CA2359390A1 - Utilisation of 2-substituted 1,2-benzisothiazole derivatives and 3-substituted tetrahydropyridopyrimidinone derivatives for the prophylaxis and therapy of cerebral ischaemia - Google Patents
Utilisation of 2-substituted 1,2-benzisothiazole derivatives and 3-substituted tetrahydropyridopyrimidinone derivatives for the prophylaxis and therapy of cerebral ischaemia Download PDFInfo
- Publication number
- CA2359390A1 CA2359390A1 CA002359390A CA2359390A CA2359390A1 CA 2359390 A1 CA2359390 A1 CA 2359390A1 CA 002359390 A CA002359390 A CA 002359390A CA 2359390 A CA2359390 A CA 2359390A CA 2359390 A1 CA2359390 A1 CA 2359390A1
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- roro
- branched
- unbranched
- substituted
- 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
- 206010008120 Cerebral ischaemia Diseases 0.000 title claims abstract description 7
- 238000011321 prophylaxis Methods 0.000 title claims abstract description 7
- 238000002560 therapeutic procedure Methods 0.000 title claims abstract description 7
- -1 2-substituted 1,2-benzisothiazole Chemical class 0.000 title description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 72
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 239000002253 acid Substances 0.000 claims abstract description 9
- 239000003814 drug Substances 0.000 claims abstract description 8
- 208000006011 Stroke Diseases 0.000 claims abstract description 4
- 150000007513 acids Chemical class 0.000 claims abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 239000001257 hydrogen Substances 0.000 claims description 19
- 229910052757 nitrogen Inorganic materials 0.000 claims description 17
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 16
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 13
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 10
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 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
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 8
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 claims description 8
- 150000001923 cyclic compounds Chemical class 0.000 claims description 8
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 6
- 229910052786 argon Inorganic materials 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- FUFZNHHSSMCXCZ-UHFFFAOYSA-N 5-piperidin-4-yl-3-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole Chemical group FC(F)(F)C1=CC=CC(C=2N=C(ON=2)C2CCNCC2)=C1 FUFZNHHSSMCXCZ-UHFFFAOYSA-N 0.000 claims description 4
- 201000006474 Brain Ischemia Diseases 0.000 claims description 4
- 206010008118 cerebral infarction Diseases 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- YBPWKEJCVLEMGU-UHFFFAOYSA-N 3-nitro-1h-pyrrole-2-carbonitrile Chemical compound [O-][N+](=O)C=1C=CNC=1C#N YBPWKEJCVLEMGU-UHFFFAOYSA-N 0.000 claims description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 52
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 239000000243 solution Substances 0.000 description 24
- 239000000203 mixture Substances 0.000 description 22
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 19
- 238000002360 preparation method Methods 0.000 description 19
- 229910052938 sodium sulfate Inorganic materials 0.000 description 19
- 235000011152 sodium sulphate Nutrition 0.000 description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 239000002904 solvent Substances 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 239000000047 product Substances 0.000 description 14
- 239000007858 starting material Substances 0.000 description 13
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 11
- 101150041968 CDC13 gene Proteins 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 239000007795 chemical reaction product Substances 0.000 description 7
- 239000005457 ice water Substances 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- 229910052721 tungsten Inorganic materials 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 101100149678 Caenorhabditis elegans snr-3 gene Proteins 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 238000003818 flash chromatography Methods 0.000 description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 4
- 230000002194 synthesizing effect Effects 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 238000010626 work up procedure Methods 0.000 description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 4
- FBPPFIPXMJEJCU-UHFFFAOYSA-N 1-(5,6,7,8-tetrahydronaphthalen-1-yl)piperazine Chemical compound C1CCCC2=C1C=CC=C2N1CCNCC1 FBPPFIPXMJEJCU-UHFFFAOYSA-N 0.000 description 3
- SSSBLYQLIOQJSB-UHFFFAOYSA-N 4-naphthalen-1-ylpiperidine Chemical compound C1CNCCC1C1=CC=CC2=CC=CC=C12 SSSBLYQLIOQJSB-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 229910052770 Uranium Inorganic materials 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 3
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 2
- DIOHEXPTUTVCNX-UHFFFAOYSA-N 1,1,1-trifluoro-n-phenyl-n-(trifluoromethylsulfonyl)methanesulfonamide Chemical compound FC(F)(F)S(=O)(=O)N(S(=O)(=O)C(F)(F)F)C1=CC=CC=C1 DIOHEXPTUTVCNX-UHFFFAOYSA-N 0.000 description 2
- FQUYSHZXSKYCSY-UHFFFAOYSA-N 1,4-diazepane Chemical compound C1CNCCNC1 FQUYSHZXSKYCSY-UHFFFAOYSA-N 0.000 description 2
- VNICFCQJUVFULD-UHFFFAOYSA-N 1-(1-naphthalenyl)piperazine Chemical compound C1CNCCN1C1=CC=CC2=CC=CC=C12 VNICFCQJUVFULD-UHFFFAOYSA-N 0.000 description 2
- GJOBEWYDAQTKDU-UHFFFAOYSA-N 1-(2,3-dihydro-1h-inden-4-yl)piperazine Chemical compound C=12CCCC2=CC=CC=1N1CCNCC1 GJOBEWYDAQTKDU-UHFFFAOYSA-N 0.000 description 2
- HGYDREHWXXUUIS-UHFFFAOYSA-N 1-(naphthalen-1-ylmethyl)piperazine Chemical compound C=1C=CC2=CC=CC=C2C=1CN1CCNCC1 HGYDREHWXXUUIS-UHFFFAOYSA-N 0.000 description 2
- IBYHHJPAARCAIE-UHFFFAOYSA-N 1-bromo-2-chloroethane Chemical compound ClCCBr IBYHHJPAARCAIE-UHFFFAOYSA-N 0.000 description 2
- SCRBSGZBTHKAHU-UHFFFAOYSA-N 4-bromoisoquinoline Chemical compound C1=CC=C2C(Br)=CN=CC2=C1 SCRBSGZBTHKAHU-UHFFFAOYSA-N 0.000 description 2
- KARYKQNFDNURNN-UHFFFAOYSA-N 4-chloro-3,3-dimethyl-2h-1,2-benzothiazole 1,1-dioxide Chemical compound C1=CC(Cl)=C2C(C)(C)NS(=O)(=O)C2=C1 KARYKQNFDNURNN-UHFFFAOYSA-N 0.000 description 2
- NIBZKHUIJGTBOX-UHFFFAOYSA-N 4-piperazin-1-ylisoquinoline Chemical compound C1CNCCN1C1=CN=CC2=CC=CC=C12 NIBZKHUIJGTBOX-UHFFFAOYSA-N 0.000 description 2
- KLTHGJYCURVMAK-UHFFFAOYSA-N 4-piperazin-1-ylquinazoline Chemical compound C1CNCCN1C1=NC=NC2=CC=CC=C12 KLTHGJYCURVMAK-UHFFFAOYSA-N 0.000 description 2
- SODWJACROGQSMM-UHFFFAOYSA-N 5,6,7,8-tetrahydronaphthalen-1-amine Chemical compound C1CCCC2=C1C=CC=C2N SODWJACROGQSMM-UHFFFAOYSA-N 0.000 description 2
- SPXJZGXITAWLIO-UHFFFAOYSA-N 6-benzyl-3-(2-chloroethyl)-7,8-dihydro-5h-pyrido[4,3-d]pyrimidin-4-one Chemical compound C1C=2C(=O)N(CCCl)C=NC=2CCN1CC1=CC=CC=C1 SPXJZGXITAWLIO-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
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- 229960000583 acetic acid Drugs 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 description 2
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- 239000002775 capsule Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 2
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- 229940043279 diisopropylamine Drugs 0.000 description 2
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- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 2
- 230000008733 trauma Effects 0.000 description 2
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- 235000005074 zinc chloride Nutrition 0.000 description 2
- FHLXQXCQSUICIN-UHFFFAOYSA-N 1,2,3,4-tetrahydropyrido[3,2-d]pyrimidine Chemical compound C1=CC=C2NCNCC2=N1 FHLXQXCQSUICIN-UHFFFAOYSA-N 0.000 description 1
- MUSOMUXTQGJZKD-UHFFFAOYSA-N 1-(2-chloroethyl)-4-(2-methoxyphenyl)piperazine Chemical compound COC1=CC=CC=C1N1CCN(CCCl)CC1 MUSOMUXTQGJZKD-UHFFFAOYSA-N 0.000 description 1
- MAIPOMCACBNHEI-UHFFFAOYSA-N 1-(2-chloroethyl)piperazine Chemical compound ClCCN1CCNCC1 MAIPOMCACBNHEI-UHFFFAOYSA-N 0.000 description 1
- OIZBMQFOSPOOIS-UHFFFAOYSA-N 1-(3-chloropropyl)-4-(2-methoxyphenyl)piperazine Chemical compound COC1=CC=CC=C1N1CCN(CCCCl)CC1 OIZBMQFOSPOOIS-UHFFFAOYSA-N 0.000 description 1
- QYHUWTWTZWQCJT-UHFFFAOYSA-N 1-(3-chloropropyl)-4-naphthalen-1-ylpiperazine Chemical compound C1CN(CCCCl)CCN1C1=CC=CC2=CC=CC=C12 QYHUWTWTZWQCJT-UHFFFAOYSA-N 0.000 description 1
- MLXIGMYNOXFJAH-UHFFFAOYSA-N 1-chloro-4-piperazin-1-ylphthalazine Chemical compound C12=CC=CC=C2C(Cl)=NN=C1N1CCNCC1 MLXIGMYNOXFJAH-UHFFFAOYSA-N 0.000 description 1
- PWMNWKMSCLDPAG-UHFFFAOYSA-N 1-naphthalen-1-ylazepane Chemical compound C1CCCCCN1C1=CC=CC2=CC=CC=C12 PWMNWKMSCLDPAG-UHFFFAOYSA-N 0.000 description 1
- DCPLVXOQIWQNDH-UHFFFAOYSA-N 1-naphthalen-1-yldiazepane Chemical compound C1CCCCNN1C1=CC=CC2=CC=CC=C12 DCPLVXOQIWQNDH-UHFFFAOYSA-N 0.000 description 1
- GFISDBXSWQMOND-UHFFFAOYSA-N 2,5-dimethoxyoxolane Chemical compound COC1CCC(OC)O1 GFISDBXSWQMOND-UHFFFAOYSA-N 0.000 description 1
- UQAWXKDXVXSCRD-UHFFFAOYSA-N 2-(2-chloroethyl)-3,3-diethyl-1,2-benzothiazole 1,1-dioxide Chemical compound C1=CC=C2C(CC)(CC)N(CCCl)S(=O)(=O)C2=C1 UQAWXKDXVXSCRD-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention relates to the utilisation of compounds of formula (I) wherein the substituents have the meanings given in the description. The invention also relates to the salts thereof comprising pharmacologically compatible acids for producing medicaments for the prophylaxis and therapy of cerebral ischaemia and strokes.
Description
UTILISATION OF 2-SUBSTITUTED 1,2-BENZISOTHIAZOLE
DINONE DERIVATIVES FOR THE PROPHYLAXIS AND
THERAPY OF CEREBRAL ISCHAEMIA
The invention relates to the use of compounds of the formula I
for the prophylaxis and therapy of cerebral ischeMia.
DE 19747063.7 describes 3-substituted tetrahydropyridopyrimidinone derivatives of the formula I
X N- A- B- Ar y I NJ (I)~
in which one of the two radicals X, Y is CHZ and the other is NR1, R1 is hydrogen, (Cl_6)-alkyl, branched or unbranched, CO-(C1_4)-alkyl, C02tBu, CO-aryl or a phenyl-C1-C4-alkyl radical which for its part may be substituted on the aromatic ring by F, C1, Br, I, C1-C4-alkyl, C1-C4-alkoxy, trifluoromethyl, hydroxyl, amino, cyano or nitro, A is branched or unbranched (C1_lo)-alkylene or straight-chain or branched (C2_1o)-alkylene which comprises at least one group Z selected from the group consisting of 0, S, NR~, cyclopropyl, CHOH, a double and a triple bond, R2 is hydrogen or C1-C4-ahky-l, B is 4-piperidine, 4-tetrahydro-1,2,3,6-pyridine, 4-piperazine or the corresponding cyclic compounds which are enlarged by a methylene group, where A is attached via a nitrogen atom of B
and Ar is phenyl which is unsubstituted or substituted by (C1_6)-alkyl, branched or unbranched, 0-(C1_6)-alkyl, branched or unbranched, OH, F, Cl, Br, I, trifluoromethyl, NR22, COzR~, cyano or phenyl, is tetralin, indane, a higher fused aromatic, such as naphthalene, which is unsubstituted or la substituted by ( Ci_, ) -alkyl or 0- ( C~_, ) -alkyl, is anthracene or a 5- or 6-membered aromatic heterocycle having 1 or 2 hetero atoms which, independently of one another, are selected from :, ~ 0050/49690 the group consisting of 0 and N, and which may be fused with other aromatic radicals.
These compounds of the formula I can be prepared by reacting a compound of the formula II
O
X N- A- Q
y I NJ (II).
in which A, X and Y are as defined above and Q is a group that can be cleaved off (for example C1, Br, I, alkanesulfonyloxy or arylsulfonyloxy), with a compound of the formula III
g-B-~ (III)r in which B and Ar are as defined above, in a manner known per se and converting the resulting compound, if appropriate, into the acid addition salt of a physiologically acceptable acid. It is also possible to react a compound of the formula IV
O
X ~ ~ B ( IV ) Y N
with a compound of the formula V
Q-A-B-Ar (V) in a manner known per se.
A further synthesis variant is the attachment of a compound of the formula VI
X I ~N- A- CHO ( VI ) ~~ J
N
to a compound of the formula III by a reductive amination, which is known per se.
The compounds of the formula III can be synthesized by :, ~ 0050/49690 -.
' 3 1. attaching compounds of the formula VII
W-B1 (VII).
where B1 is piperazine or homopiperazine and W is hydrogen or one of the customary amino protective groups (such as, for example, Boc or Cbz), to a compound of the formula VIII
P-~ (VIII), where P is B(OH)~, SnR3, OTf, Br, C1 or I and R is Cl-C,-alkyl, in a manner known per se; or 2' attaching compounds of the formula IX
W-B2-P1 (IX)~
where B~ is 4-tetrahydro-1,2,3,6-pyridine or the corresponding cyclic compounds which are enlarged by a methylene group and Pl is C1, Br, I, SnR3 -where R is C1-C4-alkyl - ~ OTf, to a compound of the formula X
P-Ar (X).
where W, P and Ar are each as defined above, and where the reactions are carried out by known processes, such as, for example, those described in S,L. Buchwald et al. J. Am. Chem. Soc. 1996, 118, 7215, J.F. Hartwig et al. Tetrahedron Z;ett. 1995, 36, 3604, J.K. Stille et al. Angew. Chem. 1986, 98, 504, S.L. Buchwald et al. Angew. Chem. 1995, 107, 1456 or J.F. Hartwig et al. J. Am. Chem. Soc 1996, 118, 7217 or J,F. Hartwig et al. J. Org. Chem. 1997, 62, 1268, S.L. Buchwald et al. J. Org. Chem. 1997, 62, 1264 and literature cited therein or S.L. Buchwald et al J. Am. Chem. Soc 1997, 119, 6054, J.R. Stille, Angew. Chem. 1986, 98, 504 or J,R. Stille et al. J. Org. Chem. 1990, 55, 3014, M. Pereyre et al. "Tin in Organic Synthesis", Butterworth 1987; or ' 0050/49690 3. reducing compounds of the formula (XI) W-B2-~ (XI).
where B2 is as defined above, to give compounds of the formula XII
W-B3-Ar (xII), in which B3 is a piperidine which is attached in 1,4 position or the corresponding cyclic compounds which are enlarged by a methylene group; or 4- cyclizing compounds of the formula XIII
W-N-(C2H4Q)2 (XIII), where W and Q are as defined above, with a compound of the formula XIV
NHZ-Ar (XIV), where Ar is as defined above, to give compounds of the formula XV
W-Bl-Ar (XV).
