CA2483241C - Novel diazabicyclononene derivatives - Google Patents
Novel diazabicyclononene derivatives Download PDFInfo
- Publication number
- CA2483241C CA2483241C CA2483241A CA2483241A CA2483241C CA 2483241 C CA2483241 C CA 2483241C CA 2483241 A CA2483241 A CA 2483241A CA 2483241 A CA2483241 A CA 2483241A CA 2483241 C CA2483241 C CA 2483241C
- Authority
- CA
- Canada
- Prior art keywords
- phenyl
- diazabicyclo
- propyl
- ene
- carboxylic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- QDFXRVAOBHEBGJ-UHFFFAOYSA-N 3-(cyclononen-1-yl)-4,5,6,7,8,9-hexahydro-1h-diazonine Chemical class C1CCCCCCC=C1C1=NNCCCCCC1 QDFXRVAOBHEBGJ-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 420
- 238000002360 preparation method Methods 0.000 claims abstract description 18
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 990
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 518
- 150000002148 esters Chemical class 0.000 claims description 374
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 312
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 301
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 278
- 125000006282 2-chlorobenzyl group Chemical group [H]C1=C([H])C(Cl)=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 136
- SASNBVQSOZSTPD-UHFFFAOYSA-N n-methylphenethylamine Chemical compound CNCCC1=CC=CC=C1 SASNBVQSOZSTPD-UHFFFAOYSA-N 0.000 claims description 96
- -1 tri-substituted phenyl Chemical group 0.000 claims description 96
- GCJYLAWVUWEHLW-UHFFFAOYSA-N n-[(2-chlorophenyl)methyl]cyclopropanamine Chemical compound ClC1=CC=CC=C1CNC1CC1 GCJYLAWVUWEHLW-UHFFFAOYSA-N 0.000 claims description 87
- 125000000217 alkyl group Chemical group 0.000 claims description 51
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 48
- 125000003070 2-(2-chlorophenyl)ethyl group Chemical group [H]C1=C([H])C(Cl)=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 29
- 125000003118 aryl group Chemical group 0.000 claims description 25
- 125000004432 carbon atom Chemical group C* 0.000 claims description 22
- BTBDLUOYLCXSMK-UHFFFAOYSA-N n-[(3,5-dimethoxyphenyl)methyl]cyclopropanamine Chemical compound COC1=CC(OC)=CC(CNC2CC2)=C1 BTBDLUOYLCXSMK-UHFFFAOYSA-N 0.000 claims description 20
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 19
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 17
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 15
- UZYPFBRRGVZJNV-UHFFFAOYSA-N n-[(2-fluorophenyl)methyl]cyclopropanamine Chemical compound FC1=CC=CC=C1CNC1CC1 UZYPFBRRGVZJNV-UHFFFAOYSA-N 0.000 claims description 15
- IBVNNEPIXJSRAS-UHFFFAOYSA-N 3-(2-chlorophenyl)propan-1-amine Chemical compound NCCCC1=CC=CC=C1Cl IBVNNEPIXJSRAS-UHFFFAOYSA-N 0.000 claims description 14
- 208000001647 Renal Insufficiency Diseases 0.000 claims description 14
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 201000006370 kidney failure Diseases 0.000 claims description 14
- WYQUCNZBUBLJHN-UHFFFAOYSA-N n-[(2-methylphenyl)methyl]cyclopropanamine Chemical compound CC1=CC=CC=C1CNC1CC1 WYQUCNZBUBLJHN-UHFFFAOYSA-N 0.000 claims description 14
- USBAUXJPPHVCTF-UHFFFAOYSA-N n-benzylcyclopropanamine Chemical compound C=1C=CC=CC=1CNC1CC1 USBAUXJPPHVCTF-UHFFFAOYSA-N 0.000 claims description 14
- IVEWTCACRDEAOB-UHFFFAOYSA-N 2-(2-methoxyphenyl)acetic acid Chemical compound COC1=CC=CC=C1CC(O)=O IVEWTCACRDEAOB-UHFFFAOYSA-N 0.000 claims description 13
- HWDVTQAXQJQROO-UHFFFAOYSA-N cyclopropylazanide Chemical compound [NH-]C1CC1 HWDVTQAXQJQROO-UHFFFAOYSA-N 0.000 claims description 13
- 125000003342 alkenyl group Chemical group 0.000 claims description 12
- 125000001072 heteroaryl group Chemical group 0.000 claims description 12
- KJYVKUQRRKDPAX-UHFFFAOYSA-N n-[(2,3-dichlorophenyl)methyl]cyclopropanamine Chemical compound ClC1=CC=CC(CNC2CC2)=C1Cl KJYVKUQRRKDPAX-UHFFFAOYSA-N 0.000 claims description 11
- 238000011282 treatment Methods 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- SBKDFWWYKALTKE-UHFFFAOYSA-N n-[(2-bromophenyl)methyl]cyclopropanamine Chemical compound BrC1=CC=CC=C1CNC1CC1 SBKDFWWYKALTKE-UHFFFAOYSA-N 0.000 claims description 10
- NJHZDGHFBLATGX-UHFFFAOYSA-N n-[2-(2-chlorophenyl)ethyl]cyclopropanamine Chemical compound ClC1=CC=CC=C1CCNC1CC1 NJHZDGHFBLATGX-UHFFFAOYSA-N 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 206010019280 Heart failures Diseases 0.000 claims description 9
- 206010020772 Hypertension Diseases 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- ILHIZUJWNGLALK-UHFFFAOYSA-N n-(2-phenylethyl)cyclopropanamine Chemical compound C1CC1NCCC1=CC=CC=C1 ILHIZUJWNGLALK-UHFFFAOYSA-N 0.000 claims description 9
- CRIMYHBFDHWKQY-UHFFFAOYSA-N n-[(2,3-dimethylphenyl)methyl]cyclopropanamine Chemical compound CC1=CC=CC(CNC2CC2)=C1C CRIMYHBFDHWKQY-UHFFFAOYSA-N 0.000 claims description 9
- LJBFNXZKZYKGFY-UHFFFAOYSA-N n-[(3-methylphenyl)methyl]cyclopropanamine Chemical compound CC1=CC=CC(CNC2CC2)=C1 LJBFNXZKZYKGFY-UHFFFAOYSA-N 0.000 claims description 9
- AOMAZSZEDRDSIF-UHFFFAOYSA-N n-[[3-(trifluoromethyl)phenyl]methyl]cyclopropanamine Chemical compound FC(F)(F)C1=CC=CC(CNC2CC2)=C1 AOMAZSZEDRDSIF-UHFFFAOYSA-N 0.000 claims description 9
- 125000002947 alkylene group Chemical group 0.000 claims description 8
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 8
- 201000010099 disease Diseases 0.000 claims description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 8
- OBNCKNCVKJNDBV-UHFFFAOYSA-N ethyl butyrate Chemical compound CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 claims description 8
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- CUPDQCKBQJVOMC-UHFFFAOYSA-N n-[(2-fluoro-5-methoxyphenyl)methyl]cyclopropanamine Chemical compound COC1=CC=C(F)C(CNC2CC2)=C1 CUPDQCKBQJVOMC-UHFFFAOYSA-N 0.000 claims description 8
- VALINFAZSMPKJJ-UHFFFAOYSA-N n-[(3-chlorophenyl)methyl]cyclopropanamine Chemical compound ClC1=CC=CC(CNC2CC2)=C1 VALINFAZSMPKJJ-UHFFFAOYSA-N 0.000 claims description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 125000004450 alkenylene group Chemical group 0.000 claims description 7
- 125000006193 alkinyl group Chemical group 0.000 claims description 7
- CEQDKNLDFWAMEL-UHFFFAOYSA-N n-[[2-chloro-3-(trifluoromethyl)phenyl]methyl]cyclopropanamine Chemical compound FC(F)(F)C1=CC=CC(CNC2CC2)=C1Cl CEQDKNLDFWAMEL-UHFFFAOYSA-N 0.000 claims description 7
- 238000011321 prophylaxis Methods 0.000 claims description 7
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 6
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 6
- 206010063897 Renal ischaemia Diseases 0.000 claims description 6
- 208000029078 coronary artery disease Diseases 0.000 claims description 6
- 208000031225 myocardial ischemia Diseases 0.000 claims description 6
