GB1576161A - Proline derivatives and related compounds - Google Patents
Proline derivatives and related compounds Download PDFInfo
- Publication number
- GB1576161A GB1576161A GB4088/77A GB408877A GB1576161A GB 1576161 A GB1576161 A GB 1576161A GB 4088/77 A GB4088/77 A GB 4088/77A GB 408877 A GB408877 A GB 408877A GB 1576161 A GB1576161 A GB 1576161A
- Authority
- GB
- United Kingdom
- Prior art keywords
- proline
- compound
- hydrogen
- acid
- lower alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 107
- 150000003147 proline derivatives Chemical class 0.000 title description 3
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 76
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 37
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 33
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 20
- -1 mercaptopropanoyl Chemical group 0.000 claims description 256
- 238000000034 method Methods 0.000 claims description 146
- 229960002429 proline Drugs 0.000 claims description 133
- 239000000243 solution Substances 0.000 claims description 111
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 105
- 239000000203 mixture Substances 0.000 claims description 101
- 239000001257 hydrogen Substances 0.000 claims description 64
- 229910052739 hydrogen Inorganic materials 0.000 claims description 64
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 53
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 32
- 150000003839 salts Chemical class 0.000 claims description 26
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 22
- 150000002431 hydrogen Chemical class 0.000 claims description 20
- 239000003981 vehicle Substances 0.000 claims description 19
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 14
- SRIPWKGWOAOUEH-GDVGLLTNSA-N (2s)-1-(2-sulfanylpropanoyl)pyrrolidine-2-carboxylic acid Chemical compound CC(S)C(=O)N1CCC[C@H]1C(O)=O SRIPWKGWOAOUEH-GDVGLLTNSA-N 0.000 claims description 11
- 230000036772 blood pressure Effects 0.000 claims description 11
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 239000003755 preservative agent Substances 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 235000019359 magnesium stearate Nutrition 0.000 claims description 7
- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 claims description 7
- 239000011780 sodium chloride Substances 0.000 claims description 7
- 102000005862 Angiotensin II Human genes 0.000 claims description 6
- 101800000734 Angiotensin-1 Proteins 0.000 claims description 6
- 102400000344 Angiotensin-1 Human genes 0.000 claims description 6
- 101800000733 Angiotensin-2 Proteins 0.000 claims description 6
- 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 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 6
- 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 claims description 6
- 229950006323 angiotensin ii Drugs 0.000 claims description 6
- 239000002775 capsule Substances 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 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 claims description 5
- 239000011230 binding agent Substances 0.000 claims description 5
- 239000000796 flavoring agent Substances 0.000 claims description 5
- 235000003599 food sweetener Nutrition 0.000 claims description 5
- 239000008101 lactose Substances 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 239000003765 sweetening agent Substances 0.000 claims description 5
- 239000008215 water for injection Substances 0.000 claims description 5
- 239000013543 active substance Substances 0.000 claims description 4
- 235000013355 food flavoring agent Nutrition 0.000 claims description 4
- 239000004615 ingredient Substances 0.000 claims description 4
- 230000002401 inhibitory effect Effects 0.000 claims description 4
- 239000000314 lubricant Substances 0.000 claims description 4
