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000005059 halophenyl group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- JUINSXZKUKVTMD-UHFFFAOYSA-N hydrogen azide Chemical compound N=[N+]=[N-] JUINSXZKUKVTMD-UHFFFAOYSA-N 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- XNXVOSBNFZWHBV-UHFFFAOYSA-N hydron;o-methylhydroxylamine;chloride Chemical compound Cl.CON XNXVOSBNFZWHBV-UHFFFAOYSA-N 0.000 description 1
- 208000021822 hypotensive Diseases 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- LSACYLWPPQLVSM-UHFFFAOYSA-N isobutyric acid anhydride Chemical compound CC(C)C(=O)OC(=O)C(C)C LSACYLWPPQLVSM-UHFFFAOYSA-N 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000003965 isoxazolidinyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- HXEACLLIILLPRG-RXMQYKEDSA-N l-pipecolic acid Natural products OC(=O)[C@H]1CCCCN1 HXEACLLIILLPRG-RXMQYKEDSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 125000001998 leucyl group Chemical group 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- QUFUZPOMGMZNNL-UHFFFAOYSA-N lithium;2h-1,3-thiazol-2-ide Chemical compound [Li+].C1=CS[C-]=N1 QUFUZPOMGMZNNL-UHFFFAOYSA-N 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 1
- NNLTYSITTKKVGV-CYBMUJFWSA-N methyl (2R)-2-carbamoyl-2-[2-(dimethylamino)ethyl-methylamino]-4-methylpentanoate Chemical compound COC(=O)[C@@](CC(C)C)(C(N)=O)N(C)CCN(C)C NNLTYSITTKKVGV-CYBMUJFWSA-N 0.000 description 1
- NPOWBGBZIALFCV-GKAPJAKFSA-N methyl (2s)-2-(2,3-dihydroxypropoxycarbonylamino)-4-methylpentanoate Chemical compound COC(=O)[C@H](CC(C)C)NC(=O)OCC(O)CO NPOWBGBZIALFCV-GKAPJAKFSA-N 0.000 description 1
- RZYNEMGDKRBFTM-VIFPVBQESA-N methyl (2s)-2-(2-cyanoethylamino)-4-methylpentanoate Chemical compound COC(=O)[C@H](CC(C)C)NCCC#N RZYNEMGDKRBFTM-VIFPVBQESA-N 0.000 description 1
- CIOLONCQVKFXFX-VIFPVBQESA-N methyl (2s)-2-(3-hydroxypropoxycarbonylamino)-4-methylpentanoate Chemical compound COC(=O)[C@H](CC(C)C)NC(=O)OCCCO CIOLONCQVKFXFX-VIFPVBQESA-N 0.000 description 1
- SDSWSVBXRBXPRL-LBPRGKRZSA-N methyl (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoate Chemical compound CC(C)(C)OC(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 SDSWSVBXRBXPRL-LBPRGKRZSA-N 0.000 description 1
- DSBQEXPSAXUTBS-AXDSSHIGSA-N methyl (2s)-2-[[2,3-dihydroxypropyl(methyl)carbamoyl]amino]-4-methylpentanoate Chemical compound COC(=O)[C@H](CC(C)C)NC(=O)N(C)CC(O)CO DSBQEXPSAXUTBS-AXDSSHIGSA-N 0.000 description 1
- NDBQJIBNNUJNHA-DFWYDOINSA-N methyl (2s)-2-amino-3-hydroxypropanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CO NDBQJIBNNUJNHA-DFWYDOINSA-N 0.000 description 1
- UWFLIWPVRTVDNO-ZETCQYMHSA-N methyl (2s)-2-isocyanato-4-methylpentanoate Chemical compound COC(=O)[C@H](CC(C)C)N=C=O UWFLIWPVRTVDNO-ZETCQYMHSA-N 0.000 description 1
- FOMIHTTUAILLQT-ZDUSSCGKSA-N methyl (2s)-3-(4-methoxyphenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate Chemical compound CC(C)(C)OC(=O)N[C@H](C(=O)OC)CC1=CC=C(OC)C=C1 FOMIHTTUAILLQT-ZDUSSCGKSA-N 0.000 description 1
- UJKMHYRWVFNCDQ-HNNXBMFYSA-N methyl (2s)-4-methyl-2-(3-phenylmethoxypropanoylamino)pentanoate Chemical compound COC(=O)[C@H](CC(C)C)NC(=O)CCOCC1=CC=CC=C1 UJKMHYRWVFNCDQ-HNNXBMFYSA-N 0.000 description 1
- FDLHAXFKGXDXBX-UHFFFAOYSA-N methyl 2-(2,3-diamino-3-phenylpropyl)cyclopentane-1-carboxylate Chemical compound COC(=O)C1CCCC1CC(N)C(N)C1=CC=CC=C1 FDLHAXFKGXDXBX-UHFFFAOYSA-N 0.000 description 1
- FOWUENGOQBUDLZ-UHFFFAOYSA-N methyl 2-(2-amino-1-hydroxy-3-phenylpropyl)cyclobutane-1-carboxylate Chemical compound COC(=O)C1CCC1C(O)C(N)CC1=CC=CC=C1 FOWUENGOQBUDLZ-UHFFFAOYSA-N 0.000 description 1
- QIJHZLIWMPLNCF-UHFFFAOYSA-N methyl 2-(2-amino-1-hydroxy-3-phenylpropyl)cyclopentane-1-carboxylate Chemical compound COC(=O)C1CCCC1C(O)C(N)CC1=CC=CC=C1 QIJHZLIWMPLNCF-UHFFFAOYSA-N 0.000 description 1
- WRRPAWQUGWUPQW-UHFFFAOYSA-N methyl 2-(2-azido-1-hydroxy-3-phenylpropyl)cyclopentane-1-carboxylate Chemical compound COC(=O)C1CCCC1C(O)C(N=[N+]=[N-])CC1=CC=CC=C1 WRRPAWQUGWUPQW-UHFFFAOYSA-N 0.000 description 1
- CMRZVXZULXMQLI-UHFFFAOYSA-N methyl 2-[1-[tert-butyl(dimethyl)silyl]oxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-(4-phenylmethoxyphenyl)propyl]cyclopentane-1-carboxylate Chemical compound COC(=O)C1CCCC1C(O[Si](C)(C)C(C)(C)C)C(NC(=O)OC(C)(C)C)CC(C=C1)=CC=C1OCC1=CC=CC=C1 CMRZVXZULXMQLI-UHFFFAOYSA-N 0.000 description 1
- HXBPUJWZAXLYOR-UHFFFAOYSA-N methyl 2-[1-[tert-butyl(dimethyl)silyl]oxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropyl]cyclobutane-1-carboxylate Chemical compound COC(=O)C1CCC1C(O[Si](C)(C)C(C)(C)C)C(NC(=O)OC(C)(C)C)CC1=CC=CC=C1 HXBPUJWZAXLYOR-UHFFFAOYSA-N 0.000 description 1
- NOZMIFTXNYRHIN-UHFFFAOYSA-N methyl 2-[1-[tert-butyl(dimethyl)silyl]oxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropyl]cyclohexane-1-carboxylate Chemical compound COC(=O)C1CCCCC1C(O[Si](C)(C)C(C)(C)C)C(NC(=O)OC(C)(C)C)CC1=CC=CC=C1 NOZMIFTXNYRHIN-UHFFFAOYSA-N 0.000 description 1
- BLHVPRFGXVJCMD-UHFFFAOYSA-N methyl 2-[1-[tert-butyl(dimethyl)silyl]oxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropyl]cyclopentane-1-carboxylate Chemical compound COC(=O)C1CCCC1C(O[Si](C)(C)C(C)(C)C)C(NC(=O)OC(C)(C)C)CC1=CC=CC=C1 BLHVPRFGXVJCMD-UHFFFAOYSA-N 0.000 description 1
- YYPHUVLRWSYYKM-UHFFFAOYSA-N methyl 2-[1-[tert-butyl(dimethyl)silyl]oxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropyl]cyclopropane-1-carboxylate Chemical compound COC(=O)C1CC1C(O[Si](C)(C)C(C)(C)C)C(NC(=O)OC(C)(C)C)CC1=CC=CC=C1 YYPHUVLRWSYYKM-UHFFFAOYSA-N 0.000 description 1
- DVPYLSKMJRXUBQ-UHFFFAOYSA-N methyl 2-[1-hydroxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropyl]cyclopentane-1-carboxylate Chemical compound COC(=O)C1CCCC1C(O)C(NC(=O)OC(C)(C)C)CC1=CC=CC=C1 DVPYLSKMJRXUBQ-UHFFFAOYSA-N 0.000 description 1
- HRDJDNNZBSREOJ-UHFFFAOYSA-N methyl 2-[2-amino-1-hydroxy-3-(4-hydroxyphenyl)propyl]cyclopentane-1-carboxylate Chemical compound COC(=O)C1CCCC1C(O)C(N)CC1=CC=C(O)C=C1 HRDJDNNZBSREOJ-UHFFFAOYSA-N 0.000 description 1
- PVSJXEDBEXYLML-UHFFFAOYSA-N methyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]acetate Chemical compound COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F PVSJXEDBEXYLML-UHFFFAOYSA-N 0.000 description 1
- OQZAJVAZYFQWLP-UHFFFAOYSA-N methyl 2-formylcyclobutane-1-carboxylate Chemical group COC(=O)C1CCC1C=O OQZAJVAZYFQWLP-UHFFFAOYSA-N 0.000 description 1
- DGHWGHPZRYEZDI-UHFFFAOYSA-N methyl 2-formylcyclohexane-1-carboxylate Chemical group COC(=O)C1CCCCC1C=O DGHWGHPZRYEZDI-UHFFFAOYSA-N 0.000 description 1
- YPCWFMYMKSRCAZ-UHFFFAOYSA-N methyl 2-formylcyclopropane-1-carboxylate Chemical group COC(=O)C1CC1C=O YPCWFMYMKSRCAZ-UHFFFAOYSA-N 0.000 description 1
- DHWHPZFRBIRAOT-KRWDZBQOSA-N methyl 6-[[(2s)-4-methyl-1-oxo-1-phenylmethoxypentan-2-yl]amino]-6-oxohexanoate Chemical compound COC(=O)CCCCC(=O)N[C@@H](CC(C)C)C(=O)OCC1=CC=CC=C1 DHWHPZFRBIRAOT-KRWDZBQOSA-N 0.000 description 1
- IIHIJFJSXPDTNO-UHFFFAOYSA-N methyl cyclopentanecarboxylate Chemical compound COC(=O)C1CCCC1 IIHIJFJSXPDTNO-UHFFFAOYSA-N 0.000 description 1
- HAMGRBXTJNITHG-UHFFFAOYSA-N methyl isocyanate Chemical compound CN=C=O HAMGRBXTJNITHG-UHFFFAOYSA-N 0.000 description 1
- LSEFCHWGJNHZNT-UHFFFAOYSA-M methyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 LSEFCHWGJNHZNT-UHFFFAOYSA-M 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- UOBSVARXACCLLH-UHFFFAOYSA-N monomethyl adipate Chemical compound COC(=O)CCCCC(O)=O UOBSVARXACCLLH-UHFFFAOYSA-N 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 238000002703 mutagenesis Methods 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- HVOYZOQVDYHUPF-UHFFFAOYSA-N n,n',n'-trimethylethane-1,2-diamine Chemical compound CNCCN(C)C HVOYZOQVDYHUPF-UHFFFAOYSA-N 0.000 description 1
- HXXYMORGVTVCOS-UHFFFAOYSA-N n-(1-hydroxy-3-methylpentan-2-yl)thiophene-3-carboxamide Chemical compound CCC(C)C(CO)NC(=O)C=1C=CSC=1 HXXYMORGVTVCOS-UHFFFAOYSA-N 0.000 description 1
- RVSGPEJAXAFVEP-UHFFFAOYSA-N n-(3-methylbutyl)cyclopentene-1-carboxamide Chemical compound CC(C)CCNC(=O)C1=CCCC1 RVSGPEJAXAFVEP-UHFFFAOYSA-N 0.000 description 1
- ZVGBNGFJLDALIZ-UHFFFAOYSA-N n-(3-methylbutyl)furan-3-carboxamide Chemical compound CC(C)CCNC(=O)C=1C=COC=1 ZVGBNGFJLDALIZ-UHFFFAOYSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- NNKPHNTWNILINE-UHFFFAOYSA-N n-cyclopropyl-3-fluoro-4-methyl-5-[3-[[1-[2-[2-(methylamino)ethoxy]phenyl]cyclopropyl]amino]-2-oxopyrazin-1-yl]benzamide Chemical compound CNCCOC1=CC=CC=C1C1(NC=2C(N(C=3C(=C(F)C=C(C=3)C(=O)NC3CC3)C)C=CN=2)=O)CC1 NNKPHNTWNILINE-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- NCCHARWOCKOHIH-UHFFFAOYSA-N n-methylbenzamide Chemical compound CNC(=O)C1=CC=CC=C1 NCCHARWOCKOHIH-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012285 osmium tetroxide Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- JDKQTIKEGOOXTJ-UHFFFAOYSA-N pent-4-enoyl chloride Chemical compound ClC(=O)CCC=C JDKQTIKEGOOXTJ-UHFFFAOYSA-N 0.000 description 1
- HLTMUYBTNSVOFY-UHFFFAOYSA-N pentylcyclohexane Chemical compound CCCCCC1CCCCC1 HLTMUYBTNSVOFY-UHFFFAOYSA-N 0.000 description 1
- 125000001151 peptidyl group Chemical group 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229940100595 phenylacetaldehyde Drugs 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 125000000405 phenylalanyl group Chemical group 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- LZMJNVRJMFMYQS-UHFFFAOYSA-N poseltinib Chemical compound C1CN(C)CCN1C(C=C1)=CC=C1NC1=NC(OC=2C=C(NC(=O)C=C)C=CC=2)=C(OC=C2)C2=N1 LZMJNVRJMFMYQS-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- CAEWJEXPFKNBQL-UHFFFAOYSA-N prop-2-enyl carbonochloridate Chemical compound ClC(=O)OCC=C CAEWJEXPFKNBQL-UHFFFAOYSA-N 0.000 description 1
- ZJLMKPKYJBQJNH-UHFFFAOYSA-N propane-1,3-dithiol Chemical compound SCCCS ZJLMKPKYJBQJNH-UHFFFAOYSA-N 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229940043230 sarcosine Drugs 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- XIIOFHFUYBLOLW-UHFFFAOYSA-N selpercatinib Chemical compound OC(COC=1C=C(C=2N(C=1)N=CC=2C#N)C=1C=NC(=CC=1)N1CC2N(C(C1)C2)CC=1C=NC(=CC=1)OC)(C)C XIIOFHFUYBLOLW-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229940099373 sudan iii Drugs 0.000 description 1
- RAHZWNYVWXNFOC-UHFFFAOYSA-N sulfur dioxide Inorganic materials O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- KHNFEQCEQIAFES-LURJTMIESA-N tert-butyl (2s)-azetidine-2-carboxylate Chemical compound CC(C)(C)OC(=O)[C@@H]1CCN1 KHNFEQCEQIAFES-LURJTMIESA-N 0.000 description 1
- FIDTXPALYOEKBR-LEWJYISDSA-N tert-butyl (4S,5R)-4-benzyl-2,2-dimethyl-5-[3-(3-methylbutylamino)-3-oxoprop-1-enyl]-1,3-oxazolidine-3-carboxylate Chemical compound CC(CCNC(C=C[C@@H]1[C@@H](N(C(O1)(C)C)C(=O)OC(C)(C)C)CC1=CC=CC=C1)=O)C FIDTXPALYOEKBR-LEWJYISDSA-N 0.000 description 1
- DVRBYRCLGGBBFL-DLBZAZTESA-N tert-butyl (4S,5R)-4-benzyl-5-(3-methoxy-3-oxoprop-1-enyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate Chemical compound C(C1=CC=CC=C1)[C@@H]1N(C(O[C@@H]1C=CC(=O)OC)(C)C)C(=O)OC(C)(C)C DVRBYRCLGGBBFL-DLBZAZTESA-N 0.000 description 1
- LVJVMMZWJRWSKJ-DKJJERJISA-N tert-butyl (4s,5r)-4-(cyclohexylmethyl)-2,2-dimethyl-5-[(2r,3r)-3-[(4r,5s)-4-methyl-2-oxo-5-phenyl-1,3-oxazolidine-3-carbonyl]oxolan-2-yl]-1,3-oxazolidine-3-carboxylate Chemical compound C([C@@H]1N(C(C)(C)O[C@H]1[C@@H]1OCC[C@H]1C(=O)N1C(=O)O[C@H]([C@H]1C)C=1C=CC=CC=1)C(=O)OC(C)(C)C)C1CCCCC1 LVJVMMZWJRWSKJ-DKJJERJISA-N 0.000 description 1
- AZFCSSVHMQBTEC-ZPAWYTMASA-N tert-butyl (4s,5r)-4-(cyclohexylmethyl)-2,2-dimethyl-5-[(4s,5s)-2-oxo-5-[(4s)-2-oxo-4-propan-2-yl-1,3-oxazolidine-3-carbonyl]-1,3-dioxolan-4-yl]-1,3-oxazolidine-3-carboxylate Chemical compound CC(C)[C@H]1COC(=O)N1C(=O)[C@@H]1[C@H]([C@H]2[C@@H](N(C(C)(C)O2)C(=O)OC(C)(C)C)CC2CCCCC2)OC(=O)O1 AZFCSSVHMQBTEC-ZPAWYTMASA-N 0.000 description 1
- QIPWDNYWPYJNIV-KFEALIJWSA-N tert-butyl (4s,5r)-5-[(1r,2s)-3-[(4s)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-2-chloro-1-hydroxy-3-oxopropyl]-4-(cyclohexylmethyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate Chemical compound C([C@@H]1N(C(O[C@H]1[C@@H](O)[C@H](Cl)C(=O)N1C(OC[C@@H]1CC=1C=CC=CC=1)=O)(C)C)C(=O)OC(C)(C)C)C1CCCCC1 QIPWDNYWPYJNIV-KFEALIJWSA-N 0.000 description 1
- FVCWCZOHKUXRCB-JQSCXEDISA-N tert-butyl (4s,5r)-5-[(1s,2r)-3-[(4r)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-2-bromo-1-(methylcarbamoyloxy)-3-oxopropyl]-4-(cyclohexylmethyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate Chemical compound C([C@H]1N(C(OC1)=O)C(=O)[C@H](Br)[C@@H](OC(=O)NC)[C@H]1[C@@H](N(C(C)(C)O1)C(=O)OC(C)(C)C)CC1CCCCC1)C1=CC=CC=C1 FVCWCZOHKUXRCB-JQSCXEDISA-N 0.000 description 1
- DNJDWBDLOGLMME-QERLCLQCSA-N tert-butyl (4s,5r)-5-[(1s,2r)-3-[(4r)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-2-bromo-1-hydroxy-3-oxopropyl]-4-(cyclohexylmethyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate Chemical compound C([C@@H]1N(C(O[C@H]1[C@H](O)[C@@H](Br)C(=O)N1C(OC[C@H]1CC=1C=CC=CC=1)=O)(C)C)C(=O)OC(C)(C)C)C1CCCCC1 DNJDWBDLOGLMME-QERLCLQCSA-N 0.000 description 1
- BUIWYMPSCXIFQP-UHFFFAOYSA-N tert-butyl 2-[1-hydroxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropyl]pyrrole-1-carboxylate Chemical compound C=1C=CN(C(=O)OC(C)(C)C)C=1C(O)C(NC(=O)OC(C)(C)C)CC1=CC=CC=C1 BUIWYMPSCXIFQP-UHFFFAOYSA-N 0.000 description 1
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
- VASDLYLCNLJXAD-UHFFFAOYSA-N tert-butyl 3-amino-2-benzyl-3-hydroxy-3-(oxolan-2-yl)propanoate Chemical compound C1CCOC1C(N)(O)C(C(=O)OC(C)(C)C)CC1=CC=CC=C1 VASDLYLCNLJXAD-UHFFFAOYSA-N 0.000 description 1
- VROCBIKZWAYGPD-UHFFFAOYSA-N tert-butyl 4-(cyclohexylmethyl)-2,2-dimethyl-5-(4-methyloxolan-2-yl)-1,3-oxazolidine-3-carboxylate Chemical compound C1C(C)COC1C1C(CC2CCCCC2)N(C(=O)OC(C)(C)C)C(C)(C)O1 VROCBIKZWAYGPD-UHFFFAOYSA-N 0.000 description 1
- MACMDWYWHXADJN-UHFFFAOYSA-N tert-butyl 4-(cyclohexylmethyl)-5-(1,4-dihydroxy-3,3-dimethylbutyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate Chemical compound OCC(C)(C)CC(O)C1OC(C)(C)N(C(=O)OC(C)(C)C)C1CC1CCCCC1 MACMDWYWHXADJN-UHFFFAOYSA-N 0.000 description 1
- HFUOFPPDQYKXPL-UHFFFAOYSA-N tert-butyl 4-(cyclohexylmethyl)-5-(1,4-dihydroxy-3-methylbutyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate Chemical compound OCC(C)CC(O)C1OC(C)(C)N(C(=O)OC(C)(C)C)C1CC1CCCCC1 HFUOFPPDQYKXPL-UHFFFAOYSA-N 0.000 description 1
- FDHUDLULPYXQKV-UHFFFAOYSA-N tert-butyl 4-(cyclohexylmethyl)-5-ethenyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate Chemical compound C=CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1CC1CCCCC1 FDHUDLULPYXQKV-UHFFFAOYSA-N 0.000 description 1
- XWNYDCXGNOTBAU-UHFFFAOYSA-N tert-butyl 4-(cyclohexylmethyl)-5-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate Chemical compound O=CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1CC1CCCCC1 XWNYDCXGNOTBAU-UHFFFAOYSA-N 0.000 description 1
- DAQUBMNBMKDYRN-UHFFFAOYSA-N tert-butyl 4-benzyl-5-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate Chemical compound O=CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1CC1=CC=CC=C1 DAQUBMNBMKDYRN-UHFFFAOYSA-N 0.000 description 1
- FRBBBWDOMGRJEQ-UHFFFAOYSA-N tert-butyl 5-formyl-4-[(4-methoxyphenyl)methyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate Chemical compound C1=CC(OC)=CC=C1CC1N(C(=O)OC(C)(C)C)C(C)(C)OC1C=O FRBBBWDOMGRJEQ-UHFFFAOYSA-N 0.000 description 1
- AOSCFFKWRZVJSP-GTPINHCMSA-N tert-butyl N-[(1S)-1-cyclohexyl-3,4-dihydroxy-6-methylheptyl]carbamate Chemical compound CC(C)CC(O)C(O)C[C@H](NC(=O)OC(C)(C)C)C1CCCCC1 AOSCFFKWRZVJSP-GTPINHCMSA-N 0.000 description 1
- AYTZSHGOPUNDMG-PXKIYYGHSA-N tert-butyl N-[(2S,3R)-1-cyclohexyl-4,5-dihydroxy-3-(2-methoxyethoxymethoxy)pentan-2-yl]carbamate Chemical compound OCC([C@@H]([C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)OCOCCOC)O AYTZSHGOPUNDMG-PXKIYYGHSA-N 0.000 description 1
- UIPXTUUPKZTHLH-UHFFFAOYSA-N tert-butyl n-(1,5-diphenylpent-3-en-2-yl)carbamate Chemical compound C=1C=CC=CC=1CC=CC(NC(=O)OC(C)(C)C)CC1=CC=CC=C1 UIPXTUUPKZTHLH-UHFFFAOYSA-N 0.000 description 1
- JDBMKQBQUVCFON-UHFFFAOYSA-N tert-butyl n-(1-cyclohexyl-3-hydroxy-4-propan-2-ylsulfanylbutan-2-yl)carbamate Chemical compound CC(C)SCC(O)C(NC(=O)OC(C)(C)C)CC1CCCCC1 JDBMKQBQUVCFON-UHFFFAOYSA-N 0.000 description 1
- UEHRVUCTAQQSDJ-UHFFFAOYSA-N tert-butyl n-(1-cyclohexyl-3-hydroxy-4-propan-2-ylsulfonylbutan-2-yl)carbamate Chemical compound CC(C)S(=O)(=O)CC(O)C(NC(=O)OC(C)(C)C)CC1CCCCC1 UEHRVUCTAQQSDJ-UHFFFAOYSA-N 0.000 description 1
- XCAHLFUIEMENMG-UHFFFAOYSA-N tert-butyl n-(1-cyclohexylbut-3-en-2-yl)carbamate Chemical compound CC(C)(C)OC(=O)NC(C=C)CC1CCCCC1 XCAHLFUIEMENMG-UHFFFAOYSA-N 0.000 description 1
- JPUNTDGVTRGAOF-UHFFFAOYSA-N tert-butyl n-(1-cyclopentyl-1-hydroxy-3-phenylpropan-2-yl)carbamate Chemical compound C1CCCC1C(O)C(NC(=O)OC(C)(C)C)CC1=CC=CC=C1 JPUNTDGVTRGAOF-UHFFFAOYSA-N 0.000 description 1
- DYHHHEIJKQGOIE-LSLKUGRBSA-N tert-butyl n-[(2s)-1-cyclohexyl-3-hydroxypent-4-en-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)C=C)CC1CCCCC1 DYHHHEIJKQGOIE-LSLKUGRBSA-N 0.000 description 1
- GMFRHHUZWNMITO-QGZVFWFLSA-N tert-butyl n-[(2s)-1-cyclohexyl-6-methylhept-3-en-2-yl]carbamate Chemical compound CC(C)CC=C[C@@H](NC(=O)OC(C)(C)C)CC1CCCCC1 GMFRHHUZWNMITO-QGZVFWFLSA-N 0.000 description 1
- CBDPMZPHJQQERH-GBESFXJTSA-N tert-butyl n-[(2s,3r,4s)-5-(aminomethylamino)-1-cyclohexyl-4-hydroxy-3-(2-methoxyethoxymethoxy)pentan-2-yl]carbamate Chemical compound COCCOCO[C@@H]([C@@H](O)CNCN)[C@@H](NC(=O)OC(C)(C)C)CC1CCCCC1 CBDPMZPHJQQERH-GBESFXJTSA-N 0.000 description 1
- CXIUCLOCMKRSRA-MELADBBJSA-N tert-butyl n-[(2s,3r,4s)-5-azido-1-cyclohexyl-3,4-dihydroxypentan-2-yl]carbamate Chemical compound [N-]=[N+]=NC[C@H](O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)CC1CCCCC1 CXIUCLOCMKRSRA-MELADBBJSA-N 0.000 description 1
- YEFVOPZIFCNWRI-GBESFXJTSA-N tert-butyl n-[(2s,3r,4s)-5-cyano-1-cyclohexyl-4-hydroxy-3-(2-methoxyethoxymethoxy)pentan-2-yl]carbamate Chemical compound COCCOCO[C@@H]([C@@H](O)CC#N)[C@@H](NC(=O)OC(C)(C)C)CC1CCCCC1 YEFVOPZIFCNWRI-GBESFXJTSA-N 0.000 description 1
- WNJBIKNSUDZULF-GBESFXJTSA-N tert-butyl n-[(2s,3r,4s)-6-amino-1-cyclohexyl-4-hydroxy-3-(2-methoxyethoxymethoxy)hexan-2-yl]carbamate Chemical compound COCCOCO[C@@H]([C@@H](O)CCN)[C@@H](NC(=O)OC(C)(C)C)CC1CCCCC1 WNJBIKNSUDZULF-GBESFXJTSA-N 0.000 description 1
- MOYDFECXCHVLON-ROUUACIJSA-N tert-butyl n-[(2s,3s)-1-cyclohexyl-3-(2-methoxyethoxymethoxy)pent-4-en-2-yl]carbamate Chemical compound COCCOCO[C@@H](C=C)[C@@H](NC(=O)OC(C)(C)C)CC1CCCCC1 MOYDFECXCHVLON-ROUUACIJSA-N 0.000 description 1
- DYHHHEIJKQGOIE-KBPBESRZSA-N tert-butyl n-[(2s,3s)-1-cyclohexyl-3-hydroxypent-4-en-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H]([C@@H](O)C=C)CC1CCCCC1 DYHHHEIJKQGOIE-KBPBESRZSA-N 0.000 description 1
- IQOARKYXGMKFDI-OALUTQOASA-N tert-butyl n-[(2s,3s)-3-[tert-butyl(dimethyl)silyl]oxy-1-cyclohexylpent-4-en-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)C=C)CC1CCCCC1 IQOARKYXGMKFDI-OALUTQOASA-N 0.000 description 1
- NMCGHYXBHRSTAZ-YVZMLIKISA-N tert-butyl n-[(2s,3s)-3-hydroxy-5-(hydroxymethyl)-6-(methylamino)-6-oxo-1-phenylhexan-2-yl]carbamate Chemical compound CNC(=O)C(CO)C[C@H](O)[C@@H](NC(=O)OC(C)(C)C)CC1=CC=CC=C1 NMCGHYXBHRSTAZ-YVZMLIKISA-N 0.000 description 1
