GB1588533A - Phenylamidine derivatives - Google Patents
Phenylamidine derivatives Download PDFInfo
- Publication number
- GB1588533A GB1588533A GB1670577A GB1670577A GB1588533A GB 1588533 A GB1588533 A GB 1588533A GB 1670577 A GB1670577 A GB 1670577A GB 1670577 A GB1670577 A GB 1670577A GB 1588533 A GB1588533 A GB 1588533A
- Authority
- GB
- United Kingdom
- Prior art keywords
- acid
- solution
- mol
- water
- acetamidoxime
- 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
- PXXJHWLDUBFPOL-UHFFFAOYSA-N benzamidine Chemical class NC(=N)C1=CC=CC=C1 PXXJHWLDUBFPOL-UHFFFAOYSA-N 0.000 title description 5
- 239000000203 mixture Substances 0.000 claims description 59
- 150000003839 salts Chemical class 0.000 claims description 37
- 239000002253 acid Substances 0.000 claims description 29
- 150000001875 compounds Chemical class 0.000 claims description 20
- 229910052751 metal Chemical class 0.000 claims description 12
- 239000002184 metal Chemical class 0.000 claims description 12
- OMFMMVLYEIZTRQ-UHFFFAOYSA-N 2-(1,3-benzodioxol-5-ylmethylsulfanyl)-n-hydroxyacetamide Chemical class ONC(=O)CSCC1=CC=C2OCOC2=C1 OMFMMVLYEIZTRQ-UHFFFAOYSA-N 0.000 claims description 4
- QLZROMPOFFWULC-UHFFFAOYSA-N 2-[(2,4-dichlorophenyl)methylsulfanyl]-n-hydroxyacetamide Chemical class ONC(=O)CSCC1=CC=C(Cl)C=C1Cl QLZROMPOFFWULC-UHFFFAOYSA-N 0.000 claims description 4
- PIALWHIVAGKZAU-UHFFFAOYSA-N 2-[(4-fluorophenyl)methylsulfanyl]-n-hydroxyacetamide Chemical class ONC(=O)CSCC1=CC=C(F)C=C1 PIALWHIVAGKZAU-UHFFFAOYSA-N 0.000 claims description 4
- CZMDRGOAMIMJGZ-UHFFFAOYSA-N 2-[(2,6-dichlorophenyl)methylsulfanyl]-n-hydroxyacetamide Chemical class ONC(=O)CSCC1=C(Cl)C=CC=C1Cl CZMDRGOAMIMJGZ-UHFFFAOYSA-N 0.000 claims description 3
- MCOUKYXHCHSNMZ-UHFFFAOYSA-N 2-[(3,4-dichlorophenyl)methylsulfanyl]-n-hydroxyacetamide Chemical class ONC(=O)CSCC1=CC=C(Cl)C(Cl)=C1 MCOUKYXHCHSNMZ-UHFFFAOYSA-N 0.000 claims description 3
- KSVGAOYXAVGYKM-UHFFFAOYSA-N 2-[(3,4-dimethoxyphenyl)methylsulfanyl]-n-hydroxyacetamide Chemical class COC1=CC=C(CSCC(=O)NO)C=C1OC KSVGAOYXAVGYKM-UHFFFAOYSA-N 0.000 claims description 3
- MEKGPEDADMMIIV-UHFFFAOYSA-N 2-[(4-chlorophenyl)methylsulfanyl]-n'-hydroxyethanimidamide Chemical compound ON=C(N)CSCC1=CC=C(Cl)C=C1 MEKGPEDADMMIIV-UHFFFAOYSA-N 0.000 claims description 3
- VMQYRAFVKGGXLW-UHFFFAOYSA-N 2-[(4-chlorophenyl)methylsulfanyl]-n-hydroxyacetamide Chemical class ONC(=O)CSCC1=CC=C(Cl)C=C1 VMQYRAFVKGGXLW-UHFFFAOYSA-N 0.000 claims description 3
- XOAWEAWYDGYKGF-UHFFFAOYSA-N 2-[(4-chlorophenyl)methylsulfanyl]-n-hydroxypropanamide Chemical class ONC(=O)C(C)SCC1=CC=C(Cl)C=C1 XOAWEAWYDGYKGF-UHFFFAOYSA-N 0.000 claims description 3
- QGVGBNFYWYDTML-UHFFFAOYSA-N n-hydroxy-2-[(4-methoxyphenyl)methylsulfanyl]acetamide Chemical class COC1=CC=C(CSCC(=O)NO)C=C1 QGVGBNFYWYDTML-UHFFFAOYSA-N 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 230000001225 therapeutic effect Effects 0.000 claims description 2
- AEXITZJSLGALNH-UHFFFAOYSA-N n'-hydroxyethanimidamide Chemical compound CC(N)=NO AEXITZJSLGALNH-UHFFFAOYSA-N 0.000 claims 5
- HHNVUWOWOZUSRD-UHFFFAOYSA-N 2-(2-chloroanilino)-n'-hydroxyethanimidamide Chemical compound ON=C(N)CNC1=CC=CC=C1Cl HHNVUWOWOZUSRD-UHFFFAOYSA-N 0.000 claims 1
- SMOUOEKXWXNCNI-UHFFFAOYSA-N 2-(2-fluoroanilino)-n'-hydroxyethanimidamide Chemical compound ON=C(N)CNC1=CC=CC=C1F SMOUOEKXWXNCNI-UHFFFAOYSA-N 0.000 claims 1
- WBGAPZNOQHLBMA-UHFFFAOYSA-N 2-(3-chloroanilino)-n'-hydroxyethanimidamide Chemical compound ON=C(N)CNC1=CC=CC(Cl)=C1 WBGAPZNOQHLBMA-UHFFFAOYSA-N 0.000 claims 1
- 150000003840 hydrochlorides Chemical class 0.000 claims 1
- OWQASBRJEWFGJI-UHFFFAOYSA-N n'-hydroxy-2-(2-methoxyanilino)ethanimidamide Chemical compound COC1=CC=CC=C1NCC(N)=NO OWQASBRJEWFGJI-UHFFFAOYSA-N 0.000 claims 1
- NEKADGNHNSREJM-UHFFFAOYSA-N n'-hydroxy-2-(3-methylanilino)ethanimidamide Chemical compound CC1=CC=CC(NCC(N)=NO)=C1 NEKADGNHNSREJM-UHFFFAOYSA-N 0.000 claims 1
- PUAXBGKZFYEXML-UHFFFAOYSA-N n'-hydroxy-2-(4-methoxyanilino)ethanimidamide Chemical compound COC1=CC=C(NCC(N)=NO)C=C1 PUAXBGKZFYEXML-UHFFFAOYSA-N 0.000 claims 1
- QJZCFCUXTLSKKG-UHFFFAOYSA-N n'-hydroxy-2-(4-methylanilino)ethanimidamide Chemical compound CC1=CC=C(NCC(N)=NO)C=C1 QJZCFCUXTLSKKG-UHFFFAOYSA-N 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 132
- 239000000243 solution Substances 0.000 description 85
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 72
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 56
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
- 238000002844 melting Methods 0.000 description 36
- 230000008018 melting Effects 0.000 description 36
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 34
- 238000010992 reflux Methods 0.000 description 32
- 239000000047 product Substances 0.000 description 28
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 27
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 18
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 238000000034 method Methods 0.000 description 15
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 239000003610 charcoal Substances 0.000 description 13
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 239000002585 base Substances 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 11
- 239000002244 precipitate Substances 0.000 description 11
- 239000000376 reactant Substances 0.000 description 10
- 101000822667 Mus musculus Something about silencing protein 10 Proteins 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 9
- 238000004809 thin layer chromatography Methods 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
- 238000001953 recrystallisation Methods 0.000 description 8
- 229910052708 sodium Inorganic materials 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- 239000007832 Na2SO4 Substances 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 7
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 7
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 7
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
- 235000019341 magnesium sulphate Nutrition 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 235000011152 sodium sulphate Nutrition 0.000 description 7
- 235000011149 sulphuric acid Nutrition 0.000 description 7
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 125000004429 atom Chemical group 0.000 description 6
- 229940106681 chloroacetic acid Drugs 0.000 description 6
- 238000000354 decomposition reaction Methods 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 5
- 238000009835 boiling Methods 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 239000000706 filtrate Substances 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
- 239000003208 petroleum Substances 0.000 description 5
- FTZQXOJYPFINKJ-UHFFFAOYSA-N 2-fluoroaniline Chemical compound NC1=CC=CC=C1F FTZQXOJYPFINKJ-UHFFFAOYSA-N 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 description 4
- 239000002249 anxiolytic agent Substances 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 230000003472 neutralizing effect Effects 0.000 description 4
