JP2001519411A - アザシクロアルキルアルカノイルプソイドテトラぺプチドの調製方法 - Google Patents
アザシクロアルキルアルカノイルプソイドテトラぺプチドの調製方法Info
- Publication number
- JP2001519411A JP2001519411A JP2000515867A JP2000515867A JP2001519411A JP 2001519411 A JP2001519411 A JP 2001519411A JP 2000515867 A JP2000515867 A JP 2000515867A JP 2000515867 A JP2000515867 A JP 2000515867A JP 2001519411 A JP2001519411 A JP 2001519411A
- Authority
- JP
- Japan
- Prior art keywords
- protecting group
- acid
- alkyl
- solution
- carboxylic acid
- 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.)
- Pending
Links
- 238000002360 preparation method Methods 0.000 title description 24
- 238000000034 method Methods 0.000 claims abstract description 149
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 87
- 125000006244 carboxylic acid protecting group Chemical group 0.000 claims abstract description 50
- 150000001875 compounds Chemical class 0.000 claims abstract description 42
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 37
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims abstract description 36
- 108010016626 Dipeptides Proteins 0.000 claims abstract description 32
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 claims abstract description 30
- 125000005120 alkyl cycloalkyl alkyl group Chemical group 0.000 claims abstract description 26
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 26
- 238000005859 coupling reaction Methods 0.000 claims abstract description 24
- 125000003118 aryl group Chemical group 0.000 claims abstract description 18
- 230000008878 coupling Effects 0.000 claims abstract description 18
- 238000010168 coupling process Methods 0.000 claims abstract description 18
- 125000002877 alkyl aryl group Chemical group 0.000 claims abstract description 9
- 125000003107 substituted aryl group Chemical group 0.000 claims abstract description 5
- -1 and J is H Chemical group 0.000 claims description 149
- 239000000243 solution Substances 0.000 claims description 123
- 239000000203 mixture Substances 0.000 claims description 115
- 150000003839 salts Chemical class 0.000 claims description 98
- 239000002253 acid Substances 0.000 claims description 82
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 74
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 72
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 41
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 37
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 37
- 239000001257 hydrogen Substances 0.000 claims description 36
- 229910052739 hydrogen Inorganic materials 0.000 claims description 36
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 35
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 30
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 29
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 29
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 28
- 239000007864 aqueous solution Substances 0.000 claims description 26
- 239000003054 catalyst Substances 0.000 claims description 26
- 150000002148 esters Chemical class 0.000 claims description 24
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 23
- 238000005984 hydrogenation reaction Methods 0.000 claims description 20
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 18
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 17
- 239000011260 aqueous acid Substances 0.000 claims description 16
- 229940002612 prodrug Drugs 0.000 claims description 16
- 239000000651 prodrug Substances 0.000 claims description 16
- 150000001732 carboxylic acid derivatives Chemical group 0.000 claims description 15
- 108010011485 Aspartame Proteins 0.000 claims description 14
- 239000000605 aspartame Substances 0.000 claims description 14
- 229960003438 aspartame Drugs 0.000 claims description 14
- 235000010357 aspartame Nutrition 0.000 claims description 14
- 229910052697 platinum Inorganic materials 0.000 claims description 14
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 claims description 12
- 229910021529 ammonia Inorganic materials 0.000 claims description 12
- 108010065338 N-ethylglycine Proteins 0.000 claims description 11
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 claims description 10
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical group [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 claims description 10
- 230000003213 activating effect Effects 0.000 claims description 9
