BG104766A - Производни на халогенирани амидиноаминокиселини, ефикасни като инхибитори на азотно - окисна синтеза - Google Patents
Производни на халогенирани амидиноаминокиселини, ефикасни като инхибитори на азотно - окисна синтеза Download PDFInfo
- Publication number
- BG104766A BG104766A BG104766A BG10476600A BG104766A BG 104766 A BG104766 A BG 104766A BG 104766 A BG104766 A BG 104766A BG 10476600 A BG10476600 A BG 10476600A BG 104766 A BG104766 A BG 104766A
- Authority
- BG
- Bulgaria
- Prior art keywords
- alkyl
- dihydrochloride
- group
- amino
- halogen
- Prior art date
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- -1 amidino amino Chemical class 0.000 title claims abstract description 131
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 title claims description 63
- 239000003112 inhibitor Substances 0.000 title description 9
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims description 86
- 125000000217 alkyl group Chemical group 0.000 claims description 67
- 229910052736 halogen Inorganic materials 0.000 claims description 54
- 150000002367 halogens Chemical class 0.000 claims description 54
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 46
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 34
- 239000001257 hydrogen Substances 0.000 claims description 32
- 229910052739 hydrogen Inorganic materials 0.000 claims description 32
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 28
- 125000001424 substituent group Chemical group 0.000 claims description 27
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 22
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 21
- 102000008299 Nitric Oxide Synthase Human genes 0.000 claims description 19
- 108010021487 Nitric Oxide Synthase Proteins 0.000 claims description 19
- 125000005865 C2-C10alkynyl group Chemical group 0.000 claims description 18
- 150000002431 hydrogen Chemical class 0.000 claims description 18
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 125000003118 aryl group Chemical group 0.000 claims description 16
- 229910052799 carbon Inorganic materials 0.000 claims description 16
- 125000000623 heterocyclic group Chemical group 0.000 claims description 16
- 229910052760 oxygen Inorganic materials 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 12
- 125000005026 carboxyaryl group Chemical group 0.000 claims description 12
- 125000001072 heteroaryl group Chemical group 0.000 claims description 12
- 150000003573 thiols Chemical class 0.000 claims description 12
- 125000004104 aryloxy group Chemical group 0.000 claims description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 10
- 125000005309 thioalkoxy group Chemical group 0.000 claims description 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 125000004450 alkenylene group Chemical group 0.000 claims description 7
- 125000004419 alkynylene group Chemical group 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- 150000001370 alpha-amino acid derivatives Chemical class 0.000 claims description 6
- 235000008206 alpha-amino acids Nutrition 0.000 claims description 6
- 239000000470 constituent Substances 0.000 claims description 6
- 125000001188 haloalkyl group Chemical group 0.000 claims description 6
- 230000005764 inhibitory process Effects 0.000 claims description 6
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
- LLAPDLPYIYKTGQ-UHFFFAOYSA-N 1-aminoethyl Chemical group C[CH]N LLAPDLPYIYKTGQ-UHFFFAOYSA-N 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 3
- 125000006832 (C1-C10) alkylene group Chemical group 0.000 claims description 3
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 3
- 125000002947 alkylene group Chemical group 0.000 claims description 3
