FI118600B - Menetelmä ACE- ja NEP-estäjinä käyttökelpoisten syklisten aminohappojohdannaisten valmistamiseksi - Google Patents

Menetelmä ACE- ja NEP-estäjinä käyttökelpoisten syklisten aminohappojohdannaisten valmistamiseksi Download PDF

Info

Publication number: FI118600B
Authority: FI; Finland
Prior art keywords: compound; lower alkyl; hydrogen; formula; phenyl
Prior art date: 1993-11-16

Application number

FI945354A

Other languages

English (en)

Finnish (fi)

Swedish (sv)

Other versions

FI945354A0 (fi

FI945354A7 (fi

Inventor

Cynthia A Fink

Original Assignee

Novartis Ag

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.)

1993-11-16

Filing date

1994-11-14

Publication date

2008-01-15

1993-11-16 Priority claimed from US08/153,395 external-priority patent/US5432186A/en

1994-11-14 Application filed by Novartis Ag filed Critical Novartis Ag

1994-11-14 Publication of FI945354A0 publication Critical patent/FI945354A0/fi

1995-05-17 Publication of FI945354A7 publication Critical patent/FI945354A7/fi

2008-01-15 Application granted granted Critical

2008-01-15 Publication of FI118600B publication Critical patent/FI118600B/fi

Links

-1 cyclic amino acid derivatives Chemical class 0.000 title claims description 116
239000003112 inhibitor Substances 0.000 title claims description 9
238000004519 manufacturing process Methods 0.000 title description 2
150000001875 compounds Chemical class 0.000 claims abstract description 185
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 61
239000001257 hydrogen Substances 0.000 claims abstract description 61
125000000217 alkyl group Chemical group 0.000 claims abstract description 38
238000000034 method Methods 0.000 claims abstract description 38
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 28
150000002148 esters Chemical class 0.000 claims abstract description 25
150000003839 salts Chemical class 0.000 claims abstract description 23
125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 12
238000002360 preparation method Methods 0.000 claims abstract description 12
125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 11
229910052799 carbon Inorganic materials 0.000 claims abstract description 10
150000001721 carbon Chemical group 0.000 claims abstract 6
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 82
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 48
125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 39
239000000203 mixture Substances 0.000 claims description 35
150000002431 hydrogen Chemical class 0.000 claims description 28
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 25
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 24
125000001589 carboacyl group Chemical group 0.000 claims description 23
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 22
102000003729 Neprilysin Human genes 0.000 claims description 21
108090000028 Neprilysin Proteins 0.000 claims description 21
125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 21
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 19
230000008569 process Effects 0.000 claims description 17
229910052717 sulfur Inorganic materials 0.000 claims description 17
125000003545 alkoxy group Chemical group 0.000 claims description 16
125000006239 protecting group Chemical group 0.000 claims description 16
239000002253 acid Substances 0.000 claims description 14
125000004432 carbon atom Chemical group C* 0.000 claims description 14
125000004423 acyloxy group Chemical group 0.000 claims description 13
125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 12
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
229910052736 halogen Inorganic materials 0.000 claims description 10
150000002367 halogens Chemical class 0.000 claims description 10
125000004076 pyridyl group Chemical group 0.000 claims description 10
125000005400 pyridylcarbonyl group Chemical group N1=C(C=CC=C1)C(=O)* 0.000 claims description 9
150000001735 carboxylic acids Chemical class 0.000 claims description 7
125000001041 indolyl group Chemical group 0.000 claims description 7
125000001544 thienyl group Chemical group 0.000 claims description 7
229940079593 drug Drugs 0.000 claims description 6
239000003814 drug Substances 0.000 claims description 6
230000003287 optical effect Effects 0.000 claims description 6
125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 4
125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 4
125000006254 cycloalkyl carbonyl group Chemical group 0.000 claims description 4
UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 4
125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 3
125000005194 alkoxycarbonyloxy group Chemical group 0.000 claims description 3
125000003282 alkyl amino group Chemical group 0.000 claims description 3
125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 3
125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 3
125000005037 alkyl phenyl group Chemical group 0.000 claims description 2
125000005170 cycloalkyloxycarbonyl group Chemical group 0.000 claims description 2
SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 claims description 2
125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims description 2
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 2
KQTGCJMBUBYSLL-UHFFFAOYSA-N 4-piperidin-1-ylmorpholine Chemical compound C1CCCCN1N1CCOCC1 KQTGCJMBUBYSLL-UHFFFAOYSA-N 0.000 claims 1
102000015427 Angiotensins Human genes 0.000 claims 1
108010064733 Angiotensins Proteins 0.000 claims 1
241001104043 Syringa Species 0.000 claims 1
235000004338 Syringa vulgaris Nutrition 0.000 claims 1
230000001681 protective effect Effects 0.000 claims 1
229930195734 saturated hydrocarbon Natural products 0.000 claims 1
241000124008 Mammalia Species 0.000 abstract description 12
230000005764 inhibitory process Effects 0.000 abstract description 7
125000002837 carbocyclic group Chemical group 0.000 abstract description 6
239000008194 pharmaceutical composition Substances 0.000 abstract description 6
125000002252 acyl group Chemical group 0.000 abstract description 5
239000000543 intermediate Substances 0.000 abstract description 4
150000002019 disulfides Chemical class 0.000 abstract description 3
229920006395 saturated elastomer Polymers 0.000 abstract description 2
125000005841 biaryl group Chemical group 0.000 abstract 2
125000000623 heterocyclic group Chemical group 0.000 abstract 2
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract 1
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 54
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 49
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 36
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 35
239000000243 solution Substances 0.000 description 35
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
238000002844 melting Methods 0.000 description 22
230000008018 melting Effects 0.000 description 22
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
241000700159 Rattus Species 0.000 description 19
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
