SE434836B - thiazolidine - Google Patents
thiazolidineInfo
- Publication number
- SE434836B SE434836B SE7807335A SE7807335A SE434836B SE 434836 B SE434836 B SE 434836B SE 7807335 A SE7807335 A SE 7807335A SE 7807335 A SE7807335 A SE 7807335A SE 434836 B SE434836 B SE 434836B
- Authority
- SE
- Sweden
- Prior art keywords
- methylpropionyl
- compound according
- mercapto
- acid
- thiazolidinecarboxylic acid
- Prior art date
Links
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 38
- -1 Thiazolidine compound Chemical class 0.000 claims description 24
- 239000002253 acid Substances 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- ULSZVNJBVJWEJE-GSVOUGTGSA-N (2r)-1,3-thiazolidin-3-ium-2-carboxylate Chemical compound [O-]C(=O)[C@@H]1[NH2+]CCS1 ULSZVNJBVJWEJE-GSVOUGTGSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 claims description 3
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 3
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 229940030600 antihypertensive agent Drugs 0.000 claims description 3
- 239000002220 antihypertensive agent Substances 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 150000003548 thiazolidines Chemical class 0.000 claims description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- HNLLOXPIKATAAX-IQYSWEBNSA-N C(C)OC1=CC=C(C=C1)C1SC[C@H](N1C(C(CS)C)=O)C(=O)O Chemical group C(C)OC1=CC=C(C=C1)C1SC[C@H](N1C(C(CS)C)=O)C(=O)O HNLLOXPIKATAAX-IQYSWEBNSA-N 0.000 claims description 2
- CNECAFLAFVOZMC-JRIBOLAGSA-N ClC1=C(C(=CC=C1)Cl)C1SC[C@H](N1C(C(CS)C)=O)C(=O)O Chemical group ClC1=C(C(=CC=C1)Cl)C1SC[C@H](N1C(C(CS)C)=O)C(=O)O CNECAFLAFVOZMC-JRIBOLAGSA-N 0.000 claims description 2
- RWZDBICNMCHKKP-PEUVISTOSA-N SCC(C(=O)N1C(SC[C@H]1C(=O)O)C1=CC(=CC=C1)OC)C Chemical group SCC(C(=O)N1C(SC[C@H]1C(=O)O)C1=CC(=CC=C1)OC)C RWZDBICNMCHKKP-PEUVISTOSA-N 0.000 claims description 2
- NIWNDAOLYHKBFL-AXDSSHIGSA-N SCC(C(=O)N1[C@@H](CSC11CCCCC1)C(=O)O)C Chemical group SCC(C(=O)N1[C@@H](CSC11CCCCC1)C(=O)O)C NIWNDAOLYHKBFL-AXDSSHIGSA-N 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 4
- 125000001424 substituent group Chemical group 0.000 claims 4
- 125000003545 alkoxy group Chemical group 0.000 claims 2
- 125000002947 alkylene group Chemical group 0.000 claims 2
- 125000001589 carboacyl group Chemical group 0.000 claims 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 2
- 229910052736 halogen Inorganic materials 0.000 claims 2
- 150000002367 halogens Chemical class 0.000 claims 2
- 150000002431 hydrogen Chemical group 0.000 claims 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 2
- CVBOMOZXEDQERR-MEXZMNCTSA-N (4R)-3-(3-acetylsulfanyl-2-methylpropanoyl)-2-(3-nitrophenyl)-1,3-thiazolidine-4-carboxylic acid Chemical group C(C)(=O)SCC(C(=O)N1C(SC[C@H]1C(=O)O)C1=CC(=CC=C1)[N+](=O)[O-])C CVBOMOZXEDQERR-MEXZMNCTSA-N 0.000 claims 1
- URLRVICMGRSFRR-MEXZMNCTSA-N (4R)-3-(3-acetylsulfanyl-2-methylpropanoyl)-2-(4-fluorophenyl)-1,3-thiazolidine-4-carboxylic acid Chemical group C(C)(=O)SCC(C(=O)N1C(SC[C@H]1C(=O)O)C1=CC=C(C=C1)F)C URLRVICMGRSFRR-MEXZMNCTSA-N 0.000 claims 1
- HUZUUTLWSUNZGF-BHKPVTDMSA-N C(C)(=O)SCC(C(=O)N1C(SC[C@H]1C(=O)O)C1=CC=C(C=C1)OC)C Chemical group C(C)(=O)SCC(C(=O)N1C(SC[C@H]1C(=O)O)C1=CC=C(C=C1)OC)C HUZUUTLWSUNZGF-BHKPVTDMSA-N 0.000 claims 1
- BEECIOWPCYAOKN-SAVVLTDYSA-N CC(CS)C(N1C(C(C=C2)=CC=C2Br)SC[C@H]1C(O)=O)=O Chemical group CC(CS)C(N1C(C(C=C2)=CC=C2Br)SC[C@H]1C(O)=O)=O BEECIOWPCYAOKN-SAVVLTDYSA-N 0.000 claims 1
- DUVGBQUPPONYGY-MEXZMNCTSA-N CC(CSC(C)=O)C(N1C(C(C=C2)=CC=C2Br)SC[C@H]1C(O)=O)=O Chemical group CC(CSC(C)=O)C(N1C(C(C=C2)=CC=C2Br)SC[C@H]1C(O)=O)=O DUVGBQUPPONYGY-MEXZMNCTSA-N 0.000 claims 1
- QURDQNGZVWEDBK-UQACVICXSA-N COC=1C=C(C=CC1OC)C1SC[C@H](N1C(C(CS)C)=O)C(=O)O Chemical group COC=1C=C(C=CC1OC)C1SC[C@H](N1C(C(CS)C)=O)C(=O)O QURDQNGZVWEDBK-UQACVICXSA-N 0.000 claims 1
- APFXLUUSVFEUIV-ZQDGQSPWSA-N SCC(C(=O)N1C(SC[C@H]1C(=O)O)C1=C(C=CC=C1)OC)C Chemical group SCC(C(=O)N1C(SC[C@H]1C(=O)O)C1=C(C=CC=C1)OC)C APFXLUUSVFEUIV-ZQDGQSPWSA-N 0.000 claims 1
- ASRXWUZFFLMQAJ-SAVVLTDYSA-N SCC(C(=O)N1C(SC[C@H]1C(=O)O)C1=CC(=CC=C1)[N+](=O)[O-])C Chemical group SCC(C(=O)N1C(SC[C@H]1C(=O)O)C1=CC(=CC=C1)[N+](=O)[O-])C ASRXWUZFFLMQAJ-SAVVLTDYSA-N 0.000 claims 1
- BYHQPGLVHQUGQT-QDYJBQRPSA-N SCC(C(=O)N1C(SC[C@H]1C(=O)O)C1=CC=CC=C1)C Chemical group SCC(C(=O)N1C(SC[C@H]1C(=O)O)C1=CC=CC=C1)C BYHQPGLVHQUGQT-QDYJBQRPSA-N 0.000 claims 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000000034 method Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000001816 cooling Methods 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 206010020772 Hypertension Diseases 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000012442 inert solvent Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 230000001631 hypertensive effect Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 201000005857 malignant hypertension Diseases 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- OVSRBUIUCONCCD-KFJBMODSSA-N (3R)-4-(3-acetylsulfanyl-2-methylpropanoyl)-1-thia-4-azaspiro[4.5]decane-3-carboxylic acid Chemical compound C(C)(=O)SCC(C(=O)N1[C@@H](CSC11CCCCC1)C(=O)O)C OVSRBUIUCONCCD-KFJBMODSSA-N 0.000 description 1