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 3
- 125000004982 dihaloalkyl group Chemical group 0.000 claims description 3
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 3
- LZCZUMFPQRUUMN-OWOJBTEDSA-N (e)-2-amino-6-[(1-amino-2-fluoroethylidene)amino]hex-4-enoic acid Chemical compound OC(=O)C(N)C\C=C\CN=C(N)CF LZCZUMFPQRUUMN-OWOJBTEDSA-N 0.000 claims description 2
- PHGPWCICCXGBIO-UHFFFAOYSA-N 2-amino-6-[(1-amino-2-fluoroethylidene)amino]-5-cyclopropylhexanoic acid Chemical compound OC(=O)C(N)CCC(CN=C(N)CF)C1CC1 PHGPWCICCXGBIO-UHFFFAOYSA-N 0.000 claims description 2
- KZAGBDIGNQQSIL-UHFFFAOYSA-N 2-amino-6-[(1-amino-2-fluoroethylidene)amino]-5-methylhexanoic acid Chemical compound OC(=O)C(N)CCC(C)CN=C(N)CF KZAGBDIGNQQSIL-UHFFFAOYSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims 6
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims 6
- 239000003814 drug Substances 0.000 claims 3
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 2
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims 1
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 1
- 125000002877 alkyl aryl group Chemical group 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 230000006698 induction Effects 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 claims 1
- 239000000236 nitric oxide synthase inhibitor Substances 0.000 abstract description 9
- CSYSULGPHGCBQD-UHFFFAOYSA-N s-ethylisothiouronium diethylphosphate Chemical compound CCSC(N)=N.CCOP(O)(=O)OCC CSYSULGPHGCBQD-UHFFFAOYSA-N 0.000 abstract description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 70
- 239000000047 product Substances 0.000 description 65
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 57
- 239000000203 mixture Substances 0.000 description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 33
- 239000000243 solution Substances 0.000 description 31
- 238000003756 stirring Methods 0.000 description 29
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 26
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 23
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 125000000304 alkynyl group Chemical group 0.000 description 21
- 125000004432 carbon atom Chemical group C* 0.000 description 17
- 239000003921 oil Substances 0.000 description 17
- 238000000034 method Methods 0.000 description 16
- 239000007787 solid Substances 0.000 description 16
- 239000011541 reaction mixture Substances 0.000 description 15
- 238000000921 elemental analysis Methods 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
- 239000002253 acid Substances 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 11
- 238000004587 chromatography analysis Methods 0.000 description 11
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 125000003342 alkenyl group Chemical group 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 9
- 239000000460 chlorine Substances 0.000 description 9
- 125000006725 C1-C10 alkenyl group Chemical group 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 8
- 150000001409 amidines Chemical group 0.000 description 8
- 150000004699 copper complex Chemical class 0.000 description 8
- 239000002158 endotoxin Substances 0.000 description 8
- MULVVEXEENBHMQ-UHFFFAOYSA-N ethyl 2-fluoroethanimidate;hydrochloride Chemical compound Cl.CCOC(=N)CF MULVVEXEENBHMQ-UHFFFAOYSA-N 0.000 description 8
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 7
- 235000014852 L-arginine Nutrition 0.000 description 7
- 229930064664 L-arginine Natural products 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 150000003254 radicals Chemical class 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 206010040070 Septic Shock Diseases 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 6