- 150000002825 nitriles Chemical class 0.000 description 4
- RNVCVTLRINQCPJ-UHFFFAOYSA-N o-toluidine Chemical compound CC1=CC=CC=C1N RNVCVTLRINQCPJ-UHFFFAOYSA-N 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- FDRCDNZGSXJAFP-UHFFFAOYSA-M sodium chloroacetate Chemical compound [Na+].[O-]C(=O)CCl FDRCDNZGSXJAFP-UHFFFAOYSA-M 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- GKQXPTHQTXCXEV-UHFFFAOYSA-N (4-chlorophenyl)methanethiol Chemical compound SCC1=CC=C(Cl)C=C1 GKQXPTHQTXCXEV-UHFFFAOYSA-N 0.000 description 3
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 229960001171 acetohydroxamic acid Drugs 0.000 description 3
- 229940008309 acetone / ethanol Drugs 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- SFZULDYEOVSIKM-UHFFFAOYSA-N chembl321317 Chemical compound C1=CC(C(=N)NO)=CC=C1C1=CC=C(C=2C=CC(=CC=2)C(=N)NO)O1 SFZULDYEOVSIKM-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000001077 hypotensive effect Effects 0.000 description 3
- PUXCOIVOISEYNC-UHFFFAOYSA-N n-hydroxy-2-[(4-nitrophenyl)methylsulfanyl]acetamide Chemical compound ONC(=O)CSCC1=CC=C([N+]([O-])=O)C=C1 PUXCOIVOISEYNC-UHFFFAOYSA-N 0.000 description 3
- 235000015320 potassium carbonate Nutrition 0.000 description 3
- 235000011181 potassium carbonates Nutrition 0.000 description 3
- 239000001117 sulphuric acid Substances 0.000 description 3
- YDENRXHJQSFQKP-UHFFFAOYSA-N 2-(4-methylanilino)acetonitrile Chemical compound CC1=CC=C(NCC#N)C=C1 YDENRXHJQSFQKP-UHFFFAOYSA-N 0.000 description 2
- UOCOWKGCPPCUMT-UHFFFAOYSA-N 2-chloro-n-(3,4-dichlorophenyl)acetamide Chemical compound ClCC(=O)NC1=CC=C(Cl)C(Cl)=C1 UOCOWKGCPPCUMT-UHFFFAOYSA-N 0.000 description 2
- HXXDPDIVNQZPCJ-UHFFFAOYSA-N 2-cyano-n-(3,4-dichlorophenyl)acetamide Chemical compound ClC1=CC=C(NC(=O)CC#N)C=C1Cl HXXDPDIVNQZPCJ-UHFFFAOYSA-N 0.000 description 2
- SDYWXFYBZPNOFX-UHFFFAOYSA-N 3,4-dichloroaniline Chemical compound NC1=CC=C(Cl)C(Cl)=C1 SDYWXFYBZPNOFX-UHFFFAOYSA-N 0.000 description 2
- ZGDVNILDUDTOLK-UHFFFAOYSA-N 3-(1,3-benzodioxol-5-yl)propanethioic s-acid Chemical compound SC(=O)CCC1=CC=C2OCOC2=C1 ZGDVNILDUDTOLK-UHFFFAOYSA-N 0.000 description 2
- UMAVEYDSGJOXTL-UHFFFAOYSA-N 3-(3,4-dichlorophenyl)propanethioic s-acid Chemical compound OC(=S)CCC1=CC=C(Cl)C(Cl)=C1 UMAVEYDSGJOXTL-UHFFFAOYSA-N 0.000 description 2
- ZZTUATIFMOAZCO-UHFFFAOYSA-N 3-(3,4-dimethoxyphenyl)propanethioic s-acid Chemical compound COC1=CC=C(CCC(S)=O)C=C1OC ZZTUATIFMOAZCO-UHFFFAOYSA-N 0.000 description 2
- XZWUVSUZOJFASL-UHFFFAOYSA-N 3-(4-fluorophenyl)propanethioic s-acid Chemical compound OC(=S)CCC1=CC=C(F)C=C1 XZWUVSUZOJFASL-UHFFFAOYSA-N 0.000 description 2
- XZHNPZMSWKUCIS-UHFFFAOYSA-N 3-(4-methoxyphenyl)propanethioic s-acid Chemical compound COC1=CC=C(CCC(O)=S)C=C1 XZHNPZMSWKUCIS-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FOWQOZBUORSJOB-UHFFFAOYSA-N acetonitrile;benzenesulfonic acid Chemical compound CC#N.OS(=O)(=O)C1=CC=CC=C1 FOWQOZBUORSJOB-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 239000012259 ether extract Substances 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- SOZGVMJZDNRJJE-UHFFFAOYSA-N methyl 2-[(4-chlorophenyl)methylsulfanyl]acetate Chemical compound COC(=O)CSCC1=CC=C(Cl)C=C1 SOZGVMJZDNRJJE-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- -1 methyl methoxy Chemical group 0.000 description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 2
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 2
- 230000003387 muscular Effects 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- ROHOWTLWKMJQNW-UHFFFAOYSA-N o-ethyl 3-(1,3-benzodioxol-5-yl)propanethioate Chemical compound CCOC(=S)CCC1=CC=C2OCOC2=C1 ROHOWTLWKMJQNW-UHFFFAOYSA-N 0.000 description 2
- XGVQABOIEDRNOS-UHFFFAOYSA-N o-ethyl 3-(2,4-dichlorophenyl)propanethioate Chemical compound CCOC(=S)CCC1=CC=C(Cl)C=C1Cl XGVQABOIEDRNOS-UHFFFAOYSA-N 0.000 description 2
- KCDXOXYPUXYEGO-UHFFFAOYSA-N o-ethyl 3-(4-fluorophenyl)propanethioate Chemical compound CCOC(=S)CCC1=CC=C(F)C=C1 KCDXOXYPUXYEGO-UHFFFAOYSA-N 0.000 description 2
- PCMBATXMSZCXPY-UHFFFAOYSA-N o-ethyl 3-(4-methoxyphenyl)propanethioate Chemical compound CCOC(=S)CCC1=CC=C(OC)C=C1 PCMBATXMSZCXPY-UHFFFAOYSA-N 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 2
- 239000000932 sedative agent Substances 0.000 description 2
- 229940125723 sedative agent Drugs 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- YZIFVWOCPGPNHB-UHFFFAOYSA-N 1,2-dichloro-4-(chloromethyl)benzene Chemical compound ClCC1=CC=C(Cl)C(Cl)=C1 YZIFVWOCPGPNHB-UHFFFAOYSA-N 0.000 description 1
- IZXWCDITFDNEBY-UHFFFAOYSA-N 1-(chloromethyl)-4-fluorobenzene Chemical compound FC1=CC=C(CCl)C=C1 IZXWCDITFDNEBY-UHFFFAOYSA-N 0.000 description 1
- IRSVDHPYXFLLDS-UHFFFAOYSA-N 2,4-dichloro-1-(chloromethyl)benzene Chemical compound ClCC1=CC=C(Cl)C=C1Cl IRSVDHPYXFLLDS-UHFFFAOYSA-N 0.000 description 1
- FUONYYFGRFQZPV-UHFFFAOYSA-N 2-(2,6-dimethylanilino)-n'-hydroxyethanimidamide;hydrochloride Chemical compound Cl.CC1=CC=CC(C)=C1NCC(N)=NO FUONYYFGRFQZPV-UHFFFAOYSA-N 0.000 description 1
- DGQXLXYAIMZQIC-UHFFFAOYSA-N 2-(2,6-dimethylanilino)acetonitrile Chemical compound CC1=CC=CC(C)=C1NCC#N DGQXLXYAIMZQIC-UHFFFAOYSA-N 0.000 description 1
- OFQVKYXHBFZSHE-UHFFFAOYSA-N 2-(2-bromoanilino)-n'-hydroxyethanimidamide;hydrochloride Chemical compound Cl.ON=C(N)CNC1=CC=CC=C1Br OFQVKYXHBFZSHE-UHFFFAOYSA-N 0.000 description 1
- DFZYZTKCCMEFGL-UHFFFAOYSA-N 2-(2-chloroanilino)-n'-hydroxyethanimidamide;hydrochloride Chemical compound Cl.ON=C(N)CNC1=CC=CC=C1Cl DFZYZTKCCMEFGL-UHFFFAOYSA-N 0.000 description 1
- UHCZDOGEXCLMFX-UHFFFAOYSA-N 2-(2-fluoroanilino)-n'-hydroxyethanimidamide;hydrochloride Chemical compound Cl.ON=C(N)CNC1=CC=CC=C1F UHCZDOGEXCLMFX-UHFFFAOYSA-N 0.000 description 1
- LSZMBTSIYMRWCM-UHFFFAOYSA-N 2-(3-chloroanilino)-n'-hydroxyethanimidamide;dihydrochloride Chemical compound Cl.Cl.ON=C(N)CNC1=CC=CC(Cl)=C1 LSZMBTSIYMRWCM-UHFFFAOYSA-N 0.000 description 1
- HVYJECHTYLIIRZ-UHFFFAOYSA-N 2-(3-chloroanilino)-n'-hydroxyethanimidamide;hydrochloride Chemical compound Cl.ON=C(N)CNC1=CC=CC(Cl)=C1 HVYJECHTYLIIRZ-UHFFFAOYSA-N 0.000 description 1
- MOQXGUQHBPOHDN-UHFFFAOYSA-N 2-(3-methylanilino)acetonitrile Chemical compound CC1=CC=CC(NCC#N)=C1 MOQXGUQHBPOHDN-UHFFFAOYSA-N 0.000 description 1
- VXHFMYHGOAWUHY-UHFFFAOYSA-N 2-(4-fluoroanilino)-n'-hydroxyethanimidamide;hydrochloride Chemical compound Cl.ON=C(N)CNC1=CC=C(F)C=C1 VXHFMYHGOAWUHY-UHFFFAOYSA-N 0.000 description 1
- JMUXEZCHNRYQJU-UHFFFAOYSA-N 2-[(4-chlorophenyl)methylsulfanyl]acetonitrile Chemical compound ClC1=CC=C(CSCC#N)C=C1 JMUXEZCHNRYQJU-UHFFFAOYSA-N 0.000 description 1
- AOPBDRUWRLBSDB-UHFFFAOYSA-N 2-bromoaniline Chemical compound NC1=CC=CC=C1Br AOPBDRUWRLBSDB-UHFFFAOYSA-N 0.000 description 1
- AKCRQHGQIJBRMN-UHFFFAOYSA-N 2-chloroaniline Chemical compound NC1=CC=CC=C1Cl AKCRQHGQIJBRMN-UHFFFAOYSA-N 0.000 description 1
- DAINKWFIXCZUPS-UHFFFAOYSA-N 3-(2,4-dichlorophenyl)propanethioic s-acid Chemical compound OC(=S)CCC1=CC=C(Cl)C=C1Cl DAINKWFIXCZUPS-UHFFFAOYSA-N 0.000 description 1
