CN1238765A - N-(imidazoly (butyl) benzenesulphonamide derivatives with anticoagulation active - Google Patents
N-(imidazoly (butyl) benzenesulphonamide derivatives with anticoagulation active Download PDFInfo
- Publication number
- CN1238765A CN1238765A CN97199986A CN97199986A CN1238765A CN 1238765 A CN1238765 A CN 1238765A CN 97199986 A CN97199986 A CN 97199986A CN 97199986 A CN97199986 A CN 97199986A CN 1238765 A CN1238765 A CN 1238765A
- Authority
- CN
- China
- Prior art keywords
- group
- alkyl
- compound
- formula
- branched
- 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.)
- Pending
Links
- IPRJXAGUEGOFGG-UHFFFAOYSA-N N-butylbenzenesulfonamide Chemical class CCCCNS(=O)(=O)C1=CC=CC=C1 IPRJXAGUEGOFGG-UHFFFAOYSA-N 0.000 title 1
- 230000010100 anticoagulation Effects 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 119
- -1 1, 2, 3, 6-tetrahydropyridin-1-yl Chemical group 0.000 claims abstract description 110
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 49
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 35
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 29
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 24
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 9
- 239000001257 hydrogen Substances 0.000 claims abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 7
- 125000006313 (C5-C8) alkyl group Chemical group 0.000 claims abstract description 6
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 5
- 239000003814 drug Substances 0.000 claims abstract 2
- 239000000203 mixture Substances 0.000 claims description 142
- 239000002585 base Substances 0.000 claims description 68
- 238000006243 chemical reaction Methods 0.000 claims description 50
- 238000000034 method Methods 0.000 claims description 44
- 125000005843 halogen group Chemical group 0.000 claims description 26
- 238000010992 reflux Methods 0.000 claims description 22
- 239000003513 alkali Substances 0.000 claims description 19
- 238000002360 preparation method Methods 0.000 claims description 17
- 239000002253 acid Substances 0.000 claims description 11
- 238000010438 heat treatment Methods 0.000 claims description 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 125000001544 thienyl group Chemical group 0.000 claims description 8
- 230000002378 acidificating effect Effects 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 5
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 150000002825 nitriles Chemical class 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 4
- 125000000335 thiazolyl group Chemical group 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- ZRNSSRODJSSVEJ-UHFFFAOYSA-N 2-methylpentacosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCC(C)C ZRNSSRODJSSVEJ-UHFFFAOYSA-N 0.000 claims description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 2
- 150000001263 acyl chlorides Chemical class 0.000 claims description 2
- 239000000654 additive Substances 0.000 claims description 2
- 230000000996 additive effect Effects 0.000 claims description 2
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 239000012948 isocyanate Substances 0.000 claims description 2
- 238000012986 modification Methods 0.000 claims description 2
- 230000004048 modification Effects 0.000 claims description 2
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- QAHVHSLSRLSVGS-UHFFFAOYSA-N sulfamoyl chloride Chemical compound NS(Cl)(=O)=O QAHVHSLSRLSVGS-UHFFFAOYSA-N 0.000 claims description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract description 17
- 229910052757 nitrogen Chemical group 0.000 abstract description 12
- 150000002431 hydrogen Chemical class 0.000 abstract description 2
- 229910052736 halogen Inorganic materials 0.000 abstract 2
- 150000002367 halogens Chemical class 0.000 abstract 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 177
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 160
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 153
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 125
- 239000000243 solution Substances 0.000 description 118
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 110
- 239000000047 product Substances 0.000 description 103
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 88
- 239000011541 reaction mixture Substances 0.000 description 68
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 64
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 60
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 57
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 54
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 53
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 48
- 238000003756 stirring Methods 0.000 description 48
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 44
- 238000010898 silica gel chromatography Methods 0.000 description 44
- 239000007864 aqueous solution Substances 0.000 description 43
- 238000005406 washing Methods 0.000 description 43
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 38
- 229910052938 sodium sulfate Inorganic materials 0.000 description 38
- 235000011152 sodium sulphate Nutrition 0.000 description 38
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 37
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 30
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 24
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 22
- 239000000843 powder Substances 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 20
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 19
- 229950001902 dimevamide Drugs 0.000 description 16
- 239000012044 organic layer Substances 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 239000007789 gas Substances 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 15
- VHWJSJBTUWUEAL-UHFFFAOYSA-N propanamide;hydrochloride Chemical compound Cl.CCC(N)=O VHWJSJBTUWUEAL-UHFFFAOYSA-N 0.000 description 15
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 14
- UFUASNAHBMBJIX-UHFFFAOYSA-N propan-1-one Chemical group CC[C]=O UFUASNAHBMBJIX-UHFFFAOYSA-N 0.000 description 13
- 229940005605 valeric acid Drugs 0.000 description 13
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 12
- 239000000460 chlorine Substances 0.000 description 12
- 239000012299 nitrogen atmosphere Substances 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 229910052801 chlorine Inorganic materials 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- 101000610640 Homo sapiens U4/U6 small nuclear ribonucleoprotein Prp3 Proteins 0.000 description 9
- 101001110823 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-A Proteins 0.000 description 9
- 101000712176 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-B Proteins 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 102100040374 U4/U6 small nuclear ribonucleoprotein Prp3 Human genes 0.000 description 9
- 238000001035 drying Methods 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- PBIUDEUWYGBHDW-UHFFFAOYSA-N 2-chloro-1-pyridin-3-ylethanone;hydrochloride Chemical compound Cl.ClCC(=O)C1=CC=CN=C1 PBIUDEUWYGBHDW-UHFFFAOYSA-N 0.000 description 8
- PNWSHHILERSSLF-UHFFFAOYSA-N 4-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=CC=C(C(O)=O)C=C1C(O)=O PNWSHHILERSSLF-UHFFFAOYSA-N 0.000 description 8
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 8
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 8
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 8
- ZSDQQJHSRVEGTJ-UHFFFAOYSA-N 2-(6-amino-1h-indol-3-yl)acetonitrile Chemical compound NC1=CC=C2C(CC#N)=CNC2=C1 ZSDQQJHSRVEGTJ-UHFFFAOYSA-N 0.000 description 7
- 229910052786 argon Inorganic materials 0.000 description 7
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 7
- 230000006837 decompression Effects 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- HNBDRPTVWVGKBR-UHFFFAOYSA-N n-pentanoic acid methyl ester Natural products CCCCC(=O)OC HNBDRPTVWVGKBR-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 6
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 6
- 238000013375 chromatographic separation Methods 0.000 description 6
- 238000003810 ethyl acetate extraction Methods 0.000 description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 6
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 6
- 125000002140 imidazol-4-yl group Chemical group [H]N1C([H])=NC([*])=C1[H] 0.000 description 6
- 239000001301 oxygen Substances 0.000 description 6
- 229910052760 oxygen Inorganic materials 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 239000012265 solid product Substances 0.000 description 6
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 5
- 238000010828 elution Methods 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical compound NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 239000004202 carbamide Substances 0.000 description 4
- 235000013877 carbamide Nutrition 0.000 description 4
- 238000005984 hydrogenation reaction Methods 0.000 description 4
- 210000002381 plasma Anatomy 0.000 description 4
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 4
- 235000002639 sodium chloride Nutrition 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- ZGMCPBIYPJEPPA-UHFFFAOYSA-N 3-cyclopentyl-2-(diacetylamino)benzenesulfonyl chloride Chemical compound C1=CC=C(S(Cl)(=O)=O)C(N(C(C)=O)C(=O)C)=C1C1CCCC1 ZGMCPBIYPJEPPA-UHFFFAOYSA-N 0.000 description 3
