IL92102A - Renin-inhibitory peptides containing difluoromethylene amide bond replacements, process for their preparation and pharmaceutical compositions containing them - Google Patents
Renin-inhibitory peptides containing difluoromethylene amide bond replacements, process for their preparation and pharmaceutical compositions containing themInfo
- Publication number
- IL92102A IL92102A IL9210289A IL9210289A IL92102A IL 92102 A IL92102 A IL 92102A IL 9210289 A IL9210289 A IL 9210289A IL 9210289 A IL9210289 A IL 9210289A IL 92102 A IL92102 A IL 92102A
- Authority
- IL
- Israel
- Prior art keywords
- methyl
- compound
- val
- amino acid
- groups
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 47
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 7
- 238000002360 preparation method Methods 0.000 title claims description 7
- 108010026906 renin inhibitory peptide Proteins 0.000 title 1
- -1 difluoro-methylene moiety Chemical group 0.000 claims abstract description 57
- 150000001412 amines Chemical group 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims description 89
- 239000000203 mixture Substances 0.000 claims description 31
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 29
- 229950003188 isovaleryl diethylamide Drugs 0.000 claims description 28
- 238000006243 chemical reaction Methods 0.000 claims description 25
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 125000006239 protecting group Chemical group 0.000 claims description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- 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 15
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 14
- 125000003118 aryl group Chemical group 0.000 claims description 13
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 12
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 10
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Chemical compound CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 claims description 9
- 235000008206 alpha-amino acids Nutrition 0.000 claims description 9
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 8
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 8
- 150000001370 alpha-amino acid derivatives Chemical class 0.000 claims description 8
- SNHRLVCMMWUAJD-SUYDQAKGSA-N betamethasone valerate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(OC(=O)CCCC)[C@@]1(C)C[C@@H]2O SNHRLVCMMWUAJD-SUYDQAKGSA-N 0.000 claims description 8
- 239000012442 inert solvent Substances 0.000 claims description 8
- 239000000376 reactant Substances 0.000 claims description 8
- 239000012298 atmosphere Substances 0.000 claims description 7
- 238000007254 oxidation reaction Methods 0.000 claims description 7
- GEYBMYRBIABFTA-VIFPVBQESA-N O-methyl-L-tyrosine Chemical compound COC1=CC=C(C[C@H](N)C(O)=O)C=C1 GEYBMYRBIABFTA-VIFPVBQESA-N 0.000 claims description 6
- 125000001153 fluoro group Chemical group F* 0.000 claims description 6
- 230000003647 oxidation Effects 0.000 claims description 6
- 125000001557 phthalyl group Chemical group C(=O)(O)C1=C(C(=O)*)C=CC=C1 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 125000006479 2-pyridyl methyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 5
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 claims description 5
- 235000001014 amino acid Nutrition 0.000 claims description 5
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 claims description 5
- 239000011541 reaction mixture Substances 0.000 claims description 5
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 238000003776 cleavage reaction Methods 0.000 claims description 4
- 150000004677 hydrates Chemical class 0.000 claims description 4
- 238000011065 in-situ storage Methods 0.000 claims description 4
- 239000002808 molecular sieve Substances 0.000 claims description 4
- 230000007017 scission Effects 0.000 claims description 4
