AU7064491A - New thiazole derivatives - Google Patents
New thiazole derivativesInfo
- Publication number
- AU7064491A AU7064491A AU70644/91A AU7064491A AU7064491A AU 7064491 A AU7064491 A AU 7064491A AU 70644/91 A AU70644/91 A AU 70644/91A AU 7064491 A AU7064491 A AU 7064491A AU 7064491 A AU7064491 A AU 7064491A
- Authority
- AU
- Australia
- Prior art keywords
- ppm
- substituted
- multiplet
- singlet
- bromo
- 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.)
- Abandoned
Links
- 150000007979 thiazole derivatives Chemical class 0.000 title description 5
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 claims description 34
- 125000000217 alkyl group Chemical group 0.000 claims description 23
- 150000001875 compounds Chemical class 0.000 claims description 23
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- -1 5H-dibenzo-[a,d]-cyclohepten-5-yl group Chemical group 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 229960001340 histamine Drugs 0.000 claims description 15
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 15
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 13
- 230000008569 process Effects 0.000 claims description 13
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 12
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 12
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 150000002357 guanidines Chemical class 0.000 claims description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 230000007062 hydrolysis Effects 0.000 claims description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- CYEBJEDOHLIWNP-UHFFFAOYSA-N methanethioamide Chemical compound NC=S CYEBJEDOHLIWNP-UHFFFAOYSA-N 0.000 claims description 5
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 3
- 230000000172 allergic effect Effects 0.000 claims description 3
- 208000010668 atopic eczema Diseases 0.000 claims description 3
- 230000004071 biological effect Effects 0.000 claims description 3
- 238000005893 bromination reaction Methods 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- 239000012634 fragment Substances 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 230000000144 pharmacologic effect Effects 0.000 claims description 3
- 206010019280 Heart failures Diseases 0.000 claims description 2
- 239000005864 Sulphur Substances 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 2
- 125000005982 diphenylmethyl group Chemical class [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 2
- 238000006698 hydrazinolysis reaction Methods 0.000 claims description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 2
- 125000005544 phthalimido group Chemical group 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 238000006798 ring closing metathesis reaction Methods 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 87
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 60
- 239000000243 solution Substances 0.000 description 60
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 56
- 238000005160 1H NMR spectroscopy Methods 0.000 description 50
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 48
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 36
- 238000003756 stirring Methods 0.000 description 36
- 238000001816 cooling Methods 0.000 description 32
- 239000011541 reaction mixture Substances 0.000 description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 22
- 238000002844 melting Methods 0.000 description 21
- 230000008018 melting Effects 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 20
- 229960004132 diethyl ether Drugs 0.000 description 20
- 239000000203 mixture Substances 0.000 description 18
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- 239000000706 filtrate Substances 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 239000012299 nitrogen atmosphere Substances 0.000 description 14
- 239000002244 precipitate Substances 0.000 description 14
- 230000000694 effects Effects 0.000 description 13
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 11
- 238000001819 mass spectrum Methods 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 235000011167 hydrochloric acid Nutrition 0.000 description 9
- 229960000443 hydrochloric acid Drugs 0.000 description 9
- IFPPZTSKNBSMHN-UHFFFAOYSA-N 2-(3-bromo-4-oxopentyl)isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(CCC(Br)C(=O)C)C(=O)C2=C1 IFPPZTSKNBSMHN-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 229910010272 inorganic material Inorganic materials 0.000 description 8
- 239000011147 inorganic material Substances 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- KKKXIWVOUGTUNV-UHFFFAOYSA-N 2-[3-(2-amino-4-methyl-1,3-thiazol-5-yl)propyl]-1-(3,3-diphenylpropyl)guanidine 2,4,6-trinitrophenol Chemical compound C1([N+](=O)[O-])=CC([N+](=O)[O-])=CC([N+](=O)[O-])=C1O.C1([N+](=O)[O-])=CC([N+](=O)[O-])=CC([N+](=O)[O-])=C1O.NC=1SC(=C(N1)C)CCCNC(=N)NCCC(C1=CC=CC=C1)C1=CC=CC=C1 KKKXIWVOUGTUNV-UHFFFAOYSA-N 0.000 description 7
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 7
- 235000019439 ethyl acetate Nutrition 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 230000008570 general process Effects 0.000 description 7
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 7
- 150000003557 thiazoles Chemical class 0.000 description 7
- FWNCNQDIENYPDJ-UHFFFAOYSA-N 2-(4-hydroxybutyl)isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(CCCCO)C(=O)C2=C1 FWNCNQDIENYPDJ-UHFFFAOYSA-N 0.000 description 6
- LZJDEPWZKBPSRS-UHFFFAOYSA-N 2-(4-methyl-1,3-thiazol-5-yl)ethanamine;dihydrochloride Chemical compound Cl.Cl.CC=1N=CSC=1CCN LZJDEPWZKBPSRS-UHFFFAOYSA-N 0.000 description 6
- KISZTEOELCMZPY-UHFFFAOYSA-N 3,3-diphenylpropylamine Chemical compound C=1C=CC=CC=1C(CCN)C1=CC=CC=C1 KISZTEOELCMZPY-UHFFFAOYSA-N 0.000 description 6
- LHVRFUVVRXGZPV-UHFFFAOYSA-N 5-(2-aminoethyl)-4-methyl-2-thiazolamine Chemical compound CC=1N=C(N)SC=1CCN LHVRFUVVRXGZPV-UHFFFAOYSA-N 0.000 description 6
- NFHWLPHEKVZKQU-UHFFFAOYSA-N 5-(3-aminopropyl)-4-methyl-1,3-thiazol-2-amine;dihydrochloride Chemical compound Cl.Cl.CC=1N=C(N)SC=1CCCN NFHWLPHEKVZKQU-UHFFFAOYSA-N 0.000 description 6
- CZGOECYPTLSLNI-UHFFFAOYSA-N 6-bromohexan-2-one Chemical compound CC(=O)CCCCBr CZGOECYPTLSLNI-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 102000000543 Histamine Receptors Human genes 0.000 description 6
- 108010002059 Histamine Receptors Proteins 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000002178 crystalline material Substances 0.000 description 6
- 229940093499 ethyl acetate Drugs 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 102000005962 receptors Human genes 0.000 description 6
- 108020003175 receptors Proteins 0.000 description 6
- HVVRQUYSKYIOJV-UHFFFAOYSA-N 2-(5-oxohexyl)isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(CCCCC(=O)C)C(=O)C2=C1 HVVRQUYSKYIOJV-UHFFFAOYSA-N 0.000 description 5
- VKPJPAPCRZIUMA-UHFFFAOYSA-N 2-[3-(1h-imidazol-5-yl)propyl]guanidine Chemical group NC(N)=NCCCC1=CN=CN1 VKPJPAPCRZIUMA-UHFFFAOYSA-N 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 5
- KZZIVOLMJPSDEP-UHFFFAOYSA-N 1-[3-(4-fluorophenyl)-3-pyridin-2-ylpropyl]-2-[3-(1h-imidazol-5-yl)propyl]guanidine Chemical compound C=1N=CNC=1CCCN=C(N)NCCC(C=1N=CC=CC=1)C1=CC=C(F)C=C1 KZZIVOLMJPSDEP-UHFFFAOYSA-N 0.000 description 4
- ONTXCMXICQNNNO-UHFFFAOYSA-N 2-(3-oxobutyl)isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(CCC(=O)C)C(=O)C2=C1 ONTXCMXICQNNNO-UHFFFAOYSA-N 0.000 description 4
- VIHXJMXDYXZGGL-UHFFFAOYSA-N 2-(4-bromo-5-oxohexyl)isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(CCCC(Br)C(=O)C)C(=O)C2=C1 VIHXJMXDYXZGGL-UHFFFAOYSA-N 0.000 description 4
- SLTUYEGLKJHGHO-UHFFFAOYSA-N 2-[3-(2-amino-4-methyl-1,3-thiazol-5-yl)propyl]-1-cyano-3-(3,3-diphenylpropyl)guanidine Chemical compound N1=C(N)SC(CCCN=C(NCCC(C=2C=CC=CC=2)C=2C=CC=CC=2)NC#N)=C1C SLTUYEGLKJHGHO-UHFFFAOYSA-N 0.000 description 4
- SUALZDCPKLVMJL-UHFFFAOYSA-N 5-(3-aminopropyl)-1,3-thiazol-2-amine;dihydrochloride Chemical compound Cl.Cl.NCCCC1=CN=C(N)S1 SUALZDCPKLVMJL-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 241000700199 Cavia porcellus Species 0.000 description 4
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
- SLIKWVTWIGHFJE-UHFFFAOYSA-N diphenoxymethylidenecyanamide Chemical compound C=1C=CC=CC=1OC(=NC#N)OC1=CC=CC=C1 SLIKWVTWIGHFJE-UHFFFAOYSA-N 0.000 description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 4
- 150000002541 isothioureas Chemical class 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- PTPZBCHKQSHXQZ-UHFFFAOYSA-N 2-(4-bromo-3-oxobutyl)isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(CCC(=O)CBr)C(=O)C2=C1 PTPZBCHKQSHXQZ-UHFFFAOYSA-N 0.000 description 3
- DPATUMDQWSJANG-UHFFFAOYSA-N 2-(4-oxopentyl)isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(CCCC(=O)C)C(=O)C2=C1 DPATUMDQWSJANG-UHFFFAOYSA-N 0.000 description 3
- PSKJVCNFAMZUFJ-UHFFFAOYSA-N 2-(5-bromo-4-oxopentyl)isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(CCCC(=O)CBr)C(=O)C2=C1 PSKJVCNFAMZUFJ-UHFFFAOYSA-N 0.000 description 3
- IPOCGIVMVZXNBQ-UHFFFAOYSA-N 2-[2-(2-amino-1,3-thiazol-4-yl)ethyl]isoindole-1,3-dione;hydrobromide Chemical compound Br.S1C(N)=NC(CCN2C(C3=CC=CC=C3C2=O)=O)=C1 IPOCGIVMVZXNBQ-UHFFFAOYSA-N 0.000 description 3
- JASQWGXCYJFBDS-UHFFFAOYSA-N 2-[2-(4-methyl-1,3-thiazol-5-yl)ethyl]isoindole-1,3-dione;hydrobromide Chemical compound Br.N1=CSC(CCN2C(C3=CC=CC=C3C2=O)=O)=C1C JASQWGXCYJFBDS-UHFFFAOYSA-N 0.000 description 3
- QAZIDPZKBKDKHT-UHFFFAOYSA-N 2-[3-(2-amino-1,3-thiazol-4-yl)propyl]isoindole-1,3-dione;hydrobromide Chemical compound Br.S1C(N)=NC(CCCN2C(C3=CC=CC=C3C2=O)=O)=C1 QAZIDPZKBKDKHT-UHFFFAOYSA-N 0.000 description 3
- WNNXALBEELVCMI-UHFFFAOYSA-N 2-bromo-5-(1,3-dioxoisoindol-2-yl)pentanal Chemical compound C1=CC=C2C(=O)N(CCCC(Br)C=O)C(=O)C2=C1 WNNXALBEELVCMI-UHFFFAOYSA-N 0.000 description 3
- BHCHUXXNTHWMGJ-UHFFFAOYSA-N 4-(3-aminopropyl)-1,3-thiazol-2-amine;dihydrochloride Chemical compound Cl.Cl.NCCCC1=CSC(N)=N1 BHCHUXXNTHWMGJ-UHFFFAOYSA-N 0.000 description 3
- NQUYKSNCKIXTQF-UHFFFAOYSA-N 5-(2-aminoethyl)-4-methyl-1,3-thiazol-2-amine;dihydrochloride Chemical compound Cl.Cl.CC=1N=C(N)SC=1CCN NQUYKSNCKIXTQF-UHFFFAOYSA-N 0.000 description 3