The substances of the formulae III and V required as starting materials for synthesizing the novel compounds are known or can be prepared according to known processes (for example Organikum Barth Dt. Verl. der Wiss. 1993 or A. R. Katritzky, C. W. Rees (ed.) Comprehensive Heterocyclic Chemistry Pergamon Press) from analogous starting materials.
The further reaction of the compounds B-B-Ar (III) prepared in this manner according to 1. to 4. with subsequent removal of any protective groups to give the compounds of the formula V is carried out by attachment to compounds of the formula XVI
Q-A-Q' (XVI), '' CA 02359390 2001-07-10 ' 0050/49690 :~
where Q and Q' are leaving groups, under conditions known per se.
The substances of the formulae II, IV, VI and of the formulae P-Ar, NHZ-Ar, W-H1 or W-B2-P1 required as starting materials for 5 synthesizing the novel compounds are known or can be prepared according to the preparation processes described in the literature from analogous starting materials (for example B.
Dumaitre, N. Dodic J. Med. Chem. 1996, 39, 1635 or A. Yokoo et al. Bull. Chem. Soc. Jpa. 1956, 29, 631 or L. Borjeson et al.
Acta Chem. Chem. 1991, 45, 621 or Organikum Barth Dt. Verl, der Wiss. 1993 or A. R. Katritzky, C. W. Rees (ed.) Comprehensive Xeterocyclic Chemistry Pergamon Press or The Chemistry of Heterocyclic Compounds J. Wiley & Sons Inc. NY and the literature cited therein in each case).
Example 1:
3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-5,6,7,8-tetra-hydro-6-benzylpyrido[4,3-d]pyrimidin-4(3H)-one Preparation of the starting materials a) 5,6,7,8-Tetrahydro-6-benzylpyrido[4,3-d]pyrimidin-4(3H)-one 4.7 g of sodium were, a little at a time, allowed to react in 250 ml of ethanol, and a suspension of 14.2 g (0.05 mol) of methyl N-benzyl-4-piperidone-3-carboxylate in ethanol was then added dropwise at 5-10°C. The mixture was stirred for 30 minutes, after which 6 g (0.075 mol) of formamidine hydrochloride were added slowly, and the reaction mixture was heated under reflux for 10 h. The solvent was removed under reduced pressure and the residue was taken up in 100 ml of water and adjusted to pH = 6.5 - 7 using 2N of hydrochloric acid, so that the product precipitated out. The crystals were filtered off with suction and dried in a vacuum drying cabinet, giving 8 g (66%), m.p.: 88°C.
5,6,7,8-Tetrahydro-7-benzylpyrido-[3,4-d]pyrimidin-4(3H)-one (m. p.: 199°C) and methyl 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one-6-carboxylate (m. p.: 160°C) were obtained similarly.
b) 1-(2-Methoxyphenyl)-4-(2-chloroeth-1-yl)piperazine At room temperature, a solution of 19.2 g (0.1 mol) of o-methoxyphenylpiperazine and 13.8 g (0.1 mol) of potassium carbonate in 200 ml of DMF was initially charged and, after '. ~ 0050/49690 °~
DINONE DERIVATIVES FOR THE PROPHYLAXIS AND
THERAPY OF CEREBRAL ISCHAEMIA
The invention relates to the use of compounds of the formula I
for the prophylaxis and therapy of cerebral ischeMia.
DE 19747063.7 describes 3-substituted tetrahydropyridopyrimidinone derivatives of the formula I
X N- A- B- Ar y I NJ (I)~
in which one of the two radicals X, Y is CHZ and the other is NR1, R1 is hydrogen, (Cl_6)-alkyl, branched or unbranched, CO-(C1_4)-alkyl, C02tBu, CO-aryl or a phenyl-C1-C4-alkyl radical which for its part may be substituted on the aromatic ring by F, C1, Br, I, C1-C4-alkyl, C1-C4-alkoxy, trifluoromethyl, hydroxyl, amino, cyano or nitro, A is branched or unbranched (C1_lo)-alkylene or straight-chain or branched (C2_1o)-alkylene which comprises at least one group Z selected from the group consisting of 0, S, NR~, cyclopropyl, CHOH, a double and a triple bond, R2 is hydrogen or C1-C4-ahky-l, B is 4-piperidine, 4-tetrahydro-1,2,3,6-pyridine, 4-piperazine or the corresponding cyclic compounds which are enlarged by a methylene group, where A is attached via a nitrogen atom of B
and Ar is phenyl which is unsubstituted or substituted by (C1_6)-alkyl, branched or unbranched, 0-(C1_6)-alkyl, branched or unbranched, OH, F, Cl, Br, I, trifluoromethyl, NR22, COzR~, cyano or phenyl, is tetralin, indane, a higher fused aromatic, such as naphthalene, which is unsubstituted or la substituted by ( Ci_, ) -alkyl or 0- ( C~_, ) -alkyl, is anthracene or a 5- or 6-membered aromatic heterocycle having 1 or 2 hetero atoms which, independently of one another, are selected from :, ~ 0050/49690 the group consisting of 0 and N, and which may be fused with other aromatic radicals.
These compounds of the formula I can be prepared by reacting a compound of the formula II
O
X N- A- Q
y I NJ (II).
in which A, X and Y are as defined above and Q is a group that can be cleaved off (for example C1, Br, I, alkanesulfonyloxy or arylsulfonyloxy), with a compound of the formula III
g-B-~ (III)r in which B and Ar are as defined above, in a manner known per se and converting the resulting compound, if appropriate, into the acid addition salt of a physiologically acceptable acid. It is also possible to react a compound of the formula IV
O
X ~ ~ B ( IV ) Y N
with a compound of the formula V
Q-A-B-Ar (V) in a manner known per se.
A further synthesis variant is the attachment of a compound of the formula VI
X I ~N- A- CHO ( VI ) ~~ J
N
to a compound of the formula III by a reductive amination, which is known per se.
The compounds of the formula III can be synthesized by :, ~ 0050/49690 -.
' 3 1. attaching compounds of the formula VII
W-B1 (VII).
where B1 is piperazine or homopiperazine and W is hydrogen or one of the customary amino protective groups (such as, for example, Boc or Cbz), to a compound of the formula VIII
P-~ (VIII), where P is B(OH)~, SnR3, OTf, Br, C1 or I and R is Cl-C,-alkyl, in a manner known per se; or 2' attaching compounds of the formula IX
W-B2-P1 (IX)~
where B~ is 4-tetrahydro-1,2,3,6-pyridine or the corresponding cyclic compounds which are enlarged by a methylene group and Pl is C1, Br, I, SnR3 -where R is C1-C4-alkyl - ~ OTf, to a compound of the formula X
P-Ar (X).
where W, P and Ar are each as defined above, and where the reactions are carried out by known processes, such as, for example, those described in S,L. Buchwald et al. J. Am. Chem. Soc. 1996, 118, 7215, J.F. Hartwig et al. Tetrahedron Z;ett. 1995, 36, 3604, J.K. Stille et al. Angew. Chem. 1986, 98, 504, S.L. Buchwald et al. Angew. Chem. 1995, 107, 1456 or J.F. Hartwig et al. J. Am. Chem. Soc 1996, 118, 7217 or J,F. Hartwig et al. J. Org. Chem. 1997, 62, 1268, S.L. Buchwald et al. J. Org. Chem. 1997, 62, 1264 and literature cited therein or S.L. Buchwald et al J. Am. Chem. Soc 1997, 119, 6054, J.R. Stille, Angew. Chem. 1986, 98, 504 or J,R. Stille et al. J. Org. Chem. 1990, 55, 3014, M. Pereyre et al. "Tin in Organic Synthesis", Butterworth 1987; or ' 0050/49690 3. reducing compounds of the formula (XI) W-B2-~ (XI).
where B2 is as defined above, to give compounds of the formula XII
W-B3-Ar (xII), in which B3 is a piperidine which is attached in 1,4 position or the corresponding cyclic compounds which are enlarged by a methylene group; or 4- cyclizing compounds of the formula XIII
W-N-(C2H4Q)2 (XIII), where W and Q are as defined above, with a compound of the formula XIV
NHZ-Ar (XIV), where Ar is as defined above, to give compounds of the formula XV
W-Bl-Ar (XV).
The substances of the formulae III and V required as starting materials for synthesizing the novel compounds are known or can be prepared according to known processes (for example Organikum Barth Dt. Verl. der Wiss. 1993 or A. R. Katritzky, C. W. Rees (ed.) Comprehensive Heterocyclic Chemistry Pergamon Press) from analogous starting materials.
The further reaction of the compounds B-B-Ar (III) prepared in this manner according to 1. to 4. with subsequent removal of any protective groups to give the compounds of the formula V is carried out by attachment to compounds of the formula XVI
Q-A-Q' (XVI), '' CA 02359390 2001-07-10 ' 0050/49690 :~
where Q and Q' are leaving groups, under conditions known per se.
The substances of the formulae II, IV, VI and of the formulae P-Ar, NHZ-Ar, W-H1 or W-B2-P1 required as starting materials for 5 synthesizing the novel compounds are known or can be prepared according to the preparation processes described in the literature from analogous starting materials (for example B.
Dumaitre, N. Dodic J. Med. Chem. 1996, 39, 1635 or A. Yokoo et al. Bull. Chem. Soc. Jpa. 1956, 29, 631 or L. Borjeson et al.
Acta Chem. Chem. 1991, 45, 621 or Organikum Barth Dt. Verl, der Wiss. 1993 or A. R. Katritzky, C. W. Rees (ed.) Comprehensive Xeterocyclic Chemistry Pergamon Press or The Chemistry of Heterocyclic Compounds J. Wiley & Sons Inc. NY and the literature cited therein in each case).
Example 1:
3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-5,6,7,8-tetra-hydro-6-benzylpyrido[4,3-d]pyrimidin-4(3H)-one Preparation of the starting materials a) 5,6,7,8-Tetrahydro-6-benzylpyrido[4,3-d]pyrimidin-4(3H)-one 4.7 g of sodium were, a little at a time, allowed to react in 250 ml of ethanol, and a suspension of 14.2 g (0.05 mol) of methyl N-benzyl-4-piperidone-3-carboxylate in ethanol was then added dropwise at 5-10°C. The mixture was stirred for 30 minutes, after which 6 g (0.075 mol) of formamidine hydrochloride were added slowly, and the reaction mixture was heated under reflux for 10 h. The solvent was removed under reduced pressure and the residue was taken up in 100 ml of water and adjusted to pH = 6.5 - 7 using 2N of hydrochloric acid, so that the product precipitated out. The crystals were filtered off with suction and dried in a vacuum drying cabinet, giving 8 g (66%), m.p.: 88°C.
5,6,7,8-Tetrahydro-7-benzylpyrido-[3,4-d]pyrimidin-4(3H)-one (m. p.: 199°C) and methyl 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one-6-carboxylate (m. p.: 160°C) were obtained similarly.
b) 1-(2-Methoxyphenyl)-4-(2-chloroeth-1-yl)piperazine At room temperature, a solution of 19.2 g (0.1 mol) of o-methoxyphenylpiperazine and 13.8 g (0.1 mol) of potassium carbonate in 200 ml of DMF was initially charged and, after '. ~ 0050/49690 °~
30 min, 30 ml (0.36 mol) of 1-bromo-2-chloroethane were added. The mixture was stirred at room temperature for 2 h.
The mixture was poured into ice-water and then extracted with methyl.tert-butyl ether, and the organic phases were washed with water, dried with sodium sulfate and subsequently concentrated. The residue was dissolved in ethyl acetate and the hydrochloride was precipitated out by addition of 30%
strength isopropanol/HC1 solution, filtered off with suction and then dried at 40°C in a vacuum drying cabinet. This gave 17 g (67%) of substance. m.p.: 200°C.
1-(2-Methoxyphenyl)-4-(3-chloroprop-1-yl)piperazine (m. p.:
217°C, hydrochloride), 1-(3,4-methylphenyl)-4-(2-chloroeth-1-yl)-piperazine (m.p.: 260°C, hydrochloride), 1-(2-pyrimidyl)-4-(2-chloroeth-1-yl)piperazine (m.p.: 270°C, hydrochloride), 1-(naphth-1-yl)-4-(3-chloroprop-1-yl)piperazine (m.p.: 217°C, hydrochloride), were obtained in a similar manner.
Two exemplary syntheses for preparing the piperazines are shown below.
1-Tetralin-5-yl-piperazine 14.7 g (0.1 mol) of 5-aminotetralin and 18 g (0.11 mol) of bis(~-chloroethyl)amine hydrochloride in 300 ml of n-butanol were refluxed for 48 h, 5.4 g of sodium carbonate were added after cooling and the mixture was once more refluxed for 20 h. The precipitate which was formed by cooling was filtered off with suction, taken up in water and admixed with 2N sodium hydroxide solution. The aqueous phase was extracted with ethyl acetate, and the extract was washed with water, dried over sodium sulfate and concentrated under reduced pressure. In this manner, it was possible to isolate 10.7 g (50%) of the product as an oil.
4-Piperazin-1-ylisoquinoline 4.51 g (21.7 mmol) of 4-bromoisoquinoline, 4.65 g (25.0 mmol) of t-butyl piperazine-N-carboxylate, 0.1 g (0.11 mmol) of tris-(dibenzylideneacetone)dipalladium, 0.11 g (0.18 mmol) of 2,2'-bis(diphenylphosphino)-1,1'-dinaphthyl and 2.92 g (30.4 mmol) of sodium t-butoxide were admixed in 50 ml of toluene and stirred at 75°C for 2 h. The reaction mixture was poured onto ice/sodium chloride and extracted with ethyl acetate, the organic phase was dried over sodium sulfate and the solvent was removed using a rotary evaporator. The product crystallized out, and it was filtered off with suction and washed with pentane. This gave :. ~ 0050/49690 5.5 g (81%) of the Boc-protected piperazine (m.p.: 111°C). 5.2 g (16.6 mmol) of this substance were taken up in 17 ml of dichloromethane and, at 0°C, slowly admixed with 17 ml (0.22 mol) of trifluoroacetic acid. The mixture was stirred at 0°C for 4 h, poured onto ice-water and extracted with dichloromethane. The aqueous phase was filtered, made alkaline and extracted with dichloromethane. After drying over sodium sulfate and substantial removal of the solvent, the residue was diluted with diethyl ether and the hydrochloride was precipitated out using ethereal hydrochloric acid. This gave 3.2 g (67%) of the product. (m. p.:
293°C) .
The following compounds were prepared similarly to the two processes described: 1-naphth-1-ylazepane (85°C, hydrochloride)., 1-naphth-1-ylmethylpiperazine (oil), 4-piperazin-1-yl-indane (oil), 1-naphth-1-ylpiperazine (82°C), 4-chloro-1-piperazin-1-ylphthalazine (205°C, decomp.) and 4-piperazin-1-ylquinazoline (320°C, hydrochloride). Other derivatives were commercially available.
Preparation of the end product 2.9 g (10 mmol) of chloroethylpiperazine [b)] and 2.8 g (20 mmol) of potassium carbonate were added to a solution of 2.4 g (10 mmol) of tetrahydropyridopyrimidine [a)] in 40 ml of DMF. The reaction mixture was reacted at 90°C for two hours and then poured onto ice-water and extracted with ethyl acetate. The organic.
phase was washed with saturated sodium chloride solution and dried over sodium sulfate, and the solvent was removed under reduced pressure. The oil that remained was taken up in acetone, and the hydrochloride was precipitated out using isopropanol/HCl.
This gave 4 g (75%) of the product (m. p.: 205°C).
NMR: CDC13 8 8.0 (s, 1H), 7.4 - 7.2 (m, 5H), 7.1 - 6.8 (m, 4H), 4.0 (t, 2H), 3.8 (s, 3H), 3.7~(s, 2H), 3.5 (s, 2H), 3.1 (brd. s, 4H), 2.8 - 2.6 (m, lOH) ppm.