- DQAJYPXRHVIJEC-PEUVISTOSA-N (4R)-2-(4-methoxyphenyl)-3-(2-methyl-3-sulfanylpropanoyl)-1,3-thiazolidine-4-carboxylic acid Chemical compound SCC(C(=O)N1C(SC[C@H]1C(=O)O)C1=CC=C(C=C1)OC)C DQAJYPXRHVIJEC-PEUVISTOSA-N 0.000 description 1
- CVBOMOZXEDQERR-XYWLETCASA-N (4R)-3-[(2S)-3-acetylsulfanyl-2-methylpropanoyl]-2-(3-nitrophenyl)-1,3-thiazolidine-4-carboxylic acid Chemical compound C(C)(=O)SC[C@H](C(=O)N1C(SC[C@H]1C(=O)O)C1=CC(=CC=C1)[N+](=O)[O-])C CVBOMOZXEDQERR-XYWLETCASA-N 0.000 description 1
- FJMBKXDYYWGXHM-KNVGNIICSA-N (4R)-3-[4-(ethylamino)-4-oxobutanethioyl]-2-(4-methylphenyl)-1,3-thiazolidine-4-carboxylic acid Chemical compound C(C)NC(=O)CCC(=S)N1C(SC[C@H]1C(=O)O)C1=CC=C(C=C1)C FJMBKXDYYWGXHM-KNVGNIICSA-N 0.000 description 1
- LESQASCTNMKKPZ-IENPIDJESA-N (4r)-2-(4-chlorophenyl)-1,3-thiazolidine-4-carboxylic acid Chemical compound N1[C@H](C(=O)O)CSC1C1=CC=C(Cl)C=C1 LESQASCTNMKKPZ-IENPIDJESA-N 0.000 description 1
- ZQRSXNJVEHLFCE-RGURZIINSA-N (4r)-2-(4-methoxyphenyl)-1,3-thiazolidine-4-carboxylic acid Chemical compound C1=CC(OC)=CC=C1C1SC[C@@H](C(O)=O)N1 ZQRSXNJVEHLFCE-RGURZIINSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 1
- VFVHNRJEYQGRGE-UHFFFAOYSA-N 3-acetylsulfanyl-2-methylpropanoic acid Chemical compound OC(=O)C(C)CSC(C)=O VFVHNRJEYQGRGE-UHFFFAOYSA-N 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 101800000734 Angiotensin-1 Proteins 0.000 description 1
- 102400000344 Angiotensin-1 Human genes 0.000 description 1
- BEECIOWPCYAOKN-HCTSQKMQSA-N BrC1=CC=C(C=C1)C1SC[C@H](N1C([C@@H](CS)C)=O)C(=O)O Chemical compound BrC1=CC=C(C=C1)C1SC[C@H](N1C([C@@H](CS)C)=O)C(=O)O BEECIOWPCYAOKN-HCTSQKMQSA-N 0.000 description 1
- 101800004538 Bradykinin Proteins 0.000 description 1
- 102400000967 Bradykinin Human genes 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- AMVIAPWSDPSLTO-MEXZMNCTSA-N C(C)(=O)SCC(C(=O)N1C(SC[C@H]1C(=O)O)C1=CC=C(C=C1)Cl)C Chemical compound C(C)(=O)SCC(C(=O)N1C(SC[C@H]1C(=O)O)C1=CC=C(C=C1)Cl)C AMVIAPWSDPSLTO-MEXZMNCTSA-N 0.000 description 1
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- VKCOGRQFLMEVLR-UHFFFAOYSA-N CCNCC.C1C=CNC1 Chemical compound CCNCC.C1C=CNC1 VKCOGRQFLMEVLR-UHFFFAOYSA-N 0.000 description 1
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- QXZGBUJJYSLZLT-UHFFFAOYSA-N H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH Natural products NC(N)=NCCCC(N)C(=O)N1CCCC1C(=O)N1C(C(=O)NCC(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CO)C(=O)N2C(CCC2)C(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CCCN=C(N)N)C(O)=O)CCC1 QXZGBUJJYSLZLT-UHFFFAOYSA-N 0.000 description 1
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- 235000019759 Maize starch Nutrition 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical class CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 description 1
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 1
- 208000001871 Tachycardia Diseases 0.000 description 1
- METKWVOCJQCWHY-UHFFFAOYSA-N [O-]C([S+]1CNCC1)=O Chemical compound [O-]C([S+]1CNCC1)=O METKWVOCJQCWHY-UHFFFAOYSA-N 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 125000005910 alkyl carbonate group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- ORWYRWWVDCYOMK-HBZPZAIKSA-N angiotensin I Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 ORWYRWWVDCYOMK-HBZPZAIKSA-N 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 229940124572 antihypotensive agent Drugs 0.000 description 1
- 150000001483 arginine derivatives Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- RRKTZKIUPZVBMF-IBTVXLQLSA-N brucine Chemical class O([C@@H]1[C@H]([C@H]2C3)[C@@H]4N(C(C1)=O)C=1C=C(C(=CC=11)OC)OC)CC=C2CN2[C@@H]3[C@]41CC2 RRKTZKIUPZVBMF-IBTVXLQLSA-N 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000009989 contractile response Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical class OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 150000002332 glycine derivatives Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000009931 harmful effect Effects 0.000 description 1
- 210000003405 ileum Anatomy 0.000 description 1
- 229910001502 inorganic halide Inorganic materials 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 150000002540 isothiocyanates Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 201000005856 malignant essential hypertension Diseases 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- XJINZNWPEQMMBV-UHFFFAOYSA-N n-methylhexan-1-amine Chemical class CCCCCCNC XJINZNWPEQMMBV-UHFFFAOYSA-N 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 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