- 239000003242 anti bacterial agent Substances 0.000 description 6
- 229940088710 antibiotic agent Drugs 0.000 description 6
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 6
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- 238000011282 treatment Methods 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- 239000004472 Lysine Substances 0.000 description 5
- NTWVQPHTOUKMDI-YFKPBYRVSA-N N-Methyl-arginine Chemical compound CN[C@H](C(O)=O)CCCN=C(N)N NTWVQPHTOUKMDI-YFKPBYRVSA-N 0.000 description 5
- 102000011779 Nitric Oxide Synthase Type II Human genes 0.000 description 5
- 108010076864 Nitric Oxide Synthase Type II Proteins 0.000 description 5
- 229910052786 argon Inorganic materials 0.000 description 5
- 230000001419 dependent effect Effects 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 239000004615 ingredient Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- WGMHMVLZFAJNOT-UHFFFAOYSA-N 1-ethoxyethylideneazanium;chloride Chemical compound [Cl-].CCOC(C)=[NH2+] WGMHMVLZFAJNOT-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- 206010044248 Toxic shock syndrome Diseases 0.000 description 4
- 231100000650 Toxic shock syndrome Toxicity 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- 210000003038 endothelium Anatomy 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 229930195733 hydrocarbon Natural products 0.000 description 4
- 230000001939 inductive effect Effects 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 238000002953 preparative HPLC Methods 0.000 description 4
- 238000004007 reversed phase HPLC Methods 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 3
- 102000000584 Calmodulin Human genes 0.000 description 3
- 108010041952 Calmodulin Proteins 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 3
- 108090000695 Cytokines Proteins 0.000 description 3
- 102000004127 Cytokines Human genes 0.000 description 3
- 208000001953 Hypotension Diseases 0.000 description 3
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 3
- 208000002193 Pain Diseases 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- 102000001708 Protein Isoforms Human genes 0.000 description 3
- 108010029485 Protein Isoforms Proteins 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 230000036543 hypotension Effects 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 208000028867 ischemia Diseases 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 235000018977 lysine Nutrition 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000007127 saponification reaction Methods 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 230000009885 systemic effect Effects 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- DENPQNAWGQXKCU-UHFFFAOYSA-N thiophene-2-carboxamide Chemical compound NC(=O)C1=CC=CS1 DENPQNAWGQXKCU-UHFFFAOYSA-N 0.000 description 3
- 125000004385 trihaloalkyl group Chemical group 0.000 description 3
- OIMQYJJMDNKKOD-YFKPBYRVSA-N (2s)-2,6-diamino-4-oxohexanoic acid Chemical compound NCCC(=O)C[C@H](N)C(O)=O OIMQYJJMDNKKOD-YFKPBYRVSA-N 0.000 description 2
- UMKVHRBXXOWEPJ-BYPYZUCNSA-N (2s)-2,6-diamino-5,5-difluorohexanoic acid Chemical compound NCC(F)(F)CC[C@H](N)C(O)=O UMKVHRBXXOWEPJ-BYPYZUCNSA-N 0.000 description 2
- HILHCIBEZCWKBD-AKGZTFGVSA-N (2s)-2,6-diamino-5-fluorohexanoic acid Chemical compound NCC(F)CC[C@H](N)C(O)=O HILHCIBEZCWKBD-AKGZTFGVSA-N 0.000 description 2
- PQADCRYOPOVXDV-LURJTMIESA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-4-sulfanylbutanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CCS PQADCRYOPOVXDV-LURJTMIESA-N 0.000 description 2
- 125000006727 (C1-C6) alkenyl group Chemical group 0.000 description 2