- PVBHRZGZGRPZTE-UHFFFAOYSA-N 3-(2,6-dichlorophenyl)propanethioic s-acid Chemical compound SC(=O)CCC1=C(Cl)C=CC=C1Cl PVBHRZGZGRPZTE-UHFFFAOYSA-N 0.000 description 1
- PNPCRKVUWYDDST-UHFFFAOYSA-N 3-chloroaniline Chemical compound NC1=CC=CC(Cl)=C1 PNPCRKVUWYDDST-UHFFFAOYSA-N 0.000 description 1
- WWHJLVMBXXXUFO-UHFFFAOYSA-N 4-(chloromethyl)-1,2-dimethoxybenzene Chemical compound COC1=CC=C(CCl)C=C1OC WWHJLVMBXXXUFO-UHFFFAOYSA-N 0.000 description 1
- MSHFRERJPWKJFX-UHFFFAOYSA-N 4-Methoxybenzyl alcohol Chemical compound COC1=CC=C(CO)C=C1 MSHFRERJPWKJFX-UHFFFAOYSA-N 0.000 description 1
- KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 description 1
- VOLRSQPSJGXRNJ-UHFFFAOYSA-N 4-nitrobenzyl bromide Chemical compound [O-][N+](=O)C1=CC=C(CBr)C=C1 VOLRSQPSJGXRNJ-UHFFFAOYSA-N 0.000 description 1
- PVFOHMXILQEIHX-UHFFFAOYSA-N 8-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-9-[2-(2-bromophenyl)ethyl]purin-6-amine Chemical compound C=1C=2OCOC=2C=C(Br)C=1SC1=NC=2C(N)=NC=NC=2N1CCC1=CC=CC=C1Br PVFOHMXILQEIHX-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- RENMDAKOXSCIGH-UHFFFAOYSA-N Chloroacetonitrile Chemical compound ClCC#N RENMDAKOXSCIGH-UHFFFAOYSA-N 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 229910017974 NH40H Inorganic materials 0.000 description 1
- BHUIUXNAPJIDOG-UHFFFAOYSA-N Piperonol Chemical compound OCC1=CC=C2OCOC2=C1 BHUIUXNAPJIDOG-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000004872 arterial blood pressure Effects 0.000 description 1
- NGYOVXUBIWJNIU-UHFFFAOYSA-N benzenesulfonate;phenylazanium Chemical compound NC1=CC=CC=C1.OS(=O)(=O)C1=CC=CC=C1 NGYOVXUBIWJNIU-UHFFFAOYSA-N 0.000 description 1
- PSFPMRTWGSYQAS-UHFFFAOYSA-N benzenesulfonic acid;2-fluoroaniline Chemical compound NC1=CC=CC=C1F.OS(=O)(=O)C1=CC=CC=C1 PSFPMRTWGSYQAS-UHFFFAOYSA-N 0.000 description 1
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- HJQRTTGFHOTIED-UHFFFAOYSA-N ethyl 2-[(4-chlorophenyl)methylsulfanyl]propanoate Chemical compound CCOC(=O)C(C)SCC1=CC=C(Cl)C=C1 HJQRTTGFHOTIED-UHFFFAOYSA-N 0.000 description 1
- PVBRSNZAOAJRKO-UHFFFAOYSA-N ethyl 2-sulfanylacetate Chemical compound CCOC(=O)CS PVBRSNZAOAJRKO-UHFFFAOYSA-N 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- QABLOFMHHSOFRJ-UHFFFAOYSA-N methyl 2-chloroacetate Chemical compound COC(=O)CCl QABLOFMHHSOFRJ-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- FXBRUNRVBDXCRX-UHFFFAOYSA-N n'-hydroxy-2-(2-methoxyanilino)ethanimidamide;dihydrochloride Chemical compound Cl.Cl.COC1=CC=CC=C1NCC(N)=NO FXBRUNRVBDXCRX-UHFFFAOYSA-N 0.000 description 1
- TYYYBVYTIRJDKG-UHFFFAOYSA-N n'-hydroxy-2-(2-methylanilino)ethanimidamide;hydrochloride Chemical compound Cl.CC1=CC=CC=C1NCC(N)=NO TYYYBVYTIRJDKG-UHFFFAOYSA-N 0.000 description 1
- OBROXBFARCISNL-UHFFFAOYSA-N n'-hydroxy-2-(3-methylanilino)ethanimidamide;dihydrochloride Chemical compound Cl.Cl.CC1=CC=CC(NCC(N)=NO)=C1 OBROXBFARCISNL-UHFFFAOYSA-N 0.000 description 1
- BBVQRWOLGWHCMX-UHFFFAOYSA-N n'-hydroxy-2-(4-methoxyanilino)ethanimidamide;dihydrochloride Chemical compound Cl.Cl.COC1=CC=C(NCC(N)=NO)C=C1 BBVQRWOLGWHCMX-UHFFFAOYSA-N 0.000 description 1
- IIZVHLFIELBQNB-UHFFFAOYSA-N n'-hydroxy-2-(4-methylanilino)ethanimidamide;dihydrochloride Chemical compound Cl.Cl.CC1=CC=C(NCC(N)=NO)C=C1 IIZVHLFIELBQNB-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- VMPITZXILSNTON-UHFFFAOYSA-N o-anisidine Chemical compound COC1=CC=CC=C1N VMPITZXILSNTON-UHFFFAOYSA-N 0.000 description 1
- BTYXNDDIYKDMEW-UHFFFAOYSA-N o-ethyl 3-(2,6-dichlorophenyl)propanethioate Chemical compound CCOC(=S)CCC1=C(Cl)C=CC=C1Cl BTYXNDDIYKDMEW-UHFFFAOYSA-N 0.000 description 1
- MUUSHDMUMPIVCA-UHFFFAOYSA-N o-ethyl 3-(4-nitrophenyl)propanethioate Chemical compound CCOC(=S)CCC1=CC=C([N+]([O-])=O)C=C1 MUUSHDMUMPIVCA-UHFFFAOYSA-N 0.000 description 1
- QYAILKUHZPHTDU-UHFFFAOYSA-N o-methyl 3-(3,4-dimethoxyphenyl)propanethioate Chemical compound COC(=S)CCC1=CC=C(OC)C(OC)=C1 QYAILKUHZPHTDU-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two 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
- C07D233/72—Two oxygen atoms, e.g. hydantoin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
- C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two 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
- C07D233/72—Two oxygen atoms, e.g. hydantoin
- C07D233/74—Two oxygen atoms, e.g. hydantoin with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to other ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two 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
- C07D233/72—Two oxygen atoms, e.g. hydantoin
- C07D233/76—Two oxygen atoms, e.g. hydantoin with substituted hydrocarbon radicals attached to the third ring carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/16—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
- C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
- C07D279/18—[b, e]-condensed with two six-membered rings
- C07D279/22—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/56—Radicals substituted by sulfur atoms
Description
(54) PHENYLAMIDINE DERIVATIVES
(71) We, LABORATOIRE L. LAFON, a French Body Corporate of 1,
Rue Georges Mederic, 94700 Maisons-Alfort, France, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- The present invention relates to new phenylamidine derivatives which are useful in therapy.
The main Patent, No. 1,538,097, describes and claims 15 compounds in free base form and their addition salts, which compounds are useful, for example, in therapy. They fall within the general class of substituted phenylamidines of the general formula:
in which:
A represents a -CR2-, -CHOR-, -CH2S-, -CH2NH-, -OCR2-, -NH-, -NHCOCH2-, -CH2NHCH2-, or -NHCH2- group,
X, represents chlorine or fluorine atom or a methyl methoxy or ethoxy group,
X2 represents a hydrogen or chlorine atom, or a methyl, methoxy or ethoxy group and,
Z represents a 2-pyrimidinyl group or a group
(where R1 represents H, R2 represents OH or CH2CO2C2Hs, or Rl and R2, considered together, form a -CR2CR2- or -N=N- group), and their addition salts.
According to the invention, there are now proposed, as new products which are useful in therapy, 24 compounds in free base form and their acid addition salts.
These compounds fall within the general class of compounds having the formula
in which:
Ar represents an a-naphthyl group, an unsubstituted phenyl group or a phenyl group substituted by one or two methyl, methoxy methylenedioxy, bromine, chlorine, fluorine or nitro groups, and either
A represents a -CR2-S- group, B represents a single bond or a methylene (-CR2-) group and Y is an oxygen atom, or
A represents an -NHCR2- or -NHCOCR2- group (reading the formula from left to right), B represents a single bond and Y represents an NH group; and their salts.
The term "salts" is herein understood to mean,
(i) addition salts of inorganic or organic acids when Y is NH, and
(II) metal salts, when Y is O.