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 150000003235 pyrrolidines Chemical class 0.000 description 1
- 206010038464 renal hypertension Diseases 0.000 description 1
- 230000036454 renin-angiotensin system Effects 0.000 description 1
- LUDPWTHDXSOXDX-SCSAIBSYSA-N s-[(2r)-3-chloro-2-methyl-3-oxopropyl] ethanethioate Chemical compound ClC(=O)[C@H](C)CSC(C)=O LUDPWTHDXSOXDX-SCSAIBSYSA-N 0.000 description 1
- LUDPWTHDXSOXDX-BYPYZUCNSA-N s-[(2s)-3-chloro-2-methyl-3-oxopropyl] ethanethioate Chemical compound ClC(=O)[C@@H](C)CSC(C)=O LUDPWTHDXSOXDX-BYPYZUCNSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229910052717 sulfur Chemical group 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 230000006794 tachycardia Effects 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D277/06—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Description
73437335-'0 ;yL_sd ' (11I)_ vari R2 och R3 har den angivna betydelsen. Det funktionella derivatet av karbonsyran med formeln (II) utgöres exempelvis av en syrahalid (såsom en.syraklorid eller en syrabromid), en syraanhydrid, en blandad syraanhydrid med ett alkylkarbo- nat eller en oorganisk halid (såsom tionylklorid, fosforoxi- klorid eller fosfortriklorid) eller en reaktionsbenägen ester (såsom p-nitrofenylester eller polyklorfenylester). Wherein R 2 and R 3 have the indicated meaning. The functional derivative of the carboxylic acid of formula (II) is, for example, an acid halide (such as an acid chloride or an acid bromide), an acid anhydride, a mixed acid anhydride with an alkyl carbonate or an inorganic halide (such as thionyl chloride, phosphorus oxychloride or phosphorus trichloride). or a reactive ester (such as p-nitrophenyl ester or polychlorophenyl ester).
Reaktionen utföres vanligen i närvaro av en syraacceptor, såsom trietylamin, dimetylanilin, pyridin, natriumvätekarbo- nat, natriumkarbonat eller kaliumkarbonat, i ett inert lös- ningsmedel, såsom vatten, metylenklorid, kloroform, etyleter, bensen, toluen, dioxan eller dimetylformamid, vid rumstempera- tur eller under upphettning eller kylning.The reaction is usually carried out in the presence of an acid acceptor such as triethylamine, dimethylaniline, pyridine, sodium bicarbonate, sodium carbonate or potassium carbonate, in an inert solvent such as water, methylene chloride, chloroform, ethyl ether, benzene, toluene, dioxamide or dimethylformamide turn or during heating or cooling.
Metod II: Denna metod, som tillämpas för framställning av föreningar med formeln (I), vari R är en väteatom, omfattar hydrolys av en förening med formeln (I), vari R har annan betydelse än väte.Method II: This method, which is applied to the preparation of compounds of formula (I), wherein R is a hydrogen atom, comprises hydrolysis of a compound of formula (I), wherein R has a meaning other than hydrogen.
Hydrolysen utföres vanligen i närvaro av en basisk substans, *såsom natriumhydroxid, kaliumhydroxid, natriumvätekarhonat, kaliumvätekarbonat, ammoniak eller hydrazin, eller i närvaro' av en mineralsyra, såsom saltsyra eller svavelsyra, i ett inert lösningsmedel, såsom vatten, metanol eller etanol, vid rumstemperatur, företrädesvis under en inert atmosfär.The hydrolysis is usually carried out in the presence of a basic substance, such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, ammonia or hydrazine, or in the presence of a mineral acid, such as hydrochloric acid or sulfuric acid, in an inert solvent such as water, methanol or ethanol. room temperature, preferably under an inert atmosphere.
Metod III = _ Denna metod, som tillämpas för framställning av föreningar med formeln (I), vari R betecknar en lägre alkanoylgrupp eller en lägre alkoxikarbonylgrupp, omfattar omsättning av en förening med formeln (I), vari R är en väteatom, dvs. en förening med formeln 7807335-Û 3 III). >Å_ 5 .I us-cflz-ca-co-N ! (ï'a) / coon . 1 2 ' i _ vari R , R och R3 har den angivna betydelsen, med en förening med formeln R - Hal (IV) vari R är en lägre alkanoylgrupp eller en lägre alkoxikarbonyl- grupp och Hal är en halogenatom (såsom Cl eller Br).Method III = This method, which is used for the preparation of compounds of formula (I), wherein R represents a lower alkanoyl group or a lower alkoxycarbonyl group, comprises reacting a compound of formula (I), wherein R is a hydrogen atom, i.e. a compound of the formula 7807335-Û 3 III). > Å_ 5 .I us-c fl z-ca-co-N! (ï'a) / coon. Wherein R, R and R 3 have the meaning given, with a compound of the formula R - Hal (IV) wherein R is a lower alkanoyl group or a lower alkoxycarbonyl group and Hal is a halogen atom (such as Cl or Br) .