- FQWGKZHQXVUBPV-UHFFFAOYSA-N 2-acetamido-6-[(1-amino-2-fluoroethylidene)amino]hex-4-ynoic acid;hydrochloride Chemical compound Cl.CC(=O)NC(C(O)=O)CC#CCNC(=N)CF FQWGKZHQXVUBPV-UHFFFAOYSA-N 0.000 description 2
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 2
- GUIPZCNIFDPABQ-UHFFFAOYSA-N 2-chloro-2,2-difluoroacetonitrile Chemical compound FC(F)(Cl)C#N GUIPZCNIFDPABQ-UHFFFAOYSA-N 0.000 description 2
- PZASAAIJIFDWSB-CKPDSHCKSA-N 8-[(1S)-1-[8-(trifluoromethyl)-7-[4-(trifluoromethyl)cyclohexyl]oxynaphthalen-2-yl]ethyl]-8-azabicyclo[3.2.1]octane-3-carboxylic acid Chemical compound FC(F)(F)C=1C2=CC([C@@H](N3C4CCC3CC(C4)C(O)=O)C)=CC=C2C=CC=1OC1CCC(C(F)(F)F)CC1 PZASAAIJIFDWSB-CKPDSHCKSA-N 0.000 description 2
- 241000220479 Acacia Species 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 229920002271 DEAE-Sepharose Polymers 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- RHGKLRLOHDJJDR-BYPYZUCNSA-N L-citrulline Chemical compound NC(=O)NCCC[C@H]([NH3+])C([O-])=O RHGKLRLOHDJJDR-BYPYZUCNSA-N 0.000 description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
- RHGKLRLOHDJJDR-UHFFFAOYSA-N Ndelta-carbamoyl-DL-ornithine Natural products OC(=O)C(N)CCCNC(N)=O RHGKLRLOHDJJDR-UHFFFAOYSA-N 0.000 description 2
- 229940123921 Nitric oxide synthase inhibitor Drugs 0.000 description 2
- 241000872198 Serjania polyphylla Species 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 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 2
- 150000001412 amines Chemical class 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 239000012736 aqueous medium Substances 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 229940049706 benzodiazepine Drugs 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 235000011089 carbon dioxide Nutrition 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 235000013477 citrulline Nutrition 0.000 description 2
- 229960002173 citrulline Drugs 0.000 description 2
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- UJRJCSCBZXLGKF-UHFFFAOYSA-N nickel rhenium Chemical compound [Ni].[Re] UJRJCSCBZXLGKF-UHFFFAOYSA-N 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
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- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 1
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- 125000003373 pyrazinyl group Chemical group 0.000 description 1
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- CUPOOAWTRIURFT-UHFFFAOYSA-N thiophene-2-carbonitrile Chemical compound N#CC1=CC=CS1 CUPOOAWTRIURFT-UHFFFAOYSA-N 0.000 description 1
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- 230000001131 transforming effect Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- VFJYIHQDILEQNR-UHFFFAOYSA-M trimethylsulfanium;iodide Chemical compound [I-].C[S+](C)C VFJYIHQDILEQNR-UHFFFAOYSA-M 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- 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
- C07D333/06—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
- C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
- C07C257/14—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to acyclic carbon atoms
-
- 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
- C07C323/57—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 the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
- C07C323/58—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 the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Physical Education & Sports Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US3828498A | 1998-03-11 | 1998-03-11 | |
| PCT/US1999/003728 WO1999046240A2 (en) | 1998-03-11 | 1999-03-04 | Halogenated amidino amino acid derivatives useful as nitric oxide synthase inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| BG104766A true BG104766A (bg) | 2001-03-30 |