- NUPAMNLYORQZRV-UHFFFAOYSA-N n-[(3-methoxyphenyl)methyl]cyclopropanamine Chemical compound COC1=CC=CC(CNC2CC2)=C1 NUPAMNLYORQZRV-UHFFFAOYSA-N 0.000 claims description 6
- DTJKAALGEAHUIV-UHFFFAOYSA-N 2-(2-chlorophenyl)-n-methylethanamine Chemical compound CNCCC1=CC=CC=C1Cl DTJKAALGEAHUIV-UHFFFAOYSA-N 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- ORZRHMRDNOCKDU-UHFFFAOYSA-N n-[(3,4-dimethoxyphenyl)methyl]cyclopropanamine Chemical compound C1=C(OC)C(OC)=CC=C1CNC1CC1 ORZRHMRDNOCKDU-UHFFFAOYSA-N 0.000 claims description 5
- VRDMJNOXKZMLTF-UHFFFAOYSA-N n-[(6-chloro-1,3-benzodioxol-5-yl)methyl]cyclopropanamine Chemical compound ClC1=CC=2OCOC=2C=C1CNC1CC1 VRDMJNOXKZMLTF-UHFFFAOYSA-N 0.000 claims description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- WRRVCXHKEDNRNB-UHFFFAOYSA-N n-[(3,5-difluorophenyl)methyl]cyclopropanamine Chemical compound FC1=CC(F)=CC(CNC2CC2)=C1 WRRVCXHKEDNRNB-UHFFFAOYSA-N 0.000 claims description 4
- ANCFTHKEGKDXKD-UHFFFAOYSA-N n-[[3-(trifluoromethoxy)phenyl]methyl]cyclopropanamine Chemical compound FC(F)(F)OC1=CC=CC(CNC2CC2)=C1 ANCFTHKEGKDXKD-UHFFFAOYSA-N 0.000 claims description 4
- 235000019260 propionic acid Nutrition 0.000 claims description 4
- 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 4
- 208000037803 restenosis Diseases 0.000 claims description 4
- 125000006179 2-methyl benzyl group Chemical group [H]C1=C([H])C(=C(C([H])=C1[H])C([H])([H])*)C([H])([H])[H] 0.000 claims description 3
- 201000001320 Atherosclerosis Diseases 0.000 claims description 3
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 3
- 208000002249 Diabetes Complications Diseases 0.000 claims description 3
- 206010012655 Diabetic complications Diseases 0.000 claims description 3
- 208000010228 Erectile Dysfunction Diseases 0.000 claims description 3
- 208000010412 Glaucoma Diseases 0.000 claims description 3
- 206010018364 Glomerulonephritis Diseases 0.000 claims description 3
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 claims description 3
- 206010038419 Renal colic Diseases 0.000 claims description 3
- 238000007675 cardiac surgery Methods 0.000 claims description 3
- 201000001881 impotence Diseases 0.000 claims description 3
- QWMNTOVGKJAROU-UHFFFAOYSA-N n-[(2-chlorophenyl)methyl]ethanamine Chemical compound CCNCC1=CC=CC=C1Cl QWMNTOVGKJAROU-UHFFFAOYSA-N 0.000 claims description 3
- 210000000056 organ Anatomy 0.000 claims description 3
- 238000002054 transplantation Methods 0.000 claims description 3
- 230000002792 vascular Effects 0.000 claims description 3
- 238000007631 vascular surgery Methods 0.000 claims description 3
- HCHZVCWKNNFIHR-AHCWXFLVSA-N (1s,5r)-3-[(2s)-2-amino-3-hydroxypropanoyl]-n-[(2-chlorophenyl)methyl]-n-cyclopropyl-7-[4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl]-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxamide Chemical compound C=1([C@]2([H])CN(C[C@@](N2)(CC=1C=1C=CC(CCCOC=2C(=C(F)C=CC=2F)F)=CC=1)[H])C(=O)[C@@H](N)CO)C(=O)N(C1CC1)CC1=CC=CC=C1Cl HCHZVCWKNNFIHR-AHCWXFLVSA-N 0.000 claims description 2
- UCAUHTUMXIYKFJ-UHFFFAOYSA-N 2-(2-methoxyphenyl)-n-methylethanamine Chemical compound CNCCC1=CC=CC=C1OC UCAUHTUMXIYKFJ-UHFFFAOYSA-N 0.000 claims description 2
- HNJWKRMESUMDQE-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-n-methylethanamine Chemical compound CNCCC1=CC=C(OC)C(OC)=C1 HNJWKRMESUMDQE-UHFFFAOYSA-N 0.000 claims description 2
- ZAIUACXHBBABJZ-UHFFFAOYSA-N 2-(3-chlorophenyl)-n-methylethanamine Chemical compound CNCCC1=CC=CC(Cl)=C1 ZAIUACXHBBABJZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000006495 3-trifluoromethyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1[H])C([H])([H])*)C(F)(F)F 0.000 claims description 2
- JCMWSVNNSPUNER-UHFFFAOYSA-N N,O-dimethyltyramine Chemical compound CNCCC1=CC=C(OC)C=C1 JCMWSVNNSPUNER-UHFFFAOYSA-N 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- VNFABSKAJCALBZ-UHFFFAOYSA-N n-[(2-chloro-6-fluorophenyl)methyl]cyclopropanamine Chemical compound FC1=CC=CC(Cl)=C1CNC1CC1 VNFABSKAJCALBZ-UHFFFAOYSA-N 0.000 claims description 2
- WOHOHPONCSKXSQ-UHFFFAOYSA-N n-ethyl-2-phenylethanamine Chemical compound CCNCCC1=CC=CC=C1 WOHOHPONCSKXSQ-UHFFFAOYSA-N 0.000 claims description 2
- 229920006063 Lamide® Polymers 0.000 claims 2
- 229940125721 immunosuppressive agent Drugs 0.000 claims 2
- 239000003018 immunosuppressive agent Substances 0.000 claims 2
- 208000002815 pulmonary hypertension Diseases 0.000 claims 2
- HCHZVCWKNNFIHR-XGJRVREISA-N (1r,5s)-3-[(2s)-2-amino-3-hydroxypropanoyl]-n-[(2-chlorophenyl)methyl]-n-cyclopropyl-7-[4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl]-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxamide Chemical compound C=1([C@@]2([H])CN(C[C@](N2)(CC=1C=1C=CC(CCCOC=2C(=C(F)C=CC=2F)F)=CC=1)[H])C(=O)[C@@H](N)CO)C(=O)N(C1CC1)CC1=CC=CC=C1Cl HCHZVCWKNNFIHR-XGJRVREISA-N 0.000 claims 1
- JUPFDVXBMWKQJS-MCCKRTAFSA-N (1r,5s)-3-[(2s)-2-aminopropanoyl]-n-[(2-chlorophenyl)methyl]-n-cyclopropyl-7-[4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl]-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxamide Chemical compound C=1([C@@]2([H])CN(C[C@](N2)(CC=1C=1C=CC(CCCOC=2C(=C(F)C=CC=2F)F)=CC=1)[H])C(=O)[C@H](C)N)C(=O)N(C1CC1)CC1=CC=CC=C1Cl JUPFDVXBMWKQJS-MCCKRTAFSA-N 0.000 claims 1
- LFGLSENCOIFTLS-MYQURODFSA-N (1r,5s)-n-[(2-chlorophenyl)methyl]-n-cyclopropyl-9-[(3s)-3-hydroxybutanoyl]-7-[4-[2-(2,3,6-trifluorophenoxy)propyl]phenyl]-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxamide Chemical compound C=1([C@@]2([H])CNC[C@](N2C(=O)C[C@H](C)O)(CC=1C=1C=CC(CC(C)OC=2C(=C(F)C=CC=2F)F)=CC=1)[H])C(=O)N(C1CC1)CC1=CC=CC=C1Cl LFGLSENCOIFTLS-MYQURODFSA-N 0.000 claims 1
- JUPFDVXBMWKQJS-GKFGHWCMSA-N (1s,5r)-3-[(2s)-2-aminopropanoyl]-n-[(2-chlorophenyl)methyl]-n-cyclopropyl-7-[4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl]-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxamide Chemical compound C=1([C@]2([H])CN(C[C@@](N2)(CC=1C=1C=CC(CCCOC=2C(=C(F)C=CC=2F)F)=CC=1)[H])C(=O)[C@H](C)N)C(=O)N(C1CC1)CC1=CC=CC=C1Cl JUPFDVXBMWKQJS-GKFGHWCMSA-N 0.000 claims 1
- HKXOGUWLPNRQOJ-UBLOXDIOSA-N (1s,5r)-n-[(2-chlorophenyl)methyl]-n-cyclopropyl-3-[(3r)-3-hydroxybutanoyl]-7-[4-[3-(2,3,6-trifluorophenoxy)propyl]phenyl]-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxamide Chemical compound C=1([C@]2([H])CN(C[C@@](N2)(CC=1C=1C=CC(CCCOC=2C(=C(F)C=CC=2F)F)=CC=1)[H])C(=O)C[C@@H](C)O)C(=O)N(C1CC1)CC1=CC=CC=C1Cl HKXOGUWLPNRQOJ-UBLOXDIOSA-N 0.000 claims 1
- VCSUCPDSYSXLEX-UHFFFAOYSA-N 2-(4-chlorophenyl)-n-methylethanamine Chemical compound CNCCC1=CC=C(Cl)C=C1 VCSUCPDSYSXLEX-UHFFFAOYSA-N 0.000 claims 1
- JLLYLQLDYORLBB-UHFFFAOYSA-N 5-bromo-n-methylthiophene-2-sulfonamide Chemical compound CNS(=O)(=O)C1=CC=C(Br)S1 JLLYLQLDYORLBB-UHFFFAOYSA-N 0.000 claims 1
- 239000002671 adjuvant Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 239000000463 material Substances 0.000 claims 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 1