- 125000002252 acyl group Chemical group 0.000 claims description 9
- 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 claims description 9
- 125000004076 pyridyl group Chemical group 0.000 claims description 9
- 238000007112 amidation reaction Methods 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 230000009467 reduction Effects 0.000 claims description 8
- 238000006722 reduction reaction Methods 0.000 claims description 8
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 claims description 7
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 7
- 230000009435 amidation Effects 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 7
- 239000011877 solvent mixture Substances 0.000 claims description 6
- 229960003692 gamma aminobutyric acid Drugs 0.000 claims description 5
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 claims description 5
- 229910003446 platinum oxide Inorganic materials 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 4
- 238000010531 catalytic reduction reaction Methods 0.000 claims description 4
- 239000003223 protective agent Substances 0.000 claims description 4
- 238000006114 decarboxylation reaction Methods 0.000 claims description 3
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 2
- 125000003158 alcohol group Chemical group 0.000 claims description 2
- 230000002862 amidating effect Effects 0.000 claims description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract description 43
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 34
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 125
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 84
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 72
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 70
- 230000002829 reductive effect Effects 0.000 description 67
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 57
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 57
- 239000011541 reaction mixture Substances 0.000 description 53
- 235000019439 ethyl acetate Nutrition 0.000 description 42
- 239000007787 solid Substances 0.000 description 38
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 36
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 34
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 33
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 33
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 33
- 239000002585 base Substances 0.000 description 32
- 125000006239 protecting group Chemical group 0.000 description 32
- 239000003921 oil Substances 0.000 description 29
- 235000019198 oils Nutrition 0.000 description 29
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 26
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 23
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 22
- 239000000706 filtrate Substances 0.000 description 22
- 239000000047 product Substances 0.000 description 22
- 238000003756 stirring Methods 0.000 description 22
- 238000006243 chemical reaction Methods 0.000 description 21
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 20
- LDECUSDQMXVUMP-UHFFFAOYSA-N benzyl 3-[6-[[2-(butylamino)-1-[3-methoxycarbonyl-4-(2-methoxy-2-oxoethoxy)phenyl]-2-oxoethyl]-hexylamino]-6-oxohexyl]-4-methyl-2-oxo-6-(4-phenylphenyl)-1,6-dihydropyrimidine-5-carboxylate Chemical compound O=C1NC(C=2C=CC(=CC=2)C=2C=CC=CC=2)C(C(=O)OCC=2C=CC=CC=2)=C(C)N1CCCCCC(=O)N(CCCCCC)C(C(=O)NCCCC)C1=CC=C(OCC(=O)OC)C(C(=O)OC)=C1 LDECUSDQMXVUMP-UHFFFAOYSA-N 0.000 description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical class OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 16
- 239000010410 layer Substances 0.000 description 16
- 239000000725 suspension Substances 0.000 description 15
- 238000001914 filtration Methods 0.000 description 14
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 14
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 14
- 102000004196 processed proteins & peptides Human genes 0.000 description 14
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 13
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 13
- 235000019341 magnesium sulphate Nutrition 0.000 description 13
- 239000012074 organic phase Substances 0.000 description 13
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 13
- 229920006395 saturated elastomer Polymers 0.000 description 13