Reaktionen utföres vanligen i närvaro av en basisk substans, såsom en sådan som nämnes i samband med metod I, i ett inert lösningsmedel, såsom ett sådant som nämnes i samband med metod I, vid rumstemperatur eller under upphettning eller kyl- ninq, företrädesvis i en inert atmosfär. , Metod IV: Denna metod, som tillämpas för framställning av föreningar med formeln (I), vari R är en lägre alkylkarbamoylgrupp eller en lägre alkyltiokarbamoylgrupp, omfattar omsättning av en förening med formeln (I-a) enligt ovan med ett isocyanat eller ett isotiocyanat med formeln R4 - N = C = X (V) vari R4 är en lägre alkylgrupp och X är en syreatom eller en .svavelatom.The reaction is usually carried out in the presence of a basic substance, such as that mentioned in connection with method I, in an inert solvent, such as that mentioned in connection with method I, at room temperature or under heating or cooling, preferably in a inert atmosphere. Method IV: This method, which is used for the preparation of compounds of formula (I), wherein R is a lower alkylcarbamoyl group or a lower alkylthiocarbamoyl group, comprises reacting a compound of formula (Ia) as above with an isocyanate or an isothiocyanate of formula R 4 - N = C = X (V) wherein R 4 is a lower alkyl group and X is an oxygen atom or a sulfur atom.
Omsättningen utföres vanligen 1 ett inert lösningsmedel, såsom metylenklorid, kloroform, bensen, toluen, dimetylformamid eller pyridin, vid rumstemperatur eller under upohettning eller kyl- ning, företrädesvis i en inert atmosfär; Föreningarna med formeln (I) kan överföras till metallsalterna, såsom natriumsalt, kaliumsalt och kalciumsalt, eller de orga- 78Û7335-Ûi 4 niska bassalterna, såsom dicyklohexylaminsalt, N-metylhexyl- aminsalt, dietanolaminsalt, N-metylpiperazinsalt, pyridinsalt, pyrrolidinsalt, dimetylaminsalt, dietylaminsalt, brucinsalt och N-metyl-D-glukaminsalt, eller aminosyrasalterna, såsom glycinsalt, lysinsalt och argininsalt.The reaction is usually carried out in an inert solvent, such as methylene chloride, chloroform, benzene, toluene, dimethylformamide or pyridine, at room temperature or under heating or cooling, preferably in an inert atmosphere; The compounds of formula (I) may be converted into the metal salts, such as sodium salt, potassium salt and calcium salt, or the organic base salts, such as dicyclohexylamine salt, N-methylhexylamine salt, diethanolamine salt, N-methylpipidine salt salt, pyrrolidine salt, pyrroline diethylamine salt, brucine salt and N-methyl-D-glucamine salt, or the amino acid salts such as glycine salt, lysine salt and arginine salt.
Tiazolidinföreningarna enligt uppfinningen föreligger såsom optiska isomerer eller stereoisomerer eller såsom blandningar av dessa isomerer. Samtliga dessa ligger inom ramen för uppfinningen.The thiazolidine compounds of the invention exist as optical isomers or stereoisomers or as mixtures of these isomers. All of these are within the scope of the invention.
En blandning av isomererna kan eventuellt separeras i de indi- viduella isomererna på konventionellt sätt, såsom fraktionerad kristallisation eller kromatografering.A mixture of the isomers may optionally be separated into the individual isomers by conventional means, such as fractional crystallization or chromatography.
Hypertension antages vara en betydelsefull riskfaktor för gerontologiska sjukdomar. Ett antal antihypertensiva medel har utvecklats och de kan klassificeras, med undantag för diuretiska medel, i två breda klasser, nämligen medel som iverkar på nervsystemet och medel som verkar direkt på det vaskulära systemet. Under senare år har avsevärd uppmärksam- het riktats mot renin-angiotensin-aldosteronsystemet såsom väsentlig bidragande faktor till hypertension. Föreliggande uppfinning har utvecklats på det faktum att tiazolidin- föreningarna med formeln (I) uppvisar en kraftig inhiberande aktivitet på angiotensin I-omvandlande enzym och de är därför ' värdefulla såsom antihypertensiva medel för behandling av renal hypertension, malign hypertension och essentiell hyper- tension. u Enligt farmakologiska försök uppvisar föreningarna enligt uppfinningen inhiberande aktivitet på vasopressorsvar hos råtta och på kontraktila svar hos isolerad ileum från marsvin mot angiotensin I, och antihypertensiv aktivitet hos spontant hypertensiv råtta och renalihypertensiv råtta. Vidare upp- visar föreningarna med formeln (I) mindre skadliga effekter, såsom takykardi, ökning av ödembildning genom karrageenin_ och smärtsvar inducerade med bradykinin hos råtta, och de uppvisar en mycket låg akut toxicitet hos råtta och mus.Hypertension is thought to be a significant risk factor for gerontological diseases. A number of antihypertensive agents have been developed and can be classified, with the exception of diuretics, into two broad classes, namely agents acting on the nervous system and agents acting directly on the vascular system. In recent years, considerable attention has been paid to the renin-angiotensin-aldosterone system as a significant contributing factor to hypertension. The present invention has been developed on the fact that the thiazolidine compounds of formula (I) exhibit a potent inhibitory activity on angiotensin I converting enzyme and are therefore valuable as antihypertensive agents for the treatment of renal hypertension, malignant hypertension and essential hypertension. According to pharmacological experiments, the compounds of the invention show inhibitory activity on rat vasopressor responses and on contractile responses in isolated guinea pig ileum against angiotensin I, and antihypertensive activity in spontaneous hypertensive rat and renal hypertensive rat. Furthermore, the compounds of formula (I) show less harmful effects, such as tachycardia, increased edema formation by carrageenin and pain responses induced by bradykinin in rats, and they show a very low acute toxicity in rats and mice.