- WVIJOUFQYFUXAY-UHFFFAOYSA-N 4-(difluoromethylidene)piperidine Chemical compound FC(F)=C1CCNCC1 WVIJOUFQYFUXAY-UHFFFAOYSA-N 0.000 description 3
- UQDYMLLPZKJOKZ-UHFFFAOYSA-N 4-cyclopropylpiperidine;hydrochloride Chemical compound Cl.C1CC1C1CCNCC1 UQDYMLLPZKJOKZ-UHFFFAOYSA-N 0.000 description 3
- YDEDPBSOZYZWTH-UHFFFAOYSA-N 4-ethylpiperidine;hydrochloride Chemical compound Cl.CCC1CCNCC1 YDEDPBSOZYZWTH-UHFFFAOYSA-N 0.000 description 3
- FOWOXWLATUAFNQ-UHFFFAOYSA-N 4-oxopiperidine-1-carboxylic acid Chemical compound OC(=O)N1CCC(=O)CC1 FOWOXWLATUAFNQ-UHFFFAOYSA-N 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 229960001143 cyclopentamine hydrochloride Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 3
- 230000002140 halogenating effect Effects 0.000 description 3
- 238000007327 hydrogenolysis reaction Methods 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridine hydrochloride Substances [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 3
- 239000012429 reaction media Substances 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 229960003766 thrombin (human) Drugs 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- YFNKIDBQEZZDLK-UHFFFAOYSA-N triglyme Chemical compound COCCOCCOCCOC YFNKIDBQEZZDLK-UHFFFAOYSA-N 0.000 description 3
- FVBHVBCCQLTLAJ-UHFFFAOYSA-N 3-cyclopentyl-2-(diacetylamino)benzenesulfonic acid Chemical compound C1=CC=C(S(O)(=O)=O)C(N(C(C)=O)C(=O)C)=C1C1CCCC1 FVBHVBCCQLTLAJ-UHFFFAOYSA-N 0.000 description 2
- NCNVPWCTEBODPS-UHFFFAOYSA-N 4-cyclopropylpiperidine Chemical class C1CC1C1CCNCC1 NCNVPWCTEBODPS-UHFFFAOYSA-N 0.000 description 2
- WLQVBFDHWAVUJN-UHFFFAOYSA-N 4-cyclopropylpyridine Chemical compound C1CC1C1=CC=NC=C1 WLQVBFDHWAVUJN-UHFFFAOYSA-N 0.000 description 2
- KWHPWBXOLZTZMJ-UHFFFAOYSA-N 4-ethylpiperidine Chemical compound CCC1CCNCC1 KWHPWBXOLZTZMJ-UHFFFAOYSA-N 0.000 description 2
- CPPOXEDHAGNMET-UHFFFAOYSA-N 4-ethylpiperidine-1-carboxylic acid Chemical group CCC1CCN(C(O)=O)CC1 CPPOXEDHAGNMET-UHFFFAOYSA-N 0.000 description 2
- OHZUEFKOZYWUFF-UHFFFAOYSA-N 4-hydroxypiperidine-1-carboxylic acid Chemical compound OC1CCN(C(O)=O)CC1 OHZUEFKOZYWUFF-UHFFFAOYSA-N 0.000 description 2
- RQFXCHOQVKBBOK-UHFFFAOYSA-N 5-ethyl-4-iodo-1h-imidazole Chemical class CCC=1NC=NC=1I RQFXCHOQVKBBOK-UHFFFAOYSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 206010053567 Coagulopathies Diseases 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 230000002785 anti-thrombosis Effects 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 230000035602 clotting Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 150000003840 hydrochlorides Chemical group 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 2
- LRQVXUYWQZZCJD-UHFFFAOYSA-N n-[4-(1h-imidazol-2-yl)butyl]benzenesulfonamide Chemical class C=1C=CC=CC=1S(=O)(=O)NCCCCC1=NC=CN1 LRQVXUYWQZZCJD-UHFFFAOYSA-N 0.000 description 2
- OHLXXFUDMGUKCG-UHFFFAOYSA-N n-methylpyrrolidin-1-amine Chemical compound CNN1CCCC1 OHLXXFUDMGUKCG-UHFFFAOYSA-N 0.000 description 2
- 239000004533 oil dispersion Substances 0.000 description 2
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 150000003053 piperidines Chemical class 0.000 description 2
- 229910003446 platinum oxide Inorganic materials 0.000 description 2
- 229960001866 silicon dioxide Drugs 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 238000010025 steaming Methods 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 229940124530 sulfonamide Drugs 0.000 description 2
- FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 238000009834 vaporization Methods 0.000 description 2
- 230000008016 vaporization Effects 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- MGCGGCMKJWCMKL-UHFFFAOYSA-N 1-bromo-1,1-difluoroethane Chemical compound CC(F)(F)Br MGCGGCMKJWCMKL-UHFFFAOYSA-N 0.000 description 1
- RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical class C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 1
- OZJZCCMIOZPPIT-UHFFFAOYSA-N 2-(2-methoxyethoxy)acetyl chloride Chemical compound COCCOCC(Cl)=O OZJZCCMIOZPPIT-UHFFFAOYSA-N 0.000 description 1
- AEJJWAKUFLSSPA-UHFFFAOYSA-N 2-amino-3-cyclopentylbenzenesulfonic acid Chemical compound C1=CC=C(S(O)(=O)=O)C(N)=C1C1CCCC1 AEJJWAKUFLSSPA-UHFFFAOYSA-N 0.000 description 1
- GKWLXQGOBFXAHT-UHFFFAOYSA-N 2-amino-3-cyclopentylbenzenesulfonyl chloride Chemical compound C1=CC=C(S(Cl)(=O)=O)C(N)=C1C1CCCC1 GKWLXQGOBFXAHT-UHFFFAOYSA-N 0.000 description 1
- ZBZQFAWRSGFJIY-UHFFFAOYSA-N 2-amino-3-thiophen-2-ylbenzenesulfonic acid Chemical compound C1=CC=C(S(O)(=O)=O)C(N)=C1C1=CC=CS1 ZBZQFAWRSGFJIY-UHFFFAOYSA-N 0.000 description 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- RDRQUUWCJTYHCT-UHFFFAOYSA-N 4-(trifluoromethyl)piperidine Chemical class FC(F)(F)C1CCNCC1 RDRQUUWCJTYHCT-UHFFFAOYSA-N 0.000 description 1
- BQNDEYAINRSUCA-UHFFFAOYSA-N 4-cyclopropylpiperidine-1-carboxylic acid Chemical compound C1CN(C(=O)O)CCC1C1CC1 BQNDEYAINRSUCA-UHFFFAOYSA-N 0.000 description 1
- NJQHZENQKNIRSY-UHFFFAOYSA-N 5-ethyl-1h-imidazole Chemical class CCC1=CNC=N1 NJQHZENQKNIRSY-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- 238000005684 Liebig rearrangement reaction Methods 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- SRUCGVWHSWAEOZ-XIFFEERXSA-N [(2S)-1-(4-ethylpiperidin-1-yl)-5-(5-ethyl-1-tritylimidazol-4-yl)-1-oxopentan-2-yl]carbamic acid Chemical compound CCC1CCN(CC1)C(=O)[C@H](CCCC2=C(N(C=N2)C(C3=CC=CC=C3)(C4=CC=CC=C4)C5=CC=CC=C5)CC)NC(=O)O SRUCGVWHSWAEOZ-XIFFEERXSA-N 0.000 description 1
- HXRDIZJXWOAWGI-UHFFFAOYSA-N [Na+].O[S-](=O)=O Chemical compound [Na+].O[S-](=O)=O HXRDIZJXWOAWGI-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- DQPBABKTKYNPMH-UHFFFAOYSA-N amino hydrogen sulfate Chemical compound NOS(O)(=O)=O DQPBABKTKYNPMH-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 229960004676 antithrombotic agent Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003593 chromogenic compound Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229960003263 cyclopentamine Drugs 0.000 description 1
- HFXKQSZZZPGLKQ-UHFFFAOYSA-N cyclopentamine Chemical compound CNC(C)CC1CCCC1 HFXKQSZZZPGLKQ-UHFFFAOYSA-N 0.000 description 1
- MVMKLHVCDDYARZ-UHFFFAOYSA-N cyclopentyl(methyl)carbamic acid Chemical compound OC(=O)N(C)C1CCCC1 MVMKLHVCDDYARZ-UHFFFAOYSA-N 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- MCWXGJITAZMZEV-UHFFFAOYSA-N dimethoate Chemical compound CNC(=O)CSP(=S)(OC)OC MCWXGJITAZMZEV-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- WUDNUHPRLBTKOJ-UHFFFAOYSA-N ethyl isocyanate Chemical compound CCN=C=O WUDNUHPRLBTKOJ-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- IHLVCKWPAMTVTG-UHFFFAOYSA-N lithium;carbanide Chemical compound [Li+].[CH3-] IHLVCKWPAMTVTG-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229940105631 nembutal Drugs 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-O oxonium Chemical compound [OH3+] XLYOFNOQVPJJNP-UHFFFAOYSA-O 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 1
- REPWBKQJAMXHFL-UHFFFAOYSA-N phenylphosphane;hydrobromide Chemical class [Br-].[PH3+]C1=CC=CC=C1 REPWBKQJAMXHFL-UHFFFAOYSA-N 0.000 description 1
- RGCLLPNLLBQHPF-HJWRWDBZSA-N phosphamidon Chemical compound CCN(CC)C(=O)C(\Cl)=C(/C)OP(=O)(OC)OC RGCLLPNLLBQHPF-HJWRWDBZSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 238000000247 postprecipitation Methods 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- WQDUMFSSJAZKTM-UHFFFAOYSA-N sodium methoxide Substances [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- XKXIQBVKMABYQJ-UHFFFAOYSA-N tert-butyl hydrogen carbonate Chemical class CC(C)(C)OC(O)=O XKXIQBVKMABYQJ-UHFFFAOYSA-N 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 230000001732 thrombotic effect Effects 0.000 description 1
- 239000011573 trace mineral Substances 0.000 description 1
- 235000013619 trace mineral Nutrition 0.000 description 1
- GYUURHMITDQTRU-UHFFFAOYSA-N tributyl(pyridin-2-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CC=CC=N1 GYUURHMITDQTRU-UHFFFAOYSA-N 0.000 description 1
- BPLUKJNHPBNVQL-UHFFFAOYSA-N triphenylarsine Chemical compound C1=CC=CC=C1[As](C=1C=CC=CC=1)C1=CC=CC=C1 BPLUKJNHPBNVQL-UHFFFAOYSA-N 0.000 description 1
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 229940038773 trisodium citrate Drugs 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/68—Halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Diabetes (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Hematology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention concerns compounds of formula (I) in which R1 and R'1 represent hydrogen, halogen or (C1-C4) alkyl, R2 represents a piperidin-1-yl group, 1, 2, 3, 6-tetrahydropyridin-1-yl optionally substituted, hexahydro-1H-azepin-1-yl, heptahydroazocin-1-yl, octahydro-1H-azonin-1-yl, (a) (A-B = -CONR'', m = 1 to 2 and p = 1 to 2), (b) (Q = carbon or nitrogen, D = (C1-C4) alkyl or -CH2CF3, and r = 1 to 3, R3 represents (C1-C5) alkyl, -COR5 [R5 being (C1-C4) alkyl, -(CH2)nOCH3, -CH2O(C2H4O)nCH3, -(CH2)nCF3, -(CH2)nOH (n = 1 to 4)], -SO2R6, -CONHR6, -SO2N(R6)2 (R6 being (C1-C4) alkyl), R4 represents hydrogen or halogen and A represents phenyl or heterocycle optionally substituted or cyclo (C5-C8) alkyl. The invention is applicable in therapeutics.