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 4
- 230000002335 preservative effect Effects 0.000 claims description 4
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 125000001589 carboacyl group Chemical group 0.000 claims description 3
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 claims description 3
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 claims description 3
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 229920001971 elastomer Polymers 0.000 claims description 2
- 239000007903 gelatin capsule Substances 0.000 claims description 2
- 229940102223 injectable solution Drugs 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 claims description 2
- 229960002216 methylparaben Drugs 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 claims description 2
- 229960003415 propylparaben Drugs 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000002253 acid Substances 0.000 abstract description 44
- 230000010933 acylation Effects 0.000 abstract description 9
- 238000005917 acylation reaction Methods 0.000 abstract description 9
- 150000003573 thiols Chemical class 0.000 abstract description 8
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 abstract description 7
- 125000001424 substituent group Chemical group 0.000 abstract description 7
- 206010020772 Hypertension Diseases 0.000 abstract description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract description 4
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 abstract description 3
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical group [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 abstract description 3
- 230000006181 N-acylation Effects 0.000 abstract 1
- 125000003647 acryloyl group Chemical group O=C([*])C([H])=C([H])[H] 0.000 abstract 1
- 239000008280 blood Substances 0.000 abstract 1
- 210000004369 blood Anatomy 0.000 abstract 1
- 125000003884 phenylalkyl group Chemical group 0.000 abstract 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 210
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 120
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 103
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 75
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 61
- 239000000047 product Substances 0.000 description 59
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 49
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 48
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 47
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 46
- HYIXVZHJZDSDBA-LURJTMIESA-N (2s)-1-(3-sulfanylpropanoyl)pyrrolidine-2-carboxylic acid Chemical compound OC(=O)[C@@H]1CCCN1C(=O)CCS HYIXVZHJZDSDBA-LURJTMIESA-N 0.000 description 45
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 45
- 239000000741 silica gel Substances 0.000 description 44
- 229910002027 silica gel Inorganic materials 0.000 description 44
- 229960000583 acetic acid Drugs 0.000 description 41
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 37
- HXEACLLIILLPRG-RXMQYKEDSA-N l-pipecolic acid Natural products OC(=O)[C@H]1CCCCN1 HXEACLLIILLPRG-RXMQYKEDSA-N 0.000 description 35
- IADUEWIQBXOCDZ-VKHMYHEASA-N Azetidine-2-carboxylic acid Natural products OC(=O)[C@@H]1CCN1 IADUEWIQBXOCDZ-VKHMYHEASA-N 0.000 description 33
- 229930182821 L-proline Natural products 0.000 description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 33
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 27
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 26
- IADUEWIQBXOCDZ-UHFFFAOYSA-N azetidine-2-carboxylic acid Chemical compound OC(=O)C1CCN1 IADUEWIQBXOCDZ-UHFFFAOYSA-N 0.000 description 26
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 24
- 239000002904 solvent Substances 0.000 description 24
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 23
