NO309303B1 - Farmasöytiske preparater, aminoderivater og aminoderivatenes anvendelse som nitrogenmonoksyd-syntaseinhibitorer - Google Patents
Farmasöytiske preparater, aminoderivater og aminoderivatenes anvendelse som nitrogenmonoksyd-syntaseinhibitorer Download PDFInfo
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- NO309303B1 NO309303B1 NO961403A NO961403A NO309303B1 NO 309303 B1 NO309303 B1 NO 309303B1 NO 961403 A NO961403 A NO 961403A NO 961403 A NO961403 A NO 961403A NO 309303 B1 NO309303 B1 NO 309303B1
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- Prior art keywords
- title compound
- mmol
- alkyl
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- product
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- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 title claims description 19
- 239000003814 drug Substances 0.000 title claims description 6
- 239000003112 inhibitor Substances 0.000 title description 11
- 150000001412 amines Chemical class 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 423
- -1 nitro, amino, carboxyl Chemical group 0.000 claims description 143
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 36
- 229910052739 hydrogen Inorganic materials 0.000 claims description 34
- 150000003839 salts Chemical class 0.000 claims description 24
- 229910052757 nitrogen Inorganic materials 0.000 claims description 22
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 21
- 125000004432 carbon atom Chemical group C* 0.000 claims description 21
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 21
- 108010021487 Nitric Oxide Synthase Proteins 0.000 claims description 18
- 102000008299 Nitric Oxide Synthase Human genes 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 18
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
- 229910052760 oxygen Inorganic materials 0.000 claims description 17
- 239000001301 oxygen Chemical group 0.000 claims description 17
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 150000002367 halogens Chemical class 0.000 claims description 15
- 238000004519 manufacturing process Methods 0.000 claims description 15
- 229910052717 sulfur Chemical group 0.000 claims description 14
- 239000011593 sulfur Chemical group 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- PZIDJKOIMRBQLL-UHFFFAOYSA-N $l^{2}-azanylidenemethane Chemical group [N]=C PZIDJKOIMRBQLL-UHFFFAOYSA-N 0.000 claims description 9
- 230000015572 biosynthetic process Effects 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- 230000005764 inhibitory process Effects 0.000 claims description 8
- 238000003786 synthesis reaction Methods 0.000 claims description 8
- 239000004215 Carbon black (E152) Substances 0.000 claims description 7
- 102100029438 Nitric oxide synthase, inducible Human genes 0.000 claims description 7
- 101710089543 Nitric oxide synthase, inducible Proteins 0.000 claims description 7
- 239000005864 Sulphur Chemical group 0.000 claims description 7
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
- 229930195733 hydrocarbon Natural products 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 6
- 239000000651 prodrug Substances 0.000 claims description 6
- 229940002612 prodrug Drugs 0.000 claims description 6
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- DHGUMNJVFYRSIG-UHFFFAOYSA-N 2,3,4,5-tetrahydropyridin-6-amine Chemical compound NC1=NCCCC1 DHGUMNJVFYRSIG-UHFFFAOYSA-N 0.000 claims description 4
- 229940079593 drug Drugs 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
- 125000001188 haloalkyl group Chemical group 0.000 claims description 3
- 230000002401 inhibitory effect Effects 0.000 claims description 3
- XFQGAYBWNGHBHC-UHFFFAOYSA-N 1-methyl-5,6-dihydro-4h-pyrimidin-2-amine Chemical compound CN1CCCN=C1N XFQGAYBWNGHBHC-UHFFFAOYSA-N 0.000 claims description 2