Description
The present invention relates to N-(imidazolyl butyl) benzenesulfonamide derivatives, its preparation method and the application in treatment.
Compound of the present invention is corresponding to the structure formula I
R wherein
1And R '
1Represent hydrogen atom or halogen atom or (C independently of one another
1-C
4) alkyl, R
2The expression piperidines-1-base, described piperidines-1-base at 4 by one or more (C that are selected from hydroxyl, straight or branched
1-C
4) alkyl, hydroxyl (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group, (C
1-C
4) alkylthio, nitrile, a methyl fluoride, difluoromethyl, trifluoromethyl, 2-fluorine oxyethyl group, 2,2,2-trifluoro ethoxy, (C
3-C
6) cycloalkyl ,-COOR ' and-CONR ' R " group (R ' be (C
1-C
4) alkyl, R " is hydrogen atom or (C
1-C
4) alkyl) and group selectivity replace, or quilt=CYZ group [Y and Z are independently from each other hydrogen atom, halogen atom and (C
1-C
4) alkyl (optionally being replaced), cyano group by one or more halogen atoms and-COOR ' group, R ' is as defined above] or
Group (r=1-3) or=NOCH
3Group replaces; Perhaps, R
2Expression spiral shell [(C
3-C
6) cycloalkyl-1,4 '-piperidines]-the 1-base; Or at 4 by (the C of straight or branched
1-C
4) alkyl (optionally being replaced by one or more halogen atoms) or (C
3-C
6) the cycloalkyl selectivity replace 1,2,3,6-tetrahydropyridine-1-base; Or 4 by trifluoromethyl or=CF
2Hexahydro-1 H-azepines-1-base that group selectivity replaces; Or seven hydrogen azocine-1-base; Or octahydro-1H-azonine-1-base; Or
Group (A-B is-CONR " group, m=1-2, p=1-2); Or
(Q is nitrogen or carbon atom to group, and D is (C
1-C
4) alkyl or-CH
2CF
3Group, r=1-3); R
3(the C of expression straight or branched
1-C
5) alkyl; Or-COR
5Group, wherein R
5Be (the C of straight or branched
1-C
4) alkyl ,-(CH
2)
nOCH
3,-CH
2O (C
2H
4O)
nCH
3,-(CH
2)
nCF
3Or-(CH
2)
nOH (n=1-4); Or-SO
2R
6Group; Or-CONHR
6Group; Or-SO
2N (R
6)
2Group, wherein R
6Be (the C of straight or branched
1-C
4) alkyl; R
4Expression hydrogen atom or halogen atom; A represents by one or more halogen atom, straight or branched (C of being selected from
1-C
4) alkyl, straight or branched (C
1-C
4) alkoxyl group, trifluoromethyl, trifluoromethoxy, formyl radical ,-CH
2OR
10,-CH
2OCOR
10,-CH
2OCONR
10R
11,-COOR
10,-CONR
10R
11, nitro ,-NR
10R
11, NHCOR
10With-NH (CH
2)
qOR
10The phenyl that replaces of substituting group selectivity, R wherein
10And R
11Be (the C of hydrogen atom or straight or branched independently of one another
1-C
4) alkyl, q is 0-6; Perhaps, A represents to be selected from the heterocycle of pyridyl, thienyl, furyl, pyrimidyl and thiazolyl, and described group can be substituted in the manner described above; Or ring (C
5-C
8) alkyl.
According to the present invention, preferred compound is following formula I compound, wherein: R
1And R '
1Represent hydrogen atom or halogen atom or (C independently of one another
1-C
4) alkyl, R
2The expression piperidines-1-base, described piperidines-1-base at 4 by one or more (C that are selected from straight or branched
1-C
4) alkyl, hydroxyl (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group, (C
1-C
4) alkylthio, nitrile, difluoromethyl, trifluoromethyl, 2,2,2-trifluoro ethoxy and (C
3-C
6) group selectivity of cycloalkyl replaces, or quilt=CYZ group (Y and Z are independently from each other hydrogen atom, halogen atom and (C
1-C
4) alkyl) or=NOCH
3Group replaces; Perhaps, R
2Expression spiral shell [(C
3-C
6) cycloalkyl-1,4 '-piperidines]-the 1-base; Or at 4 by (the C of straight or branched
1-C
4) alkyl (optionally being replaced) selectivity by one or more halogen atoms replace 1,2,3,6-tetrahydropyridine-1-base; Or at 4 quilt=CF
2Hexahydro-1 H-azepines-1-base that group selectivity replaces; Or octahydro-1H-azonine-1-base; Or
Group (A-B is-CONR " group, m=1-2, p=1-2); Or
(Q is carbon or nitrogen-atoms to group, and D is (C
1-C
4) alkyl or-CH
2CF
3Group, r=1-3); R
3(the C of expression straight or branched
1-C
5) alkyl; Or-COR
5Group, wherein R
5Be (the C of straight or branched
1-C
4) alkyl ,-CH
2O (C
2H
4O)
nCH
3,-(CH
2)
nOH ,-(CH
2)
nOCH
3Group; Or-CONHR
6Group; A represents by one or more halogen atom, straight or branched (C of being selected from
1-C
4) alkyl, straight or branched (C
1-C
4) alkoxyl group, trifluoromethyl, trifluoromethoxy and-NR
10R
11The phenyl that replaces of substituting group selectivity, R wherein
10And R
11Be (the C of hydrogen atom or straight or branched independently of one another
1-C
4) alkyl; Perhaps, A represents pyridyl or thienyl, can be substituted in the manner described above; Perhaps encircle (C
5-C
8) alkyl.
In these compounds, preferably compound is, wherein R
1Expression (C
1-C
4) alkyl and R '
1The expression hydrogen atom, R
2Be illustrated in 4 by (the C of straight or branched
1-C
4) alkyl or=CF
2Piperidines-1-base that group replaces, R
3Expression-COR
5Group and R wherein
5Be (the C of straight or branched
1-C
4) alkyl, A represents according to thienyl or ring (C with the replacement of upper type selectivity
5-C
8) alkyl.
The center amino acid moiety
Preferred configuration be [S].
Compound of the present invention can exist with the form of racemic modification or pure enantiomorph or mixture of enantiomers.This compound can also exist with the form of free acid or free alkali or pharmaceutically acceptable acid additive salt.All these forms all constitutes a part of the present invention.
In following reaction scheme ,-CPh
3Group is represented trityl.
According to the present invention, R wherein
3Expression-COR
5Group, wherein R
5Expression straight or branched (C
1-C
4) alkyl or-(CH
2)
nCF
3(I a) compound can be synthetic according to reaction scheme 1 for the formula of group (n=1-4).Formula II compound and formula III compound are reacted the compound that generates formula IV in aprotic solvent such as methylene dichloride, in the presence of alkali such as triethylamine, then with the formula IV compound acetate that obtains: ethanol, acetate: water or acetate: tetrahydrofuran (THF): water mixture is handled under reflux temperature, the R in the formula II compound
1And R '
1Represent hydrogen atom or (C respectively
1-C
4) alkyl, R
2As defined above, the A in the formula III compound represent according to the phenyl that replaces with the upper type selectivity or be selected from the heterocycle and the described heterocyclic group of pyridyl, thienyl, furyl, pyrimidyl and thiazolyl can be according to be substituted R with upper type
4And R
5As defined above.