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 4
- 125000004080 3-carboxypropanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C(O[H])=O 0.000 claims description 3
- XPDXVDYUQZHFPV-UHFFFAOYSA-N Dansyl Chloride Chemical compound C1=CC=C2C(N(C)C)=CC=CC2=C1S(Cl)(=O)=O XPDXVDYUQZHFPV-UHFFFAOYSA-N 0.000 claims description 3
- 229960000583 acetic acid Drugs 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 3
- 125000001295 dansyl group Chemical group [H]C1=C([H])C(N(C([H])([H])[H])C([H])([H])[H])=C2C([H])=C([H])C([H])=C(C2=C1[H])S(*)(=O)=O 0.000 claims description 3
- 239000012362 glacial acetic acid Substances 0.000 claims description 3
- RCBVKBFIWMOMHF-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O RCBVKBFIWMOMHF-UHFFFAOYSA-L 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 3
- RWSOTUBLDIXVET-UHFFFAOYSA-O sulfonium Chemical compound [SH3+] RWSOTUBLDIXVET-UHFFFAOYSA-O 0.000 claims description 3
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 238000010511 deprotection reaction Methods 0.000 claims description 2
- 150000003512 tertiary amines Chemical class 0.000 claims description 2
- 230000001225 therapeutic effect Effects 0.000 claims description 2
- 150000001413 amino acids Chemical class 0.000 claims 4
- 125000000174 L-prolyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(*)=O 0.000 claims 2
- 125000003275 alpha amino acid group Chemical group 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 230000001077 hypotensive effect Effects 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000001590 oxidative effect Effects 0.000 claims 1
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 17
- 125000004433 nitrogen atom Chemical group N* 0.000 abstract description 7
- 108090000783 Renin Proteins 0.000 abstract description 6
- 102100028255 Renin Human genes 0.000 abstract description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 abstract description 6
- 108091005804 Peptidases Proteins 0.000 abstract description 5
- 102000035195 Peptidases Human genes 0.000 abstract description 5
- 230000002401 inhibitory effect Effects 0.000 abstract description 5
- 235000019833 protease Nutrition 0.000 abstract description 5
- 239000000758 substrate Substances 0.000 abstract description 5
- 206010020772 Hypertension Diseases 0.000 abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 78
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 62
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 22
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 22
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 22
- 239000000741 silica gel Substances 0.000 description 22
- 229910002027 silica gel Inorganic materials 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 17
- 239000000243 solution Substances 0.000 description 17
- 150000001408 amides Chemical class 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical group N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- 239000000543 intermediate Substances 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 10
- 150000002148 esters Chemical class 0.000 description 10
- 150000002576 ketones Chemical class 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- 239000001257 hydrogen Substances 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- 150000001298 alcohols Chemical class 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 6
- IRSJDVYTJUCXRV-UHFFFAOYSA-N ethyl 2-bromo-2,2-difluoroacetate Chemical compound CCOC(=O)C(F)(F)Br IRSJDVYTJUCXRV-UHFFFAOYSA-N 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- MJAVVEZMQKZOSB-UHFFFAOYSA-N 5-cyclohexyl-2,2-difluoro-3-hydroxy-4-(phenylmethoxycarbonylamino)pentanoic acid Chemical compound C=1C=CC=CC=1COC(=O)NC(C(O)C(F)(F)C(O)=O)CC1CCCCC1 MJAVVEZMQKZOSB-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 4