- SMIKUIMODNMCCG-UHFFFAOYSA-N C1([N+](=O)[O-])=CC([N+](=O)[O-])=CC([N+](=O)[O-])=C1O.C1([N+](=O)[O-])=CC([N+](=O)[O-])=CC([N+](=O)[O-])=C1O.NC=1SC=C(N1)CCCNC(=N)NCCC(C1=CC=CC=C1)C1=CC=CC=C1 Chemical compound C1([N+](=O)[O-])=CC([N+](=O)[O-])=CC([N+](=O)[O-])=C1O.C1([N+](=O)[O-])=CC([N+](=O)[O-])=CC([N+](=O)[O-])=C1O.NC=1SC=C(N1)CCCNC(=N)NCCC(C1=CC=CC=C1)C1=CC=CC=C1 SMIKUIMODNMCCG-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Natural products C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000003042 antagnostic effect Effects 0.000 description 3
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 description 3
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- HSYTXMUILWZKFF-UHFFFAOYSA-N 1-[2-(2-amino-4-methyl-1,3-thiazol-5-yl)ethyl]-3-cyano-2-(3,3-diphenylpropyl)guanidine Chemical compound N1=C(N)SC(CCNC(NC#N)=NCCC(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1C HSYTXMUILWZKFF-UHFFFAOYSA-N 0.000 description 2
- XTRFUKPSMUKNJF-UHFFFAOYSA-N 1-[3-(2-amino-4-methyl-1,3-thiazol-5-yl)propyl]-3-cyano-2-methylguanidine Chemical compound N#CNC(=NC)NCCCC=1SC(N)=NC=1C XTRFUKPSMUKNJF-UHFFFAOYSA-N 0.000 description 2
- ZPLDPSXWSZPAQP-UHFFFAOYSA-N 2-(2,4-dimethyl-1,3-thiazol-5-yl)ethanamine;dihydrochloride Chemical compound Cl.Cl.CC1=NC(C)=C(CCN)S1 ZPLDPSXWSZPAQP-UHFFFAOYSA-N 0.000 description 2
- GZOILRFVMJAQBC-UHFFFAOYSA-N 2-(3-bromo-4-hydroxybutyl)isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(CCC(Br)CO)C(=O)C2=C1 GZOILRFVMJAQBC-UHFFFAOYSA-N 0.000 description 2
- AEQXSCZKSNBLQW-UHFFFAOYSA-N 2-(5-hydroxypentyl)isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(CCCCCO)C(=O)C2=C1 AEQXSCZKSNBLQW-UHFFFAOYSA-N 0.000 description 2
- TTYYVHIMEKPWIW-UHFFFAOYSA-N 2-[2-(2,4-dimethyl-1,3-thiazol-5-yl)ethyl]isoindole-1,3-dione;hydrobromide Chemical compound Br.S1C(C)=NC(C)=C1CCN1C(=O)C2=CC=CC=C2C1=O TTYYVHIMEKPWIW-UHFFFAOYSA-N 0.000 description 2
- FQEIHIVPLCDSGY-UHFFFAOYSA-N 2-[3-(2-amino-1,3-thiazol-5-yl)propyl]isoindole-1,3-dione;hydrobromide Chemical compound Br.S1C(N)=NC=C1CCCN1C(=O)C2=CC=CC=C2C1=O FQEIHIVPLCDSGY-UHFFFAOYSA-N 0.000 description 2
- DNLARIARHLWZRF-UHFFFAOYSA-N 2-[3-(2-amino-4-methyl-1,3-thiazol-5-yl)propyl]-1-(3,3-diphenylpropyl)guanidine Chemical compound N1=C(N)SC(CCCN=C(N)NCCC(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1C DNLARIARHLWZRF-UHFFFAOYSA-N 0.000 description 2
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- BNCFKRVOUNWXAY-UHFFFAOYSA-N 3-(3,4-dichlorophenyl)-3-pyridin-2-ylpropan-1-amine Chemical compound C=1C=CC=NC=1C(CCN)C1=CC=C(Cl)C(Cl)=C1 BNCFKRVOUNWXAY-UHFFFAOYSA-N 0.000 description 2
- HEGXJUJXMQAWMZ-UHFFFAOYSA-N 4-(2-aminoethyl)-1,3-thiazol-2-amine;dihydrochloride Chemical compound Cl.Cl.NCCC1=CSC(N)=N1 HEGXJUJXMQAWMZ-UHFFFAOYSA-N 0.000 description 2
- LZHGBLUAJMICBZ-UHFFFAOYSA-N 5-(2-aminoethyl)-1,3-thiazol-2-amine Chemical compound NCCC1=CN=C(N)S1 LZHGBLUAJMICBZ-UHFFFAOYSA-N 0.000 description 2
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- BKAWJIRCKVUVED-UHFFFAOYSA-N 5-(2-hydroxyethyl)-4-methylthiazole Chemical compound CC=1N=CSC=1CCO BKAWJIRCKVUVED-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- SQCFMBWUIGQAMI-UHFFFAOYSA-N NC(N)=N.OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O.OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O Chemical compound NC(N)=N.OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O.OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O SQCFMBWUIGQAMI-UHFFFAOYSA-N 0.000 description 2
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 2
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 2
- TZNOQFCVOYXCAM-UHFFFAOYSA-N [amino(ethylsulfanyl)methylidene]-(3,3-diphenylpropyl)azanium;bromide Chemical compound [Br-].C=1C=CC=CC=1C(CC[NH+]=C(N)SCC)C1=CC=CC=C1 TZNOQFCVOYXCAM-UHFFFAOYSA-N 0.000 description 2
- 229950009330 arpromidine Drugs 0.000 description 2
- 230000031709 bromination Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- OUJADRKXKFRDEN-UHFFFAOYSA-N guanidine dihydrobromide Chemical compound Br.Br.NC(=N)N OUJADRKXKFRDEN-UHFFFAOYSA-N 0.000 description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 2
- MURRAGMMNAYLNA-UHFFFAOYSA-N impromidine Chemical compound N1C=NC(CSCCNC(N)=NCCCC=2NC=NC=2)=C1C MURRAGMMNAYLNA-UHFFFAOYSA-N 0.000 description 2
- 229950005073 impromidine Drugs 0.000 description 2
- 239000000047 product Substances 0.000 description 2
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- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- 210000005245 right atrium Anatomy 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
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- VEFLKXRACNJHOV-UHFFFAOYSA-N 1,3-dibromopropane Chemical compound BrCCCBr VEFLKXRACNJHOV-UHFFFAOYSA-N 0.000 description 1
- PQAFKIUTENVXRS-UHFFFAOYSA-N 1-[2-(2-amino-4-methyl-1,3-thiazol-5-yl)ethyl]-2-(3,3-diphenylpropyl)guanidine Chemical compound N1=C(N)SC(CCNC(N)=NCCC(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1C PQAFKIUTENVXRS-UHFFFAOYSA-N 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N 1-butanol Substances CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- MFJVCEWOOPCROM-UHFFFAOYSA-N 2-[2-(2,4-dimethyl-1,3-thiazol-5-yl)ethyl]isoindole-1,3-dione Chemical compound S1C(C)=NC(C)=C1CCN1C(=O)C2=CC=CC=C2C1=O MFJVCEWOOPCROM-UHFFFAOYSA-N 0.000 description 1
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- VQVGTGLZTBUTQY-UHFFFAOYSA-N 2-[2-(4-methyl-1,3-thiazol-5-yl)ethyl]isoindole-1,3-dione Chemical compound N1=CSC(CCN2C(C3=CC=CC=C3C2=O)=O)=C1C VQVGTGLZTBUTQY-UHFFFAOYSA-N 0.000 description 1
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- XMNSDCYVLIMUOT-UHFFFAOYSA-N 2-bromo-4-(1,3-dioxoisoindol-2-yl)butanal Chemical compound C1=CC=C2C(=O)N(CCC(Br)C=O)C(=O)C2=C1 XMNSDCYVLIMUOT-UHFFFAOYSA-N 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
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- CSJHCQDRYAUEQH-UHFFFAOYSA-N 3-(4-methyl-1,3-thiazol-2-yl)propan-1-amine;dihydrochloride Chemical compound Cl.Cl.CC1=CSC(CCCN)=N1 CSJHCQDRYAUEQH-UHFFFAOYSA-N 0.000 description 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- KDHWOCLBMVSZPG-UHFFFAOYSA-N 3-imidazol-1-ylpropan-1-amine Chemical compound NCCCN1C=CN=C1 KDHWOCLBMVSZPG-UHFFFAOYSA-N 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- WMXADABRNBNSJC-UHFFFAOYSA-N 4-(1,3-dioxoisoindol-2-yl)butanal Chemical compound C1=CC=C2C(=O)N(CCCC=O)C(=O)C2=C1 WMXADABRNBNSJC-UHFFFAOYSA-N 0.000 description 1
- IOXZFXWMILDPTH-UHFFFAOYSA-N 4-(3-aminopropyl)-1,3-thiazol-2-amine Chemical compound NCCCC1=CSC(N)=N1 IOXZFXWMILDPTH-UHFFFAOYSA-N 0.000 description 1
- BLFRQYKZFKYQLO-UHFFFAOYSA-N 4-aminobutan-1-ol Chemical compound NCCCCO BLFRQYKZFKYQLO-UHFFFAOYSA-N 0.000 description 1
- HXHGULXINZUGJX-UHFFFAOYSA-N 4-chlorobutanol Chemical compound OCCCCCl HXHGULXINZUGJX-UHFFFAOYSA-N 0.000 description 1
- AGNFWIZBEATIAK-UHFFFAOYSA-N 4-phenylbutylamine Chemical compound NCCCCC1=CC=CC=C1 AGNFWIZBEATIAK-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical compound [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 description 1
- WMJZCJDWHBNSLB-UHFFFAOYSA-N 5-(1,3-dioxoisoindol-2-yl)pentanal Chemical compound C1=CC=C2C(=O)N(CCCCC=O)C(=O)C2=C1 WMJZCJDWHBNSLB-UHFFFAOYSA-N 0.000 description 1
- BHBQCSAJEKMSPN-UHFFFAOYSA-N 5-(2-bromoethyl)-4-methyl-1,3-thiazole;hydrobromide Chemical compound Br.CC=1N=CSC=1CCBr BHBQCSAJEKMSPN-UHFFFAOYSA-N 0.000 description 1
- RIOVLKQWIKRBIB-UHFFFAOYSA-N 5-(3-aminopropyl)-4-methyl-1,3-thiazol-2-amine Chemical compound CC=1N=C(N)SC=1CCCN RIOVLKQWIKRBIB-UHFFFAOYSA-N 0.000 description 1
- LQGKDMHENBFVRC-UHFFFAOYSA-N 5-aminopentan-1-ol Chemical compound NCCCCCO LQGKDMHENBFVRC-UHFFFAOYSA-N 0.000 description 1
- CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 description 1
- 241000208199 Buxus sempervirens Species 0.000 description 1
- NEDHHMJNFMKLBT-UHFFFAOYSA-N C1([N+](=O)[O-])=CC([N+](=O)[O-])=CC([N+](=O)[O-])=C1O.C1([N+](=O)[O-])=CC([N+](=O)[O-])=CC([N+](=O)[O-])=C1O.NC=1SC(=C(N1)C)CCCNC(=N)NCCCC1=CC=CC=C1 Chemical compound C1([N+](=O)[O-])=CC([N+](=O)[O-])=CC([N+](=O)[O-])=C1O.C1([N+](=O)[O-])=CC([N+](=O)[O-])=CC([N+](=O)[O-])=C1O.NC=1SC(=C(N1)C)CCCNC(=N)NCCCC1=CC=CC=C1 NEDHHMJNFMKLBT-UHFFFAOYSA-N 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 230000001270 agonistic effect Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- CPEKAXYCDKETEN-UHFFFAOYSA-N benzoyl isothiocyanate Chemical compound S=C=NC(=O)C1=CC=CC=C1 CPEKAXYCDKETEN-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 1
- 230000002213 calciumantagonistic effect Effects 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229960004424 carbon dioxide Drugs 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000002057 chronotropic effect Effects 0.000 description 1
- AQIXAKUUQRKLND-UHFFFAOYSA-N cimetidine Chemical compound N#C/N=C(/NC)NCCSCC=1N=CNC=1C AQIXAKUUQRKLND-UHFFFAOYSA-N 0.000 description 1
- 229960001380 cimetidine Drugs 0.000 description 1
- 239000003245 coal Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- OLHQOJYVQUNWPL-UHFFFAOYSA-N dimaprit Chemical class CN(C)CCCSC(N)=N OLHQOJYVQUNWPL-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- LUOYACCQSOFAAA-UHFFFAOYSA-N ethyl 6-methyl-3,6-dihydro-2h-pyran-5-carboxylate Chemical compound CCOC(=O)C1=CCCOC1C LUOYACCQSOFAAA-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 229940083094 guanine derivative acting on arteriolar smooth muscle Drugs 0.000 description 1
- 210000002837 heart atrium Anatomy 0.000 description 1
- 239000003386 histamine H2 receptor agonist Substances 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 125000001145 hydrido group Chemical group *[H] 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000002140 imidazol-4-yl group Chemical group [H]N1C([H])=NC([*])=C1[H] 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000000297 inotrophic effect Effects 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- VKFHVRIEURVUHM-UHFFFAOYSA-N n-(diphenoxymethylidene)benzamide Chemical compound C=1C=CC=CC=1C(=O)N=C(OC=1C=CC=CC=1)OC1=CC=CC=C1 VKFHVRIEURVUHM-UHFFFAOYSA-N 0.000 description 1
- 150000002829 nitrogen Chemical group 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- YUKQRDCYNOVPGJ-UHFFFAOYSA-N thioacetamide Chemical compound CC(N)=S YUKQRDCYNOVPGJ-UHFFFAOYSA-N 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- 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
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
- C07D277/38—Nitrogen atoms
- C07D277/40—Unsubstituted amino or imino radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Pulmonology (AREA)
- Immunology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Description
New thiazole derivatives.