The following compounds were obtained in a similar manner:
Example 2:
3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-5,6,7,8-tetra-hydro-7-benzylpyrido[3,4-d]pyrimidin-4(3H)-one (m.p.: 181°C, hydrochloride).
- ~ w5u/g9690 CA 02359390 2001-07-10 Example 3:
3-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-5,6,7,g-tetra-hydro-6-benzylpyrido[4,3-d]pyrimidin-4(38)-one (m.p,: 198°C, hydrochloride).
Example 4:
3-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-5,6,7,8-tetra-hydro-7-benzylpyrido[3,4-d]pyrimidin-4(38)-one (m.p.: 190°C, hydrochloride).
Example 5:
3-[3-[4-(2-methoxyphenyl)-1-piperazinyl]2-hydroxypropyl]-5,6,7,8-tetrahydro-6-benzylpyrido[4,3-d]pyrimidin-4-(38)-one.
Example 6:
20 t-butyl 3-[2-[4-(naphth-1-yl)-1-piperazinyl]ethyl]-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-(38)-one-6-carboxylate (m.p.: 1?0°C, hydrochloride).
Example 7:
3-[2-[4-(isoquinolin-4-yl)-1-piperazinyl]ethyl]-5,6,7,8-tetra-hydro-6--benzylpyrido[4,3-d]pyrimidin-4-(38)-one (m. p.: 268°C,~
hydrochloride).
Example 8:
3-[2-[4-(naphth-1-yl)-1-piperazinyl]ethyl]-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-(38)-one (m. p.: 272°C, hydrochloride).
Example 9:
3-[2-[4-(quinazolin-4-yl)-1-piperazinyl]ethyl]-5,6,7,8-tetra-hydro-6-benzylpyrido[4,3-d]pyrimidin-4-(38)-one (m.p.: 258°C, hydrochloride).
Example 10:
3-[2-[4-(naphth-1-yl)-1-piperazinyl]ethyl]-5,6,7,8-tetrahydro-6-benzylpyrido[4,3-d]pyrimidin-4-(38)-one (m.p.: 227°C, hydrochloride).
- ' 0050/49690 CA 02359390 2001-07-10 ', Example 11:
3-[2-[4-(naphth-1-yl)-tetrahydro-1,2,3,6-pyridin-1-yljeth-1-ylj-5,6,7,8-tetrahydro-6-benzylpyrido[4,3-djpyrimidin-4-(3H)-one (m. p.: 216~C, hydrochloride).
Synthesis of the starting materials a) N-Hoc-4-(trifluoromethanesulfonyloxy)-tetrahydro-1,2,3,6-pyridine At -78°C, a solution of 13.2 g (0.13 mol) of diisopropylamine in 200 ml of THF was deprotonated using 100 ml of nBuLi (1.6M
in hexane), and, after 30 minutes at this temperature, 20.0 g (0.1 mol) of N-Boc-piperid-4-one dissolved in 50 ml of THF
were added dropwise. After a further three hours at -78°C, a . solution of 39.3 g (0.11 mol) of N,N-bistrifluoromethanesulfonylaniline in 50 ml of THF was added, and the mixture was allowed to warm to room temperature overnight. For work-up, the mixture was admixed with water and extracted with ether, the organic phases were washed with NaHC03 solution and water and dried over sodium sulfate, and the solvent was concentrated. The crude product was purified by flash chromatography (silica gel, mobile phase heptane/ethyl acetate = 3/1).
Yield: 20.2 g (60% of theory) 1H NMR:(270 MHz,CDCl3) b = 1.4 (s, 9H); 2.4 (m,~2H); 3.6 (t, 2H); 4.1 (m, 2H); 5.8 (m, 1H) ppm b) N-Boc-4-naphth-1-yltetrahydro-1,2,3,6-pyridine 22 ml of 2M sodium carbonate solution, 7.63 g (44.4 mmol) of naphthyl-1-boronic acid, 4.13 g (97.6 mmol) of lithium chloride, 0.85 g (4.44 mmol) of copper(I) iodide and 2.1 g (1~77 mmol) of tetrakistriphenylpalladium were added successively to 14.7 g (44.4 mmol) of the compound described above dissolved in 115 ml of dimethoxyethane, and the mixture was heated at the boil for 4 h. For work-up, aqueous ammonia solution was added and the mixture was extracted with water and ethyl acetate, the extract was dried over sodium sulfate and the residue which was obtained after evaporation of the solvent was purified by flash chromatography (silica gel, mobile phase heptane/ethyl acetate = 4/1).
, vv,w~ ~~p~V CA 02359390 2001-07-10 , l Yield: 8.2 g (57% of theory) 1H-NMR (270 MHz, CDC13): 8 = 1.4 (s, 9H); 2.5 (m, 2H); 3.7 (t, 3$): 4.1 (m, 2H); 5.8 (m, 1H); 7.2-7.5(m, 3H); 7.3-8.0 (m, PPm~
c) 4-Naphth-1-yltetrahydro-1,2,3,6-pyridine 7~84 g (25.3 mmol) of N-Boc-4-naphth-1-yltetrahydro-1,2,3,6-pyridine were stirred overnight at room temperature with 200 ml of ethereal hydrochloric acid, and the precipitated product was filtered off and dried.
Yield: 5.5 g (88% of theory).
d) Preparation of the end product 0.51 g (2 mmol) of 4-naphth-1-yltetrahydro-1,2,3,6-pyridine dissolved in 30 ml of dry DMF was admixed with 0.61 g (2 mmol) of 3-(2-chloroeth-1-yl)-3,5,7,8-tetrahydro-4-oxo-6-benzylpyrido[4,3-d]pyrimidine and with 2 ml (17 mmol) of triethylamine, and the mixture was stirred at 120~C for 5 h.
The organic phase was diluted with ether, washed with water and dried over sodium sulfate, and the solvent was removed under reduced pressure. The resulting crude product was purified chromatographically, giving a white solid by precipitating the salt using ethereal hydrochloric acid solution.
Yield: 0.2 g (20% of theory) m.p.: 237°C.
Example 12 3-[2-[4-(Naphth-1-yl)piperidin-1-yljeth-1-yl]-5,6,7,8-tetrahydro-6-benzylpyrido[4,3-d]pyrimidin-4-(3H)-one 4-Naphth-1-ylpiperidine 3.7 g (15~3 mmol) of 4-naphth-1-yltetrahydro-1,2,3,6-pyridine, dissolved in methanol, were hydrogenated at room temperature with hydrogen for 48 h, with addition of 0.8 g of palladium on carbon.
The catalyst was filtered off and the solvent was concentrated.
Yield: 1.8 g (56% of theory) ' ' vv50/49690 CA 02359390 2001-07-10 1H NMR (270 MHz, CDC13) b = 1.6-1.8 (m, 2H); 2.0 (m, 2H); 2.9 (dt, 2H); 3.3 (d, 2H); 3.5 (tt, 1H); 7.4-7.6 (m, 4H); 7.7 (d, 1H); 7.9 (d, 1H); 8.1 (d, 1H) ppm.
Preparation of the end product 0.42 g (2 mmol) of 4-naphth-1-ylpiperidine, dissolved in 30 ml of dry DMF, was admixed with 0.61 g (2 mmol) of 3-(2-chloroeth-1-yl)-3,5,7,8-tetrahydro-4-oxo-6-benzylpyrido[4,3-d]pyrimidine and with 2 ml (17 mmol) of triethylamine, and the mixture was stirred at 120~C for 5 h. The organic phase was diluted with ether, washed with water and dried over sodium sulfate, and the solvent was removed under reduced pressure. The resulting crude product was purified chromatographically, giving a white solid by precipitating the salt using ethereal hydrochloric acid solution.
I
Yield: 0.24 g (27% of theory) 1H NMR (270 MHz, CDC13) b = 8.3 (s, 1H), 8.0 (d, 1H), 7.8 (d, 1H), 7.7 (t, 1H), 7.5 - 7.2 (m, 9H), 4.5 (s, 2H), 4.0 (s, 2H), 3.7 -2.3 (m, 15H), 2.1 (d, 2H) ppm.
Other preferred compounds of the formula I according to the invention are listed in the table below.
- , ' 0050/49690 o .
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c~ o, o~ o, o,0 0 0 . CA 02359390 2001-07-10 - ~. 0050/49690 DE 19746612.5 describes 2-substituted 1,2-benzisothiazole derivatives of the formula I
I
N
R4 02 ~A-B-Ar in which R1, R2 independently of one another are (C1_6)-alkyl, R3, R4 independently of one another are hydrogen, (C1_6)-alkyl, branched or unbranched, OH, O-(C1_6)-alkyl, branched or unbranched, F, C1, Br, I, trifluoromethyl, NR5R6, COZR~, nitro, cyano, pyrrole, are a phenyl-C1-C4-alkyl radical which for its part may be substituted on the aromatic ring by F, C1, Br, I, C1-CQ-alkyl, C1-C4-alkoxy, trifluoromethyl, hydroxyl, amino, cyano or vitro, R5, R6 independently of one another are hydrogen, (Cl_6)-alkyl, branched or unbranched, COPh, C02tBu, CO-(C1_4)-alkyl or together are a 5- or 6-membered ring which may contain a second nitrogen (for example piperazine), R~ is hydrogen or (C1_6)-alkyl, branched or unbranched, A is branched or unbranched (C1_lo)-alkylene or straight-chain or branched (C2_lo)-alkylene which comprises at least one group Z
selected from the group consisting of 0, S, NR~, cyclopropyl, CHOH, a double and a triple bond, B is 4-piperidine, 4-tetrahydro-1,2,3,6-pyridine, 4-piperazine and the corresponding cyclic compounds which are enlarged by a methylene group, where A is attached via a nitrogen atom of B and Ar is phenyl which is unsubstituted or substituted by (C1_6)-alkyl, branched or unbranched, 0-(C1_6)-alkyl, branched or unbranched, OH, F, C1, Br, I, trifluoromethyl, NR5R6, COZR~, cyano or phenyl, is tetraline, indane, a higher fused aromatic, such as naphthalene, which is unsubstituted or substituted by (C1_4)-alkyl or 0(C1_4)-alkyl, is anthracene or a 5- or 6-membered aromatic heterocycle having 1 or 2 hetero atoms which, independently of one another, are selected from the group consisting of O and N, and which may be fused with other aromatic radicals, for example ' 41 quinoline, isoquinoline, phthalazine, indole and quinazoline, which for its part may be substituted again by phenyl, and their salts with physiologically acceptable acids.
These compounds of the formula I can be prepared by reacting a compound of the formula II
JC I R I I r N
R4 S02 ~ A-Q
in which R1 to R4 and A are as defined above and Q is a group that can be cleaved off (for example C1, Br, I, alkanesulfonyloxy or arylsulfonyloxy), with a secondary amine of the formula III
H-B-Ar III, in which B and Ar are as defined above, in a manner known per se and converting the resulting compound; if appropriate, into the acid addition salt of a physiologically acceptable acid. It is also possible to react a compound of the formula IV
IV
N
R4 S02 ~ H
..
with a compound of the formula V
Q-A-B-Ar V
in a manner known per se. A further synthesis variant is the attachment of a compound of the formula VI
i vI
/N~
to a compound of the formula III by a reductive amination known per se.
~. 0050/49690 ~ 42 The compounds of the formula III can be synthesized by 5. attaching compounds of the formula'VII
W-B1 (VII), where B1 is piperazine or homopiperazine and W is hydrogen or one of the customary amino protective groups (such as, for example, Boc or Cbz), to a compound of the formula VIII
P-Ar (VIII), where P is B(OH)a, SnR3, OTf, Br, C1 or I and R is C1-C4-alkyl, in a manner known per se; or 6. attaching compounds of the formula IX
W-B2-P1 (IX), where B2 is 4-tetrahydro-1,2,3,6-pyridine or the corresponding cyclic compounds which are enlarged by a methylene group and P1 is C1, Br, I, SnR3 - where R is C1-C4-alkyl - , OTf, to a compound of the formula X
P-~ (X) ~
where W, P and Ar are each as defined above, and where the reactions are carried out by known processes, such as, for example, those described in S.L. Buchwald et al. J. Am. Chem. Soc. 1996, 118, 7215 J.F. Hartwig et al. Tetrahedron Lett. 1995, 36, 3604 J.K. Stille et al. Angew. Chem. 1986, 98, 504 S.L. Buchwald et al. Angew. Chem. 1995, 107, 1456 or J.F. Hartwig et al. J. Am. Chem. Soc 1996, 118, 7217 or J.F. Hartwig et al. J. Org. Chem. 1997, 62, 1268 S.L. Buchwald et al. J. Org. Chem. 1997, 62, 1264 and literature cited therein or S.L. Buchwald et al. J. Am. Chem. Soc 1997, 119, 6054 J.R. Stille, Angew. Chem. 1986, 98, 504 or J.R. Stille et al. J. Org. Chem. 1990, 55, 3014.
M. Pereyre et al. "Tin in Organic Synthesis", Butterworth 1987; or 7. reducing compounds of the formula (XI) W-B2-Ar (XI), where H2 is as defined above, to give compounds of the formula XII
W-H3-Ar (XII), in which B3 is a piperidine which is attached in 1,4-position or the corresponding cyclic compounds which are enlarged by a methylene group; or 8. cyclizing compounds of the formula XIII
W-N-(C2HqQ)y (XIII), where W and Q are as defined above, with a compound of the formula XIV
NHy-Ar (XIV), where Ar is as defined above, to give compounds of the formula XV
w-sl-Ar (xv).
The substances of the formulae III and V required as starting materials for synthesizing the novel compounds are known or can be prepared according to known processes (for example Organikum Barth Dt. Verl. der Wiss. 1993 or A. R. Katritzky, C. W. Rees (ed.) Comprehensive Heterocyclic Chemistry Pergamon Press) from analogous starting materials.
The further reaction of the compounds H-B-Ar (III) prepared in this manner according to 1. to 4. with subsequent removal of any protective groups to give the compounds of the formula V is carried out by attachment to compounds of the formula XVI
Q-A-Q' (XVI), where Q and Q' are leaving groups, under conditions known per se.
The substances of the formulae II, IV, VI and of the formulae P-Ar, NHy-Ar, W-81 or W-BZ-P1 required as starting materials for synthesizing the novel compounds are known or can be prepared according to the preparation processes described in the ~~ 0050/49690 literature from analogous starting materials (for example B.
Schulze, K. Illgen J. prakt. Chem. 1997, 339, 1 or R. Auer, E.
Hungerbiihler, R. W. Lang Chimia 1990, 44, 120 or A. Yokoo et al.
Bull. Chem. Soc. Jpn. 1956, 29, 631 or L. Borjeson et al. Acta Chem. Chem. 1991, 45, 621 or Organikum Barth Dt. Verl. der Wiss.
1993 or A. R. Katritzky, G. W. Rees (ed.) Comprehensive Heterocyclic Chemistry Pergamon Press or The Chemistry of Heterocyclic Compounds J. Wiley & Sons Inc. NY and literature cited therein).
Example 1 . 3,3-Dimethyl-2-[3-(4-tetralin-5-yl-piperazin-1-yl)prop-1-yl]-2,3-dihydro-1,2-benzisothiazole l,l-dioxide Preparation of the starting materials a) 3,3-Dimethyl-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide The preparation of this compound was carried out in a manner known from the literature (R. Auer, E. Hungerbiihler, R. W. Lang Chimia 1990, 44, 120). 3,3-Diethyl-2,3-dihydro-1,2-benzisothiazole l,l-dioxide (m.p.: 174°C) and 3,3-dimethyl-6-nitro-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (m.p.: 187°C) were obtained in a similar manner.
b) 2-(3-Chloroprop-1-yl)-3,3-dimethyl-2,3-dihydro-1,2-benziso-thiazole l,l-dioxide A solution of 5.9 g (3 mmol) of 3;3-dimethyl-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide in 150 ml of DMF was initially _.
charged at room temperature and, after addition of 3.7 g (3.3 mmol) of potassium t-butoxide, heated under nitrogen to 80°C.