- 235000019341 magnesium sulphate Nutrition 0.000 description 23
- 239000011541 reaction mixture Substances 0.000 description 23
- 238000003756 stirring Methods 0.000 description 23
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- FAKRSMQSSFJEIM-MLWJPKLSSA-N (2s)-1-(2-methyl-3-sulfanylpropanoyl)pyrrolidine-2-carboxylic acid Chemical compound SCC(C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-MLWJPKLSSA-N 0.000 description 20
- 239000003921 oil Substances 0.000 description 19
- 235000019198 oils Nutrition 0.000 description 19
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 18
- 239000000706 filtrate Substances 0.000 description 18
- 239000012044 organic layer Substances 0.000 description 17
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 16
- 239000012074 organic phase Substances 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 229910052740 iodine Inorganic materials 0.000 description 14
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 13
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 13
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 13
- RKEYKDXXZCICFZ-UHFFFAOYSA-N 5-hydroxypipecolic acid Chemical compound OC1CCC(C(O)=O)NC1 RKEYKDXXZCICFZ-UHFFFAOYSA-N 0.000 description 12
- CYJRNFFLTBEQSQ-UHFFFAOYSA-N 8-(3-methyl-1-benzothiophen-5-yl)-N-(4-methylsulfonylpyridin-3-yl)quinoxalin-6-amine Chemical compound CS(=O)(=O)C1=C(C=NC=C1)NC=1C=C2N=CC=NC2=C(C=1)C=1C=CC2=C(C(=CS2)C)C=1 CYJRNFFLTBEQSQ-UHFFFAOYSA-N 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- 150000002148 esters Chemical class 0.000 description 12
- 239000000463 material Substances 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 239000002244 precipitate Substances 0.000 description 12
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 12
- XJJBXZIKXFOMLP-ZETCQYMHSA-N tert-butyl (2s)-pyrrolidine-2-carboxylate Chemical compound CC(C)(C)OC(=O)[C@@H]1CCCN1 XJJBXZIKXFOMLP-ZETCQYMHSA-N 0.000 description 12
- 239000008346 aqueous phase Substances 0.000 description 11
- 125000004119 disulfanediyl group Chemical group *SS* 0.000 description 11
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 11
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 11
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
- 229910021529 ammonia Inorganic materials 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- ZNQRGUYIKSRYCI-NETXQHHPSA-N (2s)-1-(3-acetylsulfanyl-2-methylpropanoyl)pyrrolidine-2-carboxylic acid Chemical compound CC(=O)SCC(C)C(=O)N1CCC[C@H]1C(O)=O ZNQRGUYIKSRYCI-NETXQHHPSA-N 0.000 description 9
- VFVHNRJEYQGRGE-UHFFFAOYSA-N 3-acetylsulfanyl-2-methylpropanoic acid Chemical compound OC(=O)C(C)CSC(C)=O VFVHNRJEYQGRGE-UHFFFAOYSA-N 0.000 description 9
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 9
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 9
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 9
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 9
- 229940032007 methylethyl ketone Drugs 0.000 description 9
- HXEACLLIILLPRG-UHFFFAOYSA-N pipecolic acid Chemical group OC(=O)C1CCCCN1 HXEACLLIILLPRG-UHFFFAOYSA-N 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- HCDMJFOHIXMBOV-UHFFFAOYSA-N 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-4,7-dihydropyrrolo[4,5]pyrido[1,2-d]pyrimidin-2-one Chemical compound C=1C2=C3N(CC)C(=O)N(C=4C(=C(OC)C=C(OC)C=4F)F)CC3=CN=C2NC=1CN1CCOCC1 HCDMJFOHIXMBOV-UHFFFAOYSA-N 0.000 description 8
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 235000011114 ammonium hydroxide Nutrition 0.000 description 8
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 229960003424 phenylacetic acid Drugs 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 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 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Substances ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 7