Reaction scheme 1
In the of the present invention another kind of method shown in the reaction scheme 2, in order to prepare wherein R
5Expression straight or branched (C
1-C
4) alkyl ,-(CH
2)
nOCH
3,-CH
2O (C
2H
4O)
nCH
3,-(CH
2)
nCF
3Or-(CH
2)
n(I is compound a) for the formula of OH group (n=1-4), can be in aprotic solvent such as methylene dichloride with formula II compound and formula (V) compound, reaction generates the compound of formula VI in the presence of alkali such as triethylamine, then with the formula VI compound acetate that obtains: ethanol, acetate: water or acetate: tetrahydrofuran (THF): water mixture is handled under reflux temperature, in formula (V) compound, A represents according to the phenyl that replaces with upper type or is selected from pyridyl, thienyl, furyl, the heterocycle of pyrimidyl and thiazolyl and described heterocyclic group can be according to being substituted with upper type, perhaps A representative ring (C
5-C
8) alkyl, R
4And R
5As defined above.
Reaction scheme 2
In another kind of method of the present invention, can also use the method shown in the reaction scheme 3.With the compound of formula (VII) compound and formula (VIII) in solvent such as dimethyl formamide, catalyzer as four (triphenyl phosphine) palladium (O) in the presence of the compound of reaction production (IX), then with formula (IX) compound under the reflux temperature at acidic medium such as acetate: heat in the hydrate, in formula (VII) compound, R
1And R '
1Represent hydrogen atom or (C respectively
1-C
4) alkyl, R
2, R
4And R
5As defined above, in formula (VIII) compound, R represents (C
1-C
4) alkyl, A is as defined above.
Obtain wherein R if desired
4Be that (I is compound a), then can be with R wherein for the formula of hydrogen atom
4Be that (I is the compound hydrogenolysis a) for the corresponding formula of halogen atom.When needs obtain wherein R
1And/or R '
1(I is a) during compound, then can be with R wherein for the formula of expression halogen atom
1And/or R '
1The corresponding formula of expression hydrogen atom (handle in solvent such as dimethyl formamide with halogenating agent such as N-bromosuccinimide or N-chlorosuccinimide by I a) compound.
Reaction scheme 3
Perhaps, in order to prepare wherein R
3Expression-COR
5Group ,-SO
2R
6Group ,-CONHR
6Group or-SO
2N (R
6)
2Group, wherein R
5Be (the C of straight or branched
1-C
4) alkyl ,-(CH
2)
nOCH
3,-CH
2O (C
2H
4O)
nCH
3,-(CH
2)
nCF
3Or-(CH
2)
n(P is a protecting group to the OP group, n=1-4) and R
6Formula (I b) compound can use the method shown in the reaction scheme 4 as defined above.With the compound of formula II compound and formula (X) (wherein A and R
4The compound of reaction production (XI) as defined above) is then with the compound and the formula R of formula (XI)
5The acyl chlorides of COCl or formula R
6The alkyl isocyanate of NCO or formula R
6SO
2The SULPHURYL CHLORIDE of Cl or formula (R
6)
2NSO
2The compound of the sulfamic acid chloride of Cl reaction production (XII), then with the compound acetate of the formula (XII) that obtains: ethanol, acetate: water or acetate: tetrahydrofuran (THF): water mixture is handled under reflux temperature.
When needs obtain wherein R
1And/or R '
1During formula (I b) compound of expression halogen atom, then can be with R wherein
1And/or R '
1Corresponding formula (I b) compound of expression hydrogen atom is handled in solvent such as dimethyl formamide with halogenating agent such as N-bromosuccinimide or N-chlorosuccinimide.
Obtain wherein R if desired
4Be formula (I b) compound of hydrogen atom, then can be with R wherein
4It is corresponding formula (I b) the compound hydrogenolysis of halogen atom.
Reaction scheme 4
In order to prepare wherein R
12Corresponding to R
3And R
3(the C of expression straight or branched
1-C
5) formula (I c) compound of alkyl, can use the method shown in the reaction scheme 5.With the compound of formula II compound and formula (X IV) (R wherein
12(the C of expression straight or branched
1-C
5) alkyl, A and R
4The compound of reaction production (X V) as defined above), then with the compound acetate of formula (X V): ethanol, acetate: water or acetate: tetrahydrofuran (THF): water mixture is handled under reflux temperature.
When needs obtain wherein R
1And/or R '
1During formula (I c) compound of expression halogen atom, then can be with R wherein
1And/or R '
1Corresponding formula (I c) compound of expression hydrogen atom is handled in solvent such as dimethyl formamide with halogenating agent such as N-bromosuccinimide or N-chlorosuccinimide.
Obtain wherein R if desired
4Be formula (I c) compound of hydrogen atom, then can be with R wherein
4It is corresponding formula (I c) the compound hydrogenolysis of halogen atom.
Raw materials used be can buy or document in put down in writing, perhaps can make according to method described herein or method known to those skilled in the art.
Reaction scheme 5
Therefore, the formula II compound can be according to being similar to disclosed method preparation in the European patent application EP 0643047.Put down in writing the compound of some formula III in the European patent application EP 0718307.Formula (VII) compound is according to being similar to disclosed method preparation in the European patent application EP 0718307.The compound of formula (X) and (X IV) is recorded in European patent application EP 0713865.5-ethyl-1H-imidazoles is according to Horne D.A. (1994), heterocycle (Heterocycles), the method preparation of describing in 39,1,139.The preparation of 4-cyclopropyl pyridine is recorded in Eisch J.J., (1974), organic chemistry magazine (J.Org.Chem.), 39,21,5110.4-difluoro methylene pyridine basis is similar to (1995) such as Schmidt W., Liebigs Ann., the method preparation shown in the 1319-1326.The preparation of N-cyclopentyl methane amide is recorded in (1993) such as Bosio R., synthetic (Synthesis), 8,783-785.
Following examples 1-11 is used for illustrating the preparation of some formula II compound.Embodiment 12-27 is used for illustrating the preparation of some formula I compound of the present invention.
Trace element analysis and IR and NMR have confirmed the structure of gained compound.The numbering of the compound that is exemplified is referring to the numbering in the later on given table, and this table has illustrated the chemical structure and the physical properties of some compound of the present invention.
Ratio value representation (alkali: ratio acid) in the bracket.Embodiment 1 (S)-5-ethyl-α-[(4-ethyl piperidine-1-yl) carbonyl]-1-(trityl)-1H-imidazoles-4-butylamine hydrochloride (1: 1) 1.1 5-ethyl-4-iodo-1H-imidazoles
0 ℃ and stir down, the 800ml chloroformic solution of 22.7g (89mmol) iodine was added drop-wise in 3 hours in the 600ml2N aqueous sodium hydroxide solution of 8.6g (89mmol) 5-ethyl-1H-imidazoles.Continuation was stirred 4 hours under this temperature, removed chloroform then under reduced pressure.Water is cooled to ℃, with the neutralization of 12N hydrochloric acid and with ethyl acetate extraction (3 * 1L).Merge organic phase, with the washing of 100ml saturated nacl aqueous solution, with dried over sodium sulfate and concentrating under reduced pressure.The resistates that obtains is passed through silica gel chromatography, use methyl alcohol: methylene dichloride (1.5: 98.5) mixture wash-out.Obtain the product of 10.5g white powder.Yield=53%.Fusing point=155 ℃.1.2 alkylsulfonyl 5-ethyl-4 iodo-1-[(4-aminomethyl phenyl)]-the 1H-imidazoles
Stir down, the oil dispersion of 0.91g (22.7mmol) 60% sodium hydride is joined in the 25ml anhydrous dimethyl formamide solution of 4.8g (21.6mmol) 5-ethyl-4-iodo-1H-imidazoles under 0 ℃ and nitrogen atmosphere in batches.Continuation was stirred 0.5 hour under 0 ℃ and is added 4.35g (22.7mmol) 4-(aminomethyl phenyl) SULPHURYL CHLORIDE.Under 0 ℃, continue to stir 1 hour, make the temperature of mixture return to room temperature and continue stirring 1 hour, then with the reaction mixture concentrating under reduced pressure.Resistates is added in the 400ml ethyl acetate also successively with 100ml0.5N hydrochloric acid, 100ml water and the washing of 100ml saturated nacl aqueous solution.At last, with solution with dried over sodium sulfate and concentrating under reduced pressure.