- OXVOAAUSUVSQQN-HOTGVXAUSA-N tert-butyl n-[(2s,3s)-3-hydroxy-5-(methylcarbamoyl)-1-phenylhex-5-en-2-yl]carbamate Chemical compound CNC(=O)C(=C)C[C@H](O)[C@@H](NC(=O)OC(C)(C)C)CC1=CC=CC=C1 OXVOAAUSUVSQQN-HOTGVXAUSA-N 0.000 description 1
- GVOJLQOTWGKGGB-NPPFBWRTSA-N tert-butyl n-[(2s,3s,5r)-5-(azidomethyl)-1-cyclohexyl-3,5-dihydroxy-6-(2-methylpropylamino)-6-oxohexan-2-yl]carbamate Chemical compound CC(C)CNC(=O)[C@](O)(CN=[N+]=[N-])C[C@H](O)[C@@H](NC(=O)OC(C)(C)C)CC1CCCCC1 GVOJLQOTWGKGGB-NPPFBWRTSA-N 0.000 description 1
- VJUXHKHDZHLPFG-YDHSSHFGSA-N tert-butyl n-[(2s,3s,5s)-1-cyclohexyl-3,5-dihydroxy-5-methyl-6-(3-methylbutylamino)-6-oxohexan-2-yl]carbamate Chemical compound CC(C)CCNC(=O)[C@@](C)(O)C[C@H](O)[C@@H](NC(=O)OC(C)(C)C)CC1CCCCC1 VJUXHKHDZHLPFG-YDHSSHFGSA-N 0.000 description 1
- HFORXYBQJVPDTQ-QWRGUYRKSA-N tert-butyl n-[(3s,4s)-3-hydroxy-6-methylhept-1-en-4-yl]carbamate Chemical compound CC(C)C[C@@H]([C@@H](O)C=C)NC(=O)OC(C)(C)C HFORXYBQJVPDTQ-QWRGUYRKSA-N 0.000 description 1
- JFOBAWDEQIAWPA-UHFFFAOYSA-N tert-butyl n-[1-(1,3-benzothiazol-2-yl)-1-hydroxy-4-methylpentan-2-yl]carbamate Chemical compound C1=CC=C2SC(C(O)C(NC(=O)OC(C)(C)C)CC(C)C)=NC2=C1 JFOBAWDEQIAWPA-UHFFFAOYSA-N 0.000 description 1
- QFDHPVSJVUKABQ-UHFFFAOYSA-N tert-butyl n-[1-(2,3-dihydrofuran-5-yl)-1-hydroxy-3-phenylpropan-2-yl]carbamate Chemical compound C=1CCOC=1C(O)C(NC(=O)OC(C)(C)C)CC1=CC=CC=C1 QFDHPVSJVUKABQ-UHFFFAOYSA-N 0.000 description 1
- WJJRPPCJEIMAHJ-UHFFFAOYSA-N tert-butyl n-[1-(3,4-dihydro-2h-pyran-6-yl)-1-hydroxy-3-phenylpropan-2-yl]carbamate Chemical compound C=1CCCOC=1C(O)C(NC(=O)OC(C)(C)C)CC1=CC=CC=C1 WJJRPPCJEIMAHJ-UHFFFAOYSA-N 0.000 description 1
- SHOFORUBHJEWFA-UHFFFAOYSA-N tert-butyl n-[1-(4,4-dimethyl-5h-1,3-oxazol-2-yl)-1-hydroxy-3-phenylpropan-2-yl]carbamate Chemical compound N=1C(C)(C)COC=1C(O)C(NC(=O)OC(C)(C)C)CC1=CC=CC=C1 SHOFORUBHJEWFA-UHFFFAOYSA-N 0.000 description 1
- WLBFAOADRQHRDH-UHFFFAOYSA-N tert-butyl n-[1-(benzenesulfonyl)-3-phenylpropan-2-yl]carbamate Chemical compound C=1C=CC=CC=1S(=O)(=O)CC(NC(=O)OC(C)(C)C)CC1=CC=CC=C1 WLBFAOADRQHRDH-UHFFFAOYSA-N 0.000 description 1
- KAJNKNZDKDXNPM-UHFFFAOYSA-N tert-butyl n-[1-hydroxy-1-(1-methylimidazol-2-yl)-3-phenylpropan-2-yl]carbamate Chemical compound CN1C=CN=C1C(O)C(NC(=O)OC(C)(C)C)CC1=CC=CC=C1 KAJNKNZDKDXNPM-UHFFFAOYSA-N 0.000 description 1
- IJFDDGAVYIRVJZ-UHFFFAOYSA-N tert-butyl n-[1-hydroxy-1-(1-methyltetrazol-5-yl)-3-phenylpropan-2-yl]carbamate Chemical compound CN1N=NN=C1C(O)C(NC(=O)OC(C)(C)C)CC1=CC=CC=C1 IJFDDGAVYIRVJZ-UHFFFAOYSA-N 0.000 description 1
- VAULGCLCRFIRGH-UHFFFAOYSA-N tert-butyl n-[1-hydroxy-1-(oxolan-2-yl)-3-phenylpropan-2-yl]carbamate Chemical compound C1CCOC1C(O)C(NC(=O)OC(C)(C)C)CC1=CC=CC=C1 VAULGCLCRFIRGH-UHFFFAOYSA-N 0.000 description 1
- YMTRCUBVTFJAIE-UHFFFAOYSA-N tert-butyl n-[1-hydroxy-1-[3-[(1-hydroxy-3-methylpentan-2-yl)carbamoyl]thiophen-2-yl]-3-phenylpropan-2-yl]carbamate Chemical compound C1=CSC(C(O)C(CC=2C=CC=CC=2)NC(=O)OC(C)(C)C)=C1C(=O)NC(CO)C(C)CC YMTRCUBVTFJAIE-UHFFFAOYSA-N 0.000 description 1
- PDWROLFKWUGJEV-UHFFFAOYSA-N tert-butyl n-[1-hydroxy-3-phenyl-1-(1,3-thiazol-2-yl)propan-2-yl]carbamate Chemical compound N=1C=CSC=1C(O)C(NC(=O)OC(C)(C)C)CC1=CC=CC=C1 PDWROLFKWUGJEV-UHFFFAOYSA-N 0.000 description 1
- CVXUYYULENWBTP-NSHDSACASA-N tert-butyl n-cyclohexyl-n-[(2s)-1-oxopropan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N([C@H](C=O)C)C1CCCCC1 CVXUYYULENWBTP-NSHDSACASA-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
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000005302 thiazolylmethyl group Chemical group [H]C1=C([H])N=C(S1)C([H])([H])* 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- DAUYIKBTMNZABP-UHFFFAOYSA-N thiophene-3-carboxamide Chemical compound NC(=O)C=1C=CSC=1 DAUYIKBTMNZABP-UHFFFAOYSA-N 0.000 description 1
- YNVOMSDITJMNET-UHFFFAOYSA-N thiophene-3-carboxylic acid Chemical compound OC(=O)C=1C=CSC=1 YNVOMSDITJMNET-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- YFNGWGVTFYSJHE-UHFFFAOYSA-K trisodium;phosphonoformate Chemical compound [Na+].[Na+].[Na+].OP(O)(=O)C([O-])=O.OP(O)(=O)C([O-])=O.OP(O)(=O)C([O-])=O YFNGWGVTFYSJHE-UHFFFAOYSA-K 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 210000002845 virion Anatomy 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
- C07D239/10—Oxygen or sulfur atoms
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/30—Oxygen or sulfur atoms
- C07D233/32—One oxygen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D263/06—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by oxygen atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
- C07D263/22—Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
- C07D263/24—Oxygen atoms attached in position 2 with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
- C07D263/26—Oxygen atoms attached in position 2 with hetero atoms or acyl radicals directly attached to the ring nitrogen atom
-
- 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
- C07D265/06—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
- C07D295/205—Radicals derived from carbonic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
- C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
-
- 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
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/58—One oxygen atom, e.g. butenolide
-
- 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
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D317/34—Oxygen atoms
- C07D317/36—Alkylene carbonates; Substituted alkylene carbonates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
- C07K5/06043—Leu-amino acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1002—Tetrapeptides with the first amino acid being neutral
- C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
- C07K5/101—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1002—Tetrapeptides with the first amino acid being neutral
- C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/02—Linear peptides containing at least one abnormal peptide link
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Definitions
- patent application Serial No. 194,678, filed May 13, 1988 is also a continuation-in-part of U.S. patent application Serial No. 943,566, filed December 31, 1986, which is a continuation-in-part of U.S. patent application Serial No. 818,715, filed January 16, 1986, now abandoned, which is a continuation-in-part of U.S. patent application Serial No. 693,951, filed January; 23, 1985, now abandoned.
- U.S. patent application Serial No. 194,678, filed May 13, 1988 is also a continuation-in-part of U.S. patent application Serial No. 946,883, filed January 9, 1987, which is a continuation-in-part of U.S. patent application Serial No.
- the present invention relates to novel compounds and a composition and method for inhibiting retroviral proteases and in particular for inhibiting human immunodeficiency virus (HIV) protease, a composition and method for treating a retroviral infection and in particular an HIV infection, processes for making such compounds and synthetic intermediates employed in these processes.
- HIV human immunodeficiency virus
- Retroviruses are those viruses which utilize a ribonucleic acid (RNA) intermediate and a RNA-dependent deoxyribonucleic acid (DNA) polymerase, reverse transcriptase, during their life cycle. Retroviruses include, but are not limited to, the RNA viruses of the Retroviridae family, and also the DNA viruses of the Hepadnavirus and Caulimovirus families. Retroviruses cause a variety of disease states in man, animals and plants.
- RNA ribonucleic acid
- DNA RNA-dependent deoxyribonucleic acid
- retroviruses from a pathological standpoint include human immunodeficiency viruses (HIV-1 and HIV-2), which cause acquired immune deficiency syndrome (AIDS) in man, hepatitis B virus, which causes hepatitis and hepatic carcinomas in man, human T-cell lymphotrophic viruses I, II, IV and V, which cause human acute cell leukemia, and bovine and feline leukemia viruses which cause leukemia in domestic animals.
- HIV-1 and HIV-2 human immunodeficiency viruses
- HIV-2 acquired immune deficiency syndrome
- hepatitis B virus which causes hepatitis and hepatic carcinomas in man
- human T-cell lymphotrophic viruses I, II, IV and V which cause human acute cell leukemia
- bovine and feline leukemia viruses which cause leukemia in domestic animals.
- Proteases are enzymes which cleave proteins at specific peptide bonds. Many biological functions are controlled or mediated by proteases and their complementary protease inhibitors. For example, the protease renin cleaves the peptide angiotensinogen to produce the peptide angiotensin I. Angiotensin I is further cleaved by the protease angiotensin converting enzyme (ACE) to form the hypotensive peptide angiotensin II. Inhibitors of renin and ACE are known to reduce high blood pressure in vivo.
- retroviral protease should provide a therapeutic agent for diseases caused by the retrovirus.
- the genomes of retroviruses encode a protease that is responsible for the proteolytic processing of one or more polyprotein precursors such as the pol and ga ⁇ gene products. See Wellink, Arch. Virol. 981 (1988).
- Retroviral proteases most commonly process the gag precursor into core proteins, and also process the pol precursor into reverse transciptase and retroviral protease. In addition, retroviral proteases are sequence specific. See Pearl, Nature 328482 (1987).
- U.S. Patent No. 4,652,552 discloses methyl ketone derivatives of tetrapeptides as inhibitors of viral proteases.
- U.S. Patent No. 4,644,055 discloses halomethylketone derivatives of peptides as inhibitors of viral proteases.
- European Patent Application No. EP0246630 discloses antiviral peptides for treating herpes.
- PCT Patent Application No. WO87/07836 discloses L-glutamic acid gamma-monohydroxamate as an antiviral agent.
- the ability to inhibit retroviral proteases, and in particular HIV protease provides a method for blocking viral replication and therefore a treatment for retroviral diseases, and AIDS in particular, that has fewer or no side effects when compared to current treatments . Disclosure of the Invention
- R 14 is hydrogen, loweralkyl or aminoalkyl
- Functionalized alkyl groups include:
- R 15 and R 16 are independently selected from hydrogen, loweralkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (N-protected) aminoalkyl,
- Functionalized carbonyl and functionalized sulfonyl include R 17 C(O)B- and R 17 S (O) 2 B-, respectively, wherein B is NH, -N (alkyl)-, S, O, CH 2 or CHOH, and
- R 3 is (substituted alkyl) amino .
- (Substituted alkyl) amino includes wherein m is 1 to 5 ;
- R 6 is hydroxy, alkoxy or -NR 15 R 16 wherein R 15 and R 16 are independently as defined above and R 75 is -NHCH(R")C(O)-, -NHCH (R")C(O) NHCH (R''')C(O)-, -NHCH(R")C(O)NHCH(R''') C (O) -R 220 - or -NHCH (R") C (O) NHCH (R' ' ' ) C (O) -R 220 -R 221 - wherein R" is hydrogen, loweralkyl, cycloalkylalkyl, (phenyl) alkyl, (substituted phenyl) alkyl wherein substituted phenyl is independently as defined above, (naphthyl) alkyl or (substituted naphthyl) alkyl wherein substituted naphth
- R 7 is hydrogen, amino or hydroxy and R 8 is loweralkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, azido, azidoalkyl, amino, aminoalkyl, alkylamino, alkylaminoalkyl, dialkylamino, dialkylaminoalkyl, (N-protected) amino, (N-protected) aminoalkyl, (N-protected) (alkyl) amino, (N-protected) (alkyl) aminoalkyl, thioalkoxy, thioalkoxyalkyl, alkylsulfonyl, alkylsulfonylalkyl, thioaryloxy, thioaryloxyalkyl, phenyl, substituted phenyl independently as defined above, naphthyl, substituted naphthyl independently as defined above, heterocyclic, substituted heterocycl
- R 200 is an alkylene group
- R 201 is S, S (O) , S(O) 2 , O, NH or -N (alkyl)-
- R 202 is an alkylene group
- R 203 is phenyl, substituted phenyl independently as defined above, naphthyl or substituted naphthyl independently as defined above;
- R 5 is independently as defined above,
- G is O, S, -N (R 11 ) - or -C (R 11 ) (R 70 ) - wherein R 11 is hydrogen or loweralkyl and R 70 is hydrogen or loweralkyl,
- L is N or -C(R 5 )- wherein R 5 is independently as defined above,
- R 81 is N or -C(R 11 )- wherein R 11 is independently as defined above, R 71 is N or -C(R 11 )- wherein R 11 is independently as defined above,
- R 80 is absent, -C (R 11 ) (R 70 ) - or -N(R 11 )- wherein R 11 and R 70 are independently as defined above, R 80 is absent, or one or two substituents independently selected from loweralkyl, alkoxy, thioalkoxy, hydroxy, halogen, mercapto, nitro, amino, loweralkylamino, dialkylamino, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide,
- Q is O or -C(R 11 ) (R 70 )- wherein R 11 andR 70 are independently as defined above,
- X is O, S, -N(R 11 )-, -C(R 11 ) (R 70 )-,
- R 11 and R 70 are independently as defined above,
- R 12 is independently as defined above or
- R 5 is independently as defined above.
- R 13 is hydrogen or loweralkyl.
- R 1 is loweralkyl, benzyl, 4-methoxybenzyl, halobenzyl, (1-naphthyl) methyl or (2-naphthyl) methyl and R 2 is loweralkyl, heterocyclic alkyl or (substituted heterocyclic) alkyl and A is as defined above and R 3 is
- R 4 is loweralkyl, cycloalkylmethyl or benzyl and E is -CH(R 7 ) (R 8 ) wherein R 7 is hydroxy or amino and R 8 is loweralkyl, phenylalkyl, (substiututed phenyl) alkyl, naphthylalkyl or (substituted naphthyl) alkyl have been disclosed as renin inhibitors in copending U.S. patent applications, USSN 217,106, filed July 11, 1988 and USSN 132,356, filed December 18, 1987, both of which are hereby incorporated by reference.
- R 1 is loweralkyl, phenylalkyl, (substituted phenyl) alkyl, naphthylalkyl and (substituted naphthyl) alkyl and R 2 is loweralkyl, heterocyclic alkyl or (substituted heterocyclic) alkyl and A is hydrogen, loweralkyl, (phenyl) alkyl, (substituted phenyl) alkyl wherein substituted phenyl is as defined above, (naphthyl) alkyl, (substituted naphthyl) alkyl wherein substituted naphthyl is as defined above, -OR 14 wherein R 14 is hydrogen or loweralkyl, -NR 15 R 16 wherein R 1 and R 16 are independently selected from hydrogen and loweralkyl or R 17 C(O)B- wherein B is NH, O or CH 2 and R 17 is loweralkyl, alkoxy, (phenyl)
- R 4 is loweralkyl, cycloalkyl, cycloalkylalkyl, naphthylmethyl, benzyl or substituted benzyl and E is - CH 2 R 8 wherein R 8 is loweralkyl, alkoxy, alkylamino, (N-protected) amino, thioalkoxy, alkylsulfonyl, thioaryloxy or (phenyl) sulfonyl, (substituted phenyl) sulfonyl wherein substituted phenyl is as defined above, (naphthyl) sulfonyl, or (substituted naphthyl) sulfonyl wherein substituted naphthyl is as defined above have been disclosed as renin inhibitors in copending U.S. patent application USSN 946,881, filed January 9, 1987, which is hereby incorporated by reference.
- R 1 is loweralkyl, benzyl, 4-methoxybenzyl, halobenzyl, (1-naphthyl) methyl or (2-naphthyl) methyl and R 2 is loweralkyl, heterocyclic alkyl or (substituted heterocyclic) alkyl and A is hydrogen, loweralkyl, (phenyl) alkyl, (substituted phenyl) alkyl wherein substituted phenyl is as defined above, (naphthyl) alkyl, (substituted naphthyl) alkyl wherein substituted naphthyl is as defined above, -OR- .
- R 14 is hydrogen, loweralkyl or aminoalkyl, -NR 15 R 16 wherein R 15 and R 16 are independently selected from hydrogen, loweralkyl, aminoalkyl, cyanoalkyl or hydroxyalkyl, R 17 C(O)B- or R 17 S(O) 2 B- wherein B is NH, -N (alkyl)-, S, O, CH 2 or CHOH and R 17 is loweralkyl, cycloalkyl, phenyl, substituted phenyl as defined above, naphthyl, substituted naphthyl as defined above,
- substituted naphthyl alkyl wherein substituted naphthyl is as defined above, alkoxy, alkenyloxy, hydroxyalkoxy, dihydroxyalkoxy, (phenyl) alkoxy, (substituted phenyl) alkoxy wherein substituted phenyl is as defined above,
- R 4 is loweralkyl, cycloalkylmethyl or benzyl and E is -CH(OH)R 8 wherein R 8 is hydroxyalkyl, alkoxyalkyl, azidoalkyl, aminoalkyl, (N-protected) aminoalkyl, alkylaminoalkyl, (N-protected) (alkyl) aminoalkyl, thioalkoxyalkyl, alkylsulfonylalkyl, thioaryloxyalkyl or (phenyl) sulfonylalkyl, (substituted phenyl) sulfonylalkyl wherein substituted phenyl is as defined above, (naphthyl) sulfonylalkyl, or (substituted naphthyl) sulfonylalkyl wherein substituted naphthyl is as defined above; or E is -CHR 7 R 48 wherein R 7 R
- R 1 is loweralkyl, benzyl, 4-methoxybenzyl, halobenzyl,
- R 2 is loweralkyl, heterocyclic alkyl or (substituted heterocyclic) alkyl and A is hydrogen, loweralkyl,
- substituted phenyl alkoxy wherein substituted phenyl is as defined above, (naphthyl) alkoxy, (substituted naphthyl) alkoxy wherein substituted naphthyl is as defined above, (phenyl) alkoxyalkyl, (substituted phenyl) alkoxyalkyl wherein substituted phenyl is as defined above,
- naphthyl alkoxyalkyl
- substituted naphthyl is as defined above, amino, alkylamino, dialkylamino, (hydroxyalkyl) (alkyl) amino,
- alkyl aminoalkyl, dialkylaminoalkyl.
- carboxyalkyl alkoxycarbonylalkyl, aminocycloalkyl, aminoalkylamino, dialkylaminoalkylamino,
- phenyl alkyl (alkyl) amino (substituted phenyl) alkyl (alkyl) amino wherein substituted phenyl is as defined above, (naphthyl) alkyl (alkyl) amino, (substituted naphthyl) alkyl (alkyl) amino wherein substituted naphthyl is as defined above, alkoxyalkyl (alkyl) amino;
- R 5 is hydrogen
- R 80 is absent, -CH 2 - or -N(R 11 )- wherein R 11 is as defined above, X is O, S or NH, Y is
- R 5 is hydrogen or loweralkyl
- R 11 is hydrogen or loweralkyl
- R 70 is hydrogen or loweralkyl
- Z is -N(R 12 )- wherein R 12 is hydrogen or loweralkyl, X is O, S, -C(R 11 ) (R 70 )- or -N(R 11 )-, and R 80 is absent, -C(R 11 ) (R 7 0)- or -N(R 11 )-; or
- R 80 is -N(R 11 )-, X is O, S, -C(R 11 ) (R 70 )- or -
- N(R 11 )- and Z is O, S, -C(R 11 ) (R 70 )- or -N(R 12 )- wherein R 12 is hydrogen or loweralkyl; or (2 ) E is
- R 11 is hydrogen or loweralkyl and R 70 is hydrogen or loweralkyl;
- R 5 is hydrogen or loweralkyl and R 11 is hydrogen or loweralkyl
- L is N and R 82 is hydrogen or loweralkyl; or (ii) wherein L is -C(R 5 )- wherein R 5 is hydrogen or loweralkyl, G is -N(R 11 )- wherein R 11 is hydrogen or loweralkyl and R 82 is hydrogen or loweralkyl have been disclosed as renin inhibitors in European Patent Application No. EP0231919, published August 12, 1987.
- the chiral centers of the compounds of the invention may have either the "R” or "S” configuration.
- the terms "S” and “R” configuration are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13 - 30.
- N-protecting group or “N-protected” as used herein refers to those groups intended to protect nitrogen atoms against undesirable reactions during synthetic procedures or to prevent the attack of exopeptidases on the final compounds or to increase the solubility of the final compounds and includes but is not limited to acyl, acetyl, pivaloyl, t-butylacetyl, t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or benzoyl groups or an L- or D- aminoacyl residue, which may itself be N-protected similarly.