- 239000013078 crystal Substances 0.000 description 7
- 229910052708 sodium Inorganic materials 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 6
- 229920002261 Corn starch Polymers 0.000 description 6
- 238000005915 ammonolysis reaction Methods 0.000 description 6
- UIJGNTRUPZPVNG-UHFFFAOYSA-N benzenecarbothioic s-acid Chemical compound SC(=O)C1=CC=CC=C1 UIJGNTRUPZPVNG-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000008120 corn starch Substances 0.000 description 6
- 239000005457 ice water Substances 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- 235000011181 potassium carbonates Nutrition 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- KJXKOUXJZOOEDG-ZETCQYMHSA-N (2s)-1-(4-sulfanylbutanoyl)pyrrolidine-2-carboxylic acid Chemical compound OC(=O)[C@@H]1CCCN1C(=O)CCCS KJXKOUXJZOOEDG-ZETCQYMHSA-N 0.000 description 5
- JTNCEQNHURODLX-UHFFFAOYSA-N 2-phenylethanimidamide Chemical compound NC(=N)CC1=CC=CC=C1 JTNCEQNHURODLX-UHFFFAOYSA-N 0.000 description 5
- MXTKDWZKIQZANR-UHFFFAOYSA-N 3-[(4-methoxyphenyl)methylsulfanyl]-2-methylpropanoic acid Chemical compound COC1=CC=C(CSCC(C)C(O)=O)C=C1 MXTKDWZKIQZANR-UHFFFAOYSA-N 0.000 description 5
- IHBVNSPHKMCPST-UHFFFAOYSA-N 3-bromopropanoyl chloride Chemical compound ClC(=O)CCBr IHBVNSPHKMCPST-UHFFFAOYSA-N 0.000 description 5
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- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 5
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- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 239000000538 analytical sample Substances 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- YEESUBCSWGVPCE-UHFFFAOYSA-N azanylidyneoxidanium iron(2+) pentacyanide Chemical compound [Fe++].[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.N#[O+] YEESUBCSWGVPCE-UHFFFAOYSA-N 0.000 description 1
- QFFVPLLCYGOFPU-UHFFFAOYSA-N barium chromate Chemical compound [Ba+2].[O-][Cr]([O-])(=O)=O QFFVPLLCYGOFPU-UHFFFAOYSA-N 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- UENWRTRMUIOCKN-UHFFFAOYSA-N benzyl thiol Chemical group SCC1=CC=CC=C1 UENWRTRMUIOCKN-UHFFFAOYSA-N 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000007958 cherry flavor Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- UMFDSFPDTLREFS-UHFFFAOYSA-N chloromethylsulfanylmethylbenzene Chemical compound ClCSCC1=CC=CC=C1 UMFDSFPDTLREFS-UHFFFAOYSA-N 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 229960002433 cysteine Drugs 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 229960001305 cysteine hydrochloride Drugs 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- SRGKFVAASLQVBO-DASCVMRKSA-N dexbrompheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C1([C@H](CCN(C)C)C=2N=CC=CC=2)=CC=C(Br)C=C1 SRGKFVAASLQVBO-DASCVMRKSA-N 0.000 description 1
- ZASWJUOMEGBQCQ-UHFFFAOYSA-L dibromolead Chemical compound Br[Pb]Br ZASWJUOMEGBQCQ-UHFFFAOYSA-L 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- QILSFLSDHQAZET-UHFFFAOYSA-N diphenylmethanol Chemical compound C=1C=CC=CC=1C(O)C1=CC=CC=C1 QILSFLSDHQAZET-UHFFFAOYSA-N 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 231100000676 disease causative agent Toxicity 0.000 description 1
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- DALXXOLORVJPKB-UHFFFAOYSA-N ethyl 2-ethoxy-1,2-dihydroxyquinoline-3-carboxylate Chemical compound C1=CC=C2N(O)C(OCC)(O)C(C(=O)OCC)=CC2=C1 DALXXOLORVJPKB-UHFFFAOYSA-N 0.000 description 1
- FYLONIWABFGHJB-UHFFFAOYSA-N ethyl 4-bromo-2-methylbutanoate Chemical compound CCOC(=O)C(C)CCBr FYLONIWABFGHJB-UHFFFAOYSA-N 0.000 description 1