From ethyl acetate: post precipitation obtains 6.1g white solid product the pentane admixture.Yield=75%.Fusing point=95 ℃.1.3 (S)-2-[[(1; 1-dimethyl oxyethyl group) carbonyl] amino]-5-[5-ethyl-1-[(4-aminomethyl phenyl) alkylsulfonyl]-the 1H-imidazol-4 yl] penta-4-acetylenic acid methyl esters 1.3.1 (S)-2-[[(1; 1-dimethyl oxyethyl group) carbonyl] amino] a) (S)-2-[[(1 of penta-4-acetylenic acid methyl esters; 1-dimethyl oxyethyl group) carbonyl] amino] under penta-4-acetylenic acid nitrogen atmosphere, with 11.5g (77mmol) (S)-2-amino penta-4-acetylenic acid hydrochloride, 100ml dioxane, 50ml water and 80ml 2N sodium hydroxide solution join in the 250ml round-bottomed flask.In this solution, added 17.9g (82mmol) the two carbonic acid tert-butyl esters and stirring at room 3 hours.Add the 200ml ethyl acetate and add the 2N hcl acidifying to pH2.Separatory and with water 50ml ethyl acetate extraction.With dried over mgso and be evaporated to dried.
Obtain the product of 18.78g colorless oil and it is directly used in next step reaction.B) (S)-2-[[(1,1-dimethyl oxyethyl group) carbonyl] amino] under penta-4-acetylenic acid methyl esters nitrogen atmosphere, with 13g (154mmol) sodium bicarbonate join in the 250ml round-bottomed flask 18.78g (77mmol) (S)-2-[[(1,1-dimethyl oxyethyl group) carbonyl] amino] in the 150ml dimethyl formamide solution of penta-4-acetylenic acid.Add 20ml (318mmol) methyl iodide and with this mixture stirring at room 18 hours.Pour into mixture in the water and use ethyl acetate extraction.Organic phase is washed with water, use dried over mgso then.Be evaporated to dried.Obtain the product of 15.85g yellow oily and it is directly used in next step reaction.1.3.2 (S)-and 2-[[(1,1-dimethyl oxyethyl group) carbonyl] amino]-5-[5-ethyl-1-[(4-aminomethyl phenyl) alkylsulfonyl]-the 1H-imidazol-4 yl] penta-4-acetylenic acid methyl esters
With 9.87g (26.3mmol) 5-ethyl-4-iodo-1-[(4-aminomethyl phenyl) alkylsulfonyl]-1H-imidazoles, 8.94g (39.4mmol) (S)-2-[[(1,1-dimethyl oxyethyl group) carbonyl] amino] and penta-4-acetylenic acid methyl esters, 0.25g (1.3mmol) cupric iodide, 10.84ml (105mmol) diethylamine and the mixture of 0.92g (1.3mmol) dichloride two (triphenyl phosphine) palladium in the 26ml dimethyl formamide under hydrogen in 50 ℃ of heating 8 hours.With the reaction mixture concentrating under reduced pressure, will also wash 3 times with 100ml water and 100ml saturated nacl aqueous solution successively in the resistates adding 300ml ethyl acetate that obtain.At last, with solution with dried over sodium sulfate and concentrating under reduced pressure.Resistates by silica gel chromatography, is used ethyl acetate: the mixture wash-out of hexane (3: 7).Obtain 11g thickness buttery product.Yield=88%.1.4 (S)-and 2-[[(1,1-dimethyl oxyethyl group) carbonyl] amino]-5-[5-ethyl-1-[(4-aminomethyl phenyl) alkylsulfonyl]-the 1H-imidazol-4 yl] methyl valerate
With 13.5g (28.4mmol) (S)-2-[[(1,1-dimethyl oxyethyl group) carbonyl] amino]-5-[5-ethyl-1-[(4-aminomethyl phenyl) alkylsulfonyl]-the 1H-imidazol-4 yl] penta-4-acetylenic acid methyl esters is in room temperature hydrogenation 10 hours under 0.35MPa (50 pounds/square inch) pressure in 50ml methyl alcohol in the presence of the 1.8g10% palladium charcoal.Reaction mixture is concentrated with diatomite filtration and with filtrate decompression.Resistates by silica gel chromatography, is used hexanaphthene: the mixture wash-out of ethyl acetate (7: 3).Obtain 10.5g thickness buttery product.Yield=77%.1.5 (S)-and 2-[[(1,1-dimethyl oxyethyl group) carbonyl] amino]-5-(5-ethyl-1H-imidazoles-4-yl) methyl valerate
With 10.4g (21.6mmol) (S)-2-[[(1,1-dimethyl oxyethyl group) carbonyl] amino]-5-[5-ethyl-1-[(4-aminomethyl phenyl) alkylsulfonyl]-the 1H-imidazol-4 yl] mixture of methyl valerate and 8.79g (65.2mmol) I-hydroxybenzotriazole hydrate stirring at room 4 hours in 150ml methyl alcohol.With the reaction mixture concentrating under reduced pressure, resistates adds in the 100ml ether and uses 450ml0.7N salt acid elution.Separatory, the pH with water transfers to 8-9 and uses ethyl acetate extraction (2 * 500ml) with sodium hydrogen carbonate solution.Merge organic phase, with dried over sodium sulfate and concentrating under reduced pressure.Obtain 8.79g thickness buttery compound and it is directly used in next step reaction.Yield=88%.1.6 (S)-and 2-[[(1,1-dimethyl oxyethyl group) carbonyl] amino]-5-[5-ethyl-1-(trityl)-1H-imidazol-4 yl] methyl valerate
Under 0 ℃, with 2.9ml (20.3mmol) triethylamine and 5.77g (20.7mmol) trityl chloride join successively 5.95g (18.3mmol) (S)-2-[[(1,1-dimethyl oxyethyl group) carbonyl] amino]-the 70ml dichloromethane solution of 5-(5-ethyl-1H-imidazol-4 yl) methyl valerate in.The temperature of mixture is risen to room temperature, under this temperature, continue to stir l8 hour, then with the reaction mixture concentrating under reduced pressure.Resistates is added in the 300ml ethyl acetate, successively with 200ml0.1N hydrochloric acid, 200ml saturated sodium bicarbonate solution and the washing of 100ml saturated nacl aqueous solution.With solution with dried over mgso and concentrating under reduced pressure.The resistates that obtains is passed through silica gel chromatography, use methylene dichloride: the mixture wash-out of methyl alcohol (99: 1).Obtain 9.4g thickness buttery product.Yield=90.6%.1.7 (S)-α-[[(1,1-dimethyl oxyethyl group) carbonyl] amino]-5-ethyl-1-(trityl)-1H-imidazoles-4-valeric acid
Under 0 ℃, with 0.83g (19.8mmol) hydronium(ion) oxidation lithium under stirring, join 9.4g (16.6mmol) (S)-2-[[(1,1-dimethyl oxyethyl group) carbonyl] amino]-5-[5-ethyl-1-(trityl)-1H-imidazol-4 yl] methyl valerate is in the solution of the mixture of 48ml methyl alcohol and 16ml water.The temperature of mixture is risen to room temperature and continue stirring 24 hours under this temperature.Reduction vaporization transfers to pH2 with 1N hydrochloric acid with water down in 0 ℃, uses dichloromethane extraction (2 * 300ml) then.Merge organic phase, with the washing of 100ml saturated nacl aqueous solution, with dried over mgso and concentrating under reduced pressure.Resistates is developed in ether, filtered and drying under reduced pressure.Obtain 8.87g white powder product.Yield=96.7%.Fusing point=141 ℃.1.8 (S)-[1-[(4-ethyl piperidine-1-yl) carbonyl]-4-[5-ethyl-1-(trityl)-1H-imidazol-4 yl] butyl] carboxylamine 1,1-dimethyl ethyl ester 1.8.1 4-ethyl piperidine hydrochloride is 4-ethyl piperidine-1-carboxylic acid 1 a), 1-dimethyl ethyl ester
With 20g (190mmol) 4-vinylpridine under 0.42MPa (60 pounds/square inch) pressure, in the presence of 2g platinum oxide (IV) in 50 ℃ of hydrogenations 4 hours, reaction mixture is concentrated with diatomite filtration and with filtrate decompression.Resistates is added in the 150ml water, transfer to pH8 and drip the 100ml tetrahydrofuran solution of 44g (190mmol) two carbonic acid two-(1, the 1-dimethyl ethyl) ester with saturated aqueous sodium carbonate.The temperature of reaction mixture is risen to room temperature and continue stirring 18 hours under this temperature.Reduction vaporization and with water with ethyl acetate extraction (2 * 300ml).Merge organic phase and use the washing of 100ml saturated nacl aqueous solution.With the organic phase that merges with dried over sodium sulfate and concentrating under reduced pressure.The resistates that obtains is passed through silica gel chromatography, use hexanaphthene: the mixture wash-out of ethyl acetate (9: 1).Obtain 13.8g oily product.Yield=34%.B) 4-ethyl piperidine hydrochloride
Under 0 ℃, with 13.8g (64.8mmol) 4-ethyl piperidine-1-carboxylic acid 1, the 200ml diethyl ether solution of 1-dimethyl ethyl ester was handled 1 hour with hci gas flow.The temperature of mixture is risen to room temperature, continue under this temperature, to stir 18 hours and the mixture concentrating under reduced pressure.The resistates that obtains is developed in ether, filtered and drying under reduced pressure.Obtain 6.62g white powder product and it is directly used in next step reaction.Yield=70%.Fusing point=138 ℃.1.8.2 (S)-[1-[(4-ethyl piperidine-1-yl) carbonyl]-4-[5-ethyl-1-(trityl)-1H-imidazol-4 yl] butyl] carboxylamine 1,1-dimethyl ethyl ester
