JP2018505847A - トリペプチド化合物、その調製方法及びその用途 - Google Patents
トリペプチド化合物、その調製方法及びその用途 Download PDFInfo
- Publication number
- JP2018505847A JP2018505847A JP2017527865A JP2017527865A JP2018505847A JP 2018505847 A JP2018505847 A JP 2018505847A JP 2017527865 A JP2017527865 A JP 2017527865A JP 2017527865 A JP2017527865 A JP 2017527865A JP 2018505847 A JP2018505847 A JP 2018505847A
- Authority
- JP
- Japan
- Prior art keywords
- acid
- formula
- compound
- alkyl
- carbon
- 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.)
- Granted
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 98
- 238000002360 preparation method Methods 0.000 title abstract description 6
- 206010020772 Hypertension Diseases 0.000 claims abstract description 32
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
- 238000011282 treatment Methods 0.000 claims abstract description 12
- 230000002265 prevention Effects 0.000 claims abstract description 8
- -1 arylureido Chemical group 0.000 claims description 60
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 50
- 125000000217 alkyl group Chemical group 0.000 claims description 45
- 150000003839 salts Chemical class 0.000 claims description 34
- 125000003118 aryl group Chemical group 0.000 claims description 33
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 32
- 238000000034 method Methods 0.000 claims description 32
- 239000000203 mixture Substances 0.000 claims description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 26
- 125000001072 heteroaryl group Chemical group 0.000 claims description 25
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 21
- 239000001257 hydrogen Substances 0.000 claims description 21
- 125000004432 carbon atom Chemical group C* 0.000 claims description 19
- 125000000623 heterocyclic group Chemical group 0.000 claims description 19
- 125000003342 alkenyl group Chemical group 0.000 claims description 18
- 238000003786 synthesis reaction Methods 0.000 claims description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 239000002253 acid Substances 0.000 claims description 16
- 125000000304 alkynyl group Chemical group 0.000 claims description 16
- 230000015572 biosynthetic process Effects 0.000 claims description 16
- 150000002148 esters Chemical class 0.000 claims description 16
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 16
- 150000002431 hydrogen Chemical class 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 14
- 208000011775 arteriosclerosis disease Diseases 0.000 claims description 14
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 14
- 125000004475 heteroaralkyl group Chemical group 0.000 claims description 14
- 229910052760 oxygen Inorganic materials 0.000 claims description 14
- 239000001301 oxygen Substances 0.000 claims description 14
- 239000012453 solvate Substances 0.000 claims description 14
- 206010003210 Arteriosclerosis Diseases 0.000 claims description 13
- 125000003545 alkoxy group Chemical group 0.000 claims description 13
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 12
- 125000004414 alkyl thio group Chemical group 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 229910052717 sulfur Chemical group 0.000 claims description 12
- 239000011593 sulfur Chemical group 0.000 claims description 12
- 201000010099 disease Diseases 0.000 claims description 11
- 230000001631 hypertensive effect Effects 0.000 claims description 11
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Inorganic materials [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- 229910052700 potassium Inorganic materials 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 150000001447 alkali salts Chemical class 0.000 claims description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 206010012601 diabetes mellitus Diseases 0.000 claims description 9
- 206010019280 Heart failures Diseases 0.000 claims description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 8
- 208000017169 kidney disease Diseases 0.000 claims description 8
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 7
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 7
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 7
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 7
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 7
- 230000002792 vascular Effects 0.000 claims description 7
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 6
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 6
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 claims description 6
- 208000006011 Stroke Diseases 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 125000003435 aroyl group Chemical group 0.000 claims description 6
- 125000005110 aryl thio group Chemical group 0.000 claims description 6
- 125000004104 aryloxy group Chemical group 0.000 claims description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 6
- 230000001684 chronic effect Effects 0.000 claims description 6
- 125000004122 cyclic group Chemical group 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 6
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 6
- 125000003107 substituted aryl group Chemical group 0.000 claims description 6
- 206010002383 Angina Pectoris Diseases 0.000 claims description 5
- 201000001320 Atherosclerosis Diseases 0.000 claims description 5
- 206010007572 Cardiac hypertrophy Diseases 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 206010020571 Hyperaldosteronism Diseases 0.000 claims description 5
- 206010028594 Myocardial fibrosis Diseases 0.000 claims description 5
- 208000009525 Myocarditis Diseases 0.000 claims description 5
- 208000008589 Obesity Diseases 0.000 claims description 5
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 5
- 208000001647 Renal Insufficiency Diseases 0.000 claims description 5
- 208000007536 Thrombosis Diseases 0.000 claims description 5
- 230000002159 abnormal effect Effects 0.000 claims description 5
- 235000011054 acetic acid Nutrition 0.000 claims description 5
- 150000008043 acidic salts Chemical class 0.000 claims description 5
- 150000007513 acids Chemical class 0.000 claims description 5
- 230000033115 angiogenesis Effects 0.000 claims description 5
- 206010003119 arrhythmia Diseases 0.000 claims description 5
- 230000006793 arrhythmia Effects 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 5
- 208000029078 coronary artery disease Diseases 0.000 claims description 5
- 201000001421 hyperglycemia Diseases 0.000 claims description 5
- 210000003734 kidney Anatomy 0.000 claims description 5
- 201000006370 kidney failure Diseases 0.000 claims description 5
- 230000003902 lesion Effects 0.000 claims description 5
- 208000038015 macular disease Diseases 0.000 claims description 5
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 5
- 239000011976 maleic acid Substances 0.000 claims description 5
- 229940098895 maleic acid Drugs 0.000 claims description 5
- 230000003211 malignant effect Effects 0.000 claims description 5
- 208000010125 myocardial infarction Diseases 0.000 claims description 5
- 208000031225 myocardial ischemia Diseases 0.000 claims description 5
- 235000020824 obesity Nutrition 0.000 claims description 5
- 201000009395 primary hyperaldosteronism Diseases 0.000 claims description 5