- HROUFMHZMXWOHI-UHFFFAOYSA-N n-(1,3-benzodioxol-5-ylmethyl)cyclopropanamine Chemical compound C=1C=C2OCOC2=CC=1CNC1CC1 HROUFMHZMXWOHI-UHFFFAOYSA-N 0.000 claims 1
- MLHBZVFOTDJTPK-UHFFFAOYSA-N n-methyl-3-phenylpropan-1-amine Chemical compound CNCCCC1=CC=CC=C1 MLHBZVFOTDJTPK-UHFFFAOYSA-N 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 10
- 108090000783 Renin Proteins 0.000 abstract description 5
- 102100028255 Renin Human genes 0.000 abstract description 4
- 239000003112 inhibitor Substances 0.000 abstract description 4
- 239000004480 active ingredient Substances 0.000 abstract description 2
- 230000008569 process Effects 0.000 abstract description 2
- YJTZZSKGEPHUTF-UHFFFAOYSA-N 3,9-diazabicyclo[3.3.1]non-4-ene Chemical class C1NC=C2CCCC1N2 YJTZZSKGEPHUTF-UHFFFAOYSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 352
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 255
- 239000000203 mixture Substances 0.000 description 227
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 218
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 207
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 186
- 238000000746 purification Methods 0.000 description 180
- 235000019439 ethyl acetate Nutrition 0.000 description 177
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 119
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 112
- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-dimethylaminophenol Chemical compound CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 107
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 107
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-dimethylaminopyridine Substances CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 107
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 102
- 239000008279 sol Substances 0.000 description 95
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 93
- 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 90
- 230000002829 reductive effect Effects 0.000 description 85
- 239000002904 solvent Chemical class 0.000 description 82
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 77
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 63
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 56
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 56
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 56
- 235000019341 magnesium sulphate Nutrition 0.000 description 56
- 239000000284 extract Substances 0.000 description 55
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 46
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 42
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 39
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
- 229910001868 water Inorganic materials 0.000 description 36
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 33
- 150000001408 amides Chemical class 0.000 description 32
- 239000000543 intermediate Substances 0.000 description 32
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 28
- 239000011541 reaction mixture Substances 0.000 description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- 239000002243 precursor Substances 0.000 description 23
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- 238000010992 reflux Methods 0.000 description 16
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 15
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 15
- BNLAPXNSMIAMIO-UHFFFAOYSA-N n-[2-(4-methylphenyl)ethyl]cyclopropanamine Chemical compound C1=CC(C)=CC=C1CCNC1CC1 BNLAPXNSMIAMIO-UHFFFAOYSA-N 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 235000017557 sodium bicarbonate Nutrition 0.000 description 14
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 14
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 11
- 239000006260 foam Substances 0.000 description 11
- ISNLSWQFNKVCAT-UHFFFAOYSA-N n-[2-(2,3-difluorophenyl)ethyl]cyclopropanamine Chemical compound FC1=CC=CC(CCNC2CC2)=C1F ISNLSWQFNKVCAT-UHFFFAOYSA-N 0.000 description 11
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 10
- 239000012876 carrier material Substances 0.000 description 10
- NJDGRXSBVMPMQX-UHFFFAOYSA-N n-[2-(4-fluorophenyl)ethyl]cyclopropanamine Chemical compound C1=CC(F)=CC=C1CCNC1CC1 NJDGRXSBVMPMQX-UHFFFAOYSA-N 0.000 description 10
- GEDRFLMRWRNXGV-UHFFFAOYSA-N n-[2-(4-methoxyphenoxy)ethyl]cyclopropanamine Chemical compound C1=CC(OC)=CC=C1OCCNC1CC1 GEDRFLMRWRNXGV-UHFFFAOYSA-N 0.000 description 10
- 239000003921 oil Substances 0.000 description 10
- 235000019198 oils Nutrition 0.000 description 10
- 239000002461 renin inhibitor Substances 0.000 description 10
- 229940086526 renin-inhibitors Drugs 0.000 description 10
- POYWLSASJPZKQR-UHFFFAOYSA-N n-[2-(2-methylphenyl)ethyl]cyclopropanamine Chemical compound CC1=CC=CC=C1CCNC1CC1 POYWLSASJPZKQR-UHFFFAOYSA-N 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- 230000036454 renin-angiotensin system Effects 0.000 description 9
- 239000012346 acetyl chloride Substances 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 239000007788 liquid Substances 0.000 description 7
- STQNVRNQOXAPGG-UHFFFAOYSA-N 2-[2-[(cyclopropylamino)methyl]phenyl]ethanol Chemical compound C1(CC1)NCC1=C(C=CC=C1)CCO STQNVRNQOXAPGG-UHFFFAOYSA-N 0.000 description 6
- 239000005541 ACE inhibitor Substances 0.000 description 6
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 6
- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 6
- 230000008878 coupling Effects 0.000 description 6
- 238000010168 coupling process Methods 0.000 description 6
- 238000005859 coupling reaction Methods 0.000 description 6
- 238000010790 dilution Methods 0.000 description 6
- 239000012895 dilution Substances 0.000 description 6
- VDDXQSUSMHZCLS-UHFFFAOYSA-N ethenyl trifluoromethanesulfonate Chemical class FC(F)(F)S(=O)(=O)OC=C VDDXQSUSMHZCLS-UHFFFAOYSA-N 0.000 description 6
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 6
- 125000005647 linker group Chemical group 0.000 description 6
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 6
- 239000012279 sodium borohydride Substances 0.000 description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 description 6
- 235000017550 sodium carbonate Nutrition 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-UHFFFAOYSA-N 0.000 description 6
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 6
- 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 description 5
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 description 5
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 5
- 125000005530 alkylenedioxy group Chemical group 0.000 description 5