- 239000004471 Glycine Substances 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- 229940024606 amino acid Drugs 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 11
- 239000012267 brine Substances 0.000 description 11
- 229910052751 metal Inorganic materials 0.000 description 11
- 239000002184 metal Substances 0.000 description 11
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 10
- 235000001014 amino acid Nutrition 0.000 description 10
- 150000001413 amino acids Chemical class 0.000 description 10
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- 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 10
- BZRPDNDVXWLKCX-UHFFFAOYSA-N 4-(1-phenylmethoxycarbonylpiperidin-4-yl)butanoic acid Chemical compound C1CC(CCCC(=O)O)CCN1C(=O)OCC1=CC=CC=C1 BZRPDNDVXWLKCX-UHFFFAOYSA-N 0.000 description 9
- YPIGGYHFMKJNKV-UHFFFAOYSA-N N-ethylglycine Chemical compound CC[NH2+]CC([O-])=O YPIGGYHFMKJNKV-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 238000001816 cooling Methods 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 9
- 239000003960 organic solvent Substances 0.000 description 9
- 239000008346 aqueous phase Substances 0.000 description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 8
- 239000012071 phase Substances 0.000 description 8
- 238000001953 recrystallisation Methods 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 239000012065 filter cake Substances 0.000 description 7
- 239000012458 free base Substances 0.000 description 7
- 230000004048 modification Effects 0.000 description 7
- 238000012986 modification Methods 0.000 description 7
- 229910052763 palladium Inorganic materials 0.000 description 7
- 229910052700 potassium Inorganic materials 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 6
- WDFQVEZOEIMWCR-UHFFFAOYSA-N 2-[ethyl-[4-(1-phenylmethoxycarbonylpiperidin-4-yl)butanoyl]amino]acetic acid Chemical compound C1CC(CCCC(=O)N(CC(O)=O)CC)CCN1C(=O)OCC1=CC=CC=C1 WDFQVEZOEIMWCR-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 6
- 150000007513 acids Chemical class 0.000 description 6
- 150000001298 alcohols Chemical class 0.000 description 6
- 239000012141 concentrate Substances 0.000 description 6
- 235000008504 concentrate Nutrition 0.000 description 6
- 150000002500 ions Chemical class 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 239000011591 potassium Substances 0.000 description 6
- SSOLNOMRVKKSON-UHFFFAOYSA-N proguanil Chemical compound CC(C)\N=C(/N)N=C(N)NC1=CC=C(Cl)C=C1 SSOLNOMRVKKSON-UHFFFAOYSA-N 0.000 description 6
- 230000004224 protection Effects 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 239000007921 spray Substances 0.000 description 6
- LTEOZJKVMBWJRT-UHFFFAOYSA-N 4-pyridin-1-ium-4-ylbutanoate Chemical compound OC(=O)CCCC1=CC=NC=C1 LTEOZJKVMBWJRT-UHFFFAOYSA-N 0.000 description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- HQMLIDZJXVVKCW-REOHCLBHSA-N L-alaninamide Chemical compound C[C@H](N)C(N)=O HQMLIDZJXVVKCW-REOHCLBHSA-N 0.000 description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 101000655609 Streptomyces azureus Thiostrepton Proteins 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 239000003125 aqueous solvent Substances 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000011521 glass Substances 0.000 description 5
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 5
- 150000004702 methyl esters Chemical class 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 239000002002 slurry Substances 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 239000012258 stirred mixture Substances 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- XBNGYFFABRKICK-UHFFFAOYSA-N 2,3,4,5,6-pentafluorophenol Chemical compound OC1=C(F)C(F)=C(F)C(F)=C1F XBNGYFFABRKICK-UHFFFAOYSA-N 0.000 description 4
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 4
- 235000004279 alanine Nutrition 0.000 description 4
- 150000004703 alkoxides Chemical class 0.000 description 4
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 4
- 229910052791 calcium Inorganic materials 0.000 description 4
- 239000011575 calcium Substances 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 238000010511 deprotection reaction Methods 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 150000002170 ethers Chemical class 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 229910052744 lithium Inorganic materials 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