- 230000035755 proliferation Effects 0.000 claims description 5
- 125000006239 protecting group Chemical group 0.000 claims description 5
- 230000004224 protection Effects 0.000 claims description 5
- 238000007634 remodeling Methods 0.000 claims description 5
- 230000002207 retinal effect Effects 0.000 claims description 5
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 4
- 150000008574 D-amino acids Chemical class 0.000 claims description 4
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 4
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 4
- 150000008575 L-amino acids Chemical class 0.000 claims description 4
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 4
- 150000003862 amino acid derivatives Chemical class 0.000 claims description 4
- 125000004659 aryl alkyl thio group Chemical group 0.000 claims description 4
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 208000033679 diabetic kidney disease Diseases 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000011591 potassium Substances 0.000 claims description 4
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 3
- 239000004475 Arginine Substances 0.000 claims description 3
- 239000005711 Benzoic acid Substances 0.000 claims description 3
- LSPHULWDVZXLIL-UHFFFAOYSA-N Camphoric acid Natural products CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 claims description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 3
- 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 claims description 3
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 claims description 3
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 3
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 3
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 3
- 239000004472 Lysine Substances 0.000 claims description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 3
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 claims description 3
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 3
- 230000001154 acute effect Effects 0.000 claims description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 3
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 3
- 150000001371 alpha-amino acids Chemical class 0.000 claims description 3
- 235000008206 alpha-amino acids Nutrition 0.000 claims description 3
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 3
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 3
- 235000010323 ascorbic acid Nutrition 0.000 claims description 3
- 239000011668 ascorbic acid Substances 0.000 claims description 3
- 229960005070 ascorbic acid Drugs 0.000 claims description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 3
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 3
- 235000010233 benzoic acid Nutrition 0.000 claims description 3
- 229960004365 benzoic acid Drugs 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 239000008280 blood Substances 0.000 claims description 3
- 210000004369 blood Anatomy 0.000 claims description 3
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 3
- 239000004327 boric acid Substances 0.000 claims description 3
- 229960002645 boric acid Drugs 0.000 claims description 3
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 3
- LSPHULWDVZXLIL-QUBYGPBYSA-N camphoric acid Chemical compound CC1(C)[C@H](C(O)=O)CC[C@]1(C)C(O)=O LSPHULWDVZXLIL-QUBYGPBYSA-N 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 3
- 235000015165 citric acid Nutrition 0.000 claims description 3
- 229960004106 citric acid Drugs 0.000 claims description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 238000010511 deprotection reaction Methods 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 235000019253 formic acid Nutrition 0.000 claims description 3
- 239000001530 fumaric acid Substances 0.000 claims description 3
- 235000014304 histidine Nutrition 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 239000004310 lactic acid Substances 0.000 claims description 3
- 229910052744 lithium Inorganic materials 0.000 claims description 3
- 229910000103 lithium hydride Inorganic materials 0.000 claims description 3
- 239000001630 malic acid Substances 0.000 claims description 3
- 235000011090 malic acid Nutrition 0.000 claims description 3
- 229940099690 malic acid Drugs 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 229910017604 nitric acid Inorganic materials 0.000 claims description 3
- 229960003104 ornithine Drugs 0.000 claims description 3
- 235000006408 oxalic acid Nutrition 0.000 claims description 3
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 3
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 3
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 3
- 235000019260 propionic acid Nutrition 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 229940107700 pyruvic acid Drugs 0.000 claims description 3
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 3
- 229960004889 salicylic acid Drugs 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 3
- 239000011975 tartaric acid Substances 0.000 claims description 3
- 235000002906 tartaric acid Nutrition 0.000 claims description 3
- 229960001367 tartaric acid Drugs 0.000 claims description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- 206010007556 Cardiac failure acute Diseases 0.000 claims description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- 229910004013 NO 2 Inorganic materials 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 2
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 claims description 2
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- 125000004422 alkyl sulphonamide group Chemical group 0.000 claims description 2
- 125000005281 alkyl ureido group Chemical group 0.000 claims description 2
- 125000001769 aryl amino group Chemical group 0.000 claims description 2
- 125000004421 aryl sulphonamide group Chemical group 0.000 claims description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 2
- USOPFYZPGZGBEB-UHFFFAOYSA-N calcium lithium Chemical compound [Li].[Ca] USOPFYZPGZGBEB-UHFFFAOYSA-N 0.000 claims description 2
- 238000010931 ester hydrolysis Methods 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000000468 ketone group Chemical group 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- YQCIWBXEVYWRCW-UHFFFAOYSA-N methane;sulfane Chemical compound C.S YQCIWBXEVYWRCW-UHFFFAOYSA-N 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 claims description 2
- 238000006268 reductive amination reaction Methods 0.000 claims description 2
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 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 2
- 125000004001 thioalkyl group Chemical group 0.000 claims description 2
- 229910052727 yttrium Inorganic materials 0.000 claims description 2
- 229930194542 Keto Natural products 0.000 claims 1
- 208000034189 Sclerosis Diseases 0.000 claims 1
- 150000003857 carboxamides Chemical class 0.000 claims 1
- 125000001475 halogen functional group Chemical group 0.000 claims 1
- 150000002411 histidines Chemical class 0.000 claims 1
- XPXMKIXDFWLRAA-UHFFFAOYSA-N hydrazinide Chemical compound [NH-]N XPXMKIXDFWLRAA-UHFFFAOYSA-N 0.000 claims 1
- 238000007614 solvation Methods 0.000 claims 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims 1