Pâ basis av olika tester, inkl. de ovan nämnda, kan föreningarna 7 enligt uppfinningen med formeln (I) i bas-_eller saltform på 7807335-0 5 ett säkert sätt administreras för behandling av hypertensiva sjukdomar i form av ett farmaceutiskt preparat med en lämplig och konventionell farmaceutiskt godtagbar bärare, utan att skadligt påverka patienterna.On the basis of various tests, incl. the above-mentioned compounds of the invention of the formula (I) in base or salt form can be safely administered for the treatment of hypertensive diseases in the form of a pharmaceutical preparation with a suitable and conventional pharmaceutically acceptable carrier, without adversely affect patients.
De farmaceutiska preparaten kan föreligga i varje konventionell form, såsom tabletter, kapslar, granuler, pulver eller injek- tionslösningar.The pharmaceutical preparations may be in any conventional form, such as tablets, capsules, granules, powders or solution for injection.
Såsom exempel på kompositioner med vilka en förening enligt uppfinningen administreras för farmaceutiska ändamål kan nämnas: (a) Tabletter (100 mg) framställes med följande komposition: Förening I eller ett salt därav p 100 mg Majsstärkelse 40 mg Mikrokristallin cellulosa 30 mg Metylcellulosa 1 mg Laktos 27 mg Magnesiumstearat 2 mg (b) Injektionslösningar (50 mg/2 ml) framställes ur följande komposition: _ Förening I eller ett salt därav p 50 mg Natriumklorid 16 mg Metyl-p-hydroxibensoat 1,6 mg O 4 mg Propyl-p-hydroxibensoat en tillräcklig mängd för inställ- ning av volymen på 2 ml Vatten för injektion Den dagliga dosen av föreningen (I) eller ett salt därav för vuxna människor varierar vanligen från ungefär 30 mg till ungefär 1500 mg för oral administration, i enhets- eller multipeldoser, men den kan variera med hänsyn till ålder, kroppsvikt och/eller allvarligheten av det tillstånd som skall behandlas såväl som svaret på medicineringen.As examples of compositions with which a compound of the invention is administered for pharmaceutical purposes may be mentioned: (a) Tablets (100 mg) are prepared with the following composition: Compound I or a salt thereof p 100 mg Maize starch 40 mg Microcrystalline cellulose 30 mg Methylcellulose 1 mg Lactose 27 mg Magnesium stearate 2 mg (b) Injection solutions (50 mg / 2 ml) are prepared from the following composition: Compound I or a salt thereof p 50 mg Sodium chloride 16 mg Methyl p-hydroxybenzoate 1.6 mg O 4 mg Propyl p hydroxybenzoate a sufficient amount to adjust the volume of 2 ml Water for injection The daily dose of compound (I) or a salt thereof for adults usually ranges from about 30 mg to about 1500 mg for oral administration, in unit or multiple doses. , but it may vary with regard to age, body weight and / or the severity of the condition to be treated as well as the response to the medication.
Uppfinningen åsfiådliggöres närmare medelst följande exempel, vari de angivna temperaturerna avser Celsius-grader. 7807335-0 gxemgel 1, En lösning av 5,4 g 3-acetyltio-2-metylpropionsyra i 25 ml vattenfri bensen försättes med 7,1 g tionylklorid och bland- ningen omröres två timmar vid 50-600. Reaktionsblandningen kon- centreras under reducerat tryck. 3-acetyltio-2-metylpropionyl- kloriden erhållen på så sätt sättes till en lösning av 10,7 g 2-(p-klorfenyl)-4(R)-ti-zolidinkarbonsyra och 8,9 g trietylamin i metylenklorid under kylning vid -100 och blandningen omröres en timme vid -8 till -50 och därefter 4 timmar vid rumstempera- tur. Reaktionsblandningen koncentreras därefter under reducerat tryck. Återstoden försättes med 3N saltsyra under ískylning och den utskilda oljan extraheras med kloroform. Extraktet tvättas med en mättad natriumkloridlösning, torkas över vattenfritt magnesiumsulfat och lösningsmedlet avdestilleras under reducerat tryck. Den blekgula oljeartade återstoden löses i 50 ml aceton, varefter en lösning av 8,2 g dicyklohexylamin i 20 ml aceton tillsättes under iskylning. Fällningen tillvaratages genom filt- rering och omkristalliseras ur etanol för bildning av dicyklo- hexylaminsaltet av 3:(3-acetyltio-2-metylpropionyl)-2-(p-klor- fenyl)-4(R)-tiazolidinkarbonsyra i form av ett vitt kristallint _pulver med smältpunkten 233-2340 (sönderdelníng).The invention is further illustrated by the following examples, in which the temperatures indicated refer to degrees Celsius. 7807335-0 gxemgel 1, A solution of 5.4 g of 3-acetylthio-2-methylpropionic acid in 25 ml of anhydrous benzene is added with 7.1 g of thionyl chloride and the mixture is stirred for two hours at 50-600. The reaction mixture is concentrated under reduced pressure. The 3-acetylthio-2-methylpropionyl chloride thus obtained is added to a solution of 10.7 g of 2- (p-chlorophenyl) -4 (R) -thiazolidinecarboxylic acid and 8.9 g of triethylamine in methylene chloride while cooling at - 100 and the mixture is stirred for one hour at -8 to -50 and then for 4 hours at room temperature. The reaction mixture is then concentrated under reduced pressure. The residue is added with 3N hydrochloric acid under ice-cooling and the separated oil is extracted with chloroform. The extract is washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The pale yellow oily residue is dissolved in 50 ml of acetone, after which a solution of 8.2 g of dicyclohexylamine in 20 ml of acetone is added under ice-cooling. The precipitate is collected by filtration and recrystallized from ethanol to give the dicyclohexylamine salt of 3: (3-acetylthio-2-methylpropionyl) -2- (p-chlorophenyl) -4 (R) -thiazolidinecarboxylic acid as a white crystalline powder with melting point 233-2340 (decomposition).