- 125000006242 amine protecting group Chemical group 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 150000003254 radicals Chemical class 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 239000004474 valine Substances 0.000 description 4
- 229910052725 zinc Inorganic materials 0.000 description 4
- 239000011701 zinc Substances 0.000 description 4
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 3
- 239000005695 Ammonium acetate Substances 0.000 description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical group NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 3
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 235000019257 ammonium acetate Nutrition 0.000 description 3
- 229940043376 ammonium acetate Drugs 0.000 description 3
- 239000000010 aprotic solvent Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 229910000085 borane Inorganic materials 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000006268 reductive amination reaction Methods 0.000 description 3
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- 241000167854 Bourreria succulenta Species 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 238000006809 Jones oxidation reaction Methods 0.000 description 2
- 125000000393 L-methionino group Chemical group [H]OC(=O)[C@@]([H])(N([H])[*])C([H])([H])C(SC([H])([H])[H])([H])[H] 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 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
- 229930006000 Sucrose Natural products 0.000 description 2
- 238000006859 Swern oxidation reaction Methods 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- LTBOQUFZWDEXCI-UHFFFAOYSA-N benzyl n-(1-amino-2,2-difluoro-3-hydroxy-6-methyl-1-oxoheptan-4-yl)carbamate Chemical compound NC(=O)C(F)(F)C(O)C(CC(C)C)NC(=O)OCC1=CC=CC=C1 LTBOQUFZWDEXCI-UHFFFAOYSA-N 0.000 description 2
- MQHGQTHXEFNQFV-INIZCTEOSA-N benzyl n-[(2s)-1-cyclohexyl-3-oxopropan-2-yl]carbamate Chemical compound C([C@@H](C=O)NC(=O)OCC=1C=CC=CC=1)C1CCCCC1 MQHGQTHXEFNQFV-INIZCTEOSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 235000019693 cherries Nutrition 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 150000002081 enamines Chemical class 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- BMFVGAAISNGQNM-UHFFFAOYSA-N isopentylamine Chemical compound CC(C)CCN BMFVGAAISNGQNM-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 2
- 125000002524 organometallic group Chemical group 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 238000005897 peptide coupling reaction Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 229910052701 rubidium Inorganic materials 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- AXEOMQHKTSGLGS-VIFPVBQESA-N (2s)-2-amino-3-(4-hydroxy-2-methylphenyl)propanoic acid Chemical compound CC1=CC(O)=CC=C1C[C@H](N)C(O)=O AXEOMQHKTSGLGS-VIFPVBQESA-N 0.000 description 1
- QNGGSVANUAULGK-QRPNPIFTSA-N (2s)-2-amino-3-cyclohexylpropanoic acid;hydrochloride Chemical compound Cl.OC(=O)[C@@H](N)CC1CCCCC1 QNGGSVANUAULGK-QRPNPIFTSA-N 0.000 description 1
- MNABZONTQXNLDT-HNNXBMFYSA-N (2s)-3-cyclohexyl-2-(phenylmethoxycarbonylamino)propanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC=1C=CC=CC=1)C1CCCCC1 MNABZONTQXNLDT-HNNXBMFYSA-N 0.000 description 1
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- PIOHXJZGTGBPRN-UHFFFAOYSA-N 2,2-difluoro-3-hydroxy-5-phenyl-4-(phenylmethoxycarbonylamino)pentanoic acid Chemical compound C=1C=CC=CC=1COC(=O)NC(C(O)C(F)(F)C(O)=O)CC1=CC=CC=C1 PIOHXJZGTGBPRN-UHFFFAOYSA-N 0.000 description 1
- LZCMQBRCQWOSHZ-UHFFFAOYSA-N 2-bromo-2,2-difluoroacetic acid Chemical compound OC(=O)C(F)(F)Br LZCMQBRCQWOSHZ-UHFFFAOYSA-N 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- KCZHDRHOSNPTJZ-UHFFFAOYSA-N 3,3,3-trifluoropropanoyl 3,3,3-trifluoropropanoate Chemical compound FC(F)(F)CC(=O)OC(=O)CC(F)(F)F KCZHDRHOSNPTJZ-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