- 125000005529 alkyleneoxy group Chemical group 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 244000309464 bull Species 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 238000010511 deprotection reaction Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 125000004494 ethyl ester group Chemical group 0.000 description 5
- MGJXBDMLVWIYOQ-UHFFFAOYSA-N methylazanide Chemical compound [NH-]C MGJXBDMLVWIYOQ-UHFFFAOYSA-N 0.000 description 5
- XNHLFXQLLBVMKL-UHFFFAOYSA-N n-[2-(3,4-dimethylphenoxy)ethyl]cyclopropanamine Chemical compound C1=C(C)C(C)=CC=C1OCCNC1CC1 XNHLFXQLLBVMKL-UHFFFAOYSA-N 0.000 description 5
- LUVQDOPJNGGUDF-UHFFFAOYSA-N n-[2-(3-methylphenoxy)ethyl]cyclopropanamine Chemical compound CC1=CC=CC(OCCNC2CC2)=C1 LUVQDOPJNGGUDF-UHFFFAOYSA-N 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 229910052717 sulfur Inorganic materials 0.000 description 5
- 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 description 4
- PJQCUMVGSKEOMN-UHFFFAOYSA-N 3-cyclohexylpyrrolidine Chemical compound C1NCCC1C1CCCCC1 PJQCUMVGSKEOMN-UHFFFAOYSA-N 0.000 description 4
- 239000001828 Gelatine Substances 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 125000005603 azodicarboxylic group Chemical group 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
- 150000003335 secondary amines Chemical class 0.000 description 4
- 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 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- VLSDXINSOMDCBK-BQYQJAHWSA-N (E)-1,1'-azobis(N,N-dimethylformamide) Chemical compound CN(C)C(=O)\N=N\C(=O)N(C)C VLSDXINSOMDCBK-BQYQJAHWSA-N 0.000 description 3
- UKBFNAFIUSTHIV-UHFFFAOYSA-N 1-(3-chloropropoxymethyl)-2-methoxybenzene Chemical compound COC1=CC=CC=C1COCCCCl UKBFNAFIUSTHIV-UHFFFAOYSA-N 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- HUVAOAVBKOVPBZ-UHFFFAOYSA-N 2-bromo-5-fluorophenol Chemical compound OC1=CC(F)=CC=C1Br HUVAOAVBKOVPBZ-UHFFFAOYSA-N 0.000 description 3
- XQJYSDLBSUNHBS-UHFFFAOYSA-N 2-cyclononylcyclononan-1-one Chemical compound O=C1CCCCCCCC1C1CCCCCCCC1 XQJYSDLBSUNHBS-UHFFFAOYSA-N 0.000 description 3
- FEJUGLKDZJDVFY-UHFFFAOYSA-N 9-borabicyclo[3.3.1]nonane Substances C1CCC2CCCC1B2 FEJUGLKDZJDVFY-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 3
- 125000004104 aryloxy group Chemical group 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- PAVTYZPJUAQLOD-UHFFFAOYSA-N ethyl 2-[4-benzyl-6-(2-ethoxy-2-oxoethyl)-1-methylpiperazin-2-yl]acetate Chemical compound C1C(CC(=O)OCC)N(C)C(CC(=O)OCC)CN1CC1=CC=CC=C1 PAVTYZPJUAQLOD-UHFFFAOYSA-N 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 3
- WJFXKLXJOHUXCU-UHFFFAOYSA-N n-[2-(3-methoxyphenoxy)ethyl]cyclopropanamine Chemical compound COC1=CC=CC(OCCNC2CC2)=C1 WJFXKLXJOHUXCU-UHFFFAOYSA-N 0.000 description 3
- 125000004430 oxygen atom Chemical group O* 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 3
- 229920005862 polyol Polymers 0.000 description 3
- 150000003077 polyols Chemical class 0.000 description 3
- 238000006268 reductive amination reaction Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 125000004434 sulfur atom Chemical group 0.000 description 3
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 3
- 239000001993 wax Substances 0.000 description 3
- GMELMFSDPDSXOZ-UHFFFAOYSA-N (1,1,1-trichloro-2-methylpropan-2-yl) carbonochloridate Chemical compound ClC(Cl)(Cl)C(C)(C)OC(Cl)=O GMELMFSDPDSXOZ-UHFFFAOYSA-N 0.000 description 2
- ZBQCLJZOKDRAOW-IODNYQNNSA-N (1s)-1-phenyl-n-[(1s)-1-phenylethyl]ethanamine;hydrochloride Chemical compound Cl.C1([C@H](C)N[C@@H](C)C=2C=CC=CC=2)=CC=CC=C1 ZBQCLJZOKDRAOW-IODNYQNNSA-N 0.000 description 2
- DIOHEXPTUTVCNX-UHFFFAOYSA-N 1,1,1-trifluoro-n-phenyl-n-(trifluoromethylsulfonyl)methanesulfonamide Chemical compound FC(F)(F)S(=O)(=O)N(S(=O)(=O)C(F)(F)F)C1=CC=CC=C1 DIOHEXPTUTVCNX-UHFFFAOYSA-N 0.000 description 2
- OALMQEMOLLYBNO-UHFFFAOYSA-N 1-[2-(4-bromophenyl)ethoxy]-2,3,5-trimethylbenzene Chemical compound CC1=CC(C)=C(C)C(OCCC=2C=CC(Br)=CC=2)=C1 OALMQEMOLLYBNO-UHFFFAOYSA-N 0.000 description 2
- ZWEGOGARWMDMDR-UHFFFAOYSA-N 2,2-dimethyl-5-oxopentanoic acid Chemical compound OC(=O)C(C)(C)CCC=O ZWEGOGARWMDMDR-UHFFFAOYSA-N 0.000 description 2
- OGRAOKJKVGDSFR-UHFFFAOYSA-N 2,3,5-trimethylphenol Chemical compound CC1=CC(C)=C(C)C(O)=C1 OGRAOKJKVGDSFR-UHFFFAOYSA-N 0.000 description 2
- PMOSJSPFNDUAFY-UHFFFAOYSA-N 2-(4-bromophenyl)ethanol Chemical compound OCCC1=CC=C(Br)C=C1 PMOSJSPFNDUAFY-UHFFFAOYSA-N 0.000 description 2
- HWUZQODGTCVVBO-UHFFFAOYSA-N 2-(4-methoxyphenoxy)-n-methylethanamine Chemical compound CNCCOC1=CC=C(OC)C=C1 HWUZQODGTCVVBO-UHFFFAOYSA-N 0.000 description 2
- 125000004847 2-fluorobenzyl group Chemical group [H]C1=C([H])C(F)=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- ZGYSXQAWRWCIMF-UHFFFAOYSA-N 3-(5-bromopyridin-2-yl)oxypropan-1-ol Chemical compound OCCCOC1=CC=C(Br)C=N1 ZGYSXQAWRWCIMF-UHFFFAOYSA-N 0.000 description 2
- 101150059573 AGTR1 gene Proteins 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 102000004881 Angiotensinogen Human genes 0.000 description 2
- 108090001067 Angiotensinogen Proteins 0.000 description 2
- 101100398248 Arabidopsis thaliana KIN10 gene Proteins 0.000 description 2
- 101100407151 Arabidopsis thaliana PBL6 gene Proteins 0.000 description 2
- 108010017640 Aspartic Acid Proteases Proteins 0.000 description 2
- 102000004580 Aspartic Acid Proteases Human genes 0.000 description 2
- 101800004538 Bradykinin Proteins 0.000 description 2
- 102400000967 Bradykinin Human genes 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 102000003858 Chymases Human genes 0.000 description 2
- 108090000227 Chymases Proteins 0.000 description 2
- 239000004129 EU approved improving agent Substances 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- QXZGBUJJYSLZLT-UHFFFAOYSA-N H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH Natural products NC(N)=NCCCC(N)C(=O)N1CCCC1C(=O)N1C(C(=O)NCC(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CO)C(=O)N2C(CCC2)C(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CCCN=C(N)N)C(O)=O)CCC1 QXZGBUJJYSLZLT-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 229940095054 ammoniac Drugs 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 239000006286 aqueous extract Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000004799 bromophenyl group Chemical group 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 230000007211 cardiovascular event Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 239000013058 crude material Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 125000006317 cyclopropyl amino group Chemical group 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000003925 fat Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 125000005456 glyceride group Chemical group 0.000 description 2