- UTJJCBMDCZDYKT-UHFFFAOYSA-N 2-methyl-2,3,4,5-tetrahydropyridin-6-amine Chemical compound CC1CCCC(N)=N1 UTJJCBMDCZDYKT-UHFFFAOYSA-N 0.000 claims description 2
- NJBMZYSKLWQXLJ-UHFFFAOYSA-N 3,4-dihydro-2h-pyrrol-5-amine Chemical compound NC1=NCCC1 NJBMZYSKLWQXLJ-UHFFFAOYSA-N 0.000 claims description 2
- YAXGBZDYGZBRBQ-UHFFFAOYSA-N 4,5-dihydro-1,3-oxazol-2-amine Chemical compound NC1=NCCO1 YAXGBZDYGZBRBQ-UHFFFAOYSA-N 0.000 claims description 2
- ILLXLIKVXGHEOL-UHFFFAOYSA-N 5-(chloromethyl)-4,5-dihydro-1,3-oxazol-2-amine Chemical compound NC1=NCC(CCl)O1 ILLXLIKVXGHEOL-UHFFFAOYSA-N 0.000 claims description 2
- KIKNRRLKCBXXRD-UHFFFAOYSA-N 6-amino-3,4-dihydro-2h-pyridin-5-one Chemical compound NC1=NCCCC1=O KIKNRRLKCBXXRD-UHFFFAOYSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 231100000252 nontoxic Toxicity 0.000 claims description 2
- 230000003000 nontoxic effect Effects 0.000 claims description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 7
- 125000003545 alkoxy group Chemical group 0.000 claims 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims 2
- PEHDFSFYZKSKGH-UHFFFAOYSA-N 1,4,5,6-tetrahydropyrimidin-2-amine Chemical compound NC1=NCCCN1 PEHDFSFYZKSKGH-UHFFFAOYSA-N 0.000 claims 1
- RRCBYANJUIVMJX-UHFFFAOYSA-N 2,4-dimethyl-2,3,4,5-tetrahydropyridin-6-amine Chemical compound CC1CC(C)N=C(N)C1 RRCBYANJUIVMJX-UHFFFAOYSA-N 0.000 claims 1
- GGDLOMFAKKVDPT-UHFFFAOYSA-N 2-imino-4-methylpiperidine Chemical compound CC1CCN=C(N)C1 GGDLOMFAKKVDPT-UHFFFAOYSA-N 0.000 claims 1
- OQYPAQURYOEEGO-UHFFFAOYSA-N 3-methyl-2,3,4,5-tetrahydropyridin-6-amine Chemical compound CC1CCC(=N)NC1 OQYPAQURYOEEGO-UHFFFAOYSA-N 0.000 claims 1
- DISXFZWKRTZTRI-UHFFFAOYSA-N 4,5-dihydro-1h-imidazol-2-amine Chemical compound NC1=NCCN1 DISXFZWKRTZTRI-UHFFFAOYSA-N 0.000 claims 1
- KWOSGUYHQQCIGP-UHFFFAOYSA-N 5-methyl-2,3,4,5-tetrahydropyridin-6-amine Chemical compound CC1CCCNC1=N KWOSGUYHQQCIGP-UHFFFAOYSA-N 0.000 claims 1
- BJSKRLBQVZWBNS-UHFFFAOYSA-N 6-amino-2,3,4,5-tetrahydropyridin-5-ol Chemical compound NC1=NCCCC1O BJSKRLBQVZWBNS-UHFFFAOYSA-N 0.000 claims 1
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims 1
- 150000002430 hydrocarbons Chemical class 0.000 claims 1
- 239000000236 nitric oxide synthase inhibitor Substances 0.000 abstract description 3
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 3
- CSYSULGPHGCBQD-UHFFFAOYSA-N s-ethylisothiouronium diethylphosphate Chemical compound CCSC(N)=N.CCOP(O)(=O)OCC CSYSULGPHGCBQD-UHFFFAOYSA-N 0.000 abstract description 3
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 abstract 1
- 238000000034 method Methods 0.000 description 267
- 239000000047 product Substances 0.000 description 245
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 238
- 239000000203 mixture Substances 0.000 description 193
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 156
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 135
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 126
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 123
- 239000007787 solid Substances 0.000 description 117
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 92
- 229910001868 water Inorganic materials 0.000 description 87
- 235000019270 ammonium chloride Nutrition 0.000 description 78
- 238000000921 elemental analysis Methods 0.000 description 77
- 238000002360 preparation method Methods 0.000 description 72
- 238000005160 1H NMR spectroscopy Methods 0.000 description 71
- 238000004587 chromatography analysis Methods 0.000 description 67
- 239000000243 solution Substances 0.000 description 65
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 62
- 235000019439 ethyl acetate Nutrition 0.000 description 59
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 55