14.2 g (9 mmol) of 1-bromo-3-chloropropane were then added quickly, and the mixture was stirred at 100°C for 30 min. The mixture was poured into ice-water and extracted with ether, and the organic phases were washed with water, dried with sodium sulfate and subsequently concentrated, so that the product precipitated out in crystalline form and could be filtered off with suction. This gave 6.7 g (82%) of substance. M.p.: 107°C.
2-(3-Chloroprop-1-yl)-3,3-diethyl-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (m. p.: 70°C), 2-(3-chloroprop-1-yl)-3,3-dimethyl-6-vitro-2,3-dihydro-1,2- benzisothiazole l,l-dioxide (m. p.:
146°C), 2-(2-chloroethyl)-3,3-diethyl-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (oil), 2-(2-chloroethyl)-4-chloro-3,3-dimethyl-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide ~, 0050/49690 ' 45 (oil), 2-(3-chloro-2-methyleneprop-1-yl)-3,3-dimethyl-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (m.p.: 115°C) and 2-(3-chloroprop-1-yl)-3,3-dimethyl-6-nitro-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (m.p.: 146°C) were obtained in a similar manner.
c) 1-Tetralin-5-yl-piperazine 14.7 g (0.1 mol) of 5-aminotetraline and 18 g (0.11 mol) of bis(~-chloroethyl)amine hydrochloride in 300 ml of n-butanol were refluxed for 48 h, 5.4 g of sodium carbonate were added after cooling and the mixture was once more refluxed for 20 h. The precipitate which was forined by cooling was filtered off with suction, taken up in water and admixed with 2N sodium hydroxide solution. The aqueous phase was extracted with ethyl acetate, and the extract was washed with water, dried over sodium sulfate and concentrated under reduced pressure. In this manner, it was possible to isolate 10.? g (50%) of the product as an oil.
4-Piperazin-1-ylisoquinoline 4.51 g (21.7 mmol) of 4-bromoisoquinoline, 4.65 g (25.0 mmol) of t-butyl piperazine-N-carboxylate, 0.1 g (0.11 mmol) of tris-(dibenzylideneacetone)dipalladium, 0.11 g (0.18 mmol) of 2,2'-bis(diphenylphosphino)-1,1'-dinaphthyl and 2.92 g (30.4 mmol) of sodium t-butoxide were~admixed in 50 ml of toluene and stirred at 75C for 2 h. The reaction mixture was poured onto ice/sodium chloride and extracted with ethyl acetate, the organic phase was dried over sodium sulfate and the solvent was removed using a rotary evaporator. The product crystallized out, and it was filtered off with suction and washed with pentane. This gave 5.5 g (81%) of the Boc-protected piperazine (m.p.: 111C).
5.2 g.
(16.6 mmol) of this substance were taken up in 17 ml of dichloromethane and, at 0C, slowly admixed with 17 ml (0.22 mol) of trifluoroacetic acid. The mixture was stirred at 0C for 4 h, poured onto ice-water and extracted with dichloromethane.
The aqueous phase was filtered, made alkaline and extracted with dichloromethane. After drying over sodium sulfate and substantial removal of the solvent, the residue was diluted with diethyl ether and the hydrochloride was precipitated out using ethereal hydrochloric acid. This gave 3.2 g (67%) of the product. (m.
p.:
293C).
The following compounds were prepared similarly to the two processes described: 1-naphth-1-yldiazepane (85°C, hydrochloride), 1-naphth-1-ylmethylpiperazine (oil), 4-piperazin-1-yl-indane (oil), 1-naphth-1-ylpiperazine (82°C), 4-chloro-1-piperazin-. , CA 02359390 2001-07-10 -~. 0050/49690 ' 46 1-ylphthalazine (205~C, decomp.) and 4-piperazin-1-ylquinazoline (320~C, hydrochloride). Other derivatives were commercially available.
Preparation of the end product 1.1 g (5.2 mmol) of 1-tetralin-5-ylpiperazine, 1.5 ml of triethylamine and a trace of potassium iodide were added to a solution of 1.64 g (6.0 mmol) of 2-(3-chloroprop-1-yl)-3,3-dimethyl-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide in 40 ml of DMF. The reaction mixture was allowed to react at 100~C for four hours and then poured onto ice-water, and the resulting precipitate was filtered off with suction. Purification was carried out by recrystallization from isopropanol, giving 1 g (43%) of the product (m. p.: 140~C).
NMR: CDC13 b 7.8 (d, 1H), 7.6 (dd, lx), 7.5 (dd, 1H), 7.4 (d, lH), 7.1 (dd, 1H), 6.9 (d, 1H), 6.8 (d, 1H), 3.4 (t, 2H), 3.0-2.5 (m, 14H), 2.1 (tt, 2H), 1.8-1.7 (m, 4H), 1.5 (s, 6A) ppm.
The following compounds were obtained in a similar manner:
Example 2:
3,3-dimethyl-2-[3-(4-(2-phenylquinazolin-4-yl)piperazin-1-yl)-prop-1-yl]-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (m. p.:
269~C, hydrochloride).
Example 3:
3,3-dimethyl-2-[3-(4-quinolin-2-yl-piperazin-1-yl)prop-1-yl]-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (m.p. 63~C). -Example 4:
3,3-dimethyl-2-[3-(4-naphth-1-yl-1,4-diazepan-1-yl)prop-1-yl]-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (m. p. 126~C, hydrochloride).
Example 5:
3,3-dimethyl-2-[3-(4-(4-chlorophthalazin-1-yl)piperazin-1-yl)-eth-1-yl]-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (m. p.
190~C).
Example 6:
3,3-dimethyl-2-[3-(4-naphth-1-ylpiperazin-1-yl)-2-methyleneprop-1-yl]-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (m. p. 193~C).
', 0050/49690 Example 7:
3,3-dimethyl-2-[2-(4-quinazolin-4-ylpiperazin-1-yl)eth-1-yl]-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (m.p. 178°C, hydrochloride).
Example 8:
3,3-dimethyl-2-[2-(4-naphth-1-ylpiperazin-1-yl)eth-1-yl]-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (m.p. 282°C, hydrochloride).
Example 9:
3,3-dimethyl-2-[2-(4-isoquinolin-4-yl)piperazin-1-yl)eth-1-yl]-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (m.p. 243°C, hydrochloride).
Example 10:
3,3-diethyl-2-[2-(4-naphth-1-yl-piperazin-1-yl)eth-1-yl]-2,3-dihy dro-1,2-benzisothiazole l,l-dioxide (oil).
ZO Example 11:
3,3-dimethyl-2-[3-(4-naphth-1-ylpiperazin-1-yl)prop-1-yl]-6-pyrrol-1-yl-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (m. p.
269°C, hydrochloride).
The pyrrole ring was constructed by reacting 3,3-dimethyl-2-[3-(4-naphth-1-ylpiperazin-1-yl)prop-1-yl]-6-arnino-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide with 2,5-dimethoxytetrahydrofuran in glacial acetic acid at 100°C (lh), in a yield of 86% .
_.
Example 12:
3,3-dimethyl-2-[3-(4-naphth-1-ylpiperazin-1-yl)prop-1-yl]-6-benzoylamido-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (m. p.
12?°C ) .
Example 13:
3,3-dimethyl-2-[3-(4-naphth-1-ylpiperazin-1-yl)prop-1-yl]-6-nitro-2,3-dihydro-I,2-benzisothiazole 1,1-dioxide (m. p. 203°C).
Example 14:
3,3-dimethyl-2-[2-(4-(2,3-dimethylphenyl)piperazin-1-yl)eth-1-yl]-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (m.p. 291°C, hydrochloride).
'~ 0050/49690 Example 15:
3,3-dimethyl-2-[2-(4-indan-4-ylpiperazin-1-yl)eth-1-yl]-2,3-dihydro-1,2-benzisothiazole l,l-dioxide (m.p. 271°C, hydrochloride).
Example 16:
3,3-dimethyl-2-[3-(4-(4-chloronaphth-1-yl)piperazin-1-yl)prop-1-yl]-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (m. p. 151°C).
Example 17:
3,3-dimethyl-2-[3-(4-pyrimidin-2-ylpiperazin-1-yl)prop-1-yl]-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (m.p. 263°C, hydrochloride).
Example 18:
3,3-dimethyl-2-[2-(4-(4-methoxyphenyl)-piperazin-1-yl)eth-1-yl]-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (m.p. 207°C, hydrochloride).
Example 19:
3,3-dimethyl-2-[3-(4-(2-methoxyphenyl)piperazin-1-yl)-2.-hydroxy-prop-1-yl)-2,3-dihydro-1,2-benzisothiazole l,l-dioxide (m. p.
160°C).
Example 20:
3,3-diethyl-2-[3-(4-naphth-1-ylpiperazin-1-yl)prop-1-yl]-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (m. p. 179°C).
Example 21:
3,3-dimethyl-2-[3-(4-(2,5-dimethylphenyl)piperazin-1-yl)prop-1-yl]-2,3-dihydro-1,2-benzisothiazole l,l-dioxide (m.p. 218°C, hydrochloride).
Example 22:
3,3-dimethyl-2-[2-(4-(2-cyanophenyl)piperazin-1-yl)-eth-1-yl]-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (m.p. 228°C, hydrochloride).
Example 23:
3,3-dimethyl-2-[2-(4-naphth-1-ylpiperazin-1-yl)eth-1-yl]-4-chloro-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide ~. 0050/49690 Preparation of the starting materials a) 4-Chloro-3,3-dimethyl-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide. This compound was prepared similarly to Example 1 a). Yield 7.8 g (70%). (m. p. 121~C) b) 2-(2,2-Diethoxyeth-1-yl)-4-chloro-3,3-dimethyl-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide 7.7 g (33 mmol) of 4-chloro-3,3-dimethyl-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide, 8.25 ml (55 mmol) of bromoacetaldehyde diethyl acetal and 7.0 g of potassium carbonate were taken up in 100 ml of dry DMF and stirred at 120~C for 5 h. The reaction mixture was poured into ice-water and then extracted with ethyl acetate, and the organic phase was washed with water and dried over sodium sulfate. The solvent was removed under reduced pressure and the crude product was purified by column chromatography. This gave 7.5 g (65%) of the product as an oil.
c) 2-(2-Oxoeth-1-yl)-4-chloro-3,3-dimethyl-2,3-dihydro-1,2-benz-isothiazole 1,1-dioxide 7.5 g (21.5 mmol) of 2-(2,2-diethoxyeth-1-yl)-4-chloro-3,3-dimethyl-2,3-dihydro- 1,2-benzisothiazole l,l-dioxide and 25 ml of conc. hydrochloric acid were taken up in 25 ml of water and 150 ml of THF and stirred at 40~C for 1.5 h. The reaction mixture was neutralized using aqueous sodium hydroxide solution and extracted with ether, and the organic phase was dried over sodium sulfate and concentrated under reduced pressure. In this manner, it was possible to isolate 5.8 g (98%) of the product as an oil.
Preparation of the end product 1.5 g (5.5 mmol) of the aldehyde 24 c), 1.06 g (5 mmol) of naphthylpiperazine (prepared analogously to Example 1 c)) and 0.42 g (7 mmol) of glacial acetic acid were initially charged in 50 ml of ethanol, the mixture was stirred at room temperature for 30 minutes and 0.5 g (8 mmol) of sodium cyanoborohydride were then added slowly. The reaction mixture was stirred at room temperature for 2 h and then poured onto an ice/sodium chloride mixture and extracted with dichloromethane. The extract was dried with sodium sulfate, the solvent was distilled off and the residue was subsequently recrystallized from ethanol, giving 0.9 g (39%) of colorless crystals (m. p. 156~C).
VV~V/g'Jb~JO CA 02359390 2001-07-10 NMR:CDC13 8 = 8.3 (m, 1H), 7.8 (m, 1H), 7.7 (d, 1H), 7.6 - 7.'3 (m, 6H), 7.1 (d, 1H), 3.5 (t, 2H), 3.2 (m, 4H), 3.0 - 2.8 (m, 6H), 1.8 (s, 6H) PPm.
5 Example 24 Preparation of 3,3-dimethyl-2-[2-(4-naphth-1-yltetrahydro-1,2,3,6-pyridin-1-yl)eth-1-yl]-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide Synthesis of the starting materials a) N-Boc-4-(trifluoromethanesulfonyloxy)tetrahydro-1,2,3,6-pyridine At -78~C, a solution of 13.2 g (0.13 mol) of diisopropylamine in 200 ml of THF was deprotonated with I00 ml of nBuLi (1.6M in hexane), and, after 30 minutes at this temperature, 20.0 g (0.1 mol) of N-Boc-piperidone, dissolved in 50 ml of THF, were added dropwise. After a further three hours at -78~C, a solution of 39.3 g (0.11 mol) of N,N-bistrifluoromethanesulfonylaniline in 50 ml of THF was added, and the reaction mixture was allowed to warm to room temperature overnight. For work-up, the mixture was admixed with water and extracted with ether, the organic phases were washed with NaHC03 solution and water and dried over sodium sulfate, and the solvent was concentrated. The crude product was purified by flash chromatography (silica gel, mobile phase heptane/ethyl acetate = 3/1).
Yield: 20.2 g (60% of theory) 1H NMR:(270 MHz, CDC13) 8 = 1.4 (s, 9H); 2.4 (m, 2H); 3.6. (t, 2H);
4.1 (m, 2H); 5.8 (m, 1H) ppm.
b) N-Boc-4-naphth-1-yltetrahydro-1,2,3,6-pyridine 14.7 g (44.4 mmol) of the compound described above, dissolved in 115 ml of dimethoxyethane, were admixed successively with 22 ml of 2M sodium carbonate solution, 7.63 g (44.4 mmol) of naphthyl-1-boronic acid, 4.13 g (97.6 mmol) of lithium chloride, 0.85 g (4.44 mmol) of copper(I) iodide and 2.1 g (1.77 mmol) of tetrakistriphenylpalladium, and the mixture was heated at the boil for 4 h. For work-up, aqueous ammonia solution was added to the mixture, which was then extracted with water and ethyl acetate, the extract was dried over sodium sulfate and the residue which was obtained after evaporation of the solvent was purified by flash chromatography (silica gel, mobile phase heptane/ethyl acetate = 4/1).
Yield: 8.2 g (57% of theory) ., ~ ~ vvrv~ s7v7V
. 51 1H NMR (270 MHz, CDC13): 8 = 1.4 (s, 9H); 2.5 (m, 2H); 3.7 (t, 2H); 4.1 (m, 2H); 5.8 (m, 1H); 7.2-7.5 (m, 3H); 7.3-8.0 (m, 38) ppm.
c) 4-Naphth-1-yltetrahydro-1,2,3,6-pyridine 7.84 g (25.3 mmol) of N-Boc-4-naphth-1-yl-3,6-dihydro-2H-pyridine were stirred-overnight at room temperature with 200 ml of ethereal hydrochloric acid, and the precipitated product was filtered off and dried.
Yield: 5.5 g (88% of theory).
d) Preparation of the end product 1.0 g (4.1 mmol) of the compound 24c described above, dissolved in 20 ml of methanol, was, in the presence of 2.22 g (16.8 mmol) of zinc(II) chloride, admixed first with 1.27 g (5.3 mmol) of the aldehyde described under Example 23c and then with 0.5 g (8.14 mmol) of sodium cyanoborohydride. After 16 h at room temperature, the mixture was worked up as described and the resulting crude product was purified by chromatography (silica gel, mobile phase dichloromethane/methanol = 97/3). Precipitation of the salt using ethereal hydrochloric acid solution gave a white solid.
Yield: 0.9 g (47% of theory) 1H NMR (270 MHz, DMSO-d6): b = 1.6 (m, 6H); 2.6 (m, 1H); 3.1 (m, 1H); 3.4-3.6 (m, 6H); 4.0-4.2 (m, 2H); 5.8 (brd. s, 1H); 7.6-8.0 (m, 7H); 8.2 (d, 1H); 12.0 (s, 1H) ppm.