- loweralkyl refers to straight or branched chain alkyl radicals containing from 1 to 6 carbon atoms including but not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, n-pentyl, 1-methylbutyl, 2, 2-dimethylbutyl, 2-methylpentyl, 2, 2-dimethylpropyl, n-hexyl and the like.
- loweralkenyl refers to a loweralkyl radical which contains at least one carbon-carbon double bond.
- alkylene refers to straight or branched chain spacer radicals containing 2 to 6 carbon atoms such as -CH 2 -, -CH(CH 3 )-, -CH 2 CH 2 -, -CH 2 CH(CH 3 )- and the like.
- substituted phenyl refers to a phenyl ring substituted with one, two or three substituents independently selected from loweralkyl, alkoxy, thioalkoxy, hydroxy, halogen, mercapto, nitro, amino, loweralkylamino, dialkylamino, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide.
- substituted naphthyl refers to a naphthyl ring substituted with one, two or three substituents independently selected from loweralkyl, alkoxy, thioalkoxy, hydroxy, halogen, mercapto, nitro, amino, loweralkylamino, dialkylamino, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide.
- (phenyl) alkyl refers to a phenyl ring appended to a loweralkyl radical, including but not limited to benzyl and the like.
- (substituted phenyl) alkyl refers to a substituted phenyl ring as defined above appended to a loweralkyl radical, including but not limited to 4-hydroxybenzyl, 4-methoxybenzyl and 4-chlorobenzyl.
- (naphthyl) alkyl refers to a naphthyl ring appended to a loweralkyl radical, including but not limited to 1-naphthylmethyl and 2-naphthylmethyl.
- substituted naphthyl alkyl refers to a substituted naphthyl ring as defined above appended to a loweralkyl radical.
- aminoalkyl refers to -NH 2 appended to a loweralkyl radical.
- cyanoalkyl refers to -CN appended to a loweralkyl radical.
- hydroxyalkyl refers to -OH appended to a loweralkyl radical.
- alkylamino refers to a loweralkyl radical appended to an NH radical.
- cycloalkyl refers to an aliphatic ring having 3 to 7 carbon atoms.
- cycloalkylalkyl refers to a cycloalkyl group appended to a loweralkyl radical, including but not limited to cyclohexylmethyl.
- alkoxy and thioalkoxy refer to R 18 O- and R 18 S-, respectively, wherein R 18 is a loweralkyl group.
- alkenyloxy refers to R 19 O- wherein R 19 is a loweralkenyl group.
- hydroxyalkoxy refers to -OH appended to an alkoxy radical.
- dihydroxyalkoxy refers to an alkoxy radical which is disubstituted with -OH groups.
- (phenyl) alkoxy refers R 90 O- wherein R 90 is a (phenyl) alkyl group as defined above.
- (substituted phenyl) alkoxy refers to R 91 O- wherein R 91 is a (substituted phenyl) alkyl group as defined above.
- R 92 O- wherein R 92 is a (naphthyl) alkyl group as defined above.
- (substituted naphthyl) alkoxy refers to R 93 O- wherein R 93 is a (substituted naphthyl) alkyl group as defined above.
- (phenyl) alkoxyalkyl refers to a (phenyl) alkoxy group as defined above appended to a loweralkyl radical.
- (substituted phenyl) alkoxyalkyl refers to a (substituted phenyl) alkoxy group as defined above appended to a loweralkyl radical.
- (naphthyl) alkoxyalkyl refers to a (naphthyl) alkoxy group as defined above appended to a loweralkyl radical.
- (substituted naphthyl) alkoxyalkyl refers to a (substituted naphthyl) alkoxy group as defined above appended to a loweralkyl radical.
- (thioalkoxy) alkyl refers to thioalkoxy appended to a loweralkyl radical.
- dialkylamino refers to -NR 20 R 21 wherein R 20 and R 21 are independently selected from loweralkyl groups.
- (alkoxy) alkoxy) alkyl refers to an alkoxy group appended to an alkoxy group which is appended to a loweralkyl radical.
- (hydroxyalkyl) (alkyl) amino refers to -NR 22 R 23 wherein R 22 is hydroxyalkyl and R 23 is loweralkyl.
- N-protected aminoalkyl refers to -NHR 24 appended to a loweralkyl group, wherein R 24 is an N-protecting group.
- alkylaminoalkyl refers to NHR 25 appended to a loweralkyl radical, wherein R 25 is a loweralkyl group.
- (N-protected) (alkyl) aminoalkyl refers to -NR 24 R 25 , which is appended to a loweralkyl radical, wherein R 24 and R 25 are as defined above.
- dialkylaminoalkyl refers to -NR R which is appended to a loweralkyl radical wherein R 26 and R 27 are independently selected from loweralkyl.
- Carboxamidoalkyl refers to a -C(O)NH 2 group appended to a loweralkyl radical.
- N-hydroxycarboxamidoalkyl refers to a -C(O)NHOH group appended to a loweralkyl radical.
- azidoalkyl refers to a -N 3 group appended to a loweralkyl radical.
- carboxyalkyl refers to a carboxylic acid group (-COOH) appended to a loweralkyl radical.
- alkoxycarbonylalkyl refers to R 28 C(O)R 29 - wherein R 28 is an alkoxy group and R29 is a loweralkyl radical.
- carboxyalkoxyalkyl refers to a carboxylic acid group (-COOH) appended to an alkoxy group which is appended to a loweralkyl radical.
- alkoxycarbonylalkoxyalkyl refers to an alkoxycarbonyl group (R 30 C(O)- wherein R 30 is an alkoxy group) appended to an alkoxy group which is appended to a loweralkyl radical.
- (amino) carboxyalkyl refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and an amino group (-NH 2 ).
- (N-protected) amino) carboxyalkyl refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and -NHR 31 wherein R 31 is an N-protecting group.
- (alkylamino) carboxyalkyl refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and an alkylamino group.
- (N-protected) alkylamino) carboxyalkyl refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and an -NR 31 R 32 wherein R 31 is as defined above and R 32 is a loweralkyl group.
- dialkylamino carboxyalkyl refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and -NR 32 R 32 wherein R 32 is as defined above.
- (amino) alkoxycarbonylalkyl refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and an amino group (-NH 2 ).
- ((N-protected) amino) alkoxycarbonylalkyl refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and -NHR 31 wherein R 31 is as defined above.
- alkylamino alkoxycarbonylalkyl refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and an alkylamino group as defined above.
- (N-protected) alkylamino) alkoxycarbonylalkyl refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and -NR 31 R 32 wherein R 31 and R 32 are as defined above.
- dialkylamino alkoxycarbonylalkyl refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and -NR 32 R 32 wherein R 32 is as defined above.
- carboxyalkylamino refers to -NHR 33 wherein R 33 is a carboxyalkyl group.
- alkoxycarbonylalkylamino refers to -NHR 34 wherein R 34 is an alkoxycarbonylakyl group.
- (amino) carboxyalkylamino refers to -NHR 35 wherein R 35 is an (amino) carboxyalkyl group.
- (N-protected) amino) carboxyalkylamino refers to -NHR 36 wherein R 36 is an [ (N- protected) amino] carboxyalkyl group.
- (alkylamino) carboxyalkylamino refers to -NHR 37 wherein R 37 is an (alkylamino) carboxyalkyl group .
- ((N-protected) alkylamino)-carboxyalkylamino refers to -NHR 38 wherein
- R 38 is an ( (N-protected) alkylamino) carboxyalkyl group.
- dialkylamino carboxyalkylamino refers to -NHR 39 wherein R 39 is a (dialkylamino) carboxyalkyl group.
- (amino) alkoxycarbonylalkylamino refers to -NHR 40 wherein R 40 is an (amino) alkoxycarbonylalkyl group.
- (N-protected) amino) alkoxycarbonylalkylamino refers to -NHR 41 wherein R 41 is an ( (N-protected) amino)-alkoxycarbonylalkyl group.
- (alkylamino) alkoxycarbonylalkylamino refers to -NHR 42 wherein R 42 is an (alkylamino) alkoxycarbonylalkyl group.
- (N-protected) alkylamino) alkoxycarbonylalkylamino refers to -NHR 43 whereinR 43 - is an ( (N-protected) alkylamino)-alkoxycarbonylalkyl group.
- dialkylamino alkoxycarbonylalkylamino refers to -NHR 44 wherein R 44 is a (dialkylamino) alkoxycarbonylalkyl group.
- ammocycloalkyl refers to an NH « appended to a cycloalkyl radical.
- (alkoxy) alkoxy) alkyl refers to an alkoxy group appended to an alkoxy group which is appended to a loweralkyl radical.
- polyalkoxyalkyl refers to a polyalkoxy residue appended to a loweralkyl radical.
- polyalkoxy refers to -OR 45 wherein R 45 is a straight or branched chain containing 1-5,
- n and n' are independently selected from 1 to 3, including but not limited to methoxyethoxymethoxy, methoxymethoxy and the like.
- (phenyl) alkylamino refers to R 100 NH- wherein R 100 is a (phenyl) alkyl group as defined above .
- (substituted phenyl) alkylamino refers to R 101 NH- wherein R 101 is a (substituted phenyl) alkyl group as defined above.
- (naphthyl) alkylamino refers to R 102 NH- wherein R 100 is a (naphthyl) alkyl group as defined above.
- (substituted naphthyl) alkylamino refers to R 103 NH- wherein R 103 is a (substituted naphthyl) alkyl group as defined above.
- (phenyl) alkyl (alkyl) amino refers to R 104 R 105 N- wherein R 104 is a (phenyl) alkyl group as defined above and R 105 is a loweralkyl group.
- (substituted phenyl) alkyl (alkyl) amino refers to R 106 R 107 N- wherein R 106 is a
- R 107 is a loweralkyl group.
- (naphthyl) alkyl (alkyl) amino refers to R 108 R 109 N- wherein R 108 is a (naphthyl) alkyl group as defined above and R 109 is a loweralkyl group.
- (substituted naphthyl) alkyl (alkyl)- amino refers to R 110 R 111 N- wherein R 100 is a (substituted naphthyl) alkyl group as defined above and R 111 is a loweralkyl group.
- dialkylaminoalkyl (alkyl) amino refers to -NR 49 R 50 wherein R 49 is a dialkylamino residue appended to a loweralkyl residue and R 50 is a loweralkyl residue.
- alkylaminoalkylamino refers to -NHR 50a wherein R 50a is an alkylaminoalkyl group as previously defined.
- dialkylaminoalkylamino refers to -NHR 50b wherein R 50b is a dialkylaminoalkyl group as previously defined.
- aminoalkylamino refers to - NHR 51 wherein R 51 is an aminoalkyl residue.
- (dihydroxyalkyl) (alkyl) amino refers to a loweralkyl group which is disubstituted with - OH radicals, appended to an amino group, which amino group also has appended another loweralkyl group, including but not limited to N- (2,3-dihydroxypropyl) - N- (methyl) amine.
- di- (hydroxyalkyl) amino refers to -NR 52 R 53 , wherein R 52 and R 53 are hydroxyalkyl residues.
- alkoxyalkyl (alkyl) amino refers to -NR 54 R 55 wherein R 54 is an alkoxyalkyl group andR 55 is a loweralkyl group.
- di- (alkoxyalkyl) amino refers to -NR 56 R 57 wherein R 56 and R 57 are alkoxyalkyl groups.
- di- (polyalkoxyalkyl) amino refers to -NR 58 R 59 wherein R 58 and R 59 are polyalkoxy residues appended to loweralkyl residues.
- (polyalkoxy) alkyl) (alkyl) amino refers to -NR 60 R 61 wherein R 60 is a polyalkoxy residue appended to a loweralkyl residue and R 61 is a loweralkyl residue.
- halo or halogen as used herein refers to -Cl, -Br, -I or -F.
- haloalkyl refers to a loweralkyl radical in which one or more of the hydrogen atoms are replaced by halogen including, but not limited to, chloromethyl, trifluoromethyl, 1-chloro-2-fluoroethyl and the like.
- thioalkoxyalkyl refers to a thioalkoxy group appended to a loweralkyl radical.
- alkylsulfonyl refers to R 62 SO 2 - wherein R 62 is loweralkyl group.
- alkylsulfonylalkyl refers to an alkylsulfonyl group appended to a loweralkyl radical.
- thioaryloxy refers to R 63 S- wherein R 63 is a substituted or unsubstituted phenyl or naphthyl group as defined above, including but not limited to phenyl, naphthyl, halophenyl and alkoxyphenyl.
- thioaryloxyalkyl refers to a thioaryloxy group appended to a loweralkyl radical.
- arylsulfonyl refers to R 63 SO - wherein R 63 is as defined above.
- arylsulfonylalkyl refers to an arylsulfonyl group appended to a loweralkyl radical.
- heterocyclic ring refers to any 3- or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur, or a 5- or 6-membered ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; wherein the 5-membered ring has 0-2 double bonds and the 6-membered ring has 0-3 double bonds; wherein the nitrogen and sulfur heteroatoms are optionally oxidized; wherein the nitrogen heteroatoms are optionally quaternized; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring. Heterocyclics in which nitrogen is the heteroatom are preferred.
- heterocyclics are: pyrryl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl and benzothienyl.
- b is 1 or 2 and T is N, NH, O, S, provided that T is the point of connection only when T is N, wherein R 72 is NH, N-loweralkyl, N-haloalkyl, O, S, or SO 2 , or
- substituted heterocyclic refers to saturated heterocyclics which are monosubstituted or disubstituted with hydroxy, oxo, amino, alkylamino, dialkylamino, alkoxy, polyalkoxy, haloalkyl or loweralkyl; or unsaturated heterocyclics which are monosubstituted with hydroxy, oxo, amino, alkylamino, dialkylamino, alkoxy, polyalkoxy, haloalkyl or loweralkyl.
- heterocyclic alkyl refers to a heterocyclic group appended to a loweralkyl radical. including but not limited to imidazolylmethyl and thiazolylmethyl.
- substituted heterocyclic alkyl refers to a substituted heterocyclic group as defined above appended to a loweralkyl radical.
- heterocyclic carbonyloxy refers to R 205 C(O)O- wherein R 205 is a heterocyclic group.
- (substituted heterocyclic) carbonyloxy refers to R 206 C(O)O- wherein R 206 is a substituted heterocyclic group.
- heterocyclic carbonylamino refers to R 207 C(O)NH- wherein R 207 is a heterocyclic group.
- (substituted heterocyclic) carbonylamino refers to R 208 C(O)NH- wherein R 208 is a substititued heterocyclic group.
- amino acyl residue refers to a residue of the type -NHCH (R*) C (O) - wherein R* represents the side chain of one of the twenty naturally occuring alpha amino acids including, but not limited to alanyl, prolyl, leucyl, phenylalanyl, aspartyl and the like.
- Al Al
- Gin Leu
- Phe He
- Ser He
- Pro Pro
- the compounds of the invention can be prepared as shown in Scheme I .
- the syntheses of segments containing substituents R 3 and A-CHR 1 -CO- are described in the Examples.
- the process shown in Scheme 1 discloses the carbodiimide coupling of acid (1) to substituent R 3 to give the peptide (2).
- carbodiimide coupling of protected amino acid (3) to substituent R 3 followed byhydrogenolytic deprotection provides the amine (4).
- Reaction of (4) with the mixed anhydride (5) gives the peptide (2).
- acid halide and other activated ester derivatives of the carboxylic acid are useful for the coupling reactions with amines.
- Acid halide derivatives include the acid chloride.
- Activated ester derivatives include activated esters commonly used by those skilled in the art for activating carboxylic acid groups for coupling with an amine to form a peptide bond including, but not limited to, formic and acetic acid derived anhydrides, anhydrides derived from alkoxycarbonyl halides such as isobutyloxycarbonylchloride and the like, N-hydroxysuccinimide derived esters, N-hydroxyphthalimide derived esters, N-hydroxybenzotriazole derived esters, N- hydroxy-5-norbornene-2,3-dicarboxamide derived esters, 2,4,5-trichlorophenol derived esters and the like.
- H-R 3 represents compounds of the formula:
- m 1 to 5;
- R 6 is hydroxy, alkoxy or -NR 15 R 16 wherein R 15 and R 16 are independently as defined above and R 75 is -NHCH(R")C(O)-, -NHCH (R")C(O) NHCH (R' ' ')C(O)-, -NHCH (R")C(O) NHCH (R' ' ' )C(O)-R 220 - or -NHCH(R") C (O) NHCH (R' ' ' ) C (O) -R 220 -R 221 - wherein R" is hydrogen, loweralkyl, cycloalkylalkyl, (phenyl) alkyl, (substituted phenyl) alkyl wherein substituted phenyl is independently as defined above, (naphthyl) alkyl or (substituted naphthyl) alkyl wherein substitute
- R 7 is hydrogen, amino or hydroxy and R 8 is loweralkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, azido, azidoalkyl, amino, aminoalkyl, alkylamino, alkylaminoalkyl, dialkylamino, dialkylaminoalkyl, (N-protected) amino, (N-protected) aminoalkyl, (N-protected) (alkyl) amino, (N-protected) (alkyl) aminoalkyl, thioalkoxy, thioalkoxyalkyl, alkylsulfonyl, alkylsulfonylalkyl, thioaryloxy, thioaryloxyalkyl, phenyl, substituted phenyl independently as defined above, naphthyl, substituted naphthyl independently as defined above, heterocyclic, substituted heterocycl
- R 200 is an alkylene group
- R 201 is S, S (O) , S(O)2, O, NH or -N (alkyl)-
- R 202 is an alkylene group
- R 203 is phenyl, substituted phenyl independently as defined above, naphthyl or substituted naphthyl independently as defined above;
- R 5 is independently as defined above,
- G is O, S, -N(R 11 )- or -C(R 11 ) (R 70 )- wherein R 11 is hydrogen or loweralkyl and
- R 70 is hydrogen or loweralkyl
- L is N or -C(R 5 )- wherein R 5 is independently as defined above
- R 81 is N or -C(R 11 )- wherein R 11 is independently as defined above
- R 71 is N or -C(R 11 )- wherein R 11 is independently as defined above
- R 80 is absent, -C(R 11 ) (R 70 )- or -N(R 11 )- wherein R 11 and R 70 are independently as defined above, R 82 is absent, or one or two substituents independently selected from loweralkyl, alkoxy, thioalkoxy, hydroxy, halogen, mercapto, nitro, amino, loweralkylamino, dialkylamino, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide,
- Q is P or -C(R 11 ) (R 70 )- wherein R 11 and
- R 70 are independently as defined above,
- X is O, S, -N(R 11 )-, -C(R 11 ) (R 70 )-,
- R 11 and R 70 are independently as defined above,
- R 12 is independently as defined above or
- H-R 3 can optionally be obtained from the N-protected form of the compound.
- Example 1 N-Methyl-6-(2-(t-butyloxycarbonyl) amino-1-hydroxy- 3-phenyl) propyl-1-cyclohexenecarboxamide.
- a solution of 0.88 g (6.4 mmol) of N-methyl-1-cyclohexenecarboxamide in 30 ml of anhydrous tetrahydrofuran was cooled under nitrogen atmosphere to -78oC and treated with 5.2 ml (13.1 mmol) of n-butyllithium.
- the resulting solution was warmed to 0oC for 30 mm, recooled to -78oC, and treated with 6.4 ml (6.4 mmol) of chlorotitanium triisopropoxide in hexane.
- Example 2 N-Methyl-6-(2-amino-1-hydroxy-3-phenylpropyl)- 1-cyclohexenecarboxamide Hydrochloride.
- the resultant compound of Example 1 (0.23 g) was treated with 8 ml of 4 M HCl in dioxane. After 1 h, the solution was concentrated in vacuo to give the desired compound.
- Boc-Leu-Asn-OH A solution of 10 g (40 mmol) of Boc-Leu-OH and 4.4 ml (40 mmol) of 4-methylmorpholine in 200 ml of anhydrous tetrahydrofuran was cooled under N 2 atmosphere to -10oC and treated with 5.2 ml (40 mmol) of isobutyl chloroformate. After 15 min, the solution was treated with a mixture of 5.30 g (40 mmol) of asparagine and 25 ml of 3 N NaOH in 50 ml of tetrahydrofuran and 200 ml of water.
- Example 5 N-(3-Methylbutyl)-1-cyclopentenecarboxamide.
- 1-Cyclopentenecarboxylic acid (7.17 g, 64 mmol) was coupled to isoamylamine using the procedure of Example 4 to give, after silica gel chromatography using 7:3 hexane/ethyl acetate, 7.86 g (68%) of the desired compound as a white crystalline solid.
- Example 6 N-(3-Methylbutyl)-5-(2-(t-butyloxycarbonyl)amino- 1-hydroxy-3-phenyl)propyl-1-cyclopentenecarboxamide. Using the procedure of Example 1 but replacing N-methyl-1-cyclohexenecarboxamide with the resultant compound of Example 5 gives the desired compound as a mixture of diastereomers .
- Example 7 Boc-Leu-Asn Amide of N-(3-Methylbutyl)-5- (2-amino-1-hydroxy-3-phenyl)propyl- 1-cyclopentenecarboxamide. Using the procedures of Examples 2 and 4 with the resultant compound of Example 6 gives the desired compound.
- Example 8 ( (4-Moroholinyl) carbonyl) -Leu Methyl Ester.
- a suspension of L-leucine methyl ester hydrochloride (6 g).in toluene (125 ml) is heated to 100°C while phosgene gas is bubbled into the reaction mixture. After approximately 1.5-2 h, the mixture becomes homogeneous. The passage of phosgene is continued for an additional 15 min, keeping the temperature at 90-100°C. The toluene is then evaporated and the residue chased several times with benzene.
- Example 9 (4-Morpholinyl) carbonyl) -Leu-OH.
- a solution of lithium hydroxide (0.174 g, 4.15 mmol) in water (7.5 ml).
- the reaction mixture is diluted with cold water and extracted 2X with ether.
- the aqueous portion is acidified with 6N HCl and extracted with ether.
- the organic extract is washed with brine and evaporated to give the desired compound.
- Example 10 3-Benzyloxycarbonylamino-3-methylbutanoic Acid.
- a solution of 2,2-dimethyl-3-carbomethoxypropionic acid (LeMaul, Bull. Soc. Chim. Fr., 828 (1965), 20 g, 0.125 mol), diphenylphosphorylazide (34.3 g, 0.125 mol) and triethylamine is heated in toluene (150 ml) at 100°C for 2 h. After cooling to 5°C, the toluene solution is washed successively with 0.5 M HCl, aqueous NaHCO 3 and brine. Evaporation of the dried solution gave a residue which is chromatographed on silica gel eluting with 60/40 hexane-ether. There is obtained 13 g of methyl 3-
- Example 11 Cbz-(( ⁇ , ⁇ -di-Me)- ⁇ -Ala)-Leu-OCH 3 .
- a 4.0 g sample of 3-benzyloxycarbonylamino-3-methylbutanoic acid is coupled to leucine methyl ester hydrochloride using the mixed anhydride procedure described in Example 4. Purification of the crude product by flash chromatography gives the desired compound.
- Example 12 Cbz-(( ⁇ , ⁇ -di-Me)- ⁇ -Ala)-Leu-OH.
- a solution of Cbz-(( ⁇ , ⁇ -di-Me)- ⁇ -Ala)-Leu-OMe (3.63 mmol) in dioxane (15 ml) is added a solution of lithium hydroxide (0.174 g, 4.15 mmol) in water (7.5 ml). After stirring for 1 h at 0-5°C, the reaction mixture is diluted with cold water and extracted 2X with ether. The aqueous portion is acidified with 6N HCl and extracted with ether. The organic extract is washed with brine and evaporated to give the desired compound.
- Example 13 (4R)-3-(4-Methylpentanoyl)-4- (2-propyl)oxazolidine-2-one.
- 4-(2-propyl)-oxazolidine-2-one in anhydrous tetrahydrofuran (250 ml) under a nitrogen atmosphere at -78°C is added in a dropwise fashion a solution of a-butyllithium in hexane (50 ml, 77.4 mmol) over 5 to 10 min.
- 4-methylpentanoyl chloride (85.2 mmol) is added neat. The reaction is warmed to room temperature and stirred 1 to 2 h at the temperature.
- reaction is quenched by adding 100 ml of saturated aqueous ammonium chloride and the volatiles are removed by rotary evaporation.
- the resulting aqueous residue is extracted three times with ether and the combined organic phases. are washed with brine, dried (Na 2 SO 4 ), filtered and concentrated in vacuo. Recrystallization from hexanes/ethyl acetate provides the desired compound.
- Example 14 (4R)-3-((2-R)-2-(t-Butyloxycarbonyl)methyl-4- methylpentanoyl)-4-(2-propyl)oxazolidine-2-one.
- a stirred solution of the product resulting from Example 13 (8.72 mmol) in anhydrous tetrahydrofuran (30 ml) under a nitrogen atmosphere at -78°C is added a solution of sodium hexamethyldisilylamide (9.6 ml, 9.59 mmol) in tetrahydrofuran.
- t-butyl bromoacetate (2.21 g, 11.34 mmol) is added in anhydrous tetrahydrofuran and the resulting solution stirred 1 h at -78°C.
- the reaction is quenched by adding 20 ml of saturated aqueous ammonium chloride and partitioned between water and ether. The aqueous layer is drawn off and extracted with ether. The combined organic phases are washed with 10% aqueous HCl, saturated aqueous NaHCO 3 , and brine, dried (Na 2 SO 4 ), filtered, and concentrated in vacuo. Recrystallization from acetone/hexanes provides the desired compound.
- Example 15 Benzyl-(2R)-2-(t-Butyloxycarbonyl)methyl- 4-methylpentanoate.