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 abstract description 30
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 abstract description 30
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 abstract description 29
- 208000024172 Cardiovascular disease Diseases 0.000 abstract description 5
- 230000004071 biological effect Effects 0.000 abstract description 4
- 235000002639 sodium chloride Nutrition 0.000 description 31
- 241000700159 Rattus Species 0.000 description 27
- 238000011699 spontaneously hypertensive rat Methods 0.000 description 19
- 235000019439 ethyl acetate Nutrition 0.000 description 16
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 16
- 125000001302 tertiary amino group Chemical group 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 14
- 238000007792 addition Methods 0.000 description 13
- 230000000694 effects Effects 0.000 description 13
- 230000035488 systolic blood pressure Effects 0.000 description 13
- 239000012074 organic phase Substances 0.000 description 12
- 230000002829 reductive effect Effects 0.000 description 12
- 239000005541 ACE inhibitor Substances 0.000 description 11
- 230000036772 blood pressure Effects 0.000 description 11
- 229940079593 drug Drugs 0.000 description 11
- 239000000523 sample Substances 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 239000002220 antihypertensive agent Substances 0.000 description 10
- 229940127088 antihypertensive drug Drugs 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 9
- 125000005843 halogen group Chemical group 0.000 description 9
- 238000010898 silica gel chromatography Methods 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 8
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 7
- 230000002526 effect on cardiovascular system Effects 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 229960000830 captopril Drugs 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-dimethylaminophenol Chemical compound CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 5
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-dimethylaminopyridine Substances CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 208000026106 cerebrovascular disease Diseases 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 235000013824 polyphenols Nutrition 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 229940002612 prodrug Drugs 0.000 description 5
- 239000000651 prodrug Substances 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 125000003396 thiol group Chemical class [H]S* 0.000 description 5
- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical compound C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 description 4
- PAFLSMZLRSPALU-MRVPVSSYSA-N (2R)-3-(3,4-dihydroxyphenyl)lactic acid Chemical compound OC(=O)[C@H](O)CC1=CC=C(O)C(O)=C1 PAFLSMZLRSPALU-MRVPVSSYSA-N 0.000 description 4
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 4
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Natural products CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- PAFLSMZLRSPALU-UHFFFAOYSA-N Salvianic acid A Natural products OC(=O)C(O)CC1=CC=C(O)C(O)=C1 PAFLSMZLRSPALU-UHFFFAOYSA-N 0.000 description 4
- 230000003276 anti-hypertensive effect Effects 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 239000007822 coupling agent Substances 0.000 description 4
- DTGKSKDOIYIVQL-UHFFFAOYSA-N dl-isoborneol Natural products C1CC2(C)C(O)CC1C2(C)C DTGKSKDOIYIVQL-UHFFFAOYSA-N 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- REPVLJRCJUVQFA-UHFFFAOYSA-N (-)-isopinocampheol Natural products C1C(O)C(C)C2C(C)(C)C1C2 REPVLJRCJUVQFA-UHFFFAOYSA-N 0.000 description 3
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 3
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 3
- PAFLSMZLRSPALU-QMMMGPOBSA-N Danshensu Natural products OC(=O)[C@@H](O)CC1=CC=C(O)C(O)=C1 PAFLSMZLRSPALU-QMMMGPOBSA-N 0.000 description 3
- 238000002965 ELISA Methods 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 229940024606 amino acid Drugs 0.000 description 3
- CKDOCTFBFTVPSN-UHFFFAOYSA-N borneol Natural products C1CC2(C)C(C)CC1C2(C)C CKDOCTFBFTVPSN-UHFFFAOYSA-N 0.000 description 3
- 229940116229 borneol Drugs 0.000 description 3
- 229910001873 dinitrogen Inorganic materials 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 125000003367 polycyclic group Chemical group 0.000 description 3
- 229960002429 proline Drugs 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000012086 standard solution Substances 0.000 description 3
- 239000012089 stop solution Substances 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- FINHMKGKINIASC-UHFFFAOYSA-N tetramethyl-pyrazine Natural products CC1=NC(C)=C(C)N=C1C FINHMKGKINIASC-UHFFFAOYSA-N 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- IAJBQAYHSQIQRE-UHFFFAOYSA-N 2,4,5-trimethoxybenzaldehyde Chemical compound COC1=CC(OC)=C(C=O)C=C1OC IAJBQAYHSQIQRE-UHFFFAOYSA-N 0.000 description 2
- BWZVCCNYKMEVEX-UHFFFAOYSA-N 2,4,6-Trimethylpyridine Chemical compound CC1=CC(C)=NC(C)=C1 BWZVCCNYKMEVEX-UHFFFAOYSA-N 0.000 description 2
- IBGBGRVKPALMCQ-UHFFFAOYSA-N 3,4-dihydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1O IBGBGRVKPALMCQ-UHFFFAOYSA-N 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 2
- 108090001008 Avidin Proteins 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 229940127291 Calcium channel antagonist Drugs 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- 239000007821 HATU Substances 0.000 description 2
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 101000773741 Mus musculus Angiotensin-converting enzyme Proteins 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 2
- REFJWTPEDVJJIY-UHFFFAOYSA-N Quercetin Chemical compound C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC=C(O)C(O)=C1 REFJWTPEDVJJIY-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 238000000692 Student's t-test Methods 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 125000002102 aryl alkyloxo group Chemical group 0.000 description 2
- DNAVOCNYHNNEQI-UHFFFAOYSA-N asaronaldehyde Natural products COC1=CC(OC)=C(C=CC=O)C=C1OC DNAVOCNYHNNEQI-UHFFFAOYSA-N 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 238000009530 blood pressure measurement Methods 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 231100000517 death Toxicity 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 229960002582 perindopril Drugs 0.000 description 2
- IPVQLZZIHOAWMC-QXKUPLGCSA-N perindopril Chemical compound C1CCC[C@H]2C[C@@H](C(O)=O)N(C(=O)[C@H](C)N[C@@H](CCC)C(=O)OCC)[C@H]21 IPVQLZZIHOAWMC-QXKUPLGCSA-N 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 125000006413 ring segment Chemical group 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 239000012488 sample solution Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 150000003459 sulfonic acid esters Chemical class 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 238000012353 t test Methods 0.000 description 2
- 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 2
- 238000010998 test method Methods 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- DTGKSKDOIYIVQL-NQMVMOMDSA-N (+)-Borneol Natural products C1C[C@]2(C)[C@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-NQMVMOMDSA-N 0.000 description 1