The compounds according to the invention are the compounds of formula (I) above in which Ar, A, B and Y have the combinations of meanings set out in Table
I below and the salts of these compounds. (The salts are, of course not limited to those mentioned in Table I). The corresponding names of the compounds of the invention are set out in claims 1 to 24 hereof.
TABLE I
Try Code No. Ar A a Ô Melting point I (a) CRL 40514 H3 NHCH2 single bond NH tD r((Y rCI J V) U) a2u, M O ar re 2 (a) i 40527 NHCH2 single bond NH i Br 3 CRL 40531 NHCH2 single bond NH a:840c i (a) CRL 40522 i NHCOL single bond NH x C1 4 E m CRL 4o41o CH2S CH2 NH e N ES g i i i i tz . fs es H o u un u u} < X 4 o < < o g 4 4 - a a c) g P P g Z 4 H N < e TABLE I (continuation 1)
4 : .1 C > o o o Oh O O U PO O o o o H Code No. Ar A H H Melting Point - --- b Sco o Oi00 I 1 m tc ú iB 8 Cl U 9 CR1. 40475A a-naphthyl CH2S CH2 0 129-1300c 10 m 405llA CH2S CH2 e fS fS N fS xU 8 x xU B Q f At Q t f X H TABLE I (continuation 2)
o tr o Oo\ ego Code No. Ar A ri Y Melting IP( ci o o o P) cu cu h) CY CR1. 40516A CN2S CH2 0 l240C m a m m 14 CRL 40539A N CH2S CH2 N llS-1190c < Q fu SuSH Q u u zN z X H vo o 8 s < o q e H N w 2 H H. H TABLE I (continuation 3)
o p b cu h, o rcC o ore I a, rcO c ce > O O IP (Y 2 127-2B0C 3E 16 CR1. B CR30 t te Z j we 30 3 3 U d @ t TABLE I (continuation 4)
I Loo Code No. o o o o Melting point Cf ru O 0 r( Q) m l7(a) CRL 40492 H; NHCH2 single bond NH l840C(b) > CRL 40427 NHCH2 single bond NH 1340C 19(d) CRL 40457 C3 NHCH2 single bond NH 1720c g CRL 40477 X NHCH2 single bond g 1500C E C C C E 0 0 0 0 0 9 P A 9 > CRL 40478 NHCH2 single bond NH 1700C C L: C C C m io a m m N ES fS : N E x i i < mUm Ct 9 A WN F b rs O 08 UN b b Z q st w w w e 0q q q 0 q0 P 6 6 g X 6 e F O H X ~I ~ ~4 N 61 TABLE I (continuation 5)
I E Code No. Ar A B y Melting point 22(d) CRL 40482 CH3O NHCH2 single bond NH 1540C 23(d) CRL 40483 H3 NHCH2 single bond NH 136'C to 40487 o NHCH2 single bond to 170C cb) m n n @ @ @ > b b rl d Ul Ul 0a CS N < f mM HOb oX U N b Z q w Ú S S e g e Z X N a3 Notes (a) hydrochloride (b) with decomposition (c) the corresponding hydrochloride melts at 174 - 176 C with decomposition (d) dihydrochloride The compounds of the present invention can be prepared by a method which is in itself known. The recommended methods are those described in the main Patent.
Thus, derivatives of the "hydroxamic acid" type (Y=O) can be prepared according to the method I which is shown schematically by the reaction
(where Ar, A and B are defined as above, and Zl represents Cl, Br, CH3O, C2HsO, n-C3H70 or i-C3R7O).
Derivatives of the "amidoxime" type (Y=NH) can be prepared according to method II or method III which consist, respectively, of reacting a cyano derivative or an iminoalkyl ether derivative with hydroxylamine, according to the reactions
(where Alk represents a C1-C4-alkyl group and Ar, A and B are defined as above).
In general terms the hydroxamic acids and amidoximes of the invention can be prepared according to the reaction
where Z represents COZ1, CN or C(=NH)O-Alk.
The compounds II can be prepared according to a method which is in itself known, for example according to either of methods A and B described in the main
Patent.
The compounds of the formula I and their non-toxic salts are useful in therapy.
They act on the central nervous system as sedatives, anxiolytic agents and muscular relaxants. In addition, certain of the compounds exhibit a hypotensive effect.
According to the invention, therapeutic compositions are recommended which contain at least one compound of the invention in association with a physiologically acceptable excipient.
Other advantages and characteristics of the invention will be better understood on reading the preparation Examples which are described below by way of illustration.
EXAMPLE 1 2-(2-Methyl-anilino)-acetamidoxime hydrochloride
Code No.: CRL 40,514
This product is obtained with a yield of 27% according to the following reaction mechanism
Melting point 1620C (with decoinposition)
Measure % Cl-: 16.93%
Theoretical % Cl-: 16.47%
The purity is controlled by thin layer chromatography [eluant:benzene:acetone:NH4OH (30:70:2 v/v); plate:silica gel ("Merck" F 254); development:U.V.+Draggendorf reagent]; "Merck" is a Registered Trade Mark.
EXAMPLE 2
2-(4-Fluoro-anilino)-acetamidoxime hydrochloride
Code No.: CRL 40,527
On proceeding as indicated in Example 1, but replacing the 2-methyl-aniline by 4-fluoro-aniline, the stated product is obtained with a yield of l6Vc.
Melting point: 155-1600C (with decomposition)
Measured Vo Cl-: 16.61%
Theoretical % C-: 16.17%
The purity is controlled by thin layer chromatography, as indicated in Example 1.
EXAMPLE 3 2-(2-Bromo-anilino)-acetamidoxime hydrochloride
Code No.: CRL 40,531
On proceeding as indicated in Example 1, but replacing the 2-methyl-aniline by 2-bromo-aniline, the stated product is obtained with a yield of 13%.
Melting point: 1840C
Measured % Cl-: 12.47%
Theoretical % Cl-: 12.65%
The purity is controlled by thin layer chromatography, as indicated in Example 1.
EXAMPLE 4 2-(3 ,4-Dichloro-anilido)-acetamidoxime hydrochloride
Code No.: CRL 40,522 1) N-Chloroacetyl-3 ,4-dichloraniline
81 g (0.5 mol) of 3,4-dichloroaniline are dissolved 500 ml of acetone. 85 g (0.75 mol) of chloroacetyl chloride are poured in, over a period of 17 minutes, with stirring. The mixture is heated under reflux for 15 minutes, cooled and 350 ml of a 30% strength potassium carbonate solution in water (pH=8) are poured in. This solution is poured into a 2,000 ml Erlenmeyer flask and 500 ml of H2O+ice are added. The precipitate which appears is filtered off, washed with water, dried and recrystallised from benzene. 102 g (yield 85%) of N - chloroacetyl - 3,4 dichloroaniline are thus obtained.
2) N-cyanoacetyl-3,4-dichloroaniline
14.5 g (0.223 mol) of potassium cyanide are dissolved in 122 ml of H2O. 48.50 g (0.203 mol) of the above product, dissolved in 357 ml of 95% strength ethanol, are added (dropwise over a period of 1 hour). The mixture is left stirring, at ambient temperature (15--250C). overnight. The matter which is insoluble in the reaction mixture is filtered off and washed with water and with chloroform. The nitrile which is thus obtained (weight 22.2 g; yield 48%) is used in this state for the continuation of the synthesis.
The purity of the N - cyanoacetyl - 3,4 - dichloroaniline can be controlled by thin layer chromatography [eluant:benzene:ethanol (9:1 v/v); plate:silica gel (Merck F 254); U.V. development].
3) CRL 40,522
A solution of 0.3 mol of hydroxylamine base in methanol is mixed with a solution of 22.2 g (0.096 mol) of the above nitrile in methanol. The reaction mixture is left at ambient temperature overnight. The medium is rendered acid with concentrated hydrochloric acid and 200 ml of H2O are added. The methanol is evaporated off in vacuo. The residual aqueous phase is filtered and neutralised with
K2CO3 to an alkaline pH. The neutralised aqueous phase is extracted with ether and the ether solution washed with water and dried over MgSO4 in the presence of charcoal (3SA). The ether solution is filtered and the hydrochloride is precipitated by means of a solution of hydrogen chloride in ethanol. 5 g of CRL 40,522 are thus obtained.
Melting point: 195"C (with decomposition)
Yield: 17%
Measured % Cl-: 11.41 Theoretical % C1-: 11.89%.
The purity can be controlled, as indicated in Example I, by thin layer chromatography.
EXAMPLE 5
2-(4-Chlorobenzylmercapto)-acetamidoxime
Code No.
1) 4-Chlorobenzylmercapto-acetonitrile
13 ml (15.9 g; 0.1 mol) of 4-chlorobenzylmercaptan and a solution of 4.2 g (0.105 mol) of NaOH in 50 ml of water are mixed whilst cold. Thereafter the mixture is heated to about 60"C and then 7.5 ml (about 1.2 mols) of chloroacetonitrile are added dropwise at this temperature. At the end of this addition (the temperature is then about 80"C) the mixture is heated under reflux (100"C) for 30 to 45 minutes. After cooling, the oil which has formed is extracted with ether and the aqueous phase is discarded. The ether solution is washed with dilute NaOH and then with water until the wash waters have a neutral pH. The ether phase is dried over MgSO4 which is filtered off before the ether is evaporated.
19.7 g of the stated product are collected (yield about 100%, relative to the starting 4-chlorobenzylmercaptan); it is in the form of an oil.