The invention relates to new thiazole derivatives which are: a. a N-[ω-(thiazol-4 or 5-yl)alkyl]isourea, isothiourea or a guanidine derivative with formula 2 , wherein X represents a sulphur atom and Y represents a nitrogen atom or alternatively X represents a nitrogen atom and Y represents a sulphur atom, n is 1-6, R1 represents a hydrogen atom or a straight or branched alkyl group with 1-4 carbon atoms and R2 represents a hydrogen atom, a straight or branched alkyl group with 1-4 carbon atoms or an amino group, Z represents a sulphur atom, an oxygen atom or a NH-group respectively, R3 represents a hydrogen atom, a phenyl or an alkyl group with 1-4 carbon atoms respectively and R4 represents a hydrogen atom, a cyano or a benzoyl group respectively; b. a N-(ω-substituted alkyl)-N'-substituted-N"-[ω-(thiazol-4 or 5-yl) alkyl] guanidine with formula 3 , wherein X represents a sulphur atom and Y represents a nitrogen atom or alternatively X represents a nitrogen atom and Y represents a sulphur atom, n is 1-6, R1 represents a hydrogen atom or a straight or branched alkyl group with 1-4 carbon atoms and R2 represents a hydrogen atom, a straight or branched alkyl group with 1-4 carbon atoms or an amino group, R4 represents hydrogen, a cyano or a benzoyl group respectively, m is 1,2 or 3, A represents a sulphur or an oxygen atom, a -CH2- ox
a -CH= group respectively and Q represents a R-substituted diphenylmethyl group or a R-substituted (10,11-dihydro) optionally aza 5H-dibenzo-[a,d]-cyclohepten-5-yl group or Q represents a nitrogen atom substituted with Q1 and Q2, wherein Q1 and Q2 represent whether or not symmetrical
R-substituted (ω-)phenyl(alkyl) groups, or Q represents a R-substituted (ω-)phenyl(alkyl) group or Q represents a whether or not symmetrical mono-or disubstituted methylidene fragment, wherein R1 represents a R-substituted (10,11-dihy- dro) optionally aza 5H-dibenzo-[a,d]-cyclohepten-5-yl group or R' represents two whether or not symmetrically with R substituted phenyl groups, wherein R represents hydro
gen, alkyl, alkoxy, amino, mono- or dialkylamino, guanidino, nitro, carboxy, carbalkoxy, halogen (fluoro, chloro, bromo, iodo), mono-, di- and trihalogenmethyl or -methoxy (halogen = fluoro, chloro, bromo) etc., while in addition the R-substituted phenyl rings may be replaced by a (heterocyclic) (aromatic) ring whether or not R-substituted or by a combination of a (condensed) (aromatic) (heterocyclic) R-substituted ring with one or more (condensed) (aromatic) (heterocyclic) rings whether or not symmetrically R-substituted.
Possible present R-substituted (condensed) (heterocyclic) (aromatic) rings are for example: 2-, 3-, 4-pyridyl, 2-, 4-, or 5-pyrimidinyl, 2-, 3-, 4-[dihydro]pyridyl, 4- or 5-imidazolyl, 2-, 4- or 5-thiazolyl, 2- or 3-furyl, 2- or 3-thienyl, dihydropyridazinon-2 or 6-yl, 2-benzoimidazolyl, etc.
The invention also relates to the acid addition salts of the compounds with the formulas 2 and 3.
Histamine receptors are classified according to the present knowledge into three categories which are described, mainly for historical reasons, with the qualifications of H 1- , H2- and H3-receptor.
Each of these classes of receptors presumably has its own and biologically specific function, in as far as they are present and dependent on the location of such a receptor type in the
organism involved.
In circumstances where a failure of the normal physiological system has occurred a treatment with endogenous or exogenous compounds may be necessary which may stimulate (agonistic activity) or inhibit (antagonistic activity) the receptor system. From the above follows the great importance of compounds capable to agonize or to antagonize in a selective way the different classes of histamine receptors.
It is important to be able to dispose of selective histamine receptor active compounds in order to discriminate between the different receptor types not only from a scientific (pharma-cological) point of view, but also on therapeutic respect notably the stimulation of the histamine H2-receptor offers wide perspectives for the treatment of congestive heart diseases, accompanied by heart failure, and certain allergic disorders so that there exists a large interest from within the pharmaceutical industry for the development and application of selective, histamine H2-receptor active, compounds.
Impromidine (5), described by G.J. Durant et al. in Nature 276, p.403-405 (1978) and Dimaprint (6), described by C.R. Ganellin in Pharmacology of Histamine Receptors, p.40-44 (1982), publishers Wright.PSG., exhibit a moderately to fairly high affinity for the histamine H2-receptor.
N-(ω-substituted alkyl)-N'-[imidazol-4-yl]alkyl)guanidines with formula 7, as described in the Dutch patent application 86 01585, and Arpromidine (8) and analogues, as described by A.Buschauer in J.Med.Chem. 32, p.1963-1970 (1989) on the contrary exhibit a high to very high affinity for the H2- receptor.
Both Impromidine (5), the most active guanidine derivatives of formula 7 and Arpromidine (8) all contain under physiological circumstances a protonated N-[3-(imidazol-4-yl)propyl]- guanidine fragment.
This fragment, which has been described as SK&F 91486 (9) by M.E. Parsons et al. in Agents and Actions 5, p.464 (1975) has
been considered in the literature as an element essential for the activity of this type of compounds on the H2-receptor as described by A.Buschauer in J.Med.Chem. 32, p.1963-1970 (1989).
Further substitution at one of the free nitrogen atoms or the guanidine function of this basic element may be applied in order to increase the affinity for the H2-receptor and/or to introduce a possibly wanted additional biological activity such as: antagonism of the H1-receptor, as described by G.J.Sterk et al. in Eur.J.Med.Chem. 22, p.427-432 (1987) and the Dutch patent application 86 01585, calciumantagonism as illustrated by the guanidine derivative (10) described by V.Pfahlert et al., in Arch.Pharm. 338, R49 (1988), or phosphodiesterase inhibition as described in the European patent application 0310737 and illustrated by the guanide derivative (11).
Likewise in these compounds (10 and 11), the imidazole moiety can be replaced by a (substituted)aminothiazole.
Thus the invention also relates to a process for the preparation of a ω-aminoalkylthiazole derivative in which one prepares a histamine H2-receptor active compound, whether or not in combination with an additionally wanted biological activity, by preparing from a compound with formula 1 or its acid addition salt a compound with a substituted 4- or 5-(ω- thiazoly1-alkyl) guanidine fragment.
Examples of such compounds are the compounds with formulas 2 and 3 and their acid addition salts.
Additional substitution at the other nitrogen atom may be applied in order to change the activity for the H2-receptor into an antagonistic activity.
Although thus far a large number of (substituted) analogues of histamine, in which the imidazole term has been replaced by another heterocyclic ring system, has been described in the literature, for a review of which reference may be made to C.R. Ganellin in Pharmacology of Histamine Receptors, p.21-31 (1982), publishers Wright.PSG, none of the mentioned analogues displays an activity at the H2-receptor which is
comparable to that of histamine. Only M. Impicciatore et al. report in Agents and Actions, 20, p.3-4 (1987) about 2-amino- 5-(2-aminoethyl)-thiazole, which according to these authors is able to stimulate through an indirect pathway the histamine H2-receptor (as determined on the fundus of the guinea pig). In II Farmaco Ed.Sci., 40 (6), p.483-498 (1986) T.Vitali et al. describe this same 2-amino-5-(2-aminoethyl)thiazole reporting that this compound exhibits an activity on the right atrium of the guinea pig of 0.3% relative to the activity of histamine whereas this activity is related to the inotropic effect.
A new series of substituted ω-(thiazol-4 or 5-yl) alkyl derivatives has now been discovered which display a very selective and high histamine H2-receptor activity on the right atrium of the guinea pig, namely the above mentioned compounds with formulas 1-4 and their acid addition salts. All this is clearly illustrated by a characteristic representative of the 4- or 5-(ω-aminoalkyl)thiazoles reported under formula 1, viz. the 2-amino-5-(2-aminoethyl)-4-methylthiazole (12) which is essentially a substituted sulphur analogue of the endogenous histamine (13) or which alternatively may be considered as a closed ring analogue of dimaprit (6).
Whereas endogenous histamine (13) is able to stimulate all previously mentioned types of histamine receptors, the 2- amino-5-(2-aminoethyl)-4-methylthiazole (12) can be displaced competitatively by cimetidine, while the intrinsic activity (related to the chronotropic effect) is equal to that of histamine, thus rendering it to be a full agonist for the H2- receptor with an activity twice as high as that of histamine. The 2-amino-5-(3-aminopropyl)-4-methylthiazole (26b) is a full H2-receptor agonist with an activity 30 times as high as that of the corresponding 4 (5)-3-aminopropyl)-imidazole.
The 2-amino-5-(2-aminoethyl)-4-methylthiazole (12) shows however contrary to histamine (13), in the testing systems used not a single activity towards the H1 and H3-receptors.
The essence of the invention now relates to the replacement of the N-[3-(imidazol-4-yl)propyl]guanidine fragment (9) from the previously mentioned different classes of H2-receptor
active compounds with i.a. other combined H1-receptor antagonistic, calcium antagonistic, phosphodiesterase inhibitory activity etc, by the more H2-receptor specific and more active N-[3-(substituted thiazol-4 or 5-yl)propyl]guanidine fragments. The thiazole derivatives with formulas 2-4 thus obtained show a high to very high activity on the H2-receptor.
The 4- or 5-(ω-aminoalkyl) thiazole derivatives mentioned in the introduction with formula 1 may be obtained using a process not previously described in the literature in high yields by ring closure of a 2-bromo-ω-phthalimidoalkanal (18), a 3-bromo-ω-phthalimidoalkan-2-one (24) or a 1-bromo-ω- phthalimidoalkan-2-one (27) with thioformamide, an alkylthioamide or thiourea in dimethylformamide under mild conditions, followed by hydrazinolysis or hydrolysis with diluted hydrochloric acid of the resulting phthalimido derivatives (19, 25 or 28) as depicted in reaction schemes A and B.
As will be evident from reaction scheme A one uses as starting materials for the preparation of the 2-bromo-ω-phthalimidoalkanals (18) ω-phthalimidoalkanols (16) which may be obtained using processes known from the literature. Conversion of these ω-phthalimidoalkanols (16) into the corresponding aldehydes (17) is being carried out according to a general method using oxalylchloride/dimethylsulphoxyde, followed by proton abstraction with a mild base such as triethylamine followed by hydrolysis with water as described by K.Omura et al. in Tetrahedron 34, p. 1651-1660 (1978).
Subsequently the desired 2-bromo-ω-phthalimidoalkanals (18) are obtained in almost quantitative yield by selective α- bromination of the obtained ω-phthalimidoalkanals (17) with bromine in carbon tetrachloride.
The preparation of the 3-bromo-ω-phthalimidoalkan-2-ones (24) as indicated in reaction scheme (B) takes place by selective bromination with bromine in carbon tetrachloride of the corresponding ω-phthalimidoalkan-2-ones (23) which may be obtained according to a process described in the Dutch patent
application 8800998 in which the necessary 1-bromo-ω-phthalimidoalkan-2-ones (27) have been described as well. The necessary ω-haloketones (22) which are to be used for the preparation of the 1- and 3-bromo-ω-phthalimidoalkan-2-ones (24 and 27) are either commercially available or may be obtained in good yield according to a process described in the literature such as for example the process described in the Dutch patent application 65 11581.
The N-[ω-(thiazol-4 or 5-yl) alkyl] isourea or isothiourea derivatives with formula 2 are obtained by reaction of a 4- or 5-(ω-aminoalkyl)thiazole with formula 1, with a dialkyl-N- cyano-iminodithiocarbonate, a diphenyl-N-cyanocarbonimidate or a diphenyl-N-benzoylcarbonimidate respectively in a suitable solvent according to methods known from the literature and as indicated in reaction scheme C.
The corresponding N-[ω-(thiazol-4 or 5-yl) alkyl]guanidine derivatives are obtained by reacting a 4- or 5-(ω-aminoalkyl)thiazole with formula 1 together with a S-alkylisothiouronium derivative. The N-[ω-(thiazol-4 or 5-yl)alkyl]isourea or isothiourea derivatives thus obtained (32) are condensed with a suitable amine (33). The N-(ω-substituted alkyl)-N'- subtituted-N"-[ω-(thiazol-4 or 5-yl)alkyIguanidines with formula 3 (34) thus obtained are purified and subjected to a mild hydrolysis in diluted hydrochloric acid following which the resulting N-(ω-substituted alkyl)-N'-[ω-(thiazol-4 or 5-yl) alkyl] -guanides with formula 4 (35) can be obtained in good yield eventually after conversion to a suitable acid addition salt.
Alternatively the desired N-(ω-substituted alkyl)-N'substituted-N"-[ω-(thiazol-4 or 5-yl)alkyl]guanidines with formula 3 may be obtained by reacting a 4- or 5-(ω-aminoalkyl)thiazole with formula 1 together with the corresponding N-(ω-substituted alkyl) isourea or isothiourea derivatives (36) according to methods known from the literature and as indicated in reaction scheme D or by condensation of a 4- or 5-(ω-aminoalkyl)thiazole with formula 1 with a N-(ω-substituted alkyl)-S- alkylthiouronium derivative (41) as indicated in reaction
scheme E.
The invention also relates to a medicament or a scientific (pharmacological) adjuvant which contains as the active ingredient a compound according to one of the formulas 2-3 or an acid addition salt thereof. One may use the compounds or the medicaments according to the invention for the treatment of congestive heart diseases whether or not accompanied by hear failure or for the treatment of allergic disorders.
The invention is illustrated by the following examples:
All the chemicals and solvents used are commercially available unless stated otherwise.
Melting points were determined by a Mettler FP 5 device for the determination of melting points.