Under 0 ℃ and nitrogen atmosphere, with 0.37g (2.9mmol) diisopropylethylamine and 0.46g (1.2mmol) [(benzotriazole-1-yl) oxygen] three (dimethylamino) Phosphonium hexafluorophosphate in stir join successively down 0.6g (1.08mmol) (S)-the 8ml dichloromethane solution of the mixture of α-[[(1,1-dimethyl oxyethyl group) carbonyl] amino]-5-ethyl-1-(trityl)-1H-imidazoles-4-valeric acid and 0.18g (1.2mmol) 4-ethyl piperidine hydrochloride in.The temperature of mixture is risen to room temperature, continue under this temperature, to stir 18 hours, then with the reaction mixture concentrating under reduced pressure.Resistates is added in the 100ml ethyl acetate, successively with 80ml1N hydrochloric acid, 50ml saturated sodium bicarbonate solution and the washing of 50ml saturated nacl aqueous solution, with dried over mgso and concentrating under reduced pressure.Resistates by silica gel chromatography, is used methyl alcohol: the mixture wash-out of methylene dichloride (2: 98).Obtain 0.7g thickness oily product.Yield=98%.1.9 (S)-5-ethyl-α-[(4-ethyl piperidine-1-yl) carbonyl]-1-(trityl)-1H-imidazoles-4-butylamine hydrochloride (1: 1)
Under 0 ℃, with 0.7g (1.07mmol) (S)-[1-[(4-ethyl piperidine-1-yl) carbonyl]-4-[5-ethyl-1-(trityl)-1 H-imidazol-4 yl] butyl] carboxylamine 1, the solution of 1-dimethyl ethyl ester in 50ml benzene was handled 15 minutes with hci gas flow.The temperature of mixture is risen to room temperature, continue under this temperature, to stir 1.5 hours, then with the mixture concentrating under reduced pressure.The resistates that obtains is developed in ether, filtered and drying under reduced pressure.Obtain 0.61g white powder product and it is directly used in next step reaction.Yield=97%.Embodiment 2 (S)-5-methyl-α-[[4-(trifluoromethyl)-piperidines-1-yl] carbonyl]-1-(trityl)-1H-imidazoles-4-butylamine hydrochloride (1: 1) 2.1 (S)-[4-[5-methyl isophthalic acid-(trityl)-1H-imidazol-4 yl]-1-[[4-(trifluoromethyl) piperidines-1-yl] carbonyl] butyl] carboxylamine 1,1-dimethyl ethyl ester 2.2.1 (S)-α-[[(1,1-dimethyl oxyethyl group) carbonyl] amino]-5-methyl isophthalic acid-(trityl)-1H-imidazoles-4-valeric acid
This product is according to embodiment 1.7 described methods, from (S)-2-[[(1,1-dimethyl oxyethyl group) carbonyl] amino]-5-[5-methyl isophthalic acid-(trityl)-1H-imidazol-4 yl] methyl valerate makes.2.2.2 (S)-and [4-[5-methyl isophthalic acid-(trityl)-1H-imidazol-4 yl]-1-[[4-(trifluoromethyl) piperidines-1-yl] carbonyl] butyl] carboxylamine 1,1-dimethyl ethyl ester
Under 0 ℃, argon atmospher, with 0.834g (2.2mmol) [(benzotriazole-1-yl) oxygen] three (dimethylamino) Phosphonium hexafluorophosphate in stir join down in batches 1.08g (2mmol) (S)-the 25ml dichloromethane solution of the mixture of α-[[(1,1-dimethyl oxyethyl group) carbonyl] amino]-5-methyl isophthalic acid-(trityl)-1H-imidazoles-4-valeric acid, 0.306g (2mmol) 4-(trifluoromethyl) piperidines and 1.04ml (6mmol) diisopropylethylamine in.The temperature of mixture is risen to room temperature, continue under this temperature, to stir 18 hours, then with the reaction mixture concentrating under reduced pressure.Resistates is added in the 100ml ethyl acetate, successively with 50ml1N hydrochloric acid, 50ml saturated sodium bicarbonate solution and the washing of 50ml saturated nacl aqueous solution, with dried over sodium sulfate and concentrating under reduced pressure.Resistates by silica gel chromatography, is used methyl alcohol: the mixture wash-out of methylene dichloride (2: 98).Obtain 1.2g thickness oily product.Yield=89%.2.2 (S)-5-methyl-α-[[4-(trifluoromethyl)-piperidines-1-yl] carbonyl]-1-(trityl)-1H-imidazoles-4-butylamine hydrochloride (1: 1)
Under 0 ℃, with 1.2g (1.78mmol) (S)-[4-[5-methyl isophthalic acid-(trityl)-1H-imidazol-4 yl]-1-[[4-(trifluoromethyl) piperidines-1-yl] carbonyl] butyl] carboxylamine 1, the solution of 1-dimethyl ethyl ester in 100ml benzene was handled 20 minutes with hci gas flow.Reaction mixture is continued to stir 1 hour under this temperature, then concentrating under reduced pressure.The resistates that obtains is developed in ether, filtered and drying under reduced pressure.Obtain 1.05g white powder product and it is directly used in next step reaction.Yield: 97%.Fusing point=78 ℃.Embodiment 3 (S)-α-[(4-methoxyl group piperidines-1-yl) carbonyl]-5-methyl isophthalic acid-(trityl)-1H-imidazoles-4-butylamine hydrochloride (1: 1) 3.1 4-methoxyl group piperidine hydrochlorate 3.1.1 4-hydroxy piperidine-1-carboxylic acids 1,1-dimethyl ethyl ester
At room temperature, the 50ml methanol solution with 12g (55mmol) two carbonic acid two-(1, the 1-dimethyl ethyl) ester joins in the 50ml methanol solution of 5.06g (50mmol) piperidines-4-alcohol.Reaction mixture was stirred 2 hours under this temperature, then concentrating under reduced pressure.The resistates that obtains is passed through silica gel chromatography, use methylene dichloride: the mixture wash-out of methyl alcohol (95: 5).Obtain 9.74g oily product.Yield=97%.3.1.2 4 methoxyl groups piperidines-1-carboxylic acid 1,1-dimethyl ethyl ester
Stir down, the oil dispersion of 1.59g (39.8mmol) 60% sodium hydride is joined 8g (39.8mmol) 4-hydroxy piperidine-1-carboxylic acid 1 in batches under 0 ℃ and argon atmospher, in the 40ml dimethyl formamide solution of 1-dimethyl ethyl ester and 4.95ml (79.5mmol) methyl iodide and continue under this temperature and stirred 2 hours.Reaction mixture is poured in the 100ml saturated ammonium chloride solution also with ethyl acetate extraction (2 * 200ml).Merge organic phase, successively with 100ml water and the washing of 100ml saturated nacl aqueous solution, with dried over mgso and concentrating under reduced pressure.Resistates by silica gel chromatography, is used ethyl acetate: the mixture wash-out of hexanaphthene (2: 8).Obtain 7.1g oily product.Yield=85%.3.1.3 4-methoxyl group piperidine hydrochlorate
Under 0 ℃, with 7g (32.5mmol) 4-methoxyl group piperidines-1-carboxylic acid 1, the 100ml tetrahydrofuran solution of 1-dimethyl ethyl ester was handled 30 minutes with hci gas flow.The temperature of mixture is risen to room temperature and continue stirring 18 hours under this temperature.Develop in ether with the reaction mixture concentrating under reduced pressure and with resistates, filter and drying under reduced pressure.Obtain 4.2g white powder product and it is directly used in next step reaction.Yield=86%.Fusing point=132 ℃.3.2 (S)-[1-[(4-methoxyl group piperidines-1-yl) carbonyl]-4-[5-methyl isophthalic acid-(trityl)-1H-imidazol-4 yl] butyl] carboxylamine 1,1-dimethyl ethyl ester
Under 0 ℃ and the nitrogen atmosphere, with 0.71g (1.87mmol) [(benzotriazole-1-yl) oxygen] three (dimethylamino) Phosphonium hexafluorophosphate in stir join down in batches 0.918g (1.7mmol) (S)-the 12ml dichloromethane solution of the mixture of α-[[(1,1-dimethyl oxyethyl group) carbonyl] amino]-5-methyl isophthalic acid-(trityl)-1H-imidazoles-4-valeric acid and 0.281g (1.87mmol) 4-methoxyl group piperidine hydrochlorate and 0.63ml (3.57mmol) two and propyl group ethamine in.The temperature of mixture is risen to room temperature, continue under this temperature, to stir 18 hours, then with the reaction mixture concentrating under reduced pressure.Resistates is added in the 100ml ethyl acetate, successively with 50ml0.5N hydrochloric acid, 50ml saturated sodium bicarbonate solution and the washing of 50ml saturated nacl aqueous solution, with dried over sodium sulfate and concentrating under reduced pressure.Resistates by silica gel chromatography, is used methyl alcohol: the mixture wash-out of methylene dichloride (2: 98).Obtain 1.05g thickness oily product.Yield=97%.3.3 (S)-α-[(4-methoxyl group piperidines-1-yl) carbonyl]-5-methyl isophthalic acid-(trityl)-1H-imidazoles-4-butylamine hydrochloride (1: 1)