238000006243 chemical reaction Methods 0.000 description 16
125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 14
238000012360 testing method Methods 0.000 description 14
230000036772 blood pressure Effects 0.000 description 13
239000007787 solid Substances 0.000 description 13
239000007858 starting material Substances 0.000 description 13
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 12
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
239000012267 brine Substances 0.000 description 11
239000006260 foam Substances 0.000 description 11
239000002904 solvent Substances 0.000 description 11
IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 10
230000000694 effects Effects 0.000 description 10
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 10
206010020772 Hypertension Diseases 0.000 description 9
239000000725 suspension Substances 0.000 description 9
DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 8
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
239000004480 active ingredient Substances 0.000 description 8
229940024606 amino acid Drugs 0.000 description 8
235000001014 amino acid Nutrition 0.000 description 8
125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 8
238000000338 in vitro Methods 0.000 description 8
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
230000004044 response Effects 0.000 description 8
239000011734 sodium Substances 0.000 description 8
229910052708 sodium Inorganic materials 0.000 description 8
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
125000005907 alkyl ester group Chemical group 0.000 description 7
238000009833 condensation Methods 0.000 description 7
230000005494 condensation Effects 0.000 description 7
239000000706 filtrate Substances 0.000 description 7
239000010410 layer Substances 0.000 description 7
239000000651 prodrug Substances 0.000 description 7
229940002612 prodrug Drugs 0.000 description 7
239000000047 product Substances 0.000 description 7
229960004441 tyrosine Drugs 0.000 description 7
125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 6
102100030988 Angiotensin-converting enzyme Human genes 0.000 description 6
108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 6
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
230000004872 arterial blood pressure Effects 0.000 description 6
239000002585 base Substances 0.000 description 6
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
239000012074 organic phase Substances 0.000 description 6
230000002829 reductive effect Effects 0.000 description 6
QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 5
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
230000003276 anti-hypertensive effect Effects 0.000 description 5
238000001914 filtration Methods 0.000 description 5
238000003818 flash chromatography Methods 0.000 description 5
IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 5
229910000041 hydrogen chloride Inorganic materials 0.000 description 5
238000001727 in vivo Methods 0.000 description 5
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
239000000126 substance Substances 0.000 description 5
150000003573 thiols Chemical class 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
125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 4
125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 4
102400000344 Angiotensin-1 Human genes 0.000 description 4
101800000734 Angiotensin-1 Proteins 0.000 description 4
208000024172 Cardiovascular disease Diseases 0.000 description 4
VPGRYOFKCNULNK-ACXQXYJUSA-N Deoxycorticosterone acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)COC(=O)C)[C@@]1(C)CC2 VPGRYOFKCNULNK-ACXQXYJUSA-N 0.000 description 4
102000004190 Enzymes Human genes 0.000 description 4
108090000790 Enzymes Proteins 0.000 description 4
241001465754 Metazoa Species 0.000 description 4
KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
101500027366 Rattus norvegicus Atrial natriuretic peptide Proteins 0.000 description 4
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 4
239000008346 aqueous phase Substances 0.000 description 4
239000000872 buffer Substances 0.000 description 4
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
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 4
JBDSSBMEKXHSJF-UHFFFAOYSA-N cyclopentanecarboxylic acid Chemical compound OC(=O)C1CCCC1 JBDSSBMEKXHSJF-UHFFFAOYSA-N 0.000 description 4
229960004486 desoxycorticosterone acetate Drugs 0.000 description 4
239000002934 diuretic Substances 0.000 description 4
OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 4
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
229910052943 magnesium sulfate Inorganic materials 0.000 description 4
235000019341 magnesium sulphate Nutrition 0.000 description 4
229910000027 potassium carbonate Inorganic materials 0.000 description 4
239000011780 sodium chloride Substances 0.000 description 4
210000002700 urine Anatomy 0.000 description 4
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 3
125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 3
RSWGJHLUYNHPMX-UHFFFAOYSA-N Abietic-Saeure Natural products C12CCC(C(C)C)=CC2=CCC2C1(C)CCCC2(C)C(O)=O RSWGJHLUYNHPMX-UHFFFAOYSA-N 0.000 description 3
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical class S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 3
206010019280 Heart failures Diseases 0.000 description 3
OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 3
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 3
BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
KHPCPRHQVVSZAH-HUOMCSJISA-N Rosin Natural products O(C/C=C/c1ccccc1)[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 KHPCPRHQVVSZAH-HUOMCSJISA-N 0.000 description 3
150000001298 alcohols Chemical class 0.000 description 3
150000001413 amino acids Chemical class 0.000 description 3
239000007864 aqueous solution Substances 0.000 description 3
238000003556 assay Methods 0.000 description 3
210000004369 blood Anatomy 0.000 description 3
239000008280 blood Substances 0.000 description 3
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
229910052794 bromium Inorganic materials 0.000 description 3
239000000969 carrier Substances 0.000 description 3
239000000460 chlorine Substances 0.000 description 3
229910052801 chlorine Inorganic materials 0.000 description 3
125000004122 cyclic group Chemical group 0.000 description 3
230000001882 diuretic effect Effects 0.000 description 3
238000002474 experimental method Methods 0.000 description 3
210000001105 femoral artery Anatomy 0.000 description 3
210000003191 femoral vein Anatomy 0.000 description 3
239000012065 filter cake Substances 0.000 description 3
125000000524 functional group Chemical group 0.000 description 3
230000007062 hydrolysis Effects 0.000 description 3
238000006460 hydrolysis reaction Methods 0.000 description 3
230000001631 hypertensive effect Effects 0.000 description 3
239000012442 inert solvent Substances 0.000 description 3
210000003734 kidney Anatomy 0.000 description 3