1H-NMR-spectra were determined with a Bruker WH-90 spectrophotometer and the chemical shifts δ (in ppm) with tetramethylsilane as reference.
Mass spectra are determined on a Varian Mat CH5 spectrometer or on a Mat 90 (Finnigan Mat, San Jose, U.S.A.).
Histamine H2-activity was determined on the
right-side atrium of the guinea pig as described by
G.J. Sterk et al in Eur. J. Med. Chem., 19, p. 545-550 (1984).
Example I
ω-phthalimido-1-alkanols (16)
General process:
A mixture of 148 g (1 mole) of particulated phthalic anhydride (15) and 1 mole of a desired ω-amino-1- alkanol is heated under nitrogen with stirring
at circa 80°C. After starting the exothermal reaction with which the temperature is rising to circa 140° C,
there is heated at 140° C for three hours.After cooling the reaction mixture until circa 80°C the viscous mass is poured out in icewater with stirring. Subsequently
it is extracted with chloroform and the collected chloroformphases are extracted with a 5%-aqueous sodiumhydrogen carbonate solution, thereafter it is washed three times with demineralized water. After drying on anhydrous sodium sulfate and filtration the chloroform phase is hjgh-vacuum concentrated.
Thus there were obtained:
a.4-phthalimido-1-butanol (16a) in 91% yield, from phthalic anhydride and 4-aminobutanol.
1H-NMR (CDCl3): 1.38-1.90 ppm., mul tiplet, 4H; 2.53 ppm, singlet, 1H; 3.51-3.83 ppm, multiplet, 4H; 7.58- 7.94 ppm, multiplet, 4H.
b. 5-phthalimido-1-pentanol (16b) in 85% yield, from phtalic anhydride and 5-amino pentanol.
1H-NMR (CDCl3): 1.23-1.90 ppm., multiplet, 6H; 2.36 ppm., singlet, 1H; 3.59 ppm..triplet (J=5.4 Hz), 2H;
3.67 ppm., triplet (J=7.2 Hz), 2H; 7.58-7.92 ppm., multiplet, 4H. Example II
a. 4-Phthalimido-1-butanol (16b)
4-Phthalimido-1-butanol (16b) can, if desired, also be obtained in the following way:
A mixture of 100 g (0.92 mole) of 4-chloro-1-butanol, 135.5 g (0.92 mole) phthalimid and 127 g (0.92 mole particulated anhydrous potassium carbonate in circa
500 ml dry dimethylformamide is refluxed
under nitrogen for 12 hours. After cooling
the reaction mixture the inorganic salts are filtered off and the precipitate s rinsed with a little cold methanol, subsequently the filtrate is vacuum concentrated.
To the residue obtained circa 250 ml of ethyl- acetate is added and after standing over night at 5°C the resulting residue is removed by filtration.
The filtrate is vacuum concentrated and the
residue is taken up in circa 200 ml chloroform. After extraction with a 5%-aqueous sodium hydrogen carbonate solution there is extracted a few times in demineralized water. The chloroform phase is dried on anhydrous potassium carbonate, filtered and vacuum concentrated.
Yield 95%. The so obtained 4-phthalimido-1-butanol is
identical to the product obtained by the general
process for the ω -phthalimido-1-alkanols as described in example I. After prolonged standing the viscous oil
crystallized.
Melting point 47-49° C.
Example III
ω-phthalimido-1-alkanals (17)
The preparation of the ω-phthalimido-1-alkanals (17) occurs analogous to the method as described by K. Omura et al in Tetrahedron, 34, pages 1651-1660 (1978) for the preparation of aldehydes from aliphatic or benzylic alcohols.
General process:
To a solution of 63.5 g (0.5 mole) oxalylchloride in circa 1000 ml dry dichlororaethane in a nitrogen atmosphere
with vigorous stirring at -50°C a solution of 83 g (1.06 mole) of dry dimethylsulfoxide in circa 200 ml of dry
dichloromethane is dropwise added at such a rate that the temperature is maintained at -50°C. After the addition the stirring is continued for 15 minutes, subsequently a solution of 0.40 mole of an appropriate ω-phthalimido-1-alkanol (16) in circa 400 ml of dry dichloromethane is dropwise added at such a rate that the temperature is maintained at -50°C. After the addition the stirring is continued at -50°C for 30 minutes, subsequently 222 g (2.20 mole) of triethylamine is added thereto. Subsequently the cooling is removed and the reaction mixture is slowly brought with stirring at room temperature, thereafter circa 1250 ml of demineralized water is added. After stirring for 30 minutes at room temperature the organic phase is removed* and extracted with demineralized water to neutral reaction. The organic phase is subsequently
dried on anhydrous sodium sulfate, filtered and vacuum concentrated. The viscous oil obtained is kept in nitrogen atmosphere and is used without any further purification for the preparation of the corresponding 2-bromo-co phthalimido- alkanales (18).
* Nota bene: All the actions are carried out as much as
possible in a nitrogen atmosphere to prevent oxidation of the aldehydes obtained by atmospherical oxygen.
Thus there were obtained:
a. 4-phthal imido-1-butanal (17a) in 80% yield, from 4-phthalimidobutanol.
1H-NMR (CDCl3): 1.80-2.19 ppm., multiplet, 2H; 2.56 ppm., triplet (J=7.4 Hz), 2H; 3.74 ppm, triplet (J=6.8 Hz, 2H;
7.52-7.93 ppm., multiplet, 4H; 9.74 ppm., singlet, 1H.
b. 5-phthalimido-1-pentanal (17b) in 85% yield, from
5-phthalimidopentanol.
1H-NMR (CDCl3): 1.50-1.92 ppm., multiplet, 4H; 2.41-2.66 ppm., multiplet, 2H; 3.73 ppm., triplet (J=6.8 Hz), 2H;- 7.62-7.94 ppm., multiplet, 4H; 9.75 ppm., triplet (J=0.6 Hz), 1H.
Example IV
2-Bromo- ω -phthalimido-1-alkanals ( 18 )
General process:
To a solution of 0.5 mole of an appropriate ω-phthalimido- 1-alkanol (17) in circa 500 ml of tetrachlorocarbon in a nitrogen atmosphere stirring vigorously 80 g (0.5 mole) of bromine is cautiously added at room temperature. After decoloration of the reaction mixture stirring is continued at room temperature for 2 hours. Subsequently circa 100 ml of
chloroform and 500 ml of demineralized water are added, thereafter stirring takes place in a nitrogen atmosphere for 30 minutes. The water phase is removed and the organic phase is washed in a nitrogen atmosphere with demineralized water to neutral reaction. After drying on anhydrous sodium sulfate and filtration the organic phase is vacuum concentrated. The viscous oil obtained is used without any purification for the preparation of the corresponding 5-ω-phthalimidoalkyl- thiazoles (19).
Thus there were obtained:
a. 2-Bromo-4-phthalimido-1-butanal (18a) in 78.5 % yield, from 4-phthalimido-1-butanal (17a).
1 H-NMR (CDCl3: 2.00-2.75 ppm., multiplet, 2H; 3.87 ppm., triplet (J=6.8 Hz), 2H; 4.40 ppm, double triplet (J1 =7.2 Hz, J2= 1.8 Hz), 1H; 7.59-7.96 ppm., multiplet, 4H; 9.45 ppm., doublet (J=1.8 Hz), 1H. b. 2-bromo-5-phthalimido-1-pentanal (18b) in 68% yield, from 5-phthal imi do-1-p entanal (17b)
1H-NMR (CDCl3): 1.76-2.10 ppm.; multiplet, 4H; 3.73 ppm., triplet (J=6.3 Hz), 2H; 4.36 ppm., broad triplet, 1H; 7.60- 7.92 ppm., multiplet, 4H; 9.40 ppm., doublet (J=1.8 Hz),1H.
Example V
5-(ω-phthalimidoalkyl)thiazoles (19)
General process:
To a solution of 0.1 mole of an appropriate crude 2-bromo- phthalimido-1-alkanal (18) in circa 100 ml of dry dimethyl- formamide in a nitrogen atmosphere a solution of 0.1 mole
thioureum, respectively thioformamide, respectively an alkylthioamide in circa 50 ml of dry dimethylformamide is added with stirring. After the light exothermal reaction heating takes place at 100°C for 3 hours. After cooling the
reaction mixture is high vacuum concentrated. Subsequently a little ethanol is added to the residue, it is stirred for 30 minutes, thereafter the crystalline material is filtered off, washed with subsequently ethanol and diethylether, thereafter the precipitate is vacuum dried. If necessary it is recrystallized from an appropriate solvent.
Thus there were obtained:
a. 2-amino-5-(2-phthalimidoethyl)thiazole hydrobromide (19a) in 63% yield, from 2-bromo-4-phthalimido-1-butanol (18a) and thiourea.
The product was crystallized from an ethanol/methanol mixture.
Melting point 221-225°C.
1H-NMR (D6-DMSO): 2.98 ppm., triplet (J=6.8 Hz), 2H; 3.78 ppm., triplet (J=6.8 Hz), 2H; 7.10 ppm., singlet, 1H;
7.86 ppm., singlet, 4H; 9.08 ppm., broad singlet, 2H.
b. 2-amino-5-(3-phthalimidopropyl)thiazole hydrobromide (19b) in 78.5% yield, from 2-bromo-5-phthalimido-1-pentanal (18b) and thiourea.
1H-NMR (D6-DMSO): 1.69-21.13 ppm., multiplet, 2H; 2.72 ppm., triplet (J=7.2 Hz), 2H; 3.66 ppm., triplet (J=6.3 Hz), 2H ; 7.15 ppm., singlet, 1H; 7.90 ppm., singlet, 4H; 9.28 ppm., broad singlet, 2H.
Example VI
6-bromo-2-hexanone (22a)
6-Bromo-2-hexanone (22a) is prepared according to a modified process as described in Dutch patent application 6511581 dated March 7,1966, cf. Chem. Abstr. 65, P20151d.
A mixture of 552 g (4 mole) of particulated anhydrous potassium carbonate, 404 g (2 mole) of freshly distilled 1,3- dibromopropane, 260g (2 mole) of freshly distilled acetyl acetic ester and 700 ml of absolute ethanol is heated with vigorous stirring until circa 60°C. After the mild exothermal reaction beginning at circa 50°C, the reaction mixture is refluxed for circa 5 hours. After cooling the reaction mixture the inorganic salts are filtered off and the residue is rinsed with absolute ethanol. The combined filtrates are subsequently vacuum concentrated, thereafter to the residue circa 250 ml of demineralized water is added. Subsequently it is extracted with toluene. The collected toluene phases are combined, dried on anhydrous sodium sulfate, filtered and subsequently vacuum concentrated.
Yield 73% on the basis of G.C./M.S. Subsequently 170.0 g (1.00 mole) of the crude 2-methyl-3-carbethoxy-5,6-dihydropyrane together with 140 ml of concentrated aqueous HBr- solution (48%) is refluxed with vigorous stirring for
3 hours, and a violent evolution of carbondioxide gas
takes place. After cooling the reaction mixture the formed 6-bromo-2-hexanone (22a) is extracted by means of chloroform, the collected chloroform phases are washed with demineralized water
to neutral reaction, thereafter dried on anhydrous sodium sulfate, filtered and vacuum concentrated. Subsequently the residue is subjected to fractionated distillation.
Yield 104 g (0.58 mole) which corresponds with 79.4%.
Boiling point 102-106°C/18 mm Hg . Reference: (Chem. Abstr., 65, P 20151d).
94-98°C/12 mm Hg.
Mass spectrum M/Z (intensity in %) . 180(0.14): 178(0.11);
137(6.3); 99 (100).
1H-NMR (CDCl3): 1.50-2.06 ppm., broad multiplet, 4H; 2.14 ppm., singlet, 3H; 2.48 ppm., triplet (J=6.3 Hz),
2H; 3.40 ppm., triplet (J=6.8 Hz), 2H.
Examole VII
a. 4-phthalimido-2-butanone (23a)
The 4-phthalimido-2-butanone (23a) was prepared according to a modified process by H. Irai et al., Kogyo Kagaku
Zasschi, 62, pages 82-85 (1959) cf. Chem.Abstr., 58, 5659 b (1963) and such as described in Dutch patent application
8800998, April 18,1988.
Melting point 108.5-110°C (Reference: H.Irai et al., 111-113°C). 1H-NMR (CDCl3): 2.22 ppm, singlet, 3H; 2.96 ppm., triplet (J=7.0 Hz), 2H; 3.96 ppm, triplet (J=7.0 Hz), 2H; 7.62- 7.96 ppm., multiplet, 4H.
b . 5-phthal imido-2-pentanone ( 23b )
The 5-phthalimido-2-pentanone ( 23a) is prepared according to Dutch patent app lication 8800998 , April 18 , 1988.
Yield 53%
Melting point 72-74°C.
1H-NMR (CDCl3): 1.89-2.12 ppm., multiplet, 2H; 2.15 ppm., singlet, 3H; 2.51 ppm., triplet (J=7.2 Hz), 2H;
3.72 ppm., triplet (J=6.6 Hz), 2H; 7.67-7.92 ppm., multiplet, 4H.
c. 6-phthalimido-2-hexanone (23c)
The 6-phthalimido-2-hexanone (23b) is prepared as described for the 5-phthalimido-2-pentanone (23a) in Dutch patent application 8800998, April 18,1988.