Example 25 Preparation of 3,3-dimethyl-2-[2-(4-naphth-1-ylpiperidin-1-yl)eth-1-yl]-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide a) 4-Naphth-1-ylpiperidine 3.7 g (15.3 mmol) of 4-naphth-1-yltetrahydro-1,2,3,6-pyridine, dissolved in methanol, were hydrogenated with hydrogen for 48 h at room temperature, with addition of 0.8 g of palladium on carbon. The catalyst was filtered off and the solvent was concentrated.
Yield: 1.8 g (56% of theory) 1H NMR (270 MHz, CDC13) b = 1.6-1.8 (m, 2H); 2.0 (m, 2H); 2.9 (dt, 2H); 3.3 (d, 2H); 3.5 (tt, 1H); 7.4-7.6 (m, 4H); 7.7 (d, iH); 7.9 (d, 1H); 8.1 (d, 1H) ppm.
' . CA 02359390 2001-07-10 ' S2 Preparation of the end product A solution of 1.5 g (7.1 mmol) of the amine 25a in 20 ml of methanol was admixed first with 3.8 g (28.4 mmol) of zinc chloride and then with 2.21 g (9,2 mmol) of the aldehyde described under Example 23 c, dissolved in 15 ml of methanol, and 0~89 g (14.2 mmol) of sodium cyanoborohydride was then added a little at a time. The mixture was stirred for six hours, undissolved particles were then filtered off, the mother liquor was concentrated and the residue was taken up in ethyl acetate.
The organic phase was washed with water and saturated sodium chloride solution, dried over sodium sulfate and filtered, giving, on concentration, a yellowish oil.
Yield: 2.2 g (65% of theory) 1H NMR (270 MHz, CDC13): 8 = 1.7-1.9 (m, 8H); 2.0 (m, 2H); 2.7-3.0 (m, 4H); 3.2 .(m, 2H); 3.5 (m, 1H); 3,7 (t, 2H); 7.1 (d, 1H);
7.3-7.7 (m, 9H); 8.2 (d, 1H) ppm.
Other preferred compounds of the formula I according to the invention are listed in the table below.
These compounds are suitable for preparing medicaments for the prophylaxis and therapy of neurodegeneration, cerebral trauma and cerebral ischemia, in particular stroke, and of diseases which are caused by these disorders.
A use according to the invention also relates to neuroprotection.
The preparation of these compounds is described in the patents mentioned at the outset.
The preparation as a medicament is carried out using a compound of the formula I or its pharmacologically acceptable acid addition salt as active compound, together with customary excipients and diluents.
The use according to the invention can be carried out in a customary manner, orally or parenterally, intravenously or intramuscularly.
The dosage depends on the age, on the state and the weight of the patient and on the type of administration. In general, the daily dose of active compound is between approximately 1 and 100 mg/kg of body weight in the case of oral administration and between 0.1 and 10 mg/kg of body weight in the case of parenteral administration.
The medicaments can be used in solid or liquid form in customary pharmaceutical administration forms, for example as tablets, film-coated tablets, capsules, powders, granules, sugar-coated tablets, suppositories, solutions, ointments, creams or sprays.
These are prepared in a customary manner. Sere, the active compounds can be processed with the customary pharmaceutical auxiliaries, such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, sustained-release agents, antioxidants and/or propellants (cf. B. Sucker et al.:
Pharmazeutische Technologie [Pharmaceutical Technology], Thieme-Verlag, Stuttgart, 1978). The resulting administration forms generally comprise the active compound in an amount of from 1 to 99% by weight.
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The mixture was poured into ice-water and then extracted with methyl.tert-butyl ether, and the organic phases were washed with water, dried with sodium sulfate and subsequently concentrated. The residue was dissolved in ethyl acetate and the hydrochloride was precipitated out by addition of 30%
strength isopropanol/HC1 solution, filtered off with suction and then dried at 40°C in a vacuum drying cabinet. This gave 17 g (67%) of substance. m.p.: 200°C.
1-(2-Methoxyphenyl)-4-(3-chloroprop-1-yl)piperazine (m. p.:
217°C, hydrochloride), 1-(3,4-methylphenyl)-4-(2-chloroeth-1-yl)-piperazine (m.p.: 260°C, hydrochloride), 1-(2-pyrimidyl)-4-(2-chloroeth-1-yl)piperazine (m.p.: 270°C, hydrochloride), 1-(naphth-1-yl)-4-(3-chloroprop-1-yl)piperazine (m.p.: 217°C, hydrochloride), were obtained in a similar manner.
Two exemplary syntheses for preparing the piperazines are shown below.
1-Tetralin-5-yl-piperazine 14.7 g (0.1 mol) of 5-aminotetralin and 18 g (0.11 mol) of bis(~-chloroethyl)amine hydrochloride in 300 ml of n-butanol were refluxed for 48 h, 5.4 g of sodium carbonate were added after cooling and the mixture was once more refluxed for 20 h. The precipitate which was formed by cooling was filtered off with suction, taken up in water and admixed with 2N sodium hydroxide solution. The aqueous phase was extracted with ethyl acetate, and the extract was washed with water, dried over sodium sulfate and concentrated under reduced pressure. In this manner, it was possible to isolate 10.7 g (50%) of the product as an oil.
4-Piperazin-1-ylisoquinoline 4.51 g (21.7 mmol) of 4-bromoisoquinoline, 4.65 g (25.0 mmol) of t-butyl piperazine-N-carboxylate, 0.1 g (0.11 mmol) of tris-(dibenzylideneacetone)dipalladium, 0.11 g (0.18 mmol) of 2,2'-bis(diphenylphosphino)-1,1'-dinaphthyl and 2.92 g (30.4 mmol) of sodium t-butoxide were admixed in 50 ml of toluene and stirred at 75°C for 2 h. The reaction mixture was poured onto ice/sodium chloride and extracted with ethyl acetate, the organic phase was dried over sodium sulfate and the solvent was removed using a rotary evaporator. The product crystallized out, and it was filtered off with suction and washed with pentane. This gave :. ~ 0050/49690 5.5 g (81%) of the Boc-protected piperazine (m.p.: 111°C). 5.2 g (16.6 mmol) of this substance were taken up in 17 ml of dichloromethane and, at 0°C, slowly admixed with 17 ml (0.22 mol) of trifluoroacetic acid. The mixture was stirred at 0°C for 4 h, poured onto ice-water and extracted with dichloromethane. The aqueous phase was filtered, made alkaline and extracted with dichloromethane. After drying over sodium sulfate and substantial removal of the solvent, the residue was diluted with diethyl ether and the hydrochloride was precipitated out using ethereal hydrochloric acid. This gave 3.2 g (67%) of the product. (m. p.:
293°C) .
The following compounds were prepared similarly to the two processes described: 1-naphth-1-ylazepane (85°C, hydrochloride)., 1-naphth-1-ylmethylpiperazine (oil), 4-piperazin-1-yl-indane (oil), 1-naphth-1-ylpiperazine (82°C), 4-chloro-1-piperazin-1-ylphthalazine (205°C, decomp.) and 4-piperazin-1-ylquinazoline (320°C, hydrochloride). Other derivatives were commercially available.
Preparation of the end product 2.9 g (10 mmol) of chloroethylpiperazine [b)] and 2.8 g (20 mmol) of potassium carbonate were added to a solution of 2.4 g (10 mmol) of tetrahydropyridopyrimidine [a)] in 40 ml of DMF. The reaction mixture was reacted at 90°C for two hours and then poured onto ice-water and extracted with ethyl acetate. The organic.
phase was washed with saturated sodium chloride solution and dried over sodium sulfate, and the solvent was removed under reduced pressure. The oil that remained was taken up in acetone, and the hydrochloride was precipitated out using isopropanol/HCl.
This gave 4 g (75%) of the product (m. p.: 205°C).
NMR: CDC13 8 8.0 (s, 1H), 7.4 - 7.2 (m, 5H), 7.1 - 6.8 (m, 4H), 4.0 (t, 2H), 3.8 (s, 3H), 3.7~(s, 2H), 3.5 (s, 2H), 3.1 (brd. s, 4H), 2.8 - 2.6 (m, lOH) ppm.
The following compounds were obtained in a similar manner:
Example 2:
3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-5,6,7,8-tetra-hydro-7-benzylpyrido[3,4-d]pyrimidin-4(3H)-one (m.p.: 181°C, hydrochloride).
- ~ w5u/g9690 CA 02359390 2001-07-10 Example 3:
3-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-5,6,7,g-tetra-hydro-6-benzylpyrido[4,3-d]pyrimidin-4(38)-one (m.p,: 198°C, hydrochloride).
Example 4:
3-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-5,6,7,8-tetra-hydro-7-benzylpyrido[3,4-d]pyrimidin-4(38)-one (m.p.: 190°C, hydrochloride).
Example 5:
3-[3-[4-(2-methoxyphenyl)-1-piperazinyl]2-hydroxypropyl]-5,6,7,8-tetrahydro-6-benzylpyrido[4,3-d]pyrimidin-4-(38)-one.
Example 6:
20 t-butyl 3-[2-[4-(naphth-1-yl)-1-piperazinyl]ethyl]-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-(38)-one-6-carboxylate (m.p.: 1?0°C, hydrochloride).
Example 7:
3-[2-[4-(isoquinolin-4-yl)-1-piperazinyl]ethyl]-5,6,7,8-tetra-hydro-6--benzylpyrido[4,3-d]pyrimidin-4-(38)-one (m. p.: 268°C,~
hydrochloride).
Example 8:
3-[2-[4-(naphth-1-yl)-1-piperazinyl]ethyl]-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-(38)-one (m. p.: 272°C, hydrochloride).
Example 9:
3-[2-[4-(quinazolin-4-yl)-1-piperazinyl]ethyl]-5,6,7,8-tetra-hydro-6-benzylpyrido[4,3-d]pyrimidin-4-(38)-one (m.p.: 258°C, hydrochloride).
Example 10:
3-[2-[4-(naphth-1-yl)-1-piperazinyl]ethyl]-5,6,7,8-tetrahydro-6-benzylpyrido[4,3-d]pyrimidin-4-(38)-one (m.p.: 227°C, hydrochloride).
- ' 0050/49690 CA 02359390 2001-07-10 ', Example 11:
3-[2-[4-(naphth-1-yl)-tetrahydro-1,2,3,6-pyridin-1-yljeth-1-ylj-5,6,7,8-tetrahydro-6-benzylpyrido[4,3-djpyrimidin-4-(3H)-one (m. p.: 216~C, hydrochloride).
Synthesis of the starting materials a) N-Hoc-4-(trifluoromethanesulfonyloxy)-tetrahydro-1,2,3,6-pyridine At -78°C, a solution of 13.2 g (0.13 mol) of diisopropylamine in 200 ml of THF was deprotonated using 100 ml of nBuLi (1.6M
in hexane), and, after 30 minutes at this temperature, 20.0 g (0.1 mol) of N-Boc-piperid-4-one dissolved in 50 ml of THF
were added dropwise. After a further three hours at -78°C, a . solution of 39.3 g (0.11 mol) of N,N-bistrifluoromethanesulfonylaniline in 50 ml of THF was added, and the mixture was allowed to warm to room temperature overnight. For work-up, the mixture was admixed with water and extracted with ether, the organic phases were washed with NaHC03 solution and water and dried over sodium sulfate, and the solvent was concentrated. The crude product was purified by flash chromatography (silica gel, mobile phase heptane/ethyl acetate = 3/1).
Yield: 20.2 g (60% of theory) 1H NMR:(270 MHz,CDCl3) b = 1.4 (s, 9H); 2.4 (m,~2H); 3.6 (t, 2H); 4.1 (m, 2H); 5.8 (m, 1H) ppm b) N-Boc-4-naphth-1-yltetrahydro-1,2,3,6-pyridine 22 ml of 2M sodium carbonate solution, 7.63 g (44.4 mmol) of naphthyl-1-boronic acid, 4.13 g (97.6 mmol) of lithium chloride, 0.85 g (4.44 mmol) of copper(I) iodide and 2.1 g (1~77 mmol) of tetrakistriphenylpalladium were added successively to 14.7 g (44.4 mmol) of the compound described above dissolved in 115 ml of dimethoxyethane, and the mixture was heated at the boil for 4 h. For work-up, aqueous ammonia solution was added and the mixture was extracted with water and ethyl acetate, the extract was dried over sodium sulfate and the residue which was obtained after evaporation of the solvent was purified by flash chromatography (silica gel, mobile phase heptane/ethyl acetate = 4/1).
, vv,w~ ~~p~V CA 02359390 2001-07-10 , l Yield: 8.2 g (57% of theory) 1H-NMR (270 MHz, CDC13): 8 = 1.4 (s, 9H); 2.5 (m, 2H); 3.7 (t, 3$): 4.1 (m, 2H); 5.8 (m, 1H); 7.2-7.5(m, 3H); 7.3-8.0 (m, PPm~
c) 4-Naphth-1-yltetrahydro-1,2,3,6-pyridine 7~84 g (25.3 mmol) of N-Boc-4-naphth-1-yltetrahydro-1,2,3,6-pyridine were stirred overnight at room temperature with 200 ml of ethereal hydrochloric acid, and the precipitated product was filtered off and dried.
Yield: 5.5 g (88% of theory).
d) Preparation of the end product 0.51 g (2 mmol) of 4-naphth-1-yltetrahydro-1,2,3,6-pyridine dissolved in 30 ml of dry DMF was admixed with 0.61 g (2 mmol) of 3-(2-chloroeth-1-yl)-3,5,7,8-tetrahydro-4-oxo-6-benzylpyrido[4,3-d]pyrimidine and with 2 ml (17 mmol) of triethylamine, and the mixture was stirred at 120~C for 5 h.
The organic phase was diluted with ether, washed with water and dried over sodium sulfate, and the solvent was removed under reduced pressure. The resulting crude product was purified chromatographically, giving a white solid by precipitating the salt using ethereal hydrochloric acid solution.
Yield: 0.2 g (20% of theory) m.p.: 237°C.
Example 12 3-[2-[4-(Naphth-1-yl)piperidin-1-yljeth-1-yl]-5,6,7,8-tetrahydro-6-benzylpyrido[4,3-d]pyrimidin-4-(3H)-one 4-Naphth-1-ylpiperidine 3.7 g (15~3 mmol) of 4-naphth-1-yltetrahydro-1,2,3,6-pyridine, dissolved in methanol, were hydrogenated at room temperature with hydrogen for 48 h, with addition of 0.8 g of palladium on carbon.
The catalyst was filtered off and the solvent was concentrated.
Yield: 1.8 g (56% of theory) ' ' vv50/49690 CA 02359390 2001-07-10 1H NMR (270 MHz, CDC13) b = 1.6-1.8 (m, 2H); 2.0 (m, 2H); 2.9 (dt, 2H); 3.3 (d, 2H); 3.5 (tt, 1H); 7.4-7.6 (m, 4H); 7.7 (d, 1H); 7.9 (d, 1H); 8.1 (d, 1H) ppm.
Preparation of the end product 0.42 g (2 mmol) of 4-naphth-1-ylpiperidine, dissolved in 30 ml of dry DMF, was admixed with 0.61 g (2 mmol) of 3-(2-chloroeth-1-yl)-3,5,7,8-tetrahydro-4-oxo-6-benzylpyrido[4,3-d]pyrimidine and with 2 ml (17 mmol) of triethylamine, and the mixture was stirred at 120~C for 5 h. The organic phase was diluted with ether, washed with water and dried over sodium sulfate, and the solvent was removed under reduced pressure. The resulting crude product was purified chromatographically, giving a white solid by precipitating the salt using ethereal hydrochloric acid solution.
I
Yield: 0.24 g (27% of theory) 1H NMR (270 MHz, CDC13) b = 8.3 (s, 1H), 8.0 (d, 1H), 7.8 (d, 1H), 7.7 (t, 1H), 7.5 - 7.2 (m, 9H), 4.5 (s, 2H), 4.0 (s, 2H), 3.7 -2.3 (m, 15H), 2.1 (d, 2H) ppm.
Other preferred compounds of the formula I according to the invention are listed in the table below.