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Classifications
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/20—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/16—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/18—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by doubly-bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
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- 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
- C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
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- 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
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Landscapes
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- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Peptides Or Proteins (AREA)
- Luminescent Compositions (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Compounds Of Unknown Constitution (AREA)
- Pyridine Compounds (AREA)
- Pyrrole Compounds (AREA)
- Measuring Pulse, Heart Rate, Blood Pressure Or Blood Flow (AREA)
- Measurement And Recording Of Electrical Phenomena And Electrical Characteristics Of The Living Body (AREA)
- Radio Relay Systems (AREA)
- Inspection Of Paper Currency And Valuable Securities (AREA)
- Photoreceptors In Electrophotography (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP88402735A EP0371179A1 (de) | 1988-10-28 | 1988-10-28 | Analoge von Peptidase-Substraten |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IL92102A0 IL92102A0 (en) | 1990-07-12 |
| IL92102A true IL92102A (en) | 1994-07-31 |
Family
ID=8200435
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL9210289A IL92102A (en) | 1988-10-28 | 1989-10-24 | Renin-inhibitory peptides containing difluoromethylene amide bond replacements, process for their preparation and pharmaceutical compositions containing them |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US5114927A (de) |
| EP (2) | EP0371179A1 (de) |
| JP (1) | JP2899327B2 (de) |
| CN (1) | CN1031880C (de) |
| AT (1) | ATE147405T1 (de) |
| AU (1) | AU622723B2 (de) |
| CA (1) | CA2001265C (de) |
| DE (1) | DE68927630T2 (de) |
| DK (1) | DK537589A (de) |
| ES (1) | ES2099072T3 (de) |
| FI (1) | FI95272C (de) |
| GR (1) | GR3023027T3 (de) |
| HU (1) | HU209311B (de) |
| IL (1) | IL92102A (de) |
| NO (1) | NO301074B1 (de) |
| PH (1) | PH27239A (de) |
| PT (1) | PT92140B (de) |
| ZA (1) | ZA898026B (de) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0356595A1 (de) * | 1988-09-01 | 1990-03-07 | Merrell Dow Pharmaceuticals Inc. | Peptidase-Hemmer |
| CA2021660A1 (en) * | 1989-07-26 | 1991-01-27 | Philippe Bey | Peptidase inhibitors |
| IL95380A0 (en) * | 1989-09-05 | 1991-06-30 | Abbott Lab | Peptidyl difluorodiol renin inhibitors |
| US5714470A (en) | 1991-08-22 | 1998-02-03 | Merrell Pharmaceuticals, Inc. | Orally-active elastase inhibitors |
| US5478811A (en) * | 1991-08-22 | 1995-12-26 | Merrell Dow Pharmaceuticals Inc. | Orally-active elastase inhibitors |
| ES2161293T3 (es) * | 1994-06-02 | 2001-12-01 | Merrell Pharma Inc | Derivados de enol acilados como profarmacos de inhibidores de la elastasa. |
| DK0763055T3 (da) * | 1994-06-02 | 2000-05-08 | Merrell Pharma Inc | Perflouralkylketon-inhibitorer af elastase og fremgangsmåde til fremstilling deraf |
| US6172044B1 (en) | 1995-12-01 | 2001-01-09 | Aventis Pharmaceuticals Inc. | Acylated enol derivative of α-ketoesters and α-ketoamides |
| US5948886A (en) * | 1996-11-20 | 1999-09-07 | Hoechst Marion Roussel, Inc. | Acylated enol derivatives of α-ketoesters and α-ketoamides |
| CZ298749B6 (cs) * | 1996-10-18 | 2008-01-16 | Vertex Pharmaceuticals Incorporated | Inhibitory serinových proteáz a farmaceutické prostředky s jejich obsahem |
| PE20050374A1 (es) | 2003-09-05 | 2005-05-30 | Vertex Pharma | Inhibidores de proteasas de serina, en particular proteasa ns3-ns4a del vhc |