2) 2-(4-Chlorobenzylmercaptan)-acetamidoxime hydrochloride
The above product (about 0.1 mol) is taken up in 100 ml of n-butanol and the solution is mixed, whilst cold, with an aqueous solution (50 ml) of 0.2 mol (14 g) of hydroxylamine. The whole is heated at the reflux temperature of the nbutanol/water mixture, with vigorous stirring, for from 2 hours 30 minutes to 3 hours. Thereafter the butanol/water mixture is evaporated and the residue is taken up in water; the base (4-chlorobenzylmercaptoacetamidoxime) crystallises; the mixture is allowed to stand for several hours at 5--100C and then the base is filtered off and dried. 19.6 g of the said base (instantaneous melting point 76"C; yield 85%) are thus collected. The hydrochloride is prepared by dissolving the base in ether and adding a solution of hydrogen chloride in ethanol. After filtration and drying in vacuo, 21 g of the expected product are collected.
Instantaneous melting point: 174--176"C (with decomposition)
Yield: 78.5%.
EXAMPLE 6
2-(4-Chlorobenzylmercapto)-acetohydroxamic acid
Code No.: CRL
1) Anhydrous acetone (100 ml), potassium carbonate (21 g), pchlorobenzylmercaptan (19.5 ml), methyl chloroacetate (13.2 ml) and potassium iodide (0.1 g) are mixed whilst cold. The mixture which is thus obtained is stirred and heated under reflux for 7 hours. It is then cooled, the precipitate (K2CO3) is filtered off, the acetone is evaporated from the filtrate and the residue is taken up in ether. The ether solution is washed with 4N NaOH and then with water until the wash waters have a neutral pH. It is then dried over MgSO4, the ether is evaporated off and 34.5 g (yield 100%) of methyl 2 - (4 - chlorobenzylmercapto) - acetate are collected in the form of a chromatographically pure oil.
2) A solution of 0.15 mol of methyl 2 - (4 - chlorobenzylmercapto) - acetate in 50 ml of methanol is mixed with a solution of 0.225 mol of hydroxylamine (base) and 0.15 mol of NaOCH3 in 150 ml of methanol.
The resulting mixture is kept overnight at ambient temperature (15-250C), the methanol is evaporated off and the residue is taken up in water and acidified with 3N HCI in order to precipitate 2- (4- chlorobenzylmercapto) acetohydroxamic acid. 31.7 g of the said acid are collected.
Yield 91%: melting point about 1300C.
EXAMPLE 7
2-(3,4-Dichlorobenzylmercapto)acetohydroxamic acid
Code No.: CRL 1) 3,4-Dichlorobenzylthio-acetic acid
A mixture of 19.5 (0.1 mol) of 3,4-dichlorobenzylchloride and 7.6 g (0.1 mol) of thiourea in 50 ml of water is heated under reflux for 30 minutes, with stirring, and then, at 6(w700C, a solution of 16 g (0.4 mol) of NaOH in 25 ml of water is run in; the mixture is heated under reflux for 15 minutes and a solution of 15 g (0.15 mol) of chloroacetic acid, 7 g of sodium carbonate and 50 ml of water are run in at 60- 70"C, and the reaction mixture is maintained under reflux for I hour. The mixture is acidified, whilst cold, with concentrated HCI, and is extracted with ether, and the ether extract washed with water, dried and evaporated. The residue is taken up in petroleum ether and the product filtered off. 21 g (yield 83) of the stated product are obtained. Melting point 63--640C.
2) 2-(3,4-Dichlorobenzylmercapto)-acetohydroxamic acid
20.2 g (0.08 mol) of 3,4-dichlorobenzylthioacetic acid are esterified with 10 ml of methanol, 0.6 ml of concentrated H2SO4 and 100 ml of dichloroethane. The mixture is heated under reflux for 4 hours, washed with water and with dilute bicarbonate and dried. The solvent is evaporated in vacuo. The oily residue is treated in methanol with a solution of hydroxylamine (0.1 mol) in the presence of 0.18 mol of sodium methylate. After leaving the reactants in contact overnight, the mixture is evaporated to dryness in vacuo, the residue is taken up in water, the solution is filtered over charcoal and the product is precipitated with 3N HC1, the mixture is extracted with ether, the ether extract is dried, the ether is evaporated and the residue is crystallised from diisopropyl ether. 15 g (yield 71%) of the stated product are obtained; melting point: 75-760C EXAMPLE 8
2-(4-Chlorobenzylmercapto)-propionohydroxamic acid
Code No.: CRL 1) Ethyl 2-(4-chlorobenzylthio)-propionate
A mixture of 19.5 ml (0.15 mol) of 4-chlorobenzylmercaptan, 27.1 g (0.15 mol) of ethyl a-bromopropionate, 21 g of potassium carbonate and 0.1 g of potassium iodide in 100 ml of anhydrous acetone is maintained under reflux for 6 hours. The mixture is filtered, the precipitate is washed with acetone and the filtrate is evaporated in vacuo. 200 ml of ether are added to the residue and the ether solution is washed with dilute NaOH, dilute HCI and water. It is then dried and evaporated in vacuo.
2) 2-(4-Chlorobenzylmercapto)-propionohydroxamic acid
10.5 g (0.15 mol) of hydroxylamine hydrochloride are treated with a solution of sodium methylate prepared with 5.75 g (0.25 gram atom) of sodium in 200 ml of methanol. The sodium chloride is filtered off and 25.85 g (0.1 mol) of ethyl 2-(pchlorobenzylthio)-propionate are added to the filtrate. After leaving the reactants in contact overnight, the mixture is evaporated in vacuo, the residue is taken up with 200 ml of water, the solution is filtered and the product precipitated with 3N
HCI, filtered off, washed with water and dried; 20.2 g (yield; 82%) of the stated hydroxamic acid are obtained. Melting point: 104--1050C.
EXAMPLE 9 a-Naphthylmethylenemercapto-acetohydroxamic acid
Code No.: CRL
1) a-Naphthylmethylene-thioacetic acid
A solution of 15.2 g (0.2 mol) of thiourea in 100 ml of water is introduced into a 1 litre three-necked flask equipped with a magnetic stirrer, a condenser and a dropping funnel, and 35.3 g (0.2 mol) of a-chloromethyl-naphthalene are added, all at once, at 50--600C. The reaction mixture is heated to the reflux temperature and boiling is maintained for a quarter of an hour. The thiouronium salt precipitates.
Thereafter the mixture is cooled and a solution of 32 g of sodium hydroxide (0.8 mol) in 50 ml of water is added dropwise at about 60"C. The resulting mixture is heated under reflux until the solution becomes limpid, and is cooled and a solution of about 0.28 mol of sodium chloroacetate (obtained by neutralising 26.36 g of chloroacetic. acid in 200 ml of water with 23.52 g of sodium bicarbonate) is added dropwise at 60--700C. The whole is then heated under reflux for half an hour, cooled and acidified cold by the addition of 3N HCI. s4-Naphthylmethylene- thioacetic acid thus precipitates, and is filtered off. 44.5 g of product are collected.
(Yield: 95%). Instantaneous melting point: 102--1030C.
2) Ethyl a-naphthylmethylene-thioacetate
19.72 g (0.085 mol) of the above product are dissolved in 160 ml of 1,2dichloroethane and 16 ml of anhydrous ethanol and 1.6 ml of concentrated sulphuric acid are added. The mixture is heated under reflux for at least 2 hours and cooled, the organic phase is decanted and the water formed discarded. The organic phase is washed with a dilute solution of sodium hydroxide and then with water. It is then dried over MgSO4 and the solvent is evaporated. 19.8 g of ethyl a- naphthylmethylene-thioacetate [overall yield: 890/,] are thus obtained, this product being in the form of a limpid orange-coloured oil.
3) a-Naphthylmethylenemercapto-acetohydroxamic acid
The ester obtained above (0.076 mol), diluted with 50 ml of methanol, is added to a solution of hydroxylamine, prepared from 7.92 g (0.114 mol) of hydroxylamine hydrochloride in 190 ml of methanol and 4.37 g (0.19 gram atom) of sodium in 190 ml of anhydrous methanol. After leaving the reactants in contact overnight at 20"C, the methanol is evaporated, the residue is taken up in water (alkaline medium), the mixture is filtered over charcoal and acidified by adding 3N HCI, and a - naphthylmethylene - thio - acetohydroxamic acid is thus precipitated; it is filtered off, washed with water and then with ether, and dried, 11.2 g (0.0453 mol) of the product (overall yield: 59%) are collected after recrystallisation from ethyl acetate. Instantaneous melting point: 129--1300C.
EXAMPLE 10
2-(4-Fluorobenzylmercapto)-acetohydroxamic acid
Code No.: CRL
1) p-Fluorobenzylthioacetic acid
A solution of 15.2 g (0.2 mol) of thiourea in 100 ml of water is introduced into a
1 litre three-necked flask equipped with a magnetic stirrer, a condenser and a
dropping funnel, and 28.9 g (0.2 mol) of p-fluorobenzyl chloride are added all at
once, at 5600C. The mixture is heated to reflux temperature, boiling is
maintained for about 15 minutes and the solution becomes limpid. Thereafter the
solution is cooled and a solution of 32 g (0.8 mol) of NaOH in water is added
dropwise at about 60"C. The whole is heated under reflux for about 30 minutes, the
mixture is cooled and a solution of about 0.28 mol of sodium chloroacetate
(obtained by neutralising 26.46 g of chloroacetic acid in 200 ml of water with 23.52
g of sodium bicarbonate) is added drdpwise at 60--700C. Thereafter the whole is
heated under reflux for 30 minutes and then cooled. The mixture is acidified with 3H HC1 and the oil which is obtained is taken up in methylene chloride, this mixture
is washed with a dilute sodium bicarbonate solution, filtered over charcoal and
acidified once more with 3N HCI; p-fluorobenzylthioacetic acid is thus
precipitated, and is filtered off. After recrystallising from cyclohexane, 33.4 g
(yield: 83%) of the said acid are collected. Instantaneous melting point: 68--69"C.