- benzyl alcohol 0.55 ml, 5.33 mmol
- anhydrous tetrahydrofuran 18 ml
- n-butyllithium 2.58 ml; 4.00 mmol
- To this solution is added the product from Example 55 in anhydrous tetrahydrofuran (10 ml). After stirring 1 h at 0°C the reaction is quenched by adding excess saturated aqueous ammonium chloride.
- Example 16 Benzyl-(2R)-2-(Carboxymethyl)-4-methylpentanoate.
- the resultant compound from Example 15 (1.47 mmol) is dissolved in a 1:1 (v:v) solution (6 ml) of trifluoroacetic acid and dichloromethane and stirred at room temperature for 1 h.
- the volatiles are removed in vacuo to provide the desired compound.
- the unpurified material is of sufficient purity to employ in subsequent steps.
- Example 17 Benzyl (2R) -2-Isobutyl-3-morpholinocarbonylpropionate.
- the resultant compound of Example 16 is coupled to morpholine using the mixed anhydride procedure as described in Example 4 to give the desired compound.
- Example 18 (3, 4-cis-Dihydroxypyrrolidinylcarbonyl)-Leu Methyl Ester.
- a suspension of L-leucine methyl ester hydrochloride (10 g) in toluene (f200 ml) is heated to 100°C while phosgene gas was bubbled into the reaction mixture. After approximately 2 h the mixture becomes homogeneous. The bubbling of phosgene is continued for 15 more minutes keeping the temperature at 100°C. The toluene is then evaporated and the residue chased with benzene several
- Example 19 ( (4-Thiomorpholinyl)carbonyl)-Leu Methyl Ester.
- a suspension of L-leucine methyl ester hydrochloride (6 g) in toluene (125 ml) is heated to 100°C and phosgene gas is bubbled into the reaction mixture. After approximately 1.5 h, the mixture becomes homogeneous. The bubbling of phosgene is continued for 10 more min. The solvent is then evaporated and the residue chased with benzene several times. The residue is then dissolved in 100 ml of methylene chloride and cooled to 0°C, and 1.1 equivalent of thiomorpholine is added dropwise. After 10 min the solution is washed with 1N HCl and the organic layer was dried with MgSO 4 . Evaporation of solvent gives the desired compound.
- Example 21 Boc-6-aminohexanoic acid.
- a mixture of 3.0 g (0.02 mol) of 6-aminohexanoic acid, 5.04 g (0.02 mol) of di-t-butyldicarbonate and 3.84 g (0.05 mol) of NaHCO 3 in 160 ml of 1:1 H 2 O/tetrahydrofuran is stirred vigorously for 24 h. After concentration of the solvent, the mixture is acidified with HCl, saturated with NaCl, extracted with ethyl acetate, dried over MgSO 4 and concentrated in vacuo to give the desired product (R f 0.48, 9:1 chloroform/methanol).
- Example 22 Boc-6-aminohexanoyl-Leu benzyl ester.
- Example 23 Boc-6-aminohexanoyl-Leu-OH.
- a mixture of 1.07 mmol of the resultant compound of Example 22 and 30 mg of 10% palladium on carbon in 50 ml of methanol is stirred under an H 2 atmosphere for 3.5 h. After filtration through Celite, concentration in vacuo gives the desired compound.
- Example 24 N-Methyl-N-(2-(N,N-dimethylamino) ethyl) carbamoyl- leucine methyl ester.
- a solution of 2.1 mmol of a-isocyanoto-leucine methyl ester in 50 ml of dichloromethane is cooled to 0°C and treated with 0.3 ml (2.3 mmol) of N,N,N'-trimethylethylenediamine. After being allowed to stir for 16 h, the solution is concentrated and the desired compound is isolated by flash column chromatography.
- Example 25 N-Methyl-N-(2-(N,N-dimethylamino) ethyl) carbamoyl- leucine lithium salt.
- a solution of the resultant compound of Example 24 in dioxane is cooled to 0°C, treated with 1.05 equiv. of aqueous lithium hydroxide (0.5 M) and stirred for 1.5 h.
- the resulting solution is concentrated in vacuo to give the desired compound as a white solid.
- Example 26 (2R)-2-Isobutyl-3-morpholinocarbonylpropionic Acid.
- the resultant compound of Example 17 is a hydrogenolyzed according to the procedure of Example 23 to provide the desired compound.
- Example 27 (3.4-cis-Dihydroxypyrrolidinylcarbonyl)-Leu-OH.
- the resultant compound of Example 18 is hydrolyzed according to the procedure of Example 9 to provide the desired compound.
- Example 28 (4-Thiomorpholinylcarbonyl)-Leu-OH.
- the resultant compound of Example 19 is hydrolyzed according to the procedure of Example 9 to provide the desired compound.
- Example 29 (4-Sulphonylmorpholinylcarbonyl)-Leu-OH.
- the resultant compound of Example 20 is hydrolyzed according to the procedure of Example 9 to provide the desired compound.
- Example 31 (((4-Morpholinyl) carbonyl) oxy)-4-methylpentanoic Acid.
- the resultant compound of Example 30 is hydrolyzed according to the procedure of Example 9 to provide the desired compound.
- Example 32 Benzyl-(2R)-2-isobutyl-3- ( ( (4-morpholinyl) carbonyl) amino)-propionate.
- the product from Example 16 (1.47 mmol), diphenylphosphoryl azide (1.47 mmol), and triethylamine (1.47 mmol) in dry benzene (6 ml) are refluxed for 3 to 5 h to provide a solution of the derived isocyanate which is cooled to 0°C and treated with morpholine (1.6 mmol).
- the cooling bath is removed and the reaction stirred for 1 h.
- the reaction mixture is poured into 10% aqueous HCl and extracted two times with ether.
- the combined organic layers are washed successively with saturated aqueous NaHCO 3 and brine, dried (Na 2 SO 4 ), filtered and concentrated in vacuo to provide the unpurified product.
- the desired product is obtained in pure form after chromatography on SiO 2 .
- Example 33 Benzyl-(2R)-2-isobutyl-3- ( (ethoxvcarbonyl) amino)-propionate. Using the procedure of Example 32 but replacing morpholine with ethanol gives the desired compound.
- Example 34 (2R)-2-Isobutyl-3- (((4-morpholinyl) carbonyl) amino) propionic Acid.
- the resultant compound of Example 32 is hydrolyzed according to the procedures of Example 9 to give the desired compound.
- Example 35 (2R)-2-Isobutyl-3- ( (ethoxycarbonyl) amino) propionic Acid.
- the resultant compound of Example 33 is hydrolyzed according to the procedures of Example 9 to give the desired compound.
- Example 36 1-Benzyloxycarbonylamino-2,3-propanediol.
- 1-Amino-2,3-propanediol (15.2 g, 167 mmol) and NaOH (8.1 g, 204 mmol) in water (70 ml) at -10°C was treated dropwise with benzyl chloroformate (28.5 ml, 200 mmol) in ether (30 ml) over 20 min. The reaction was stirred at 0°C for 30 min then at room temperature for 2 h. The mixture was acidified with 2 M HCl and extracted with ethyl acetate which was washed with 0.5 M H 3 PO 4 and brine, then dried over Na 2 SO 4 and evaporated.
- Lithium aluminum hydride (7.20 g, 189 mmol) in tetrahydrofuran (THF, 300 ml) was heated to reflux and the resultant compound from Example 36 (17.0 g, 75.5 mmol) in THF (150 ml) was added dropwise over 10 min.
- the mixture was refluxed for 2 h, cooled, quenched sequentially with water (10 ml), 3 M NaOH (40 ml) and water (20 ml), then filtered and concentrated. The residue was dissolved in water which was washed with ether and evaporated. Bulb to bulb distillation of the residue afforded 2.0 g (25%) of the desired compound as an oil.
- Example 19 Using the procedure of Example 19 but replacing thiomorpholine with the resultant compound of Example 37 gives the desired compound.
- Example 38 is hydrolyzed according to the procedures of Example 9 to give the desired compound.
- Example 40 5-(Methoxycarbonyl) pentanoyl-leucine Benzyl Ester.
- Adipic acid monomethyl ester is coupled to leucine benzyl ester hydrochloride using the mixed anhydride procedure described in Example 4 to provide the desired compound.
- Example 41 5-(Methoxycarbonyl) pentanoyl-leucine.
- the resultant compound of Example 40 is hydrogenolyzed according to the procedure of Example 23 to provide the desired compound.
- aqueous phase is acidified with concentrated HCl then extracted with ethyl acetate which is dried over Na 2 SO 4 and evaporated. Trituration with hot ethyl acetate affords the desired compound.
- Example 43 N-Benzyloxycarbonyl-N-methyl-2-aminoethanol. To N-methylethanolamine (149 mmol) in methylene chloride (100 ml) at 0°C was added benzyl chloroformate (70 mmol). The mixture was stirred at 0°C for 30 min, then at room temperature for 1 h, poured into ethyl acetate, washed with 2 M HCl, saturated NaHCO 3 solution, and brine, then dried over Na 2 SO 4 and evaporated to provide the desired compound.
- 1 H NMR (CDCl 3 ,TMS) ⁇ 7.36 (m,5H), 5.14 (s,2H), 3.78 (m,2H), 3.47 (m,2H), 3.01 (s,3H).
- Example 44 1-Methoxyethoxymethoxy-2-(N-methyl- N-benzyloxycarbonylamino) ethane.
- diisopropylethylamme 138 mmol
- 2-methoxyethoxymethyl chloride 132 mmol
- the mixture was evaporated, dissolved in ethyl acetate, washed with 0.5 M H 3 PO 4 , saturated NaHCO 3 solution, and brine, then dried over Na 2 SO 4 , and evaporated to afford the desired product as an oil, b.p. 150-170°C (0.3 mm).
- Example 45 1-Methylamino-2-methoxyethoxymethoxyethane.
- the resultant compound from Example 44 (31 mmol) and 10% palladium on carbon (3 g) in methanol (60 ml) were stirred under a hydrogen atmosphere for 24 h.
- the mixture was filtered, evaporated and distilled to afford the desired product as an oil, b.p. 130-140°C (45 mm).
- the resultant compound of Example 16 is coupled to the resultant compound of Example 45 using the mixed anhydride procedure of Example 4 to give the desired compound.
- Example 47 (2R)-2-Isobutyl-3-(N-methyl-N-(2-methoxyethoxy methoxyethyl) aminocarbonyl) propionic Acid.
- the resultant compound of Example 46 is hydrolyzed according to the procedure of Example 9 to give the desired compound.
- Example 48 N-(2-Cyanoethyl) leucine Methyl Ester.
- a solution of leucine methyl ester (0.590 mmol) in acrylonitrile (2 ml) is heated at reflux. Evaporation provides a residue which is chromatographed on silica gel to give desired compound.
- Example 49 N-(3-Benzyloxycarbonylaminopropyl) leucine Methyl Ester.
- the resultant compound of Example 48 (0.135 mmol) is hydrogenated (4 atmospheres H 2 ) over Raney Nickel (85 mg) in anhydrous methanol/ammonia (20 ml/5 ml) for 3 h. Filtration and evaporation provide the crude amine which is taken up in dichloromethane and treated with 0.14 mmol of N-(benzyloxycarbonyloxy) succinimide. After 2 h, the solution is washed with aqueous NaHCO 3 , dried over Na 2 SO 4 , and concentrated. Silica gel chromatography gives the desired compound.
- Example 50 N-(3-Benzyloxycarbonylaminopropyl) leucine.
- the resultant compound of Example 49 is hydrolyzed according to the procedure of Example 9 to give the desired compound.
- Example 51 Cbz-Sar-Leu Methyl Ester.
- Cbz-sarcosine is coupled to leucine methyl ester using the mixed anhydride procedure of Example 4 to give the desired compound.
- Example 52 Cbz-Sar-Leu-OH.
- the resultant compound of Example 51 is hydrolyzed according to the procedure of Example 9 to give the desired compound.
- Example 53 (N,N-Dimethyl)-Gly-Leu-OCH 3 .
- the resultant product of Example 51 (0.243 mmol) is hydrogenated (1 atmosphere H 2 ) with 10% Pd/C (39 mg) in methanol/formalin (12 ml/5 ml) for 8 h. Filtering and evaporating (high vacuum) provides a residue which is chromatographed on silica gel to give the desired- compound.
- Example 54 (N,N-Dimethyl)-Gly-Leu-O-Li + The resultant compound of Example 53 is hydrolyzed according to the procedure of Example 25 to give the desired compound.
- Example 55 (N-(Benzyloxycarbonyl)pipiridin-4-yl) carbonyl- leucine Methyl Ester.
- Cbz-isonipecotic acid is coupled to leucine methyl ester using the mixed anhydride procedure of Example 4 to give the desired compound.
- Example 56 (N-(Benzyloxycarbonyl) pipiridin-4-yl) carbonyl-ieucine.
- the resultant compound of Example 55 is hydrolyzed according to the procedure of Example 9 to give the desired compound.
- Example 57 N-(Allyloxycarbonyl)-leucine Methyl Ester.
- a solution of leucine methyl ester (5 mmol) and triethylamine (10 mmol) in dichloromethane (50 ml) is cooled to 0°C and treated dropwise with allyl chloroformate. After addition, the solution is stirred at ambient temperature for 2 h, diluted with dichloromethane, washed successively with 1 N HCl and aqueous NaHCO 3 , dried over Na 2 SO 4 , and concentrated to give the desired compound.
- Example 58 N-(Allyloxycarbonyl)-leucine Methyl Ester.
- a solution of leucine methyl ester (5 mmol) and triethylamine (10 mmol) in dichloromethane (50 ml) is cooled to 0°C and treated dropwise with allyl chloroformate. After addition, the solution is stirred at ambient temperature for 2 h
- Example 59 N-(3-Hydroxypropyloxycarbonyl)-leucine.
- the resultant compound of Example 58 is hydrolyzed according to the procedure of Example 9 to give the desired compound.
- Example 60 N-(2,3-Dihydroxypropyloxycarbonyl)-leucine Methyl Ester.
- OsO 4 2.8 ml of a 2.5% solution in t-butanol
- N-methylmorpholine N-oxide 68.7 mmol.
- the mixture is partitioned between ether (200 ml) and brine (100 ml).
- the aqueous layer is back-extracted with ether (2x100 ml), and the combined organic phase is washed with 10% Na 2 SO 3 , 0.1 M H 3 PO 4 , and brine. Drying (MgSO 4 ) and evaporating provides a residue which is chromatographed on silica gel to give the desired compound.
- Example 61 3-Benzyloxycarbonyl-4-(4-carboxybutyl) oxazolidin-5-one.
- a solution of 3.0 g (17.1 mmol) of d1- ⁇ -aminopimelic acid in 30 ml of dioxane and 10 ml of water was treated simultaneously in a dropwise fashion with 4.8 g (18.8 mmol) of N-(benzyloxycarbonyloxy) succinimide in 10 ml of dioxane and 17 ml (51 mmol) of 3 N NaOH. After the addition was complete, the reaction mixture was stirred for 1.5 h and concentrated in vacuo.
- Example 63 N-(3-Benzyloxypropanoyl)-leucine.
- the resultant compound of Example 62 is hydrolyzed according to the procedure of Example 9 to give the desired compound.
- Example 64 N-(2,3-Dihydroxypropyloxycarbonyl)-leucine.
- the resultant compound of Example 60 is hydrolyzed according to the procedure of Example 9 to give the desired compound.
- Example 65 (3S.5S,1'R,2'S)-5-(2-Amino-3-cyclohexyl- 1-hydroxypropyl)-3-methyldihydrofuran- 2(3H)-one Hydrochloride.
- the resultant compound of Example 106 (1.13 g, 2.86 mmol) was dissolved in 10 ml of anhydrous ethanol.
- the resulting solution was treated with 75 ml of HCl in dioxane (4 M) and stirred at ambient temperature for 1 h. Concentration of the solution in vacuo gave the desired compound as an off-white foam.
- Example 66 (3S.5S,1'R,2'S)-5-(2-Amino-3-cyclohexyl- 1-hydroxypropyl)-3-methyldihydrofuran- 2(3H)-one Hydrochloride.
- the resultant compound of Example 106 (1.13 g, 2.86 mmol) was dissolved in 10 ml of anhydrous ethanol.
- Boc-Leu-Asn Amide of (3S, 5S.1 'R.2'S)-5-(2-Amino- 3-cyclohexyl-1-hydroxypropyl)-3-methyldihydrofuran- 2(3H)-one A solution of 0.20 g (0.69 mmol) of the resultant compound of Example 65, 0.24 g (2.1 mmol) of 1-hydroxybenzotriazole and 0.15 ml (1.4 mmol) of 4-methylmorpholine in 5 ml of dimethylformamide was cooled under N 2 atmosphere to -23°C and treated with 0.13 g (0.69 mmol) of N-ethylN'-(dimethylaminopropyl) carbodiimide.
- Example 68 Cbz-Leu-Asn-OH Cbz-Leu-OH (19.8 g, 75 mmol) was coupled to asparagine (9.9 g, 75 mmol) using the mixed anhydride procedure described in Example 3. After extraction into chloroform and washing with water, the product formed a white precipitate in the organic layer. The mixture was filtered, and the residue was washed with chloroform and dried in vacuo at 50°C to provide 10.37 g (37%) of the desired compound.
- Example 69 Cbz-Leu-Asn Amide of N-(3-Methylbutyl)-2-(2(S)-amino- 1(R)-hydroxy-3-phenylpropyl) furan-3-carboxamide.
- the resultant 1' (R) ,2' (S) -diastereomer of Example 102 was deprotected according to the procedure of Example 2 and coupled to Cbz-Leu-Asn-OH according to the procedure of Example 66 to provide, after silica gel chromatography using 7.5% methanol in chloroform, the desired compound in 87% yield.
- Example 104 Boc-Leu-Asn Amide of N-(1-Hydroxy-3-methylpent-2-yl)- 2-(2-amino-1-hydroxy-3-phenylpropyl) thiophene- 3-carboxamide.
- the resultant compound of Example 104 is deprotected according to the procedure of Example 2 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
- Example 71 Boc-Leu-Asn Amide of (5S, 1 'R, 2 ' S)-5-(2-Amino- 3-cyclohexyl-1-hydroxypropyl)- 3-methylenedihydrofuran-2(4H)-one.
- the resultant compound of Example 105 is deprotected according to the procedure of Example 65 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
- Example 72 Boc-Leu-Asn Amide of (2S, 3R.4S, 6S)-2-Amino- 1-cyclohexyl-6-methyl-3,4,7-trihydroxyheptane.
- the resultant compound of Example 107 is deprotected according to the procedure of Example 65 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
- Example 73 Boc-Leu-Asn Amide of (5S, 1 'R, 2 'S)-5-(2-Amino- 3-cyclohexyl-1-hydroxypropyl)-3,3- dimethyldihydrofuran-2(3H)-one.
- the resultant compound of Example 169 is deprotected according to the procedure of Example 65 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
- Example 74 Boc-Leu-Asn Amide of (2S, 3R, 4S)-2-Amino-1- cyclohexyl-6,6-dimethyl-3,4,7-trihydroxyheptane.
- the resultant compound of Example 170 is deprotected according to the procedure of Example 65 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
- Example 75 2N-Boc-Leu-Asn Amide of (2S, 3R, 4S,6S)- 2-Amino-7-(benzylamino)-1-cyclohexyl-3,4- dihydroxy-6-methylheptane.
- the resultant compound of Example 109B is deprotected according to the procedure of Example 65 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
- Example 76 2N-Boc-Leu-Asn Amide of (2S, 3R, 4S, 6S)-1-Cyclohexyl- 2,7-diamino-3,4-dihydroxy-6-methylheptane.
- the resultant compound of Example 75 is hydrogenolyzed according to the procedure of Example 23 to provide the desired compound.
- Example 77 Cbz-Asn Amide of (2S , 4S, 1 'R, 2 ' S) -2-(2-Amino- 3-cyclohexyl-1-hydroxypropyl)- 4-methyltetrahydrofuran.
- the resultant compound of Example 108 is deprotected according to the procedure of Example 55 and coupled to Cbz-Asn-OH according to the procedure of Example 66 to provide the desired compound.
- Example 78 Boc-(6-aminohexanoyl) Leu-Asn Amide of (2S, 4S.1 'R, 2'S)- 2-(2-Amino-3-cyclohexyl-1-hydroxypropyl)- 4-methyltetrahydrofuran.
- the resultant compound of Example 77 is hydrogenolyzed according to the procedure of Example 23 and coupled to the resultant compound of Example 23 according to the procedure of Example 4 to provide the desired compound.
- Example 79 (6-Aminohexanoyl) Leu-Asn Amide of (2S, 4S, 1 'R,2'S)- 2-(2-Amino-3-cyclohexyl-1-hydroxypropyl)- 4-methyltetrahydrofuran.
- the resultant compound of Example 78 is deprotected according to the procedure of Example 2.
- the crude product is partitioned between ethyl acetate and aqueous NaHCO 3 , dried over MgSO 4 , and concentrated. Chromatography on silica gel provides the desired compound.
- Example 80 Cbz-Asn Amide of 2-Amino-1-cyclopentyl-1-hydroxy- 3-phenylpropane.
- the resultant compound of Example 110 is deprotected according to the procedure of Example 2 and coupled to Cbz-Asn-OH according to the procedure of Example 66 to provide the desired compound.
- Example 81 (N-Methyl-N-(2-(N,N-dimethylamino) ethyl) carbamoyl)- Leu-Asn Amide of 2-Amino-1-cyclopentyl-1-hydroxy- 3-phenylpropane.
- the resultant compound of Example 80 is hydrogenolyzed according to the procedure of Example 23 and coupled to the resultant compound of Example 25 according to the procedure of Example 4 to provide the desired compound.
- Example 82 2-(((4-Morpholinyl) carbonyl) oxy)-4-methylpentanoyl- Asn Amide of 2-Amino-1-cyclopentyl-1-hydroxy- 3-phenylpropane.
- the resultant compound of Example 80 is hydrogenolyzed according to the procedure of Example 23 and coupled to the resultant compound of Example 31 according to the procedure of Example 4 to provide the desired compound.
- Example 83 (2R)-2-Isobutyl-3- ( ( (4-morpholinyl) carbonyl) amino) propanoyl)-Asn Amide of 2-Amino-1-cyclopentyl-1-hydroxy-3-phenylpropane.
- the resultant compound of Example 80 is hydrogenolyzed according to the procedure of Example 23 and coupled to the resultant compound of Example 34 according to the procedure of Example 4 to provide the desired compound.
- Example 84 (2R)-2-Isobutyl-3-((ethoxycarbonyl) amino) propanoyl)- Asn Amide of 2-Amino-1-cyclopentyl-1-hydroxy- 3-phenylpropane.
- the resultant compound of Example 80 is hydrogenolyzed according to the procedure of Example 23 and coupled to the resultant compound of Example 35 according to the procedure of Example 4 to provide the desired compound.
- Example 85 Boc-Leu-Asn Amide of N-(3-Methylbutyl)-2-(2-amino- 3-cyclohexyl-1-hydroxypropyl) cyclopentanecarboxamide.
- the resultant compound of Example 111 is deprotected according to the procedure of Example 65 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
- Example 86 Boc-Leu-Asn Amide of (1 'R, 2 'S.5S)-5-(2-Amino-3- cyclohexyl-1-hydroxypropyl)-3-ethyloxazolidin-2-one.
- the resultant compound of Example 118 is deprotected according to the procedure of Example 65 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
- Example 87 Boc-Leu-Asn Amide of (1 'R,2'S , 5S)-5-(2-Amino-3- cyclohexyl-1-hydroxypropyl)-3-methoxyoxazolidin-2-one.
- the resultant compound of Example 119 is deprotected according to the procedure of Example 65 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
- Example 120 Boc-Leu-Asn Amide of (1 'R.2 ' S, 5S)-5-(2-Amino-3- cyclohexyl-1-hydroxypropyl)-3-(N-benzyloxycarbonyl- N-methylamino)oxazolidin-2-one.
- the resultant compound of Example 120 is deprotected according to the procedure of Example 65 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
- Example 89 Boc-Leu-Asn Amide of (1 'R, 2 ' S, 5S)-5-(2-Amino-3-cyclohexyl- 1-hydroxypropyl)-3-(methylamino) oxazolidin-2-one.
- the resultant compound of Example 88 is hydrogenolyzed according to the procedure of Example 23 to provide the desired compound.
- Example 128 Boc-Leu-Asn Amide of (1 'R, 2 ' S , 4S) -4-(2-Amino- 3-cyclohexyl-1-hydroxypropyl) dioxolan-2-one.
- the resultant compound of Example 128 is deprotected according to the procedure of Example 65 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
- Example 91 Boc-Leu-Asn Amide of (1 'R, 2 ' S, 5S)-5-(2-Amino-3- cyclohexyl-1-hydroxypropyl)-3-ethylimidazolidin-2-one.
- the resultant compound of Example 124 is deprotected according to the procedure of Example 65 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
- Example 92 Boc-Leu-Asn Amide of (1 'R, 2 'S, 6S)-6-(2-Amino-3- cyclohexyl-1-hydroxypropyl)-3-aza-2-oxotetrahydrooyran.
- the resultant compound of Example 127 is deprotected according to the procedure of Example 65 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
- Example 93 Boc-Leu-Asn Amide of (1 'R, 2'S, 4S)-4-(2-Amino- 3-cyclohexyl-1-hydroxypropyl)-3-azapiperidin-2-one.
- the resultant compound of Example 132 is deprotected according to the procedure of Example 65 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
- Example 94 Boc-Leu-Asn Amide of (1 'R, 2 'S.6S)-6-(2-Amino- 3-cyclohexyl-1-hydroxypropyl)-3.4-diaza-2-oxo- 4-methyltetrahydropyran.
- the resultant compound of Example 135 is deprotected according to the procedure of Example 65 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
- Example 139 Boc-Leu-Asn Amide of (1 'R.2'S.5S)-5-(2-Amino-3- cyclohexyl-1-hydroxypropyl)-3-(hydroxyethyl) oxazolidin- 2-one.