Family
ID=21899068
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| BG104766A BG104766A (bg) | 1998-03-11 | 2000-09-14 | Производни на халогенирани амидиноаминокиселини, ефикасни като инхибитори на азотно - окисна синтеза |
Country Status (35)
| Country | Link |
|---|---|
| US (1) | US6344483B1 (de) |
| EP (2) | EP1415982A1 (de) |
| JP (1) | JP2002506056A (de) |
| KR (1) | KR20010034598A (de) |
| CN (1) | CN1171861C (de) |
| AP (1) | AP2000001900A0 (de) |
| AR (1) | AR018159A1 (de) |
| AT (1) | ATE277894T1 (de) |
| AU (1) | AU746235B2 (de) |
| BG (1) | BG104766A (de) |
| BR (1) | BR9908702A (de) |
| CA (1) | CA2322873A1 (de) |
| CU (1) | CU23047A3 (de) |
| DE (1) | DE69920670T2 (de) |
| EA (1) | EA200000826A1 (de) |
| EE (1) | EE200000519A (de) |
| ES (1) | ES2239839T3 (de) |
| GE (1) | GEP20043179B (de) |
| HR (1) | HRP20000595A2 (de) |
| HU (1) | HUP0101467A3 (de) |
| ID (1) | ID26208A (de) |
| IL (1) | IL137654A0 (de) |
| IS (1) | IS5583A (de) |
| NO (1) | NO20004531L (de) |
| NZ (1) | NZ506721A (de) |
| OA (1) | OA11901A (de) |
| PL (1) | PL343380A1 (de) |
| PT (1) | PT1062201E (de) |
| SI (1) | SI1062201T1 (de) |
| SK (1) | SK13012000A3 (de) |
| TR (1) | TR200002605T2 (de) |
| UA (1) | UA67767C2 (de) |
| WO (1) | WO1999046240A2 (de) |
| YU (1) | YU52200A (de) |
| ZA (1) | ZA991894B (de) |
Families Citing this family (23)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GEP20094625B (en) | 2000-03-24 | 2009-03-10 | Pharmacia Corp | Amidino compound and salts thereof useful as nitric oxide synthase inhibitors |
| US6956131B2 (en) * | 2000-04-13 | 2005-10-18 | Pharmacia Corporation | 2-amino-3, 4 heptenoic compounds useful as nitric oxide synthase inhibitors |
| US6787668B2 (en) | 2000-04-13 | 2004-09-07 | Pharmacia Corporation | 2-amino-4,5 heptenoic acid derivatives useful as nitric oxide synthase inhibitors |
| AR032318A1 (es) | 2000-04-13 | 2003-11-05 | Pharmacia Corp | Compuesto derivado halogenado del acido 2-amino-5,6 heptenoico; composicion farmaceutica que lo comprende y su uso en la fabricacion de un medicamento util como inhibidor de la oxido nitrico sintetasa |
| AR034120A1 (es) | 2000-04-13 | 2004-02-04 | Pharmacia Corp | Compuesto derivado halogenado del acido 2-amino-4,5 heptenoico, composicion farmaceutica que lo comprende y el uso de dicho compuesto y dicha composicion en la fabricacion de un medicamento para inhibir o modular la sintesis de acido nitrico |
| US6545170B2 (en) | 2000-04-13 | 2003-04-08 | Pharmacia Corporation | 2-amino-5, 6 heptenoic acid derivatives useful as nitric oxide synthase inhibitors |
| AR030416A1 (es) | 2000-04-13 | 2003-08-20 | Pharmacia Corp | COMPUESTO DERIVADO HALOGENADO DEL ACIDO 2-AMINO-3,4 HEPTENOICO, COMPOSICION FARMACEUTICA QUE LO COMPRENDE Y SU USO EN LA FABRICACION DE UN MEDICAMENTO uTIL COMO INHIBIDOR DE LA OXIDO NITRICO SINTETASA |
| AR035585A1 (es) * | 2000-09-15 | 2004-06-16 | Pharmacia Corp | Derivados del acido 2-amino-2-alquil-4-heptenoico, composicion farmaceutica y su uso en la fabricacion de medicamentos |
| AR031609A1 (es) * | 2000-09-15 | 2003-09-24 | Pharmacia Corp | Derivados de acido 2-amino-2-alquil-3 heptenoico y heptinoico utiles como inhibidores de oxido nitrico sintetasa |
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| EP2399893B1 (de) | 2004-12-22 | 2018-08-15 | Ambrx, Inc. | Zusammensetzungen und Verfahren mit sowie Verwendungen von nichtnatürlichen Aminosäuren und Polypeptiden |
| AU2006223482A1 (en) * | 2005-03-14 | 2006-09-21 | Janssen Pharmaceutica, N.V. | Process for the preparation of opioid modulators |
| CN101400646A (zh) | 2005-11-08 | 2009-04-01 | Ambrx公司 | 用于修饰非天然氨基酸和非天然氨基酸多肽的促进剂 |