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 1
- ZQEBQGAAWMOMAI-ZETCQYMHSA-N (2s)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1C(O)=O ZQEBQGAAWMOMAI-ZETCQYMHSA-N 0.000 description 1
- JXGVXCZADZNAMJ-NSHDSACASA-N (2s)-1-phenylmethoxycarbonylpyrrolidine-2-carboxylic acid Chemical compound OC(=O)[C@@H]1CCCN1C(=O)OCC1=CC=CC=C1 JXGVXCZADZNAMJ-NSHDSACASA-N 0.000 description 1
- QVHJQCGUWFKTSE-YFKPBYRVSA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound OC(=O)[C@H](C)NC(=O)OC(C)(C)C QVHJQCGUWFKTSE-YFKPBYRVSA-N 0.000 description 1
- BIDNLKIUORFRQP-XYGFDPSESA-N (2s,4s)-4-cyclohexyl-1-[2-[[(1s)-2-methyl-1-propanoyloxypropoxy]-(4-phenylbutyl)phosphoryl]acetyl]pyrrolidine-2-carboxylic acid Chemical compound C([P@@](=O)(O[C@H](OC(=O)CC)C(C)C)CC(=O)N1[C@@H](C[C@H](C1)C1CCCCC1)C(O)=O)CCCC1=CC=CC=C1 BIDNLKIUORFRQP-XYGFDPSESA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- TUSDEZXZIZRFGC-UHFFFAOYSA-N 1-O-galloyl-3,6-(R)-HHDP-beta-D-glucose Natural products OC1C(O2)COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC1C(O)C2OC(=O)C1=CC(O)=C(O)C(O)=C1 TUSDEZXZIZRFGC-UHFFFAOYSA-N 0.000 description 1
- DFPYXQYWILNVAU-UHFFFAOYSA-N 1-hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1.C1=CC=C2N(O)N=NC2=C1 DFPYXQYWILNVAU-UHFFFAOYSA-N 0.000 description 1
- HVHZEKKZMFRULH-UHFFFAOYSA-N 2,6-ditert-butyl-4-methylpyridine Chemical compound CC1=CC(C(C)(C)C)=NC(C(C)(C)C)=C1 HVHZEKKZMFRULH-UHFFFAOYSA-N 0.000 description 1
- SNKFFCBZYFGCQN-UHFFFAOYSA-N 2-[3-[3-[1-carboxy-2-(3,4-dihydroxyphenyl)ethoxy]carbonyl-2-(3,4-dihydroxyphenyl)-7-hydroxy-2,3-dihydro-1-benzofuran-4-yl]prop-2-enoyloxy]-3-(3,4-dihydroxyphenyl)propanoic acid Chemical compound C=1C=C(O)C=2OC(C=3C=C(O)C(O)=CC=3)C(C(=O)OC(CC=3C=C(O)C(O)=CC=3)C(O)=O)C=2C=1C=CC(=O)OC(C(=O)O)CC1=CC=C(O)C(O)=C1 SNKFFCBZYFGCQN-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 125000006479 2-pyridyl methyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- 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 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- FHHHOYXPRDYHEZ-COXVUDFISA-N Alacepril Chemical compound CC(=O)SC[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 FHHHOYXPRDYHEZ-COXVUDFISA-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
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 102000008873 Angiotensin II receptor Human genes 0.000 description 1
- 108050000824 Angiotensin II receptor Proteins 0.000 description 1
- 101800000734 Angiotensin-1 Proteins 0.000 description 1
- 102400000344 Angiotensin-1 Human genes 0.000 description 1
- 101710129690 Angiotensin-converting enzyme inhibitor Proteins 0.000 description 1
- 241000758794 Asarum Species 0.000 description 1
- XPCFTKFZXHTYIP-PMACEKPBSA-N Benazepril Chemical compound C([C@@H](C(=O)OCC)N[C@@H]1C(N(CC(O)=O)C2=CC=CC=C2CC1)=O)CC1=CC=CC=C1 XPCFTKFZXHTYIP-PMACEKPBSA-N 0.000 description 1
- 101710086378 Bradykinin-potentiating and C-type natriuretic peptides Proteins 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 108010061435 Enalapril Proteins 0.000 description 1
- 102000018389 Exopeptidases Human genes 0.000 description 1
- 108010091443 Exopeptidases Proteins 0.000 description 1
- 239000001263 FEMA 3042 Substances 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 238000012449 Kunming mouse Methods 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- 229930182821 L-proline Natural products 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- 108010007859 Lisinopril Proteins 0.000 description 1
- SNKFFCBZYFGCQN-VWUOOIFGSA-N Lithospermic acid B Natural products C([C@H](C(=O)O)OC(=O)\C=C\C=1C=2[C@H](C(=O)O[C@H](CC=3C=C(O)C(O)=CC=3)C(O)=O)[C@H](OC=2C(O)=CC=1)C=1C=C(O)C(O)=CC=1)C1=CC=C(O)C(O)=C1 SNKFFCBZYFGCQN-VWUOOIFGSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- UWWDHYUMIORJTA-HSQYWUDLSA-N Moexipril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CC2=CC(OC)=C(OC)C=C2C1)C(O)=O)CC1=CC=CC=C1 UWWDHYUMIORJTA-HSQYWUDLSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 208000031662 Noncommunicable disease Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- LRBQNJMCXXYXIU-PPKXGCFTSA-N Penta-digallate-beta-D-glucose Natural products OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-PPKXGCFTSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 206010036618 Premenstrual syndrome Diseases 0.000 description 1
- ZVOLCUVKHLEPEV-UHFFFAOYSA-N Quercetagetin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=C(O)C(O)=C(O)C=C2O1 ZVOLCUVKHLEPEV-UHFFFAOYSA-N 0.000 description 1
- 230000002292 Radical scavenging effect Effects 0.000 description 1
- HWTZYBCRDDUBJY-UHFFFAOYSA-N Rhynchosin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=CC(O)=C(O)C=C2O1 HWTZYBCRDDUBJY-UHFFFAOYSA-N 0.000 description 1
- 241000304195 Salvia miltiorrhiza Species 0.000 description 1
- 235000011135 Salvia miltiorrhiza Nutrition 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- VXFJYXUZANRPDJ-WTNASJBWSA-N Trandopril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](C[C@H]2CCCC[C@@H]21)C(O)=O)CC1=CC=CC=C1 VXFJYXUZANRPDJ-WTNASJBWSA-N 0.000 description 1
- 102000010913 Type 1 Angiotensin Receptor Human genes 0.000 description 1
- 108010062481 Type 1 Angiotensin Receptor Proteins 0.000 description 1
- 238000005411 Van der Waals force Methods 0.000 description 1
- 206010047141 Vasodilatation Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 description 1
- DGYIJVNZSDYBOE-UHFFFAOYSA-N [CH2]C1=CC=NC=C1 Chemical group [CH2]C1=CC=NC=C1 DGYIJVNZSDYBOE-UHFFFAOYSA-N 0.000 description 1
- QRSFFHRCBYCWBS-UHFFFAOYSA-N [O].[O] Chemical compound [O].[O] QRSFFHRCBYCWBS-UHFFFAOYSA-N 0.000 description 1
- XOCUXOWLYLLJLV-UHFFFAOYSA-N [O].[S] Chemical compound [O].[S] XOCUXOWLYLLJLV-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 229950007884 alacepril Drugs 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 150000001294 alanine derivatives Chemical class 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- HAXFWIACAGNFHA-UHFFFAOYSA-N aldrithiol Chemical compound C=1C=CC=NC=1SSC1=CC=CC=N1 HAXFWIACAGNFHA-UHFFFAOYSA-N 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- ORWYRWWVDCYOMK-HBZPZAIKSA-N angiotensin I Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 ORWYRWWVDCYOMK-HBZPZAIKSA-N 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 229960004530 benazepril Drugs 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 150000008107 benzenesulfonic acids Chemical class 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 150000001576 beta-amino acids Chemical class 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229950005499 carbon tetrachloride Drugs 0.000 description 1
- 125000005392 carboxamide group Chemical group NC(=O)* 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960001701 chloroform Drugs 0.000 description 1
- 239000003593 chromogenic compound Substances 0.000 description 1
- 229960005025 cilazapril Drugs 0.000 description 1
- HHHKFGXWKKUNCY-FHWLQOOXSA-N cilazapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H]1C(N2[C@@H](CCCN2CCC1)C(O)=O)=O)CC1=CC=CC=C1 HHHKFGXWKKUNCY-FHWLQOOXSA-N 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 230000007012 clinical effect Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 235000013365 dairy product Nutrition 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 229960005227 delapril Drugs 0.000 description 1