- 239000003921 oil Substances 0.000 description 46
- 235000019198 oils Nutrition 0.000 description 46
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 45
- 239000011541 reaction mixture Substances 0.000 description 44
- GKIRPKYJQBWNGO-OCEACIFDSA-N clomifene Chemical compound C1=CC(OCCN(CC)CC)=CC=C1C(\C=1C=CC=CC=1)=C(\Cl)C1=CC=CC=C1 GKIRPKYJQBWNGO-OCEACIFDSA-N 0.000 description 43
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 36
- 238000004458 analytical method Methods 0.000 description 36
- 239000002904 solvent Substances 0.000 description 31
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 30
- 239000000460 chlorine Substances 0.000 description 29
- 238000010992 reflux Methods 0.000 description 25
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 23
- QNJYWSIQJFUBOR-UHFFFAOYSA-N acetic acid;4-methyl-2,3,4,5-tetrahydropyridin-6-amine Chemical compound CC(O)=O.CC1CCN=C(N)C1 QNJYWSIQJFUBOR-UHFFFAOYSA-N 0.000 description 23
- 235000019441 ethanol Nutrition 0.000 description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- 238000001819 mass spectrum Methods 0.000 description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 230000002829 reductive effect Effects 0.000 description 21
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 17
- 239000003054 catalyst Substances 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 17
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- 238000005481 NMR spectroscopy Methods 0.000 description 15
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 15
- 229910003446 platinum oxide Inorganic materials 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
- 238000009472 formulation Methods 0.000 description 14
- 239000007788 liquid Substances 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000000706 filtrate Substances 0.000 description 12
- 239000010410 layer Substances 0.000 description 12
- 238000002844 melting Methods 0.000 description 12
- 230000008018 melting Effects 0.000 description 12
- 239000011780 sodium chloride Substances 0.000 description 12
- 239000004480 active ingredient Substances 0.000 description 11
- 238000000746 purification Methods 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 238000001704 evaporation Methods 0.000 description 10
- 230000008020 evaporation Effects 0.000 description 10
- 239000000463 material Substances 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- 229920006395 saturated elastomer Polymers 0.000 description 10
- 238000001816 cooling Methods 0.000 description 9
- 239000002158 endotoxin Substances 0.000 description 9
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 9
- ODUCDPQEXGNKDN-UHFFFAOYSA-N nitroxyl Chemical compound O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- 238000001665 trituration Methods 0.000 description 8
- 102000004190 Enzymes Human genes 0.000 description 7
- 108090000790 Enzymes Proteins 0.000 description 7
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 7
- 229930064664 L-arginine Natural products 0.000 description 7
- 235000014852 L-arginine Nutrition 0.000 description 7
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 7
- 150000002923 oximes Chemical class 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 7
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- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
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- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 6
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical class I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 6
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- 239000012258 stirred mixture Substances 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 6
- 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 6