| WO2007070659A2 (en) * | 2005-12-14 | 2007-06-21 | Ambrx, Inc. | Compositions containing, methods involving, and uses of non-natural amino acids and polypeptides |
| KR101103720B1 (ko) * | 2011-06-02 | 2012-01-11 | 한국건설기술연구원 | 자연환기에 의한 중공층의 온도제어가 가능한 일체형 다중유리 복합창짝 |
| EP3043810B1 (de) | 2013-09-09 | 2019-10-23 | CanImGuide Therapeutics AB | Immunsystemmodulatoren |
| WO2016144650A1 (en) | 2015-03-06 | 2016-09-15 | Canimguide Therapeutics Ab | Immune system modulators and compositions |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9127376D0 (en) | 1991-12-24 | 1992-02-19 | Wellcome Found | Amidino derivatives |
| GB9312761D0 (en) * | 1993-06-21 | 1993-08-04 | Wellcome Found | Amino acid derivatives |
| DE69529101T2 (de) | 1994-06-15 | 2003-11-13 | Wellcome Found | Zwischenprodukte verwendbar in der Herstellung von Enzym-Inhibitoren |
| GB9425701D0 (en) * | 1994-12-20 | 1995-02-22 | Wellcome Found | Enzyme inhibitors |
| US5981511A (en) * | 1996-03-06 | 1999-11-09 | G.D. Searle & Co. | Hydroxyamidino derivatives useful as nitric oxide synthase inhibitors |
| US5945408A (en) | 1996-03-06 | 1999-08-31 | G.D. Searle & Co. | Hydroxyanidino derivatives useful as nitric oxide synthase inhibitors |
-
1999
- 1999-03-04 EP EP20040001236 patent/EP1415982A1/de not_active Withdrawn
- 1999-03-04 JP JP2000535621A patent/JP2002506056A/ja active Pending
- 1999-03-04 CU CU20000199A patent/CU23047A3/es unknown
- 1999-03-04 EA EA200000826A patent/EA200000826A1/ru unknown
- 1999-03-04 OA OA1200000239A patent/OA11901A/en unknown
- 1999-03-04 NZ NZ506721A patent/NZ506721A/en unknown
- 1999-03-04 WO PCT/US1999/003728 patent/WO1999046240A2/en not_active Ceased
- 1999-03-04 PL PL99343380A patent/PL343380A1/xx unknown
- 1999-03-04 AT AT99908324T patent/ATE277894T1/de not_active IP Right Cessation
- 1999-03-04 HR HR20000595A patent/HRP20000595A2/hr not_active Application Discontinuation
- 1999-03-04 SI SI9930718T patent/SI1062201T1/xx unknown
- 1999-03-04 TR TR2000/02605T patent/TR200002605T2/xx unknown
- 1999-03-04 US US09/402,953 patent/US6344483B1/en not_active Expired - Fee Related
- 1999-03-04 SK SK1301-2000A patent/SK13012000A3/sk unknown
- 1999-03-04 ES ES99908324T patent/ES2239839T3/es not_active Expired - Lifetime
- 1999-03-04 BR BR9908702-2A patent/BR9908702A/pt not_active Application Discontinuation
- 1999-03-04 GE GEAP19995542A patent/GEP20043179B/en unknown
- 1999-03-04 YU YU52200A patent/YU52200A/sh unknown
- 1999-03-04 EP EP99908324A patent/EP1062201B1/de not_active Expired - Lifetime
- 1999-03-04 HU HU0101467A patent/HUP0101467A3/hu unknown
- 1999-03-04 AU AU27786/99A patent/AU746235B2/en not_active Ceased
- 1999-03-04 CA CA002322873A patent/CA2322873A1/en not_active Abandoned
- 1999-03-04 DE DE69920670T patent/DE69920670T2/de not_active Expired - Fee Related
- 1999-03-04 CN CNB998037907A patent/CN1171861C/zh not_active Expired - Fee Related
- 1999-03-04 PT PT99908324T patent/PT1062201E/pt unknown
- 1999-03-04 IL IL13765499A patent/IL137654A0/xx unknown
- 1999-03-04 AP APAP/P/2000/001900A patent/AP2000001900A0/en unknown
- 1999-03-04 EE EEP200000519A patent/EE200000519A/xx unknown
- 1999-03-04 KR KR1020007010096A patent/KR20010034598A/ko not_active Ceased
- 1999-03-04 ID IDW20001739A patent/ID26208A/id unknown
- 1999-03-09 ZA ZA9901894A patent/ZA991894B/xx unknown
- 1999-03-11 AR ARP990101062A patent/AR018159A1/es unknown
- 1999-04-03 UA UA2000095233A patent/UA67767C2/uk unknown
-
2000
- 2000-08-04 IS IS5583A patent/IS5583A/is unknown
- 2000-09-11 NO NO20004531A patent/NO20004531L/no not_active Application Discontinuation
- 2000-09-14 BG BG104766A patent/BG104766A/bg unknown
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