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethyl mercaptane Natural products CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- WMYNMYVRWWCRPS-UHFFFAOYSA-N ethynoxyethane Chemical group CCOC#C WMYNMYVRWWCRPS-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000010685 fatty oil Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical compound CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- XGIHQYAWBCFNPY-AZOCGYLKSA-N hydrabamine Chemical class C([C@@H]12)CC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC[C@@]1(C)CNCCNC[C@@]1(C)[C@@H]2CCC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC1 XGIHQYAWBCFNPY-AZOCGYLKSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- JPEUGMSNLURYBF-UHFFFAOYSA-N hydroxy-(2-phenylethyl)-sulfanylidene-lambda4-sulfane Chemical group OS(=S)CCC1=CC=CC=C1 JPEUGMSNLURYBF-UHFFFAOYSA-N 0.000 description 1
- WYASEAQTEQVOJE-UHFFFAOYSA-N hydroxy-phenyl-sulfanylidene-$l^{4}-sulfane Chemical group OS(=S)C1=CC=CC=C1 WYASEAQTEQVOJE-UHFFFAOYSA-N 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 229960002591 hydroxyproline Drugs 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 238000004255 ion exchange chromatography Methods 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
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 238000002955 isolation Methods 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
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002540 isothiocyanates Chemical class 0.000 description 1
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 229910000000 metal hydroxide Inorganic materials 0.000 description 1
- 150000004692 metal hydroxides Chemical class 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 229940043265 methyl isobutyl ketone Drugs 0.000 description 1
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229960002460 nitroprusside Drugs 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000007968 orange flavor Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical group O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 229920000172 poly(styrenesulfonic acid) Polymers 0.000 description 1
- 229940005642 polystyrene sulfonic acid Drugs 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- LYBYDGJWQLTRAI-UHFFFAOYSA-N potassium;ethylsulfanylmethanedithioic acid Chemical compound [K+].CCSC(S)=S LYBYDGJWQLTRAI-UHFFFAOYSA-N 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- GAPYKZAARZMMGP-UHFFFAOYSA-N pyridin-1-ium;acetate Chemical compound CC(O)=O.C1=CC=NC=C1 GAPYKZAARZMMGP-UHFFFAOYSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- XEYWOETXQNDSED-UHFFFAOYSA-N s-(3-chloro-3-oxopropyl) ethanethioate Chemical compound CC(=O)SCCC(Cl)=O XEYWOETXQNDSED-UHFFFAOYSA-N 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- XIIOFHFUYBLOLW-UHFFFAOYSA-N selpercatinib Chemical compound OC(COC=1C=C(C=2N(C=1)N=CC=2C#N)C=1C=NC(=CC=1)N1CC2N(C(C1)C2)CC=1C=NC(=CC=1)OC)(C)C XIIOFHFUYBLOLW-UHFFFAOYSA-N 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- QXKXDIKCIPXUPL-UHFFFAOYSA-N sulfanylidenemercury Chemical compound [Hg]=S QXKXDIKCIPXUPL-UHFFFAOYSA-N 0.000 description 1
- 239000003774 sulfhydryl reagent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- DTMHTVJOHYTUHE-UHFFFAOYSA-N thiocyanogen Chemical compound N#CSSC#N DTMHTVJOHYTUHE-UHFFFAOYSA-N 0.000 description 1
- 150000008111 thiosulfinates Chemical class 0.000 description 1
- GWIKYPMLNBTJHR-UHFFFAOYSA-M thiosulfonate group Chemical group S(=S)(=O)[O-] GWIKYPMLNBTJHR-UHFFFAOYSA-M 0.000 description 1
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000009637 wintergreen oil Substances 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C321/00—Thiols, sulfides, hydropolysulfides or polysulfides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C327/00—Thiocarboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
- C07C53/15—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen containing halogen
- C07C53/19—Acids containing three or more carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/52—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen
- C07C57/58—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Hydrogenated Pyridines (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US05/657,792 US4046889A (en) | 1976-02-13 | 1976-02-13 | Azetidine-2-carboxylic acid derivatives |
| US69843276A | 1976-06-21 | 1976-06-21 | |
| US05/751,851 US4105776A (en) | 1976-06-21 | 1976-12-22 | Proline derivatives and related compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB1576161A true GB1576161A (en) | 1980-10-01 |
Family
ID=27417986
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB4088/77A Expired GB1576161A (en) | 1976-02-13 | 1977-02-13 | Proline derivatives and related compounds |
Country Status (31)
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AT387381B (de) * | 1986-06-27 | 1989-01-10 | Egyt Gyogyszervegyeszeti Gyar | Verfahren zur herstellung von einem mercapto-acylprolin |
| US5438046A (en) * | 1993-07-30 | 1995-08-01 | Zambon Group S.P.A. | N-heteroaryl substituted derivatives of propanamide useful in the treatment of cardiovascular diseases |
| WO1998039311A1 (en) * | 1997-03-05 | 1998-09-11 | Smithkline Beecham P.L.C. | Antibacterial heterocyclic amino acid derivatives |
| WO2003014072A1 (en) * | 2001-08-07 | 2003-02-20 | Sunesis Pharmaceuticals, Inc. | Disulfide and thiosulfonate ligands and libraries comprising these ligands |
Families Citing this family (50)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4206122A (en) * | 1978-04-14 | 1980-06-03 | E. R. Squibb & Sons, Inc. | Derivatives of pyrrolidinecarboxaldehyde and piperidinecarboxaldehyde and intermediates therefor |
| US4053651A (en) | 1976-05-10 | 1977-10-11 | E. R. Squibb & Sons, Inc. | Compounds and method for alleviating angiotensin related hypertension |
| AU518147B2 (en) * | 1976-12-03 | 1981-09-17 | E.R. Squibb & Sons, Inc. | Derivatives of thiazolidine, thiazine and morpholine carboxylic acids |
| US4129566A (en) * | 1978-02-15 | 1978-12-12 | E. R. Squibb & Sons, Inc. | Derivatives of dehydrocyclicimino acids |
| US4113715A (en) * | 1977-01-17 | 1978-09-12 | E. R. Squibb & Sons, Inc. | Amino acid derivatives |
| FR2412537A1 (fr) * | 1977-12-22 | 1979-07-20 | Science Union & Cie | Nouveaux thiobutyramides substitues, leurs procedes d'obtention et leur application pharmaceutique |
| CA1120400A (en) * | 1977-12-27 | 1982-03-23 | Zola P. Horovitz | Method of treating hypertension and medicaments therefor |
| PH15381A (en) * | 1978-02-21 | 1982-12-17 | Squibb & Sons Inc | Halogen substituted mercaptoacylamino acids |
| JPS559058A (en) * | 1978-07-06 | 1980-01-22 | Dainippon Pharmaceut Co Ltd | 1-(3-mercapto-2-methylpropanoyl)prolyl amino acid derivative |
| CA1109475A (en) * | 1978-07-27 | 1981-09-22 | Miguel A. Ondetti | Thiopropanoylamino acid derivatives |
| CA1144930A (en) * | 1978-08-11 | 1983-04-19 | Miguel A. Ondetti | Mercaptoacyl derivatives of substituted prolines |
| NZ190995A (en) * | 1978-09-05 | 1982-03-09 | American Cyanamid Co | Substituted omega propionyl or butyryl l-prolines and pharmaceutical compositions |
| NL7809121A (nl) * | 1978-09-07 | 1980-03-11 | Oce Andeno B V Grubbenvorsterw | Optisch aktieve derivaten van mercapto-isoboterzuur. |
| NL7809120A (nl) * | 1978-09-07 | 1980-03-11 | Oce Andeno B V Grubbenvorsterw | Werkwijze voor de bereiding van proline-derivaten. |
| US4690937A (en) * | 1979-08-14 | 1987-09-01 | University Of Miami | Anti-hypertensive agents |
| ZA794723B (en) * | 1978-09-11 | 1980-08-27 | Univ Miami | Anti-hypertensive agents |
| GR73585B (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) * | 1978-09-11 | 1984-03-26 | Univ Miami | |
| JPS5540622A (en) * | 1978-09-14 | 1980-03-22 | Santen Pharmaceut Co Ltd | Hypotensive agent |
| US4483861A (en) * | 1978-10-31 | 1984-11-20 | Santen Pharmaceutical Co., Ltd. | Antihypertensive sulfur-containing compounds |