2) Ethyl p-fluorobenzylthioacetate
17 g (0.085 mol) of the acid obtained above are dissolved in 160 ml of 1,2 dichloroethane and 16 ml of anhydrous methanol and 1.6 ml of concentrated
H2SO4 are added. The whole is heated under reflux for about 6 hours and then cooled, the organic phase is decanted and the water which forms is discarded, and the organic phase is washed with a dilute sodium bicarbonate solution and then with water. The solution is then dried over Na2SO4 and the solvent evaporated. 17.4 g of a yellow oil are thus collected; this is ethyl p-fluorobenzylthioacetate (overall yield: 89).
3) 2-(4-Fluorobenzylmercapto)-acetohydroxamic acid
The ester obtained above (0.0763 mol) is added to a solution of hydroxylamine prepared from 7.92 g (0.114 mol) of hydroxylamine hydrochloride in 190 ml of methanol and 4.37 g of sodium in 190 ml of anhydrous methanol. After leaving the reactants in contact overnight at ambient temperature, the methanol is evaporated, the residue is taken up in water, the solution is filtered over charcoal and acidified with 3N HCI and 2 -(4 - fluorobenzylmercapto) - acetohydroxamic acid is thus precipitated; it is filtered off and washed with water. 11.2 g (yield: 680/,) of the said acid are collected. Instantaneous melting point: 115--1160C.
EXAMPLE 11
2-(4-Methoxybenzylmercapto)-acetohydroxamic acid
Code No.: CRL 1) p-Methoxybenzylthio-acetic acid
A solution of 18.24 g (0.24 mol) of thiourea in 104 ml of 48% strength hydrobromic acid and 20 ml of water is introduced into a 1 litre three-necked flask equipped with a magnetic stirrer and a condenser. The mixture is heated at 600C and 27.6 g (0.2 mol) of p-methoxybenzyl alcohol are introduced. The temperature is raised to 950C and the mixture is allowed to cool. Crystals of the thiouronium salt appear; these are filtered off and dried. The precipitate obtained above is introduced into a 500 ml three-necked flask with 60 ml of NaOH. The mixture is heated to 700C and a solution of 15.6 g (0.164 mol) of chloroacetic acid dissolved in 30 ml of water is added dropwise. Thereafter the whole is heated under reflux for half an hour and then cooled. The mixture is acidified with 3N HCI, the oil obtained is taken up in methylene chloride, and the mixture is washed with a dilute sodium bicarbonate solution, filtered over charcoal, and acidified once more with 3N HCI in order to precipitate p-methoxybenzylthio-acetic acid. 25.7 g (yield 60%) of the said acid are collected (melting point 600 C).
2) Ethyl p-methoxybenzylthio-acetate
24 g (0.112 mol) of the acid obtained above are dissolved in 210 ml of 1,2dichloroethane and 22 ml of anhydrous ethanol and 2.2 ml of concentrated sulphuric acid are added. The whole is heated under reflux for about 6 hours, cooled, the organic phase is decanted and the water which forms discarded, and the organic phase is washed with a dilute bicarbonate solution and then with water.
The solution is then dried over Na2SO4 and the solvent evaporated. 26.5 g of a limpid yellow oil are thus collected; this is ethyl p-methoxybenzylthio-acetate (overall yield: 96%).
3) 2-(4-Methoxybenzylmercapto)-acetohydroxamic acid
The above product (0.110 mol), diluted in 50 ml of methanol, is added to a solution of hydroxylamine prepared from 11.63 g (0.165 mol) of hydroxylamine hydrochloride in 275 ml of methanol and 6.32 g of sodium in 275 ml of anhydrous methanol. After leaving the reactants in contact overnight at ambient temperature,
EXAMPLE 12 2-(2,4-Dichlorobenzylmercapto)-acetohydroxamic acid
Code No.: CRL
1) 2,4-Dichlorobenzylthio-acetic acid
15.2 g (0.2 mol) of thiourea in 100 ml of water are introduced into a 1 litre three-necked flask. The mixture is heated at 50--600C and 39.1 g (0.2 mol) of 2,4
dichlorobenzyl chloride are added all at once. The mixture is heated to reflux and boiling is maintained for 15 minutes; the solution becomes limpid. It is then cooled and a solution of 32 g (0.8 mol) of NaOH in 50 ml of water is added dropwise at about 60"C. The mixture is again heated under reflux for 30 minutes, cooled and a solution of about 0.28 mol of sodium chloroacetate (obtained by neutralising 26.46 g of chloroacetic acid in 200 ml of water with 23.52 g of NaHCO3) is added dropwise at 60--700C. Thereafter the whole is heated under reflux for 30 minutes, cooled, filtered and acidified with 3N HCI; the precipitate obtained is filtered off and redissolved whilst cold in dilute bicarbonate solution, and this solution is washed with methylene chloride, filtered and acidified once more. 41.7 g (yield 83%) of the product are thus collected. Instantaneous melting point 72--73"C.
2) Ethyl 2,4-dichlorobenzylthio-acetate
37.65 g (0.15 mol) of the above acid are dissolved in 283 ml of 1,2dichloroethane and 28.5 ml of anhydrous ethanol and 2.9 ml of concentrated H2SO4 are added. The whole is heated under reflux for 6 hours and then cooled, the organic phase is decanted and the water which forms discarded, and the organic phase is washed with a dilute bicarbonate solution and then with water. Thereafter the solution is dried over Na2SO4 and the solvent evaporated. 43.6 g of a yellow oil are thus collected: this is ethyl 2,4 - dichlorobenzylthio - acetate (overall yield: 90%).
3) 2-(2,4-Dichlorobenzylmercapto)-acetohydroxamic acid
The above ester (0.156 mol) is added to a solution of hydroxylamine prepared from 16.38 g (0.235 mol) of hydroxylamine hydrochloride in 300 ml of methanol and 9 g (0.391 gram atom) of sodium in 300 ml of anhydrous methanol. After leaving the reactants in contact overnight at ambient temperature, the methanol is evaporated, the residue is taken up in water, and the solution is filtered over charcoal and acidified with 3N HCI in order to precipitate 2 - (2,4 - dichlorobenzylmercapto) acetohydroxamic acid, which is filtered off and washed with water. 28 g (yield: 67%) of the said acid are collected. Instantaneous melting point: 116"C.
EXAMPLE 13
2-(2,6-Dichlorobenzylmercapto)-acetohydroxamic acid
Code No.: CRL
On carrying out the process as indicated in Example 12, but replacing the 2,4 (Cl2)C6H3CH2CI with 2,6-(CI2)C6H3CH2CI, there are obtained successively:
1) 2,6 - dichlorobenzylthio - acetic acid (yield 83; instantaneous melting point: 81-820C), 2) ethyl 2,6 - dichlorobenzylthio - acetate (yield 89%)which is in the form of a yellow oil, and
3) 2 - (2,6 - dichlorobenzylmercapto) - acetohydroxamic acid (yield 71; instantaneous melting point: 124 C).
EXAMPLE 14 2-(4-Nitrobenzylmercapto)-acetohydroxamic acid
Code No.: CRL
1) Ethyl 4-nitrobenzylthioacetate
43.2 g (0.2 mol) of p-nitrobenzyl bromide, 200 ml of acetone, 0.2 g of potassium iodide, 24 ml of ethyl thioglycollate (that is to say a slight excess) and 27.6 g (0.2 mol) of potassium carbonate are introduced successively into a 1 litre three-necked flask. The mixture is heated under reflux for about 4 hours until the complete disappearance of the bromo derivative; the acetone is evaporated, the oil obtained is taken up in ether and in water, the ether phase is washed with a dilute NaOH solution, so as to eliminate the excess thiol, and then with a dilute HCI solution, and is dried over Na2SO4, and the solvent is evaporated. 49 g (yield: g5%) of the stated product are obtained, which is in the form of an orange-coloured oil.
2) 2-(4-Nitrobenzylmercapto)-acetohydroxamic acid
The above ester (0.156 mol), diluted in 50 ml of methanol, is added to a solution of hydroxylamine prepared from 16.38 g (0.235 mol) of hydroxylamine hydrochloride in 300 ml of methanol and 9 g (0.391 gram atom) of sodium in 300 ml of anhydrous methanol. The reactants are left in contact overnight at ambient temperature, the sodium chloride formed is filtered off, the reaction mixture is acidified immediately, the solvent is evaporated, and the precipitate obtained is taken up in water and filtered off. After recrystallisation from isopropyl alcohol, 27 g of 2- (4 - nitrobenzylmercapto) - acetohydroxamic acid are obtained.
Instantaneous melting point: 118--1190C; yield: 72%.