- LCSAFGRUAPRSPW-UHFFFAOYSA-N 6-methyl-4-(trifluoromethyl)pyridin-2-amine Chemical compound CC1=CC(C(F)(F)F)=CC(N)=N1 LCSAFGRUAPRSPW-UHFFFAOYSA-N 0.000 description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 5
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- RHGKLRLOHDJJDR-BYPYZUCNSA-N L-citrulline Chemical compound NC(=O)NCCC[C@H]([NH3+])C([O-])=O RHGKLRLOHDJJDR-BYPYZUCNSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
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- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- KXLPFITUXCBXAV-UHFFFAOYSA-N acetic acid;5-methyl-2,3,4,5-tetrahydropyridin-6-amine Chemical compound CC(O)=O.CC1CCCN=C1N KXLPFITUXCBXAV-UHFFFAOYSA-N 0.000 description 4
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- 230000001419 dependent effect Effects 0.000 description 4
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 4
- 238000004817 gas chromatography Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
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- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000004187 tetrahydropyran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
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Classifications
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
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US14116893A | 1993-10-21 | 1993-10-21 | |
PCT/US1994/011832 WO1995011231A1 (en) | 1993-10-21 | 1994-10-20 | Amidino derivatives useful as nitric oxide synthase inhibitors |
Publications (3)
Publication Number | Publication Date |
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NO961403L NO961403L (no) | 1996-04-09 |
NO961403D0 NO961403D0 (no) | 1996-04-09 |
NO309303B1 true NO309303B1 (no) | 2001-01-15 |
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NO961403A NO309303B1 (no) | 1993-10-21 | 1996-04-09 | Farmasöytiske preparater, aminoderivater og aminoderivatenes anvendelse som nitrogenmonoksyd-syntaseinhibitorer |
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US (4) | US5854234A (de) |
EP (2) | EP0724570B1 (de) |
JP (1) | JPH09504028A (de) |
KR (1) | KR100342275B1 (de) |
CN (1) | CN1077886C (de) |
AT (1) | ATE177078T1 (de) |
AU (1) | AU688811B2 (de) |
CA (1) | CA2173468A1 (de) |
DE (1) | DE69416848T2 (de) |
DK (1) | DK0724570T3 (de) |
ES (1) | ES2129679T3 (de) |
GR (1) | GR3030167T3 (de) |
NO (1) | NO309303B1 (de) |
RU (1) | RU2136661C1 (de) |
WO (1) | WO1995011231A1 (de) |
Families Citing this family (88)
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CN1077886C (zh) * | 1993-10-21 | 2002-01-16 | G·D·瑟尔公司 | 用作一氧化一氮合酶抑制剂的脒基衍生物 |
ATE182889T1 (de) * | 1994-05-07 | 1999-08-15 | Astra Ab | Bicyclische amidinderivate als no-synthetase inhibitoren |
US5629322A (en) * | 1994-11-15 | 1997-05-13 | Merck & Co., Inc. | Cyclic amidine analogs as inhibitors of nitric oxide synthase |
DE4442116A1 (de) * | 1994-11-25 | 1996-05-30 | Cassella Ag | 2-Amino-1,3-thiazine als Hemmstoffe der Stickstoffmonoxid-Synthase |
IT1277486B1 (it) * | 1994-12-14 | 1997-11-10 | Japan Tobacco Inc | Derivati di tiazina o di tiazepina |
JPH08333258A (ja) * | 1994-12-14 | 1996-12-17 | Japan Tobacco Inc | チアジン又はチアゼピン誘導体及びそれら化合物を含有してなる一酸化窒素合成酵素阻害剤 |
WO1996021445A1 (en) * | 1995-01-13 | 1996-07-18 | The General Hospital Corporation | Methods of inhibiting neurodegenerative diseases |
US6011028A (en) * | 1995-04-20 | 2000-01-04 | G.D. Searle & Co. | Cyclic amidino agents useful as nitric oxide synthase inhibitors |
KR19990014671A (ko) * | 1995-05-10 | 1999-02-25 | 윌리암스로저에이. | 고리형 아미딘으로부터 유도된 산화질소 신타제 저해제 |
AU6945096A (en) * | 1995-09-14 | 1997-04-01 | Nippon Kayaku Kabushiki Kaisha | Nitrogen monoxide synthetase inhibitor comprising 2-aminopyridines as active ingredient |