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- 150000002823 nitrates Chemical class 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- GUWZGMWHDAJAOC-UHFFFAOYSA-N oxoplatinum;hydrate Chemical compound O.[Pt]=O GUWZGMWHDAJAOC-UHFFFAOYSA-N 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 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
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- KIDBBTHHMJOMAU-UHFFFAOYSA-N propan-1-ol;hydrate Chemical compound O.CCCO KIDBBTHHMJOMAU-UHFFFAOYSA-N 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- ZHNFLHYOFXQIOW-LPYZJUEESA-N quinine sulfate dihydrate Chemical compound [H+].[H+].O.O.[O-]S([O-])(=O)=O.C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21.C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 ZHNFLHYOFXQIOW-LPYZJUEESA-N 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 239000002151 riboflavin Substances 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 229910052594 sapphire Inorganic materials 0.000 description 1
- 239000010980 sapphire Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- GYBMSOFSBPZKCX-UHFFFAOYSA-N sodium;ethanol;ethanolate Chemical compound [Na+].CCO.CC[O-] GYBMSOFSBPZKCX-UHFFFAOYSA-N 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000006467 substitution reaction 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
- 229960002317 succinimide Drugs 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- UJJDEOLXODWCGK-UHFFFAOYSA-N tert-butyl carbonochloridate Chemical compound CC(C)(C)OC(Cl)=O UJJDEOLXODWCGK-UHFFFAOYSA-N 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 230000009974 thixotropic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 235000020234 walnut Nutrition 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- UGZADUVQMDAIAO-UHFFFAOYSA-L zinc hydroxide Chemical compound [OH-].[OH-].[Zn+2] UGZADUVQMDAIAO-UHFFFAOYSA-L 0.000 description 1
- 229940007718 zinc hydroxide Drugs 0.000 description 1
- 229910021511 zinc hydroxide Inorganic materials 0.000 description 1
- ORQXBVXKBGUSBA-QMMMGPOBSA-N β-cyclohexyl-alanine Chemical compound OC(=O)[C@@H](N)CC1CCCCC1 ORQXBVXKBGUSBA-QMMMGPOBSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon 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
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/021—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)n-C(=0)-, n being 5 or 6; for n > 6, classification in C07K5/06 - C07K5/10, according to the moiety having normal peptide bonds
-
- 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
- C07K5/06104—Dipeptides with the first amino acid being acidic
- C07K5/06113—Asp- or Asn-amino acid
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Crystallography & Structural Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Urology & Nephrology (AREA)
- Heart & Thoracic Surgery (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Hydrogenated Pyridines (AREA)
- Pyridine Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US6171997P | 1997-10-10 | 1997-10-10 | |
| US60/061,719 | 1997-10-10 | ||
| PCT/US1998/021326 WO1999019294A1 (en) | 1997-05-14 | 1998-10-09 | Process for the preparation of azacycloalkylalkanoyl pseudotetrapeptides |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2001519411A true JP2001519411A (ja) | 2001-10-23 |
| JP2001519411A5 JP2001519411A5 (cg-RX-API-DMAC7.html) | 2006-01-05 |
Family
ID=22037674
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2000515867A Pending JP2001519411A (ja) | 1997-10-10 | 1998-10-09 | アザシクロアルキルアルカノイルプソイドテトラぺプチドの調製方法 |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US6180759B1 (cg-RX-API-DMAC7.html) |
| EP (1) | EP1030831A4 (cg-RX-API-DMAC7.html) |
| JP (1) | JP2001519411A (cg-RX-API-DMAC7.html) |
| KR (1) | KR20010024467A (cg-RX-API-DMAC7.html) |
| CN (1) | CN1278791A (cg-RX-API-DMAC7.html) |
| AP (1) | AP1057A (cg-RX-API-DMAC7.html) |
| AU (1) | AU738114B2 (cg-RX-API-DMAC7.html) |
| BG (1) | BG104408A (cg-RX-API-DMAC7.html) |
| BR (1) | BR9814068A (cg-RX-API-DMAC7.html) |
| CA (1) | CA2306823A1 (cg-RX-API-DMAC7.html) |
| EA (1) | EA002724B1 (cg-RX-API-DMAC7.html) |
| HU (1) | HUP0003788A3 (cg-RX-API-DMAC7.html) |
| IL (1) | IL135553A0 (cg-RX-API-DMAC7.html) |
| NO (1) | NO20001793D0 (cg-RX-API-DMAC7.html) |
| OA (1) | OA11369A (cg-RX-API-DMAC7.html) |
| PL (1) | PL340915A1 (cg-RX-API-DMAC7.html) |
| SK (1) | SK4332000A3 (cg-RX-API-DMAC7.html) |