EXAMPLE 15 2-(3 ,4-Methylenedioxybenzylmercapto)-acetohydroxamic acid
Code No.: CRL
1) 3,4-Methylenedioxybenzylthio-acetic acid
A solution of 18.24 g (0.24 mol) of thiourea in 104 ml of 48 strength hydrobromic acid and 20 ml of water is introduced into a one litre three-necked flask equipped with a magnetic stirrer and a condenser. The mixture is heated to 60"C and 30.4 g (0.2 mol) of piperonyl alcohol are introduced. The temperature is raised to 95"C and the mixture is left to cool. Crystals of the thiouronium salt
appear; these are filtered off and dried. The precipitate thus obtained is introduced
into a 500 ml three-necked flask with 60 ml of sodium hydroxide solution. The
mixture is heated to 700C and 15.6 g (0.164 mol) of chloroacetic acid in 30 ml of water are added dropwise. Thereafter the whole is heated under reflux for half an
hour and then cooled. The mixture is acidified with 3N HC1, the precipitate
obtained is redissolved in a dilute bicarbonate solution, and the solution is washed with methylene chloride, filtered over charcoal and acidified once more with 3N
HCI in order to precipitate 3,4-methylenedioxybenzylthio-acetic acid, which is
filtered off. After recrystallisation from a diisopropyl ether/petroleum ether
mixture (1:1 v/v), 18.2 g (yield 40%) of the said acid are collected (instantaneous
melting point: 87"C).
2) Ethyl 3,4-methylenedioxybenzylthio-acetate
18.08 g (0.08 mol) of the above acid are dissolved in 160 ml of 1,2
dichloroethane and 16 ml of anhydrous ethanol and 1.6 ml of concentrated H2SO4
are added. The whole is heated under reflux for about 6 hours, cooled, the organic phase decanted and the water which forms discarded, and the organic phase is washed with a dilute bicarbonate solution and then with water. Thereafter the solution is dried over Na2SO4 and the solvent evaporated. 21 g of an orangecoloured oil are obtained: this is ethyl 3,4-methylenedioxybenzylthio-acetate (yield: 96%).
3) 2-(3 ,4-Methylenedioxybenzylmercapto)-acetohydroxamic acid
The above product (0.085 mol) is added to a solution of hydroxylamine prepared from 8.76 g (0.126 mol) of hydroxylamine hydrochloride in 210 ml of methanol and 4.83 g (0.21 gram atom) of sodium in 210 ml of anhydrous methanol.
The reactants are left in contact overnight at ambient temperature, the methanol is evaporated, the residue is taken up in water, the solution is filtered over charcoal and acidified with 3N HC1, and the precipitate obtained is filtered off and washed with water. 14.5 g (yield: 70%) of 2 - (3,4 - methylenedioxybenzylmercapto) acetohydroxamic acid are obtained. Instantaneous melting point: 127--128"C, (yield: 70%).
EXAMPLE 16 2-(3,4-Dimethoxybenzylmercapto)-acetohydroxamic acid
Code No.: CRL 1) 3,4-Dimethoxybenzylthio-acetic acid
13.07 g (0.172 mol) of thiourea and 86 ml of water are charged into a 1 litre three-necked flask equipped with a magnetic stirrer and a condenser. The mixture is heated to 50--600C and 32 g (0.172 mol) of 3,4-dimethoxybenzyl chloride are added all at once. The mixture is heated under reflux and boiling is maintained for 15 minutes; the solution becomes limpid. Thereafter the solution is cooled and a solution of 27.52 g (0.688 mol) of NaOH in 43 ml of water is added dropwise at about 60"C. The mixture is again heated under reflux for 30 minutes, cooled and a solution of sodium chloroacetate (obtained by neutralising 22.76 g of chloroacetic acid in 172 ml of water with 20.23 g of NaRCO3) is added dropwise at 60---700C.
Thereafter the whole is heated under reflux for 30 minutes, cooled and filtered and the filtrate then acidified with 3N HCI. After recrystallisation from toluene, 28.7 g of 3,4 - dimethoxybenzylthio - acetic acid are obtained. Yield: 69%. Instantaneous melting point: 94"C.
2) Methyl 3,4-dimethoxybenzylthio-acetate
24.2 g (0.1 mol) of the above acid are dissolved in 200 ml of anhydrous methanol and 4 ml of concentrated sulphuric acid are added. The whole is heated under reflux for about 3 hours, the methanol is evaporated and the oil which is obtained is taken up in ether, the organic phase is washed with a dilute sodium bicarbonate solution and then with water and dried over Na2SO4, and the solvent evaporated. 24.2 g (yield: 94%) of the stated product, which is in the form of an orange-coloured oil, are thus collected.
3) 2-(3,4-Dimethoxybenzylmercapto)-acetohydroxamic acid
The above product (0.0945 mol) is added to a solution of hydroxylamine prepared from 9.95 g (0.143 mol) of hydroxylamine hydrochloride in 200 ml of
methanol and from 5.45 g (0.237 gram atom) of sodium in 200 ml of anhydrous methanol. The reactants are left in contact overnight at ambient temperature, the mixture is filtered, the methanol is evaporated, the residue is taken up in water, the
solution is filtered over charcoal and acidified with 3N HCI, the oil obtained is taken up in methylene chloride, the solution is dried over Na2SO4, the solvent is
evaporated and the residue is taken up in ethyl acetate. After filtration and washing with ether, 16.9 g (yield 70%) of the stated product are obtained. Instantaneous
melting point: 780C.
EXAMPLE 17 2-(2,6-Dimethyl-anilino)-acetamidoxime hydrochloride
Code No.: CRL 40,492
1) Benzenesulfphonate-acetonitrile (C5H5SO3-CH2CN) 104 g (1.6 mols) of potassium cyanide are dissolved in 100 ml of water. 160 g (1.6 mols) of a 30% strength formaldehyde solution are introduced at between 5 and 10"C. The mixture is stirred for 30 minutes. 212 g (1.2 mols) of benzenesulphonyl chloride are introduced dropwise at a temperature of between 10 and 20"C. The mixture is stirred at this temperature for 6 hours. The product is extracted with benzene. The benzene is washed with water. The benzene phase is decanted.
Traces of water are removed by distilling the C6H6. H2O azeotrope. The benzene is evaporated to dryness and the residue is distilled in vacuo.
Weight: 158.5 g
Yield: 67%
Melting point: 32--34"C Density: 1.3089 NDO 1.5252
Boiling point 5 mm HD: 165--170"C.
2) 2-(2,6-Dimethyl-anilino)-acetonitrile
A solution of 158.5 g (0.804 mol) of benzene-sulphonate-acetonitrile in 200 ml of ethyl acetate is run dropwise into a solution of 193.6 g (1.608 mols) of 2,6 zdimethyl-aniline in 400 ml of ethyl acetate. The mixture is heated under reflux for 3 hours, cooled and the excess aniline benzenesulphonate is filtered off. The filtrate is evaporated to dryness. The residue is taken up in ether. Insoluble material is again filtered off and discarded. The ether is evaporated to dryness. The residue is taken up in a mixture of petroleum ether/benzene (3:4 v/v). The crystals which form are filtered off.
Weight: 84.2 g.
Yield: 65%.
3) CRL 40,492
84.2 g (0.526 mol) of the above nitrile are dissolved in methanol and this solution is run into a solution of 2.4 mols of hydroxylamine base in methanol (this solution of hydroxylamine base having been obtained by running a solution of 129.6 g (2.4 mols) of sodium methylate in 500 ml of methanol into a solution of 166.8 g (2.4 mols) of hydroxylamine hydrochloride in 1 litre of methanol and filtering off the NaCI formed).
The mixture is stirred overnight at ambient temperature (15-250C). 300 ml of water are added to the reaction mixture and the methanol is evaporated. The pH of the residual aqueous phase is adjusted to 11 with K2CO3 and the alkaline phase is extracted with ethyl acetate. The ethyl acetate is washed with 3 times 200 ml of water. The solvent is dried over MgSO4 in the presence of 3 SA charcoal. The amidoxime hydrochloride is precipitated with 150 ml of a 7N hydrogen chloride solution in ethanol. The crystals are filtered off and recrystallised from an acetone/ethanol mixture in order to obtain CRL 40,492.
Weight: 32 g
Yield: 26.4%
Melting point: 1840C (with decomposition)
Measured % Cl-: 15.44%
Theoretical C1-: 15.46%.
The purity of CRL 40,492 is controlled by thin layer chromatography [eluant: C6H6/CH3COCH3/NH4OH (30:70:2 v/v); plate:silica gel (Merck F 254); development:U.V.+Draggendorf reagent].
EXAMPLE 18 2-(3-Chloro-anilino)-acetamidoxime hydrochloride
Code No.: CRL 40,427
The procedure followed is as indicated in Example 13 of the main application (synthesis of CRL 40,375), replacing the 3,4-dichloro-aniline with 3-chloro-aniline.
4.2 g (yield: 4.4%) of CRL 40,427 are obtained.
Melting point: 134"C.
Analysis shows that the product obtained according to this method contains traces of 2 - (3 - chloro - anilino) - acetamidoxime dihydrochloride, since the chlorine percentages are as follows:
Measured % Cl-=16.37%
Theoretical % C1-=15.04%.
EXAMPLE 19 2-(4-Methylanilino)-acetamidoxime dihydrochloride
Code No. CRL 40,457
0.105 Mol of 2 - (4 - methylanilino) - acetonitrile in solution in methanol are treated with a solution of hydroxylamine base in methanol prepared as indicated above. The reactants are left in contact overnight at ambient temperature. Thin layer chromatography [eluant:toluene/acetone/NH40H (30:70:2 v/v); plate:silica gel (Merck F 254); development:U.V.+Draggendorf reagent] makes it possible to demonstrate the disappearance of the nitrile and the appearance of the amidoxime.