US6043358A (en) * | 1995-11-01 | 2000-03-28 | Merck & Co., Inc. | Hexahydro-5-imino-1,4-heteroazepine derivatives as inhibitors of nitric oxide synthases |
JP3188715B2 (ja) * | 1995-11-01 | 2001-07-16 | メルク エンド カンパニー インコーポレーテッド | 一酸化窒素シンターゼの阻害物質としてのヘキサヒドロ−5−イミノ−1,4−ヘテロアゼピン誘導体 |
US5908842A (en) * | 1995-12-08 | 1999-06-01 | Merck & Co., Inc. | Substituted 2-acylamino-pyridines as inhibitors of nitric oxide synthase |
CZ291647B6 (cs) * | 1996-03-29 | 2003-04-16 | Pfizer Inc. | 6-Fenylpyridyl-2-aminové deriváty, jejich použití a farmaceutické kompozice na jejich bázi |
AU706110B2 (en) * | 1996-04-13 | 1999-06-10 | Astrazeneca Ab | Aminoisoquinolines and aminothienopyridine derivatives and their use as anti-inflammatory agents |
US5872124A (en) * | 1996-07-31 | 1999-02-16 | Thomas Jefferson University | Treatment of diseases of the central nervous system using uric acid as a scavenger of peroxynitrite |
US6090839A (en) * | 1996-12-23 | 2000-07-18 | Merck & Co., Inc. | Antidiabetic agents |
US6160000A (en) * | 1996-12-23 | 2000-12-12 | Merck & Co., Inc. | Antidiabetic agents based on aryl and heteroarylacetic acids |
YU35699A (sh) * | 1997-02-10 | 2002-06-19 | Pfizer Products Inc. | 2-amino-6-(2-supstituisan-4-fenoksi)-supstituisani piridini |
US6110930A (en) * | 1997-04-10 | 2000-08-29 | Ono Pharmaceutical Co., Ltd. | Condensed piperidine compound |
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1994
- 1994-10-20 CN CN94194397A patent/CN1077886C/zh not_active Expired - Fee Related
- 1994-10-20 AT AT94931893T patent/ATE177078T1/de not_active IP Right Cessation
- 1994-10-20 WO PCT/US1994/011832 patent/WO1995011231A1/en active IP Right Grant
- 1994-10-20 CA CA002173468A patent/CA2173468A1/en not_active Abandoned
- 1994-10-20 RU RU96109321A patent/RU2136661C1/ru not_active IP Right Cessation
- 1994-10-20 JP JP7512153A patent/JPH09504028A/ja active Pending
- 1994-10-20 EP EP94931893A patent/EP0724570B1/de not_active Expired - Lifetime
- 1994-10-20 AU AU80811/94A patent/AU688811B2/en not_active Ceased
- 1994-10-20 DE DE69416848T patent/DE69416848T2/de not_active Expired - Fee Related
- 1994-10-20 ES ES94931893T patent/ES2129679T3/es not_active Expired - Lifetime
- 1994-10-20 US US08/448,473 patent/US5854234A/en not_active Expired - Fee Related
- 1994-10-20 DK DK94931893T patent/DK0724570T3/da active
- 1994-10-20 EP EP98114519A patent/EP0897912A1/de not_active Withdrawn
- 1994-10-20 KR KR1019960702062A patent/KR100342275B1/ko not_active IP Right Cessation
-
1996
- 1996-04-09 NO NO961403A patent/NO309303B1/no not_active IP Right Cessation
-
1998
- 1998-05-06 US US09/073,929 patent/US6046211A/en not_active Expired - Fee Related
- 1998-07-28 US US09/123,822 patent/US6071906A/en not_active Expired - Fee Related
- 1998-07-28 US US09/123,720 patent/US6448286B1/en not_active Expired - Fee Related
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1999
- 1999-05-07 GR GR990401248T patent/GR3030167T3/el unknown
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JPH09504028A (ja) | 1997-04-22 |
AU688811B2 (en) | 1998-03-19 |
ES2129679T3 (es) | 1999-06-16 |
ATE177078T1 (de) | 1999-03-15 |
DE69416848T2 (de) | 1999-07-08 |
EP0724570B1 (de) | 1999-03-03 |
DE69416848D1 (en) | 1999-04-08 |
RU2136661C1 (ru) | 1999-09-10 |
US5854234A (en) | 1998-12-29 |
WO1995011231A1 (en) | 1995-04-27 |
NO961403L (no) | 1996-04-09 |
US6046211A (en) | 2000-04-04 |
CN1137268A (zh) | 1996-12-04 |
US6448286B1 (en) | 2002-09-10 |
KR960705777A (ko) | 1996-11-08 |
DK0724570T3 (da) | 1999-09-27 |
NO961403D0 (no) | 1996-04-09 |
US6071906A (en) | 2000-06-06 |
EP0897912A1 (de) | 1999-02-24 |
CA2173468A1 (en) | 1995-04-27 |
CN1077886C (zh) | 2002-01-16 |
AU8081194A (en) | 1995-05-08 |
GR3030167T3 (en) | 1999-08-31 |
KR100342275B1 (ko) | 2002-12-05 |
EP0724570A1 (de) | 1996-08-07 |
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