Yield 80%, viscous oil.
1H=NMR (CDCl3): 1.48-1.80 ppm., multiplet, 4H; 2.14 ppm., singlet, 3H; 2.52 ppm., triplet (J-6.8 Hz), 2H; 3.70 ppm., triplet (J=6.3 Hz), 2H+ 7.66-7.90 ppm., multiplet, 4H.
Example VIII
3-Bromo- ω -phthal imi do-2-alkanones ( 24 )
General process:
To a solution of 0.5 mole of an appropriate ω-phthal- imido-2-alkanone (23) in circa 500 ml of tetrachlorocarbon is cautiously added, with vigorous stirring, 80 g (0.5 mole) bromine at room temperature. After decoloration of the reaction mixture the stirring is continued at room temperature for circa 2 hours. Subsequently there is added circa 100 ml chloroform and 500 ml of demineralized water, thereafter it is stirred for 30 minutes. The water phase is subsequently removed and the organic phase is washed with
demineralized water until neutral reaction. The organic phase is subsequently dried on anhydrous sodium sulfate, filtered and vacuum concentrated. The residue (viscous oil) is
used without any purification for the preparation of the
2-amino-4-methy-5-(Co-phthalimidoalkyl)thiazoles (25).
Thus there were obtained:
a. 3-Bromo-5-phthalimido-2-pentanone (24a)
yield 95%, from 5-phthalimido-2-pentanone (23b).
1H-NMR (CDCl3): 2.10-2.59 ppm., multiplet, 2H; 2.40 ppm., singlet, 3H; 3.82 ppm., triplet (J=6.3 HZ), 2H; 4.34 ppm., triplet (J=7.5 Hz), 1H; 7.69 ppm., multiplet, 4H.
b. 3-Bromo-6-phthalimido-2-hexanone (24b)
yield 93%, from 6-phthalimido-2-hexanone (23c).
1H-NMR (CDCl3): 1.74-2.22 ppm, multiplet, 4H; 2.36 ppm., singlet, 3H; 3.46-3.90 ppm., multiplet, 2H; 4.36 ppm., triplet, (J=7.2 Hz), 1H; 7.60-7.95 ppm., multiplet, 4H.
Example IX
5-(ω-phthalimidoalkyl)-4-methylthiazoles (25)
General process:
To a solution of 0.2 mole of a crude 3-bromo-ω-phthalimido-2-alkanone (24) in circa 100 ml of anhydrous dimethyl- formamide a solution of 0.2 mole of thiourea respectively thioformamide, respectively an alkylthioamide in circa 100 ml of dry dimethylformamide is added with stirring. After
the exothermal reaction the temperature may rise to circa 100°C, there is heated at circa 100°C for circa 3 hours. After cooling the reaction mixture is high vacuum concentrated, thereafter to the residue an ethylacetate/methanol mixture (1:1 v/v) is added. After stirring circa 30 minutes the precipifete obtained is filtered off, washed subsequently with ethylacetate and diethyl ether, thereafter the precipitate is vacuum dried.
Thus were obtained:
a. 2-Amino-5-(2-phthalimidoethyl)-4-methylthiazole- hydrobomide (25a)
yield 50%, from 3-bromo-5-phthalimido-2-pentanone (24a) and thioureum.
1H-NMR (D6-DMSO): 1.98 ppm., singlet, 3H; 2.98 ppm., triplet (J=6.5 Hz), 2H; 3.78 ppm., triplet (J=6.5 Hz) 2H; 7.91 ppm., singlet, 4H; 9.06 ppm., broad singlet, 2H.
b. 2-amino-5-(3-phthalimidopropyl)-4-methyl thiazole
hydrobromide (25b)
Yield 51%, from 3-bromo-6-phthalimido-2-hexanone (24b) and thioureum.
1H-NMR (D6-DMSO): 1.61-2.04 ppm., multiplet, 2H, 2.15 ppm., singlet, 3H; 2.70 ppm., triplet ( J=8.1 Hz), 2H; 3.64 ppm., triplet (J=6.6 Hz), 2H; 7.88 ppm., singlet, 4Ht 9.23 ppm., broad singlet, 2H.
c. 5-(2-phthalimidoethyl)-4-methylthiazole hydrobromide (25c) yield 40%, from 3-bromo-5-phthalimido-2-pentanone (24a) and thioformamide.
Melting point 207.4-210.6°C.
1H-NMR (D6-DMSO): 1.99 ppm., singlet, 3H; 2.96 ppm., triplet
(J=6.3 Hz), 2H; 3.76 ppm., triplet (J-6.3 Hz), 2H; 7.92 ppm., singlet, 4H; 9.23 ppm., broad singlet, 2H. d. 5-(2-phthalimidoethyl)-2,4-dimethylthiazole hydrobromide (25d)
yield 50%, from 3-bromo-5-phthalimido-2-pentanone (24a) and thioacetamide.
1H-NMR (D6-DMSO): 2.13 ppm., singlet, 3H; 2.70 ppm., singlet, 3H; 3.15 ppm., triplet (J=6.3 Hz), 2H ; 3.78 ppm., triplet (J=6.3 Hz9, wH; 7.84 ppm., singlet, 4H ; 8.78 ppm., broad singlet, 1H.
Example X
1-bromo-ω-phthalimido-2-alkanones (27)
The 1-bromo-ω-phthalimido-2-alkanones (27) are prepared according to Dutch patent application 8800998, April 18,1988.
Thus there were obtained:
a. 1-bromo-4-phthalimido-2-butanone (27a). Yield 60%.
Melting point 120-122°C (reference: R.G. Jones et al
J. Amer. Chem. Soc., 72, pages 4526-4529 (1950) 119-120°C).
1H-NMR (CDCl3): 3.13 ppm., triplet (J=7.2 Hz), 2H-; 3.92 ppm., singlet, 2H; 4.04 ppm., triplet (J=7.2 Hz), 2H; 7.60-7.96 ppm., multiplet, 4H.
b. 1-bromo-5-phthalimido-2-pentanone (27b).
Yield 52%. Melting point 131-133.4°C (Reference: S.Elz and
W. Schunack, Z.Natur. Forsch., 42b, p. 238-242 (1987) 122-125°C,
J. Michalksky et al, Chem. Listy, 49, p. 1379-1384 (1955) cf. Chem. Abstr., 50, 5681 d (1956) 139°C).
1H-NMR (CDCl3): 1.82-2.24 ppm., multiplet, 2H; 2.74 ppm., triplet (J=7.2 Hz), 2H; 3.74 ppm., triplet (J=7.2 Hz),
2H; 3.94 ppm., singlet, 2H; 7.64-7.88 ppm., multiplet, 4H.
Example XI
4-(ω-phthalimidoalkyl)thiazoles (28)
The 4-(ω -phthalimidoalkyl)thiazoles (28) are prepared as described for the 5-(ω-phthalimidoalkyl)thiazoles (25) in example IX.
Thus there were obtained:
a. 2-amino-4-(2-phthalimidoethyl)thiazole hydrobromide (28a) Yield 95%, from 1-bromo-4-phthalimido-2-butanone (27a) and thioureum.
1H-NMR (D6-DMSO): 2.95 ppm., triplet (J=5.9 Hz), 2H;
3.87 ppm., triplet (J=5.9 Hz), 2H; 6.57 ppm., singlet, 1H; 7.86 ppm., singlet, 4H; 8.98 ppm., broad singlet, 2H.
b. 2-amino-4-(3-phthalimidopropyl)thiazole hydrobromide (28b)
Yield 80%, from 1-bromo-5-phthalimido-2-pentanone (27b) and thioureum.
1H-NMR (D6-DMSO): 1.72-2.13 ppm., multiplet, 2H; 2.60 ppm., triplet (J=7.2 Hz), 2H; 3.62 ppm., triplet (J=6.3 Hz), 2H; 6.56 ppm., singlet, 4H; 9.12 ppm., broad singlet, 2H.
Example XII
4- or 5-(ω-aminoalkyl)thiazoles (20, 26, 29)
General process:
A solution of 0.1 mole of an appropriate ω-phthalimido- alkyl thiazole hydrobromide (25) in circa 400 ml of anhydrous methanol is refluxed with 0.2 mole of an 80%-aqueous hydrazine-hydrate solution for 5 hours. After cooling in ice the crystallized phthalhydrazine is filtered off and the clear filtrate is vacuum concentrated. Subsequently 105 ml of a 1 molar aqueous sodium hydroxide solution is added to the residue, thereafter there is high-vacuum concentrated at room temperature. The residue obtained is stirred with warm absolute ethanol, which is high-vacuum concentrated after filtration. After taking up the residue in absolute ethanol there is acidified with a concentrated aqueous
37%- hydrochloric acid solution until circa pH = 2,
thereafter the mixture is high-vacuum concentrated at
room temperature and residual water are azeotropically
removed by using toluene. To the residue obtained
acetone is subsequently added, thereafter the crystalline material is filtered off, rinsedwith acetone and diethylether, thereafter it is vacuum dried, If necessary there is
recrystallized from an appropriate solvent.
Thus were obtained:
a. 2-amino-5-(2-aminoethyl)thiazole dihydrochloride (20a) Yield 70%, from 2-amino-5-(2-phthalimidoethyl)thiazole
hydrobromide (29a).
Crystallized from methanol. Melting point 226-230°C.
1H-NMR (D6-DMSO): 2.88-3.14 ppm, broad singlet, 4H; 7.20 ppm., singlet, 1H; 8.29 ppm, broad singlet, 3H; 9.35 ppm., singlet, 2H.
Mass spectrum M/Z (intensity in %): 143 (19.3); 127(3.4); 114 (100).
M+ = 143.054 (calculated for C5H9N3S: 143.052)
b. 2-amino-5-(3-aminopropyl)thiazole dihydrochloride (20b)
Yield 83%, from 2-amino-5-(3-phthalimidopropyl)thiazole hydrobromide (19b).
Crystallized from an ethanol/methanol mixture.
1H-NMR (D6-DMSO): 1.68-2.10 ppm, multiplet, 2H; 2.79 ppm, broad triplet, 4H; 7.20 ppm, singlet, 1H; 8.20 ppm,
broad singlet, 3H; 9.46 ppm, broad singlet, 2H.
Mass spectrum M/Z (intensity in %): 157.(13.3): 141 (53.6); 127(100); 113 (9.5).
M+ = 157.0 63 (calculated for C6H11N3S: 157.067) c. 2-amino-5-(2-aminoethyl)-4-methylthiazole dihydrochloride (26a)
Yield 82%, from 2-amino-5-(2-phthalimidoethyl)-4-methyl- thiazole hydrobromide (25a).
1H-NMR (D6-DMSO): 2.19 ppm., singlet, 3H; 2.82-3.07 ppm. broad singlet, 4H; 8.34 ppm., broad singlet, 3H; 9.32 ppm., broad singlet, 2H.
Mass spectrum M/Z (intensity in %): 157(5.0); 141(3.8);
127(5.0); 114(8.3).
M+ = 157.065 (calculated for C6H11N3S: 157.067)
d. 2-amino-5-(3-aminopropyl)-4-methylthiazole dihydrochloride (26b). Yield 90%, from 2-amino-5-(3-phthalimido- propyl)-4-methylthiazole hydrobromide (25b).
1H-NMR (D6-DMSO): 1.66-2.02 ppm., multiplet, 2H; 2.16 ppm., singlet, 3H; 2.57-3.03 ppm, multiplet, 4H; 8.15 ppm, broad singlet, 3H; 9.32 ppm., broad singlet, 2H.
Mass spectrum M/Z (intensity in %) : 171(28.9); 154(75.1); 127(100); 115(9.7).
M+ = 171.080 (calculated for C7H13N3S: 171.083).
e. 2-amino-4-(2-aminoethyl)thiazole dihydrochloride (29a)
Yield 64%, from 2-amino-4-(2-phthalimidoethyl)thiazole hydrobromide (28a).
1H-NMR (D6-DMSO): 2.96 ppm., triplet (J=6.3 Hz), 2H;
3.12 ppm., triplet (J=6.3 Hz), 2H; 6.72 ppm., singlet, 1H; 8.04 ppm., broad singlet, 3H; 9.28 ppm., broad
singlet, 2H.
Mass spectrum M/Z (intensity in %): 143(4.4); 127(9.9);
114(100).
M+ = 143.052 (calculated for C5H9N3S: 143.052).
f. 2-amino-4-(3-aminopropyl)thiazole dihydrochloride (29b)
Yield 70%, from 2-amino-4-(3-phthalimidopropyl)thiazole hydrobromide (28b).
1H-NMR (D6-DMSO): 1.70-2.10 ppm., multiplet, 2H; 2.43-2.96 ppm., multiplet, 4H; 6.58 ppm., singlet, 1H; 8.31 ppm., broad singlet, 3H; 9.40 ppm., broad singlet, 2H.
Mass spectrum M/Z (intensity in %): 157 (24.2); 140(42.5);
127(8.6); 113(30.0).
M+ = 157.067 (calculated for C6H11N3S: 157.067) q. 5-(2-aminoethyl)-4-methylthiazole dihydrochloride (26c) Yield 65%, from 5-(2-phthalimidoethyl)-4-methylthiazole (25c) by mild hydrolysis with hydrochloric acid as described by J.W. Black et al. in U.S. patent specification 3 736 331 dated May 29,1973.