| FR2914920B1 (fr) | 2007-04-11 | 2011-09-09 | Clariant Specialty Fine Chem F | Procede de deacetalisation d'alpha-aminoacetals. |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4518528A (en) * | 1983-05-19 | 1985-05-21 | Rasnick David W | α Amino fluoro ketones |
| ZA86746B (en) * | 1985-02-04 | 1986-09-24 | Merrell Dow Pharma | Novel peptidase inhibitors |
| DE3674131D1 (de) * | 1985-04-19 | 1990-10-18 | Upjohn Co | Substituierte dihalo-statin-reninhemmungsmittel. |
| EP0204571B1 (de) * | 1985-06-07 | 1992-01-22 | Ici Americas Inc. | Selektionierte Difluorverbindungen |
| JPS63503380A (ja) * | 1986-01-16 | 1988-12-08 | アボット・ラボラトリーズ | ペプチド類似体 |
| GB8711748D0 (en) * | 1986-06-05 | 1987-06-24 | Ici America Inc | Difluoro keto compounds |
| NZ223148A (en) * | 1987-01-16 | 1989-10-27 | Merrell Dow Pharma | Peptide derivatives having peptidase inhibition activity |
-
1988
- 1988-10-28 EP EP88402735A patent/EP0371179A1/de not_active Withdrawn
-
1989
- 1989-10-23 CA CA002001265A patent/CA2001265C/en not_active Expired - Fee Related
- 1989-10-23 ZA ZA898026A patent/ZA898026B/xx unknown
- 1989-10-24 IL IL9210289A patent/IL92102A/en not_active IP Right Cessation
- 1989-10-27 DE DE68927630T patent/DE68927630T2/de not_active Expired - Fee Related
- 1989-10-27 JP JP1278753A patent/JP2899327B2/ja not_active Expired - Fee Related
- 1989-10-27 PH PH39423A patent/PH27239A/en unknown
- 1989-10-27 HU HU895473A patent/HU209311B/hu not_active IP Right Cessation
- 1989-10-27 DK DK537589A patent/DK537589A/da not_active Application Discontinuation
- 1989-10-27 EP EP89402976A patent/EP0368719B1/de not_active Expired - Lifetime
- 1989-10-27 ES ES89402976T patent/ES2099072T3/es not_active Expired - Lifetime
- 1989-10-27 NO NO894300A patent/NO301074B1/no not_active IP Right Cessation
- 1989-10-27 FI FI895109A patent/FI95272C/fi not_active IP Right Cessation
- 1989-10-27 AU AU43867/89A patent/AU622723B2/en not_active Ceased
- 1989-10-27 AT AT89402976T patent/ATE147405T1/de not_active IP Right Cessation
- 1989-10-27 PT PT92140A patent/PT92140B/pt not_active IP Right Cessation
- 1989-10-28 CN CN89108935A patent/CN1031880C/zh not_active Expired - Fee Related
-
1991
- 1991-09-05 US US07/759,057 patent/US5114927A/en not_active Expired - Fee Related
-
1997
- 1997-04-03 GR GR970400694T patent/GR3023027T3/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU4386789A (en) | 1990-05-03 |
| PT92140B (pt) | 1996-03-29 |
| PH27239A (en) | 1993-05-04 |
| US5114927A (en) | 1992-05-19 |
| ZA898026B (en) | 1990-07-25 |
| JPH02172961A (ja) | 1990-07-04 |
| HU895473D0 (en) | 1990-01-28 |
| JP2899327B2 (ja) | 1999-06-02 |
| CA2001265C (en) | 2001-05-01 |
| DK537589D0 (da) | 1989-10-27 |
| GR3023027T3 (en) | 1997-07-30 |
| DE68927630T2 (de) | 1997-06-12 |
| EP0368719A2 (de) | 1990-05-16 |
| HUT51649A (en) | 1990-05-28 |
| EP0371179A1 (de) | 1990-06-06 |
| EP0368719B1 (de) | 1997-01-08 |
| CN1043504A (zh) | 1990-07-04 |
| CN1031880C (zh) | 1996-05-29 |
| EP0368719A3 (de) | 1991-10-02 |
| NO894300L (no) | 1990-04-30 |
| DE68927630D1 (de) | 1997-02-20 |
| CA2001265A1 (en) | 1990-04-28 |
| ES2099072T3 (es) | 1997-05-16 |
| NO301074B1 (no) | 1997-09-08 |
| FI95272C (fi) | 1996-01-10 |
| IL92102A0 (en) | 1990-07-12 |
| NO894300D0 (no) | 1989-10-27 |
| DK537589A (da) | 1990-04-29 |
| PT92140A (pt) | 1990-04-30 |
| FI895109A0 (fi) | 1989-10-27 |
| ATE147405T1 (de) | 1997-01-15 |
| HU209311B (en) | 1994-04-28 |
| FI95272B (fi) | 1995-09-29 |
| AU622723B2 (en) | 1992-04-16 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| KB | Patent renewed | ||
| KB | Patent renewed | ||
| HC | Change of name of proprietor(s) |
Owner name: AVENTIS INC. Free format text: FORMER NAME:MERRELL PHARMACEUTICALS INC. |
|
| MM9K | Patent not in force due to non-payment of renewal fees |