239000008101 lactose Substances 0.000 description 3
239000012044 organic layer Substances 0.000 description 3
239000002244 precipitate Substances 0.000 description 3
108090000765 processed proteins & peptides Proteins 0.000 description 3
125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 3
239000011541 reaction mixture Substances 0.000 description 3
239000000741 silica gel Substances 0.000 description 3
229910002027 silica gel Inorganic materials 0.000 description 3
238000003756 stirring Methods 0.000 description 3
125000001424 substituent group Chemical group 0.000 description 3
238000003786 synthesis reaction Methods 0.000 description 3
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
KHPCPRHQVVSZAH-UHFFFAOYSA-N trans-cinnamyl beta-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OCC=CC1=CC=CC=C1 KHPCPRHQVVSZAH-UHFFFAOYSA-N 0.000 description 3
YBZCSKVLXBOFSL-UHFFFAOYSA-N 1-[(2-methylpropan-2-yl)oxycarbonylamino]cyclopentane-1-carboxylic acid Chemical compound CC(C)(C)OC(=O)NC1(C(O)=O)CCCC1 YBZCSKVLXBOFSL-UHFFFAOYSA-N 0.000 description 2
NILQLFBWTXNUOE-UHFFFAOYSA-N 1-aminocyclopentanecarboxylic acid Chemical compound OC(=O)C1(N)CCCC1 NILQLFBWTXNUOE-UHFFFAOYSA-N 0.000 description 2
FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 2
YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 2
JBIJLHTVPXGSAM-UHFFFAOYSA-N 2-naphthylamine Chemical compound C1=CC=CC2=CC(N)=CC=C21 JBIJLHTVPXGSAM-UHFFFAOYSA-N 0.000 description 2
125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 2
ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
206010007559 Cardiac failure congestive Diseases 0.000 description 2
VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
206010021036 Hyponatraemia Diseases 0.000 description 2
FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
206010030113 Oedema Diseases 0.000 description 2
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 2
239000007983 Tris buffer Substances 0.000 description 2
125000003342 alkenyl group Chemical group 0.000 description 2
150000008064 anhydrides Chemical class 0.000 description 2
239000002220 antihypertensive agent Substances 0.000 description 2
159000000007 calcium salts Chemical class 0.000 description 2
239000002775 capsule Substances 0.000 description 2
150000001733 carboxylic acid esters Chemical class 0.000 description 2
239000001913 cellulose Substances 0.000 description 2
235000010980 cellulose Nutrition 0.000 description 2
229920002678 cellulose Polymers 0.000 description 2
239000003153 chemical reaction reagent Substances 0.000 description 2
HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
238000004587 chromatography analysis Methods 0.000 description 2
LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 2
GVPFVAHMJGGAJG-UHFFFAOYSA-L cobalt dichloride Chemical compound [Cl-].[Cl-].[Co+2] GVPFVAHMJGGAJG-UHFFFAOYSA-L 0.000 description 2
239000012043 crude product Substances 0.000 description 2
230000007423 decrease Effects 0.000 description 2
239000003085 diluting agent Substances 0.000 description 2
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
125000004494 ethyl ester group Chemical group 0.000 description 2
150000004820 halides Chemical class 0.000 description 2
238000001802 infusion Methods 0.000 description 2
230000002401 inhibitory effect Effects 0.000 description 2
238000001990 intravenous administration Methods 0.000 description 2
239000011630 iodine Substances 0.000 description 2
229910052740 iodine Inorganic materials 0.000 description 2
239000011777 magnesium Substances 0.000 description 2
229910052749 magnesium Inorganic materials 0.000 description 2
235000019359 magnesium stearate Nutrition 0.000 description 2
238000005259 measurement Methods 0.000 description 2
VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 2
230000001452 natriuretic effect Effects 0.000 description 2
239000012299 nitrogen atmosphere Substances 0.000 description 2
235000012149 noodles Nutrition 0.000 description 2
238000007911 parenteral administration Methods 0.000 description 2
239000008188 pellet Substances 0.000 description 2
125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
150000002989 phenols Chemical class 0.000 description 2
239000001267 polyvinylpyrrolidone Substances 0.000 description 2
229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
235000018102 proteins Nutrition 0.000 description 2
102000004169 proteins and genes Human genes 0.000 description 2
108090000623 proteins and genes Proteins 0.000 description 2
125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 2
LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 description 2
238000000926 separation method Methods 0.000 description 2
229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
235000017557 sodium bicarbonate Nutrition 0.000 description 2
238000003797 solvolysis reaction Methods 0.000 description 2
238000013222 sprague-dawley male rat Methods 0.000 description 2
238000006467 substitution reaction Methods 0.000 description 2
239000000758 substrate Substances 0.000 description 2
239000006228 supernatant Substances 0.000 description 2
230000035488 systolic blood pressure Effects 0.000 description 2
125000003396 thiol group Chemical group [H]S* 0.000 description 2
230000037317 transdermal delivery Effects 0.000 description 2
LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
230000002485 urinary effect Effects 0.000 description 2
AAXWBCKQYLBQKY-IRXDYDNUSA-N (2s)-2-[[(2s)-2-[(2-benzamidoacetyl)amino]-3-(1h-imidazol-5-yl)propanoyl]amino]-4-methylpentanoic acid Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)CNC(=O)C=1C=CC=CC=1)C1=CN=CN1 AAXWBCKQYLBQKY-IRXDYDNUSA-N 0.000 description 1
XYMGIUGZGBRXOH-LURJTMIESA-N (2s)-2-acetylsulfanyl-3-methylbutanoic acid Chemical compound CC(C)[C@@H](C(O)=O)SC(C)=O XYMGIUGZGBRXOH-LURJTMIESA-N 0.000 description 1
GFJNZHJXBMHSFR-INIZCTEOSA-N (2s)-3-(4-hydroxyphenyl)-2-[[1-[(1-sulfanylcyclopentanecarbonyl)amino]cyclopentanecarbonyl]amino]propanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)C1(CCCC1)NC(=O)C1(S)CCCC1)C1=CC=C(O)C=C1 GFJNZHJXBMHSFR-INIZCTEOSA-N 0.000 description 1
CUKWUWBLQQDQAC-VEQWQPCFSA-N (3s)-3-amino-4-[[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2s,3s)-1-[[(2s)-1-[(2s)-2-[[(1s)-1-carboxyethyl]carbamoyl]pyrrolidin-1-yl]-3-(1h-imidazol-5-yl)-1-oxopropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-methyl-1-ox 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](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 CUKWUWBLQQDQAC-VEQWQPCFSA-N 0.000 description 1
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
JTATVNVLVDZAGB-UHFFFAOYSA-N 1-azabicyclo[4.2.0]octane Chemical compound C1CCCC2CCN21 JTATVNVLVDZAGB-UHFFFAOYSA-N 0.000 description 1
LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
QLGHFCXWSWFYNG-UHFFFAOYSA-N 1-morpholin-4-ylpiperidin-2-one Chemical compound O=C1CCCCN1N1CCOCC1 QLGHFCXWSWFYNG-UHFFFAOYSA-N 0.000 description 1
RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 description 1