Under 0 ℃, with 1.05g (1.65mmol) (S)-[1-[(4-methoxyl group piperidines-1-yl) carbonyl]-4-[5-methyl isophthalic acid-(trityl)-1H-imidazol-4 yl] butyl] carboxylamine 1, the solution of 1-dimethyl ethyl ester in 50ml benzene was handled 20 minutes with hci gas flow.Mixture was stirred 30 minutes under this temperature, then concentrating under reduced pressure.The resistates that obtains is developed in ether, filtered and drying under reduced pressure.Obtain 0.93g white powder product and it is directly used in next step reaction.Yield=98%.Fusing point=112 ℃.Embodiment 4 (S)-5-methyl-α-[(4-methylenepiperidines-1-yl) carbonyl]-1-(trityl)-1H-imidazoles-4-butylamine hydrochloride (1: 1) 4.1 4-methylenepiperidines hydrochloride 4.1.1 4-methylenepiperidines-1-carboxylic acids 1,1-dimethyl ethyl ester
Under the room temperature and under the nitrogen atmosphere, the hexane solution of 17ml1.6M n-Butyl Lithium is joined in the mixture of 9.81g (27.5mmol) first base three phenyl phosphonium bromides and 60ml anhydrous tetrahydro furan.With this mixture stirring at room 4 hours, add 5g (25mmol) 4-oxo-piperidine-1-carboxylic acid 1 then rapidly, the 20ml anhydrous tetrahydrofuran solution of 1-dimethyl ethyl ester.Reaction mixture was heated 10 hours under reflux temperature, pour in the 400ml saturated ammonium chloride solution also with extracted with diethyl ether (2 * 300ml).Merge organic phase, with dried over sodium sulfate and concentrating under reduced pressure.Resistates by silica gel chromatography, is used ethyl acetate: the mixture wash-out of normal hexane (5: 95).Obtain the transparent oily product of 2.8g.Yield=57%.4.1.2 4-methylenepiperidines hydrochloride
This product is according to the described method of embodiment 3.1.3, and from 4-methylenepiperidines-1-carboxylic acid 1,1-dimethyl ethyl ester makes.4.2 (S)-5-methyl-α-[(4-methylenepiperidines-1-yl) carbonyl]-1-(trityl)-1H-imidazoles-4-butylamine hydrochloride (1: 1)
With (S)-α-[[(1,1-dimethyl oxyethyl group) carbonyl] amino]-5-methyl isophthalic acid-(trityl)-1H-imidazoles-4-valeric acid and 4-methylenepiperidines hydrochloride be according to embodiment 3.2 described methods reactions, make amorphous product (S)-[4-[5-methyl isophthalic acid-(trityl)-1H-imidazoles 4-yl]-1-[(4-methylenepiperidines-1-yl) carbonyl] butyl] carboxylamine 1,1-dimethyl ethyl ester.
This product is handled with hci gas flow according to the method that embodiment 3.3 describes.Obtain the 0.74g product.Yield=100%.Fusing point=148 ℃.Embodiment 5 (S)-α-[(4-cyclopropyl piperidine-1-yl) carbonyl]-5-methyl isophthalic acid-(trityl)-1H-imidazoles-4-butylamine hydrochloride (1: 1) 5.1 4-cyclopropyl piperidine hydrochloride 5.1.1 4-cyclopropyl piperidines
With the 150ml acetic acid solution of 13g (109mmol) 4-cyclopropyl pyridine in the Parr device, in the presence of 0.35MPa (50 pounds/square inch) pressure and 0.7g platinum oxide (IV), carry out hydrogenation in 50 ℃.Reaction mixture is concentrated with diatomite filtration and with filtrate decompression.Obtain the 12.8g product and it is directly used in next step reaction.Yield=94%.5.1.2 4-cyclopropyl piperidine-1-carboxylic acid 1,1-dimethyl ethyl ester
5g (40mmol) 4-cyclopropyl piperidine is dissolved in the 40ml methylene dichloride, this mixture is cooled to 0 ℃ and drip 6.98g (32mmol) two carbonic acid two-(1, the 1-dimethyl ethyl) ester and 4.85g (48mmol) triethylamine.Reaction mixture concentrated and with resistates by silica gel chromatography, use methylene dichloride: the mixture wash-out of methyl alcohol (99: 1).Obtain the 4g product.Yield=44%.5.1.3 4-cyclopropyl piperidine hydrochloride
Under 0 ℃, with 6.5g (28.8mmol) 4-cyclopropyl piperidine-1-carboxylic acid 1, the 100ml benzole soln of 1-dimethyl ethyl ester was handled 30 minutes with hci gas flow.The temperature of reaction medium is risen to room temperature, under this temperature, continue to stir 4 hours, then with the reaction mixture concentrating under reduced pressure.The resistates that obtains is developed in ether, filtered and drying under reduced pressure.Obtain 4.1g white powder product and it is directly used in next step reaction.Yield=88%.Fusing point=186 ℃.5.2 (S)-[1-[(4-cyclopropyl piperidine-1-yl) carbonyl]-4-[5-methyl isophthalic acid-(trityl)-1H-imidazol-4 yl] butyl] carboxylamine 1,1-dimethyl ethyl ester
With 6g (11mmol) (S)-α-[[(1,1-dimethyl oxyethyl group) carbonyl] amino]-the 100ml dichloromethane solution of the mixture of 5-methyl isophthalic acid-(trityl)-1H-imidazoles-4-valeric acid, 1.79g (11mmol) 4-cyclopropyl piperidine hydrochloride and 9.6g (55.5mmol) diisopropylethylamine stirs and under 0 ℃ and nitrogen atmosphere, stirs to add 4.62g (12.2mmol) [(benzotriazole-1-yl) oxygen] three (dimethylamino) Phosphonium hexafluorophosphates down in batches.The temperature of mixture is risen to room temperature, continue under this temperature, to stir 4 hours, then with the reaction mixture concentrating under reduced pressure.Resistates is added in the 300ml ethyl acetate, successively with 100ml1N hydrochloric acid, 100ml saturated sodium bicarbonate solution and the washing of 100ml saturated nacl aqueous solution, with dried over sodium sulfate and concentrating under reduced pressure.Resistates by silica gel chromatography, is used methyl alcohol: the mixture wash-out of methylene dichloride (1: 99).Obtain the 5g product.Yield=70%.5.3 (S)-α-[(4-cyclopropyl piperidine-1-yl) carbonyl]-5-methyl isophthalic acid-(trityl)-1H-imidazoles-4-butylamine hydrochloride (1: 1)
Under 0 ℃, with 5.3g (8mmol) (S)-[1-[(4-cyclopropyl piperidine-1-yl) carbonyl]-4-[5-methyl isophthalic acid-(trityl)-1H-imidazol-4 yl] butyl] carboxylamine 1, the solution of 1-dimethyl ethyl ester in 200ml benzene was handled 30 minutes with hci gas flow.The temperature of reaction mixture is risen to room temperature, continue to stir 3 hours, then with the reaction mixture concentrating under reduced pressure.The resistates that obtains is added in the methylene dichloride (2 * 280ml) and drying under reduced pressure.Obtain 4.7g white powder product and it is directly used in next step reaction.Yield=100%.Fusing point=124 ℃.Embodiment 6 (S)-5-methyl-α-[[4-(difluoro methylene)-piperidines-1-yl] carbonyl]-1-(trityl)-1H-imidazoles-4-butylamine hydrochloride (1: 1) 6.1 4-(difluoro methylene) piperidine hydrochlorate 6.1.1 4-(difluoro methylene) piperidines-1-carboxylic acid 1,1-dimethyl ethyl ester
Under 0 ℃ and the argon atmospher, the 30ml triglyme drips of solution of 45.6ml (252mmol) hexamethyl idol phosphamide is added in the 180ml triglyme solution of 12ml (120mmol) the difluoro monobromethane in the stirring.The temperature of reaction mixture is risen to room temperature, under this temperature, continue to stir 30 minutes, then reaction mixture is cooled to 0 ℃ once more.Add 11.94g (60mmol) 4-oxo-piperidine-1-carboxylic acid 1, the 30ml triglyme solution of 1-dimethyl ethyl ester returns to the temperature of mixture room temperature and reaction mixture is continued stirring 30 minutes under this temperature.In 80 ℃ of heating 2 hours, cooling was poured in 1 premium on currency and with pentane and is extracted (3 * 400ml) with reaction mixture.Wash with water, with dried over sodium sulfate and evaporation.Resistates by silica gel chromatography, is used hexanaphthene: the mixture wash-out of ethyl acetate (97: 3).Obtain the 8.5g product.Yield=61%.6.1.2 4-(difluoro methylene) piperidine hydrochlorate
According to the method for embodiment 3.1.3, from 4-(difluoro methylene) piperidines-1-carboxylic acid 1,1-dimethyl ethyl ester makes the white powder product.Yield=100%.Fusing point=196 ℃.6.2 (S)-5-methyl-α-[[4-(difluoro methylene) piperidines-1-yl] carbonyl]-1-(trityl)-1H-imidazoles-4-butylamine hydrochloride (1: 1)
With (S)-α-[[(1,1-dimethyl oxyethyl group) carbonyl] amino]-method reaction that 5-methyl isophthalic acid-(trityl)-1H-imidazoles-4-valeric acid and 4-(difluoro methylene) piperidine hydrochlorate are described according to embodiment 3.2, make hyaloid solid state (S)-[4-[5-methyl isophthalic acid-(trityl)-1H-imidazol-4 yl]-1-[[4-(difluoro methylene) piperidines-1-yl] carbonyl] butyl] carboxylamine 1,1-dimethyl ethyl ester.Yield=75%.Fusing point=86 ℃.