Exemgel 2. _ . _ 6 g 3-(3~acetyltio-2-metylpropionyl)-2-(p~klorfenyl)-4(R)- -tiazolidinkarbonsyra sättes långsamt till 50 ml 3N natrium- hydroxidlösning under kväveatmosfär och blandningen omröres 2 timmar vid rumstemperatur. Reaktionsblandningen försättes med 30 ml 30%-ig svavelsyra under iskylning och den utskilda oljan extraheras med etyleter. Extraktet tvättas med en mättad natriumkloridlösning och torkas över vattenfritt magnesiumsulfat och lösningsmedlet avdestilleras under reducerat tryck. Den såsom återstod erhållna fasta substansen omkristalliseras ur en blandning av etylacetat och hexan för bildning av 2-(p-klorfenyl)- -3-(3-merkapto-2-metylpropionyl)-4(R)-tiazolidinkarbonsyra i form av ett vitt kristallint pulver med smältpunkten 100-1030.Example 2. _. 6 g of 3- (3-acetylthio-2-methylpropionyl) -2- (p-chlorophenyl) -4 (R) -thiazolidinecarboxylic acid are slowly added to 50 ml of 3N sodium hydroxide solution under a nitrogen atmosphere and the mixture is stirred for 2 hours at room temperature. The reaction mixture is added with 30 ml of 30% sulfuric acid under ice-cooling and the separated oil is extracted with ethyl ether. The extract is washed with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The solid obtained as a residue is recrystallized from a mixture of ethyl acetate and hexane to give 2- (p-chlorophenyl) -3- (3-mercapto-2-methylpropionyl) -4 (R) -thiazolidinecarboxylic acid as a white crystalline powder with a melting point of 100-1030.
Exemgel 3, -En blandning av 6,6 g 3-acetyltio-2(S)-metylpropionylklorid, ll g 2-(p-metoxifenyl)-4(R)-tiazolidinkarbonsyra och 9 g trij etylamin i metylenklorid behandlas enligt exempel l_för_bild- 7807335-0 7 ning av 3-(3~acetyltio-2(S)ëmetylpropíonyl)-2-(p-metoxifenyl)- -4(R)-tiazolidinkarbonsyra i form av en blekgul olja. lalšs = +78,5 (metanol).Example Gel 3, -A mixture of 6.6 g of 3-acetylthio-2 (S) -methylpropionyl chloride, 11 g of 2- (p-methoxyphenyl) -4 (R) -thiazolidinecarboxylic acid and 9 g of triethylamine in methylene chloride is treated according to Example 1 7807335-0 7 3- (3-acetylthio-2 (S) methylpropionyl) -2- (p-methoxyphenyl) -4- (R) -thiazolidinecarboxylic acid as a pale yellow oil. lalšs = +78.5 (methanol).
Denna produkt hydrolyseras enligt exempel 2. På så sätt, erhåller man 3-(3-merkapto-2(S)-metylpropionyl)-2-(p-metoxi- feny1>-4(R)-tiazoliainkarbonsyra med en smältpunkt av 130-1s2°. [a]â5 = +l22,9 (metanol). I Följande föreningar framställes på analogt sätt: (a) 3-(3-acetyltio-2(S)-metylpropionyl)-2-(3,4,5-trimetoxi- fenyl)-4(R)ftiazolidinkarbonsyra, olja; [a]š5 = +66,l (metanol) (b) 3-(3-acetyltio-2(S)-metylpropionyl)-2-(m-nitrofenyl)-4(R)- -tiazolidinkarbonsyra, olja; [a]š = +35,8 (metanol) (c) 3-(e-acetyltio-2(S)-metylpropionyl)-2-(p-fluorfenyl)-4(R)- -tiazolidinkarbonsyra, olja; [alš = +5l,5 (metanol) (d) 3~(3-acetyltio-2(S)-metylpropionyl)-2-(p-bromfenyl)-4(R)- ~tiazolidinkarbonsyra, olja; lalšs = +65,3 (metanol) (e) 3-(3-merkapto-2(S)-metylpropionyl)-2-(3,4,5-trimetoxi- fenyl)-4(R)-tiazoliainkarbonsyra, olja; [a1š5.= +1zs,ss (metanol) (f) 3-(3-merkapto-2(S)-metylpropionyl)-2-(m-nitrofenyl)-4(R)- -tiazolidinkarbonsyra, amorft pulver; smältpunkt ll7-1250 (g) 2-(p-fluorfenyl)-3-(3-merkapto-2(S)-metylpropionyl)-4(R)- -tiazolidinkarbonsyra, amorft pulver; smältpunkt 141-1440 (h) 2-(p-bromfenyl)-3-(3-merkapto-2(S)-metylpropionyl)~4(R)- ~tiazolidinkarbonsyra, smältpunkt 151-1560.This product is hydrolyzed according to Example 2. There is thus obtained 3- (3-mercapto-2 (S) -methylpropionyl) -2- (p-methoxyphenyl) -4 (R) -thiazoliainecarboxylic acid with a melting point of 130- The following compounds are prepared in an analogous manner: (a) 3- (3-acetylthio-2 (S) -methylpropionyl) -2- (3,4,5 -trimethoxyphenyl) -4 (R) phthiazolidinecarboxylic acid, oil; [a] š5 = + 66.1 (methanol) (b) 3- (3-acetylthio-2 (S) -methylpropionyl) -2- (m-nitrophenyl ) -4 (R) -thiazolidinecarboxylic acid, oil; [α] D = +35.8 (methanol) (c) 3- (e-acetylthio-2 (S) -methylpropionyl) -2- (p-fluorophenyl) - 4 (R) - -thiazolidinecarboxylic acid, oil; [.alpha. =. thiazolidinecarboxylic acid, oil; lalis = +65.3 (methanol) (e) 3- (3-mercapto-2 (S) -methylpropionyl) -2- (3,4,5-trimethoxyphenyl) -4 (R ) -thiazolinecarboxylic acid, oil; [a1s5. = + 1zs, ss (methanol) (f) 3- (3-mercapto-2 (S) -methylpropionyl) -2- (m-nitrophenyl) -4 (R) -thiazolidinecarboxylic acid , amorphous powder; mp 17-1250 (g) 2- (p-fluorophenyl) -3- (3-m erkapto-2 (S) -methylpropionyl) -4 (R) -thiazolidinecarboxylic acid, amorphous powder; mp 141-1440 (h) 2- (p-bromophenyl) -3- (3-mercapto-2 (S) -methylpropionyl) -4 (R) -thiazolidinecarboxylic acid, mp 151-1560.