1H-NMR (D6-DMSO): 2.42 ppm., singlet, 3H; 2.84-3.40 ppm., multiplet, 4H; 8.01-8.51 ppm., broad singlet, 3H;
8.93 ppm., singlet, 1H; 9.55 ppm., singlet, 1H.
Mass spectrum M/Z (intensity in %): 143(12.4); 126(6.8);
113(32.9).
M+ = 142.054 (calculated for C6H10N2S: 142.056) h. 5-(2-aminoethyl)-2,4-dimethylthiazole dihydrochloride (26d) Yield 98%, from 5-(2-phthalimidoethyl)-2,4- dimethylthiazole (25d).
Melting point 159.5-163.3°C.
1H-NMR (D6-DMSO): 2.41 ppm., singlet, 3H; 2.86 ppm., singlet, 3H; 2.94-3.33 ppm., multiplet, 4H; 8.47 ppm., broad singlet, 3H.
Mass spectrum M/Z (intensity in %): 156(2.1): 127(100); 85(3.8).
Example XIII
5-(2-aminoethyl)-4-methylthiazole dihydrochloride (26c)
The 5-(2-(aminoethyl)-4-methylthiazoledihydro- chloride (26c) may, if desired, also obtained in the following manner:
A solution of 25.0 g (o,175 mole) of 5-(2-hydroxyethyl)- 4-methylthiazole (Fluka A.G., Chem. Fabrik, CH-9470 Buchs) in 150 ml of aqueous-48% hydrogen bromide solution is refluxed for 48 hours. After cooling the reaction mixture is
vacuum concentrated and the residual water is removed azeotropically with toluene. Subsequently to the residue circa 50 ml of ethylacetate and 25 ml of absolute ethanol are added and stirred for 30 minutes at room temperature. The obtained precipitate is subsequently filtered off and vacuum dried.
Yield 64% 5-(2-bromomethyl)-4-methylthiazole hydrobromide. 1H-NMR (D6-DMSO): 2.46 ppm., singlet, 3H; 3.00 ppm., triplet
(J=5.4 Hz), 2H; 3.65 ppm., triplet (J=5.4 Hz), 2H; 9.95 ppm. singlet, 1H.
A solution of 17.0 g (0.06 mole) of 5-(2-bromo- ethyl)-4-methyl thiazole hydrobromide in circa 150 ml of absolute ethanol is saturated with ammonia gas at 0°C, thereafter the mixture is heated in an autoclave at circa 100°C for 16 hours. After cooling the reaction mixture is vacuum concentrated and the residue is taken up in demineralized water, then 11.76 g (0.14 mole) of sodium- hydrogen carbonate is added thereto, subsequently there is stirred at room temperature for circa one hour. After filtering the filtrate is vacuum concentrated and the residual water is removed azeotropically by absolute ethanol. The residue is subsequently treated with warm methanol, the organic salts are filtered off and the filtrate is brought at pH = 1 by using a concentrated hydrochloric acid solution. After vacuum concentration the residue is
subsequently crystallized from an ethanol/methanol mixture..
Yield 20%. Melting point 209-210°C.
The 1H-NMR-spectrum is identical to the spectrum as obtained with the preparation of the 5-(2-aminoethyl)-4-methylthiazole- dihydrochloride (26c) as described in example Xllg.
Example XIV
a. N-[3-(2-amino-4-methylthiazole-5-yl)propyl]-N'-cyano-0- phenylisoureum (32a)
T.o a solution of 4.88 g (0.02 mole) of 2-amino-5- ( 3-aminopropyl)-4-methyl thiazole dihydrochloride (26b) in circa 50 ml of absolute ethanol 0.04 mole of a freshly prepared sodium ethoxide solution in circa 25 ml of
absolute ethanol is added with stirring. After heating at circa 50°C for 15 min., the inorganic material is filtered off and the filtrate is vacuum concentrated. The residue is subsequently taken up in 50 ml of dry freshly distilled pyridine, then 5.76 g (0.02 mole) of diphenyl cyanocarbonimidate (31a) is added thereto. After reflux for 2 hours, after cooling the reaction mixture is vacuum concentrated, thereafter the residue is washed a few times with dry
diethylether. The crystalline material is subsequently vacuum dried.
Yield 100%.
1H-NMR (CDCl3): 1.65-2.04 ppm., multiplet, 2H; 2.63 ppm., triplet (J=7.2 Hz), 2H-; 3.41 ppm., triplet (J=6.3 Hz), 2H;
5.30 ppm., broad singlet, 2H; 7.00-7.19 ppm., multiplet, 2H; 7.19-7.53 ppm., multiplet, 3H.
b. N-[3-(2-aminothiazole-5-yl)propyl]-N'-cyano-S-methylisothioureum (32b)
To a solution of 4.60 g (0.02 mole) of 2-amino-5- (3-aminopropyl)thiazole dihydrochloride (20b) in circa 50 ml of absolute ethanol 0.04 mole of a freshly prepared sodium ethoxide solution in circa 25 mol of absolute ethanol is added with stirring. After heating at circa 50°C for
15 minutes the inorganic material is filtered off and 2.92 g (0.02 mole) of bis[methylthio]cyanocarbodiimide (31b) is added thereto, subsequently there is refluxed for 12 hours. After cooling the reaction mixture is filtered and the filtrate is vacuum concentrated.
Yield 95%.
1H-NMR (CDCl3): 1.54-2.04 ppm., multiplet, 2H; 2.58 ppm., singlet, 3H; 2.68 ppm., triplet (J=5.4 Hz), 2H; 3.30 ppm., triplet (J=7.2 Hz), 2H; 6.63 ppm., singlet, 1H; 6.70 ppm., singlet, 2H; 8.36 ppm., broad singlet, 1H.
c. N-[3-(2-amino-4-methylthiazole-5-yl)propyl]-N'-cyano-S- methylisothioureum (32c). To a solution of 4.88 g (0.02 mole) of 2-amino-5-
(3-aminopropyl)-4-methylthiazole dihydrochloride (26b) in circa 50 ml of absolute ethanol 0.04 mole of a freshly prepared sodium ethoxide solution in circa 25 ml of
absolute ethanol is added with stirring. After heating at circa 50°C for 15 min., the inorganic material is filtered off and the filtrate is vacuum concentrated. Subsequently the
the residue is taken up in 100 ml of dry freshly distilled pyridine, thereto 2.92 g (0.02 mole) of bis[methylthio]- cyanocarbodiimide (31b) is added. After reflux for 2 hours, the reaction mixture is vacuum concentrated and the residual pyridine is removed by codistillation with toluene. The residue is subsequently recrystallized from ethanol.
Yield: 85% melting point 172.0-172.4°C.
1H-NMR (D6-DMSO): 1.50-1.94 ppm., multiplet, 2H; 2.36-2.75 ppm. (under DMSO-signal), 2H; 2.60 ppm., singlet, 3H;
3.33 ppm., triplet (J=7.2 Hz), 2H; 6.65 ppm., singlet, 2H;
8.40 ppm., singlet, 1H.
Example XV
a. N-[3-(2-amino-4-methy1thiazole-5-yl)propyl]guanidine dihydrobromide (32b)
To a solution of 4.88 g (0.02 mole) of 2-amino-5-(3-amino- propyl)-4-methylthiazoledihydrochlori de (26b) in circa
50 ml of absolute ethanol 0.04 mole of a freshly prepared sodium ethoxide solution in circa 25 ml of absolute
ethanol is added with stirring. After heating at circa
50°C for 15 min., the inorganic material is filtered off and 3.70 g (0.02 mole) of S-ethylisothiouroniumbromide is added, then there is refluxed for 6 hours. After cooling the
reaction mixture is filtered off and aicidified with concentrated aqueous hydrogen bromide solution to circa pH = 1, subsequently there is vacuum concentrated and the residue is recrystallized from a mixture of isopropyl alcohol and methanol.
Yield 85%.
1H-NMR (D6-DMSO): 1.43-1.88 ppm., multiplet, 2H; 2.08 ppm. , singlet, 3H; 2.20-2.72 ppm. (partially under DMSO) ,
multiplet, 2H; 2.83-3.29 ppm., multiplet, 2H; 7.32-7.88 ppm. , broad singlet, 3H; 8.64 ppm., singlet, 4H; 9.10 ppm.,
singlet, 2H.
Example XVI
a. N-cyano-N'-(3.3-diphenylpropyl)-O-phenylisoureum (36a)
A solution of 10.55 g (0.05 mole) of 3,3-diphenyl- propylamine (33a) and 11.90 g (0.05 mole) of diphenylcyano- carbonimidate (31a) in 100 ml dry dichloromethane is
refluxed in nitrogen for 30 minutes. After cooling the reaction mixture , it is vacuum concentrated, thereafter 100 ml of dry diethylether is added to the residue. Subsequently there is stirred in nitrogen at room temperature for 15 minutes, thereafter the white crystalline material is filtered off, washed with dry diethyl ether and vacuum dried.
Yield 87%, melting point 171-174°C.
1H-NMR (D6-DMSO): 2.14-2.60 ppm., multiplet, 2H; 3.00-3.48 ppm., multiplet, 2H; 3.90-4.16 ppm., multiplet, 1H;
7.00-7.65 ppm., multiplet, 15H; 8.73 ppm., broad singlet,
1H.
b. N-cyano-N'-(3.3-diphenylpropyl)-S-methylisothioureum (36b)
To a solution of 21.1 g (0.1 mole) of 3.3-diphenyl- propylamine (33a) in circa 100 ml of dry diethylether a clear solution of 14.6 g (0.1 mole) of bis[methylthio]cyanocarbodiimide (31b) in circa 100 ml of dry diethylether is added, then there is stirred at room temperature for circa 30 min.
The precipitate obtained is subsequently filtered off and washed
with dry diethyl ether, thereafter the crystalline material is vacuum dried.
Yield 80%
1H=NMR (CDCl3): 2.14-2.58 ppm., multiplet, 2H; 2.30 ppm., singlet, 3H; 3.16-3.50 ppm., multiplet, 2H; 3.95 ppm., triplet ( J=8.1 Hz), 1H; 7.26 ppm., multiplet, 10H; 7.58 ppm., broad singlet, 1H.
Example XVII
a. N-benzoyl-N'-(3,3-diphenylpropyl)thioureum (38a).
To a solution of 21.1 g (0.1 mole) of 3,3-diphenyl- propylamine in 400 ml of dry diethyl ether in nitrogen atmosphere slowly and vigorously stirring a solution of 16.3 g (0.1 mole) of freshly distilled benzoylisothiocyanate (37) in circa 50 ml of dry diethyl ether is added, then it is stirred at room temperature for 1 hour. The precipitate obtained is filtered off, washed with dry diethylether and vacuum dried.
Yield 74%, melting point 124-125°C.
1H-NMR (CDCl3): 3.26-3.54 ppm., multiplet, 2H; 4.40-4.70 ppm., multiplet, 2H; 5.06 ppm., triplet (J=7.9 Hz), 1H;
8.06-8.68 ppm., multiplet, 13H; 8.94 ppm., double doublet. (J1=8.6 Hz, J2 = 2.0. Hz), 2H; 11.95 ppm., broad singlet, 1H.
b. N-(3,3-diphenylpropyl)thioureum (39a)
To a solution of 26.2 g (0.07 mole) of N-benzoyl-N'- (3.3-diphenylpropyl)thioureum (38) in 500 ml of anhydrous methanol a saturated solution of 10.0 g (0.072 mole) of potassium carbonate in demineralized water is added, then it is refluxed with stirring for circa 6 hours. After cooling the formed precipitate is filtered off, washed with successively demineralized water and absolute methanol, then the precipitate is vacuum dried.
Yield 95%, melting point 198-199°C.
1H-NMR (D6-DMSO): 3.10-3.28 ppm., multiplet, 2H; 3.94-4.58 ppm., broad multiplet, 2H; 4.22 ppm., singlet, 2H; 5.03 ppm., triplet (J=7.7 Hz), 1H; 8.02-8.60 ppm., multiplet, 10H; 8.83 ppm., singlet, 1H.
c. S-ethyl-N-(3,3-diphenylpropyl)isothiouroniumbromide (40a)
A solution of 13.5 g (0.05 mole) of N-3,3-diphenyl- propyl)thioureum (39a) in circa 250 ml of absolute ethanol and 25 ml of bromomethane is refluxed for 5 hours.
After cooling the solution is filtered and the filtrate is partially vacuum concentrated. The crystalline material is filtered off, washed with dry diethyl ether and vacuum dried.
Yield 63%, melting point 176-180°C.
1H-NMR (D6-DMSO): 1.27 ppm., triplet (J=7.2 Hz), 3H; 2.16-2.53 ppm., multiplet, 2H; 3.08-3.40 ppm., multiplet, 4H; 4.06 ppm., triplet (J=7.7 Hz), 1H; 7.07-7.46 ppm., multiplet, 10H; 9.13 ppm., broad singlet, 1H; 9.56 ppm., triplet
J=4.5 Hz), 1H.