- 125000005553 heteroaryloxy group Chemical group 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- OBWFJXLKRAFEDI-UHFFFAOYSA-N methyl cyanoformate Chemical compound COC(=O)C#N OBWFJXLKRAFEDI-UHFFFAOYSA-N 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- XOJVVFBFDXDTEG-UHFFFAOYSA-N pristane Chemical compound CC(C)CCCC(C)CCCC(C)CCCC(C)C XOJVVFBFDXDTEG-UHFFFAOYSA-N 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000007127 saponification reaction Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- DNFOKPHRKDUAFC-PICIMBCMSA-N (1r,5s)-7-[4-[2-(2-chloro-4,5-dimethylphenoxy)ethoxy]phenyl]-n-[(2-chlorophenyl)methyl]-n-cyclopropyl-3-[(2s,4r)-4-hydroxypyrrolidine-2-carbonyl]-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxamide Chemical compound C=1([C@@]2([H])CN(C[C@](N2)(CC=1C=1C=CC(OCCOC=2C(=CC(C)=C(C)C=2)Cl)=CC=1)[H])C(=O)[C@H]1NC[C@H](O)C1)C(=O)N(C1CC1)CC1=CC=CC=C1Cl DNFOKPHRKDUAFC-PICIMBCMSA-N 0.000 description 1
- AAYYEGRUYMEWCL-HTCLOLTESA-N (1r,5s)-7-[4-[3-(2-bromo-5-fluorophenoxy)propyl]phenyl]-n-cyclopropyl-n-[(3,5-dimethoxyphenyl)methyl]-3-[(2s,4r)-4-hydroxypyrrolidine-2-carbonyl]-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxamide Chemical compound C=1([C@@]2([H])CN(C[C@](N2)(CC=1C=1C=CC(CCCOC=2C(=CC=C(F)C=2)Br)=CC=1)[H])C(=O)[C@H]1NC[C@H](O)C1)C(=O)N(C1CC1)CC1=CC(OC)=CC(OC)=C1 AAYYEGRUYMEWCL-HTCLOLTESA-N 0.000 description 1
- AAYYEGRUYMEWCL-JCESUESDSA-N (1s,5r)-7-[4-[3-(2-bromo-5-fluorophenoxy)propyl]phenyl]-n-cyclopropyl-n-[(3,5-dimethoxyphenyl)methyl]-3-[(2s,4r)-4-hydroxypyrrolidine-2-carbonyl]-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxamide Chemical compound C=1([C@]2([H])CN(C[C@@](N2)(CC=1C=1C=CC(CCCOC=2C(=CC=C(F)C=2)Br)=CC=1)[H])C(=O)[C@H]1NC[C@H](O)C1)C(=O)N(C1CC1)CC1=CC(OC)=CC(OC)=C1 AAYYEGRUYMEWCL-JCESUESDSA-N 0.000 description 1
- 125000005940 1,4-dioxanyl group Chemical group 0.000 description 1
- UAWVMPOAIVZWFQ-UHFFFAOYSA-N 1-(chloromethyl)-2-methoxybenzene Chemical compound COC1=CC=CC=C1CCl UAWVMPOAIVZWFQ-UHFFFAOYSA-N 0.000 description 1
- PDQPSFDHZOCBPS-UHFFFAOYSA-N 1-bromo-4-[3-(2-chlorophenoxy)propyl]benzene Chemical compound ClC1=CC=CC=C1OCCCC1=CC=C(Br)C=C1 PDQPSFDHZOCBPS-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- QSFGUSFDWCVXNR-UHFFFAOYSA-N 2,3,6-trifluorophenol Chemical compound OC1=C(F)C=CC(F)=C1F QSFGUSFDWCVXNR-UHFFFAOYSA-N 0.000 description 1
- FMEVAQARAVDUNY-UHFFFAOYSA-N 2-(2-aminoethyl)phenol Chemical compound NCCC1=CC=CC=C1O FMEVAQARAVDUNY-UHFFFAOYSA-N 0.000 description 1
- RZBOMSOHMOVUES-UHFFFAOYSA-N 2-(2-chlorophenyl)ethanamine Chemical compound NCCC1=CC=CC=C1Cl RZBOMSOHMOVUES-UHFFFAOYSA-N 0.000 description 1
- WSWPCNMLEVZGSM-UHFFFAOYSA-N 2-(2-methoxyphenyl)ethanamine Chemical compound COC1=CC=CC=C1CCN WSWPCNMLEVZGSM-UHFFFAOYSA-N 0.000 description 1
- MWOLPDQWBBJNJU-UHFFFAOYSA-N 2-(3-methoxyphenoxy)ethanamine Chemical compound COC1=CC=CC(OCCN)=C1 MWOLPDQWBBJNJU-UHFFFAOYSA-N 0.000 description 1
- MCGDBHZRFQKLBT-UHFFFAOYSA-N 2-(3-methoxyphenyl)-n-methylethanamine Chemical compound CNCCC1=CC=CC(OC)=C1 MCGDBHZRFQKLBT-UHFFFAOYSA-N 0.000 description 1
- XQQJFOBOGNCTRJ-UHFFFAOYSA-N 2-(4-bromophenoxy)ethoxy-tert-butyl-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)OCCOC1=CC=C(Br)C=C1 XQQJFOBOGNCTRJ-UHFFFAOYSA-N 0.000 description 1
- WBKZIAKOQWXXSA-UHFFFAOYSA-N 2-(4-bromophenyl)ethoxy-tert-butyl-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](C=1C=CC=CC=1)(C(C)(C)C)OCCC1=CC=C(Br)C=C1 WBKZIAKOQWXXSA-UHFFFAOYSA-N 0.000 description 1
- RGLUIFRWIKUDEI-UHFFFAOYSA-N 2-(4-chlorophenoxy)-n-methylethanamine Chemical compound CNCCOC1=CC=C(Cl)C=C1 RGLUIFRWIKUDEI-UHFFFAOYSA-N 0.000 description 1
- PEFKLFPOCHHHQA-UHFFFAOYSA-N 2-[(4-bromophenoxy)methoxy]ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCOC1=CC=C(Br)C=C1 PEFKLFPOCHHHQA-UHFFFAOYSA-N 0.000 description 1
- NDOPHXWIAZIXPR-UHFFFAOYSA-N 2-bromobenzaldehyde Chemical compound BrC1=CC=CC=C1C=O NDOPHXWIAZIXPR-UHFFFAOYSA-N 0.000 description 1
- ISPYQTSUDJAMAB-UHFFFAOYSA-N 2-chlorophenol Chemical compound OC1=CC=CC=C1Cl ISPYQTSUDJAMAB-UHFFFAOYSA-N 0.000 description 1
- WPGDIKSWKZLNRR-UHFFFAOYSA-N 2-hydroxy-5-oxopentanoic acid Chemical compound OC(=O)C(O)CCC=O WPGDIKSWKZLNRR-UHFFFAOYSA-N 0.000 description 1
- FZTDYEUXQXNEER-UHFFFAOYSA-N 2-prop-2-enylbenzaldehyde Chemical compound C=CCC1=CC=CC=C1C=O FZTDYEUXQXNEER-UHFFFAOYSA-N 0.000 description 1
- QQOMQLYQAXGHSU-UHFFFAOYSA-N 236TMPh Natural products CC1=CC=C(C)C(O)=C1C QQOMQLYQAXGHSU-UHFFFAOYSA-N 0.000 description 1
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 1
- ZPXKZQIHSNWFNW-UHFFFAOYSA-N 3-(1,3-benzodioxol-5-yl)-n-methylpropan-1-amine Chemical compound CNCCCC1=CC=C2OCOC2=C1 ZPXKZQIHSNWFNW-UHFFFAOYSA-N 0.000 description 1
- WODKXGCVVOOEIJ-UHFFFAOYSA-N 3-(4-bromophenyl)propan-1-ol Chemical compound OCCCC1=CC=C(Br)C=C1 WODKXGCVVOOEIJ-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- GZFGOTFRPZRKDS-UHFFFAOYSA-N 4-bromophenol Chemical compound OC1=CC=C(Br)C=C1 GZFGOTFRPZRKDS-UHFFFAOYSA-N 0.000 description 1
- MDVDCPHFRKFALI-UHFFFAOYSA-N 5-bromo-2-[3-[(2-methoxyphenyl)methoxy]propoxy]pyridine Chemical compound COC1=CC=CC=C1COCCCOC1=CC=C(Br)C=N1 MDVDCPHFRKFALI-UHFFFAOYSA-N 0.000 description 1
- VBKPPDYGFUZOAJ-UHFFFAOYSA-N 5-oxopentanoic acid Chemical compound OC(=O)CCCC=O VBKPPDYGFUZOAJ-UHFFFAOYSA-N 0.000 description 1
- AMKGKYQBASDDJB-UHFFFAOYSA-N 9$l^{2}-borabicyclo[3.3.1]nonane Chemical compound C1CCC2CCCC1[B]2 AMKGKYQBASDDJB-UHFFFAOYSA-N 0.000 description 1
- 208000028185 Angioedema Diseases 0.000 description 1
- 101800000734 Angiotensin-1 Proteins 0.000 description 1
- 102400000344 Angiotensin-1 Human genes 0.000 description 1
- 101800000733 Angiotensin-2 Proteins 0.000 description 1
- 102400000345 Angiotensin-2 Human genes 0.000 description 1
- 108010064733 Angiotensins Proteins 0.000 description 1
- 102000015427 Angiotensins Human genes 0.000 description 1
- 101100496169 Arabidopsis thaliana CLH1 gene Proteins 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 239000002083 C09CA01 - Losartan Substances 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 241000222122 Candida albicans Species 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- BORSBYXULUJLQW-UHFFFAOYSA-N Cl.COC1=CC=CC=C1COCCCCl Chemical compound Cl.COC1=CC=CC=C1COCCCCl BORSBYXULUJLQW-UHFFFAOYSA-N 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 229930105110 Cyclosporin A Natural products 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 102000010180 Endothelin receptor Human genes 0.000 description 1
- 108050001739 Endothelin receptor Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000020897 Formins Human genes 0.000 description 1
- 108091022623 Formins Proteins 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- 101000610640 Homo sapiens U4/U6 small nuclear ribonucleoprotein Prp3 Proteins 0.000 description 1