Försöken enligt exemplen 1-2 upprepas, varvid man använder en ekvi- valent mängd av lämpliga utgångsmaterial och erhåller följande före- ningar: I (1) 3-(3-acetyltio-2-metylpropionyl)-2-(2,4-diklorfenyl)-4(Rl~ -tiazolidinkarbonsyra-dicyklohcxylaminsalt, smältpunkt 230-2329; (2) 3-(3-acetyltio-2-metylpropionyl)-2-(2,6-diklorfenyl)~4(R)“ -tiazolidinkarbonsyra, smältpunkt l70~l75°; (3) 3-(3-acetyltio-2-metY1Pr°Pi°flY1)'2'fe:Y1'4(R)'tiaZ°1idin" karbonsyra-brucinsalt, smältPunkt 122'l23 7 <4; 3-(s-aCety1ti°-2-mecylPr°Pi°flY1>'2'(m'met°*ife“Y1)"4(“)' . 2 _ . -tiazoliainkarbonsyrfl. olna: IQID - +128f° (meta“°1)' (5) 3-(3~acetyltio-2-metylpropionyl)-2-(p-etoxifenyl)~4(R)- .. 25 _ . -tiazolidinkarbonsyra; olja; IGID - +121f5 (m°ta“9l)' “7âÛ7355-0 8 (6) 3-(3-etylkarbamoyltiøpropionyl)-2-(p-tolyl)-4(R)-tiazoli- dinkarbonsyra, olja; (7) 4-(3-acetyltio-2-metylpropionyl)-1-tia-4-azaspiro[4,5]dekan- -3(R)-karbonsyra, smältpunkt les-1ss°; ( 8) 2-(2,4-diklorfenyl)-3-(3-merkapto-2-metylpropionyl)-4(R)- -tiazo1idinkarbonsyra-dicyklohexylaminsalt, smältpunkt 200-2030; (_97 2-(2,6-diklorfenyl)-3-(3-merkapto-2-metylpropionyl)-4(R)- ~tiazolidinkarbonsyra, smältpunkt 202-2030 (sönderdelning); (10) 3-(3-merkapto-2-metylpropionyl)-2-fenyl-4(R)-tiazolidin-7 karbonsyra, olja; nås = l,5795; [alâs = ~78,2 (metanol); (11) 2-(3,4-dimetoxifenyl)-3-(3-merkapto~2-metylpropionyl)-4(R)- -tiazolidingarbonsyra, amorft pulver; [a]š5 = +l35,9 (metanol); (12) 3-(3~merkapto-2-metylprcpionyl)-2-(o-metoxifenyl)-4(R)- -tiazolidinkarbonsyra, amørft pulver; Ialšs = +l69,0 (metanol); (13) 3-(3-merkapto-2-metylpropionyl)-2-(m-metoxifenyl)-4(R)- -tiazolidínkarbonsyra, smältpunkt 116-1200; ' (14) 3-(3-merkapto-2-metylpropionyl)~2-(p-metoxifenyl)-4(R)- -tiazølidinkarbonsyra, smältpunkz 152-1s4°; (15) 2-(p-etoxifenyl)-3-(3-merkapto-2-metylpropionyl)-4(R)- -tiazolidinkarbonsyra, smältpunkt 147-l48°; (16) 3-(3-merkaptopropionyl)-2-(p-tolyl)-4(R)-tiazolidinkarbon- syra, olja; (17) 4-(3-merkapto-2-metylpropionyl)-l-tia-4-azaspiro[4.5]dekan- -3(R)-karbonsyra, smältpunkt 175-17s°.The experiments of Examples 1-2 are repeated, using an equivalent amount of suitable starting materials to give the following compounds: I (1) 3- (3-acetylthio-2-methylpropionyl) -2- (2,4-dichlorophenyl ) -4 (R 1 - -thiazolidinecarboxylic acid dicycloxylamine salt, m.p. 230-2329; (2) 3- (3-acetylthio-2-methylpropionyl) -2- (2,6-dichlorophenyl) -4 (R) -thiazolidinecarboxylic acid, m.p. 170 ° / 75 °; (3) 3- (3-acetylthio-2-methylPr ° Pi ° P Y1) '2'fe: Y1'4 (R)' thiaZ ° 1idine "carbonic acid-brucine salt, melting point 122'l23 7 <4 ; 3- (s-aCetylTi--2-mecylPr ° Pi ° fl Y1> '2' (m'met ° * ife “Y1)" 4 (“) '. 2 _. -Thiazoliaicarboxylic acid fl. (meta '° 1)' (5) 3- (3-acetylthio-2-methylpropionyl) -2- (p-ethoxyphenyl) -4 (R) - .. 25 -.-thiazolidinecarboxylic acid; oil; IGID - + 121f5 ( (91) 3- (3-ethylcarbamoylthiopropionyl) -2- (p-tolyl) -4 (R) -thiazolidinecarboxylic acid, oil; (7) 4- (3- acetylthio-2-methylpropionyl) -1-thia-4-azaspiro [4,5] decane--3 (R) -carboxylic acid, melting point les-1 ° C; (8) 2- (2,4-dichlorophenyl) -3- (3-mercapto-2-methylpropionyl) -4 (R) - -t iazolidinecarboxylic acid dicyclohexylamine salt, m.p. 200-2030; (_97 2- (2,6-Dichlorophenyl) -3- (3-mercapto-2-methylpropionyl) -4 (R) -thiazolidinecarboxylic acid, m.p. 202-2030 (dec.); (10) 3- (3-mercapto 2-methylpropionyl) -2-phenyl-4 (R) -thiazolidine-7-carboxylic acid, oil; reach = 1.59595; [alâs = 7878.2 (methanol); (11) 2- (3,4-dimethoxyphenyl) -3- (3-mercapto-2-methylpropionyl) -4 (R) -thiazolidiningarboxylic acid, amorphous powder; [α] D 25 = + 135.9 (methanol); (12) 3- (3-mercapto-2-methylpropionyl) ) -2- (o-methoxyphenyl) -4 (R) -thiazolidinecarboxylic acid, amorphous powder; Ialss = + 169.0 (methanol); (13) 3- (3-mercapto-2-methylpropionyl) -2- (m -methoxyphenyl) -4 (R) -thiazolidinecarboxylic acid, m.p. 116-1200; (14) 3- (3-mercapto-2-methylpropionyl) -2- (p-methoxyphenyl) -4 (R) -thiazolidinecarboxylic acid, m.p. (15) 2- (p-ethoxyphenyl) -3- (3-mercapto-2-methylpropionyl) -4 (R) -thiazolidinecarboxylic acid, m.p. 147-148 °; (16) 3- (3- mercaptopropionyl) -2- (p-tolyl) -4 (R) -thiazolidinecarboxylic acid, oil; (17) 4- (3-mercapto-2-methylpropionyl) -1-thia-4-azaspiro [4.5] decane- 3 (R) -carboxylic acid, m.p. 175-17 °.