- the resultant compound of Example 139 is deprotected according to the procedure of Example 65 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
- Example 96 Boc-Leu-Asn Amide of (2S, 3R, 4S)-(2-Amino- 1-cyclohexyl-3,4-dihydroxy-6-methylheptane.
- the resultant compound of Example 141 is deprotected according to the procedure of Example 65 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
- Example 97 Boc-Leu-Asn Amide of 3-Amino-4-cyclohexyl- 2-hydroxy-1-(isopropylmercapto) butane.
- the resultant compound of Example 144 is deprotected according to the procedure of Example 65 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
- Example 98 Boc-Leu-Asn Amide of 3-Amino-4-cyclohexyl- 2-hydroxy-1-(isopropylsulfonyl) butane.
- the resultant compound of Example 145 is deprotected according to the procedure of Example 65 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
- Example 99 Boc-Leu-Asn Amide of (2S, 3R.4S) -4-Amino-1-azido- 5-cyclohexyl-2,3-dihydroxypentane.
- the resultant compound of Example 149 is deprotected according to the procedure of Example 65 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
- Example 100 Boc-Leu-Asn Amide of 2-(2-Amino-1-hydroxy- 3-phenylpropyl) pyrrole.
- the resultant compound of Example 150 is deprotected according to the procedure of Example 2 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
- Example 102 N-(3-Methylbutyl)-2-(2-(t-butyloxycarbonylamino)- 1-hydroxy-3-phenylpropyl) furan-3-carboxamide. Using the procedure of Example 1 but replacing N-methyl-1-cyclohexenecarboxamide with the resultant compound of Example 102 gives the desired compound.
- Example 103 N-(1-Hydroxy-3-methylpent-2-yl) thiophene- 3-carboxamide. Thiophene-3-carboxylic acid is coupled to isoleucinol using the mixed anhydride procedure of Example 4 to give the desired compound.
- Example 104 N-(1-Hydroxy-3-methylpent-2-yl)-2- (2-(t-butyloxycarbonylamino)-1-hydroxy- 3-phenylpropyl)thiophene-3-carboxamide. Using the procedure of Example 1 but replacing N-methyl-1-cyclohexenecarboxamide with the resultant compound of Example 103 and using one additional equivalent of n-butyllithium gives the desired compound.
- Example 105 (5S,4'S.5'R)-5-(3-(t-Butyloxycarbonyl)- 4-(cyclohexylmethyl)-2.2-dimethyloxazolidin-5-yl)- 3-methylenedihydrofuran-2(4H)-one.
- a solution of 16.52 g (51 mmol) of the resultant compound of Example 241 in 15 ml of anhydrous tetrahydrofuran was treated with 3.98 g (61 mmol) of freshly activated zinc dust. With vigorous stirring, the mixture was treated with 10 g (56 mmol) of methyl 2- (bromomethyl) aerylate at a rate which maintained the temperature at 50-60°C.
- Example 106 (3S,5S,4'S.5'R)-5-(3-(t-Butyloxycarbonyl)- 4-(cyclohexylmethyl)-2,2-dimethyloxazolidin-5-yl)- 3-methyldihydrofuran-2(3H)-one.
- Example 107 3-(t-Butyloxycarbonyl)-4-(cyclohexylmethyl)-5- (1,4-dihydroxy-3-methylbutyl)-2,2-dimethyloxazolidine.
- a mixture of 0.50 g (1.26 mmol) of the resultant compound of Example 106 and 0.15 g (4 mmol) of sodium borohydride in 50 ml of tetrahydrofuran was heated at reflux under N 2 atmosphere for 48 h. After being allowed to cool, the mixture was treated cautiously with aqueous NH 4 Cl, extracted with ether, washed with saturated brine, dried over MgSO 4 , and concentrated in vacuo.
- Example 108 3-(t-Butyloxycarbonyl)-4-(cyclohexylmethyl)-2,2- dimethyl-5-(4-methyltetrahydrofuran-2- yl)oxazolidine.
- a solution of 51 mg (0.13 mmol) of the resultant compound of Example 107 and 0.037 ml (0.27 mmol) of triethylamine in 2 ml of dichloromethane was cooled to 0°C under N 2 atmosphere and treated with 0.012 mol (0.15 mmol) of methanesulfonyl chloride.
- Example 109 A (3S,5S,4'S,5'R)-5-(3-(t-Butyloxycarbonyl)- 4-(cyclohexylmethyl)-2,2-dimethyloxazolidin-5-yl)- 2-hydroxy-3-methyItetrahydrofuran.
- a solution of 1.00 g (2.5 mmol) of the resultant compound of Example 106 in 30 ml of anhydrous dichloromethane was cooled under N 2 atmosphere to -78°C and treated dropwise with 3.03 ml (3.0 mmol) of precooled diisobutylaluminum hydride (1.0 M in dichloromethane).
- Example 110 2-(t-Butyloxycarbonylamino)-1-cyclopentyl- 1-hydroxy-3-phenylpropane.
- a solution of Boc-phenylalininal (1 mmol) in dry tetrahydrofuran is cooled under N 2 atmosphere to -78°C and treated dropwise with 1.2 mmol of cyclopentylmagnesium chloride (2.0 M in diethylether). After 2 h, the solution is neutralized, extracted with ether, washed with saturated brine, dried over MgSO 4 , and concentrated in vacuo. Silica gel chromatography using hexane/ethyl acetate gives the desired compound.
- Example 111 N-(3-Methylbutyl)-2-(2-(t-butyloxycarbonylamino)- 1-hydroxy-3-phenylpropyl) cyclopentane-1-carboxamide.
- a mixture of the resultant compound of Example 6 and 10% palladium on carbon in methanol is shaken under four atmospheres of H 2 for 4 h. Filtration and concentration of the resulting solution gives the desired compound.
- Example 115 (3S, 4S)-3-Hydroxy-4-tert-butyloxycarbonylamino- 5-cyclohexyl-1-pentene.
- methylene chloride 20 ml
- di-tert-butyldicarbonate 1.93 g, 8.84 mmol
- the mixture was stirred for 14 h, diluted with ethyl acetate, washed sequentially with 0.5 M H 3 PO 4 , saturated NaHCO 3 solution and brine, then dried over Na 2 SO 4 and evaporated to afford 2.51 g (100%) of the desired compound.
- Example 116 (3S, 4S)-3-Methoxyethoxymethoxy-4-tert- butyloxycarbonylamino-5-cyclohexyl-1-pentene.
- diisopropyl ethylamine (4.60 ml, 26.4 mmol)
- methoxyethoxy chloromethane (3.00 ml, 26.3 mmol).
- the mixture was concentrated, diluted with ethyl acetate, washed with 0.5 M H 3 PO 4 , saturated NaHCO 3 solution, then brine, dried over Na 2 SO 4 , and evaporated. Chromatography on silica gel with ethyl acetate/hexane mixtures afforded 2.63 g (80%) of the desired product as an oil.
- Example 117 (2RS, 3R, 4S)-3-Methoxyethoxymethoxy-4-tert- butyloxycarbonylamino-5-cyclohexyl-1,2-oxopentane.
- To the resultant compound from Example 116 (5.41 g, 14.56 mmol) in methylene chloride (50 ml) was added 3-chloroperbenzoic acid (6.28 g).
- Example 119 (2'S,1'R,5S)-3-Methoxy-5-(1'-methoxyethoxymethoxy-2'- tert-butyloxycarbonylamino-3'-cyclohexylpropyl)- oxazolidin-2-one.
- Example 120 (2 'S, 1 'R.5S)-3-(Benzyloxycarbonylmethylamino)-5- (1'-methoxyethoxymethoxy)-2'-tert-butyloxycarbonylamino- 3'-cyclohexylpropyl)-oxazolidin-2-one. Prepared from the resultant compound of Example 117 using the procedure of Example 118 and replacing the ethyl amine with one equivalent of 1-methyl-1-benzyloxycarbonylhydrazine.
- Example 116 To the resultant compound from Example 116 (1.00 g, 2.69 mmol) in tetrahydrofuran (20 ml) at 0°C was added osmium tetroxide (0.75 ml of a 2.5% solution in tert-butanol) and N-methylmorpholine N-oxide (347 mg, 2.95 mmol). The mixture was stirred at room temperature 16 h, diluted with ethyl acetate, washed with NaHSO 3 solution, saturated NaHCO 3 solution and brine, then dried over Na 2 SO 4 and evaporated. Chromatography of the residue on silica gel with methanol/methylene chloride mixtures provided 887 mg (81%) of the desired product.
- Example 124 (2'S, 1'R, 5S)-3-Ethyl-5-(1 , -methoxyethoxymethoxy-2'- tert-butyloxycarbonylamino-3'-cyclohexylpropyl)- imidazolidin-2-one.
- Example 125 (3S, 4R, 5S)-3-Hydroxy-4-methoxyethoxymethoxy-5-tert- butyloxycarbonylamino-6-cyclohexylhexane nitrile.
- potassium cyanide 320 mg, 4.91 mmol
- the mixture was stirred for 32 h, concentrated, diluted with ethyl acetate, washed with water and brine, then dried over Na 2 SO 4 and evaporated. Chromatography on silica gel with 2:1 hexane/ethyl acetate afforded 209 mg (31%) of the desired 3S-isomer as a solid followed by 150 mg (22%) of the 3R-isomer.
- Example 127 ( 6S, 1'R,2'S)-3-Aza-2-oxo-6-(1'-methoxyethoxymethoxy- 2'-tert-butyloxycarbonylamino-3'- cyclchexylpropyl) tetrahydropyran.
- the resultant compound from Example 126 (59.0 mg, 0.141 mmol) in methylene chloride (2 ml) at 0°C was treated with triethylamine (100 ) 1, 0.71 mmol) then phosgene in toluene (0.22 mmol in 180 ) 1).
- Example 128 (2'S,1'R,4S)-2-Oxo-4-(1'-methoxyethoxymethoxy-2'- tert-butyloxycarbonylamino-3'-cyclohexylpropyl)- dioxolane.
- the resultant compound of Example 121 was treated according to the procedure of Example 127 to provide the desired product as an oil.
- Example 129 (3R, 4R, 5S)-1-Amino-3-hvdroxy-4-methoxyethoxymethoxy-5- tert-butyloxycarbonylamino-6-cyclohexylhexane.
- the resultant 3R-isomer from Example 125 was treated according to the procedure for Example 126 to provide the desired product.
- Example 129 The resultant compound from Example 129 was treated according to the procedure for Example 127 except that the phosgene in toluene was replaced with benzyl chloroformate to provide the desired product.
- Example 131 (3S,4R,5S)-1-Benzyloxycarbonylamino-3-azido- 4-methoxyethoxymethoxy-5-tert-butyloxycarbonylamino- 6-cyclohoxylpentane.
- the resultant compound from Example 130 was treated according to the procedure of Example 123 to provide the desired product.
- Example 132 (4S,1'R,2'S)-3-Aza-4-(1'-methoxyethoxymethoxy-2'- tert-butyloxycarbonylamino-3'-cyclohexylpropyl)- piperidin-2-one.
- the resultant compound from Example 131 was treated according to the procedure of Example 124 to provide the desired product.
- Example 133 (2S, 3R, 4S)-1-(Benzyloxycarbonylamino) methylamino- 2-hydroxy-3-methoxyethoxymethoxy-4-tert- butyloxycarbonylamino-5-cyclohexylpentane.
- the desired product was isolated by chromatography on silica gel.
- Example 134 (2S, 3R, 4S)-1-(Amino)methylamino-2-hydroxy- 3-methoxyethoxymethoxy-4-tert-butyloxycarbonylamino- 5-cyclohexylpentane.
- the resultant compound from Example 133 and an equal weight of 10% palladium on carbon in methanol were stirred under a hydrogen atmosphere for 6 h.
- the mixture was filtered and evaporated to provide the desired product.
- Example 135 ( 6S, 1'R,2'S)-3,4-Diaza-2-oxo-4-methyl-6- (1'-methoxyethoxymethoxy-2'-tert-butyloxycarbonylamino- 3'-cyclohexylpropyl) tetrahydropyran.
- the resultant compound from Example 134 was treated according to the procedure of Example 118 to provide the desired product.
- Example 136 N-Benzyloxycarbonyl-2-aminoethanol.
- benzyl chloroformate 10.0 ml, 70 mmol.
- the mixture was stirred at 0°C for 30 min, then at room temperature for 1 h, poured into ethyl acetate, washed with 2 M HCl, saturated NaHCO 3 solution, and brine, then dried over Na 2 SO 4 and evaporated to provide 12.91 g (94%) of the desired compound as a white solid.
- 1 H NMR (CDCl 3 ,TMS) ⁇ 7.47 (m, 5H) , 5.11 (s,2H), 3.73 (m,2H), 3.38 (m, 2H).
- Example 137 1-Methoxymethoxy-2-benzyloxycarbonylaminoethane. To the resultant compound from Example 136 (12.91 g, 66.1 mmol) in methylene chloride (100 ml) was added diisopropylethylamine (24.0 ml, 138 mmol) and chloromethylmethylether (10.0 ml, 132 mmol). After 4 h the mixture was evaporated, dissolved in ethyl acetate, washed with 0.5 M H 3 PO 4 , saturated NaHCO 3 solution, and brine, then dried over Na 2 SO 4 , and evaporated to afford 15.27 g (97%) of the desired product as an oil.
- Example 138 1-Methoxymethoxy-2-aminoethane.
- the resultant compound from Example 137 (7.60 g, 31.2 mmol) and 10% palladium on carbon (3 g) in methanol (60 ml) were stirred under a hydrogen atmosphere for 24 h. The mixture was filtered, evaporated and distilled to afford 2.02 g (60%) of the desired product as an oil.
- Example 139 (2 'S,1'R,5S)-3-(2-Methoxymethoxyethyl)-5'- (1'-methoxyethoxymethoxy-2'-tert-butyloxycarbonylamino- 3'-cyclohexylpropyl)-oxazolidin-2-one.
- Example 117 The resultant compound from Example 117 was treated accordingly to the procedure for Example 118 except that the ethyl amine was replaced with three equivalents of the resultant compound from Example 138 to provide the desired product as an oil.
- Example 140 (S)-t-Butyloxycarbonylamino-1-cyclohexyl- 6-methylhept-3-ene.
- Boc-cyclohexylalanine methyl ester 40 g, 140 mmol
- diisobutylaluminum hydride 130 M%, 1.5 M solution in toluene, 121.4 ml
- the -78°C aldehyde solution prepared above was then added via cannula. After stirring at -78°C for 15 minutes, the mixture was allowed to slowly warm to room temperature and then heated to 40°C for 12 hours. The mixture was then cooled to room temperature and quenched with methanol (7.65 ml) followed by aqueous Rochelle salts (100 ml saturated solution and 500 ml H 2 O). The mixture was then extracted with ethyl acetate (2x). The combined extracts were washed with water and brine.
- Example 141 2 (S)-t-Butyloxycarbonylamino-1-cyclohexyl-3,4-dihydroxy- 6-methylheptane : The 3 (R) 4 (S), 3 (S) 4 (S), 3 (R) 4 (R), and 3(S)4(R) Diastereomers.
- Example 140 To a solution of the resultant compound of Example 140 (8.50, 27.5 mmol) in dry THF (150 ml) were added OsO 4 (2.8 ml of a 2.5% solution in t-butanol and N-methylmorpholine N-oxide (9.28 g, 68.7 mmol). After 4 days the mixture was partitioned between ether (200 ml) and brine (100 ml). The aqueous layer was back-extracted with ether (2 ⁇ 100 ml), and the combined organic phase was washed with 10% Na 2 SO 3 , 0.1 M H 3 PO 4 , and brine. Drying (MgSO 4 ) and evaporating provided a residue (10.81 g) which was chromatographed on silica gel to elute a 60% yield of the 4 diols in the following order.
- OsO 4 2.8 ml of a 2.5% solution in t-butanol and N-methylmorpholine N-oxid
- Example 142 2-t-Butyloxycarbonylamino-1-cyclohexylbut-3-ene.
- methyltriphenyl phosphonium bromide 10.97 g, 30.70 mmol
- n-butyllithium (19.8 ml of a 1.55 M hexane solution) dropwise over the course of 5 min.
- the -78°C bath was replaced with a 0°C bath for .5 h, at which time the resulting orange solution was cooled again to -78°C.
- Example 143 3-t-Butyloxycarbonylamino-4-cyclohexyl-1,2-oxobutane.
- dichloromethane 20 ml
- MCPBA m-chloroperbenzoic acid
- Example 144 3-t-Butyloxycarbonylamino-4-cyclohexyl- 2-hydroxy-1-isopropylmercaptobutane.
- methanol 8.7 ml
- isopropyl mercaptan 0.87 mmol
- triethylamine 0.87 mmol
- the resultant solution was refluxed for 2 h and then evaporated to give a residue which was chromatographed on 15 g of 40 ) SiO 2 (7/3, hexane/ether) to give the desired compound.
- Mass spectrum: (M+H) + 346.
- Example 146 (3S, 4S)-3-tert-Butyldimethylsilyloxy-4-tert- butoxycarbonylamino-5-cyclohexyl-1-pentene.
- tert- butyldimethylsilyl chloride (0.300 g, 1.99 mmol)
- imidazole 0.269 g, 3.95 mmol.
- Example 147 (2RS,3R,4S)-3-tert-Butyldimethylsilyloxy-4-tert- butoxycarbonylamino-5-cyclohexyl-1,2-oxopentane.
- the resultant compound from Example 146 (0.355 g, 0.893 mmol) in methylene chloride (8 ml) was treated with m-chloroperbenzoic acid (0.758 g, 3.51 mmol) and stirred at ambient temperature for 14 hours.
- the mixture was concentrated, dissolved in ethyl acetate, washed sequentially with cold 10% aqueous Na 2 SO 3 solution, saturated NaHCO 3 solution and brine, and then dried over
- Example 148 (2RS, 3R, 4S)-3-Hydroxy-4-tert-butoxycarbonylamino- 5-cyclohexyl-l,2-oxopentane.
- the resultant compound from Example 147 (2.10 g, 5.07 mmol) was treated with 1 M tetrabutylammonium fluoride in tetrahydrofuran (10 ml) .
- the mixture was stirred at 0°C for 1 hour, poured into ethyl acetate, washed with water and brine, then dried over Na 2 SO 4 and evaporated. Chromatography on silica gel (u.5% methanol in chloroform) afforded 1.3 g (74%) of the desired compound.
- Mass spectrum: (M+H) + 300.
- Example 149 (2S, 3R, 4S) -1-Azido-2,3-dihydroxy-4-tert- butoxycarbonylamino-5-cyclohexylpentane.
- the resultant compound from Example 148 (1.12 g, 3.74 mmol), ammonium chloride (0.374 g, 6.98 mmol) and sodium azide (0.580 g, 8.92 mmol) were refluxed in methanol (25 ml) for 12 hours. The mixture was concentrated, then taken up in ethyl acetate, washed with water and brine, dried over Na 2 SO 4 and evaporated.
- Example 150 1-(t-Butyloxycarbonyl)-2-(2-(t-butyloxycarbonylamino)- 1-hydroxy-3-phenylpropyl) pyrrole.
- a solution of 1-Boc-2-lithiopyrrole (J. Org. Chem. 1981, 46, 157) is cooled to -78°C and treated with Boc-phenylalaninal (Chem. Pharm. Bull. 1982, 30 , 1921). After 0.5 h, the solution is treated with saturated NH 4 Cl, extracted with ether, dried over MgSO 4 , and concentrated to the crude product which is purified by silica gel chromatography to give the desired compound.
- Example 151 5-(2-(t-Butyloxycarbonylamino)-1-hydroxy- 3-phenylprnpyl)-1-methylpyrrazole Using the procedure of Example 150, 5-lithio-1-methylpyrrazole (Justus Liebigs Ann. Chem. 1959, 625, 55) is condensed with Boc-phenylalaninal to give the desired compound.
- Example 152 2-(2-(t-Butyloxycarbonylamino)-1-hydroxy- 3-phenylpropyl)-1-methylimidazole. Using the procedure of Example 150, 2-lithio-1-methylimidazole (J. Org. Chem. 1973, 15., 3762) is condensed with Boc-phenylalaninal to give the desired compound.
- Example 153 5-(2-(t-Butyloxycarbonylamino)-1-hydroxy- 3-phenylpropyl)-1-methyltetrazole. Using the procedure of Example 150, 5-lithio-1-methyltetrazole (Can. J. Chem. 1971, 49, 2139) is condensed with Boc-phenylalaninal to give the desired compound.
- Example 154 2-(2-(t-Butyloxycarbonylamino)-1-hydroxy- 3-phenylpropyl)-4.5-dihydrofuran. Using the procedure of Example 150, 2-lithio-4,5- dihydrofuran (Tetrahedron Lett. 1977, 4187) is condensed with Boc-phenylalaninal to give the desired compound.
- Example 155 6-(2-(t-Butyloxycarbonylamino)-1-hydroxy- 3-phenylpropyl)-3,4-dihydro(2H) pyran. Using the procedure of Example 150, 6-lithio-3,4-dihydro (2H)pyran (Acad. Sci., Paris, Ser. C, 1977, 284. 281) is condensed with Boc-phenylalaninal to give the desired compound.
- Example 156 2-(2-(t-Butyloxycarbonylamino)-1-hydroxy- 3-phenylpropyl)-4,4-dimethyloxazoline. Using the procedure of Example 150, 2-lithio-4,4-dimethyloxazoline (J. Amer. Chem. Soc. 1970, 92, 6676) is condensed with Boc-phenylalaninal to give the desired compound.
- Example 157 5-(2-(t-Butyloxycarbonylamino)-1-hydroxy- 3-phenylpropyl) isothiazole-4-carboxylic Acid. Using the procedure of Example 150, lithium 5-lithioisothiazole-4-carboxylate (J. Chem. Soc. 1964, 446) is condensed with Boc-phenylalaninal to give the desired compound.
- Example 158 2-(2-(t-Butyloxycarbonylamino)-1-hydroxy- 3-phenylpropyl) thiazole. Using the procedure of Example 150, 2-lithiothiazole (Bull. Soc. Chim. Fr. 1962, 2072) is condensed with Boc-phenylalaninal to give the desired compound.
- Example 159 2-(2-(t-Butyloxycarbonylamino)-1-hydroxy- 3-phenylpropyl) tetrahydrofuran. Using the procedure of Example 106, the resultant compound of Example 154 is hydrogenated to give the desired compound.
- Example 160 2-(2-(t-Butyloxycarbonylaminot-1-hydroxy- 3-phenylpropyl) tetrahydro (2H) pyran. Using the procedure of Example 106, the resultant compound of Example 155 is hydrogenated to give the desired compound.
- Example 162 (3S,4S)-4-t-Butyloxycarbonylamino-3-hydroxy- 6-methyl-1-heptene.
- Boc-leucinal 1.5 g, 6.97 mmol
- THF tetrahydrofuran
- a -78°C solution of vinyl magnesium bromide 7 mmol
- anhydrous THF 40 ml
- the organic phase was separated, washed with brine (2 ⁇ 10 ml) and dried (Na 2 SO 4 ). Filtration and evaporation provided an oil which was purified by flash chromatography on silica gel with 7/3 hexane-ether. There was obtained a 53% yield of product, mp 57-59°C.
- Example 163 4 (S) -Isobutyl-5 (S)-vinyl-2-oxazolidinone. To a solution of (3S,4S)-4-t-butyloxycarbonylamino-3-hydroxy-6-methyl-1-heptane (10.5 g, 0.043 mol) in dimethylformamide (DMF) (100 ml) was added sodium hydride
- Example 164 4 (S)-Isobutyl-5(S)-(2-mesyloxyethyl)-2-oxazolidinone.
- 4 (S) -isobutyl-5(S)-vinyl-2-oxazolidinone (4.7 g, 0.028 mol) in THF (20 ml) was added 9-BBN (9-borabicyclo(3.3.1)nonane, 75 ml, 0.0375 mol in THF) by dropwise addition. After stirring for 5 h at room temperature, the reaction was quenched by the addition of water (1 ml).
- Example 166 4 (S)-Isobutyl-5(S)-(2-(phenethylsulfonyl) ethyl)- 2-oxazolidinone.
- 4 (S)-isobutyl-5(S)-(2-(phenethylmercapto) ethyl)-2-oxazolidinone (0.49 g, 1.59 mmol) in methylene chloride (6 ml) was added 0.756 g (3.5 mmol) of in-chloroperoxybenzoic acid. After stirring for 1 h at room temperature, the methylene chloride solution was washed successively with aqueous NaHS03 and aqueous NaOH. The organic layer was dried and evaporated to a solid product.
- Example 168 (3S,4S)-4-Amino-3-hydroxy-6-methyl- 1-phenethylsulfonylheotane. Using the procedure of Example 167 with the resultant compound of Example 166, gave the desired compound, mp 153-154°C.
- Example 170 3-(t-Butyloxycarbonyl)-4-(cyclohexylmethyl)-5-(1,4- dihydroxy-3,3-dimethylbutyl)-2,2-dimethyloxazolidine.
- Example 107 3-(t-Butyloxycarbonyl)-4-(cyclohexylmethyl)-5-(1,4- dihydroxy-3,3-dimethylbutyl)-2,2-dimethyloxazolidine.
- Example 107 3-(t-Butyloxycarbonyl)-4-(cyclohexylmethyl)-5-(1,4- dihydroxy-3,3-dimethylbutyl)-2,2-dimethyloxazolidine.
- Example 171 Boc-Gly-Asn Amide of 5-(2-Amino-1-hydroxy- 3-phenylpropyl)-1-methylpyrrazole.