RKJOOIOSIFQDFV-UHFFFAOYSA-N 1-sulfanylcyclopentane-1-carboxylic acid Chemical compound OC(=O)C1(S)CCCC1 RKJOOIOSIFQDFV-UHFFFAOYSA-N 0.000 description 1
QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
JTNCEQNHURODLX-UHFFFAOYSA-N 2-phenylethanimidamide Chemical compound NC(=N)CC1=CC=CC=C1 JTNCEQNHURODLX-UHFFFAOYSA-N 0.000 description 1
VQNDBXJTIJKJPV-UHFFFAOYSA-N 2h-triazolo[4,5-b]pyridine Chemical compound C1=CC=NC2=NNN=C21 VQNDBXJTIJKJPV-UHFFFAOYSA-N 0.000 description 1
OXTWVUPVFQGOTI-UHFFFAOYSA-N 4-(chloromethoxy)triazine Chemical compound ClCOC1=CC=NN=N1 OXTWVUPVFQGOTI-UHFFFAOYSA-N 0.000 description 1
UZFMOKQJFYMBGY-UHFFFAOYSA-N 4-hydroxy-TEMPO Chemical compound CC1(C)CC(O)CC(C)(C)N1[O] UZFMOKQJFYMBGY-UHFFFAOYSA-N 0.000 description 1
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 1
239000005541 ACE inhibitor Substances 0.000 description 1
229920001817 Agar Polymers 0.000 description 1
GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
206010002383 Angina Pectoris Diseases 0.000 description 1
102400000345 Angiotensin-2 Human genes 0.000 description 1
101800000733 Angiotensin-2 Proteins 0.000 description 1
206010003445 Ascites Diseases 0.000 description 1
201000001320 Atherosclerosis Diseases 0.000 description 1
101800001288 Atrial natriuretic factor Proteins 0.000 description 1
101800001890 Atrial natriuretic peptide Proteins 0.000 description 1
102400001282 Atrial natriuretic peptide Human genes 0.000 description 1
208000027796 Blood pressure disease Diseases 0.000 description 1
108091003079 Bovine Serum Albumin Proteins 0.000 description 1
241000282472 Canis lupus familiaris Species 0.000 description 1
241000283707 Capra Species 0.000 description 1
239000004215 Carbon black (E152) Substances 0.000 description 1
241000282693 Cercopithecidae Species 0.000 description 1
235000001258 Cinchona calisaya Nutrition 0.000 description 1
FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
206010012735 Diarrhoea Diseases 0.000 description 1
108010016626 Dipeptides Proteins 0.000 description 1
KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
241000282326 Felis catus Species 0.000 description 1
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
208000018522 Gastrointestinal disease Diseases 0.000 description 1
208000010412 Glaucoma Diseases 0.000 description 1
WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
206010020590 Hypercalciuria Diseases 0.000 description 1
206010020601 Hyperchlorhydria Diseases 0.000 description 1
208000029422 Hypernatremia Diseases 0.000 description 1
YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 1
150000008575 L-amino acids Chemical class 0.000 description 1
ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
108010004098 Leucyl aminopeptidase Proteins 0.000 description 1
102000002704 Leucyl aminopeptidase Human genes 0.000 description 1
229930195725 Mannitol Natural products 0.000 description 1
229920000168 Microcrystalline cellulose Polymers 0.000 description 1
241000907681 Morpho Species 0.000 description 1
241000699670 Mus sp. Species 0.000 description 1
WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
241000283973 Oryctolagus cuniculus Species 0.000 description 1
208000002193 Pain Diseases 0.000 description 1
239000002202 Polyethylene glycol Substances 0.000 description 1
229920001213 Polysorbate 20 Polymers 0.000 description 1
208000004880 Polyuria Diseases 0.000 description 1
206010036618 Premenstrual syndrome Diseases 0.000 description 1
208000028017 Psychotic disease Diseases 0.000 description 1
206010037423 Pulmonary oedema Diseases 0.000 description 1
239000007868 Raney catalyst Substances 0.000 description 1
NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
229910000564 Raney nickel Inorganic materials 0.000 description 1
208000001647 Renal Insufficiency Diseases 0.000 description 1
229910004298 SiO 2 Inorganic materials 0.000 description 1
VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
229920002472 Starch Polymers 0.000 description 1
235000021355 Stearic acid Nutrition 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
206010043376 Tetanus Diseases 0.000 description 1
241001122767 Theaceae Species 0.000 description 1
HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
BQULAXAVRFIAHN-PPHPATTJSA-N [(2s)-1-ethoxy-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]azanium;chloride Chemical compound Cl.CCOC(=O)[C@@H](N)CC1=CC=C(O)C=C1 BQULAXAVRFIAHN-PPHPATTJSA-N 0.000 description 1
LQWNHFDGXWPGQF-UHFFFAOYSA-N [Cl-].COC1=CC(OC)=N[NH+]=N1 Chemical compound [Cl-].COC1=CC(OC)=N[NH+]=N1 LQWNHFDGXWPGQF-UHFFFAOYSA-N 0.000 description 1
NOSIYYJFMPDDSA-UHFFFAOYSA-N acepromazine Chemical compound C1=C(C(C)=O)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 NOSIYYJFMPDDSA-UHFFFAOYSA-N 0.000 description 1
229960005054 acepromazine Drugs 0.000 description 1
MOQOOKGPCBQMCY-UHFFFAOYSA-N acetic acid;hexane Chemical compound CC(O)=O.CCCCCC MOQOOKGPCBQMCY-UHFFFAOYSA-N 0.000 description 1
125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
150000008065 acid anhydrides Chemical class 0.000 description 1
239000003377 acid catalyst Substances 0.000 description 1
230000002378 acidificating effect Effects 0.000 description 1
150000007513 acids Chemical class 0.000 description 1
239000012042 active reagent Substances 0.000 description 1
230000010933 acylation Effects 0.000 description 1
238000005917 acylation reaction Methods 0.000 description 1
239000002671 adjuvant Substances 0.000 description 1
239000003463 adsorbent Substances 0.000 description 1
239000008272 agar Substances 0.000 description 1
235000010419 agar Nutrition 0.000 description 1
230000001476 alcoholic effect Effects 0.000 description 1
150000001299 aldehydes Chemical class 0.000 description 1
239000000783 alginic acid Substances 0.000 description 1
235000010443 alginic acid Nutrition 0.000 description 1
229920000615 alginic acid Polymers 0.000 description 1
229960001126 alginic acid Drugs 0.000 description 1
150000004781 alginic acids Chemical class 0.000 description 1
239000003513 alkali Substances 0.000 description 1
229910001854 alkali hydroxide Inorganic materials 0.000 description 1
229910052783 alkali metal Inorganic materials 0.000 description 1
229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
150000008041 alkali metal carbonates Chemical class 0.000 description 1
229910052784 alkaline earth metal Inorganic materials 0.000 description 1
238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
125000004457 alkyl amino carbonyl group Chemical group 0.000 description 1
125000002947 alkylene group Chemical group 0.000 description 1
125000006383 alkylpyridyl group Chemical group 0.000 description 1
150000001371 alpha-amino acids Chemical class 0.000 description 1
235000008206 alpha-amino acids Nutrition 0.000 description 1
150000001408 amides Chemical class 0.000 description 1
150000001412 amines Chemical class 0.000 description 1
125000000539 amino acid group Chemical group 0.000 description 1