Example XVIII
a. N-[2-(2-amino-4-methylthiazole-5-yl)ethyl]-N'- (3.3-diphenylpropyl)guanidine dipicrate (35a)
To a solution of 2.3 g (0.01 mole) of 2-amino-5- ( 2-aminoethyl)-4-methylthiazole dihydrochloride (26a) in
50 ml of absolute ethanol a freshly prepared solution of
0.02 mole of sodium ethoxide in circa 25 ml of absolute ethanol is added. After stirring at circa 50°C for 15 min. it is cooled and the inorganic material is filtered off, then 3.55 g (0.01 mole) of N-cyano-N'-(3,3-diphenylpropyl)- 0-phenylisoureum (36a) is added thereto. Subsequently it is refluxed for 16 hours. After cooling and vacuum concentration the residue obtained is extracted a few times with dry diethylether. Subsequently circa 50 ml of heat ethylacetate is added, stirred for 15 minutes, the insoluble material is filtered off and the filtrate is vacuum concentrated. The viscous oil obtained, comprising crude N-[2-(2-amino-4- methylthiazole-5-yl)ethyl]-N'-cyano-N"-(3,3-diphenylpropyl)- guanidine (34a) is subsequently taken up without any purification in 100 ml of 2N aqueous hydrochloric acid, thereafter there is refluxed for 3 hours. After cooling there is vacuum concentrated and the residue dissolved in absolute methanol. After filtration a solution of 0.02 mole of
picric acid in circa 50 ml of methanol is added. After stirring the precipitate obtained is filtered off andrecrystalized from a mixture of methanol and water.
Yield 10%.
1H-NMR (D6-DMSO): 2.12-2.46 ppm, broad multiplet, 2H;
2.70-3.53 ppm., broad multiplet, 6H; 4.02 ppm.,
triplet (J=7.2 Hz), 1H; 7.07-7.60 ppm., multiplet, 13H;
8.64 ppm., singlet, 4H; 8.97 ppm., broad singlet, 2H;
9.06-9.74 ppm, broad singlet, 1H.
b. N-[3-(2-amino-4-methylthiazole-5-yl)propyl]-N'- (3,3-diphenylpropyl) guanidine dipicrate (35b)
The N-[3-(2-amino-4-methylthiazole-5-yl)propyl]- N'-(3,3-diphenylpropyl)guanidine (35b) was prepared in a manner analogous to that of the N-[2-(2-amino-4-methyl- thiazole-5-yl)ethyl]-N'-(3,3-diphenylpropyl)guanidine (35a), as described in example XVIIIa, from N-cyano-N'-(3,3- diphenylpropyl)-0-phenylisoureum (37a) and 2-amino-5-(3- aminopropyl)-4-methylthiazole dihydrochloride (26b) with the proviso that the reaction mixture was refluxed for
48 hours.
Yield 45%
1H-NMR (D6-DMSO): 1.54-1.97 ppm., multiplet, 2H; 2.12 ppm., singlet, 3H; 2.22-2.50 ppm., multiplet, 2H; 2.98-3.48 ppm., multiplet, 6H; 4.04 ppm., triplet, 1H; 7.04-7.60 ppm., multiplet, 13H; 8.63 ppm., singlet, 4H ; 9.12 ppm., broad singlet, 2H; 9.16-9.45 ppm., broad singlet, 1H.
Example XIX
a. N-[3-(2-aminothiazole-5-yl)propyl)]-N'-(3,3-diphenyl- propyl)guanidine dipicrate (35c)
To a solution of 2.30 g (0.01 mole) of 2-amino-5- ( 3-aminopropyl)thiazole dihydrochloride (26b) in circa 50ml
of absolute ethanol, a freshly prepared solution of 0.02 mole of sodium ethoxide in circa 25 ml of absolute ethanol is added. After stirring at 50°C for 15 min. there is cooled and the inorganic material is filtered off, thereafter to the filtrate 3.79 g (0.01 mole) of S-ethyl-N-(3,3-diphenyl- propyl)isothiouronimbromide (40a) is added. After refluxing for 48 hours the reaction mixture is decolorised with activated carbon, filtered and the filtrate is vacuum concentrated.
The residue is taken up in circa 50 ml of methanol, then a solution of 0.02 mole of picric acid in 50 ml of methanol is added. After stirring for 2 hours the precipitate obtained is filtered off and recrystallized from a mixture of methanol and water.
Yield 30%
1H-NMR (D6-DMSO): 1.56-1.98 ppm., multiplet, 2H; 2.00-2.80 ppm., multiplet, 4H; 2.90-3.34 ppm., multiplet, 4H; 4.01 ppm., triplet (J=7.2 Hz), 1H; 7.13 ppm., singlet, 1H;
7.31 ppm., broad singlet, 13H; 8.64 ppm., singlet, 4H;
9.12 ppm., broad singlet, 2H.
Example XX
a. N-[3-(2-aminothiazole-4-yl)propyl]-N'-(3,3-diphenylpropyl) guanidine dipicrate (35d)
To a solution of 3.14 g (0.02 mole) of 2-amino-4- (3-aminopropyl)thiazole (free base of 2-amino-4-(3-amino- propyl)thiazole dihydrochloride (29b) in circa 100 ml of absolute ethanol 6.18 g (0.02 mole) of N-cyano-N'-(3,3- diphenylpropyl)-S-methylisothioureum (36b) is added,
then there is refluxed for 96 hours. After cooling the
reaction mixture is decolorised with activated carbon, filtered and vacuum concentrated. The residue is subsequently taken up in 100 ml of 2N aqueous hydrochloric acid
solution and refluxed for 4 hours. After cooling there is vacuum concentrated, thereafter the residue is taken up in circa 100 ml of absolute ethanol and the inorganic material is filtered off To the filtrate subsequently a solution of
0.04 mole of picric acid in circa 50 ml of ethanol is added. After stirring at room temperature for 3 hours, the precipitate obtained is filtered off and recrystallized from a mixture of methanol and water.
Yield 30% D6DMSO.
1H-NMR (D6DMSO): 1.54-1.95 ppm., multiplet, 2H; 2.09-2.74 ppm., multiplet, 4H; 2.87-3.30 ppm., multiplet, 4H; 3.98 ppm. triplet (J=7.2 Hz), 1H; 6.50 ppm., singlet, 1H; 7.16 ppm., broad singlet, 13H; 8.60 ppm., singlet, 4H; 8.96 ppm., broad singlet, 2H.
Example XXI
a. N-[3-(2-amino-4-methylthiazole-5-yl)propyl]-N'- (3,3-diphenylpropyl) guanidine dipicrate (35b)
A solution of 3.05 g (0.01 mole) of N-[3-(2-amino- 4.methylthiazole-5-yl)propyl]-N'-cyano-0-phenylisoureum (32a) and 4.22 g (0.02 mole) of 3,3-diphenylpropylamine (33a) in circa 100 ml of freshly distilled anhydrous pyridine is refluxed for 16 hours. After cooling the reaction mixture is vacuum concentrated. The residue is subsequently washed with successively demineralized water and diethyl ether, thereafter the residue is taken up in circa 100 ml of hot ethyl
acetate. After decoloration with activated coal and filtration the filtrate is vacuum concentrated. The viscous oil obtained comprising N-[3-(2-amino-4-methylthiazole-5-yl)propyl]-N'- cyano-N"-(3,3-diphenylpropyl)guanidine (34b) is hydroly zed after column chromatography (Kieselgel 60-80, eluent
methanol/NH3) by 2N aqueous hydrochloric acid solution and converted into the dipicrate as described for the N-[3-(2- aminothiazole-4-yl)propyl]-N'-(3,3-diphenylpropyl)guanidine dipicrate (35d) in example XXa.
Yield 65%
1H-NMR (D6-DMSO): identical to the spectrum as described for the N-[3-(2-amino-4-methylthiazole-5-yl)propyl]-N'-(3,3- diphenylpropyl)guanidine dipricate (35b) in example XVIIIb.
Example XXII
a. N,N'-bis[3-(2-amino-4-methylthiazole-5-yl)propyl]
guanidine dipicrate (35e)
To a solution of 2.44 g (o.01 mole) of 2-amino-5- ( 3-aminopropyl)-4-methylthiazole dihydrochloride (26b) in circa 50 ml of absolute ethanol a solution of 0.02 mole of freshly prepared sodium ethoxide in 25 ml of absolute ethanol is added. After stirring at 50°C for 15 minutes there is cooled and the inorganic material is filtered off, then the filtrate is vacuum concentrated. Subsequently the residue is taken up in circa 100 ml of freshly distilled anhydrous pyridine, thereto 2.69 g (0.01 mole) of N-[3,2- amino-4-methylthiazole-5-yl)propyl]-N'-cyano-S-methylisothioureum (32c) is added, thereafter the mixture is refluxed for 12 hours. After cooling the reaction mixture is processed
as described for the N-[3-(2-amino-4-methylthiazole-5-yl)- propyl]-N'-(3,3-diphenylpropyl)-guanidine dipicrate (35b) as described in example XXIa.
Yield 50%
1H-NMR (D6-DMSO): 1.43-1.88 ppm., multiplet, 4H; 2.08 ppm., singlet, 6H; 2.20-2.72 ppm., (partially under DMSO), multiplet, 4H; 2.83-3.29 ppm., multiplet, 4H ; 7.32-7.88 ppm., broad singlet, 3H; 8.64 ppm., singlet, 6H; 9.10 ppm., singlet, 4H.
Example XXIII
N-[3-(2-amino-4-methylthiazole-5-yl)propyl]-N'-cyano-N"- methylguanidine (34c)
To a solution of 1.34 g (0.005 mole) of N-[3-(2-amino-4- methylthiazole-5-yl)propyl]-N -cyano-3-methylisothioureum (32c) in circa 25 ml of absolute ethanol 5 g of methylamine in 50 ml of absolute ethanol is added, thereafter with
stirring for circa 5 hours there is refluxed. After cooling the reaction mixture is vacuum concentrated, thereafter the residue is crystallized from absolute ethanol.
Yield 92%. Melting point 167.8-172°C (decomposition)
1H=NMR (D6-DMSO): 1.49-1.82 ppm., multiplet, 2H; 1.97 ppm., singlet, 3H; 2.32-2.50 ppm., multiplet, 2H ; partially
under DMSO); 2.67 ppm., doublet (J= 5.0 Hz), 3H; 2.95-3.28 ppm., multiplet, 2H; 6.60 ppm., broad singlet, 2H; 6.84- 7.10 ppm., multiplet, 2H.
Example XXIV
N-[3-(2-amino-4-methylthiazole-5-yl)propyl]-N'-cyano-N"- [3-(4-morpholino)propyl]guanidine (34d)
To a solution of 1.34 g (0.005 mole) of N-[3-(2-amino-4- methylthiazole-5-yl)propyl]-N'-cyano-5-methyl isothioureum (32c) in circa 50 ml of pyridine 1.44 g (0.01 mole) of
3-(4-morpholino)propylamine is added, then with stirring in a nitrogen atmosphere for 48 hours there is refluxed. After cooling the reaction mixture is vacuum concentrated, thereafter the residue is extracted a few times with diethylether. Subsequently it is recrystallized from a mixture of absolute ethanol and methanol.
Yield 48%. Melting point 149.0-151.2°C.
1H-NMR (D6-DMSO); 1.70-1.90 ppm., multiplet, 4H; 2.01 ppm., singlet, 3H; 2.11-2.70 ppm., multiplet, 8H; 3.00-3.36 ppm., multiplet, 4H; 3.54-3.78 ppm., multiplet, 4H; 6.65 ppm., singlet, 2H; 7.12-7.46 ppm, multiplet, 2H.
Example XXV
N-[-3-(2-amino-4-methylthiazole-5-yl)propyl]-N'-cyano-N"- (3-phenylbutyl)guanidine (34e)
To a solution of 1.34 g (0.005 mole) N-[3-(2-amino- 4-methylthiazole-5-yl)propyl]-N'-cyano-S-methylisothioureum (32c) in circa 50 ml of pyridine 1.499 (0.01 mole) of
4-phenylbutylamine is added, thereafter with stirring in a nitrogen atmosphere for 48 hours there is refluxed. After cooling the reaction mixture is vacuum concentrated, thereafter the residue is extracted a few times with diethyl ether. Subsequently it is recrystallized from absolute ethanol.
Yield 51%. Melting point 159.3-161.9°C.
1H-NMR (D6-DMSO): 1.30-1.85 ppm., multiplet, 6H; 1.98 ppm., singlet, 3H; 2.32-2.75 ppm., multiplet, 4H (partially
under DMSO): 2.96-3.38 ppm, multiplet, 4H; 6.62 ppm., singlet,
2H; 6.97-7.18 ppm., multiplet, 2H; 7.26 ppm., singlet, 5H.
Example XXVI
N-[3-(2-amino-4-methylthiazole-5-yl)propyl]-N'-cyano-N"- (3,3-diphenylpropyl)guanidine (34f)
To a solution of 1.34 g (0.005 mole) N-[3-(2-amino- 4-methylthiazole-5-yl)propyl]-N'-cyano-S-methylisothioureum (32c) in circa 50 ml of pyridine 2.11 g (0.01 mole) of
3,3-diphenylpropylamine is added, then with stirring in a nitrogen atmosphere for 48 hours there is refluxed. After cooling the reaction mixture is vacuum concentrated, thereafter the residue is extracted a few times with diethyl- ether. Subsequently it is recrystallized from absolute
ethanol.