- WOUOLAUOZXOLJQ-MBSDFSHPSA-N delapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N(CC(O)=O)C1CC2=CC=CC=C2C1)CC1=CC=CC=C1 WOUOLAUOZXOLJQ-MBSDFSHPSA-N 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical class CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 229960000873 enalapril Drugs 0.000 description 1
- GBXSMTUPTTWBMN-XIRDDKMYSA-N enalapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 GBXSMTUPTTWBMN-XIRDDKMYSA-N 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- OCLXJTCGWSSVOE-UHFFFAOYSA-N ethanol etoh Chemical compound CCO.CCO OCLXJTCGWSSVOE-UHFFFAOYSA-N 0.000 description 1
- 125000006125 ethylsulfonyl group Chemical group 0.000 description 1
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229960002490 fosinopril Drugs 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000005555 hypertensive agent Substances 0.000 description 1
- 229960001195 imidapril Drugs 0.000 description 1
- KLZWOWYOHUKJIG-BPUTZDHNSA-N imidapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1C(N(C)C[C@H]1C(O)=O)=O)CC1=CC=CC=C1 KLZWOWYOHUKJIG-BPUTZDHNSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000005462 in vivo assay Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229940039009 isoproterenol Drugs 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- MWDZOUNAPSSOEL-UHFFFAOYSA-N kaempferol Natural products OC1=C(C(=O)c2cc(O)cc(O)c2O1)c3ccc(O)cc3 MWDZOUNAPSSOEL-UHFFFAOYSA-N 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical group CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 229960004873 levomenthol Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 229960002394 lisinopril Drugs 0.000 description 1
- CZRQXSDBMCMPNJ-ZUIPZQNBSA-N lisinopril dihydrate Chemical compound O.O.C([C@H](N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 CZRQXSDBMCMPNJ-ZUIPZQNBSA-N 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 150000002689 maleic acids Chemical class 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229960005170 moexipril Drugs 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- TYRGLVWXHJRKMT-QMMMGPOBSA-N n-benzyloxycarbonyl-l-serine-betalactone Chemical compound OC(=O)[C@H](C)NC(=O)OCC1=CC=CC=C1 TYRGLVWXHJRKMT-QMMMGPOBSA-N 0.000 description 1
- WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 1
- 125000005146 naphthylsulfonyl group Chemical group C1(=CC=CC2=CC=CC=C12)S(=O)(=O)* 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical class CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 125000000006 phenylethylthio group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])S* 0.000 description 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 238000009160 phytotherapy Methods 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- MHZDONKZSXBOGL-UHFFFAOYSA-N propyl dihydrogen phosphate Chemical compound CCCOP(O)(O)=O MHZDONKZSXBOGL-UHFFFAOYSA-N 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 229960003371 protocatechualdehyde Drugs 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 229960001285 quercetin Drugs 0.000 description 1
- 235000005875 quercetin Nutrition 0.000 description 1
- 229960001455 quinapril Drugs 0.000 description 1
- JSDRRTOADPPCHY-HSQYWUDLSA-N quinapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CC2=CC=CC=C2C1)C(O)=O)CC1=CC=CC=C1 JSDRRTOADPPCHY-HSQYWUDLSA-N 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 229960003401 ramipril Drugs 0.000 description 1
- HDACQVRGBOVJII-JBDAPHQKSA-N ramipril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](C[C@@H]2CCC[C@@H]21)C(O)=O)CC1=CC=CC=C1 HDACQVRGBOVJII-JBDAPHQKSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000012925 reference material Substances 0.000 description 1
- 210000005084 renal tissue Anatomy 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 238000010079 rubber tapping Methods 0.000 description 1
- 235000002020 sage Nutrition 0.000 description 1
- STCJJTBMWHMRCD-UHFFFAOYSA-N salvianolic acid B Natural products OC(=O)C(Cc1ccc(O)c(O)c1)OC(=O)C=Cc2cc(O)c(O)c3OC(C(C(=O)OC(Cc4ccc(O)c(O)c4)C(=O)O)c23)c5ccc(O)c(O)c5 STCJJTBMWHMRCD-UHFFFAOYSA-N 0.000 description 1
- 238000003118 sandwich ELISA Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910001388 sodium aluminate Inorganic materials 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- UIICPZFWHBJNIG-UHFFFAOYSA-N sodium;2-methoxyethanolate Chemical compound [Na+].COCC[O-] UIICPZFWHBJNIG-UHFFFAOYSA-N 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229960002909 spirapril Drugs 0.000 description 1
- HRWCVUIFMSZDJS-SZMVWBNQSA-N spirapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CC2(C1)SCCS2)C(O)=O)CC1=CC=CC=C1 HRWCVUIFMSZDJS-SZMVWBNQSA-N 0.000 description 1
- 108700035424 spirapril Proteins 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- 125000004426 substituted alkynyl group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 125000004354 sulfur functional group Chemical group 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- LRBQNJMCXXYXIU-NRMVVENXSA-N tannic acid Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-NRMVVENXSA-N 0.000 description 1
- 235000015523 tannic acid Nutrition 0.000 description 1
- 229940033123 tannic acid Drugs 0.000 description 1
- 229920002258 tannic acid Polymers 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229960004084 temocapril Drugs 0.000 description 1
- FIQOFIRCTOWDOW-BJLQDIEVSA-N temocapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H]1C(N(CC(O)=O)C[C@H](SC1)C=1SC=CC=1)=O)CC1=CC=CC=C1 FIQOFIRCTOWDOW-BJLQDIEVSA-N 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004149 thio group Chemical group *S* 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 229950001139 timonacic Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 229940126680 traditional chinese medicines Drugs 0.000 description 1
- 229960002051 trandolapril Drugs 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 230000004865 vascular response Effects 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229960002769 zofenopril Drugs 0.000 description 1
- IAIDUHCBNLFXEF-MNEFBYGVSA-N zofenopril Chemical compound C([C@@H](C)C(=O)N1[C@@H](C[C@@H](C1)SC=1C=CC=CC=1)C(O)=O)SC(=O)C1=CC=CC=C1 IAIDUHCBNLFXEF-MNEFBYGVSA-N 0.000 description 1
Classifications
-
- 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
- C07K5/08—Tripeptides
- C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
- C07K5/0823—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp and Pro-amino acid; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
-
- 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
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/05—Dipeptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/06—Tripeptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
-
- 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
-
- 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
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- 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
- A61P9/06—Antiarrhythmics
-
- 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