- the resultant compound of Example 151 is deprotected according to the procedure of Example 2 and coupled to Cbz-asparagine according to the procedure of Example 66. After purification, the resulting compound is hydrogenolyzed according to the procedure of Example 23 and coupled to Boc-glycine according to the mixed anhydride procedure of Example 4 to provide the desired compound.
- Example 172 Cbz-Ser-Ile Amide of 2-(2-Amino-1-hydroxy- 3-phenylpropyl)-1-methylimidazole.
- the resultant compound of Example 152 is deprotected according to the procedure of Example 2 and coupled to Boc-Ile-OH according to the procedure of Example 4. After purification, the resulting compound is deprotected according to the procedure of Example 2 and coupled to Cbz-serine according to the procedure of Example 66 to provide the desired compound.
- Example 173 Boc-Leu-Asn Amide of 5-(2-Amino-1-hydroxy- 3-phenylpropyl)-1-methyltetrazole.
- the resultant compound of Example 153 is deprotected according to the procedure of Example 2 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
- Example 174 Boc-Leu-Asn Amide of 2-(2-Amino-1-hydroxy- 3-phenylpropyl)-4,5-dihydrofuran.
- the resultant compound of Example 154 is deprotected according to the procedure of Example 2 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
- Example 175 Boc-Leu-Asn Amide of 6-(2-Amino-1-hydroxy- 3-phenylpropyl)-3,4-dihydro (2H) pyran.
- the resultant compound of Example 155 is deprotected according to the procedure of Example 2 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
- Example 176 Boc-Leu-Asn Amide of 2-(2-Amino-1-hydroxy- 3-phenylpropyl)-4,4-dimethyloxazoline.
- the resultant compound of Example 156 is deprotected according to the procedure of Example 2 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
- Example 177 Boc-Leu-Asn Amide of 2-(2-Amino-1-hydroxy- 3-phenylpropyl) thiazole.
- the resultant compound of Example 158 is deprotected according to the procedure of Example 2 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
- Example 178 Boc-Gln-Asn Amide of 2-(2-Amino-1-hydroxy- 3-phenylpropyl) tetrahydro (2H) pyran.
- the resultant compound of Example 160 is deprotected according to the procedure of Example 2 and coupled to Cbz-asparagine according to the procedure of Example 66. After purification, the resulting compound is hydrogenolyzed according to the procedure of Example 23 and coupled to Boc-glutamine according to the procedure of Example 66 to provide the desired compound.
- Example 179 Boc-Leu-Asn Amide of 2-(2-Amino-1-hydroxy- 4-methylpentyl)benzothiazole.
- the resultant compound of Example 161 is deprotected according to the procedure of Example 2 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
- Example 167 The resultant compound of Example 167 is coupled to
- Example 181 Boc-Leu-Asn Amide of (3S,45)-4-Amino-3-hydroxy- 6-methyl-1-(phenethylsulfonyl) heptane.
- the resultant compound of Example 168 is coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
- Example 182 Cbz-Leu-Asn Amide of 2-(2-Amino-1-hydroxy- 3-phenylpropyl) tetrahydrofuran.
- the resultant compound of Example 159 is deprotected according to the procedure of Example 2 and coupled to Cbz-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
- Example 183 (5-(3-(Benzyloxycarbonyl) oxazolidin-5-on- 4-yl)pentanoyl)-Leu-Asn Amide of 2-(2-Amino- 1-hydroxy-3-phenylpropyl) tetrahydrofuran.
- the resultant compound of Example 182 is hydrogenolyzed according to the procedure of Example 23 and coupled to the resultant compound of Example 61 according to the procedure of Example 4 to provide the desired compound.
- Example 184 Boc-Leu-Asn Amide of 5-(2-Amino-1-hydroxy- 3-phenylpropyl) isothiazole-4-carboxylic Acid.
- the resultant compound of Example 157 is deprotected according to the procedure of Example 2 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 3 to provide the desired compound.
- Example 185 Boc-Leu-Asn Amide of (2S, 4 S , 5S)-N-(3-Methylbutyl)- 5-amino-6-cyclohexylhexan-2,4-diol-2-carboxamide.
- Example 186 Boc-Leu-Asn Amide of (4S,5S)-N-Methvl-5-amino- 6-phenylhexan-1,4-diol-2-carboxamide.
- (4S,5S)-N-Methyl-5-(t-butyloxycarbonylamino)-6-phenyl-hexan-1,4-diol-2-carboxamide J. Org. Chem. 1986, 51, 3921
- Example 2 was deprotected according to the procedure of Example 2 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to give the desired compound.
- Mass spectrum: (M+H) + 576.
- Example 187 Boc-Leu-Asn Amide of (2S, 4S, 5S)-N-Isobutyl-5-amino- 1-chloro-6-cyclohexylhexan-2,4-diol-2-carboxamide.
- (2R, 4S, 5S)-5-(t-Butyloxycarbonylamino)-6-cyclohexyl-2- (N-isobutylcarboxamido)-1-hexen-4-ol-1,2-oxide J. Med. Chem. 1987, 30, 1978
- Example 188 Boc-Leu-Asn Amide of (2R, 4S, 5S)-N-Isobutyl-5-amino- 1-azido-6-cyclohexylhexan-2,4-diol-2-carboxamide.
- (2R,4S,5S)-N-Isobutyl-1-azido-5-(t-butyloxycarbonyl-amino)-6-cyclohexylhexan-2,4-diol-2-carboxamide J. Med. Chem. 1987, 30, 1978
- Example 2 is deprotected according to the procedure of Example 2 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to give the desired compound.
- Example 189 6-Carboxy-6-(dimethylamino) hexanoyl-Leu-Asn Amide of 2-(2-Amino-1-hydroxy-3-phenylpropyl) tetrahydrofuran.
- the resulting mixture is filtered through Celite, diluted with chloroform, dried over Na 2 SO 4 , and concentrated.
- the crude product is purified by silica gel chromatography to give the desired compound.
- Example 190 6-(Benzyloxycarbonyl) amino-6-carboxyhexanoyl-Leu-Asn Amide of 2-(2-Amino-1-hydroxy-3- phenyloropyl) tetrahydrofuran.
- a solution of 0.042 mmol of the resultant compound of Example 183 in 2 ml of tetrahydrofuran and 1 ml of water is treated with 1.9 mg (0.046 mmol) of lithium hydroxide monohydrate. After completion of the reaction, the solution is acidified with HCl, extracted with chloroform, dried over MgSO 4 , and concentrated to give the desired compound.
- Example 191 6-(Benzyloxycarbonylamino)-6-(methoxycarbonyl) hexanoic Acid.
- a solution of 0.20 g (0.62 mmol) of the resultant compound of Example 61 in methanol was treated with sodium methoxide and stirred at ambient temperature for 2 h.
- the solvent was removed in vacuo, and the residue was acidified with 1N HCl, extracted with chloroform, and concentrated to give 159 mg of the desired compound.
- Example 192 6-(Benzyloxycarbonylamino)-6-(methoxycarbonyl)hexanoyl- Leu-Asn Amide of 2-(2-Amino-1-hydroxy- 3-phenylpropyl) tetrahydrofuran.
- the resultant compound of Example 182 is hydrogenolyzed according to the procedure of Example 23 and coupled to the resultant compound of Example 191 using the mixed anhydride procedure of Example 4 to give the desired compound.
- Example 193 6-Amino-6-(methoxycarbonyl) hexanoyl-Leu-Asn Amide of 2-(2-Amino-1-hydroxy-3-phenylpropyl) tetrahydrofuran.
- the resultant compound of Example 192 is hydrogenated using the procedure of Example 23 to give the desired compound.
- Example 194 6-Amino-6-carboxyhexanoyl-Leu-Asn Amide of 2-(2-Amino- 1-hydroxy-3-phenylpropyl) tetrahydrofuran. Using the procedure of Example 190 with the resultant compound of Example 193 gives a crude lithium salt which is neutralized to pH 7 and extracted with chloroform to give the desired compound.
- Example 195 Cbz-Ile-Ser-OMe.
- H-Ser-OMe-HCl 5.7 g, 36.6 mmol
- DMF dimethylformamide
- 4-methylmorpholine 3.7 g, 36.6 mmol
- Cbz-Ile-OH 9.8 g, 37 mmol
- 1-hydroxybenzotriazole (HOBT) monohydrate 5.4 g, 40 mm
- EDAC N-ethyl-N'- (dimethylaminopropyl) carbodiimide
- Example 196 H-Ile-Ser-OMe HCl
- the resultant compound of Example 195 (3.4 g, 9.29 mmol) was hydrogenated at 4 atm H 2 with 20% Pd/C in methanol/HCl to obtain 2 g (80%) of the desired product.
- 1 H NMR (DMSO, TMS) ⁇ 0.8-1.0 (m, 6H) , 3.65 (s,3H), 3.8 (m, 2H), 4.4 (m, 1H) , 5.3 (t,1H).
- Mass spectrum: (M+H) + 233.
- Example 197 Cbz-Phe-Pro-O-t-Bu.
- a mixture of Cbz-Phe-OH (3.89 g, 13 mmol) and H-Pro-O-t-Bu (2 g, 11.7 mmol) in 50 ml anhydrous DMF was added with HOBT monohydrate (2 g, 15 mmol) and EDAC (2.2 g, 11.9 mmol) at 0°C.
- the mixture was stirred at 0-5°C for 3 h and then at room temperature for 16 h.
- the mixture was poured into ethyl acetate, washed with citric acid, dilute NaHCO 3 solution, and then water.
- Example 198 Cbz-Phe- R Pro-OH
- the resultant compound of Example 197 (3.3 g, 7.29 mmol) was dissolved in 300 ml anhydrous tetrahydrofuran (THF) and 14 ml of 1 M BH 3 in THF (14 mmol) was added at - 20°C. After addition was complete, the reaction mixture was stirred at -20°C for 4 h, and at room temperature for 12 h. The reaction mixture was cooled back to -20°C and methanol was added dropwise until H 2 ceased to evolve. The solvent was evaporated under reduced pressure to a residual liquid. Some methanol was added and evaporated again. The residual oil was chromatographed on silica gel* eluting with ethyl acetate:hexane (1:4) to afford 1.4 g (37.6%) of pure product.
- Example 199 Cbz-Phe- R Pro-Ile-Ser-OMe.
- the resultant compounds of Example 198 600 mg, 1.43 mmol) and Example 196 (376 mg, 1.4 mmol) were mixed in 8 ml anhydrous DMF. After cooling to 0°C, 4-methylmorpholine (303 mg, 3.0 mmol) was added followed by HOBT monohydrate (270 mg, 2 mmol) and EDAC (287 mg, 1.5 mmol). The mixture was stirred at 0-5°C for 3 h and at room temperature for 12 h. The mixture was poured into ethyl acetate, washed with dilute NaHCO 3 solution, water, dried, and filtered.
- Example 199 The resultant compound of Example 199 (300 mg, 0.5 mmol) was hydrogenated with 20% Pd/C at 4 atm H2 in methanol/HCl to obtain 180 mg (69.8%) of the deprotected product which was used in the next step without further purification.
- Example 202 Boc-Leu-Asn-Phe- R Pro-NHCH 2 Ph.
- the resultant compound from Example 201 is deprotected and coupled as described in Example 200 to give the desired compound.
- Example 203 Boc-L ⁇ u-Asn-Phe- R Pip-NHCH 2 Ph.
- Cbz Phe- R Tip-OH is prepared starting from (L) - pipecolinic acid t-butyl ester (Pip-O-t-Bu) using the procedures described in Examples 197 and 198. This material is coupled sequentially to benzylamine and then to Boc-Leu-Asn-OH as described in Examples 199 and 200 to give the desired compound.
- Example 204 Boc-Leu-Asn-Phe- R Azd-NHCH 2 Ph.
- Example 198 replacing Pro-O-t-Bu in Examples 197 and 198 with (S)-(-)-2-azetidine carboxylic acid tert-butyl ester (Azd-O-t-Bu) gives Cbz-Phe- R Azd-OH. This is coupled as described in Examples 199 and 200 with benzylamine and Boc-Leu-Asn-OH to give the desired product.
- Example 205 3-(3(R)-(3-(tert-Butyloxycarbonyl)-2,2- dimethyl-4(S)-(cyclohexylmethyl)-5(R)-oxazolidinyl)- 2(S)-chloro-3-hydroxy-1-oxopropyl)-4(S)- (phenylmethyl)-2-oxazolidinone.
- the cooling bath was removed after 5 min, and the resulting mixture was stirred at ambient temperature for 2 hr.
- the mixture was recooled to -78°C, then treated dropwise with a solution of the resultant compound from Example 241 (1.30 g, 3.98 mmol) in 10 ml ether.
- the reaction is quenched with 20 ml 0.5 M aqueous NaHS04 and 30 ml Et 2 O at 0°C.
- the aqueous phase is further extracted with 2 X 20 ml Et 2 O, and the combined organic phases are washed with 20 ml H 2 O, and the organic phase concentrated under reduced pressure.
- aqueous phase was further extracted with CH 2 Cl 2 (2 X 10 ml), and the combined organic phases were washed with 15 ml brine, dried (MgSO 4 ), filtered and concentrated under reduced pressure to produce 109 mg of crude mixture of products (oxazolidinone plus carboxylic acid).
- This mixture was dissolved in 5 mL dry DMF, the solution was cooled to 0° under an argon atmosphere, and a solution of potassium tert-butoxide (0.90 ml, 1.0 M in THF, 0.90 mmol) was introduced into the reaction.
- Example 208 5 (S)-(3-(tert-Butyloxycarbonyl)-2,2-dimethyl-4(S)- (cyclohexylmethyl)-5(R)-oxazolidinyl)-4(R)-(n- butylcarboxamido)-3-ethyl-2-oxazolidinone.
- the resultant compound from Example 207 (34.3 mg, 0.0755 mmol) was coupled to n-butylamine (7.4 mg, 0.10 mmol) to provide the desired compound.
- Example 209 5 (S)-(2(S)-Amino-3-cyclohexyl-1-hydroxypropyl)-4(R)-(n- butylcarboxamido)-3-ethyl-2-oxazolidinone.
- the resultant compound from Example 208 (6.4 mg, 0.013 mmol) was dissolved in 0.6 ml dry CH 2 CI 2 , cooled to -10° (N 2 ), and the resulting solution treated with 0.6 ml trifluoroacetic acid. After 1.5 h at -10° to 0°, the solvent was removed under reduced pressure without warming, then the residue was dissolved in 1 ml THF and 0.5 ml H 2 O.
- the resulting solution was stirred at ambient temperature for 2.5 hr, at which time the solution was concentrated under reduced pressure and the residue partitioned between 15 ml CH 2 CI 2 and 10 ml 1.0 M Na 2 CO 3 .
- the aqueous phase was further extracted (2 X 10 ml CH 2 CI 2 ) 1 and the combined organic phases were washed with 15 ml brine, dried (Na2S04) and concentrated to yield 5.1 mg (109%) of the desired product as a viscous oil.
- the resultant compound of Example 209 is coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to give the desired compound.
- Example 211 3-(3(S)-(3-(tert-Butyloxycarbonyl)-2,2-dimethyl- 4(S)-(cyclohexylmethyl)-5(R)-oxazolidinyl)-2(R)-bromo- 3-hydroxy-1-oxopropyl)-4(R)-(phenylmethyl)- 2-oxazolidinone.
- the boryl enolate derived from the resultant compound from Example 206 is allowed to react with the resultant compound from Example 241, to provide the desired product.
- Example 208 3-(3(S)-(3-(tert-Butyloxycarbonyl)-2,2-dimethyl- 4(S)-(cyclohexylmethyl)-5(R)-oxazolidinyl)-2(R)-bromo- 3-(N-methylcarbamoyloxy)-1-oxopropyl)-4(R)- (phenylmethyl)-2-oxazolidinone.
- the resultant compound from Example 211 is treated with methyl isocyanate to provide the desired compound.
- Example 213 3(S)-(3-(tert-Butyloxycarbonyl)-2,2-dimethyl-4(S)- (cyclohexylmethyl)-5(R)-oxazolidinyl)-2(R)-bromo-3- (N-methylcarbamoyloxy) propanoic acid.
- the resultant compound from Example 212 is hydrolyzed with lithium hydroxide-monohydrate to afford the desired product.
- Example 213 5(R)-(3-(tert-Butyloxycarbonyl)-2,2-dimethyl-4(S)- (cyclohexylmethyl)-5(R)-oxazolidinyl)-4(S)-carboxyl-3- methyl-2-oxazolidinone.
- the resultant compound from Example 213 is cyclized with potassium tert- butoxide in DMF, affording the desired compound.
- reaction is quenched with 1 ml pH 7 phosphate buffer, and the resulting mixture is partitioned between 15 ml CH 2 Cl 2 and 5 ml water.
- the aqueous phase is extracted (2 X 5 ml CH 2 Cl 2 ), and the combined organic phases are washed (5 ml saturated aqueous CuSO 4 , 5 ml water, 5 ml brine), dried over MgSO 4 , filtered and concentrated under reduced pressure. The residue is further dried under high vacuum to afford the crude mesylate.
- the mesylate is then dissolved in 2 ml DMF, cooled to 0°C and treated with sodium hydride (16 mg, 0.40 mmol). The reaction mixture is allowed to warm to room temperature and stir until TLC indicates complete reaction.
- the DMF is removed under high vacuum, and the residue is partitioned between 15 ml CH 2 Cl 2 and 5 ml H 2 O.
- the aqueous phase is extracted (2 X 5 ml CH 2 Cl 2 ), and the combined organic phases are washed with 5 ml brine, dried over MgSO 4 , and! the filtrate concentrated under reduced pressure. Purification by column chromatography produces the desired compound.
- Example 216 3-(3(R)-(3-(tert-Butyloxycarbonyl)-2,2-dimethyl- 4(S)-(4-methoxyphenyl) methyl)-5(R)-oxazolidinyl)- 3-hydroxy-2(R)-(2-propenyl)-1-oxooropyl)-4(R)-methyl- 5(S)-phenyl-2-oxazolidinone.
- the resultant compound from Example 243 is allowed to react with the boryl enolate derived from the resultant compound from Example 215 to afford the desired product.
- a solution of the resultant compound from Example 220 (292 mg, 0.500 mmol) in 2 ml ether is treated with 2 ml of saturated aqueous NaHCO 3 , cooled to 0°C, and a solution of iodine (127 mg, 0.500 mmol) in 0.5 ml ether.
- the iodomethyl-tetrahydrofuran is isolated by extraction with Et 2 O, and the ether extract is washed with 5% aqueous NaHCO 3 , brine, then concentrated under reduced pressure.
- Example 2 (R)-(3-(tert-Butyloxycarbonyl)-2,2-dimethyl-4(S)- (cyclohexylmethyl)-5(R)-oxazolidinyl)-5(R,S)-methyl- 2,3,4,5-tetrahydrofuran-3(R)-carboxylic Acid.
- the resultant compound from Example 221 is hydrolyzed with lithium hydroxide-monohydrate to produce the desired compound.
- a solution of the resultant compound from Example 216 (175 mg, 0.299 mmol) is dissolved in 0.7 ml dry CH 2 Cl 2 and 0.7 ml dry methanol, cooled to 0°C under a nitrogen atmosphere, and treated with a mixture resulting from the addition of methylmagnesium bromide (1.31 mmol) to 2.0 ml methanol.
- the resulting mixture is stirred at 0°C for 3 hr, and at room temperature for 0.5 hr.
- the mixture is quenched with pH 7 phosphate buffer and extracted with CH 2 Cl 2 (4 X 25 ml).
- the combined organic phases were dried over MgSO 4 , and the filtrate is concentrated in vacuo. The residue is purified by column chromatography to afford the desired compound.
- Example 225 Methyl 3 (R)-(3-(tert-Butyloxycarbonyl)-2,2-dimethyl- 4(S)-(cyclohexylmethyl)-5(R)-oxazolidinyl)-3-hydroxy- 2(R)-(3-hydroxypropyl) propionate.
- the procedure of D.A. Evans and A.E. Weber J. Am. Chem. Soc. 1987, 109, 7151) is adapted.
- To a 0°C suspension of di-cyclohexylborane (1.5 equivalents) in dry CH 2 Cl 2 is added a solution of the resultant compound from Example 224 (1.0 equivalents).
- the cooling bath is removed, and the resulting mixture is stirred at room temperature for 5 hr.
- the mixture is recooled to 0°C and treated with 30% aqueous H 2 O 2 in 1.0 M NaOH. After 1 hr, the mixture is partitioned between H 2 O and CH 2 Cl 2 , then the organic phase dried over MgSO 4 , and the filtrate concentrated under reduced pressure. Purification of the residue by column chromatography affords the desired product.
- Example 226 2(R)-(3-(tert-Butyloxycarbonyl)-2,2-dimethyl-4(S)- (cyclohexylmethyl)-5(R)-oxazolidinyl)-3(R)- (methoxycarbonyl)-2,3,4,5-tetrahydropyran. Using the procedure of Example 218, the resultant compound from Example 225 is cyclized to afford the desired compound.
- Example 210 The resultant compound of Example 210 is coupled to H-Ile-Ser-OMe according to the procedure of Example 66 to give the desired compound.
- Example 227 N-(Boc-Leu-Asn Amide of 5(S)-(2(S)-Amino- 3-cyclohexyl-1(R)-hydroxypropyl)-3-methyl- 2-oxazolidinon-4(R)-carbonyl)- Ile-Ser Methyl Ester.
- the resultant compound of Example 227 is deprotected according to the procedure of Example 2 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to give the desired compound.
- Example 229 5(R)-(3-(tert-Butyloxycarbonyl)-2,2-dimethyl-4(S)- (cyclohexylmethyl)-5(R)-oxazolidinyl)-3-methyl- 4(S)-(N-(2-methylbutyl) carbamoyl)-2-oxazolidinone.
- the resultant compound of Example 214 is coupled to (2-methylbutyl) amine according to the procedure of Example 66 to give the desired compound.
- Example 229 is deprotected according to the procedure of Example 2 and coupled to Cbz-Asn-OH according to the procedure of Example 66. After purification, the above compound is deprotected according to the procedure of Example 23 and coupled to the resultant compound of Example 26 using the mixed anhydride procedure of Example 4 to give the desired compound.
- Example 231 N-(2(R)-(3-(tert-Butyloxycarbonyl)-2,2-dimethyl- 4(S)-(cyclohexylmethyl)-5(R)-oxazolidinyl)-2,3,4,5- tetrahydrofuran-3(R)-carbonyl)-Ile-Ser Methyl Ester.
- the resultant compound of Example 219 is coupled to H- Ile-Ser-OMe according to the procedure of Example 66 to give the desired compound.
- Example 232 N-(2(R)-((3,4-cis-Dihydroxypyrrolidinylcarbonyl)- Leu-Asn Amide of 2(S)-Amino-3-cyclohe ⁇ yl-1(R)- hydroxypropyl)-2,3,4,5-tetrahydrofuran-3(R)- carbonvl)-Ile-Ser Methyl Ester.
- the resultant compound of Example 231 is deprotected according to the procedure of Example 2 and coupled to Cbz-Asn-OH according to the procedure of Example 66. After purification, the above compound is deprotected according to the procedure of Example 23 and coupled to the resultant compound of Example 27 using the procedure of Example 66 to give the desired compound.
- Example 233 N-(2(R)-(3-(tert-Butyloxycarbonyl)-2,2-dimethyl- 4(S)-((4-methoxyphenyl) methyl)-5(R)-oxazolidinyl)- 5-methyl-2,3,4,5-tetrahydrofuran-3(R)-carbonyl)- Ile-Ser Methyl Ester.
- the resultant compound of Example 222 is coupled to H-Ile-Ser-OMe according to the procedure of Example 66 to give the desired compound.
- Example 235 2(R)-(3-(tert-Butyloxycarbonyl)-2,2-dimethyl-4(S)- ((4-hydroxyphenyl) methyl)-5(R)-oxazolidinyl)- 5-methyl-3(R)-(N-(2-methylbutyl) carbamoyl)- 2,3,4,5-tetrahydrofuran.
- the resultant compound of Example 223 is coupled to (2- methylbutyl) amine according to the procedure of Example 66 to give the desired compound.
- Example 236 2 (R)-((3-Benzyloxycarbonylaminopropyl)-Leu-Asn Amide of 2(S)-Amino-1(R)-hydroxy-3- (4-methoxyphenyl) propyl)-5-methyl-3(R)-(N-(2- methylbutyl) carbamoyl)-2,3,4,5-tetrahydrofuran.
- the resultant compound of Example 235 is deprotected according to the procedure of Example 2 and coupled to Cbz-Asn-OH according to the procedure of Example 66. After purification, the above compound is deprotected according to the procedure of Example 23 and coupled to the resultant compound of Example 50 using the procedure of Example 66 to give the desired compound.
- Example 237 2(R)-(Cbz-Sar-Leu-Asn Amide of 2(S)-Amino- 3-cyclohexvl-1(R)-hydroxypropyl)-3(R)- methoxycarbonyl-2,3,4,5-tetrahydropyran.
- the resultant compound of Example 226 is deprotected according to the procedure of Example 2 and coupled to Cbz-Asn-OH according to the procedure of Example 66. After purification, the above compound is deprotected according to the procedure of Example 23 and coupled to the resultant compound of Example 52 using the mixed anhydride procedure of Example 4 to give the desired compound.
- Example 236 is deprotected according to the procedure of Example 23 to give the desired compound.
- Example 237 (R)-(H-Sar-Leu-Asn Amide of 2 (S)-Amino-3-cyclohexyl- 1(R)-hydroxypropyl)-3(R)-methoxycarbonyl-2,3,4,5- tetrahydropyran.
- the resultant compound of Example 237 is deprotected according to the procedure of Example 23 to give the desired compound.
- Example 240 3-(t-Butyloxycarbonyl)-4-(cyclohexylmethyl)- 2,2-dimethyl-5-vinyloxazolidine.