Yield 60% Melting point 164.7-168.8°C.
1H-NMR (D6-DMSO): 1.44-1.82 ppm., multiplet, 2H; 1.92 ppm., singlet, 3H; 2.14-2.50 ppm., multiplet, 2H (partially
under DMSO); 2.86-3.24 ppm., multiplet, 4H; 3.24-3.60 ppm. , multiplet, 2H; 3.98 ppm., triplet (J=8.0 Hz), 1H; 6.58 ppm., broad singlet, 2H; 6.86-7.25 ppm., multiplet, 12H.
Example XXVII
N-[3-(2-amino-4-methylthiazole-5-yl)propyl]-N'-[3-(3,4- dichlorophenyl)-3-(2-pyridyl)propyl]guanidine tripicrate(35f)
A solution of 1.34 g (0.005 mole) of N-[3-(2-amino- 4-methy1thiazole-5-yl)propyl]-N'-cyano-S-methylisothioureum (32c) and 1.41 g (0.005 mole) of 2-[3-amino-1-(3,4-dichlorophenyl)propyl]pyridine* in circa 50 ml of pyridine is
refluxed with stirring in a nitrogen atmosphere for 72 hours. After cooling the reaction mixture is vacuum concentrated and the residue is washed a few times with diethyl ether.
Subsequently 25 ml of 6M hydrochloric acid solution is added thereto and there is refluxed for 6 hours. After cooling the reaction mixture is vacuum concentrated and the residue is taken up in circa 25 ml of methanol, thereto 4.5 g of pitric acid in circa 50 ml of hot methanol is added.
Subsequently circa 5 ml of demineralized water is added and the precipitate obtained is filtered off, then
it is recrystallized from an ethanol/acetone mixture.
Yield 53%. 1H-NMR (D6-DMSO): 1.59-1.83 ppm., multiplet, 2H; 2.10 ppm., singlet, 3H; 2.30-2.71 ppm., multiplet, 4H; 3.00-3.39 ppm., multiplet, 4H; 4.42 ppm., triplet (J=6.7 Hz), 1H; 7.20-8.97 ppm., multiplet, 9H; 8.10-8.31 ppm., multiplet, 1H; 8.59 ppm., singlet, 6H; 8.65-8.80 ppm., multiplet, 1H; 9.15 ppm., singlet, 2H.
Example XXVIII
N-[3-(2-amino-4-methylthiazole-5-yl)propyl]-N'-(3-phenyl propyl)guanidine dipicrate (35g)
A solution of 1.34 g (0.005 mole) of N-[3-(2-amino-
4-methylthiazole-5-yl)propyl]-N'-cyano-S-methylisothioureum
(32c) and 1.35 g (0.01 mole) of 3-phenylpropylamino in circa * 2-[3-amino-1-(3,4-dichlorophenyl)propyl]pyridine was obtained in a modified process as described by A. Buschauer et al. Archiv.der Pharm., 322(3), 165-171 (1989)
50 ml of pyridine with stirring in a nitrogen atmosphere for 72 hours there is refluxed. After cooling the reaction mixture is vacuum concentrated and the residue is washed a few times with diethylether. Subsequently 25 ml of 6M hydrochloric acid solution is added and there is refluxed for
6 hours. After cooling the reaction mixture is vacuum concentrated and the residue is taken up in circa 25 ml of methanol, then 3.05 g of picric acid in circa 50 ml of
methanol is added thereto. Subsequently circa 5 ml of
demineralized water is added thereto and the precipitate obtained is filtered off, then recrystallized from a methanol/water mixture.
Yield 62%.
1H-NMR (D6-DMSO): 1.53-2.20 ppm., multiplet, 4H; 2.07 ppm., singlet, 3H; 2.40-2.78 ppm., multiplet, 4H (partially
under DMSO); 3.00-3.76 ppm., multiplet, 4H; 7.00-7.26 ppm., multiplet, 8H; 8.62 ppm., singlet, 4H; 9.14 ppm., singlet, 2H.
Example XXIX
N-[3-(2-amino-4-methylthiazole-5-yl)propyl]-N'-(1-imidazolyl- propyl)guanidine dipicrate (35h)
A solution of 1.34 g (0.005 mole) of N-[3-(2-amino-4-methyl- thiazole-5-yl)propyl]-N'-cyano-S-methylisothioureum (32c) and 1.25 g (0.01 mole) of N-(3-aminopropyl)imidazole in circa 50 ml of pyridine is refluxed with stirring in a nitrogen atmosphere for 72 hours. After cooling the reaction mixture is vacuum concentrated and the residue is washed a few times with cold methanol. Subsequently 25 ml of 6M hydro
chloric acid solution is added thereto and there is refluxed for 6 hours. After cooling the reaction mixture is vacuum concentrated and the residue is taken up in circa 25 ml of methanol, thereto 3.05 g of picric acid in circa 50 ml of methanol is added. Subsequently circa 5 ml of demineralized water is added thereto and the precipitate obtained is
filtered off, then it is recrystallized from a methanol/water mixture.
Yield 38%.
1H-NMR (D6-DMSO); 1.60-1.90 ppm., multiplet, 2H; 2.06 ppm., singlet, 3H; 2.06-2.34 ppm., multiplet, 2H; 2.54-2.98 ppm., multiplet, 4H; 3.14-3.60 ppm., multiplet, 2H; 4.28 ppm., triplet (J=7.2 Hz), 2H; 7.22-7.92 ppm., multiplet, 5H; 8.59 ppm., singlet, 4H; 9.10 ppm., singlet, 2H.
a
Claims (7)
1. A substituted ω-aminoalkylthiazole, characterized in that it is
a. a N-[ω-(thiazol-4 or 5-yl)alkyl]isourea, isothiourea or a guanidine derivative with formula 2 , wherein X represents a sulphur atom and Y represents a nitrogen atom or alternatively
X represents a nitrogen atom and Y represents a sulphur atom, n is 1-6, R-L represents a hydrogen atom or a straight or branched alkyl group with 1-4 carbon atoms and R2 represents a
hydrogen atom, a straight or branched alkyl group with 1-4 carbon atoms or an amino group, Z represents a sulphur atom, an oxygen atom or a NH-group respectively, R3 represents a hydrogen atom, a phenyl or an alkyl group with 1-4 carbon atoms respectively and R4 represents a hydrogen atom, a cyano or a benzoyl group respectively;
b. a N-(ω-substituted alkyl)-N'-substituted-N"-[ω-(thiazol-4 or 5-yl)alkyl]guanidine with formula 3, wherein X represents a sulphur atom and Y represents a nitrogen atom or alternatively X represents a nitrogen atom and Y represents a sulphur atom, n is 1-6, R1 represents a hydrogen atom or a straight or branched alkyl group with 1-4 carbon atoms and R2 represents a hydrogen atom, a straight or branched alkyl group with 1-4 carbon atoms or an amino group, R4 represents hydrogen, a cyano or a benzoyl group respectively, m is 1,2 or 3, A represents a sulphur or an oxygen atom, a -CH2- or a -CH= group respectively and Q represents a R-substituted diphenyl- methyl group or a R-substituted (10,11-dihydro) optionally aza 5H-dibenzo-[a,d]-cyclohepten-5-yl group or Q represents a nitrogen atom substituted with Q1 and Q2, wherein Q1 and Q2 represent whether or not symmetrical R-substituted (ω-)- phenyl(alkyl) groups, or Q represents a R-substituted (ω- )phenyl(alkyl) group or Q represents a whether or not symme- trical mono-or disubstituted methylidene fragment, wherein R1 represents a R-substituted (10,11-dihydro) optionally aza 5H- dibenzo-[a,d]-cyclohepten-5-yl group or R' represents two whether or not symmetrically with R substituted phenyl groups, wherein R represents hydrogen, alkyl, alkoxy, amino, mono- or dialkylamino, guanidino, nitro, carboxy, carbalkoxy, halogen (fluoro, chloro, bromo, iodo), mono-, di- and trihalogenmethyl or -methoxy (halogen = fluoro, chloro, bromo) etc., while in addition the R-substituted phenyl rings may be replaced by a (heterocyclic) (aromatic) ring whether or not R-substituted or by a combination of a (condensed) (aromatic) (heterocyclic) R-substituted ring with one or more (condensed) (aromatic) (heterocyclic) rings whether or not symmetrically R-substituted.
2. A process for the preparation of an ω-aminoalkylthiazole, characterized in that one prepares a 4- or 5-(ω-aminoalkyl)- thiazole derivative with formula 1 in which R1 and R2 have the same meaning as in claim by ring closure of a 2-bromo-ω- phthalimidoalkanal (18), a 3-bromo-ω-phthalimidoalkan-2-one (24) or a 1-bromo-ω-phthal-imidoalkan-2-one (27) with thioformamide, an alkylthioamide or thiourea in dimethylformamide under mild conditions, followed by hydrazinolysis or hydrolysis with diluted hydrochloric acid of the resulting phthalimido derivatives (19, 25 or 28).
3. A process for the preparation of a histamine H2-receptor active compound whether or not in combination with additionally desired biological activity characterized by preparing from a corresponding compound according to formula 1 or 2 or an acid addition salt thereof a compound with a substituted 4- or 5-(ω-thiazolylalkyl)guanidine fragment.
4. Medicament, or scientific (pharmacological) adjuvant, characterized in that it contains as the active ingredient a compound according to one of the formulas 2-3 or a compound obtained according to claim 3 or an acid addition salt thereof.
5. Use of a compound or medicament according to one of the previous claims for the treatment of congestive heart diseases whether or not accompanied by heart failure or for the treatment of allergic disorders.
6. A process for the preparation of 2-bromo-ω-phthalimidoalkanals characterized by selective α-bromination of the corresponding ω-phthalimidoalkanals with bromine in carbon tetrachloride.
7. 2-Bromo-ω-phthalimido-1-alkanals.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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NL9000132A NL9000132A (en) | 1990-01-19 | 1990-01-19 | NEW THIAZOLE DERIVATIVES. |
NL9000132 | 1990-01-19 |
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AU70644/91A Abandoned AU7064491A (en) | 1990-01-19 | 1991-01-18 | New thiazole derivatives |
AU70581/91A Abandoned AU7058191A (en) | 1990-01-19 | 1991-01-18 | Thiazole derivatives |
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AU70581/91A Abandoned AU7058191A (en) | 1990-01-19 | 1991-01-18 | Thiazole derivatives |
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JP (2) | JPH05503694A (en) |
AU (2) | AU7064491A (en) |
CA (2) | CA2074175A1 (en) |
IE (2) | IE910172A1 (en) |
IL (2) | IL96997A0 (en) |
NL (1) | NL9000132A (en) |
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US2636037A (en) * | 1947-10-10 | 1953-04-21 | Sharp & Dohme Inc | 2-amino-4-piperidinoethyl-thiazole |
FR2073427A1 (en) * | 1969-11-28 | 1971-10-01 | Sogeras | 4-methyl-5-ethyl-n-heterocyclic thiazoles - with antianoxic activity |
FR2361111A1 (en) * | 1976-08-11 | 1978-03-10 | Roussel Uclaf | NEW DERIVATIVES OF 5-THIAZOLE ALKYLAMINE, A PROCESS FOR THEIR PREPARATION AND THEIR APPLICATION AS MEDICINAL PRODUCTS |
US4166860A (en) * | 1977-10-11 | 1979-09-04 | William H. Rorer, Inc. | Imidazole amidinoureas for stimulating H2 -receptors |
US4474794A (en) * | 1982-03-19 | 1984-10-02 | Eli Lilly And Company | N-Thiazolylmethylthioalkyl-N1 -alkenyl (or alkynyl)guanidines and related compounds |
NL8601585A (en) * | 1986-06-19 | 1988-01-18 | Vereniging Voor Christelijk Wetenschappelijk Onderwijs | N- (2-SUBSTITUTED ALKYL) -N-IMIDAZOL-4-YL ALKYL GUANIDINE. |
NL8800998A (en) * | 1988-04-18 | 1989-11-16 | Cedona Pharm Bv | PROCESS FOR PREPARING AN SUBSTITUTION OR SUBSTITUTED 4 (5) - (OMEGA-AMINOALKYL) IMIDAZOLE. |
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1990
- 1990-01-19 NL NL9000132A patent/NL9000132A/en not_active Application Discontinuation
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- 1991-01-18 AU AU70644/91A patent/AU7064491A/en not_active Abandoned
- 1991-01-18 WO PCT/NL1991/000008 patent/WO1991010657A1/en not_active Application Discontinuation
- 1991-01-18 EP EP91902805A patent/EP0511271A1/en not_active Withdrawn
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- 1991-01-18 CA CA002074175A patent/CA2074175A1/en not_active Abandoned
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JPH05503096A (en) | 1993-05-27 |
WO1991010657A1 (en) | 1991-07-25 |
CA2074175A1 (en) | 1991-07-20 |
IE910172A1 (en) | 1991-07-31 |
ZA91419B (en) | 1991-10-30 |
EP0511271A1 (en) | 1992-11-04 |
AU7058191A (en) | 1991-08-05 |
IL96997A0 (en) | 1992-03-29 |
CA2074180A1 (en) | 1991-07-20 |
JPH05503694A (en) | 1993-06-17 |
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WO1991010656A1 (en) | 1991-07-25 |
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