| US4198515A (en) * | 1978-12-08 | 1980-04-15 | E. R. Squibb & Sons, Inc. | Mercaptoacyl derivatives of 4,5-dihydro-1H-pyrrole-2-carboxylic acids and 1,4,5,6-tetrahydropyridine-2-carboxylic acids |
| US4347371A (en) * | 1978-12-30 | 1982-08-31 | Santen Pharmaceutical Co., Ltd. | Disulfide compounds |
| US4410542A (en) | 1978-12-30 | 1983-10-18 | Santen Pharmaceutical Co., Ltd. | Disulfide compounds |
| CA1138452A (en) * | 1979-01-15 | 1982-12-28 | John Krapcho | Carbamate derivatives of mercaptoacyl hydroxy prolines |
| US4461896A (en) * | 1979-02-07 | 1984-07-24 | Norwich Eaton Pharmaceuticals, Inc. | 1-[Acylthio) and (mercapto)-1-oxoalkyl]-1,2,3,4-tetrahydroquinoline-2-carboxylic acids |
| US4220791A (en) * | 1979-03-08 | 1980-09-02 | E. R. Squibb & Sons, Inc. | Mercaptoacylpyrazolidinone carboxylic acid derivatives |
| ZA802420B (en) * | 1979-05-18 | 1981-04-29 | Squibb & Sons Inc | Aminoacyl derivatives of mercaptoacyl amino acids |
| US4234489A (en) * | 1979-06-25 | 1980-11-18 | E. R. Squibb & Sons, Inc. | Pyroglutamic acid derivatives and analogs |
| JPS5629403U (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) * | 1979-08-13 | 1981-03-20 | ||
| DE2937779A1 (de) * | 1979-09-19 | 1981-04-09 | Hoechst Ag, 6000 Frankfurt | Aminosaeurederivate und verfahren zu ihrer herstellung |
| GB2066240A (en) * | 1979-12-10 | 1981-07-08 | Squibb & Sons Inc | Derivatives of mercaptoacyl amino acids |
| GB2065643B (en) * | 1979-12-13 | 1983-08-24 | Kanegafuchi Chemical Ind | Optically active n-mercaptoalkanoylamino acids |
| JPS5683483A (en) * | 1979-12-13 | 1981-07-08 | Santen Pharmaceut Co Ltd | Thiazolidine compound |
| US4692458A (en) * | 1980-03-05 | 1987-09-08 | University Of Miami | Anti-hypertensive agents |
| GB2070586A (en) * | 1980-03-21 | 1981-09-09 | Squibb & Sons Inc | Derivatives of Proline or Pipecolic Acid |
| DE3011239A1 (de) * | 1980-03-22 | 1981-10-01 | C.H. Boehringer Sohn, 6507 Ingelheim | Substituierte alkylthioacylaminosaeuren, verfahren zu ihrer herstellung und pharmazeutische zusammensetzungen |
| SE8203245L (sv) * | 1981-05-27 | 1982-11-28 | Crc Ricerca Chim | Forfarande for enantioselektiv framstellning av n-substituerade prolinderivat |
| KR860001391B1 (ko) * | 1984-07-23 | 1986-09-22 | 보령제약 주식회사 | 피롤리딘 유도체의 제조방법 |
| JPH06740B2 (ja) * | 1984-08-16 | 1994-01-05 | 三菱レイヨン株式会社 | 光学活性カルボン酸アミドの製造法 |
| HU196369B (en) * | 1984-10-18 | 1988-11-28 | Egyt Gyogyszervegyeszeti Gyar | New process for producing n-acylized l-prolin derivatives |
| KR870001570B1 (ko) * | 1984-12-19 | 1987-09-04 | 보령제약 주식회사 | 피롤리딘 유도체의 제조방법 |
| KR870001569B1 (ko) * | 1985-02-11 | 1987-09-04 | 보령제약 주식회사 | 피롤리딘 유도체의 제조방법 |
| JP2863534B2 (ja) * | 1988-10-24 | 1999-03-03 | マリオン ラボラトリーズ，インコーポレイティド | 医薬組成物 |
| US5026873A (en) * | 1989-11-06 | 1991-06-25 | E. R. Squibb & Sons, Inc. | Process for direct isolation of captopril |
| ATE150960T1 (de) * | 1992-08-26 | 1997-04-15 | Beiersdorf Ag | Verwendung von radikalfängern als immunmodulierende agentien in kosmetischen und dermatologischen zubereitungen |
| DE4228455A1 (de) * | 1992-08-26 | 1994-09-15 | Beiersdorf Ag | Kosmetische und dermatologische Lichtschutzformulierungen mit einem Gehalt an Thiolen und/oder Thiolderivaten |
| US7056935B2 (en) | 1995-06-07 | 2006-06-06 | Gpi Nil Holdings, Inc. | Rotamase enzyme activity inhibitors |
| ATE224366T1 (de) | 1997-10-31 | 2002-10-15 | Hoffmann La Roche | D-prolinderivate |
| CN100361971C (zh) * | 2005-09-19 | 2008-01-16 | 华中师范大学 | 催化活性可调的双官能团l-脯氨酸衍生物及制备 |
| MX2011001887A (es) | 2008-08-22 | 2011-04-04 | Baxter Int | Derivados de bencil carbonato polimericos. |
| JP6189937B2 (ja) | 2012-04-27 | 2017-08-30 | ダウ アグロサイエンシィズ エルエルシー | 農薬組成物およびそれらに関する方法 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA946836A (en) * | 1970-03-18 | 1974-05-07 | Miguel A. Ondetti | Enzyme inhibitor |
-
1977