BIGPRXCJEDHCLP-UHFFFAOYSA-N ammonium bisulfate Chemical compound [NH4+].OS([O-])(=O)=O BIGPRXCJEDHCLP-UHFFFAOYSA-N 0.000 description 1
229950006323 angiotensin ii Drugs 0.000 description 1
229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
229940127088 antihypertensive drug Drugs 0.000 description 1
210000001367 artery Anatomy 0.000 description 1
125000003118 aryl group Chemical group 0.000 description 1
125000005279 aryl sulfonyloxy group Chemical group 0.000 description 1
239000012131 assay buffer Substances 0.000 description 1
208000006673 asthma Diseases 0.000 description 1
239000012298 atmosphere Substances 0.000 description 1
230000001746 atrial effect Effects 0.000 description 1
230000002238 attenuated effect Effects 0.000 description 1
230000004888 barrier function Effects 0.000 description 1
150000001555 benzenes Chemical class 0.000 description 1
QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
239000012964 benzotriazole Substances 0.000 description 1
WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
230000015572 biosynthetic process Effects 0.000 description 1
239000012455 biphasic mixture Substances 0.000 description 1
230000017531 blood circulation Effects 0.000 description 1
238000009530 blood pressure measurement Methods 0.000 description 1
230000037396 body weight Effects 0.000 description 1
238000009835 boiling Methods 0.000 description 1
229940098773 bovine serum albumin Drugs 0.000 description 1
210000004556 brain Anatomy 0.000 description 1
RRKTZKIUPZVBMF-IBTVXLQLSA-N brucine Chemical compound O([C@@H]1[C@H]([C@H]2C3)[C@@H]4N(C(C1)=O)C=1C=C(C(=CC=11)OC)OC)CC=C2CN2[C@@H]3[C@]41CC2 RRKTZKIUPZVBMF-IBTVXLQLSA-N 0.000 description 1
RRKTZKIUPZVBMF-UHFFFAOYSA-N brucine Natural products C1=2C=C(OC)C(OC)=CC=2N(C(C2)=O)C3C(C4C5)C2OCC=C4CN2C5C31CC2 RRKTZKIUPZVBMF-UHFFFAOYSA-N 0.000 description 1
125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
230000000711 cancerogenic effect Effects 0.000 description 1
IGAAUQWWGNYORG-UHFFFAOYSA-N carbonochloridoyl 2-methylpropanoate Chemical compound CC(C)C(=O)OC(Cl)=O IGAAUQWWGNYORG-UHFFFAOYSA-N 0.000 description 1
231100000315 carcinogenic Toxicity 0.000 description 1
NSQLIUXCMFBZME-MPVJKSABSA-N carperitide Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)=O)[C@@H](C)CC)C1=CC=CC=C1 NSQLIUXCMFBZME-MPVJKSABSA-N 0.000 description 1
239000003054 catalyst Substances 0.000 description 1
230000001413 cellular effect Effects 0.000 description 1
239000007795 chemical reaction product Substances 0.000 description 1
239000003638 chemical reducing agent Substances 0.000 description 1
239000003795 chemical substances by application Substances 0.000 description 1
239000003245 coal Substances 0.000 description 1
238000000576 coating method Methods 0.000 description 1
208000010877 cognitive disease Diseases 0.000 description 1
239000003086 colorant Substances 0.000 description 1
230000002301 combined effect Effects 0.000 description 1
230000001276 controlling effect Effects 0.000 description 1
238000007796 conventional method Methods 0.000 description 1
239000013058 crude material Substances 0.000 description 1
239000013078 crystal Substances 0.000 description 1
238000002425 crystallisation Methods 0.000 description 1
230000008025 crystallization Effects 0.000 description 1
125000006638 cyclopentyl carbonyl group Chemical group 0.000 description 1
238000005947 deacylation reaction Methods 0.000 description 1
238000006264 debenzylation reaction Methods 0.000 description 1
230000000779 depleting effect Effects 0.000 description 1
239000008121 dextrose Substances 0.000 description 1
150000001993 dienes Chemical class 0.000 description 1
VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
230000008034 disappearance Effects 0.000 description 1
201000010099 disease Diseases 0.000 description 1
239000007884 disintegrant Substances 0.000 description 1
208000035475 disorder Diseases 0.000 description 1
230000035619 diuresis Effects 0.000 description 1
239000002552 dosage form Substances 0.000 description 1
239000003651 drinking water Substances 0.000 description 1
235000020188 drinking water Nutrition 0.000 description 1
239000003937 drug carrier Substances 0.000 description 1
238000001035 drying Methods 0.000 description 1
230000002526 effect on cardiovascular system Effects 0.000 description 1
229920001971 elastomer Polymers 0.000 description 1
239000003995 emulsifying agent Substances 0.000 description 1
239000000839 emulsion Substances 0.000 description 1
125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
SBBWEQLNKVHYCX-JTQLQIEISA-N ethyl L-tyrosinate Chemical compound CCOC(=O)[C@@H](N)CC1=CC=C(O)C=C1 SBBWEQLNKVHYCX-JTQLQIEISA-N 0.000 description 1
238000001704 evaporation Methods 0.000 description 1
230000008020 evaporation Effects 0.000 description 1
230000029142 excretion Effects 0.000 description 1
238000005048 flame photometry Methods 0.000 description 1
229910052731 fluorine Inorganic materials 0.000 description 1
239000011737 fluorine Substances 0.000 description 1
235000003599 food sweetener Nutrition 0.000 description 1
238000001640 fractional crystallisation Methods 0.000 description 1
239000007789 gas Substances 0.000 description 1
230000002496 gastric effect Effects 0.000 description 1
239000007903 gelatin capsule Substances 0.000 description 1
125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 1
238000005469 granulation Methods 0.000 description 1
230000003179 granulation Effects 0.000 description 1
125000001475 halogen functional group Chemical group 0.000 description 1
208000019622 heart disease Diseases 0.000 description 1
238000010438 heat treatment Methods 0.000 description 1
238000004128 high performance liquid chromatography Methods 0.000 description 1
108010016268 hippuryl-histidyl-leucine Proteins 0.000 description 1
229930195733 hydrocarbon Natural products 0.000 description 1
150000002430 hydrocarbons Chemical class 0.000 description 1
150000004679 hydroxides Chemical class 0.000 description 1
125000004464 hydroxyphenyl group Chemical group 0.000 description 1
238000000099 in vitro assay Methods 0.000 description 1
238000011534 incubation Methods 0.000 description 1
239000007972 injectable composition Substances 0.000 description 1
150000007529 inorganic bases Chemical class 0.000 description 1
230000002452 interceptive effect Effects 0.000 description 1
PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
208000002551 irritable bowel syndrome Diseases 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
125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
239000000644 isotonic solution Substances 0.000 description 1
229960003299 ketamine Drugs 0.000 description 1
150000002576 ketones Chemical class 0.000 description 1
201000006370 kidney failure Diseases 0.000 description 1
230000000670 limiting effect Effects 0.000 description 1
239000000314 lubricant Substances 0.000 description 1
230000005291 magnetic effect Effects 0.000 description 1
239000000594 mannitol Substances 0.000 description 1