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I
N
R4 02 ~A-B-Ar in which R1, R2 independently of one another are (C1_6)-alkyl, R3, R4 independently of one another are hydrogen, (C1_6)-alkyl, branched or unbranched, OH, O-(C1_6)-alkyl, branched or unbranched, F, C1, Br, I, trifluoromethyl, NR5R6, COZR~, nitro, cyano, pyrrole, are a phenyl-C1-C4-alkyl radical which for its part may be substituted on the aromatic ring by F, C1, Br, I, C1-CQ-alkyl, C1-C4-alkoxy, trifluoromethyl, hydroxyl, amino, cyano or vitro, R5, R6 independently of one another are hydrogen, (Cl_6)-alkyl, branched or unbranched, COPh, C02tBu, CO-(C1_4)-alkyl or together are a 5- or 6-membered ring which may contain a second nitrogen (for example piperazine), R~ is hydrogen or (C1_6)-alkyl, branched or unbranched, A is branched or unbranched (C1_lo)-alkylene or straight-chain or branched (C2_lo)-alkylene which comprises at least one group Z
selected from the group consisting of 0, S, NR~, cyclopropyl, CHOH, a double and a triple bond, B is 4-piperidine, 4-tetrahydro-1,2,3,6-pyridine, 4-piperazine and the corresponding cyclic compounds which are enlarged by a methylene group, where A is attached via a nitrogen atom of B and Ar is phenyl which is unsubstituted or substituted by (C1_6)-alkyl, branched or unbranched, 0-(C1_6)-alkyl, branched or unbranched, OH, F, C1, Br, I, trifluoromethyl, NR5R6, COZR~, cyano or phenyl, is tetraline, indane, a higher fused aromatic, such as naphthalene, which is unsubstituted or substituted by (C1_4)-alkyl or 0(C1_4)-alkyl, is anthracene or a 5- or 6-membered aromatic heterocycle having 1 or 2 hetero atoms which, independently of one another, are selected from the group consisting of O and N, and which may be fused with other aromatic radicals, for example ' 41 quinoline, isoquinoline, phthalazine, indole and quinazoline, which for its part may be substituted again by phenyl, and their salts with physiologically acceptable acids.
These compounds of the formula I can be prepared by reacting a compound of the formula II
JC I R I I r N
R4 S02 ~ A-Q
in which R1 to R4 and A are as defined above and Q is a group that can be cleaved off (for example C1, Br, I, alkanesulfonyloxy or arylsulfonyloxy), with a secondary amine of the formula III
H-B-Ar III, in which B and Ar are as defined above, in a manner known per se and converting the resulting compound; if appropriate, into the acid addition salt of a physiologically acceptable acid. It is also possible to react a compound of the formula IV
IV
N
R4 S02 ~ H
..
with a compound of the formula V
Q-A-B-Ar V
in a manner known per se. A further synthesis variant is the attachment of a compound of the formula VI
i vI
/N~
to a compound of the formula III by a reductive amination known per se.
~. 0050/49690 ~ 42 The compounds of the formula III can be synthesized by 5. attaching compounds of the formula'VII
W-B1 (VII), where B1 is piperazine or homopiperazine and W is hydrogen or one of the customary amino protective groups (such as, for example, Boc or Cbz), to a compound of the formula VIII
P-Ar (VIII), where P is B(OH)a, SnR3, OTf, Br, C1 or I and R is C1-C4-alkyl, in a manner known per se; or 6. attaching compounds of the formula IX
W-B2-P1 (IX), where B2 is 4-tetrahydro-1,2,3,6-pyridine or the corresponding cyclic compounds which are enlarged by a methylene group and P1 is C1, Br, I, SnR3 - where R is C1-C4-alkyl - , OTf, to a compound of the formula X
P-~ (X) ~
where W, P and Ar are each as defined above, and where the reactions are carried out by known processes, such as, for example, those described in S.L. Buchwald et al. J. Am. Chem. Soc. 1996, 118, 7215 J.F. Hartwig et al. Tetrahedron Lett. 1995, 36, 3604 J.K. Stille et al. Angew. Chem. 1986, 98, 504 S.L. Buchwald et al. Angew. Chem. 1995, 107, 1456 or J.F. Hartwig et al. J. Am. Chem. Soc 1996, 118, 7217 or J.F. Hartwig et al. J. Org. Chem. 1997, 62, 1268 S.L. Buchwald et al. J. Org. Chem. 1997, 62, 1264 and literature cited therein or S.L. Buchwald et al. J. Am. Chem. Soc 1997, 119, 6054 J.R. Stille, Angew. Chem. 1986, 98, 504 or J.R. Stille et al. J. Org. Chem. 1990, 55, 3014.
M. Pereyre et al. "Tin in Organic Synthesis", Butterworth 1987; or 7. reducing compounds of the formula (XI) W-B2-Ar (XI), where H2 is as defined above, to give compounds of the formula XII
W-H3-Ar (XII), in which B3 is a piperidine which is attached in 1,4-position or the corresponding cyclic compounds which are enlarged by a methylene group; or 8. cyclizing compounds of the formula XIII
W-N-(C2HqQ)y (XIII), where W and Q are as defined above, with a compound of the formula XIV
NHy-Ar (XIV), where Ar is as defined above, to give compounds of the formula XV
w-sl-Ar (xv).
The substances of the formulae III and V required as starting materials for synthesizing the novel compounds are known or can be prepared according to known processes (for example Organikum Barth Dt. Verl. der Wiss. 1993 or A. R. Katritzky, C. W. Rees (ed.) Comprehensive Heterocyclic Chemistry Pergamon Press) from analogous starting materials.
The further reaction of the compounds H-B-Ar (III) prepared in this manner according to 1. to 4. with subsequent removal of any protective groups to give the compounds of the formula V is carried out by attachment to compounds of the formula XVI
Q-A-Q' (XVI), where Q and Q' are leaving groups, under conditions known per se.
The substances of the formulae II, IV, VI and of the formulae P-Ar, NHy-Ar, W-81 or W-BZ-P1 required as starting materials for synthesizing the novel compounds are known or can be prepared according to the preparation processes described in the ~~ 0050/49690 literature from analogous starting materials (for example B.
Schulze, K. Illgen J. prakt. Chem. 1997, 339, 1 or R. Auer, E.
Hungerbiihler, R. W. Lang Chimia 1990, 44, 120 or A. Yokoo et al.
Bull. Chem. Soc. Jpn. 1956, 29, 631 or L. Borjeson et al. Acta Chem. Chem. 1991, 45, 621 or Organikum Barth Dt. Verl. der Wiss.
1993 or A. R. Katritzky, G. W. Rees (ed.) Comprehensive Heterocyclic Chemistry Pergamon Press or The Chemistry of Heterocyclic Compounds J. Wiley & Sons Inc. NY and literature cited therein).
Example 1 . 3,3-Dimethyl-2-[3-(4-tetralin-5-yl-piperazin-1-yl)prop-1-yl]-2,3-dihydro-1,2-benzisothiazole l,l-dioxide Preparation of the starting materials a) 3,3-Dimethyl-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide The preparation of this compound was carried out in a manner known from the literature (R. Auer, E. Hungerbiihler, R. W. Lang Chimia 1990, 44, 120). 3,3-Diethyl-2,3-dihydro-1,2-benzisothiazole l,l-dioxide (m.p.: 174°C) and 3,3-dimethyl-6-nitro-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (m.p.: 187°C) were obtained in a similar manner.
b) 2-(3-Chloroprop-1-yl)-3,3-dimethyl-2,3-dihydro-1,2-benziso-thiazole l,l-dioxide A solution of 5.9 g (3 mmol) of 3;3-dimethyl-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide in 150 ml of DMF was initially _.
charged at room temperature and, after addition of 3.7 g (3.3 mmol) of potassium t-butoxide, heated under nitrogen to 80°C.
14.2 g (9 mmol) of 1-bromo-3-chloropropane were then added quickly, and the mixture was stirred at 100°C for 30 min. The mixture was poured into ice-water and extracted with ether, and the organic phases were washed with water, dried with sodium sulfate and subsequently concentrated, so that the product precipitated out in crystalline form and could be filtered off with suction. This gave 6.7 g (82%) of substance. M.p.: 107°C.
2-(3-Chloroprop-1-yl)-3,3-diethyl-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (m. p.: 70°C), 2-(3-chloroprop-1-yl)-3,3-dimethyl-6-vitro-2,3-dihydro-1,2- benzisothiazole l,l-dioxide (m. p.:
146°C), 2-(2-chloroethyl)-3,3-diethyl-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (oil), 2-(2-chloroethyl)-4-chloro-3,3-dimethyl-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide ~, 0050/49690 ' 45 (oil), 2-(3-chloro-2-methyleneprop-1-yl)-3,3-dimethyl-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (m.p.: 115°C) and 2-(3-chloroprop-1-yl)-3,3-dimethyl-6-nitro-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (m.p.: 146°C) were obtained in a similar manner.
c) 1-Tetralin-5-yl-piperazine 14.7 g (0.1 mol) of 5-aminotetraline and 18 g (0.11 mol) of bis(~-chloroethyl)amine hydrochloride in 300 ml of n-butanol were refluxed for 48 h, 5.4 g of sodium carbonate were added after cooling and the mixture was once more refluxed for 20 h. The precipitate which was forined by cooling was filtered off with suction, taken up in water and admixed with 2N sodium hydroxide solution. The aqueous phase was extracted with ethyl acetate, and the extract was washed with water, dried over sodium sulfate and concentrated under reduced pressure. In this manner, it was possible to isolate 10.? g (50%) of the product as an oil.
4-Piperazin-1-ylisoquinoline 4.51 g (21.7 mmol) of 4-bromoisoquinoline, 4.65 g (25.0 mmol) of t-butyl piperazine-N-carboxylate, 0.1 g (0.11 mmol) of tris-(dibenzylideneacetone)dipalladium, 0.11 g (0.18 mmol) of 2,2'-bis(diphenylphosphino)-1,1'-dinaphthyl and 2.92 g (30.4 mmol) of sodium t-butoxide were~admixed in 50 ml of toluene and stirred at 75C for 2 h. The reaction mixture was poured onto ice/sodium chloride and extracted with ethyl acetate, the organic phase was dried over sodium sulfate and the solvent was removed using a rotary evaporator. The product crystallized out, and it was filtered off with suction and washed with pentane. This gave 5.5 g (81%) of the Boc-protected piperazine (m.p.: 111C).
5.2 g.
(16.6 mmol) of this substance were taken up in 17 ml of dichloromethane and, at 0C, slowly admixed with 17 ml (0.22 mol) of trifluoroacetic acid. The mixture was stirred at 0C for 4 h, poured onto ice-water and extracted with dichloromethane.
The aqueous phase was filtered, made alkaline and extracted with dichloromethane. After drying over sodium sulfate and substantial removal of the solvent, the residue was diluted with diethyl ether and the hydrochloride was precipitated out using ethereal hydrochloric acid. This gave 3.2 g (67%) of the product. (m.
p.:
293C).
The following compounds were prepared similarly to the two processes described: 1-naphth-1-yldiazepane (85°C, hydrochloride), 1-naphth-1-ylmethylpiperazine (oil), 4-piperazin-1-yl-indane (oil), 1-naphth-1-ylpiperazine (82°C), 4-chloro-1-piperazin-. , CA 02359390 2001-07-10 -~. 0050/49690 ' 46 1-ylphthalazine (205~C, decomp.) and 4-piperazin-1-ylquinazoline (320~C, hydrochloride). Other derivatives were commercially available.
Preparation of the end product 1.1 g (5.2 mmol) of 1-tetralin-5-ylpiperazine, 1.5 ml of triethylamine and a trace of potassium iodide were added to a solution of 1.64 g (6.0 mmol) of 2-(3-chloroprop-1-yl)-3,3-dimethyl-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide in 40 ml of DMF. The reaction mixture was allowed to react at 100~C for four hours and then poured onto ice-water, and the resulting precipitate was filtered off with suction. Purification was carried out by recrystallization from isopropanol, giving 1 g (43%) of the product (m. p.: 140~C).
NMR: CDC13 b 7.8 (d, 1H), 7.6 (dd, lx), 7.5 (dd, 1H), 7.4 (d, lH), 7.1 (dd, 1H), 6.9 (d, 1H), 6.8 (d, 1H), 3.4 (t, 2H), 3.0-2.5 (m, 14H), 2.1 (tt, 2H), 1.8-1.7 (m, 4H), 1.5 (s, 6A) ppm.
The following compounds were obtained in a similar manner:
Example 2:
3,3-dimethyl-2-[3-(4-(2-phenylquinazolin-4-yl)piperazin-1-yl)-prop-1-yl]-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (m. p.:
269~C, hydrochloride).
Example 3:
3,3-dimethyl-2-[3-(4-quinolin-2-yl-piperazin-1-yl)prop-1-yl]-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (m.p. 63~C). -Example 4:
3,3-dimethyl-2-[3-(4-naphth-1-yl-1,4-diazepan-1-yl)prop-1-yl]-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (m. p. 126~C, hydrochloride).
Example 5:
3,3-dimethyl-2-[3-(4-(4-chlorophthalazin-1-yl)piperazin-1-yl)-eth-1-yl]-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (m. p.
190~C).
Example 6:
3,3-dimethyl-2-[3-(4-naphth-1-ylpiperazin-1-yl)-2-methyleneprop-1-yl]-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (m. p. 193~C).
', 0050/49690 Example 7:
3,3-dimethyl-2-[2-(4-quinazolin-4-ylpiperazin-1-yl)eth-1-yl]-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (m.p. 178°C, hydrochloride).
Example 8:
3,3-dimethyl-2-[2-(4-naphth-1-ylpiperazin-1-yl)eth-1-yl]-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (m.p. 282°C, hydrochloride).
Example 9:
3,3-dimethyl-2-[2-(4-isoquinolin-4-yl)piperazin-1-yl)eth-1-yl]-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (m.p. 243°C, hydrochloride).
Example 10:
3,3-diethyl-2-[2-(4-naphth-1-yl-piperazin-1-yl)eth-1-yl]-2,3-dihy dro-1,2-benzisothiazole l,l-dioxide (oil).
ZO Example 11:
3,3-dimethyl-2-[3-(4-naphth-1-ylpiperazin-1-yl)prop-1-yl]-6-pyrrol-1-yl-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (m. p.
269°C, hydrochloride).
The pyrrole ring was constructed by reacting 3,3-dimethyl-2-[3-(4-naphth-1-ylpiperazin-1-yl)prop-1-yl]-6-arnino-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide with 2,5-dimethoxytetrahydrofuran in glacial acetic acid at 100°C (lh), in a yield of 86% .
_.
Example 12:
3,3-dimethyl-2-[3-(4-naphth-1-ylpiperazin-1-yl)prop-1-yl]-6-benzoylamido-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (m. p.
12?°C ) .
Example 13:
3,3-dimethyl-2-[3-(4-naphth-1-ylpiperazin-1-yl)prop-1-yl]-6-nitro-2,3-dihydro-I,2-benzisothiazole 1,1-dioxide (m. p. 203°C).
Example 14:
3,3-dimethyl-2-[2-(4-(2,3-dimethylphenyl)piperazin-1-yl)eth-1-yl]-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (m.p. 291°C, hydrochloride).
'~ 0050/49690 Example 15:
3,3-dimethyl-2-[2-(4-indan-4-ylpiperazin-1-yl)eth-1-yl]-2,3-dihydro-1,2-benzisothiazole l,l-dioxide (m.p. 271°C, hydrochloride).
Example 16:
3,3-dimethyl-2-[3-(4-(4-chloronaphth-1-yl)piperazin-1-yl)prop-1-yl]-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (m. p. 151°C).
Example 17:
3,3-dimethyl-2-[3-(4-pyrimidin-2-ylpiperazin-1-yl)prop-1-yl]-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (m.p. 263°C, hydrochloride).
Example 18:
3,3-dimethyl-2-[2-(4-(4-methoxyphenyl)-piperazin-1-yl)eth-1-yl]-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (m.p. 207°C, hydrochloride).