| ZA (1) | ZA989241B (cg-RX-API-DMAC7.html) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2007513997A (ja) * | 2003-12-16 | 2007-05-31 | エスケー ケミカルズ カンパニー リミテッド | アムロジピンのゲンチシン酸塩及びその製造方法 |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL331772A1 (en) * | 1996-08-21 | 1999-08-02 | Rhone Poulenc Rorer Pharma | Stable non-hygroscopic crystalline form of n-[n-n-(4-piperidin-4-yl)-n-ethylglycin] compounds |
| CN100422147C (zh) * | 2002-11-01 | 2008-10-01 | 北京天衡药物研究院 | 一种制备0-取代磺酰酪氨酸类化合物的方法 |
| CN103254265B (zh) * | 2012-02-21 | 2016-07-13 | 上海希迈医药科技有限公司 | 醋酸阿比特龙三氟乙酸盐及其制备方法和应用 |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1042487A (en) * | 1964-06-25 | 1966-09-14 | Ici Ltd | Polypeptide derivatives |
| JPS6322081A (ja) * | 1986-07-11 | 1988-01-29 | Kissei Pharmaceut Co Ltd | 新規なアミノ酸誘導体 |
| CA2008116C (en) * | 1989-02-23 | 2001-11-20 | Thomas Weller | Glycine derivatives |
| IE902238A1 (en) * | 1989-06-30 | 1991-01-16 | Abbott Lab | Tetrapeptide type-b cck receptor ligands |
| IE914334A1 (en) * | 1990-12-17 | 1992-06-17 | Black James Foundation | Tetrapeptide derivatives and analogues |
| US5780590A (en) * | 1993-10-15 | 1998-07-14 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Antithrombotic azacycloalkylalkanoyl peptides and pseudopeptides |
| UA44258C2 (uk) * | 1993-10-15 | 2002-02-15 | Рон-Пуленк Рорер Фармасьютікалз Інк. | Антитромботичні азациклоалкілалканоілпептиди та псевдопептиди, фармацевтична композиція, що їх містить, спосіб профілактики або лікування тромбозу у ссавців (варіанти) |
| GB9516994D0 (en) * | 1995-08-18 | 1995-10-18 | Iaf Biochem Int | Solution synthesis of peripheral acting analgestic opioid tetrapeptides |
| EP0768384B1 (en) * | 1995-10-11 | 2001-06-13 | Holland Sweetener Company V.o.F. | Improved enzymatic coupling reaction of N-protected-L-aspartic acid and phenylalanine methyl ester |
| PL331772A1 (en) * | 1996-08-21 | 1999-08-02 | Rhone Poulenc Rorer Pharma | Stable non-hygroscopic crystalline form of n-[n-n-(4-piperidin-4-yl)-n-ethylglycin] compounds |
| NL1005808C2 (nl) * | 1997-04-14 | 1998-10-19 | Dsm Nv | Hexahydro-aspartaamamiden en werkwijze voor de bereiding ervan. |
-
1998
- 1998-10-09 EA EA200000399A patent/EA002724B1/ru not_active IP Right Cessation
- 1998-10-09 JP JP2000515867A patent/JP2001519411A/ja active Pending
- 1998-10-09 IL IL13555398A patent/IL135553A0/xx unknown
- 1998-10-09 ZA ZA989241A patent/ZA989241B/xx unknown
- 1998-10-09 CN CN98810983A patent/CN1278791A/zh active Pending
- 1998-10-09 KR KR1020007003829A patent/KR20010024467A/ko not_active Withdrawn
- 1998-10-09 PL PL98340915A patent/PL340915A1/xx unknown
- 1998-10-09 AP APAP/P/2000/001781A patent/AP1057A/en active
- 1998-10-09 EP EP98953345A patent/EP1030831A4/en not_active Withdrawn
- 1998-10-09 SK SK433-2000A patent/SK4332000A3/sk unknown
- 1998-10-09 CA CA002306823A patent/CA2306823A1/en not_active Abandoned
- 1998-10-09 AU AU10746/99A patent/AU738114B2/en not_active Ceased
- 1998-10-09 HU HU0003788A patent/HUP0003788A3/hu unknown
- 1998-10-09 BR BR9814068-0A patent/BR9814068A/pt not_active IP Right Cessation
-
2000
- 2000-03-31 OA OA1200000096A patent/OA11369A/en unknown
- 2000-04-06 NO NO20001793A patent/NO20001793D0/no not_active Application Discontinuation
- 2000-04-07 US US09/544,680 patent/US6180759B1/en not_active Expired - Fee Related
- 2000-05-08 BG BG104408A patent/BG104408A/bg unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2007513997A (ja) * | 2003-12-16 | 2007-05-31 | エスケー ケミカルズ カンパニー リミテッド | アムロジピンのゲンチシン酸塩及びその製造方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20010024467A (ko) | 2001-03-26 |
| BR9814068A (pt) | 2000-09-26 |
| CN1278791A (zh) | 2001-01-03 |
| EP1030831A1 (en) | 2000-08-30 |
| SK4332000A3 (en) | 2000-12-11 |
| EA200000399A1 (ru) | 2000-10-30 |
| AP2000001781A0 (en) | 2000-06-30 |
| OA11369A (en) | 2004-01-27 |
| US6180759B1 (en) | 2001-01-30 |
| AU738114B2 (en) | 2001-09-06 |
| BG104408A (bg) | 2000-12-29 |
| EP1030831A4 (en) | 2003-01-02 |
| IL135553A0 (en) | 2001-05-20 |
| HUP0003788A2 (hu) | 2001-04-28 |
| ZA989241B (en) | 1999-06-04 |
| NO20001793L (no) | 2000-04-06 |
| AU1074699A (en) | 1999-05-03 |
| CA2306823A1 (en) | 1999-04-22 |
| AP1057A (en) | 2002-04-08 |
| PL340915A1 (en) | 2001-03-12 |
| HUP0003788A3 (en) | 2001-05-28 |
| EA002724B1 (ru) | 2002-08-29 |
| NO20001793D0 (no) | 2000-04-06 |
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