235000010355 mannitol Nutrition 0.000 description 1
125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
VPBNMNXCRSCEGU-OALUTQOASA-N methyl (2s)-2-[[1-[[(2s)-2-acetylsulfanyl-3-methylbutanoyl]amino]cyclopentanecarbonyl]amino]-3-(4-hydroxyphenyl)propanoate Chemical compound C([C@@H](C(=O)OC)NC(=O)C1(CCCC1)NC(=O)[C@@H](SC(C)=O)C(C)C)C1=CC=C(O)C=C1 VPBNMNXCRSCEGU-OALUTQOASA-N 0.000 description 1
VXYFARNRGZWHTJ-FVGYRXGTSA-N methyl (2s)-2-amino-3-(4-hydroxyphenyl)propanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CC1=CC=C(O)C=C1 VXYFARNRGZWHTJ-FVGYRXGTSA-N 0.000 description 1
150000004702 methyl esters Chemical class 0.000 description 1
235000019813 microcrystalline cellulose Nutrition 0.000 description 1
239000008108 microcrystalline cellulose Substances 0.000 description 1
229940016286 microcrystalline cellulose Drugs 0.000 description 1
150000007522 mineralic acids Chemical class 0.000 description 1
238000002156 mixing Methods 0.000 description 1
BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 1
125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
239000002833 natriuretic agent Substances 0.000 description 1
238000006386 neutralization reaction Methods 0.000 description 1
231100000252 nontoxic Toxicity 0.000 description 1
230000003000 nontoxic effect Effects 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
210000000056 organ Anatomy 0.000 description 1
150000007524 organic acids Chemical class 0.000 description 1
150000007530 organic bases Chemical class 0.000 description 1
230000003204 osmotic effect Effects 0.000 description 1
239000007800 oxidant agent Substances 0.000 description 1
230000003647 oxidation Effects 0.000 description 1
238000007254 oxidation reaction Methods 0.000 description 1
125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 description 1
229910052760 oxygen Inorganic materials 0.000 description 1
230000005298 paramagnetic effect Effects 0.000 description 1
230000036961 partial effect Effects 0.000 description 1
239000002245 particle Substances 0.000 description 1
229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 1
239000000546 pharmaceutical excipient Substances 0.000 description 1
ZWLUXSQADUDCSB-UHFFFAOYSA-N phthalaldehyde Chemical compound O=CC1=CC=CC=C1C=O ZWLUXSQADUDCSB-UHFFFAOYSA-N 0.000 description 1
230000004962 physiological condition Effects 0.000 description 1
239000002798 polar solvent Substances 0.000 description 1
229920001223 polyethylene glycol Polymers 0.000 description 1
239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
229910000343 potassium bisulfate Inorganic materials 0.000 description 1
159000000001 potassium salts Chemical class 0.000 description 1
230000003389 potentiating effect Effects 0.000 description 1
239000003755 preservative agent Substances 0.000 description 1
230000003449 preventive effect Effects 0.000 description 1
102000004196 processed proteins & peptides Human genes 0.000 description 1
125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
208000005333 pulmonary edema Diseases 0.000 description 1
239000008213 purified water Substances 0.000 description 1
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 1
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
238000010791 quenching Methods 0.000 description 1
229960001404 quinidine Drugs 0.000 description 1
229960000948 quinine Drugs 0.000 description 1
150000003254 radicals Chemical class 0.000 description 1
238000003127 radioimmunoassay Methods 0.000 description 1
239000001044 red dye Substances 0.000 description 1
238000006894 reductive elimination reaction Methods 0.000 description 1
230000001105 regulatory effect Effects 0.000 description 1
238000004007 reversed phase HPLC Methods 0.000 description 1
230000000894 saliuretic effect Effects 0.000 description 1
DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
230000028327 secretion Effects 0.000 description 1
210000002966 serum Anatomy 0.000 description 1
238000007086 side reaction Methods 0.000 description 1
239000004460 silage Substances 0.000 description 1
239000000377 silicon dioxide Substances 0.000 description 1
150000003385 sodium Chemical class 0.000 description 1
239000001632 sodium acetate Substances 0.000 description 1
235000017281 sodium acetate Nutrition 0.000 description 1
239000012279 sodium borohydride Substances 0.000 description 1
229910000033 sodium borohydride Inorganic materials 0.000 description 1
159000000000 sodium salts Chemical class 0.000 description 1
SLZHLQUFNFXTHB-UHFFFAOYSA-M sodium;5-butan-2-yl-5-ethyl-2-sulfanylidenepyrimidin-3-ide-4,6-dione Chemical compound [Na+].CCC(C)C1(CC)C([O-])=NC(=S)NC1=O SLZHLQUFNFXTHB-UHFFFAOYSA-M 0.000 description 1
239000000600 sorbitol Substances 0.000 description 1
235000010356 sorbitol Nutrition 0.000 description 1
241000894007 species Species 0.000 description 1
238000001228 spectrum Methods 0.000 description 1
238000011699 spontaneously hypertensive rat Methods 0.000 description 1
239000003381 stabilizer Substances 0.000 description 1
230000000087 stabilizing effect Effects 0.000 description 1
238000010561 standard procedure Methods 0.000 description 1
235000019698 starch Nutrition 0.000 description 1
239000008117 stearic acid Substances 0.000 description 1
239000012258 stirred mixture Substances 0.000 description 1
QMGVPVSNSZLJIA-FVWCLLPLSA-N strychnine Chemical class O([C@H]1CC(N([C@H]2[C@H]1[C@H]1C3)C=4C5=CC=CC=4)=O)CC=C1CN1[C@@H]3[C@]25CC1 QMGVPVSNSZLJIA-FVWCLLPLSA-N 0.000 description 1
239000005720 sucrose Substances 0.000 description 1
125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
239000011593 sulfur Substances 0.000 description 1
239000000829 suppository Substances 0.000 description 1
230000002459 sustained effect Effects 0.000 description 1
239000003765 sweetening agent Substances 0.000 description 1
208000011580 syndromic disease Diseases 0.000 description 1
239000000454 talc Substances 0.000 description 1
229910052623 talc Inorganic materials 0.000 description 1
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 1
QIQITDHWZYEEPA-UHFFFAOYSA-N thiophene-2-carbonyl chloride Chemical compound ClC(=O)C1=CC=CS1 QIQITDHWZYEEPA-UHFFFAOYSA-N 0.000 description 1
238000012546 transfer Methods 0.000 description 1
TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
238000009736 wetting Methods 0.000 description 1
239000000080 wetting agent Substances 0.000 description 1
239000011701 zinc Substances 0.000 description 1
229910052725 zinc Inorganic materials 0.000 description 1
IPSRAFUHLHIWAR-UHFFFAOYSA-N zinc;ethane Chemical group [Zn+2].[CH2-]C.[CH2-]C IPSRAFUHLHIWAR-UHFFFAOYSA-N 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- 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
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
- 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
- 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
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
- 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
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides

Landscapes

Health & Medical Sciences (AREA)
Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Medicinal Chemistry (AREA)
General Health & Medical Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Chemical Kinetics & Catalysis (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
General Chemical & Material Sciences (AREA)
Pharmacology & Pharmacy (AREA)
Public Health (AREA)
Animal Behavior & Ethology (AREA)
Veterinary Medicine (AREA)
Molecular Biology (AREA)
Biochemistry (AREA)
Proteomics, Peptides & Aminoacids (AREA)
Genetics & Genomics (AREA)
Biophysics (AREA)
Diabetes (AREA)
Hematology (AREA)
Cardiology (AREA)
Heart & Thoracic Surgery (AREA)
Obesity (AREA)
Urology & Nephrology (AREA)
Reproductive Health (AREA)
Endocrinology (AREA)
Vascular Medicine (AREA)
Pulmonology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Peptides Or Proteins (AREA)
Hydrogenated Pyridines (AREA)

FI945354A 1993-11-16 1994-11-14 Menetelmä ACE- ja NEP-estäjinä käyttökelpoisten syklisten aminohappojohdannaisten valmistamiseksi FI118600B (fi)

Applications Claiming Priority (4)

Application Number	Priority Date	Filing Date	Title
US15339593		1993-11-16
US08/153,395 US5432186A (en)	1993-11-16	1993-11-16	Cyclic amino acid derivatives
US26385994		1994-06-22
US08/263,859 US5506244A (en)	1993-11-16	1994-06-22	Cyclic amino acid derivatives

Publications (3)

Publication Number	Publication Date
FI945354A0 FI945354A0 (fi)	1994-11-14
FI945354A7 FI945354A7 (fi)	1995-05-17
FI118600B true FI118600B (fi)	2008-01-15

Family

ID=26850506

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
FI945354A FI118600B (fi)	1993-11-16	1994-11-14	Menetelmä ACE- ja NEP-estäjinä käyttökelpoisten syklisten aminohappojohdannaisten valmistamiseksi

Country Status (19)

Country	Link
US (1)	US5668158A (zh)
EP (1)	EP0655461B1 (zh)
JP (1)	JP3647914B2 (zh)
CN (1)	CN1058019C (zh)
AT (1)	ATE193706T1 (zh)
AU (1)	AU687444B2 (zh)
CA (1)	CA2135711A1 (zh)
CY (1)	CY2234B1 (zh)
DE (1)	DE69424846T2 (zh)
DK (1)	DK0655461T3 (zh)
ES (1)	ES2148305T3 (zh)
FI (1)	FI118600B (zh)
GR (1)	GR3033829T3 (zh)
HU (1)	HU226300B1 (zh)
IL (1)	IL111581A (zh)
NO (1)	NO311224B1 (zh)
NZ (1)	NZ264913A (zh)
PH (1)	PH31056A (zh)
PT (1)	PT655461E (zh)

Families Citing this family (17)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
IT1273455B (it) *	1995-01-27	1997-07-08	Zambon Spa	Derivati tiolici ad attivita' inibitrice delle metallopeptidasi
JPH08325263A (ja) *	1995-05-31	1996-12-10	Sumitomo Metal Ind Ltd	新規２−アミノ−３−フェニルプロピオン酸誘導体
WO1997011717A1 (en) *	1995-09-27	1997-04-03	Novartis Ag	Treatment of chronic progressive renal failure
EP0894003A4 (en) *	1996-04-12	2000-10-04	Bristol Myers Squibb Co	N-FORMYL HYDROXYLAMINE-BASED COMPOUNDS SUITABLE AS INCEPTIENTS OF THE ACE ENZYME AND / OR ENDOPEPTIDASE NEP
US6777550B1 (en)	1996-04-12	2004-08-17	Bristol-Myers Squibb Company	N-formyl hydroxylamine containing compounds useful as ACE inhibitors and/or NEP inhibitors
US6423727B1 (en)	1998-04-23	2002-07-23	Novartis Ag	Certain thiol inhibitors of endothelin-converting enzyme
HUP0101640A3 (en) *	1998-04-23	2002-10-28	Novartis Ag	Certain thoil inhibitors of endothelin-converting enzyme
US6426354B1 (en)	1998-04-23	2002-07-30	Novartis Ag	Certain heteroaryl substituted thiol inhibitors of endothelin-converting enzyme
IL144285A0 (en) *	1999-03-29	2002-05-23	Bristol Myers Squibb Co	Pharmaceutical compositions containing a vasopeptidase inhibitor
US6509330B2 (en)	2000-02-17	2003-01-21	Bristol-Myers Squibb Company	Hydroxamic acid containing compounds useful as ACE inhibitors and/or NEP inhibotors
CN1304415C (zh) *	2001-09-21	2007-03-14	诺瓦提斯公司	作为ace和nep抑制剂的吡喃衍生物
US6919343B2 (en)	2002-02-08	2005-07-19	Merck & Co., Inc.	N-biphenyl(substituted methyl) aminocycloalkane-carboxamide derivatives
ES2256727T3 (es)	2002-02-08	2006-07-16	MERCK & CO., INC.	Derivados de n-bifenilmetil aminocicloalcanocarboxamida.
US7045653B2 (en)	2002-12-23	2006-05-16	Pfizer, Inc.	Pharmaceuticals
EP2127658A4 (en) *	2007-01-10	2011-04-27	Kowa Co	THERAPEUTIC AGENT AGAINST MORBUS MENIERE
CN105670160A (zh) *	2015-10-12	2016-06-15	陆思烨	一种防紫外抗老化电线电缆料及其制备方法
UY38072A (es)	2018-02-07	2019-10-01	Novartis Ag	Compuestos derivados de éster butanoico sustituido con bisfenilo como inhibidores de nep, composiciones y combinaciones de los mismos

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US4093739A (en) *	1977-06-15	1978-06-06	Mead Johnson & Company	Mercaptoacylamidobenzoyl glycine and mucolytic process
GB8820844D0 (en) *	1988-09-05	1988-10-05	Pfizer Ltd	Therapeutic agents
GB9004260D0 (en) *	1990-02-26	1990-04-18	Pfizer Ltd	Therapeutic agents
FR2679564A1 (fr) *	1991-07-23	1993-01-29	Inst Nat Sante Rech Med	Nouveaux acylmercaptoalcanoldipeptides, leur preparation et les compositions qui les contiennent.
US5208236A (en) *	1992-09-23	1993-05-04	Schering Corporation	N-(acylaminomethyl)glutaryl amino acids and use