- the procedure of S. Thaisrivong J. Med. Chem. 1987, 30, 976) was employed.
- a solution of 40 g of the resultant compound of Example 112 and 102 g of 2-methoxypropene in 250 ml of dichloromethane was stirred at room temperature.
- Solid pyridinium p-toluenesulfonate (PPTS) (177 g) was added slowly to the reaction mixture. After addition was complete, the reaction was stirred for 1 h and neutralized by addition of solid sodium bicarbonate. The solids were filtered and the filtrate was concentrated.
- PPTS Solid pyridinium p-toluenesulfonate
- Example 241 3-(t-Butyloxycarbonyl)-4-(cyclohexylmethyl)-2,2- dimethyloxazolidine-5-carboxaldehyde.
- the reaction mixture was cannulated into a suspension of 8 g zinc dust, 8 ml glacial acetic acid, 200 ml water, and 200 ml of methanol cooled to -45°C.
- Example 242 3-(t-Butyloxycarbonyl)-2,2-dimethyl-4-(phenylmethyl)- oxazolidine-5-carboxaldehyde. Using the procedures of Examples 112, 240, and 241 but replacing Boc-cyclohexylalanine methyl ester with Boc-phenylalanine methyl ester gives the desired compound.
- Example 243 3- (t-Butyloxycarbonyl)-2,2-dimethyl-4- ((4-methoxyphenyl)methyl)-oxazolidine- 5-carboxaldehyde. Using the procedures of Examples 112, 240, and 241 but replacing Boc-cyclohexylalanine methyl ester with Boc-(4-methoxy)phenylalanine methyl ester gives the desired compound.
- Example 246 3-(3(R)-(3-(tert-Butyloxycarbonyl)-2,2-dimethyl- 4(S)-cyclohexylmethyl-5(R)-oxazolidinyl)-2(S),3- dihydroxy-1-oxopropyl)-4(S)-isopropyl- 2-oxazolidinone.
- a solution of the resultant compound from Example 245 (0.5 mmol) in 5 ml ethanol is exposed to 1 atmosphere of hydrogen gas in the presence of 0.5 g of 10% palladium on carbon at ambient temperature. The mixture is stirred for 18 hr, then filtered through a pad of celite, and the filtrate is concentrated under reduced pressure to give the desired product.
- Example 247 3-((5(S)-(3-(tert-Butyloxycarbonyl)-2,2-dimethyl- 4(S)-cyclohexylmethyl-5(R)-oxazolidinyl)-1,3-dioxolan- 2-one-4(S)-yl)carbonyl)-4(S)-isopropyl- 2-oxazolidinone.
- the solution is cooled, diluted with 40 ml CH 2 Cl 2 , and washed with 20 ml 0:1 M NaHSO 4 .
- the organic phase is washed with 20 ml brine, dried (Na 2 SO 4 ), and the filtrate is concentrated under reduced pressure to afford the desired product.
- Example 249 (4R, 5S)-4-Methyl-5-phenylpxazolidine-2-one.
- the flask was fitted for distillation through a 12" Vigreux column and placed in an oil bath pre-equilibrated to 150°C. The stirred solution was heated until ethanol distillation ceased (overnight).
- Example 250 5 (S)-(3-(tert-Butyloxycarbonyl)-2.2-dimethyl-4(S)- benzyl-5(R)-oxazolidinyl)-4(R)-carboxy-1,3- dioxolan-2-one.
- Example 251 3-(Bromoacetyl)-4(S)-isopropyl-2-oxazolidinone. Using the procedure of Example 244, 4 (S) -isopropyl-2-oxazolidinone was acylated with bromoacetyl bromide to give the desired product.
- 1 H NMR (CDCl 3 ) ⁇ 0.92 (d,3H), 0.95 (d,3H), 2.42 (m, 1H) , 4.27 (dd, 1H), 4.35 (t,1H), 4.43 (d,1H), 4.47 (m,1H), 4.61 (d, 1H).
- Mass spectrum: (M+NH 4 ) + 267.
- Example 253 3-(5(S)-(3-(tert-Butyloxycarbonyl)-2,2-dimethyl- 4(S)-cyclohexylmethyl-5(R)-oxazolidinyl)- 2-thionooxazolidinyl)-4(S)-carbonyl)- (4S) -isopropyl-2-oxazolidinone.
- the procedure of D.A. Evans and A.E. Weber J. Am. Chem. Soc. 1987, 109, 7151) is adapted.
- Example 224 Using the procedure of Example 224 with the resultant compound of Example 253 gives the desired compound.
- Example 255 5 (S)-(3-(tert-Butyloxycarbonyl)-2,2-dimethyl- 4 (S)-cyclohexylmethyl-5(R)-oxazolidinyl)- 4 (S)-methoxycarbonyl-2-oxazolidinone.
- the procedure of D. Hoppe and R. Follmann (Chem. Ber. 1976, 109. 3047) is adapted.
- a 1 M solution of the resultant compound from Example 254 in formic acid is cooled to 0°C and treated with 2 equivalents of 30% aqueous H 2 O 2 .
- Example 248 is coupled to H-Ile-Ser-OMe according to the procedure of Example 66.
- the resulting compound from that coupling is deprotected according to the procedure of Example 2 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to give the desired compound.
- Example 257 N- (Boc-Leu-Asn Amide of 5 (S)-(2(S)-Amino- 3-phenyl-1 (R)-hydroxypropyl)-1,3-dioxolan-2-on- 4(S)-carbonyl)-Ile-Ser Methyl Ester.
- the resultant compound of Example 250 is. coupled to H-Ile-Ser-OMe according to the procedure of Example 66.
- the resulting compound from that coupling is deprotected according to the procedure of Example 2 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to give the desired compound.
- Example 258 Boc-Leu-Asn Amide of 5 (S) - (2 (S) -Amino-3-cyclohexyl- 1 (R) -hydroxypropyl)-4(S)-(methoxycarbonyl)-2- thionooxazolidine.
- the resultant compound of Example 254 is deprotected according to the procedure of Example 2 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to give the desired compound.
- Example 259 Boc-Leu-Asn Amide of 5 (S)-(2(S)-Amino-3-cyclohexyl- 1(R)-hydroxypropyl)-4(S)-(methoxycarbonyl)- oxazolidine-2-one.
- the resultant compound of Example 255 is deprotected according to the procedure of Example 2 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to give the desired compound.
- Example 260 (N-Methyl-2,3-dihydroxypropylamino) carbonyl-Leu-Asn Amide of N-(3-Methylbutyl)-2-(2-amino- 1-hydroxy-3-phenylpropyl) furan-3-carboxamide.
- the resultant compound of Example 102 is deprotected according to the procedure of Example 2 and coupled to Cbz-Asn-OH according to the procedure of Example 66. After purification, the above compound is deprotected according to the procedure of Example 23 and coupled to the resultant compound of Example 39 using the procedure of Example 66 to give the desired compound.
- Example 261 5-(Methoxycarbonyl)pentanoyl-Leu-Asn Amide of N-(3-Methylbutyl)-2-(2-amino-1-hydroxy- 3-phenylpropyl) furan-3-carboxamide.
- the resultant compound of Example 102 is deprotected according to the procedure of Example 2 and coupled to Cbz-Asn-OH according to the procedure of Example 66. After purification, the above compound is deprotected according to the procedure of Example 23 and coupled to the resultant compound of Example 41 using the mixed anhydride procedure of Example 4 to give the desired compound.
- Example 261 The resultant compound of Example 261 is hydrolyzed according to the procedure of Example 9 to provide the desired compound.
- Example 263 2-Methylpropanoyl-Leu-Asn Amide of N-(3-Methylbutyl)-2-(2-amino-1-hydroxy- 3-phenylpropyl) furan-3-carboxamide.
- the resultant compound of Example 102 is deprotected according to the procedure of Example 2 and coupled to Cbz-Asn-OH according to the procedure of Example 66. After purification, the above compound is deprotected according to the procedure of Example 23 and coupled to the resultant compound of Example 42 using the mixed anhydride procedure of Example 4 to give the desired compound.
- Example 264 (2R)-2-Isobutyl-3-(N-methyl-N- (2-methoxyethoxymethoxyethyl) aminocarbonyl) propannyl- Asn Amide of N-(3-Methylbutyl)-2-(2-amino- 1-hydroxy-3-phenylpropyl) furan-3-carboxamids.
- the resultant compound of Example 102 is deprotected according to the procedure of Example 2 and coupled to Cbz-Asn-OH according to the procedure of Example 66. After purification, the above compound is deprotected according to the procedure of Example 23 and coupled to the. resultant compound of Example 47 using the mixed anhydride procedure of Example 4 to give the desired compound.
- Example 265 (3-Hydroxypropyloxycarbonyl)-Leu-Asn Amide of N-(3-Methylbutyl)-2-(2-amino-1-hydroxy- 3-phenylpropyl) furan-3-carboxamide.
- the resultant compound of Example 102 is deprotected according to the procedure of Example 2 and coupled to Cbz-Asn-OH according to the procedure of Example 66. After purification, the above compound is deprotected according to the procedure of Example 23 and coupled to the resultant compound of Example 59 using the procedure of Example 66 to give the desired compound.
- Example 102 (2,3-Dihydroxypropyloxycarbonyl)-Leu-Asn Amide of N-(3-Methylbutyl)-2-(2-amino-1-hydroxy- 3-phenylpropyl) furan-3-carboxamide.
- the resultant compound of Example 102 is deprotected according to the procedure of Example 2 and coupled to Cbz-Asn-OH according to the procedure of Example 66. After purification, the above compound is deprotected according to the procedure of Example 23 and coupled to the resultant compound of Example 64 using the procedure of Example 66 to give the desired compound.
- Example 269 2-(3-Phenyl-2-azido-1-hydroxyprop- 1-yl) cyclopentanecarboxylic Acid Methvl Ester.
- Example 270 2-(3-Phenyl-2-t-butyloxycarbonylamino- 1-hydroxyprop-1-yl) cyclopentanecarboxylic Acid Methyl Ester.
- a stirred solution of 30.3 g (100 mmol) of the resultant compound of Example 269 in 500 ml of MeOH is hydrogenated over 1 g of 10% Pd-C.
- the reaction is degassed, the catalyst removed by filtration, and the filtrate treated with a slight excess of di-t-butyldicarbonate. Removal of the solvent and chromatography of the residue on silica gel affords the desired product.
- Example 271 2-(3-Phenyl-2-t-butyloxycarbonylamino- 1-t-butyldimethylsilyloxyprop- 1-yl) cyclopentanecarboxylic Acid Methyl Ester.
- To a stirred solution of 37.7 g (100 mmol) of the resultant compound of Example 270 in 500 ml of dichloromethane is added 23.0 ml of t-butyldimethylsilyl trifluoromethane sulfonate and 12.8 ml of 2,6-lutidine. After 6 h, the solution is washed with water, dried over MgSO 4 , and concentrated. Chromatography of the residue on silica gel affords the desired product.
- Example 274 2-(3-Phenyl-2-t-butyloxycarbonylamino- 1-t-butyldimethylsilyloxyprop- 1-yl) cyclohexanecarboxylic Acid Methyl Ester. Using the procedures of Examples 267, 268, 269, 270, and 271 but substituting 2-formylcyclohexanecarboxylic acid methyl ester for 2-formylcyclopentanecarboxylic methyl ester affords the desired product.
- Example 275 2-(3-Phenyl-2-t-butyloxycarbonylamino- 1-t-butyldimethylsilyloxyprop- 1-yl)cyclobutanecarboxylic Acid Methyl Ester. Using the procedures of Examples 267, 268, 269, 270, and 271 but substituting 2-formylcyclobutanecarboxylic acid methyl ester for 2-formylcyclopentanecarboxylic acid methyl ester affords the desired product.
- Example 276 2-(3-Phenyl-2-t-butyloxycarbonylamino- 1-t-butyldimethylsilyloxyprop- 1-yl)benzenecarboxylic Acid. To a stirred solution of 2.01 g (10 mmol) of 2-bromobenzoic acid in 100 ml of THF at -100°C is added 20 ml of 1 M n-BuLi in hexane. After 15 m, a solution of 2.49 g (10 mmol) N-t-butyloxycarbonylphenylalaninal is added, and the solution allowed to warm to -78°C.
- Example 277 2- (3-Phenyl-2-t-butyloxycarbonylamino- 1-t-butyldimethylsilyloxyprop- 1-yl) cyclopent-1-enecarboxylic Acid. Using the procedure described in Example 276, but substituting 2-bromocyclopent-1-enecarboxylic acid for 2-bromobenzoic acid affords the desired product .
- Example 279 6-Phenyl-5-t-butyloxycarbonylamino- 4-t-butyldimethylsilyloxy-2-hexenoic Acid. Using the procedure described in Example 276, but substituting 2-bromo ⁇ ropenoic acid for 2-bromobenzoic acid affords the desired product.
- Example 280 2-(3-(4-Benzyloxy-1-phenyl)-2-t-butoxycarbonylamino- 1-t-butyldimethylsilyloxvprop-1-yl) cyclopent- 1-enecarboxylic Acid. Using the procedure described in Example 277, but substituting N-t-butyloxycarbonyl-0-benzyltyrosinal for N-t-butyloxycarbonylphenylalaninal affords the desired product.
- Example 281 2-(3-Pheny1-2-t-butyloxycarbonylamino-1-azidoprop- 1-yl) cyclopentanecarboxylic Acid Methyl Ester.
- Example 282 ( 4-Morpholinyl) carbonyl)-Leu-Asn-Amide of 2-(3-Phenyl-2-amino-1-hydroxyprop- 1-yl) cyclopentanecarboxylic Acid Methyl Ester.
- the resultant compound of Example 271 is deprotected according to the procedure of Example 2 and coupled to Cbz-asparagine using the carbodiimide coupling procedure of Example 66.
- the resulting compound is then hydrogenolyzed according to the procedure of Example 23 and then coupled to the resultant compound of Example 9 using the mixed anhydride method of Example 4 to provide the desired compound.
- Example 283 Cbz-(( ⁇ , ⁇ -di-Me) ⁇ -Ala)-Leu-Asn-Amide of 2- (3-(4-hydroxyphenyl)-2-amino-1-hydroxyprop- 1-yl) cyclopentanecarboxylic Acid Methyl Ester.
- the resultant compound of Example 272 is deprotected according to the procedure of Example 2 and coupled to Cbz-asparagine using the carbodiimide coupling procedure of Example 66.
- the resulting compound is then hydrogenolyzed according to the procedure of Example 23 and then coupled to the resultant compound of Example 12 using the mixed anhydride method of Example 4 to provide the desired compound.
- Example 284 ( ⁇ , ⁇ -di-Me) ⁇ -Ala)-Leu-Asn-Amide of 2-(3- Phenyl-2-amino-1-hydroxyprop-yl) cyclopropanecarboxylic
- Example 273 The resultant compound of Example 273 is deprotected according to the procedure of Example 2 and coupled to Cbz-asparagine using the carbodiimide coupling procedure of Example 66. The resulting compound is then hydrogenolyzed according to the procedure of Example 23 and then coupled to the resultant compound of Example 12 using the mixed anhydride method of Example 4. The resultant compound is then hydrogenolyzed according to the procedure of Example 23 to afford the desired compound.
- Example 274 The resultant compound of Example 274 is deprotected according to the procedure of Example 2 and coupled to Cbz-asparagine using the carbodiimide coupling procedure of Example 66. The resulting compound is then hydrogenolyzed according to the procedure of Example 23 and then coupled to the resultant compound of Example 54 using the procedure of Example 66 to provide the desired compound.
- Example 286 N-((N-Cbz-4-piperidinyl) carbonyl)-Leu-Asn Amide of 2-(3-Phenyl-2-amino-1-hydroxyprop- 1-yl) cyclobutanecarboxylic Acid Methyl Ester.
- the resultant compound of Example 275 is deprotected according to the procedure of Example 2 and coupled to Cbz-asparagine using the carbodiimide coupling procedure of Example 66.
- the resulting compound is then hydrogenolyzed according to the procedure of Example 23 and then coupled to the resultant compound of Example 56 using the mixed anhydride method of Example 4 to provide the desired compound .
- Example 276 The resultant compound of Example 276 is deprotected according to the procedure of Example 2 and coupled to Cbz-asparagine using the carbodiimide coupling procedure of Example 66. The resulting compound is then hydrogenolyzed according to the procedure of Example 23 and then coupled to the resultant compound of Example 56 using the mixed anhydride method of Example 4. The resulting compound is then hydrogenolyzed according to the procedure of Example 23. Treatment of the resulting compound under the conditions of Example 9 effects hydrolysis to afford the desired compound.
- Example 277 The resultant compound of Example 277 is deprotected according to the procedure of Example 2 and coupled to Cbz-asparagine using the carbodiimide coupling procedure of Example 66. The resulting compound is then hydrogenolyzed according to the procedure of Example 23 and then coupled to the resultant compound of Example 63 using the mixed anhydride procedure of Example 4. Treatment of the resulting compound under the conditions of Example 9 effects hydrolysis to provide the desired compound.
- Example 278 The resultant compound of Example 278 is deprotected according to the procedure of Example 2 and coupled to Cbz-asparagine using the carbodiimide coupling procedure of Example 66. The resulting compound is then hydrogenolyzed according to the procedure of Example 23 and then coupled to the resultant compound of Example 63 using the mixed anhydride method of Example 4. Hydrogenolysis of the resulting compound according to the procedure of Example 23 followed by treatment under the conditions of Example 9 effects hydrolysis to afford the desired compound.
- Example 290 Boc-Gln-Ala Amide of 6-Phenyl-5-amino-4-hydroxy- 2-hexenoic Acid.
- the resultant compound of Example 279 is deprotected according to the procedure of Example 2 and coupled to Boc-alanine using the mixed anhydride coupling procedure of Example 4.
- the resulting compound is then deprotected according to the procedure of Example 2 and then coupled to Boc-glutamine using the carbodiimide coupling procedure of Example 66.
- Treatment of the resulting compound under the conditions of Example 9 effects hydrolysis to afford the desired compound.
- Example 291 Boc-Leu-Asn Amide of 2 (3-(4-Hydroxyphenyl)-2-amino-1- hydroxypr ⁇ p-1-yl) cyclopent-1-enecarboxylic Acid.
- the resultant compound of Example 280 is deprotected according to the procedure of Example 2 and coupled to the resultant compound of Example 3 using the carbodiimide coupling procedure of Example 66.
- Treatment of the resulting compound under the conditions of Example 9 effects hydrolysis to afford the desired compound.
- Example 292 Boc-Leu-Asn-3-Amide of 2-(3-Phenvl-2,3-diaminoprop- 1-yl)cyclopentanecarboxylic Acid Methvl Ester.
- the resultant compound of Example 281 is deprotected according to the procedure of Example 2 and coupled to Boc—Leu-Asn-OH using the carbodiimide coupling procedure of Example 66. Hydrogenolysis under the conditions of Example 23 affords the desired compound.
- Example 106 Cbz-Leu-Asn Amide of 5 (S)-(2(S)-Amino-3-cyclohexyl- 1(R)-hydroxy)-3(S)-methyl-2,3,4,5-tetrahydrofuran- 2-one.
- the resultant compound of Example 106 was deprotected according to the procedure of Example 2 and coupled to Cbz-Leu-Asn-OH according to the procedure of Example 66 to provide, after silica gel chromatography using 5% methanol in chloroform, a 70% yield of the desired compound.
- Example 295 N-(5-(Methoxycarbonyl)pentanoyl)-Leu-Asn Amide of 5 (S) - (2 (S) -Amino-3-cyclohexyl-1(R)-hydroxy)-3(S)- methyl-2,3.4.5-tetrahydrofuran-2-one.
- the resultant compound of Example 294 (0.51 g, 0.83 mmol) was added to a mixture of 0.06 g of 10% palladium on carbon in 15 ml of methanol and stirred under 1 atmosphere of H 2 for 24 h.
- the mixture was filtered through Celite and concentrated to the crude amine, a portion (0.30 g, 0.62 mmol) of which was taken up in 10 ml of dichloromethane and 0.5 ml of dimethylformamide, treated with 0.20 g (0.80 mmol) of N-(5- (methoxycarbonyl)pentanoyloxy) succinimide, and stirred at ambient temperature for 16 h.
- the resulting mixture was concentrated in vacuo, taken up in ethyl acetate, washed sequentially with 10% citric acid, water, aqueous NaHCO 3 , and saturated brine, dried over MgSO 4 , and concentrated.
- Example 296 2-(t-Butyloxycarbonylamino)-1,5-diphenylpent-3-ene, A suspension of 20 g (53 mmol) of phenyl 2-(t- butyloxycarbonylamino)-3-phenylpropyl sulfone (Tetrahedron Lett. 1986, 27, 2095) in 500 ml of dry tetrahydrofuran was cooled under inert atmosphere to - 78°C and treated with 65 ml (135 mmol) of n-butyllithium. The resulting suspension was warmed to 0°C and stirred for 5 min during which the solution became homogenous.
- the crude residue was taken up in 500 ml of dry dichloromethane, treated sequentially with 0.8 g (7.3 mmol) of 4-dimethylaminopyridine, 13 mi (93 mmol) of triethylamine, and 7.5 ml (80 mmol) of acetic anhydride.
- the resulting solution was stirred for 2 h at ambient temperature, treated with water, stirred for 10 min, washed sequentially with 10% aqueous citric acid and aqueous NaHCO 3 , dried over MgSO 4 , and concentrated in vacuo.
- the resulting crude mixture was taken up in 500 ml of methanol, cooled to 0°C, and treated with 150 g (0.32 mol) of 5% sodium amalgam.
- Example 296A 160 mg, 0.47 mmol was deprotected according to the procedure of Example 2 and coupled to Ac-Val-Val-OH according to the procedure of Example 66 to give a crude product which was triturated with ether, filtered, and air-dried to give 111 mg (49%) of the desired compound.
- Mass spectrum (M+l)+ 478.
- Example 297 A 1-(2-Furanyl)-1-hydroxy-3-phenyl-2- (triphenylmethyl) aminopropane.
- a solution of 18 mmol of n-butyllithium in 40 ml of tetrahydrofuran/hexane was cooled to -78°C and treated with 1.3 ml (18 mmol) of furan.
- the resulting solution was stirred at -23°C for 4 h, recooled to -78°C, and treated with a solution of 2.35 g (6 mmol) of N-(triphenylmethyl)-phenylalaninal in 20 ml of tetrahydrofuran.
- Example 297B C. Cbz-Leu-Asn Amide of 2-amino-1-(2-tetrahydrofuranyl)- 1-hydroxy-3-phenylpropane.
- the resultant compound of Example 297B (26 mg, 0.08 mmol) was deprotected according to the procedure of Example 2 and coupled to Cbz-Leu-Asn-OH according to the procedure of Example 66 to give, after purification by flash chromatography using 6.5% methanol in chloroform, 34 mg (72%) of the desired compound, m.p. 198-200°C.
- Mass spectrum (M+1) + 583.
- Example 299 A 4-Benzyl-3-(t-butyloxycarbonyl)-2,2-dimpthyl-5- (hydroxymethyl)-oxazolidine.
- a precooled (0°C) solution of sodium borohydride (40 mg, 1.05 mmol) in 2 ml of methanol was treated with a solution of 218 mg (0.68 mmol) of the resultant compound of Example 242 in 3 ml of 1:1 methanol:tetrahydrofuran. After being allowed to stir at ambient temperature for 2 h, the solution was quenched with aqueous NH 4 CI, extracted with ether, washed with 1 N NaOH and saturated brine, dried oyer MgSO 4 , and concentrated.
- Example 299A Cbz-Leu-Asn Amide of 3-Amino-1,2-dihydroxy-4- phenylbutane.
- the resultant compound of Example 299A was deprotected according to the procedure of Example 2 and coupled to Cbz-Leu-Asn-OH according to the procedure of Example 66 to give, after trituration with 2% methanol in chloroform, filtration, washings with chloroform, and air-drying, the desired compound (41 mg, 48%) as a white solid, m.p. 214-215°C.
- Mass spectrum: (M+H) + 543.
- Example 300B (cis) -N-(3-Methylbutyl)-3-(4-benzyl-3-(t- butyloxycarbonyl)-2.2-dimethyl-oxazolidin-5- yl)propenamide.
- the resultant compound of Example 300B was coupled to isoamylamine to give 251 mg (100%) of the desired compound as a colorless oil.
- the resulting suspension was treated with 9 ml of dry tetrahydrofuran, allowed to warm to 0°C for 20 min, recooled to -78°C, and treated with a solution of 1.0 g (2.5 mmol) of N- (triphenylmethyl)- phenylalaninal in 10 ml of tetrahydrofuran.
- the resulting solution was stirred at - 78°C for 10 min, warmed to 0°C for 5 min, and quenched cautiously with aqueous ammonium chloride.
- the product was extracted with ether, dried over MgSO 4 , and concentrated in vacuo to give the desired compound as a crude foam.
- Example 302A 2-(2-Amino-1-hydroxy-3-phenyl) propyl-2-hydroxy- 2,3,4,5-tetrahydrofuran.
- the resultant compound of Example 302A (1.37 g, 2.5 mmol) was treated with 50 ml of tetrahydrofuran and 50 ml of 1 N HCl and heated at reflux for 0.5 h. After being allowed to cool, the mixture was concentrated in vacuo, taken up in dilute aqueous HCl, washed with three portions of hexane, concentrated in vacuo, taken up in methanol/chloroform, and concentrated to a brown foam.
- Example 303 A N-Methyl-2-(1-hydroxy-3-phenyl-2- (triphenylmethylamino) propyl-benzamide.
- a solution of 0.29 g (2.1 mmol) of N-methylbenzamide in 15 ml of tetrahydrofuran was cooled under inert atmosphere to -78°C and treated with 2.1 ml (4.4 mmol) of n-butyllithium.