-
- 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
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
- C07K5/06043—Leu-amino acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/0606—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06086—Dipeptides with the first amino acid being basic
-
- 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
- C07K5/06086—Dipeptides with the first amino acid being basic
- C07K5/06095—Arg-amino acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06104—Dipeptides with the first amino acid being acidic
-
- 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
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
-
- 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
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
- C07K5/06156—Dipeptides with the first amino acid being heterocyclic and Trp-amino acid; Derivatives thereof
-
- 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
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
- C07K5/06165—Dipeptides with the first amino acid being heterocyclic and Pro-amino acid; Derivatives thereof
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Diabetes (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Hematology (AREA)
- Gastroenterology & Hepatology (AREA)
- Obesity (AREA)
- Urology & Nephrology (AREA)
- Endocrinology (AREA)
- Child & Adolescent Psychology (AREA)
- Emergency Medicine (AREA)
- Hospice & Palliative Care (AREA)
- Ophthalmology & Optometry (AREA)
- Vascular Medicine (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Peptides Or Proteins (AREA)
Abstract
Description
Rは式(II):
ここで式(II)において、
R1は水素、アルキル、シクロアルキル、ヘテロアルキル、ヘテロシクリル、アルケニル、アルキニル、アシル、アロイル、アリール、アラルキル、ヘテロアリール又はヘテロアラルキルから選択され、
R2は水素、アルキル、シクロアルキル、ヘテロアルキル、ヘテロシクリル、アルケニル、アルキニル、アシル、アロイル、アリール、アラルキル、ヘテロアリール、ヘテロアラルキル、アルキルチオ、アラルキルチオ、アリールチオ、F、Cl、Br、I、NO2又はCNから選択され、
R1及びR2は同じであるか又は異なり、
n=0、1、2、3、4又は5であり、n≧2である場合、複数のR1は同じであるか又は異なり、
m=0、1、2、3、4又は5であり、m≧2である場合、複数のR2は同じであるか又は異なり、
Wは、
Xは酸素又は水素から選択され、
ここで式(I)において、
R’は式(III):
R’がL−アミノ酸若しくはD−アミノ酸、又はアミノ酸誘導体の残基である場合、
R’が存在しない場合、
ここで式(III)においてR4及びR5は各々独立して水素、アルキル、シクロアルキル、ヘテロアルキル、ヘテロシクリル、アルケニル、アルキニル、アリール、アラルキル、ヘテロアリール又はヘテロアラルキルから選択され、R4及びR5は同じであるか又は異なり、
ここで式(I)において、
R’’は式(IV):
ここで式(IV)において、
Yは酸素、窒素又は硫黄から選択され、
Yが窒素である場合、R’’’’はR7及びR8であり、R’’は、
Yが酸素である場合、R’’’’はR9であり、R’’は−OR9であり、
Yが硫黄である場合、R’’’’はR10であり、R’’は−SR10であり、
ここでR7、R8、R9及びR10は同じであっても又は異なっていてもよく、各々独立して水素、アルキル、シクロアルキル、ヘテロアルキル、ヘテロシクリル、アルケニル、アルキニル、アリール、アラルキル、ヘテロアリール又はヘテロアラルキルから選択され、
ここで式(I)において、
R’’’は水素又はアルキルから選択され、
A=炭素であり、
Lは水素、アルキル、置換アルキル、アリール又は置換アリールから選択され、
Dは炭素であるか又は存在せず、t=0、1、2、3であり、
Dが炭素であり、かつBが炭素である場合、Aは炭素−炭素二重結合若しくは炭素−炭素単結合によってBに連結し、K及びB及びDは環系内にあるか、又はAは炭素−炭素二重結合若しくは炭素−炭素単結合によってBに連結し、KはBに連結し、Dに連結せず、
K及びB及びDが環系内にある場合、Kは炭素数2〜8のアルキル若しくはヘテロアルキル若しくは炭素数3〜8のアルケニルから選択されるか、又はKがB及びDとともにアリール、置換アリール、ヘテロアリール若しくは置換ヘテロアリールを形成し、
KがBに連結し、Dに連結しない場合、Kは水素、アルキル、ヘテロアルキル、シクロアルキル、ヘテロシクリル、アルケニル、アルキニル、ヒドロキシ、アルコキシ、アリールオキシ、アリール、アラルキル、ヘテロアリール又はヘテロアラルキルから選択され、
Dが炭素であり、かつBが硫黄である場合、Aは炭素−硫黄単結合を介してBに連結し、Kは存在せず、
Dが存在しない場合、Bは炭素であり、Kは水素であり、
ここでアルキル基、シクロアルキル基、ヘテロアルキル基、ヘテロシクリル基、アルケニル基、アルキニル基、アリール基、アラルキル基、ヘテロアリール基及びヘテロアラルキル基は各々非置換であっても、又はヒドロキシ基、アルコキシ基、アリールオキシ基、チオ基、チオアルキル基、アリールチオ基、アミノ基、アミド基、アルキルアミノ基、アリールアミノ基、アルキルスルホニル基、アリールスルホニル基、スルホンアミド基、アルキル基、アリール基、ヘテロアリール基、アルキルスルホンアミド基、アリールスルホンアミド基、ケト基、カルボキシ基、アルコキシカルボニル基、カルボキサミド基、アルコキシカルボニルアミノ基、アルコキシカルボニルオキシ基、アルキルウレイド基、アリールウレイド基、ハロ基、シアノ基若しくはニトロ基から選択される1つ若しくは複数の置換基で任意に置換されていてもよい)。
Yが窒素又は硫黄から選択される場合、工程(2)は化合物(I’)の合成後に終了するか、又は工程(2’)は化合物(I’’)の合成後に終了し、
A、B、D、L、K、n、m、R1、R2、R4、R5、R’’’、R’’’’、t、W及びYは請求項1〜7のいずれか一項に記載の通りである;
a:α−アミノ酸のアミノの保護;Pは好適な保護基を表し、tert−ブトキシカルボニル(Boc)、アリルオキシカルボニル(Alloc)、ベンジルオキシカルボニル、トリチル、ベンジルオキシメチル、フルオレニルメトキシカルボニル(Fmoc)、フタロイル、ジチオスクシニル、メトキシホルミル、エトキシホルミル、ベンゼンスルホニル、p−トルエンスルホニル、2−(トリメチルシリル)エタンスルホニル、ベンジル(Bn)、トリチル(Tr)又はアリルから選択される;
b:ペプチド結合の合成の条件;
c:工程aに対応する脱保護;
e:bと同じ;
f:cと同じ;
g:bと同じ;
g’:還元的アミノ化;
h:エステル加水分解の条件;
ここで「*」は不斉中心を表し、「*」を含む化合物にはその構造式の全てのキラル異性体が含まれる)を提供する。
本発明において設計されるトリペプチド及びその類似体には、その「プロドラッグ」、「溶媒和物」、「塩」(「酸性塩」、「塩基性塩」及び分子内塩を含む)及び「エステル」も含まれる。トリペプチドの「プロドラッグ」、「溶媒和物」、「塩」及び「エステル」は全て本発明の範囲内に含まれる。「溶媒和物」及び「塩」は対応する化合物の遊離形態に相当する。
硫酸、硫酸水素塩、塩酸、臭化水素酸、リン酸、硝酸、炭酸、ホウ酸、メタンスルホン酸、ベンゼンスルホン酸、p−トルエンスルホン酸、ギ酸、酢酸、プロピオン酸、酪酸、ピルビン酸、マレイン酸、リンゴ酸、酒石酸、クエン酸、アスコルビン酸、安息香酸、樟脳酸、フマル酸、シュウ酸、コハク酸、カンファースルホン酸、マレイン酸、サリチル酸及びα−乳酸。加えて、P. Stahl, Camille G. eds. Handbook of Pharmaceutical Salts. Properties, Selection and Use, 2002, Zurich: Wiley-VCHに記載の薬学的に許容可能な塩を形成する酸が引用することにより本明細書の一部をなす。
リチウム、ナトリウム及びカリウム等のアルカリ金属;マグネシウム及びカルシウム等のアルカリ土類金属;水酸化リチウム、水酸化ナトリウム、水酸化カリウム、水素化リチウム、水素化ナトリウム、ブチルリチウム、アンモニウム、トリエチルアミン、ジイソプロピルエチルアミン、オルニチン、アルギニン、リシン又はヒスチジン等の塩基性アミノ酸。
「組成物」という用語は特定の量の特定の成分を含む生成物、及び特定の量の特定の成分の組合せにより直接又は間接的に形成される任意の生成物を指す。
本発明の化合物(I)、並びに薬学的に許容可能な(非毒性の生理学的に許容可能な)塩、エステル及び医薬組成物は心血管疾患及び脳血管疾患、特に高血圧と関連する心血管疾患及び脳血管疾患、並びにその合併症の予防、治療又は遅延に有用である。
(1)化合物Vと化合物VIとを脂肪アルコール及び触媒の存在下で反応させて、化合物VIIを得ることと:
(2)化合物VIIを還元して化合物VIIIを得ることと:
略称:
EDCI 1−エチル−(3−ジメチルアミノプロピル)カルボジイミド塩酸塩
DCC ジシクロヘキシルカルボジイミド
Alloc アリルオキシカルボニル
Fmoc フルオレニルメトキシカルボニル
Bn ベンジルトリチル
Tr トリチル
T3P(商標) 1−プロピルリン酸無水物
HOBt 1−ヒドロキシベンゾトリアゾール
THF テトラヒドロフラン
EtOAc 酢酸エチル
MeOH メタノール
EtOH エタノール
TFA トリフルオロ酢酸
DCM ジクロロメタン
DIPEA ジイソプロピルエチルアミン
DMF N,N−ジメチルアセトアミド
DMSO ジメチルスルホキシド
DMAP 4−N,N−ジメチルピリジン
HATU 2−(7−アゾベンゾトリアゾール)−N,N,N’,N’−テトラメチルウロニウムヘキサフルオロホスフェート
PyBOP 1H−ベンゾトリアゾール−1−イルオキシトリピロリジルヘキサフルオロホスフェート
Boc tert−ブトキシカルボニル
Cbz ベンジルオキシカルボニル
NMR 核磁気共鳴
MS 質量分析
上述の実施例19に記載の手順に従い、以下の化合物を適切な出発物質及び試薬を用いて調製した。
工程1:
LC−QTOF MS & MS/MS条件:HPLC機器:Agilent 1200 Infinity LC;カラム:Agilent HC−C18 4.6×250mm、5μm;流量:0.6mL/分;カラム温度:30℃;移動相:A−H2O、0.1%酢酸/B−メタノール、A:B=20:80;MS機器:Agilent 6520 QTOF;イオン源:Dual ESI;イオンモード:ポジティブ;イオンスプレー電圧:3500V;乾燥ガス温度:350℃;乾燥ガス流量:10.0L/分(N2);噴霧器圧:45psi(N2);ブレーカー電圧:130V;衝突エネルギー:それぞれ10eV、25eV及び40eV。
in vitro ACE活性試験
高速液体クロマトグラフィーアッセイ:Cushman et al. (Biochemical Pharmacology, 1971, 20 (7): 1637-1648.; Journal of Dairy Science, 1995, 78 (4): 777-783.)に記載の方法を参照し、本発明の化合物のアンジオテンシン変換酵素活性を報告されている方法を用いてアッセイした。この方法は、ACE活性の連続モニタリングに好適なAng I模倣ヒプリル−ヒスチジル−ロイシン(HHL)の加水分解物である馬尿酸(Hip)の含量に基づくものであった。ACE阻害薬を添加することで反応の進行を阻害し、それにより馬尿酸の産生を低減することができる。このため、ACE阻害活性は阻害薬の添加の前後に産生される馬尿酸の228nmでのUV吸光度の変化を測定することによって得られる。
(1)材料:
実験装置:
25μlのサンプル溶液(50mM HEPES塩酸緩衝液(pH=8.3)に溶解した、300mM NaClを含有する、50μmol)及び200μlの3%基質HHL(同じ緩衝液に溶解した)の混合物を37℃で6分間維持した。50μlのACE(0.5U、1.5mLの同じ緩衝剤に溶解した)を添加した後、反応を37℃で15分間行い、次いで250μlの1mol/L塩酸を添加して反応を停止させた。反応混合物を均一に混合し、5分間静置した。2mLの酢酸エチルを添加した後、混合物を60秒間激しく振盪し、1000×gで10分間遠心分離した。上清を15分間沸騰水浴内に入れ、3mLの脱イオン水を添加した後、混合し、静置した。馬尿酸を逆相高速液体クロマトグラフィーによって検出するために20uLの反応物をロードした(loaded)。ACEに対するサンプルの阻害効果を産生される馬尿酸の量によって判断し、緩衝液をサンプル溶液の代わりにブランク対照として使用した。ACEに対するサンプルの阻害率(%)=(対照馬尿酸のピーク値−サンプル馬尿酸のピーク値)/対照馬尿酸のピーク値×100%。
紫外線検出器;波長:228nm;カラム:Agilent HC−C18 4.6×250mm、5μm;流量:1.0mL/分;注入量:20μL;カラム温度:30℃;移動相:アセトニトリル−水(80/20)。結果を表5に示す。
材料及び方法:
実験装置:
二重抗体サンドイッチELISA法によるACE含量の決定:抗マウスACE抗体を酵素プレートにコーティングし、実験時にサンプル又は標準物質中のマウスACEがコーティングした抗体に結合し、遊離成分を洗い流した。ビオチン化抗マウスACE抗体及びホースラディッシュペルオキシダーゼ標識アビジンを順次添加した。抗マウスACE抗体がコーティングした抗体に結合したマウスACEに結合し、ビオチンがアビジンに特異的に結合することで免疫複合体が形成され、遊離成分を洗い流した。発色基質(TMB)を添加するが、これはホースラディッシュペルオキシダーゼの触媒作用下で青色を示し、停止液の添加後に黄色となった。OD値を450nmの波長でマイクロプレートリーダーを用いて測定した。ACE濃度とOD450値との間で二次非線形関係が示され、標準曲線を作成することによってサンプル中のACEの濃度を算出した。
(1)実験動物の処理
体重20±2gの108匹の雄性Kunmingマウスを、それぞれ1群当たり6匹のマウスで正常対照群、陽性対照カプトプリル群及び化合物221S群を含む18個の群に無作為に分けた。各群の動物に、7日連続で1日1回0.05mmol/kg(10ml/kg)での胃内投与を行った。最終胃内投与の2時間後に、マウスを頚椎脱臼によって屠殺し、心臓、肝臓、脳、肺、腎臓及び血液を採取した。腎臓を試験に使用し、他の組織サンプルは他の実験的試験に使用した。腎臓をPBSで10倍希釈し、ホモジナイズし、遠心分離し、上清をアッセイに使用するか又は−20℃で保管した。