Example 19:
3,3-dimethyl-2-[3-(4-(2-methoxyphenyl)piperazin-1-yl)-2.-hydroxy-prop-1-yl)-2,3-dihydro-1,2-benzisothiazole l,l-dioxide (m. p.
160°C).
Example 20:
3,3-diethyl-2-[3-(4-naphth-1-ylpiperazin-1-yl)prop-1-yl]-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (m. p. 179°C).
Example 21:
3,3-dimethyl-2-[3-(4-(2,5-dimethylphenyl)piperazin-1-yl)prop-1-yl]-2,3-dihydro-1,2-benzisothiazole l,l-dioxide (m.p. 218°C, hydrochloride).
Example 22:
3,3-dimethyl-2-[2-(4-(2-cyanophenyl)piperazin-1-yl)-eth-1-yl]-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (m.p. 228°C, hydrochloride).
Example 23:
3,3-dimethyl-2-[2-(4-naphth-1-ylpiperazin-1-yl)eth-1-yl]-4-chloro-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide ~. 0050/49690 Preparation of the starting materials a) 4-Chloro-3,3-dimethyl-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide. This compound was prepared similarly to Example 1 a). Yield 7.8 g (70%). (m. p. 121~C) b) 2-(2,2-Diethoxyeth-1-yl)-4-chloro-3,3-dimethyl-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide 7.7 g (33 mmol) of 4-chloro-3,3-dimethyl-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide, 8.25 ml (55 mmol) of bromoacetaldehyde diethyl acetal and 7.0 g of potassium carbonate were taken up in 100 ml of dry DMF and stirred at 120~C for 5 h. The reaction mixture was poured into ice-water and then extracted with ethyl acetate, and the organic phase was washed with water and dried over sodium sulfate. The solvent was removed under reduced pressure and the crude product was purified by column chromatography. This gave 7.5 g (65%) of the product as an oil.
c) 2-(2-Oxoeth-1-yl)-4-chloro-3,3-dimethyl-2,3-dihydro-1,2-benz-isothiazole 1,1-dioxide 7.5 g (21.5 mmol) of 2-(2,2-diethoxyeth-1-yl)-4-chloro-3,3-dimethyl-2,3-dihydro- 1,2-benzisothiazole l,l-dioxide and 25 ml of conc. hydrochloric acid were taken up in 25 ml of water and 150 ml of THF and stirred at 40~C for 1.5 h. The reaction mixture was neutralized using aqueous sodium hydroxide solution and extracted with ether, and the organic phase was dried over sodium sulfate and concentrated under reduced pressure. In this manner, it was possible to isolate 5.8 g (98%) of the product as an oil.
Preparation of the end product 1.5 g (5.5 mmol) of the aldehyde 24 c), 1.06 g (5 mmol) of naphthylpiperazine (prepared analogously to Example 1 c)) and 0.42 g (7 mmol) of glacial acetic acid were initially charged in 50 ml of ethanol, the mixture was stirred at room temperature for 30 minutes and 0.5 g (8 mmol) of sodium cyanoborohydride were then added slowly. The reaction mixture was stirred at room temperature for 2 h and then poured onto an ice/sodium chloride mixture and extracted with dichloromethane. The extract was dried with sodium sulfate, the solvent was distilled off and the residue was subsequently recrystallized from ethanol, giving 0.9 g (39%) of colorless crystals (m. p. 156~C).
VV~V/g'Jb~JO CA 02359390 2001-07-10 NMR:CDC13 8 = 8.3 (m, 1H), 7.8 (m, 1H), 7.7 (d, 1H), 7.6 - 7.'3 (m, 6H), 7.1 (d, 1H), 3.5 (t, 2H), 3.2 (m, 4H), 3.0 - 2.8 (m, 6H), 1.8 (s, 6H) PPm.
5 Example 24 Preparation of 3,3-dimethyl-2-[2-(4-naphth-1-yltetrahydro-1,2,3,6-pyridin-1-yl)eth-1-yl]-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide Synthesis of the starting materials a) N-Boc-4-(trifluoromethanesulfonyloxy)tetrahydro-1,2,3,6-pyridine At -78~C, a solution of 13.2 g (0.13 mol) of diisopropylamine in 200 ml of THF was deprotonated with I00 ml of nBuLi (1.6M in hexane), and, after 30 minutes at this temperature, 20.0 g (0.1 mol) of N-Boc-piperidone, dissolved in 50 ml of THF, were added dropwise. After a further three hours at -78~C, a solution of 39.3 g (0.11 mol) of N,N-bistrifluoromethanesulfonylaniline in 50 ml of THF was added, and the reaction mixture was allowed to warm to room temperature overnight. For work-up, the mixture was admixed with water and extracted with ether, the organic phases were washed with NaHC03 solution and water and dried over sodium sulfate, and the solvent was concentrated. The crude product was purified by flash chromatography (silica gel, mobile phase heptane/ethyl acetate = 3/1).
Yield: 20.2 g (60% of theory) 1H NMR:(270 MHz, CDC13) 8 = 1.4 (s, 9H); 2.4 (m, 2H); 3.6. (t, 2H);
4.1 (m, 2H); 5.8 (m, 1H) ppm.
b) N-Boc-4-naphth-1-yltetrahydro-1,2,3,6-pyridine 14.7 g (44.4 mmol) of the compound described above, dissolved in 115 ml of dimethoxyethane, were admixed successively with 22 ml of 2M sodium carbonate solution, 7.63 g (44.4 mmol) of naphthyl-1-boronic acid, 4.13 g (97.6 mmol) of lithium chloride, 0.85 g (4.44 mmol) of copper(I) iodide and 2.1 g (1.77 mmol) of tetrakistriphenylpalladium, and the mixture was heated at the boil for 4 h. For work-up, aqueous ammonia solution was added to the mixture, which was then extracted with water and ethyl acetate, the extract was dried over sodium sulfate and the residue which was obtained after evaporation of the solvent was purified by flash chromatography (silica gel, mobile phase heptane/ethyl acetate = 4/1).
Yield: 8.2 g (57% of theory) ., ~ ~ vvrv~ s7v7V
. 51 1H NMR (270 MHz, CDC13): 8 = 1.4 (s, 9H); 2.5 (m, 2H); 3.7 (t, 2H); 4.1 (m, 2H); 5.8 (m, 1H); 7.2-7.5 (m, 3H); 7.3-8.0 (m, 38) ppm.
c) 4-Naphth-1-yltetrahydro-1,2,3,6-pyridine 7.84 g (25.3 mmol) of N-Boc-4-naphth-1-yl-3,6-dihydro-2H-pyridine were stirred-overnight at room temperature with 200 ml of ethereal hydrochloric acid, and the precipitated product was filtered off and dried.
Yield: 5.5 g (88% of theory).
d) Preparation of the end product 1.0 g (4.1 mmol) of the compound 24c described above, dissolved in 20 ml of methanol, was, in the presence of 2.22 g (16.8 mmol) of zinc(II) chloride, admixed first with 1.27 g (5.3 mmol) of the aldehyde described under Example 23c and then with 0.5 g (8.14 mmol) of sodium cyanoborohydride. After 16 h at room temperature, the mixture was worked up as described and the resulting crude product was purified by chromatography (silica gel, mobile phase dichloromethane/methanol = 97/3). Precipitation of the salt using ethereal hydrochloric acid solution gave a white solid.
Yield: 0.9 g (47% of theory) 1H NMR (270 MHz, DMSO-d6): b = 1.6 (m, 6H); 2.6 (m, 1H); 3.1 (m, 1H); 3.4-3.6 (m, 6H); 4.0-4.2 (m, 2H); 5.8 (brd. s, 1H); 7.6-8.0 (m, 7H); 8.2 (d, 1H); 12.0 (s, 1H) ppm.
Example 25 Preparation of 3,3-dimethyl-2-[2-(4-naphth-1-ylpiperidin-1-yl)eth-1-yl]-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide a) 4-Naphth-1-ylpiperidine 3.7 g (15.3 mmol) of 4-naphth-1-yltetrahydro-1,2,3,6-pyridine, dissolved in methanol, were hydrogenated with hydrogen for 48 h at room temperature, with addition of 0.8 g of palladium on carbon. The catalyst was filtered off and the solvent was concentrated.
Yield: 1.8 g (56% of theory) 1H NMR (270 MHz, CDC13) b = 1.6-1.8 (m, 2H); 2.0 (m, 2H); 2.9 (dt, 2H); 3.3 (d, 2H); 3.5 (tt, 1H); 7.4-7.6 (m, 4H); 7.7 (d, iH); 7.9 (d, 1H); 8.1 (d, 1H) ppm.
' . CA 02359390 2001-07-10 ' S2 Preparation of the end product A solution of 1.5 g (7.1 mmol) of the amine 25a in 20 ml of methanol was admixed first with 3.8 g (28.4 mmol) of zinc chloride and then with 2.21 g (9,2 mmol) of the aldehyde described under Example 23 c, dissolved in 15 ml of methanol, and 0~89 g (14.2 mmol) of sodium cyanoborohydride was then added a little at a time. The mixture was stirred for six hours, undissolved particles were then filtered off, the mother liquor was concentrated and the residue was taken up in ethyl acetate.
The organic phase was washed with water and saturated sodium chloride solution, dried over sodium sulfate and filtered, giving, on concentration, a yellowish oil.
Yield: 2.2 g (65% of theory) 1H NMR (270 MHz, CDC13): 8 = 1.7-1.9 (m, 8H); 2.0 (m, 2H); 2.7-3.0 (m, 4H); 3.2 .(m, 2H); 3.5 (m, 1H); 3,7 (t, 2H); 7.1 (d, 1H);
7.3-7.7 (m, 9H); 8.2 (d, 1H) ppm.
Other preferred compounds of the formula I according to the invention are listed in the table below.
These compounds are suitable for preparing medicaments for the prophylaxis and therapy of neurodegeneration, cerebral trauma and cerebral ischemia, in particular stroke, and of diseases which are caused by these disorders.
A use according to the invention also relates to neuroprotection.
The preparation of these compounds is described in the patents mentioned at the outset.
The preparation as a medicament is carried out using a compound of the formula I or its pharmacologically acceptable acid addition salt as active compound, together with customary excipients and diluents.
The use according to the invention can be carried out in a customary manner, orally or parenterally, intravenously or intramuscularly.
The dosage depends on the age, on the state and the weight of the patient and on the type of administration. In general, the daily dose of active compound is between approximately 1 and 100 mg/kg of body weight in the case of oral administration and between 0.1 and 10 mg/kg of body weight in the case of parenteral administration.
The medicaments can be used in solid or liquid form in customary pharmaceutical administration forms, for example as tablets, film-coated tablets, capsules, powders, granules, sugar-coated tablets, suppositories, solutions, ointments, creams or sprays.
These are prepared in a customary manner. Sere, the active compounds can be processed with the customary pharmaceutical auxiliaries, such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, sustained-release agents, antioxidants and/or propellants (cf. B. Sucker et al.:
Pharmazeutische Technologie [Pharmaceutical Technology], Thieme-Verlag, Stuttgart, 1978). The resulting administration forms generally comprise the active compound in an amount of from 1 to 99% by weight.
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'~Zatf1 Ifl r ~ CA 02359390 2001-07-10 ' ', 0050/49690 These compounds are suitable for the treatment of mood disorders caused by the central nervous system, such as seasonal affective disorders and dysthymia. These also include anxieties, such as 5 generalized anxiety disorder, panic attacks, sociophobia, compulsive neuroses and post-traumatic stress symptoms, memory disorders including dementia, amnesia and senile dementia, and also psychogenic eating disorders, such as anorexia nervosa and bulimia nervosa.
It has now been found that compounds of the formula I
N- A- H- Ar ( I ) r in Which A is branched or unbranched (C1_lo)-alkylene or straight-chain or branched (C~_,o)-alkylene which comprises at least one group Z
selected from the group consisting of O, S, NRe, cyclopropyl, COz, CHOH, a double and a triple bond, B is 4-piperidine, 4-tetrahydro-1,2,3,6-pyridine, 4-piperazine or the corresponding cyclic compounds which are enlarged by a methylene group, where A is attached via a nitrogen atom of B
and ' Ar is phenyl which is unsubstituted or substituted by (C1_c)-alkyl, branched or unbranched, O-(C1_6)-alkyl, branched or unbranched, OH, F, Cl, Br, I, trifluoromethyl, NR22, CO~Rs, cyano or phenyl, is tetraline, indane, a higher fused aromatic, such as naphthalene, which is unsubstituted or substituted by (C1_,)-alkyl or O-(Cl_,)-alkyl, is anthracene or a 5- or 6-membered aromatic heterocycle having 1 or 2 hetero atoms which, independently of one another, are selected from the group consisting of O and N, and which may be fused with other aromatic radicals, N- is X N- or I R , y I J O /Nw one of the two radicals X, Y being CH2 and the other being NR9 , ~ CA 02359390 2001-07-10 ' ', 0050/49690 w R1, RZ independently of one another are C1-C6-alkyl, R3, R4 independently of one another are hydrogen, (C1_6)-alkyl, branched or unbranched, OH, O-(C1_6)-alkyl, branched or unbranched, F, C1, Br, I, trifluoromethyl, NR5R6, C02R~, nitro, cyano, pyrrole, are a phenyl-C1-C4-alkyl radical which for its part may be substituted on the aromatic ring by F, C1, Br, I, C1-C4-alkyl, C1-C4-alkoxy, trifluoromethyl, hydroxyl, amino, cyano or nitro, R5, R6 independently of one another are hydrogen, (C1_6)-alkyl, branched or unbranched, COPh, C02tBu, CO-(C1_4)-alkyl or together are a 5- or 6-membered ring which may contain a second nitrogen (for example piperazine), R~ is hydrogen or (Cl_6)-alkyl, branched or unbranched, Re is hydrogen or C1-C4-alkyl, R9 is hydrogen, (C1_6)-alkyl, branched or unbranched, CO-(C1_4)-alkyl, C02tBu, CO-aryl. or a phenyl-C1-C4-alkyl radical which for its part may be substituted on the aromatic ring by F, C1, Br, I, C1-C4-alkyl,. C1-C4-alkoxy, trifluoromethyl, hydroxyl, amino, cyano or nitro, and salts thereof, are suitable for preparing medicaments for the prophylaxis and therapy of neurodegeneration, cerebral trauma and cerebral ischemia, in particular stroke, and of diseases which are caused by these disorders.
A use according to the invention also relates to neuroprotection.
The preparation of these pyrimidine derivatives is described in the patents mentioned at the outset.
The preparation as a medicament is carried out using a compound of the formula I or its pharmacologically acceptable acid addition salt as active compound, together with customary excipients and diluents.
The use according to the invention can be carried out in a customary manner, orally or parenterally, intravenously or intramuscularly.
~ 0050/49690 CA 02359390 2001-07-10 v 10~
The dosage depends on the age, on the state and the weight of the patient and on the type of administration. In general, the daily dose of active compound is between approximately 1 and 100 mg/kg of body weight in the case of oral administration and between 0.1 and 10 mg/kg of body weight in the case of parenteral administration.
The medicaments can be used in solid or liquid form in customary pharmaceutical administration forms, for example as tablets, film-coated tablets, capsules, powders, granules, sugar-coated tablets, suppositories, solutions, ointments, creams or sprays.
These are prepared in a customary manner. Here, the active compounds can be processed with the customary pharmaceutical auxiliaries, such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, Wetting agents, dispersants, emulsifiers, solvents, sustained-release agents, antioxidants and/or propellants (cf. H. Sucker et al.:
Pharmazeutische Technologie [Pharmaceutical Technology], Thieme-Verlag, Stuttgart, 1978). The resulting administration forms generally comprise the active compound in an amount of from 1 to 99% by weight.
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'~Zatf1 Ifl r ~ CA 02359390 2001-07-10 ' ', 0050/49690 These compounds are suitable for the treatment of mood disorders caused by the central nervous system, such as seasonal affective disorders and dysthymia. These also include anxieties, such as 5 generalized anxiety disorder, panic attacks, sociophobia, compulsive neuroses and post-traumatic stress symptoms, memory disorders including dementia, amnesia and senile dementia, and also psychogenic eating disorders, such as anorexia nervosa and bulimia nervosa.