100 ml of water are added to the reaction mixture and the methanol is evaporated. The base is extracted with ethyl acetate. The ethyl acetate is washed with water, dried over MgSO4 in the presence of 3 SA charcoal and filtered. The dihydrochloride is precipitated with a hydrogen chloride solution in ethanol. CRL 40,457 is obtained by recrystallisation from an acetone/ethanol mixture (1:1 v/v).
Weight: 5.65 g
Yield: 22%
Melting point: 172"C Measured% Cl-: 28.42%
Theoretical % Cl-: 28.17%.
EXAMPLE 20
2-(3-Methylanilino)-acetamidoxime dihydrochloride
Code No.: CRL 40,477
The procedure followed is as indicated in Example 19, replacing the 2 - (4 methylanilino) - acetonitrile with 0.105 mol of 2- (3 - methylanilino)acetonitrile. CRL 40,477 is obtained by recrystallisation from an ethyl acetate/ethanol mixture (the recrystallisation is aided by the addition of petroleum ether to the ethyl acetate/ethanol mixture).
Weight: 12 g
Yield: 15%
Melting point: 150 C
Measured % Cl-: 27.80 /,, Theoretical /" Cl-: 27.77%.
EXAMPLE 21
2-(2-Fluoroanilino)-acetamidoxime hydrochloride
Code No.: CRL 40,478
A solution of 59.1 g of benzenesulphonate-acetonitrile is run into a solution of 66.6 g (0.6 mol) of 2-fluoroaniline in 300 ml of ethyl acetate. The mixture is heated under reflux for 3 hours. The insoluble matter (2-fluoroaniline benzenesulphonate) is filtered off and the ethyl acetate is evaporated. The resulting residue is treated with a solution of 0.6 mol of hydroxylamine base in methanol, prepared as indicated above.
The mixture is allowed to stand overnight at ambient temperature (l5-250C).
100 ml of water are added and that methanol is evaporated. The aqueous phase is extracted with ethyl acetate. The solvent is washed with water, decanted, and is dried over MgSO4 in the presence of 3 SA charcoal. The insoluble matter is filtered off. The hydrochloride is precipitated with a solution of hydrogen chloride in ethanol. The crystals are recrystallised from an ethyl acetate/ethanol mixture using petroleum ether to facilitate the crystallisation. CRL 40,478 is thus obtained.
Weight: 5 g
Yield: 7.5%- Melting point: 170 C
Measured % Cl-: 16.54%
Theoretical C1-: 16.17%.
The purity can be checked by thin layer chromatography [eluant:toluene/acetone/NH4OH (30:70:2 v/v); plate:silica gel (Merck F 254); development:U.V.+Draggendorf reagent].
EXAMPLE 22
2-(4-Methoxyanilino)-acetamidoxime dihydrochloride
Code No.: CRL 40,482
The procedure is followed as indicated in Example 21, replacing the 2fluoroaniline with 0.2 mol of 4-methoxyaniline. CRL 40,482 is thus obtained.
Weight: 5 g
Yield: 20% Melting point: 154 C Measured % Cl-: 26.04%
Theoretical % Cl-: 26.49%.
The purity can be checked by thin layer chromatography [eluant:benzene/acetone/NH4OH (30:70:2 v/v); plate:silica gel (Merck F 254); development:U.V.+Draggendorf reagent].
EXAMPLE 23 2-(2-Methoxy-anilino)-acetamidoxime dihydrochloride
Code No.: CRL 40.483
The procedure followed is as indicated in Example 21, replacing the 2-fluoroaniline with 2-methoxy-aniline. 4.5 g (yield: 10%) of CRL 40,483 are obtained by recrystallisation from an acetone/ethanol mixture (1:1 v/v).
The purity can be checked as indicated in Example 22.
EXAMPLE 24
2-(2-Chloroanilino)-acetamidoxime hydrochloride
Code No.: CRL 40,487
The procedure followed is as indicated in Example 21, replacing the 2-fluoroaniline with 2-chloro-aniline. 5 g (yield: 10%) of CRL 40,487 are thus obtained.
The purity can be checked as indicated in Example 22.
The pharmacological tests which have been carried out with the compounds according to the invention have made it possible to show their action on the central nervous system. More precisely, the compounds of the invention are sedatives, anxiolytic agents and/or muscular relaxants. Moreover, CRL 40,522 (the product of
Example 4) exhibits, in addition to these actions on the central nervous system, a hypotensive effect at a dose of 50 mg/kg (administered orally in aqueous solution at a concentration of 5 g/l of CRL 40,522) in genetically hypertensive rats. The reduction in arterial pressure is about 17% and the hypotensive effect disappears 24 hours after administration of the product.
The compounds are thus indicated for treatment of neuropsychic ailments.
Claims (27)
1. 2-(2-Methylanilino) acetamidoxime and its acid addition salts.
2. 2-(4-Fluoroanilino) acetamidoxime and its acid addition salts.
3. 2-(2-Bromoanilino) acetamidoxime and its acid addition salts.
4. 2-(3,4-Dichloroanilino) acetamidoxime and its acid addition salts.
5. 2-(4-Chlorobenzylmercapto)acetamidoxime and its acid addition salts.
6. 2-(4-Chlorobenzylmercapto)acetohydroxamic acid and its metal salts.
7. 2-(3,4-Dichlorobenzylmercapto)acetohydroxamic acid and its metal salts.
8. 2-(4-Chlorobenzylmercapto)propionhydroxamic acid and its metal salts.
9. a-Naphthylmethylenemercaptoacetohydroxamic acid and its metal salts.
10. 2-(4-Fluorobenzylmercapto)acetohydroxamic acid and its metal salts.
11. 2-(4-Methoxybenzylmercapto)acetohydroxamic acid and its metal salts.
12. 2-(2,4-Dichlorobenzylmercapto)acetohydroxamic and its metal salts.
13. 2-(2,6-Dichlorobenzylmercapto)acetohydroxamic acid and its metal salts.
14. 2-(4-Nitrobenzylmercaptoacetohydroxamic acid and its metal salts.
15. 2-(3,4-Methylenedioxybenzylmercapto)acetohydroxamic acid and its metal salts.
16. 2-(3,4-Dimethoxybenzylmercapto)acetohydroxamic acid and its metal salts.
17. 2-(2,6-Dimethylanilo)acetamidoxime and its acid addition salts.
18. 2-(3-Chloroanilino)acetamidoxime and its acid addition salts.
19. 2-(4-Methylanilino)acetamidoxime and its acid addition salts.
20. 2-(3-Methylanilino)acetamidoxime and its acid addition salts.
21. 2-(2-Fluoroanilino)acetamidoxime and its acid addition salts.
22. 2-(4-Methoxyanilino)acetamidoxime and its acid addition salts.
23. 2-(2-Methoxyanilino)acetamidoxime and its adid addition salts.
24. 2-(2-Chloroanilino)acetamidoxime and its acid addition salts.
25. Compounds according to any one of claims 1, 2, 4, 5, 6, 17, 18, 21 and 24 in the form of hydrochlorides.
26. Compounds according to any one of claims 19, 20, 22 and 23 in the form of dihydrochlorides.
27. A therapeutic composition comprising a compound according to any one of claims I to 26 in association with a physiologically acceptable excipient.
Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB1670577A GB1588533A (en) | 1977-04-21 | 1977-04-21 | Phenylamidine derivatives |
CH118978A CH630606A5 (en) | 1977-02-15 | 1978-02-03 | Phenylamidine derivatives useful especially in therapeutics |
DE19782804576 DE2804576A1 (en) | 1977-02-15 | 1978-02-03 | PHENYLAMIDINE DERIVATIVES, PROCESS FOR THEIR PRODUCTION AND PHARMACEUTICAL COMPOSITIONS THEREOF |
ES466887A ES466887A2 (en) | 1977-01-24 | 1978-02-10 | A procedure for the preparation of a substitute phenylamidine. (Machine-translation by Google Translate, not legally binding) |
CA296,767A CA1133920A (en) | 1977-02-15 | 1978-02-10 | Phenylamidine derivatives |
FR7804019A FR2380256A2 (en) | 1976-01-26 | 1978-02-13 | Phenyl aceto-hydroxamic acids and amidoxime(s) - used as sedatives, anxiolytics, muscle relaxants and hypotensives |
BE185158A BE863947R (en) | 1977-02-15 | 1978-02-14 | SUBSTITUTED PHENYL-AMIDINES |
IT67297/78A IT1156441B (en) | 1977-02-15 | 1978-02-14 | PROCEDURE FOR THE PREPARATION OF FENYL AMMIDINE DERIVATIVES |
JP1639078A JPS53103430A (en) | 1977-02-15 | 1978-02-14 | Phenylamidine derivatives |
US06/107,609 US4325964A (en) | 1977-02-15 | 1979-12-27 | Phenylamidine derivatives |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB1670577A GB1588533A (en) | 1977-04-21 | 1977-04-21 | Phenylamidine derivatives |
Publications (1)
Publication Number | Publication Date |
---|---|
GB1588533A true GB1588533A (en) | 1981-04-23 |
Family
ID=10082185
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB1670577A Expired GB1588533A (en) | 1976-01-26 | 1977-04-21 | Phenylamidine derivatives |
Country Status (1)
Country | Link |
---|---|
GB (1) | GB1588533A (en) |
-
1977
- 1977-04-21 GB GB1670577A patent/GB1588533A/en not_active Expired
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
PS | Patent sealed | ||
746 | Register noted 'licences of right' (sect. 46/1977) |