- the resulting solution was warmed to 0°C for 30 min, recooled to -78°C, and treated with a solution of 0.42 g (1.1 mmol) of N- (triphenylmethyl)-phenylalaninal in 5 ml of tetrahydrofuran.
- Example 304 Cbz-Leu-Asn Amide of 2-Amino-1-cyclohexyl-3.4-dihydroxy- 6-methylheptane.
- the resultant compound of Example 141 (1.39 mmol) was deprotected according to the procedure of Example 2 and coupled to Cbz-Leu-Asn-OH according to the procedure of Example 66 to give a crude product, which crystallized from ethyl acetate to give 204 mg (24%) of the desired compound as a white solid, m.p. 189-190°C.
- Mass spectrum: (M+H) +
- Example 305 (5 (S)-(3-tert-Butyloxycarbonyl)-2,2-dimethyl-4(S)- cyclohexylmethyl-5(R)-oxazolidinyl)-2-thionoxazolidinon- 4(S)-carbonyl)-Ile-Ser Methyl Ester.
- the resultant compound from Example 253 (1.18 g, 2.13 mmol) was reacted according to the procedure of Example 213 to provide 865 mg (92%) of the desired compound.
- Example 306 N-Boc-Leu-Asn Amide of (5 (S)-(3-tert-Butyloxycarbonyl)- 2,2-dimethyl-4(S)-cyclohexylmethyl-5(R)-oxazolidinyl)-2- thionooxazolidinon-4(S)-carbonyl)-Ile-Ser Methyl Ester.
- the resultant compound from Example 305 (183 mg, 0.279 mmol) was dissolved in 2 ml methanol and treated with acetyl chloride (0.119 ml, 131 mg, 1.67 mmol). The resulting solution was stirred overnight at room temperature.
- Example 307 3-(5(R)-(3-(tert-Butyloxycarbonyl)-2,2-dimethyl-4(S)- cyclohexylmethyl-5(R)-oxazolidinyl)-2-thionooxazolidnyl)- 4(R)-carbonyl)-4(R)-phenylmethyl-2-oxazolidinone.
- the procedure of D.A. Evans and A. E. Weber J. Am . Chem . Soc. 1987, 109. 7151) is adapted.
- Example 309 (5 (R) - (3- (tert-Butyloxycarbonyl)-2,2-dimethyl-4(S)- cyclohexylmethyl-5(R)-oxazolidinyl)-2-thioxazolidinon- 4(R)-carbonyl)-Ile-Ser Methyl Ester.
- the resultant compound of Example 308 (174 mg, 0.393 mmol) was coupled to H-Ile-Ser-OMe (105 mg, 0.393 mmol) to provide 73 mg (28%) of the desired compound after column chromatography (2% MeOH-CHCl 3 ).
- Example 310 N-(Boc-Leu-Asn Amide of 5 (R) -(3-(tert-Butyloxycarbonyl)- 2,2-dimethyl-4(S)-cyclohexylmethyl-5(R)-oxazolidinyl)-2- thioxazolidinon-4(R)-carbonyl)-Ile-Ser Methyl Ester.
- the resultant compound from Example 309 (307 mg, 0.467 mmol) was dissolved in 5 ml methylene chloride, cooled to 0° under a nitrogen atmosphere, and 5 ml trifluoroacetic acid was added.
- Example 66 Using the procedure of Example 66, in which the above crude amino alcohol replaced the resultant compound from Example 196, the desired compound (30mg, 40%) was obtained after column chromatography on silica gel (7% MeOH-CH 2 Cl 2 ).
- Mass spectrum: (M+H) + 844.
- the compounds of the present invention can be used in the form of salts derived from inorganic or organic acids. These salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pa
- the basic nitrogen-containing groups can be quaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl., and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.
- loweralkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides
- dialkyl sulfates like dimethyl, diethyl, dibutyl., and diamyl sulfates
- acids which may be employed to form pharmaceutically, acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.
- Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases.
- the compounds of the present invention can also be used in the form of esters.
- esters include a hydroxyl-substituted compound of formula I which has been acylated with a blocked or unblocked amino acid residue, a phosphate function, or a hemisuccinate residue.
- the amino acid esters of particular interest are glycine and lysine; however, other amino acid residues can also be used.
- These esters serve as pro-drugs of the compounds of the present invention and serve to increase the solubility of these substances in the gastrointestinal tract. These pro-drugs are metabolized in vivo to provide the hydroxyl- substituted compound of formula I.
- the preparation of the pro-drug esters is carried out by reacting a hydroxyl- substituted compound of formula I with an activated amino acyl, phosphoryl or hemisuccinyl derivative. The resulting product is then deprotected to provide the desired pro-drug ester.
- novel compounds of the present invention are inhibitors of retroviral proteases and in particular are inhibitors of HIV-1 protease and HIV-2 protease.
- Compounds of the invention inhibit HIV-1 protease in the range of 22-91% at concentrations of 04-1.0 mM.
- the novel compounds of the present invention are useful for the treatment or prophylaxis of diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection.
- Total daily dose administered to a host in single or divided doses may be in amounts, for example, from 0.001 to 10 mg/kg body weight daily and more usually 0.01 to 1 mg. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose.
- the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
- the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy.
- the compounds of the present invention may be administered orally, parenterally, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices.
- parenteral as used herein includes subcutaneous injections, intravenous. intramuscular, intrasternal injection, or infusion techniques.
- sterile injectable preparations for example, sterile injectable aqueous or oleagenous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
- the sterile injectable preparation may also be a sterile i ⁇ j.ectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
- acceptable vehicles and solvents that may be employed are water. Ringer's solution, and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil may be employed including synthetic mono- or diglycerides.
- fatty acids such as oleic acid find use in the preparation of injectables.
- Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
- a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
- Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules.
- the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch.
- Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate.
- the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
- Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water.
- Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
- the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more immunomodulators, antiviral agents or other antiinfective agents.
- the therapeutic agents can be formulated as separate compositions which are given at the same time or different times, or the therapeutic agents can be given as a single composition.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US19467888A | 1988-05-13 | 1988-05-13 | |
US194678 | 1988-05-13 |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0415981A1 true EP0415981A1 (fr) | 1991-03-13 |
EP0415981A4 EP0415981A4 (en) | 1991-10-09 |
Family
ID=22718499
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP19890108590 Pending EP0342541A3 (fr) | 1988-05-13 | 1989-05-12 | Inhibiteurs de protéases rétrovirales |
EP19890905856 Ceased EP0415981A4 (en) | 1988-05-13 | 1989-05-12 | Retroviral protease inhibitors |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP19890108590 Pending EP0342541A3 (fr) | 1988-05-13 | 1989-05-12 | Inhibiteurs de protéases rétrovirales |
Country Status (5)
Country | Link |
---|---|
EP (2) | EP0342541A3 (fr) |
JP (1) | JPH03504247A (fr) |
AU (1) | AU3566089A (fr) |
IL (1) | IL90218A0 (fr) |
WO (1) | WO1989010752A1 (fr) |
Families Citing this family (72)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5142056A (en) * | 1989-05-23 | 1992-08-25 | Abbott Laboratories | Retroviral protease inhibiting compounds |
CA1340588C (fr) * | 1988-06-13 | 1999-06-08 | Balraj Krishan Handa | Derive d'aminoacides |
US5539122A (en) * | 1989-05-23 | 1996-07-23 | Abbott Laboratories | Retroviral protease inhibiting compounds |
US5614522A (en) * | 1990-11-19 | 1997-03-25 | G.D. Searle & Co. | Retroviral protease inhibitors |
US5475027A (en) * | 1990-11-19 | 1995-12-12 | G.D. Searle & Co. | Retroviral protease inhibitors |
US5482947A (en) | 1990-11-19 | 1996-01-09 | Talley; John J. | Retroviral protease inhibitors |
US5708004A (en) * | 1990-11-19 | 1998-01-13 | Monsanto Company | Retroviral protease inhibitors |
US5475013A (en) * | 1990-11-19 | 1995-12-12 | Monsanto Company | Retroviral protease inhibitors |
DE69132423T2 (de) | 1990-11-19 | 2001-04-26 | Monsanto Co., St. Louis | Inhibitoren retroviraler Proteasen |
US5583238A (en) * | 1990-11-19 | 1996-12-10 | G. D. Searle & Co. | Method for making intermediates useful in synthesis of retroviral protease inhibitors |
US5648511A (en) * | 1990-11-19 | 1997-07-15 | G.D. Searle & Co. | Method for making intermediates useful in the synthesis of retroviral protease inhibitors |
CA2055685A1 (fr) * | 1990-11-19 | 1992-05-20 | Samuel L. Graham | Inhibiteurs de la protease du vih ayant des substituts de polyether |
US5554728A (en) * | 1991-07-23 | 1996-09-10 | Nexstar Pharmaceuticals, Inc. | Lipid conjugates of therapeutic peptides and protease inhibitors |
DE4126485A1 (de) * | 1991-08-10 | 1993-02-11 | Bayer Ag | Trifluormethyl-haltige pseudopeptide |
RU2131420C1 (ru) | 1991-10-11 | 1999-06-10 | Дзе Дюпон Мерк Фармасьютикал Компани | Циклические мочевины, способ ингибирования роста ретровирусов и фармацевтическая композиция |
USRE37781E1 (en) | 1991-10-11 | 2002-07-02 | Dupont Pharmaceuticals Company | Substituted cyclic carbonyls and derivatives thereof useful as retroviral protease inhibitors |
US5610294A (en) | 1991-10-11 | 1997-03-11 | The Du Pont Merck Pharmaceutical Company | Substituted cyclic carbonyls and derivatives thereof useful as retroviral protease inhibitors |
US5413999A (en) * | 1991-11-08 | 1995-05-09 | Merck & Co., Inc. | HIV protease inhibitors useful for the treatment of AIDS |
US6071895A (en) * | 1992-03-11 | 2000-06-06 | Narhex Limited | Polar-substituted hydrocarbons |
MXPA93002392A (es) | 1992-03-11 | 2005-02-04 | Narhex Ltd | Derivados amino de hidrocarburos-oxo e hidroxi-substituidos. |
US5888992A (en) * | 1992-03-11 | 1999-03-30 | Narhex Limited | Polar substituted hydrocarbons |
BR9306058A (pt) * | 1992-03-11 | 1997-11-18 | Narhex Ltd | Derivados de amina de hidrocarbonetos oxo- e hidroxi- substituidos |
JPH07508020A (ja) | 1992-05-21 | 1995-09-07 | ジー.ディー.サール アンド カンパニー | レトロウイルスプロテアーゼインヒビター |
US5559256A (en) * | 1992-07-20 | 1996-09-24 | E. R. Squibb & Sons, Inc. | Aminediol protease inhibitors |
US5463104A (en) * | 1992-08-25 | 1995-10-31 | G. D. Searle & Co. | Succinoylamino hydroxyethylamino sulfonamides useful as retroviral protease inhibitors |
RU2146668C1 (ru) | 1992-08-25 | 2000-03-20 | Джи Ди Сирл энд Компани | Сульфонилалканоиламино-гидроксиэтиламино-сульфонамидное соединение, фармацевтические композиции и способы лечения и ингибирования ретровирусных протеаз |
DK0656887T3 (da) | 1992-08-25 | 1999-07-05 | Searle & Co | Hydroxyethylaminosulfonamider til anvendelse som inhibitorer af retrovirale proteaser |
US5760076A (en) * | 1992-08-25 | 1998-06-02 | G.D Searle & Co. | Succinoylamino hydroxyethylamino sulfonamides useful as retroviral protease inhibitors |
US7141609B2 (en) | 1992-08-25 | 2006-11-28 | G.D. Searle & Co. | α- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors |
US5968942A (en) | 1992-08-25 | 1999-10-19 | G. D. Searle & Co. | α- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors |
US6022994A (en) | 1992-08-25 | 2000-02-08 | G. D. Searle &. Co. | Succinoylamino hydroxyethylamino sulfonamides useful as retroviral protease inhibitors |
US6743929B1 (en) | 1992-08-25 | 2004-06-01 | G. D. Searle & Co. | Sulfonylalkanoylamino hydroxyethylamino sulfonamides useful as retroviral protease inhibitors |
US6046190A (en) * | 1992-08-25 | 2000-04-04 | G.D. Searle & Co. | Hydroxyethylamino sulphonamides useful as retroviral protease inhibitors |
US5830897A (en) * | 1992-08-27 | 1998-11-03 | G. D. Searle & Co. | α- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors |
ES2134924T3 (es) * | 1992-10-30 | 1999-10-16 | Searle & Co | Acidos sulfonilalcanoilamino-hidroxietilamino-sulfamicos utiles como inhibidores de proteasas retrovirales. |
DE69331421T2 (de) | 1992-10-30 | 2002-08-01 | G.D. SEARLE & CO., CHICAGO | N-substituierte Hydroxyethylaminosulfamidsäure-Derivate verwendbar als Inhibitoren retroviraler Proteasen |
US5578606A (en) | 1992-10-30 | 1996-11-26 | G. D. Searle & Co. | α- and β-amino acid hydroxyethylamino sulfonyl urea derivatives useful as retroviral protease inhibitors |
US6337398B1 (en) | 1992-10-30 | 2002-01-08 | G.D. Searle & Co. | Succinoylamino hydroxyethylamino sulfonyl urea derivatives useful as retroviral protease inhibitors |
US5514801A (en) | 1992-12-29 | 1996-05-07 | Monsanto Company | Cyclic sulfone containing retroviral protease inhibitors |
GB9300048D0 (en) * | 1993-01-04 | 1993-03-03 | Wellcome Found | Endothelin converting enzyme inhibitors |
US5830888A (en) * | 1993-04-16 | 1998-11-03 | Monsanto Company | Macrocyclic retroviral protease inhibitors |
US5750648A (en) * | 1993-08-20 | 1998-05-12 | G.D. Searle & Co. | Retroviral protease inhibitors and combinations thereof |
US5602119A (en) * | 1993-10-29 | 1997-02-11 | Vazquez; Michael L. | Succinoylamino hydroxyethylamino sulfamic acid derivatives useful as retroviral protease inhibitors |
US6133444A (en) * | 1993-12-22 | 2000-10-17 | Perseptive Biosystems, Inc. | Synthons for the synthesis and deprotection of peptide nucleic acids under mild conditions |
US5733882A (en) * | 1994-01-17 | 1998-03-31 | Smithkline Beecham Corporation | Retroviral protease inhibitors |
US5508400A (en) * | 1994-04-20 | 1996-04-16 | The Du Pont Merck Pharmaceutical Company | Preparation of cyclic urea compounds |
UA49803C2 (uk) * | 1994-06-03 | 2002-10-15 | Дж.Д. Сьорль Енд Ко | Спосіб лікування ретровірусних інфекцій |
US5831117A (en) | 1995-01-20 | 1998-11-03 | G. D. Searle & Co. | Method of preparing retroviral protease inhibitor intermediates |
JP4014220B2 (ja) | 1995-01-20 | 2007-11-28 | ジー.ディー.サール アンド カンパニー | ビス−スルホンアミドヒドロキシエチルアミノ レトロ ウイルスプロテアーゼインヒビター |
US5756533A (en) * | 1995-03-10 | 1998-05-26 | G.D. Searle & Co. | Amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors |
US6140505A (en) | 1995-03-10 | 2000-10-31 | G. D. Searle & Co. | Synthesis of benzo fused heterocyclic sulfonyl chlorides |
EP1188766A1 (fr) | 1995-03-10 | 2002-03-20 | G.D. Searle & Co. | Hydroxyethylamino sulfonamide de bis-aminoacide comme inhibiteurs de proteases de retrovirus |
US5705500A (en) * | 1995-03-10 | 1998-01-06 | G.D. Searle & Co. | Sulfonylalkanoylamino hydroxyethylamino sulfonamide retroviral protease inhibitors |
US7339078B2 (en) | 1995-03-10 | 2008-03-04 | G.D. Searle Llc | Bis-amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors |
US6861539B1 (en) | 1995-03-10 | 2005-03-01 | G. D. Searle & Co. | Bis-amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors |
US6667307B2 (en) | 1997-12-19 | 2003-12-23 | G.D. Searle & Co. | Sulfonylalkanoylamino hydroxyethylamino sulfonamide retroviral protease inhibitors |
US6169085B1 (en) | 1995-03-10 | 2001-01-02 | G. D. Searle & Company | Sulfonylalkanoylamino hydroxyethylamino sulfonamide retroviral protease inhibitors |
US6407134B1 (en) | 1995-03-10 | 2002-06-18 | G. D. Searle & Co. | Heterocyclecarbonyl amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors |
JP4124818B2 (ja) * | 1995-03-10 | 2008-07-23 | ジー.ディー.サール アンド カンパニー | ヘテロシクロカルボニルアミノ酸ヒドロキシエチルアミノスルホンアミドレトロウイルスプロテアーゼインヒビター |
US5776971A (en) * | 1995-03-10 | 1998-07-07 | G.D. Searle & Co. | Heterocyclecarbonyl amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors |
US6150556A (en) | 1995-03-10 | 2000-11-21 | G. D. Dearle & Co. | Bis-amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors |
US5985870A (en) * | 1995-03-10 | 1999-11-16 | G.D. Searle & Co. | Sulfonylalkanoylamino hydroxyethylamino sulfonamide retroviral protease inhibitors |
CA2236236A1 (fr) * | 1995-11-15 | 1997-05-22 | G.D. Searle & Co. | Inhibiteurs de proteases retrovirales a base de sulfonylalcanoylamino hydroxyethylamino sulfonamides substitues |
EP0876353A1 (fr) * | 1995-12-13 | 1998-11-11 | Abbott Laboratories | Composes inhibiteurs de proteases retrovirales |
US5914332A (en) | 1995-12-13 | 1999-06-22 | Abbott Laboratories | Retroviral protease inhibiting compounds |
WO1999025685A1 (fr) * | 1997-11-18 | 1999-05-27 | Merck & Co., Inc. | Derives de 4-piperidine carboxamides 4-substitues |
EP1095022A1 (fr) | 1998-07-08 | 2001-05-02 | G.D. Searle & Co. | Inhibiteurs de la protease retrovirale |
US6313110B1 (en) | 1999-06-02 | 2001-11-06 | Dupont Pharmaceuticals Company | Substituted 2H-1,3-diazapin-2-one useful as an HIV protease inhibitor |
EP1362846A4 (fr) | 2001-01-26 | 2006-10-04 | Takeda Pharmaceutical | Derives aminoethanol |
US7834043B2 (en) | 2003-12-11 | 2010-11-16 | Abbott Laboratories | HIV protease inhibiting compounds |
JP5229278B2 (ja) | 2010-06-21 | 2013-07-03 | 信越化学工業株式会社 | ナフタレン誘導体、レジスト下層膜材料、レジスト下層膜形成方法及びパターン形成方法 |
JP5598489B2 (ja) | 2011-03-28 | 2014-10-01 | 信越化学工業株式会社 | ビフェニル誘導体、レジスト下層膜材料、レジスト下層膜形成方法及びパターン形成方法 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1984000365A1 (fr) * | 1982-07-19 | 1984-02-02 | Nat Res Dev | Peptides synthetiques et leur preparation |
WO1984004301A1 (fr) * | 1983-05-05 | 1984-11-08 | Nat Res Dev | Nouveaux aldehydes d'oligopeptides utilises comme inhibiteurs specifiques de l'enterokinase |
EP0128762A2 (fr) * | 1983-06-09 | 1984-12-19 | Sankyo Company Limited | Peptides ayant une activité hypotensive, leur préparation et utilisation |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4609643A (en) * | 1980-08-06 | 1986-09-02 | Aktiebolaget Hassle | Renin inhibitors, treatments and dipeptide synthesis |
US4645759A (en) * | 1984-06-22 | 1987-02-24 | Abbott Laboratories | Renin inhibiting compounds |
US4652551A (en) * | 1984-06-22 | 1987-03-24 | Abbott Laboratories | Renin inhibiting compounds |
US4680284A (en) * | 1985-01-23 | 1987-07-14 | Abbott Laboratories | Modified phenylalanine peptidylaminodiols |
US4725583A (en) * | 1985-01-23 | 1988-02-16 | Abbott Laboratories | Functionalized peptidylaminoalcohols |
US4657931A (en) * | 1985-05-15 | 1987-04-14 | G. D. Searle & Co. | N-(acyldipeptidyl)-aminoglycols |
US4826815A (en) * | 1985-05-17 | 1989-05-02 | Abbott Laboratories | Renin inhibiting compounds |
US4699898A (en) * | 1985-12-26 | 1987-10-13 | Imreg, Inc. | Tripeptides affecting immune response |
ZA87563B (en) * | 1986-02-03 | 1987-09-30 | Squibb & Sons Inc | N-heterocyclic alcohol renin inhibitors |
US4725584A (en) * | 1986-02-19 | 1988-02-16 | Abbott Laboratories | Peptidyl-1-amino-2,4-diols |
-
1989
- 1989-05-08 IL IL90218A patent/IL90218A0/xx unknown
- 1989-05-12 EP EP19890108590 patent/EP0342541A3/fr active Pending
- 1989-05-12 JP JP1506033A patent/JPH03504247A/ja active Pending
- 1989-05-12 AU AU35660/89A patent/AU3566089A/en not_active Abandoned
- 1989-05-12 WO PCT/US1989/002055 patent/WO1989010752A1/fr not_active Application Discontinuation
- 1989-05-12 EP EP19890905856 patent/EP0415981A4/en not_active Ceased
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1984000365A1 (fr) * | 1982-07-19 | 1984-02-02 | Nat Res Dev | Peptides synthetiques et leur preparation |
WO1984004301A1 (fr) * | 1983-05-05 | 1984-11-08 | Nat Res Dev | Nouveaux aldehydes d'oligopeptides utilises comme inhibiteurs specifiques de l'enterokinase |
EP0128762A2 (fr) * | 1983-06-09 | 1984-12-19 | Sankyo Company Limited | Peptides ayant une activité hypotensive, leur préparation et utilisation |
Non-Patent Citations (3)
Title |
---|
Nature, Vol. 329, 15th October 1987, pages 654-656; I. KATOH et al.: "Inhibition of retroviral protease activity by an aspartyl proteinase inhibitor", whole article. * |
Science, Vol. 175, 1975, page 656; P. GROSS et al.: "Inhibition of the renin-angiotensinogen reaction by pepstatin", whole article. * |
See also references of WO8910752A1 * |
Also Published As
Publication number | Publication date |
---|---|
EP0342541A2 (fr) | 1989-11-23 |
IL90218A0 (en) | 1989-12-15 |
WO1989010752A1 (fr) | 1989-11-16 |
AU3566089A (en) | 1989-11-29 |
EP0415981A4 (en) | 1991-10-09 |
EP0342541A3 (fr) | 1991-11-06 |
JPH03504247A (ja) | 1991-09-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO1989010752A1 (fr) | Inhibiteurs de protease retrovirale | |
KR0184866B1 (ko) | 레트로바이러스성 프로테아제 억제 화합물 | |
US4826815A (en) | Renin inhibiting compounds | |
US5151438A (en) | Retroviral protease inhibiting compounds | |
JP3207901B2 (ja) | レトロウイルス阻害性化合物 | |
US5032577A (en) | Peptidylaminodiols | |
AU639212B2 (en) | Non-peptide renin inhibitors | |
EP1302468B1 (fr) | Procédés et intermédiaires pour la préparation d'inhibiteurs de protéase rétrovirale | |
US5597926A (en) | Retroviral protease inhibiting compounds | |
WO1987004349A1 (fr) | Analogues de peptides | |
US11530182B2 (en) | YAP1 inhibitors that target the interaction of YAP1 with Oct4 | |
CA2022692A1 (fr) | Inhibiteurs de la renine | |
EP0307837A2 (fr) | Peptidylhétérocycles inhibant la rénine | |
US5256677A (en) | Retroviral protease inhibiting compounds | |
WO1998049190A9 (fr) | Inhibiteurs de l'oxadiazole cysteine protease a substitution | |
JPH08507061A (ja) | レトロウィルスプロテアーゼ抑制性化合物 | |
IE922316A1 (en) | Retroviral protease inhibitors | |
HUT61744A (en) | Process for producing renin inhibiting alkylaminocarbonyl group-substituted heterocyclic compounds | |
WO1999054317A1 (fr) | Inhibiteurs de cysteine proteases | |
CA2176415A1 (fr) | Azepinone et piperidinone condensees avec un noyau benzenique, utiles pour l'inhibition d'ace et de nep | |
CA2021740A1 (fr) | Peptidyl aminodiol inhibiteur de la remine | |
EP0603309A1 (fr) | Isosteres peptidiques contenant un heterocycle utilises comme inhibiteurs du v.i.h. | |
US5258362A (en) | Renin inhibiting compounds | |
US5268374A (en) | Non-peptide renin inhibitors | |
WO1990005531A1 (fr) | Procede de traitement de maladies vasculaires |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 19901109 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH DE FR GB IT LI LU NL SE |
|
A4 | Supplementary search report drawn up and despatched |
Effective date: 19910819 |
|
AK | Designated contracting states |
Kind code of ref document: A4 Designated state(s): AT BE CH DE FR GB IT LI LU NL SE |
|
RAP1 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: ABBOTT LABORATORIES |
|
RBV | Designated contracting states (corrected) |
Designated state(s): AT BE CH DE ES FR GB GR IT LI LU NL SE |
|
XX | Miscellaneous (additional remarks) |
Free format text: VERBUNDEN MIT 89108590.4/0342541 (EUROPAEISCHE ANMELDENUMMER/VEROEFFENTLICHUNGSNUMMER) DURCH ENTSCHEIDUNG VOM 14.07.92. |
|
17Q | First examination report despatched |
Effective date: 19921014 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION HAS BEEN REFUSED |
|
18R | Application refused |
Effective date: 19940709 |