It has now been found that compounds of the formula I
N- A- H- Ar ( I ) r in Which A is branched or unbranched (C1_lo)-alkylene or straight-chain or branched (C~_,o)-alkylene which comprises at least one group Z
selected from the group consisting of O, S, NRe, cyclopropyl, COz, CHOH, a double and a triple bond, B is 4-piperidine, 4-tetrahydro-1,2,3,6-pyridine, 4-piperazine or the corresponding cyclic compounds which are enlarged by a methylene group, where A is attached via a nitrogen atom of B
and ' Ar is phenyl which is unsubstituted or substituted by (C1_c)-alkyl, branched or unbranched, O-(C1_6)-alkyl, branched or unbranched, OH, F, Cl, Br, I, trifluoromethyl, NR22, CO~Rs, cyano or phenyl, is tetraline, indane, a higher fused aromatic, such as naphthalene, which is unsubstituted or substituted by (C1_,)-alkyl or O-(Cl_,)-alkyl, is anthracene or a 5- or 6-membered aromatic heterocycle having 1 or 2 hetero atoms which, independently of one another, are selected from the group consisting of O and N, and which may be fused with other aromatic radicals, N- is X N- or I R , y I J O /Nw one of the two radicals X, Y being CH2 and the other being NR9 , ~ CA 02359390 2001-07-10 ' ', 0050/49690 w R1, RZ independently of one another are C1-C6-alkyl, R3, R4 independently of one another are hydrogen, (C1_6)-alkyl, branched or unbranched, OH, O-(C1_6)-alkyl, branched or unbranched, F, C1, Br, I, trifluoromethyl, NR5R6, C02R~, nitro, cyano, pyrrole, are a phenyl-C1-C4-alkyl radical which for its part may be substituted on the aromatic ring by F, C1, Br, I, C1-C4-alkyl, C1-C4-alkoxy, trifluoromethyl, hydroxyl, amino, cyano or nitro, R5, R6 independently of one another are hydrogen, (C1_6)-alkyl, branched or unbranched, COPh, C02tBu, CO-(C1_4)-alkyl or together are a 5- or 6-membered ring which may contain a second nitrogen (for example piperazine), R~ is hydrogen or (Cl_6)-alkyl, branched or unbranched, Re is hydrogen or C1-C4-alkyl, R9 is hydrogen, (C1_6)-alkyl, branched or unbranched, CO-(C1_4)-alkyl, C02tBu, CO-aryl. or a phenyl-C1-C4-alkyl radical which for its part may be substituted on the aromatic ring by F, C1, Br, I, C1-C4-alkyl,. C1-C4-alkoxy, trifluoromethyl, hydroxyl, amino, cyano or nitro, and salts thereof, are suitable for preparing medicaments for the prophylaxis and therapy of neurodegeneration, cerebral trauma and cerebral ischemia, in particular stroke, and of diseases which are caused by these disorders.
A use according to the invention also relates to neuroprotection.
The preparation of these pyrimidine derivatives is described in the patents mentioned at the outset.
The preparation as a medicament is carried out using a compound of the formula I or its pharmacologically acceptable acid addition salt as active compound, together with customary excipients and diluents.
The use according to the invention can be carried out in a customary manner, orally or parenterally, intravenously or intramuscularly.
~ 0050/49690 CA 02359390 2001-07-10 v 10~
The dosage depends on the age, on the state and the weight of the patient and on the type of administration. In general, the daily dose of active compound is between approximately 1 and 100 mg/kg of body weight in the case of oral administration and between 0.1 and 10 mg/kg of body weight in the case of parenteral administration.
The medicaments can be used in solid or liquid form in customary pharmaceutical administration forms, for example as tablets, film-coated tablets, capsules, powders, granules, sugar-coated tablets, suppositories, solutions, ointments, creams or sprays.
These are prepared in a customary manner. Here, the active compounds can be processed with the customary pharmaceutical auxiliaries, such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, Wetting agents, dispersants, emulsifiers, solvents, sustained-release agents, antioxidants and/or propellants (cf. H. Sucker et al.:
Pharmazeutische Technologie [Pharmaceutical Technology], Thieme-Verlag, Stuttgart, 1978). The resulting administration forms generally comprise the active compound in an amount of from 1 to 99% by weight.
Claims
1. The use of compounds of the formula I
in which A is branched or unbranched (C1-10)-alkylene or straight-chain or branched (C2-10)-alkylene which comprises at least one group Z selected from the group consisting of O, S, NR~, cyclopropyl, CO2, CHOH, a double and a triple bond, B is 4-piperidine, 4-tetrahydro-1,2,3,6-pyridine, 4-piperazine or the corresponding cyclic compounds which are enlarged by a methylene group, where A is attached via a nitrogen atom of B and Ar is phenyl which is unsubstituted or substituted by (C1-6) -alkyl, branched or unbranched, 0- (C1-6) -alkyl, branched or unbranched, OH, F, Cl, Br, I, trifluoromethyl, NR2 2, CO2R2, cyano or phenyl, is tetralin, indane, a higher fused aromatic, such as naphthalene, which is unsubstituted or substituted by (C1-4)-alkyl or O-(C1-4) -alkyl, is anthracene or a 5- or 6-membered aromatic heterocycle having 1 or 2 hetero atoms which, independently of one another, are selected from the group consisting of O and N, and which may be fused with other aromatic radicals, one of the two radicals X, Y being CH2 and the other being NR9, R1, R2 independently of one another are C1-C6-alkyl, R3, R4 independently of one another are hydrogen, (C1-6)-alkyl, branched or unbranched, OH, O-(C1-6)-alkyl, branched or unbranched, F, Cl, Br, I, trifluoromethyl, NR5R6, CO2R7, nitro, cyano, pyrrole, are a phenyl-C1-C4-alkyl radical which for its part may be substituted on the aromatic ring by F, Cl, Br, I, C1-C4-alkyl, C1-C4-alkoxy, trifluoromethyl, hydroxyl, amino, cyano or nitro, R5, R6 independently of one another are hydrogen, (C1-6)-alkyl, branched or unbranched, COPh, CO2tBu, CO-(C1-4)-alkyl or together are a 5- or 6-membered ring which may contain a second nitrogen (for example piperazine), R7 is hydrogen or (C1-6)-alkyl, branched or unbranched, R8 is hydrogen or C1-C4-alkyl, R9 is hydrogen, (C1-6)-alkyl, branched or unbranched, CO-(C1-4)-alkyl, CO2tBu, CO-aryl or a phenyl-C1-C4-alkyl radical Which for its part may be substituted on the aromatic ring by F, Cl, Br, I, C1-C4-alkyl, C1-C4-alkoxy, trifluoromethyl, hydroxyl, amino, cyano or nitro, and their salts with pharmacologically acceptable acids for preparing medicaments for the prophylaxis and therapy of cerebral ischemia and stroke.
in which A is branched or unbranched (C1-10)-alkylene or straight-chain or branched (C2-10)-alkylene which comprises at least one group Z selected from the group consisting of O, S, NR~, cyclopropyl, CO2, CHOH, a double and a triple bond, B is 4-piperidine, 4-tetrahydro-1,2,3,6-pyridine, 4-piperazine or the corresponding cyclic compounds which are enlarged by a methylene group, where A is attached via a nitrogen atom of B and Ar is phenyl which is unsubstituted or substituted by (C1-6) -alkyl, branched or unbranched, 0- (C1-6) -alkyl, branched or unbranched, OH, F, Cl, Br, I, trifluoromethyl, NR2 2, CO2R2, cyano or phenyl, is tetralin, indane, a higher fused aromatic, such as naphthalene, which is unsubstituted or substituted by (C1-4)-alkyl or O-(C1-4) -alkyl, is anthracene or a 5- or 6-membered aromatic heterocycle having 1 or 2 hetero atoms which, independently of one another, are selected from the group consisting of O and N, and which may be fused with other aromatic radicals, one of the two radicals X, Y being CH2 and the other being NR9, R1, R2 independently of one another are C1-C6-alkyl, R3, R4 independently of one another are hydrogen, (C1-6)-alkyl, branched or unbranched, OH, O-(C1-6)-alkyl, branched or unbranched, F, Cl, Br, I, trifluoromethyl, NR5R6, CO2R7, nitro, cyano, pyrrole, are a phenyl-C1-C4-alkyl radical which for its part may be substituted on the aromatic ring by F, Cl, Br, I, C1-C4-alkyl, C1-C4-alkoxy, trifluoromethyl, hydroxyl, amino, cyano or nitro, R5, R6 independently of one another are hydrogen, (C1-6)-alkyl, branched or unbranched, COPh, CO2tBu, CO-(C1-4)-alkyl or together are a 5- or 6-membered ring which may contain a second nitrogen (for example piperazine), R7 is hydrogen or (C1-6)-alkyl, branched or unbranched, R8 is hydrogen or C1-C4-alkyl, R9 is hydrogen, (C1-6)-alkyl, branched or unbranched, CO-(C1-4)-alkyl, CO2tBu, CO-aryl or a phenyl-C1-C4-alkyl radical Which for its part may be substituted on the aromatic ring by F, Cl, Br, I, C1-C4-alkyl, C1-C4-alkoxy, trifluoromethyl, hydroxyl, amino, cyano or nitro, and their salts with pharmacologically acceptable acids for preparing medicaments for the prophylaxis and therapy of cerebral ischemia and stroke.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19900544.3 | 1999-01-11 | ||
DE19900544A DE19900544A1 (en) | 1999-01-11 | 1999-01-11 | Use of compounds of formula I for the prophylaxis and therapy of cerebral ischemia |
PCT/EP1999/010275 WO2000041697A1 (en) | 1999-01-11 | 1999-12-22 | Utilisation of 2-substituted 1,2-benzisothiazole derivatives and 3-substituted tetrahydropyridopyrimidinone derivatives for the prophylaxis and therapy of cerebral ischaemia |
Publications (1)
Publication Number | Publication Date |
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CA2359390A1 true CA2359390A1 (en) | 2000-07-20 |
Family
ID=7893835
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002359390A Abandoned CA2359390A1 (en) | 1999-01-11 | 1999-12-22 | Utilisation of 2-substituted 1,2-benzisothiazole derivatives and 3-substituted tetrahydropyridopyrimidinone derivatives for the prophylaxis and therapy of cerebral ischaemia |
Country Status (19)
Country | Link |
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EP (1) | EP1140099A1 (en) |
JP (1) | JP2002534467A (en) |
KR (1) | KR20010101440A (en) |
CN (1) | CN1333685A (en) |
AR (1) | AR029741A1 (en) |
AU (1) | AU2285100A (en) |
BG (1) | BG105688A (en) |
BR (1) | BR9916888A (en) |
CA (1) | CA2359390A1 (en) |
DE (1) | DE19900544A1 (en) |
HU (1) | HUP0200520A3 (en) |
IL (1) | IL144145A0 (en) |
MX (1) | MXPA01006966A (en) |
NO (1) | NO20013408L (en) |
PL (1) | PL348916A1 (en) |
SK (1) | SK9682001A3 (en) |
TR (1) | TR200102009T2 (en) |
WO (1) | WO2000041697A1 (en) |
ZA (1) | ZA200105473B (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7618959B2 (en) | 2002-11-05 | 2009-11-17 | Smithklinebeecham Corp | Antibacterial agents |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
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EP1667979A4 (en) * | 2003-09-23 | 2007-04-18 | Merck & Co Inc | Isoquinoline potassium channel inhibitors |
BRPI0615248A2 (en) * | 2005-08-26 | 2009-07-14 | Shionogi & Co | derivative having ppar agonist activity |
KR20100063087A (en) * | 2007-09-20 | 2010-06-10 | 코텍스 파마슈티칼스, 인크. | 3-substituted 1,2,3-triazin-4-one's and 3-substituted 1,3-pyrimidinone's for enhancing glutamatergic synaptic responses |
MA41168A (en) | 2014-12-17 | 2017-10-24 | Acraf | NEW ANTIBACTERIAL COMPOUNDS |
CN108484594B (en) * | 2018-02-09 | 2020-08-04 | 福建医科大学 | Alkoxy substituted tetrahydropyridopyrimidine compound or available salt thereof, and preparation method and application thereof |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3620643A1 (en) * | 1985-06-22 | 1987-01-22 | Sandoz Ag | Thiazoles, their preparation and use |
DE3831888A1 (en) * | 1988-09-20 | 1990-03-29 | Troponwerke Gmbh & Co Kg | MEDICINES FOR TREATING APOPLEXIA CEREBRI |
JP3036789B2 (en) * | 1990-06-22 | 2000-04-24 | 三井化学株式会社 | Novel heterocyclic compounds and pharmaceutical compositions |
DE19746612A1 (en) * | 1997-10-22 | 1999-04-29 | Basf Ag | New 2-substituted 1,2-benzisothiazole derivatives |
DE19747063A1 (en) * | 1997-10-24 | 1999-04-29 | Basf Ag | New 3-substituted tetrahydropyridopyrimidinone derivatives |
-
1999
- 1999-01-11 DE DE19900544A patent/DE19900544A1/en not_active Withdrawn
- 1999-12-22 EP EP99966990A patent/EP1140099A1/en not_active Withdrawn
- 1999-12-22 MX MXPA01006966A patent/MXPA01006966A/en unknown
- 1999-12-22 KR KR1020017008690A patent/KR20010101440A/en not_active Application Discontinuation
- 1999-12-22 PL PL99348916A patent/PL348916A1/en not_active Application Discontinuation
- 1999-12-22 JP JP2000593308A patent/JP2002534467A/en active Pending
- 1999-12-22 CN CN99815452A patent/CN1333685A/en active Pending
- 1999-12-22 IL IL14414599A patent/IL144145A0/en unknown
- 1999-12-22 HU HU0200520A patent/HUP0200520A3/en unknown
- 1999-12-22 WO PCT/EP1999/010275 patent/WO2000041697A1/en not_active Application Discontinuation
- 1999-12-22 CA CA002359390A patent/CA2359390A1/en not_active Abandoned
- 1999-12-22 AU AU22851/00A patent/AU2285100A/en not_active Abandoned
- 1999-12-22 TR TR2001/02009T patent/TR200102009T2/en unknown
- 1999-12-22 BR BR9916888-0A patent/BR9916888A/en not_active IP Right Cessation
- 1999-12-22 SK SK968-2001A patent/SK9682001A3/en unknown
-
2000
- 2000-01-06 AR ARP000100036A patent/AR029741A1/en unknown
-
2001
- 2001-07-03 ZA ZA200105473A patent/ZA200105473B/en unknown
- 2001-07-10 NO NO20013408A patent/NO20013408L/en not_active Application Discontinuation
- 2001-07-10 BG BG105688A patent/BG105688A/en unknown
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7618959B2 (en) | 2002-11-05 | 2009-11-17 | Smithklinebeecham Corp | Antibacterial agents |
Also Published As
Publication number | Publication date |
---|---|
HUP0200520A2 (en) | 2002-07-29 |
BR9916888A (en) | 2001-11-20 |
DE19900544A1 (en) | 2000-07-13 |
AR029741A1 (en) | 2003-07-16 |
JP2002534467A (en) | 2002-10-15 |
KR20010101440A (en) | 2001-11-14 |
BG105688A (en) | 2002-02-28 |
WO2000041697A1 (en) | 2000-07-20 |
MXPA01006966A (en) | 2002-04-10 |
AU2285100A (en) | 2000-08-01 |
CN1333685A (en) | 2002-01-30 |
HUP0200520A3 (en) | 2003-04-28 |
TR200102009T2 (en) | 2002-01-21 |
ZA200105473B (en) | 2002-10-03 |
NO20013408L (en) | 2001-08-21 |
IL144145A0 (en) | 2002-05-23 |
NO20013408D0 (en) | 2001-07-10 |
PL348916A1 (en) | 2002-06-17 |
SK9682001A3 (en) | 2002-03-05 |
EP1140099A1 (en) | 2001-10-10 |
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