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II 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-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 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
- 101100044057 Mesocricetus auratus SYCP3 gene Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 238000006751 Mitsunobu reaction Methods 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- QTOPAGRYIXCNRU-UHFFFAOYSA-N N-[(2-chlorophenyl)methyl]cyclopropanamine formic acid Chemical compound OC=O.ClC1=CC=CC=C1CNC1CC1 QTOPAGRYIXCNRU-UHFFFAOYSA-N 0.000 description 1
- NSGDYZCDUPSTQT-UHFFFAOYSA-N N-[5-bromo-1-[(4-fluorophenyl)methyl]-4-methyl-2-oxopyridin-3-yl]cycloheptanecarboxamide Chemical compound Cc1c(Br)cn(Cc2ccc(F)cc2)c(=O)c1NC(=O)C1CCCCCC1 NSGDYZCDUPSTQT-UHFFFAOYSA-N 0.000 description 1
- AEENDDWWNGAUBR-UHFFFAOYSA-N N-cyclopropyl-N-[(3-fluoro-2-methylphenyl)methyl]-1,2-diazabicyclo[3.3.1]non-6-ene-6-carboxamide Chemical compound C1(CC1)N(C(=O)C=1C2CCNN(CC1)C2)CC2=C(C(=CC=C2)F)C AEENDDWWNGAUBR-UHFFFAOYSA-N 0.000 description 1
- 208000025047 Non-histaminic angioedema Diseases 0.000 description 1
- 101001110823 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-A Proteins 0.000 description 1
- 101000712176 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-B Proteins 0.000 description 1
- 101100080600 Schizosaccharomyces pombe (strain 972 / ATCC 24843) nse6 gene Proteins 0.000 description 1
- 102000012479 Serine Proteases Human genes 0.000 description 1
- 108010022999 Serine Proteases Proteins 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229930182558 Sterol Chemical class 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
- 229930006000 Sucrose Natural products 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 102100040374 U4/U6 small nuclear ribonucleoprotein Prp3 Human genes 0.000 description 1
- 208000032594 Vascular Remodeling Diseases 0.000 description 1
- 238000006959 Williamson synthesis reaction Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- YBCVMFKXIKNREZ-UHFFFAOYSA-N acoh acetic acid Chemical compound CC(O)=O.CC(O)=O YBCVMFKXIKNREZ-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 238000005937 allylation reaction Methods 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000002399 angioplasty Methods 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
- 229950006323 angiotensin ii Drugs 0.000 description 1
- 229940127282 angiotensin receptor antagonist Drugs 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 150000001499 aryl bromides Chemical class 0.000 description 1
- 150000008378 aryl ethers Chemical class 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 125000001743 benzylic group Chemical group 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
- UUQMNUMQCIQDMZ-UHFFFAOYSA-N betahistine Chemical compound CNCCC1=CC=CC=N1 UUQMNUMQCIQDMZ-UHFFFAOYSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- AZWXAPCAJCYGIA-UHFFFAOYSA-N bis(2-methylpropyl)alumane Chemical compound CC(C)C[AlH]CC(C)C AZWXAPCAJCYGIA-UHFFFAOYSA-N 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 239000012888 bovine serum Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000005569 butenylene group Chemical group 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 229940095731 candida albicans Drugs 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000001913 cellulose Chemical class 0.000 description 1
- 229920002678 cellulose Chemical class 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 125000000068 chlorophenyl group Chemical group 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- RKTYLMNFRDHKIL-UHFFFAOYSA-N copper;5,10,15,20-tetraphenylporphyrin-22,24-diide Chemical compound [Cu+2].C1=CC(C(=C2C=CC([N-]2)=C(C=2C=CC=CC=2)C=2C=CC(N=2)=C(C=2C=CC=CC=2)C2=CC=C3[N-]2)C=2C=CC=CC=2)=NC1=C3C1=CC=CC=C1 RKTYLMNFRDHKIL-UHFFFAOYSA-N 0.000 description 1
- 101150111293 cor-1 gene Proteins 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 125000000332 coumarinyl group Chemical group O1C(=O)C(=CC2=CC=CC=C12)* 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 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 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 1
- UZBQIPPOMKBLAS-UHFFFAOYSA-N diethylazanide Chemical compound CC[N-]CC UZBQIPPOMKBLAS-UHFFFAOYSA-N 0.000 description 1
- 125000004212 difluorophenyl group Chemical group 0.000 description 1
- 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 description 1
- 125000005052 dihydropyrazolyl group Chemical group N1(NCC=C1)* 0.000 description 1
- 125000005054 dihydropyrrolyl group Chemical group [H]C1=C([H])C([H])([H])C([H])([H])N1* 0.000 description 1
- 125000005044 dihydroquinolinyl group Chemical group N1(CC=CC2=CC=CC=C12)* 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 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
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002085 enols Chemical group 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 150000002314 glycerols Chemical class 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229960004903 invert sugar Drugs 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 description 1
- 229960004773 losartan Drugs 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- INJAMPFEUYMVHZ-UHFFFAOYSA-N n-[(2,3-difluorophenyl)methyl]cyclopropanamine Chemical compound FC1=CC=CC(CNC2CC2)=C1F INJAMPFEUYMVHZ-UHFFFAOYSA-N 0.000 description 1
- AHXJNCOFVXXIAS-UHFFFAOYSA-N n-[(2-chlorophenyl)methyl]propan-2-amine Chemical compound CC(C)NCC1=CC=CC=C1Cl AHXJNCOFVXXIAS-UHFFFAOYSA-N 0.000 description 1
- GOOPSPCKQDXAKN-UHFFFAOYSA-N n-[(2-methoxyphenyl)methyl]cyclopropanamine Chemical compound COC1=CC=CC=C1CNC1CC1 GOOPSPCKQDXAKN-UHFFFAOYSA-N 0.000 description 1
- UNKYCOQTXFUTHF-UHFFFAOYSA-N n-[(3,4-dimethylphenoxy)methyl]cyclopropanamine Chemical compound C1=C(C)C(C)=CC=C1OCNC1CC1 UNKYCOQTXFUTHF-UHFFFAOYSA-N 0.000 description 1
- GVMDEMXDMJPZFM-UHFFFAOYSA-N n-[(3-methylphenoxy)methyl]cyclopropanamine Chemical compound CC1=CC=CC(OCNC2CC2)=C1 GVMDEMXDMJPZFM-UHFFFAOYSA-N 0.000 description 1
- WIZJLQNTAZUODZ-UHFFFAOYSA-N n-[(4-methoxyphenoxy)methyl]cyclopropanamine Chemical compound C1=CC(OC)=CC=C1OCNC1CC1 WIZJLQNTAZUODZ-UHFFFAOYSA-N 0.000 description 1
- XQHXNPAQDTTZAW-UHFFFAOYSA-N n-[(5-fluoro-2-methoxyphenyl)methyl]cyclopropanamine Chemical compound COC1=CC=C(F)C=C1CNC1CC1 XQHXNPAQDTTZAW-UHFFFAOYSA-N 0.000 description 1
- HLVCVSCYDWMBRE-UHFFFAOYSA-N n-[2-(2-methoxyphenoxy)ethyl]cyclopropanamine Chemical compound COC1=CC=CC=C1OCCNC1CC1 HLVCVSCYDWMBRE-UHFFFAOYSA-N 0.000 description 1
- JRROPZMURBZYCD-UHFFFAOYSA-N n-[2-(4-methylphenoxy)ethyl]cyclopropanamine Chemical compound C1=CC(C)=CC=C1OCCNC1CC1 JRROPZMURBZYCD-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 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
- JFLPPELZYKHKQZ-UHFFFAOYSA-N n-methyl-1-[3-(trifluoromethyl)phenyl]methanamine Chemical compound CNCC1=CC=CC(C(F)(F)F)=C1 JFLPPELZYKHKQZ-UHFFFAOYSA-N 0.000 description 1
- OPRIBHSVYMOUOG-UHFFFAOYSA-N n-methyl-2-(4-methylphenoxy)ethanamine Chemical compound CNCCOC1=CC=C(C)C=C1 OPRIBHSVYMOUOG-UHFFFAOYSA-N 0.000 description 1
- SBOUHGZVYFYWMK-UHFFFAOYSA-N n-methyl-3-phenoxypropan-1-amine Chemical compound CNCCCOC1=CC=CC=C1 SBOUHGZVYFYWMK-UHFFFAOYSA-N 0.000 description 1
- TXYKOQZEJZWJEN-UHFFFAOYSA-N n-methyl-4-phenylbutan-1-amine Chemical compound CNCCCCC1=CC=CC=C1 TXYKOQZEJZWJEN-UHFFFAOYSA-N 0.000 description 1
- CKQBCZKJIAESAV-UHFFFAOYSA-N n-methyl-4-phenylpentan-1-amine Chemical compound CNCCCC(C)C1=CC=CC=C1 CKQBCZKJIAESAV-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound 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
- 239000002674 ointment Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000816 peptidomimetic Substances 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 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 Chemical class 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000003072 pyrazolidinyl 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
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000029865 regulation of blood pressure Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- LUEXHAXZRPWKEQ-UHFFFAOYSA-N tert-butyl 9-methyl-7-oxo-3,9-diazabicyclo[3.3.1]nonane-3-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC2CC(=O)CC1N2C LUEXHAXZRPWKEQ-UHFFFAOYSA-N 0.000 description 1
- UJJDEOLXODWCGK-UHFFFAOYSA-N tert-butyl carbonochloridate Chemical compound CC(C)(C)OC(Cl)=O UJJDEOLXODWCGK-UHFFFAOYSA-N 0.000 description 1
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000004305 thiazinyl group Chemical group S1NC(=CC=C1)* 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- 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
- A61P27/06—Antiglaucoma agents or miotics
-
- 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
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- 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
- A61P9/10—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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Cardiology (AREA)
- Diabetes (AREA)
- Heart & Thoracic Surgery (AREA)
- Immunology (AREA)
- Endocrinology (AREA)
- Ophthalmology & Optometry (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Emergency Medicine (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Gynecology & Obstetrics (AREA)
- Reproductive Health (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP0204705 | 2002-04-29 | ||
| EPPCT/EP02/04705 | 2002-04-29 | ||
| PCT/EP2003/003721 WO2003093267A1 (en) | 2002-04-29 | 2003-04-08 | 7-aryl-3,9-diazabicyclo(3.3.1)non-6-ene derivatives and their use as renin inhibitors in the treatment of hypertension, cardiovascular or renal diseases |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2483241A1 CA2483241A1 (en) | 2003-11-13 |
| CA2483241C true CA2483241C (en) | 2011-05-31 |
Family
ID=29286070
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2483241A Expired - Fee Related CA2483241C (en) | 2002-04-29 | 2003-04-08 | Novel diazabicyclononene derivatives |
Country Status (26)
| Country | Link |
|---|---|
| US (2) | US7427613B2 (https=) |
| EP (1) | EP1501830B1 (https=) |
| JP (1) | JP4041123B2 (https=) |
| KR (1) | KR100783863B1 (https=) |
| CN (1) | CN1649870A (https=) |
| AT (1) | ATE527261T1 (https=) |
| AU (1) | AU2003233963B2 (https=) |
| BR (1) | BR0309498A (https=) |
| CA (1) | CA2483241C (https=) |
| CL (1) | CL2003002042A1 (https=) |
| CO (1) | CO5631443A2 (https=) |
| EC (1) | ECSP045378A (https=) |
| ES (1) | ES2372931T3 (https=) |
| HR (1) | HRP20041132A2 (https=) |
| IL (1) | IL164767A0 (https=) |
| IS (1) | IS7545A (https=) |
| MA (1) | MA27305A1 (https=) |
| MX (1) | MXPA04010608A (https=) |
| NO (1) | NO20045042L (https=) |
| NZ (1) | NZ536750A (https=) |
| PL (1) | PL372141A1 (https=) |
| RU (1) | RU2343153C2 (https=) |
| TW (1) | TW200514786A (https=) |
| UA (1) | UA80821C2 (https=) |
| WO (1) | WO2003093267A1 (https=) |
| ZA (1) | ZA200408283B (https=) |
Families Citing this family (29)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004096804A1 (en) * | 2003-04-28 | 2004-11-11 | Actelion Pharmaceuticals Ltd | Diazabicyclononene and tetrahydropyridine derivatives as renin inhibitors |
| AU2004233575A1 (en) * | 2003-04-30 | 2004-11-11 | Actelion Pharmaceuticals Ltd | 9-azabicyclo'3.3.1!non-6-ee derivatives with a heteroatom at the 3-position as renin inhibitors |
| JP2006524657A (ja) * | 2003-04-30 | 2006-11-02 | アクテリオン ファマシューティカルズ リミテッド | 新規トロパン誘導体 |
| US20060235044A1 (en) * | 2003-04-30 | 2006-10-19 | Olivier Bezencon | Azabicyclononene derivatives |
| JP2006525259A (ja) * | 2003-05-02 | 2006-11-09 | アクテリオン ファマシューティカルズ リミテッド | 新規ジアザビシクロノネン誘導体 |
| WO2004105762A1 (en) * | 2003-05-30 | 2004-12-09 | Actelion Pharmaceuticals Ltd | Medical use of diazabicyclononene derivatives as inhibitors of parasite aspartic proteases |
| CN1863773A (zh) * | 2003-10-09 | 2006-11-15 | 埃科特莱茵药品有限公司 | 四氢吡啶衍生物 |
| EP1678176A1 (en) * | 2003-10-13 | 2006-07-12 | Actelion Pharmaceuticals Ltd. | Diazabicyclononene derivatives and their use as renin inhibitors |
| CN1930170A (zh) * | 2003-10-23 | 2007-03-14 | 埃科特莱茵药品有限公司 | 二氮杂二环壬烯及四氢吡啶衍生物用作肾素抑制剂 |
| WO2005054243A1 (en) * | 2003-12-05 | 2005-06-16 | Actelion Pharmaceuticals Ltd | Diazabicyclononene derivatives and their use as renin inhibitors |
| US20070135406A1 (en) * | 2003-12-05 | 2007-06-14 | Olivier Bezencon | Diazabicyclononene and tetrahydropyridine derivatives with a new side-chain |
| EP1786814B1 (en) * | 2004-08-25 | 2010-03-31 | Actelion Pharmaceuticals Ltd. | Bicyclononene derivatives as renin inhibitors |
| WO2006021403A1 (en) * | 2004-08-25 | 2006-03-02 | Actelion Pharmaceuticals Ltd | Bicyclononene derivatives |
| WO2006021401A2 (en) * | 2004-08-25 | 2006-03-02 | Actelion Pharmaceuticals Ltd | Bicylononene derivatives |
| WO2006021399A2 (en) * | 2004-08-25 | 2006-03-02 | Actelion Pharmaceuticals Ltd | Azabicyclononene derivatives as renin inhibitors |
| AR052263A1 (es) * | 2004-12-08 | 2007-03-07 | Actelion Pharmaceuticals Ltd | Derivado de diazabiciclononeno |
| WO2006063610A1 (en) * | 2004-12-17 | 2006-06-22 | Actelion Pharmaceuticals Ltd | Heteroaryl substituted diazabicyclononene derivatives |
| GB0428526D0 (en) | 2004-12-30 | 2005-02-09 | Novartis Ag | Organic compounds |
| CA2595986A1 (en) * | 2005-01-28 | 2006-08-03 | Actelion Pharmaceuticals Ltd | 7-{4-[2-(2,6-dichlor0-4-methylphenoxy)-ethoxy]phenyl}-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3-dimethylbenzyl)amides as inhibitors of renin for the treatment of hypertension |
| EP1893578A2 (en) * | 2005-05-27 | 2008-03-05 | Actelion Pharmaceuticals Ltd. | Novel piperidine carboxylic acid amide derivatives |
| GB0514203D0 (en) | 2005-07-11 | 2005-08-17 | Novartis Ag | Organic compounds |
| JP5306821B2 (ja) | 2005-12-30 | 2013-10-02 | ノバルティス アーゲー | レニン阻害剤としての３，５−置換ピペリジン化合物 |
| NZ570828A (en) | 2006-02-02 | 2011-07-29 | Actelion Pharmaceuticals Ltd | Secondary amines as renin inhibitors |
| AU2007224368A1 (en) * | 2006-03-08 | 2007-09-13 | Actelion Pharmaceuticals Ltd | New amines |
| JP2010527942A (ja) | 2007-05-24 | 2010-08-19 | メルク フロスト カナダ リミテツド | 新規類のレニン阻害剤 |
| NZ582098A (en) | 2007-06-25 | 2012-03-30 | Novartis Ag | N5-(2-ethoxyethyl)-n3-(2-pyridinyl)-3,5-piperidinedicarboxamide derivatives for use as renin inhibitors |
| AU2008288648A1 (en) | 2007-08-20 | 2009-02-26 | Merck Frosst Canada Ltd. | Renin inhibitors |
| CN102015682B (zh) | 2008-05-05 | 2014-07-16 | 埃科特莱茵药品有限公司 | 作为肾素抑制剂的3,4-取代的哌啶衍生物 |
| CN109721613B (zh) * | 2017-10-27 | 2021-07-30 | 四川科伦博泰生物医药股份有限公司 | 含季铵离子的大环酰胺化合物及其药物组合物和用途 |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3509161A (en) | 1967-07-10 | 1970-04-28 | Boehringer & Soehne Gmbh | 3-phenyl-granatene-(2)-derivatives |
| GB9020927D0 (en) | 1990-09-26 | 1990-11-07 | Beecham Group Plc | Pharmaceuticals |
| US5268361A (en) * | 1991-06-07 | 1993-12-07 | Sri International | Hydroxyazido derivatives and related compounds as renin inhibitors |
| US5374719A (en) * | 1993-06-04 | 1994-12-20 | Eli Lilly And Company | Process for converting loracarbef dihydrate to loracarbef monohydrate |
| RU2167865C2 (ru) * | 1995-09-07 | 2001-05-27 | Ф. Хоффманн-Ля Рош Аг | Производные пиперидина, способ их получения, фармацевтическая композиция на их основе и промежуточные вещества |
| EP0966464B1 (en) | 1997-03-03 | 2003-05-28 | Basilea Pharmaceutica AG | Substituted 2,4-diaminopyrimidines |
| US20060223795A1 (en) * | 2003-05-02 | 2006-10-05 | Oliver Bezencon | Novel diazabicyclononene derivatives |
| WO2005054243A1 (en) * | 2003-12-05 | 2005-06-16 | Actelion Pharmaceuticals Ltd | Diazabicyclononene derivatives and their use as renin inhibitors |
-
2003
- 2003-04-08 HR HR20041132A patent/HRP20041132A2/xx not_active Application Discontinuation
- 2003-04-08 NZ NZ536750A patent/NZ536750A/xx unknown
- 2003-04-08 WO PCT/EP2003/003721 patent/WO2003093267A1/en not_active Ceased
- 2003-04-08 AU AU2003233963A patent/AU2003233963B2/en not_active Ceased
- 2003-04-08 EP EP03727287A patent/EP1501830B1/en not_active Expired - Lifetime
- 2003-04-08 RU RU2004134320/04A patent/RU2343153C2/ru not_active IP Right Cessation
- 2003-04-08 MX MXPA04010608A patent/MXPA04010608A/es not_active Application Discontinuation
- 2003-04-08 US US10/513,103 patent/US7427613B2/en not_active Expired - Fee Related
- 2003-04-08 CA CA2483241A patent/CA2483241C/en not_active Expired - Fee Related
- 2003-04-08 KR KR1020047016845A patent/KR100783863B1/ko not_active Expired - Fee Related
- 2003-04-08 PL PL03372141A patent/PL372141A1/xx not_active Application Discontinuation
- 2003-04-08 JP JP2004501406A patent/JP4041123B2/ja not_active Expired - Fee Related
- 2003-04-08 BR BR0309498-7A patent/BR0309498A/pt not_active IP Right Cessation
- 2003-04-08 CN CNA038097664A patent/CN1649870A/zh active Pending
- 2003-04-08 IL IL16476703A patent/IL164767A0/xx unknown
- 2003-04-08 AT AT03727287T patent/ATE527261T1/de not_active IP Right Cessation
- 2003-04-08 ES ES03727287T patent/ES2372931T3/es not_active Expired - Lifetime
- 2003-08-04 UA UA20041109469A patent/UA80821C2/uk unknown
- 2003-10-10 CL CL200302042A patent/CL2003002042A1/es unknown
- 2003-10-23 TW TW092129421A patent/TW200514786A/zh unknown
-
2004
- 2004-10-13 ZA ZA200408283A patent/ZA200408283B/xx unknown
- 2004-10-22 EC EC2004005378A patent/ECSP045378A/es unknown
- 2004-10-22 MA MA27914A patent/MA27305A1/fr unknown
- 2004-10-22 CO CO04106347A patent/CO5631443A2/es not_active Application Discontinuation
- 2004-11-19 NO NO20045042A patent/NO20045042L/no not_active Application Discontinuation
- 2004-11-22 IS IS7545A patent/IS7545A/is unknown
-
2008
- 2008-07-07 US US12/168,666 patent/US20080312242A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| HRP20041132A2 (en) | 2006-07-31 |
| EP1501830A1 (en) | 2005-02-02 |
| US20080312242A1 (en) | 2008-12-18 |
| CO5631443A2 (es) | 2006-04-28 |
| ATE527261T1 (de) | 2011-10-15 |
| MXPA04010608A (es) | 2004-12-13 |
| IS7545A (is) | 2004-11-22 |
| US20050176700A1 (en) | 2005-08-11 |
| AU2003233963A1 (en) | 2003-11-17 |
| TW200514786A (en) | 2005-05-01 |
| KR100783863B1 (ko) | 2007-12-10 |
| ECSP045378A (es) | 2004-11-26 |
| IL164767A0 (en) | 2005-12-18 |
| BR0309498A (pt) | 2005-02-15 |
| RU2004134320A (ru) | 2005-08-27 |
| RU2343153C2 (ru) | 2009-01-10 |
| US7427613B2 (en) | 2008-09-23 |
| NO20045042L (no) | 2004-11-19 |
| ES2372931T3 (es) | 2012-01-27 |
| WO2003093267A1 (en) | 2003-11-13 |
| CN1649870A (zh) | 2005-08-03 |
| UA80821C2 (en) | 2007-11-12 |
| JP4041123B2 (ja) | 2008-01-30 |
| EP1501830B1 (en) | 2011-10-05 |
| ZA200408283B (en) | 2006-05-31 |
| KR20040101546A (ko) | 2004-12-02 |
| NZ536750A (en) | 2007-02-23 |
| MA27305A1 (fr) | 2005-05-02 |
| CA2483241A1 (en) | 2003-11-13 |
| PL372141A1 (en) | 2005-07-11 |
| AU2003233963B2 (en) | 2008-09-11 |
| CL2003002042A1 (es) | 2005-02-04 |
| JP2005527602A (ja) | 2005-09-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2483241C (en) | Novel diazabicyclononene derivatives | |
| WO2004002957A1 (en) | Novel tetrahydropyridine derivatives as renin inhibitors | |
| WO2004096116A2 (en) | Diazabicyclononene derivatives | |
| JP2006524656A (ja) | 新規ジアザビシクロノネンおよびテトラヒドロピリジン誘導体 | |
| AU2004295092A1 (en) | Azabicyclooctene and other tetrahydropyridine derivatives with a new side-chain | |
| CA2521938A1 (en) | 9-azabicyclo[3.3.1]non-6-ene derivatives with a heteroatom at the 3-position as renin inhibitors | |
| JP2006524654A (ja) | 新規アザビシクロノネン誘導体 | |
| CA2521957A1 (en) | Tropane derivatives and their use as ace inhibitors | |
| AU2004283821A1 (en) | Diazabicyclononene derivatives and their use as renin inhibitors | |
| WO2004105762A1 (en) | Medical use of diazabicyclononene derivatives as inhibitors of parasite aspartic proteases | |
| CA2547547A1 (en) | Diazabicyclononene derivatives and their use as renin inhibitors | |
| US20070135405A1 (en) | Novel diazabicyclononene and tetrahydropyridine derivatives with a new polar side-chain | |
| EP1692132A2 (en) | Azabicyclooctene and other tetrahydropyridine derivatives with a new side-chain | |
| EP1622906A1 (en) | Diazabicyclononene and tetrahydropyridine derivatives as renin inhibitors |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |
Effective date: 20130408 |