マウスの腎組織におけるACEのレベルをELISAによって検出した。全ての工程を取扱説明書に厳密に従って行った。主な工程は以下のようにした。
実験装置及び試薬
実験装置
SPFグレードの雄性自然発生高血圧モデルラット(SHR)(雄性、12週齢、体重200g±20g)を各群6匹のラットでブランク群、対照群及びサンプル群の3つの群に分けた。動物を西北大学生命科学院(School of Life Sciences of Northwest University)の陝西省生物医学動物実験室(Shaanxi Provincial Biomedical Animal Laboratory)に温度22℃及び湿度50%、12時間の明/暗サイクルで餌及び水を自由摂取させて収容した。SHRラットを5日間環境に適応させた後、血圧測定に適応するように訓練した。投与前に各群のラットの基礎血圧を測定し、収縮期血圧は190±5mmHgであった。
実験ラットの収縮期血圧を尾パルス間接圧力測定(tail pulse indirect pressure measurement)によって測定した。
上記の方法及び用量に従ってラットに7日連続で1日1回胃内投与した。血圧を投与の2時間後に測定した。投与の終了後に、血圧を7日連続で1日1回測定し、血圧の変化を記録した。
Claims (16)
- 式(1)の構造を有するトリペプチド化合物:
Rは式(II):
ここで式(II)において、
R1は水素、アルキル、シクロアルキル、ヘテロアルキル、ヘテロシクリル、アルケニル、アルキニル、アシル、アロイル、アリール、アラルキル、ヘテロアリール又はヘテロアラルキルから選択され、
R2は水素、アルキル、シクロアルキル、ヘテロアルキル、ヘテロシクリル、アルケニル、アルキニル、アシル、アロイル、アリール、アラルキル、ヘテロアリール、ヘテロアラルキル、アルキルチオ、アラルキルチオ、アリールチオ、F、Cl、Br、I、NO2又はCNから選択され、
R1及びR2は同じであるか又は異なり、
n=0、1、2、3、4又は5であり、n≧2である場合、複数のR1は同じであるか又は異なり、
m=0、1、2、3、4又は5であり、m≧2である場合、複数のR2は同じであるか又は異なり、
Wは、
Xは酸素又は水素から選択され、
ここで式(I)において、
R’は式(III):
R’がL−アミノ酸若しくはD−アミノ酸、又はアミノ酸誘導体の残基である場合、
R’が存在しない場合、
ここで式(III)においてR4及びR5は各々独立して水素、アルキル、シクロアルキル、ヘテロアルキル、ヘテロシクリル、アルケニル、アルキニル、アリール、アラルキル、ヘテロアリール及びヘテロアラルキルから選択され、R4及びR5は同じであるか又は異なり、
ここで式(I)において、
R’’は式(IV):
ここで式(IV)において、
Yは酸素、窒素又は硫黄から選択され、
Yが窒素である場合、R’’’’はR7及びR8であり、R’’は、
Yが酸素である場合、R’’’’はR9であり、R’’は−OR9であり、
Yが硫黄である場合、R’’’’はR10であり、R’’は−SR10であり、
ここでR7、R8、R9及びR10は同じであっても又は異なっていてもよく、各々独立して水素、アルキル、シクロアルキル、ヘテロアルキル、ヘテロシクリル、アルケニル、アルキニル、アリール、アラルキル、ヘテロアリール又はヘテロアラルキルから選択され、
ここで式(I)において、
R’’’は水素又はアルキルから選択され、
A=炭素であり、
Lは水素、アルキル、置換アルキル、アリール又は置換アリールから選択され、
Dは炭素であるか又は存在せず、t=0、1、2、3であり、
Dが炭素であり、かつBが炭素である場合、Aは炭素−炭素二重結合若しくは炭素−炭素単結合によってBに連結し、K及びB及びDは環系内にあるか、又はAは炭素−炭素二重結合若しくは炭素−炭素単結合によってBに連結し、KはBに連結し、Dに連結せず、
K及びB及びDが環系内にある場合、Kは炭素数2〜8のアルキル若しくはヘテロアルキル若しくは炭素数3〜8のアルケニルから選択されるか、又はKがB及びDとともにアリール、置換アリール、ヘテロアリール若しくは置換ヘテロアリールを形成し、
KがBに連結し、Dに連結しない場合、Kは水素、アルキル、ヘテロアルキル、シクロアルキル、ヘテロシクリル、アルケニル、アルキニル、ヒドロキシ、アルコキシ、アリールオキシ、アリール、アラルキル、ヘテロアリール又はヘテロアラルキルから選択され、
Dが炭素であり、かつBが硫黄である場合、Aは炭素−硫黄単結合を介してBに連結し、Kは存在せず、
Dが存在しない場合、Bは炭素であり、Kは水素であり、
ここで前記アルキル、シクロアルキル、ヘテロアルキル、ヘテロシクリル、アルケニル、アルキニル、アリール、アラルキル、ヘテロアリール及びヘテロアラルキルは各々非置換であっても、又はヒドロキシ、アルコキシ、アリールオキシ、チオ、チオアルキル、アリールチオ、アミノ、アミド、アルキルアミノ、アリールアミノ、アルキルスルホニル、アリールスルホニル、スルホンアミド、アルキル、アリール、ヘテロアリール、アルキルスルホンアミド、アリールスルホンアミド、ケト、カルボキシ、アルコキシカルボニル、カルボキサミド、アルコキシカルボニルアミノ、アルコキシカルボニルオキシ、アルキルウレイド、アリールウレイド、ハロ、シアノ若しくはニトロから選択される1つ若しくは複数の置換基で任意に置換されていてもよい)。 - R基:
- R’基:
- Yが酸素である場合、R9はメチル、エチル、プロピル、イソプロピル、n−ブチル、イソブチル、tert−ブチル、n−ペンチル、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル又は以下の構造:
- Yが窒素である場合、R’’は、
- Yが硫黄である場合、R’’は、
- 式(I)が以下の式の構造:
- 以下の構造:
- Yが酸素である請求項1、4、7又は8に記載の化合物の加水分解物。
- 請求項1〜8のいずれか一項に記載の化合物の鏡像異性体、互変異性体、立体異性体、回転異性体、ジアステレオ異性体又はラセミ体。
- 請求項1〜8のいずれか一項に記載の化合物の薬学的に許容可能な塩及び薬学的に許容可能なエステルであって、該薬学的に許容可能な塩が薬学的に許容可能な酸性塩及び薬学的に許容可能な塩基性塩を含み、前記薬学的に許容可能な酸性塩が以下の酸:硫酸、硫酸水素塩、塩酸、臭化水素酸、リン酸、硝酸、炭酸、ホウ酸、メタンスルホン酸、ベンゼンスルホン酸、p−トルエンスルホン酸、ギ酸、酢酸、プロピオン酸、酪酸、ピルビン酸、マレイン酸、リンゴ酸、酒石酸、クエン酸、アスコルビン酸、安息香酸、樟脳酸、フマル酸、シュウ酸、コハク酸、カンファースルホン酸、マレイン酸、サリチル酸又はα−乳酸の1つにより形成される塩を含み、前記薬学的に許容可能な塩基性塩が以下の塩基:リチウム、ナトリウム及びカリウムを含むアルカリ金属;マグネシウム及びカルシウムを含むアルカリ土類金属;水酸化リチウム、水酸化ナトリウム、水酸化カリウム、水素化リチウム、水素化ナトリウム、ブチルリチウム、アンモニウム、トリエチルアミン、ジイソプロピルエチルアミン、オルニチン、アルギニン、リシン又はヒスチジンの1つにより形成される塩を含み、該薬学的に許容可能なエステルが前記化合物中のヒドロキシル基又はフェノール性ヒドロキシル基と酸とにより形成されるエステルを含む、薬学的に許容可能な塩及び薬学的に許容可能なエステル。
- 請求項1〜8のいずれか一項に記載の化合物の溶媒和混合物であって、溶媒和物が水、メタノール、エタノール、イソプロパノール、ブタノール、酢酸エチル及びDMSOから選択される1つ、又はそれらの組合せである、溶媒和混合物。
- 請求項1に記載の化合物を調製する方法であって、
Yが窒素又は硫黄から選択される場合、工程(2)は化合物(I’)の合成後に終了するか、又は工程(2’)は化合物(I’’)の合成後に終了し、
A、B、D、L、K、n、m、R1、R2、R4、R5、R’’’、R’’’’、t、W及びYは請求項1〜7のいずれか一項に規定される通りである;
a:α−アミノ酸のアミノの保護;Pは好適な保護基を表し、tert−ブトキシカルボニル(Boc)、アリルオキシカルボニル(Alloc)、ベンジルオキシカルボニル、トリチル、ベンジルオキシメチル、フルオレニルメトキシカルボニル(Fmoc)、フタロイル、ジチオスクシニル、メトキシホルミル、エトキシホルミル、ベンゼンスルホニル、p−トルエンスルホニル、2−(トリメチルシリル)エタンスルホニル、ベンジル(Bn)、トリチル(Tr)又はアリルから選択される;
b:ペプチド結合の合成の条件;
c:工程aに対応する脱保護;
e:bと同じ;
f:cと同じ;
g:bと同じ;
g’:還元的アミノ化;
h:エステル加水分解の条件;
ここで「*」は不斉中心を表し、「*」を含む化合物にはその構造式の全てのキラル異性体が含まれる)。 - 高血圧及びその合併症の予防法、治療又は遅延のための薬剤の製造における請求項1〜8のいずれか一項に記載の化合物の使用であって、該合併症が冠動脈性心疾患、狭心症、急性心不全、慢性鬱血性心不全、心筋梗塞及び後遺症、鬱血性心疾患、心筋虚血、心筋炎、心筋線維症、心筋肥大、アテローム性動脈硬化症、良性小動脈性腎硬化症、悪性小動脈性腎硬化症、血管増殖異常及びリモデリング、血管新生関連疾患(新生血管黄斑症等)、高アルドステロン症、不整脈、腎疾患、糖尿病、脳卒中、血栓症、腎不全(糖尿病性腎症等)、高脂血症、肥満、高血糖、網膜動脈硬化症並びに高血圧性眼底病変の1つ又は複数を含む、使用。
- 請求項1〜8のいずれか一項に記載の化合物、請求項1〜8のいずれか一項に記載の化合物の薬学的に許容可能な塩、請求項1〜8のいずれか一項に記載の化合物の薬学的に許容可能な担体、賦形剤及び希釈剤を含む医薬組成物。
- 高血圧及びその合併症の予防法、治療又は遅延のための薬剤の製造における請求項14に記載の医薬組成物の使用であって、該合併症が冠動脈性心疾患、狭心症、心不全(急性又は慢性鬱血性心不全)、心筋梗塞及び後遺症、鬱血性心疾患、心筋虚血、心筋炎、心筋線維症、心筋肥大、アテローム性動脈硬化症、良性小動脈性腎硬化症、悪性小動脈性腎硬化症、血管増殖異常及びリモデリング、血管新生関連疾患(新生血管黄斑症等)、高アルドステロン症、不整脈、腎疾患、糖尿病、脳卒中、血栓症、腎不全(糖尿病性腎症等)、高脂血症、肥満、高血糖、網膜動脈硬化症並びに高血圧性眼底病変の1つ又は複数を含む、使用。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410705180.3A CN105693817B (zh) | 2014-11-27 | 2014-11-27 | 一类三肽化合物及其制备方法与应用 |
CN201410705180.3 | 2014-11-27 | ||
PCT/CN2015/095758 WO2016082786A1 (zh) | 2014-11-27 | 2015-11-27 | 一类三肽化合物及其制备方法与应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2018505847A true JP2018505847A (ja) | 2018-03-01 |
JP6689848B2 JP6689848B2 (ja) | 2020-04-28 |
Family
ID=56073634
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2017527865A Active JP6689848B2 (ja) | 2014-11-27 | 2015-11-27 | トリペプチド化合物、その調製方法及びその用途 |
Country Status (21)
Country | Link |
---|---|
US (1) | US11358985B2 (ja) |
EP (1) | EP3225627B9 (ja) |
JP (1) | JP6689848B2 (ja) |
KR (1) | KR102098783B1 (ja) |
CN (1) | CN105693817B (ja) |
AU (1) | AU2015353118B2 (ja) |
CA (1) | CA2968595C (ja) |
CY (1) | CY1125043T1 (ja) |
DK (1) | DK3225627T5 (ja) |
ES (1) | ES2897916T3 (ja) |
HK (1) | HK1243437A1 (ja) |
HU (1) | HUE056645T2 (ja) |
IL (1) | IL252448B (ja) |
MY (1) | MY193996A (ja) |
NZ (1) | NZ732301A (ja) |
PL (1) | PL3225627T3 (ja) |
PT (1) | PT3225627T (ja) |
RU (1) | RU2685709C2 (ja) |
SG (1) | SG11201704235SA (ja) |
SI (1) | SI3225627T1 (ja) |
WO (1) | WO2016082786A1 (ja) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107056788A (zh) * | 2017-03-23 | 2017-08-18 | 河南工程学院 | 一种咪唑烷酮类衍生物及其合成方法 |
CN107337712A (zh) * | 2017-07-26 | 2017-11-10 | 盐城卫生职业技术学院 | 一种抗高血压活性肽Orn‑Hyp‑Pro及应用和药物组合物 |
CN107337711A (zh) * | 2017-07-26 | 2017-11-10 | 盐城卫生职业技术学院 | 一种抗高血压活性肽Citn‑Pro‑Hyp及应用和药物组合物 |
CN112830884B (zh) * | 2019-11-22 | 2024-06-14 | 深圳市高盈医药科技开发有限公司 | 一种丹参素衍生物及其制备方法及其医药用途 |
WO2022119888A1 (en) * | 2020-12-03 | 2022-06-09 | Merck Sharp & Dohme Corp. | 3-heteroaryl pyrrolidine and piperidine orexin receptor agonists |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004024754A1 (ja) * | 2002-09-11 | 2004-03-25 | Toaeiyo Ltd. | プロリンエステル類及びそれを含有する経皮投与製剤 |
Family Cites Families (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE252191C (ja) | ||||
IL60888A (en) * | 1978-06-16 | 1984-07-31 | Yeda Res & Dev | Substrates and process for the quantitative assay of enzymes |
DE3315464A1 (de) | 1983-04-28 | 1984-10-31 | Hoechst Ag, 6230 Frankfurt | Verfahren zur herstellung von n-alkylierten dipeptiden und deren estern |
DE3619633A1 (de) * | 1986-06-11 | 1987-12-17 | Hoechst Ag | Peptide mit einfluss auf die diurese und natriurese, verfahren zu ihrer herstellung, diese enthaltende mittel und ihre verwendung |
KR900008794B1 (ko) * | 1986-06-11 | 1990-11-29 | 티 디 케이 가부시끼가이샤 | 방전 램프장치 |
DE3839127A1 (de) * | 1988-11-19 | 1990-05-23 | Hoechst Ag | Pyrrolidon-2-carbonsaeure-derivate mit psychotroper wirkung |