Claims (6)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP52078179A JPS5834474B2 (en) | 1977-06-29 | 1977-06-29 | Method for producing thiazolidine derivatives |
| JP9802477A JPS6047264B2 (en) | 1977-08-15 | 1977-08-15 | Thiazolidine derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| SE7807335L SE7807335L (en) | 1978-12-30 |
| SE434836B true SE434836B (en) | 1984-08-20 |
Family
ID=26419266
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SE7807335A SE434836B (en) | 1977-06-29 | 1978-06-28 | thiazolidine |
Country Status (7)
| Country | Link |
|---|---|
| DE (1) | DE2828578C2 (en) |
| ES (1) | ES471239A1 (en) |
| FR (1) | FR2395998A1 (en) |
| GB (1) | GB2000508B (en) |
| IT (1) | IT1105731B (en) |
| NL (1) | NL7807023A (en) |
| SE (1) | SE434836B (en) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU528115B2 (en) | 1978-04-08 | 1983-04-14 | Santen Pharmaceutical Co. Ltd. | Antihypertensive 4-thiazolidine/carboxylic acids |
| US4483861A (en) * | 1978-10-31 | 1984-11-20 | Santen Pharmaceutical Co., Ltd. | Antihypertensive sulfur-containing compounds |
| JPS5572169A (en) * | 1978-11-27 | 1980-05-30 | Tanabe Seiyaku Co Ltd | Isoquinoline derivative and its preparation |
| JPS5683483A (en) * | 1979-12-13 | 1981-07-08 | Santen Pharmaceut Co Ltd | Thiazolidine compound |
| DE3011239A1 (en) * | 1980-03-22 | 1981-10-01 | C.H. Boehringer Sohn, 6507 Ingelheim | SUBSTITUTED ALKYLTHIOACYLAMINO ACIDS, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITIONS |
| JPS56139455A (en) * | 1980-04-02 | 1981-10-30 | Santen Pharmaceut Co Ltd | Sulfur-containing acylaminoacid |
| AU543804B2 (en) * | 1980-10-31 | 1985-05-02 | Takeda Chemical Industries Ltd. | Amides having bicyclic substituents on nitrogen |
| DE3204373A1 (en) * | 1982-02-09 | 1983-08-18 | Luitpold-Werk, Chemisch-pharmazeutische Fabrik GmbH & Co, 8000 München | THIAZA SPIRIT DERIVATIVES, METHOD FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS |
| US4552889A (en) * | 1983-06-09 | 1985-11-12 | Eli Lilly And Company | 3-Mercaptomethyl-2-oxo-1-pyrrolidine acetic acids and use for hypertension |
| USD583254S1 (en) * | 2007-12-18 | 2008-12-23 | New York & Company, Inc. | Pump container |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2446100C3 (en) * | 1974-09-26 | 1982-01-14 | Ludwig Merckle Kg Chem. Pharm. Fabrik, 7902 Blaubeuren | Phenoxyalkanecarboxamides of thiazolidinecarboxylic acids, process for their preparation and pharmaceuticals |
| AU518147B2 (en) * | 1976-12-03 | 1981-09-17 | E.R. Squibb & Sons, Inc. | Derivatives of thiazolidine, thiazine and morpholine carboxylic acids |
| JPS5455565A (en) * | 1977-10-06 | 1979-05-02 | Santen Pharmaceut Co Ltd | Novel thiazolidine derivative |
-
1978
- 1978-06-27 IT IT50037/78A patent/IT1105731B/en active
- 1978-06-27 FR FR7819125A patent/FR2395998A1/en active Granted
- 1978-06-28 SE SE7807335A patent/SE434836B/en not_active IP Right Cessation
- 1978-06-28 ES ES471239A patent/ES471239A1/en not_active Expired
- 1978-06-28 GB GB7828177A patent/GB2000508B/en not_active Expired
- 1978-06-29 DE DE2828578A patent/DE2828578C2/en not_active Expired
- 1978-06-29 NL NL7807023A patent/NL7807023A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| GB2000508A (en) | 1979-01-10 |
| IT1105731B (en) | 1985-11-04 |
| DE2828578C2 (en) | 1983-12-15 |
| SE7807335L (en) | 1978-12-30 |
| IT7850037A0 (en) | 1978-06-27 |
| FR2395998A1 (en) | 1979-01-26 |
| FR2395998B1 (en) | 1982-07-23 |
| DE2828578A1 (en) | 1979-01-11 |
| ES471239A1 (en) | 1979-01-16 |
| NL7807023A (en) | 1979-01-03 |
| GB2000508B (en) | 1982-05-19 |
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