- 1977-01-14 AU AU21347/77A patent/AU509899B2/en not_active Expired
- 1977-01-19 NZ NZ183130A patent/NZ183130A/xx unknown
- 1977-01-20 IL IL51297A patent/IL51297A/xx unknown
- 1977-01-21 CA CA270,184A patent/CA1101864A/en not_active Expired
- 1977-01-27 PH PH19390A patent/PH12970A/en unknown
- 1977-01-31 DE DE2759862A patent/DE2759862C2/de not_active Expired
- 1977-01-31 DE DE2703828A patent/DE2703828C2/de not_active Expired
- 1977-02-08 YU YU331/77A patent/YU40664B/xx unknown
- 1977-02-08 GR GR52745A patent/GR69811B/el unknown
- 1977-02-09 RO RO7789327A patent/RO69941A/ro unknown
- 1977-02-10 ES ES455803A patent/ES455803A1/es not_active Expired
- 1977-02-10 FI FI770437A patent/FI66596C/fi not_active IP Right Cessation
- 1977-02-11 NO NO770464A patent/NO146985C/no unknown
- 1977-02-11 HU HU77SU939A patent/HU181965B/hu unknown
- 1977-02-11 SE SE7701561A patent/SE423812B/xx not_active IP Right Cessation
- 1977-02-11 BG BG062893A patent/BG37074A3/xx unknown
- 1977-02-11 DD DD77197339A patent/DD129442B3/de unknown
- 1977-02-11 DK DK059677A patent/DK157487C/da active
- 1977-02-11 CH CH170377A patent/CH622503A5/fr not_active IP Right Cessation
- 1977-02-11 IT IT48008/77A patent/IT1062293B/it active Protection Beyond IP Right Term
- 1977-02-11 BG BG035398A patent/BG37375A3/xx unknown
- 1977-02-11 AR AR266525A patent/AR222445A1/es active
- 1977-02-11 SU SU772450455A patent/SU747422A3/ru active
- 1977-02-11 IE IE305/77A patent/IE44707B1/en not_active IP Right Cessation
- 1977-02-11 NL NLAANVRAGE7701457,A patent/NL168509C/xx not_active IP Right Cessation
- 1977-02-11 BG BG062894A patent/BG37075A3/xx unknown
- 1977-02-12 JP JP52014542A patent/JPS604815B2/ja not_active Expired
- 1977-02-12 PL PL1977195965A patent/PL118161B1/pl not_active IP Right Cessation
- 1977-02-13 GB GB4088/77A patent/GB1576161A/en not_active Expired
- 1977-02-14 AT AT0098977A patent/AT365569B/de not_active IP Right Cessation
- 1977-02-14 FR FR7704122A patent/FR2340932A1/fr active Granted
- 1977-10-31 AR AR269793A patent/AR222783A1/es active
- 1977-10-31 AR AR269794A patent/AR214649A1/es active
-
1978
- 1978-02-16 ES ES467050A patent/ES467050A1/es not_active Expired
- 1978-02-16 ES ES467052A patent/ES467052A1/es not_active Expired
- 1978-02-16 ES ES467053A patent/ES467053A1/es not_active Expired
- 1978-05-16 ES ES467051A patent/ES467051A1/es not_active Expired
-
1979
- 1979-09-11 AR AR278014A patent/AR226290A1/es active
-
1980
- 1980-02-21 CH CH141080A patent/CH624932A5/fr not_active IP Right Cessation
- 1980-02-21 CH CH140980A patent/CH624931A5/fr not_active IP Right Cessation
-
1981
- 1981-05-14 HK HK202/81A patent/HK20281A/xx unknown
- 1981-06-18 KE KE3136A patent/KE3136A/xx unknown
- 1981-08-03 SE SE8104660A patent/SE426697B/sv not_active IP Right Cessation
-
1982
- 1982-12-30 MY MY75/82A patent/MY8200075A/xx unknown
-
1987
- 1987-09-30 MY MYPI87002538A patent/MY102705A/en unknown
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AT387381B (de) * | 1986-06-27 | 1989-01-10 | Egyt Gyogyszervegyeszeti Gyar | Verfahren zur herstellung von einem mercapto-acylprolin |
| US5438046A (en) * | 1993-07-30 | 1995-08-01 | Zambon Group S.P.A. | N-heteroaryl substituted derivatives of propanamide useful in the treatment of cardiovascular diseases |
| WO1998039311A1 (en) * | 1997-03-05 | 1998-09-11 | Smithkline Beecham P.L.C. | Antibacterial heterocyclic amino acid derivatives |
| WO2003014072A1 (en) * | 2001-08-07 | 2003-02-20 | Sunesis Pharmaceuticals, Inc. | Disulfide and thiosulfonate ligands and libraries comprising these ligands |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PS | Patent sealed [section 19, patents act 1949] | ||
| 704A | Declaration that licence is not available as of right for an excepted use (par. 4a/1977) | ||
| PE20 | Patent expired after termination of 20 years |
Effective date: 19970212 |