DE69733968T2 (de) * | 1996-09-18 | 2006-06-01 | Applied Genetics Inc. Dermatics | Norbornen- und norbornandiolen zur behandlung von pigmentierungsstörungen, neurodegenerativen erkrankungen oder proliferativen hauterkrankungen |
GB2395195A (en) * | 2002-11-18 | 2004-05-19 | Cipla Ltd | Preparation of perindopril from carboxy-protected precursor, & perindopril monohydrates for use as angiotensin converting enzyme (ACE) inhibitors |
KR101115560B1 (ko) | 2003-08-01 | 2012-03-13 | 칼피스가부시키가이샤 | 생체내 비분해성 펩티드, 안지오텐신 변환효소 저해제, 의약 및 기능성 식품 |
CN1939912A (zh) * | 2005-10-01 | 2007-04-04 | 代斌 | N-[2-(3-苯基-2-丙烯酰氨基)丙酰基]-噻唑烷酸及其衍生物制备方法 |
CN100415709C (zh) * | 2006-05-15 | 2008-09-03 | 西北大学 | β-(3,4-二羟基苯基)-α-羟基丙酸冰片酯、其合成方法和用途 |
CA2759821A1 (en) | 2009-04-23 | 2010-10-28 | Invasc Therapeutics, Inc. | Compositions and methods for treatment of cardiovascular disease |
CN101607907B (zh) * | 2009-06-22 | 2013-01-23 | 西北大学 | 取代的苯甲酸衍生物及其合成方法和用途 |
JP5799842B2 (ja) | 2012-02-03 | 2015-10-28 | 秋田県 | アンジオテンシン変換酵素阻害ペプチド、該ペプチドを含有するアンジオテンシン変換酵素阻害剤、組成物及び食品、並びに、該ペプチドの製造方法 |
CN102757479B (zh) | 2012-05-09 | 2014-04-30 | 北京林业大学 | 高活性降血压肽及其制备方法 |
JP2014141462A (ja) | 2012-12-27 | 2014-08-07 | Raffinee International Co Ltd | ペプチド、並びに、アンジオテンシン変換酵素阻害剤、抗高血圧剤、及び飲食品 |
CN104945469B (zh) * | 2015-06-30 | 2018-09-28 | 石狮海星食品有限公司 | Ace抑制三肽 |
-
2014
- 2014-11-27 CN CN201410705180.3A patent/CN105693817B/zh active Active
-
2015
- 2015-11-27 AU AU2015353118A patent/AU2015353118B2/en active Active
- 2015-11-27 WO PCT/CN2015/095758 patent/WO2016082786A1/zh active Application Filing
- 2015-11-27 SI SI201531768T patent/SI3225627T1/sl unknown
- 2015-11-27 JP JP2017527865A patent/JP6689848B2/ja active Active
- 2015-11-27 NZ NZ732301A patent/NZ732301A/en unknown
- 2015-11-27 SG SG11201704235SA patent/SG11201704235SA/en unknown
- 2015-11-27 US US15/529,633 patent/US11358985B2/en active Active
- 2015-11-27 CA CA2968595A patent/CA2968595C/en active Active
- 2015-11-27 RU RU2017121590A patent/RU2685709C2/ru active
- 2015-11-27 KR KR1020177017351A patent/KR102098783B1/ko active IP Right Grant
- 2015-11-27 HU HUE15863217A patent/HUE056645T2/hu unknown
- 2015-11-27 ES ES15863217T patent/ES2897916T3/es active Active
- 2015-11-27 EP EP15863217.4A patent/EP3225627B9/en active Active
- 2015-11-27 PT PT158632174T patent/PT3225627T/pt unknown
- 2015-11-27 PL PL15863217T patent/PL3225627T3/pl unknown
- 2015-11-27 MY MYPI2017701895A patent/MY193996A/en unknown
- 2015-11-27 DK DK15863217.4T patent/DK3225627T5/da active
-
2017
- 2017-05-23 IL IL252448A patent/IL252448B/en active IP Right Grant
-
2018
- 2018-03-01 HK HK18102948.9A patent/HK1243437A1/zh unknown
-
2021
- 2021-11-11 CY CY20211100983T patent/CY1125043T1/el unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004024754A1 (ja) * | 2002-09-11 | 2004-03-25 | Toaeiyo Ltd. | プロリンエステル類及びそれを含有する経皮投与製剤 |
Non-Patent Citations (5)
Title |
---|
ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY, vol. Vol.198A, JPN6018022119, 1986, pages 427 - 433 * |
BIOCHEMISTRY, vol. Vol.22, JPN6018022114, 1983, pages 1990 - 1995 * |
JOURNAL OF MEDICINAL CHEMISTRY, vol. 39, no. 13, JPN6018022109, 1996, pages 2594 - 2608 * |
JOURNAL OF THE CHEMICAL SOCIETY, PERKINSON TRANSACTIONS I, vol. Vol.1984, JPN6018022116, 1984, pages 29 - 39 * |
TETRAHEDRON LTTERS, vol. 27, no. 16, JPN6018022112, 1986, pages 1757 - 1758 * |
Also Published As
Publication number | Publication date |
---|---|
SI3225627T1 (sl) | 2022-02-28 |
RU2017121590A3 (ja) | 2018-12-27 |
RU2685709C2 (ru) | 2019-04-23 |
MY193996A (en) | 2022-11-07 |
EP3225627A1 (en) | 2017-10-04 |
KR20170087497A (ko) | 2017-07-28 |
WO2016082786A1 (zh) | 2016-06-02 |
EP3225627B1 (en) | 2021-11-03 |
HUE056645T2 (hu) | 2022-02-28 |
EP3225627A4 (en) | 2018-08-22 |
ES2897916T3 (es) | 2022-03-03 |
IL252448B (en) | 2019-09-26 |
IL252448A0 (en) | 2017-07-31 |
US20170267718A1 (en) | 2017-09-21 |
CA2968595A1 (en) | 2016-06-02 |
NZ732301A (en) | 2018-05-25 |
HK1243437A1 (zh) | 2018-07-13 |
CN105693817B (zh) | 2020-06-05 |
SG11201704235SA (en) | 2017-06-29 |
CN105693817A (zh) | 2016-06-22 |
AU2015353118B2 (en) | 2018-12-13 |
DK3225627T5 (da) | 2022-02-28 |
PL3225627T3 (pl) | 2022-02-28 |
AU2015353118A1 (en) | 2017-06-15 |
EP3225627B9 (en) | 2022-01-05 |
DK3225627T3 (ja) | 2021-11-29 |
CY1125043T1 (el) | 2023-06-09 |
CA2968595C (en) | 2019-09-24 |
PT3225627T (pt) | 2021-11-17 |
US11358985B2 (en) | 2022-06-14 |
JP6689848B2 (ja) | 2020-04-28 |
RU2017121590A (ru) | 2018-12-27 |
KR102098783B1 (ko) | 2020-04-10 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6689848B2 (ja) | トリペプチド化合物、その調製方法及びその用途 | |
JP4691549B2 (ja) | Iapの阻害剤 | |
EP1679309A1 (en) | Antistress drug and medical use thereof | |
US8173643B2 (en) | N-substituted thiomorpholine derivatives as the inhibitors of dipeptidyl peptidase IV and the pharmaceutical uses thereof | |
JPS6327468A (ja) | コレシストキニン拮抗物質としてのアミノ酸アナログ | |
JP4904561B2 (ja) | アザビシクロオクタン−3−オン誘導体及びその使用 | |
Saito et al. | Discovery and structure–activity relationship of thienopyridine derivatives as bone anabolic agents | |
CN101641325A (zh) | 鸟氨酸衍生物 | |
WO2006113376A1 (en) | 2 -aminocarbonyl substituted piperazine or diaza-cyclic compounds as apoptosis protein inhibitor (iap) modulators | |
CA2962917A1 (en) | Novel pyridopyrimidinone compounds for modulating the catalytic activity of histone lysine demethylases (kdms) | |
AU2015288381A1 (en) | Substituted 2-thioxo-imidazolidin-4-ones and spiro analogues thereof, active anti-cancer ingredient, pharmaceutical composition, medicinal preparation, method for treating prostate cancer | |
Omar et al. | Design, synthesis and biological evaluation of new pyrrolidine carboxamide analogues as potential chemotherapeutic agents for hepatocellular carcinoma | |
KR20160002743A (ko) | 디카르복실산 화합물 | |
CN111205291B (zh) | 三唑并环类化合物、其制备方法、中间体和应用 | |
Zajdel et al. | Novel class of arylpiperazines containing N-acylated amino acids: Their synthesis, 5-HT1A, 5-HT2A receptor affinity, and in vivo pharmacological evaluation | |
US8530453B2 (en) | Compounds and methods for the treatment of pain and other diseases | |
RU2386627C2 (ru) | Селективные ингибиторы бутирилхолинэстеразы | |
US20070082922A1 (en) | Huperzine a prodrugs and uses thereof | |
KR20100116175A (ko) | 3,8-디아미노테트라하이드로퀴놀린 유도체 | |
AU2003221636B2 (en) | Amino acid analogues | |
WO2016107542A1 (zh) | 吡咯酰胺类化合物及其制备方法与用途 | |
TW201136938A (en) | Spiropiperidine benzylamines as beta-tryptase inhibitors | |
CN113620887A (zh) | 一类sirt5蛋白抑制剂及其用途 | |
TW201343610A (zh) | mGlu 2/3拮抗劑 | |
JPS6013715A (ja) | 高血圧症治療剤 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20170721 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20180619 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20180914 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20190115 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20190409 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20191001 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20191216 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20200310 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20200408 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6689848 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |