TW200407310A - Compounds - Google Patents

Compounds Download PDF

Info

Publication number: TW200407310A
Authority: TW; Taiwan
Prior art keywords: compound; formula; volume; scope; minutes
Prior art date: 2002-06-07

Application number

TW092115163A

Other languages

English (en)

Chinese (zh)

Inventor

Anthony William James Cooper

Jacqueline Elizabeth Mordaunt

Simon Peace

Paul William Smith

Steven Smith

Original Assignee

Glaxo Group Ltd

Priority date (The priority date 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 date listed.)

2002-06-07

Filing date

2003-06-05

Publication date

2004-05-16

2002-06-07 Priority claimed from GB0213119A external-priority patent/GB0213119D0/en

2002-07-19 Priority claimed from GB0216856A external-priority patent/GB0216856D0/en

2002-09-09 Priority claimed from GB0220875A external-priority patent/GB0220875D0/en

2003-02-04 Priority claimed from GB0302543A external-priority patent/GB0302543D0/en

2003-06-05 Application filed by Glaxo Group Ltd filed Critical Glaxo Group Ltd

2004-05-16 Publication of TW200407310A publication Critical patent/TW200407310A/zh

Links

150000001875 compounds Chemical class 0.000 title claims abstract description 159
102000003729 Neprilysin Human genes 0.000 claims abstract description 22
108090000028 Neprilysin Proteins 0.000 claims abstract description 22
239000003112 inhibitor Substances 0.000 claims abstract description 12
239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
239000003814 drug Substances 0.000 claims abstract description 8
125000003226 pyrazolyl group Chemical group 0.000 claims abstract description 6
CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical group C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims abstract description 5
-1 mercaptofluorenyl Chemical group 0.000 claims description 43
238000000034 method Methods 0.000 claims description 34
230000002079 cooperative effect Effects 0.000 claims description 20
125000000217 alkyl group Chemical group 0.000 claims description 16
229960005190 phenylalanine Drugs 0.000 claims description 14
239000002253 acid Substances 0.000 claims description 13
201000010099 disease Diseases 0.000 claims description 13
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 13
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
125000006239 protecting group Chemical group 0.000 claims description 11
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 10
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 10
COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 7
239000000546 pharmaceutical excipient Substances 0.000 claims description 7
238000010511 deprotection reaction Methods 0.000 claims description 6
239000003937 drug carrier Substances 0.000 claims description 5
COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims description 4
239000000126 substance Substances 0.000 claims description 4
238000004519 manufacturing process Methods 0.000 claims description 3
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
UTIMBUCRNZURQB-UHFFFAOYSA-N 2-(propylamino)propanoic acid Chemical compound CCCNC(C)C(O)=O UTIMBUCRNZURQB-UHFFFAOYSA-N 0.000 claims 1
230000009286 beneficial effect Effects 0.000 claims 1
125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 1
239000000203 mixture Substances 0.000 description 67
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 64
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 60
239000000243 solution Substances 0.000 description 51
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 45
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 42
239000002904 solvent Substances 0.000 description 33
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 26
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
238000006243 chemical reaction Methods 0.000 description 24
239000000543 intermediate Substances 0.000 description 21
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 21
239000012071 phase Substances 0.000 description 20
238000004895 liquid chromatography mass spectrometry Methods 0.000 description 19
239000007787 solid Substances 0.000 description 19
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
238000004128 high performance liquid chromatography Methods 0.000 description 16
229910052757 nitrogen Inorganic materials 0.000 description 14
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
230000002401 inhibitory effect Effects 0.000 description 12
GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 12
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
238000009472 formulation Methods 0.000 description 11
229910000027 potassium carbonate Inorganic materials 0.000 description 11
150000003839 salts Chemical class 0.000 description 11
BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 10
230000008569 process Effects 0.000 description 10
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 9
JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 9
229940011051 isopropyl acetate Drugs 0.000 description 9
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
239000012044 organic layer Substances 0.000 description 9
238000002360 preparation method Methods 0.000 description 9
239000000047 product Substances 0.000 description 9
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
101000773743 Homo sapiens Angiotensin-converting enzyme Proteins 0.000 description 8
WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 8
238000004458 analytical method Methods 0.000 description 8
102000056252 human ACE Human genes 0.000 description 8
239000010410 layer Substances 0.000 description 8
235000011181 potassium carbonates Nutrition 0.000 description 8
239000000843 powder Substances 0.000 description 8
230000002829 reductive effect Effects 0.000 description 8
FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
235000004279 alanine Nutrition 0.000 description 7
125000006242 amine protecting group Chemical group 0.000 description 7
238000001914 filtration Methods 0.000 description 7
239000003921 oil Substances 0.000 description 7
235000019198 oils Nutrition 0.000 description 7
229910052938 sodium sulfate Inorganic materials 0.000 description 7
235000011152 sodium sulphate Nutrition 0.000 description 7
239000012453 solvate Substances 0.000 description 7
238000003786 synthesis reaction Methods 0.000 description 7
KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 6
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 6
125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 6
235000019253 formic acid Nutrition 0.000 description 6
238000002347 injection Methods 0.000 description 6
239000007924 injection Substances 0.000 description 6
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
239000002002 slurry Substances 0.000 description 6
NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 5
QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 5
229910002666 PdCl2 Inorganic materials 0.000 description 5
125000003277 amino group Chemical group 0.000 description 5
239000002585 base Substances 0.000 description 5
230000015572 biosynthetic process Effects 0.000 description 5
229910000024 caesium carbonate Inorganic materials 0.000 description 5
239000003054 catalyst Substances 0.000 description 5
239000012043 crude product Substances 0.000 description 5
238000002425 crystallisation Methods 0.000 description 5
230000008025 crystallization Effects 0.000 description 5
238000004821 distillation Methods 0.000 description 5
150000002148 esters Chemical class 0.000 description 5
229910052751 metal Inorganic materials 0.000 description 5
239000002184 metal Substances 0.000 description 5
PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 5
238000010898 silica gel chromatography Methods 0.000 description 5
238000003756 stirring Methods 0.000 description 5
SJHPCNCNNSSLPL-CSKARUKUSA-N (4e)-4-(ethoxymethylidene)-2-phenyl-1,3-oxazol-5-one Chemical compound O1C(=O)C(=C/OCC)\N=C1C1=CC=CC=C1 SJHPCNCNNSSLPL-CSKARUKUSA-N 0.000 description 4
WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 4
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 4
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 4
241000283973 Oryctolagus cuniculus Species 0.000 description 4
KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 4
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
PZBFGYYEXUXCOF-UHFFFAOYSA-N TCEP Chemical compound OC(=O)CCP(CCC(O)=O)CCC(O)=O PZBFGYYEXUXCOF-UHFFFAOYSA-N 0.000 description 4
235000011054 acetic acid Nutrition 0.000 description 4
229960000583 acetic acid Drugs 0.000 description 4
239000000443 aerosol Substances 0.000 description 4
239000003153 chemical reaction reagent Substances 0.000 description 4
230000000694 effects Effects 0.000 description 4
235000019441 ethanol Nutrition 0.000 description 4
239000007789 gas Substances 0.000 description 4
210000003734 kidney Anatomy 0.000 description 4
239000011159 matrix material Substances 0.000 description 4
VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 4
239000012074 organic phase Substances 0.000 description 4
239000003208 petroleum Substances 0.000 description 4
108090000765 processed proteins & peptides Proteins 0.000 description 4
239000007858 starting material Substances 0.000 description 4
239000000725 suspension Substances 0.000 description 4
KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 3
ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
206010019280 Heart failures Diseases 0.000 description 3
WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 3
150000007513 acids Chemical class 0.000 description 3
150000003862 amino acid derivatives Chemical class 0.000 description 3
229910021529 ammonia Inorganic materials 0.000 description 3
239000008346 aqueous phase Substances 0.000 description 3
230000002051 biphasic effect Effects 0.000 description 3
239000008280 blood Substances 0.000 description 3
210000004369 blood Anatomy 0.000 description 3
230000036772 blood pressure Effects 0.000 description 3
KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 3
239000004327 boric acid Substances 0.000 description 3
239000012267 brine Substances 0.000 description 3
230000008859 change Effects 0.000 description 3
238000007796 conventional method Methods 0.000 description 3
230000008878 coupling Effects 0.000 description 3
238000010168 coupling process Methods 0.000 description 3
238000005859 coupling reaction Methods 0.000 description 3
KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 3
229960002179 ephedrine Drugs 0.000 description 3
125000004705 ethylthio group Chemical group C(C)S* 0.000 description 3
125000000623 heterocyclic group Chemical group 0.000 description 3
229910052739 hydrogen Inorganic materials 0.000 description 3
239000001257 hydrogen Substances 0.000 description 3
125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
229910052740 iodine Inorganic materials 0.000 description 3
239000011630 iodine Substances 0.000 description 3
239000007788 liquid Substances 0.000 description 3
150000004702 methyl esters Chemical class 0.000 description 3
235000008729 phenylalanine Nutrition 0.000 description 3
239000002244 precipitate Substances 0.000 description 3
229940002612 prodrug Drugs 0.000 description 3
239000000651 prodrug Substances 0.000 description 3
KOUKXHPPRFNWPP-UHFFFAOYSA-N pyrazine-2,5-dicarboxylic acid;hydrate Chemical compound O.OC(=O)C1=CN=C(C(O)=O)C=N1 KOUKXHPPRFNWPP-UHFFFAOYSA-N 0.000 description 3
239000011541 reaction mixture Substances 0.000 description 3
238000010992 reflux Methods 0.000 description 3
239000011734 sodium Substances 0.000 description 3
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
239000003826 tablet Substances 0.000 description 3
125000003396 thiol group Chemical class [H]S* 0.000 description 3
230000000699 topical effect Effects 0.000 description 3
TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 3
125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
238000000825 ultraviolet detection Methods 0.000 description 3
HUOYGRNYKOUAFE-QMMMGPOBSA-N (2s)-2-(iodoamino)-3-phenylpropanoic acid Chemical compound OC(=O)[C@@H](NI)CC1=CC=CC=C1 HUOYGRNYKOUAFE-QMMMGPOBSA-N 0.000 description 2
KVGZZAHHUNAVKZ-UHFFFAOYSA-N 1,4-Dioxin Chemical compound O1C=COC=C1 KVGZZAHHUNAVKZ-UHFFFAOYSA-N 0.000 description 2
ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 2
NYPYPOZNGOXYSU-UHFFFAOYSA-N 3-bromopyridine Chemical compound BrC1=CC=CN=C1 NYPYPOZNGOXYSU-UHFFFAOYSA-N 0.000 description 2
102400000345 Angiotensin-2 Human genes 0.000 description 2
101800000733 Angiotensin-2 Proteins 0.000 description 2
108010064733 Angiotensins Proteins 0.000 description 2
102000015427 Angiotensins Human genes 0.000 description 2
FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
206010007559 Cardiac failure congestive Diseases 0.000 description 2
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
102000004190 Enzymes Human genes 0.000 description 2
108090000790 Enzymes Proteins 0.000 description 2
241000282412 Homo Species 0.000 description 2
MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
206010020772 Hypertension Diseases 0.000 description 2
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 2
NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 description 2
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 2
241001465754 Metazoa Species 0.000 description 2
MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
244000061456 Solanum tuberosum Species 0.000 description 2
235000002595 Solanum tuberosum Nutrition 0.000 description 2
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
230000003213 activating effect Effects 0.000 description 2
239000004480 active ingredient Substances 0.000 description 2
230000032683 aging Effects 0.000 description 2
230000001668 ameliorated effect Effects 0.000 description 2
150000001412 amines Chemical class 0.000 description 2
229950006323 angiotensin ii Drugs 0.000 description 2
239000007864 aqueous solution Substances 0.000 description 2
125000006615 aromatic heterocyclic group Chemical group 0.000 description 2
125000003118 aryl group Chemical group 0.000 description 2
125000004429 atom Chemical group 0.000 description 2
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
239000000872 buffer Substances 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
125000004432 carbon atom Chemical group C* 0.000 description 2
125000002843 carboxylic acid group Chemical group 0.000 description 2
239000000969 carrier Substances 0.000 description 2
NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
238000001816 cooling Methods 0.000 description 2
OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 2
239000013078 crystal Substances 0.000 description 2
XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
238000001035 drying Methods 0.000 description 2
239000000839 emulsion Substances 0.000 description 2
229940088598 enzyme Drugs 0.000 description 2
125000004185 ester group Chemical group 0.000 description 2
125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
239000012065 filter cake Substances 0.000 description 2
125000005842 heteroatom Chemical group 0.000 description 2
238000004255 ion exchange chromatography Methods 0.000 description 2
DWKPPFQULDPWHX-VKHMYHEASA-N l-alanyl ester Chemical compound COC(=O)[C@H](C)N DWKPPFQULDPWHX-VKHMYHEASA-N 0.000 description 2
239000008101 lactose Substances 0.000 description 2
239000000463 material Substances 0.000 description 2
GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 2
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241000894007 species Species 0.000 description 1
239000003381 stabilizer Substances 0.000 description 1
230000000087 stabilizing effect Effects 0.000 description 1
239000008107 starch Substances 0.000 description 1
235000019698 starch Nutrition 0.000 description 1
239000004575 stone Substances 0.000 description 1
235000011149 sulphuric acid Nutrition 0.000 description 1
239000002511 suppository base Substances 0.000 description 1
239000000375 suspending agent Substances 0.000 description 1
239000003765 sweetening agent Substances 0.000 description 1
208000024891 symptom Diseases 0.000 description 1
239000000454 talc Substances 0.000 description 1
229910052623 talc Inorganic materials 0.000 description 1
RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical group CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 1
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
238000002560 therapeutic procedure Methods 0.000 description 1
229910052723 transition metal Inorganic materials 0.000 description 1
150000003624 transition metals Chemical class 0.000 description 1
229960001082 trimethoprim Drugs 0.000 description 1
MAAKQSASDHJHIR-UHFFFAOYSA-N trioxolane Chemical compound C1COOO1 MAAKQSASDHJHIR-UHFFFAOYSA-N 0.000 description 1
JEJAMASKDTUEBZ-UHFFFAOYSA-N tris(1,1,3-tribromo-2,2-dimethylpropyl) phosphate Chemical compound BrCC(C)(C)C(Br)(Br)OP(=O)(OC(Br)(Br)C(C)(C)CBr)OC(Br)(Br)C(C)(C)CBr JEJAMASKDTUEBZ-UHFFFAOYSA-N 0.000 description 1
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 description 1
210000002700 urine Anatomy 0.000 description 1
229940005605 valeric acid Drugs 0.000 description 1
230000025033 vasoconstriction Effects 0.000 description 1
230000024883 vasodilation Effects 0.000 description 1
230000001457 vasomotor Effects 0.000 description 1
235000015112 vegetable and seed oil Nutrition 0.000 description 1
239000008158 vegetable oil Substances 0.000 description 1
229920002554 vinyl polymer Polymers 0.000 description 1
238000005406 washing Methods 0.000 description 1
239000000080 wetting agent Substances 0.000 description 1
239000004246 zinc acetate Substances 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- 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
- A61P9/08—Vasodilators for multiple indications
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Cardiology (AREA)
Heart & Thoracic Surgery (AREA)
Chemical Kinetics & Catalysis (AREA)
General Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Pharmacology & Pharmacy (AREA)
Life Sciences & Earth Sciences (AREA)
Animal Behavior & Ethology (AREA)
General Health & Medical Sciences (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Plural Heterocyclic Compounds (AREA)

TW092115163A 2002-06-07 2003-06-05 Compounds TW200407310A (en)

Applications Claiming Priority (4)

Application Number	Priority Date	Filing Date	Title
GB0213119A GB0213119D0 (en)	2002-06-07	2002-06-07	Compounds
GB0216856A GB0216856D0 (en)	2002-07-19	2002-07-19	Compounds
GB0220875A GB0220875D0 (en)	2002-09-09	2002-09-09	Compounds
GB0302543A GB0302543D0 (en)	2003-02-04	2003-02-04	Compounds

Publications (1)

Publication Number	Publication Date
TW200407310A true TW200407310A (en)	2004-05-16

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ID=29740912

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
TW092115163A TW200407310A (en)	2002-06-07	2003-06-05	Compounds

Country Status (4)

Country	Link
AR (1)	AR040441A1 (es)
AU (1)	AU2003232941A1 (es)
TW (1)	TW200407310A (es)
WO (1)	WO2003104200A1 (es)

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WO2005094897A2 (en)	2004-04-01	2005-10-13	Cardiome Pharma Corp.	Pegylated ion channel modulating compounds
EP1984344B1 (en)	2005-12-29	2012-09-26	Lexicon Pharmaceuticals, Inc.	Multicyclic amino acid derivatives and methods of their use
US7897763B2 (en)	2005-12-29	2011-03-01	Lexicon Pharmaceuticals, Inc.	Process for the preparation of substituted phenylalanines
US7855291B2 (en)	2005-12-29	2010-12-21	Lexicon Pharmaceuticals, Inc.	Process for the preparation of substituted phenylalanines
CN101801384B (zh)	2007-08-24	2012-03-21	莱西肯医药有限公司	制备基于4-苯基-6-(2，2，2-三氟-1-苯基乙氧基)嘧啶的化合物的方法
EP2234608A2 (en)	2007-12-11	2010-10-06	Viamet Pharmaceuticals, Inc.	Metalloenzyme inhibitors using metal binding moieties in combination with targeting moieties
US8993631B2 (en)	2010-11-16	2015-03-31	Novartis Ag	Method of treating contrast-induced nephropathy
UY35144A (es)	2012-11-20	2014-06-30	Novartis Ag	Miméticos lineales sintéticos de apelina para el tratamiento de insuficiencia cardiaca
TW201518323A (zh)	2013-07-25	2015-05-16	Novartis Ag	合成ａｐｅｌｉｎ多肽之生物結合物
TN2016000031A1 (en)	2013-07-25	2017-07-05	Novartis Ag	Cyclic polypeptides for the treatment of heart failure
PE20171328A1 (es)	2015-01-23	2017-09-12	Novartis Ag	Conjugados de acidos grasos y apelina sintetica con mayor vida media
UY38485A (es)	2018-11-27	2020-06-30	Novartis Ag	Compuestos tetrámeros cíclicos como inhibidores de proproteína convertasa subtilisina/kexina tipo 9 (pcsk9), método de tratamiento, uso y su preparación
CN113166101A (zh)	2018-11-27	2021-07-23	诺华股份有限公司	作为治疗代谢障碍的蛋白质原转换酶枯草杆菌蛋白酶/kexin 9型（PCSK9）抑制剂的环状五聚体化合物
WO2020110011A1 (en)	2018-11-27	2020-06-04	Novartis Ag	Cyclic peptides as proprotein convertase subtilisin/kexin type 9 (pcsk9) inhibitors for the treatment of metabolic disorders
WO2023084449A1 (en)	2021-11-12	2023-05-19	Novartis Ag	Diaminocyclopentylpyridine derivatives for the treatment of a disease or disorder

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Publication number	Priority date	Publication date	Assignee	Title
IT1277737B1 (it) *	1995-12-28	1997-11-12	Zambon Spa	Derivati tiolici ad attivita' inibitrice delle metallopeptidasi
US5760241A (en) *	1995-12-28	1998-06-02	Zambon Group S.P.A.	Thiol derivatives with metallopeptidase inhibitory activity

2003
- 2003-06-05 TW TW092115163A patent/TW200407310A/zh unknown
- 2003-06-05 WO PCT/GB2003/002446 patent/WO2003104200A1/en not_active Application Discontinuation
- 2003-06-05 AR AR20030102004A patent/AR040441A1/es not_active Application Discontinuation
- 2003-06-05 AU AU2003232941A patent/AU2003232941A1/en not_active Abandoned

Also Published As

Publication number	Publication date
WO2003104200A1 (en)	2003-12-18
AR040441A1 (es)	2005-04-06
AU2003232941A1 (en)	2003-12-22

Publication	Publication Date	Title
AU2010311678B2 (en)	2015-09-03	Substituted 3-phenylpropionic acids and the use thereof
US9018258B2 (en)	2015-04-28	Substituted 1-benzylcycloalkylcarboxylic acids and the use thereof
JP6138243B2 (ja)	2017-05-31	置換ピペリジノアセトアミドおよびその使用
TW200407310A (en)	2004-05-16	Compounds
FR2518088A1 (fr)	1983-06-17	Nouveaux derives d'aminoacides, et leur application therapeutique
JPH1160551A (ja)	1999-03-02	スルホニルアミノカルボン酸
JPH08508027A (ja)	1996-08-27	金属タンパク加水分解酵素阻害剤である天然アミノ酸誘導体
RU2233278C9 (ru)	2009-11-27	Пиримидиноновые соединения, способ их получения и фармацевтическая композиция
FR2620121A1 (fr)	1989-03-10	((pyrimidinyl-2)-aminoalkyl)-1 piperidines, leur preparation et leur application en therapeutique
KR100300566B1 (ko)	2001-11-22	피리미디논유도체와그의제조방법및용도
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JPH07502255A (ja)	1995-03-09	抗ウイルス化合物類
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JPH0154349B2 (es)	1989-11-17
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EP0588797B1 (en)	1996-02-21	N- 4,5-dihydroxy- and 4,5,8-trihydroxy-9,10-dihydro-9,10-dioxo-2-anthracene-yl]carbonyl]amino acids useful in the therapy of osteoarticular affections
FR2758329A1 (fr)	1998-07-17	Derives d'imidazole-4-butane boronique, leur preparation et leur utilisation en therapeutique
EP2226329A1 (en)	2010-09-08	Metal-containing platensimycin analogues
JP2017513934A5 (es)	2018-04-26
JP2017513934A (ja)	2017-06-01	フェナントロリンホスホン酸誘導体及びその調製方法と応用
EP0718307A2 (fr)	1996-06-26	Dérivés de 1-oxo-2-(phénylsulfonyl-amino)pentylpipéridine, leur préparation et leur application en thérapeutique
CN102241665B (zh)	2013-05-08	4-(4,5-二甲氧羰基-1,3-二硫戊环-2-基)苯甲酰-l-氨基酸苄酯及其合成方法和应用
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