1994
- 1994-11-07 AT AT94810642T patent/ATE193706T1/de not_active IP Right Cessation
- 1994-11-07 PT PT94810642T patent/PT655461E/pt unknown
- 1994-11-07 EP EP94810642A patent/EP0655461B1/en not_active Expired - Lifetime
- 1994-11-07 DE DE69424846T patent/DE69424846T2/de not_active Expired - Fee Related
- 1994-11-07 ES ES94810642T patent/ES2148305T3/es not_active Expired - Lifetime
- 1994-11-07 DK DK94810642T patent/DK0655461T3/da active
- 1994-11-09 AU AU77729/94A patent/AU687444B2/en not_active Ceased
- 1994-11-10 IL IL11158194A patent/IL111581A/xx not_active IP Right Cessation
- 1994-11-11 PH PH49353A patent/PH31056A/en unknown
- 1994-11-14 NZ NZ264913A patent/NZ264913A/en not_active IP Right Cessation
- 1994-11-14 FI FI945354A patent/FI118600B/fi not_active IP Right Cessation
- 1994-11-14 CA CA002135711A patent/CA2135711A1/en not_active Abandoned
- 1994-11-15 NO NO19944364A patent/NO311224B1/no unknown
- 1994-11-15 JP JP28078594A patent/JP3647914B2/ja not_active Expired - Fee Related
- 1994-11-15 HU HU9403276A patent/HU226300B1/hu not_active IP Right Cessation
- 1994-11-15 CN CN94118911A patent/CN1058019C/zh not_active Expired - Fee Related
1996
- 1996-02-14 US US08/601,626 patent/US5668158A/en not_active Expired - Fee Related
2000
- 2000-06-30 GR GR20000401530T patent/GR3033829T3/el not_active IP Right Cessation
2001
- 2001-09-07 CY CY0100025A patent/CY2234B1/xx unknown

Also Published As

Publication number	Publication date
CY2234B1 (en)	2003-04-18
NO944364D0 (no)	1994-11-15
AU7772994A (en)	1995-05-25
HUT71423A (en)	1995-11-28
CN1058019C (zh)	2000-11-01
NO311224B1 (no)	2001-10-29
EP0655461B1 (en)	2000-06-07
GR3033829T3 (en)	2000-10-31
DE69424846D1 (de)	2000-07-13
HU226300B1 (en)	2008-08-28
NO944364L (no)	1995-05-18
ATE193706T1 (de)	2000-06-15
HU9403276D0 (en)	1995-01-30
NZ264913A (en)	1997-02-24
PH31056A (en)	1998-02-03
FI945354A0 (fi)	1994-11-14
IL111581A (en)	1999-07-14
JP3647914B2 (ja)	2005-05-18
JPH07196685A (ja)	1995-08-01
EP0655461A1 (en)	1995-05-31
US5668158A (en)	1997-09-16
FI945354A7 (fi)	1995-05-17
CN1107857A (zh)	1995-09-06
ES2148305T3 (es)	2000-10-16
DK0655461T3 (da)	2000-10-02
PT655461E (pt)	2000-11-30
CA2135711A1 (en)	1995-05-17
DE69424846T2 (de)	2000-11-16
IL111581A0 (en)	1995-01-24
AU687444B2 (en)	1998-02-26

Publication	Publication Date	Title
FI118600B (fi)	2008-01-15	Menetelmä ACE- ja NEP-estäjinä käyttökelpoisten syklisten aminohappojohdannaisten valmistamiseksi
KR100462974B1 (ko)	2004-12-23	트롬빈 억제제
EP1808440B1 (en)	2011-07-27	Non-covalent inhibitors of urokinase and blood vessel formation
US6271232B1 (en)	2001-08-07	Collagenase-1 and stromelysin-1 inhibitors, pharmaceutical compositions comprising same and methods of their use
US5508266A (en)	1996-04-16	Gem-disubstituted amino acid derivatives
US20020061844A1 (en)	2002-05-23	Fc receptor modulators and uses thereof
KR20010023126A (ko)	2001-03-26	엔-아로일페닐알라닌 유도체
JPH0629228B2 (ja)	1994-04-20	ヒドロキシルアミン誘導体
US6500802B1 (en)	2002-12-31	Peptidyl-2-amino-1-hydroxyalkanesulfonic acid cysteine protease inhibitors
JPH08503475A (ja)	1996-04-16	抗変性活性剤としてのカルボキシ−ペプチジル誘導体
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
KR100432618B1 (ko)	2004-08-31	시클릭아미노산유도체
CZ20013577A3 (cs)	2002-07-17	Inhibitory komplementních proteáz s nízkou molekulovou hmotností
HUP0101640A2 (hu)	2001-09-28	Endotelinkonvertáló enzimet gátló tiolvegyületek
HUP0101899A2 (hu)	2001-11-28	Cisztein-aktivitástól függő enzimeket gátló hatású tiadiazolvegyületek, azokat tartalmazó gyógyszerkészítmények és alkalmazásuk
CA2212356A1 (en)	1996-10-17	Novel 4-substituted-3-peptidyl-azetidin-2-one derivatives useful as cysteine proteinase inhibitor
US20050119190A1 (en)	2005-06-02	Inhibitors of the blood-clotting factor xa, production thereof and use of the same
KR940006770B1 (ko)	1994-07-27	머캅토-아실아미노산 고혈압 치료제
US5644055A (en)	1997-07-01	Antihypertensive tricyclic azepine derivatives useful as inhibitors of enkephalinase and ACE
HU201005B (en)	1990-09-28	Process for producing new n-substituted mercaptopropaneamide derivatives and pharmaceutical compositions comprising such compounds
JP2000086618A (ja)	2000-03-28	新規なヒドロキサム酸化合物、それらの製造法、及びそれらを含む製薬的組成物
JPH06503315A (ja)	1994-04-14	シクロヘキシルスタチン型のレニン−抑制性ペプチド類、それらの製造方法および薬品中におけるそれらの使用
IE65539B1 (en)	1995-11-01	Trifluoromethyl mercaptan and mercaptoacyl derivatives and method of using same
KR100242264B1 (ko)	2000-02-01	N-알킬-n-알콕시아민 구조를 갖는 신규한 트롬빈 억제제
WO2021262708A1 (en)	2021-12-30	Prodrugs of mitochodria-targeting oligopeptides

Legal Events

Date	Code	Title	Description
1997-08-13	GB	Transfer or assigment of application	Owner name: NOVARTIS AG
2008-01-15	FG	Patent granted	Ref document number: 118600 Country of ref document: FI
2009-05-31	MA	Patent expired

Date

Code

Title

Description

1997-08-13

Transfer or assigment of application

Owner name: NOVARTIS AG