This product is handled with hci gas flow according to the method that embodiment 3.3 describes.Obtain the white powder product.Yield=99%.Fusing point=117 ℃.Embodiment 7 (S)-5-methyl-α-[[4-(methylthio group)-piperidines-1-yl] carbonyl]-1-(trityl)-1H-imidazoles-4-butylamine hydrochloride (1: 1) 7.1 4-(methylthio group) piperidine hydrochlorate 7.1.1 4-[(methylsulfonyl) oxygen] piperidines-1-carboxylic acid 1,1-dimethyl ethyl ester
Under 0 ℃ and the nitrogen, 5.6ml (72mmol) methylsulfonyl chloride is added drop-wise to 13.9g (69mmol) 4-hydroxy piperidine-1-carboxylic acid 1, in the 80ml dichloromethane solution of 1-dimethyl ethyl ester and 5.6ml (76mmol) triethylamine.Reaction mixture was stirred 6 hours under this temperature, then concentrating under reduced pressure.Resistates is added in the 200ml ethyl acetate, successively 2 * 100ml1N hydrochloric acid, 100ml water and the washing of 100ml saturated nacl aqueous solution.With organic layer with dried over sodium sulfate and concentrating under reduced pressure.Resistates by silica gel chromatography, is used eluent ethyl acetate.
Obtain 16.2g white crystals shape product.Yield=95%.Fusing point=93.9 ℃.7.1.2 4-(methylthio group) piperidines-1-carboxylic acid 1,1-dimethyl ethyl ester
With 2.47g (10mmol) 4-[(methylsulfonyl) oxygen] piperidines-1-carboxylic acid 1; the 10ml tetrahydrofuran solution stirring at room of the mixture of 1-dimethyl ethyl ester, 0.71g (10.1mmol) sulfo-sodium methylate and 0.37g (1mmol) tetrabutylammonium iodide 72 hours is then with this mixture concentrating under reduced pressure.Resistates by silica gel chromatography, is used normal hexane: the mixture wash-out of ethyl acetate (9: 1).
Obtain 1.5g thickness oily product.Yield=63%.7.1.3 4-(methylthio group) piperidine hydrochlorate
The method that this compound is described according to embodiment 3.1.3, from 4-(methylthio group) piperidines-1-carboxylic acid 1,1-dimethyl ethyl ester makes.Yield=100%.Fusing point=156.5 ℃.7.2 (S)-5-methyl-α-[[4-(methylthio group) piperidines-1-yl] carbonyl]-1-(trityl)-1H-imidazoles-4-butylamine hydrochloride (1: 1)
With (S)-α-[[(1,1-dimethyl oxyethyl group) carbonyl] amino]-method reaction that 5-methyl isophthalic acid-(trityl)-1H-imidazoles-4-valeric acid and 4-(methylthio group) piperidine hydrochlorate are described according to embodiment 3.2, make amorphous powder (S) [4-[5-methyl isophthalic acid-(trityl)-1H-imidazol-4 yl]-1-[[4-(methylthio group) piperidines-1-yl] carbonyl] butyl] carboxylamine 1,1-dimethyl ethyl ester.Yield=93%.Fusing point=101.2 ℃.
This product is handled with hci gas flow according to the method that embodiment 3.3 describes.Obtain the amorphous powder product.Yield=100%.Fusing point=127.7 ℃.Embodiment 8 (S)-5-methyl-α-[(4-methyl isophthalic acid, 2,3,6-tetrahydrochysene-pyridine-1-yl) carbonyl]-1-(trityl)-1H-imidazoles-4-butylamine hydrochloride (1: 1) 8.1 4-methyl isophthalic acids, 2,3,6-tetrahydrochysene-pyridine hydrochloride 8.1.1 4-methyl isophthalic acid, 2,3,6-tetrahydrochysene-pyridine-1-carboxylic acid 1,1-dimethyl ethyl ester
Under 0 ℃ and the nitrogen, the diethyl ether solution of 18ml (28.8mmol) lithium methide is joined 4.95g (25mmol) 4-oxo-piperidine-1-carboxylic acid 1, continue to stir 2 hours in the 30ml anhydrous tetrahydrofuran solution of 1-dimethyl ethyl ester and under this temperature.Drip 3ml (38mmol) methylsulfonyl chloride, stirred 4 hours down in 0 ℃, then with the reaction mixture concentrating under reduced pressure.Resistates added in the 200ml ethyl acetate and use 2 * 100ml0.1N hydrochloric acid, 100ml water and the washing of 100ml saturated nacl aqueous solution successively.With organic layer with dried over sodium sulfate and concentrating under reduced pressure.Resistates is added in 100ml toluene and the 15ml triethylamine, heated 18 hours down in reflux temperature, then concentrating under reduced pressure.Resistates by silica gel chromatography, is used normal hexane: the mixture wash-out of ether (95: 5).
Obtain 0.9g thickness oily product.Yield=18%.8.1.2 the 4-methyl isophthalic acid, 2,3,6-tetrahydrochysene-pyridine hydrochloride
The method that this compound is described according to embodiment 3.1.3, from the 4-methyl isophthalic acid, 2,3,6-tetrahydrochysene-pyridine-1-formic acid 1,1-dimethyl ethyl ester makes.Yield=100%.8.2 (S)-5-methyl-α-[(4-methyl isophthalic acid, 2,3,6-tetrahydrochysene-pyridine-1-yl) carbonyl]-1-(trityl)-1H-imidazoles-4-butylamine hydrochloride (1: 1)
With (S)-α-[[(1,1-dimethyl oxyethyl group) carbonyl] amino]-5-methyl isophthalic acid-(trityl)-1H-imidazoles-4-valeric acid and 4-methyl isophthalic acid, 2,3,6-tetrahydrochysene-pyridine hydrochloride makes amorphous powder (S)-[4-[5-methyl isophthalic acid-(trityl)-1H-imidazol-4 yl]-1-[(4-methyl isophthalic acid according to the method reaction that embodiment 3.2 describes, 2,3,6-tetrahydrochysene-pyridine-1-yl) carbonyl] butyl] carboxylamine 1,1-dimethyl ethyl ester.Yield=90%.Fusing point=90.7 ℃.
This product is handled with hci gas flow according to the method that embodiment 3.3 describes.Obtain the white powder product.Yield=100%.Fusing point=118 ℃.Embodiment 91-[2-amino-5-[5-methyl isophthalic acid-(trityl)-1H-imidazol-4 yl]-1-oxo amyl group]-six hydrogen-5H-1,4-diaza -5-keto hydrochloride 9.1 6 hydrogen-5H-1,4-diaza -5-keto hydrochloride 9.1.1 1-(phenmethyl)-six hydrogen-5H-1,4-diaza -5-ketone
The acetic acid solution of 9.86g (87.18mmol) hydroxylamine-o-sulfonic acid was joined in 10 minutes in the 60ml formic acid solution of 11g (58.12mmol) 1-phenmethyl piperidines-3-ketone.Reaction mixture was heated 4 hours down in reflux temperature.With mixture cooling and pour in the mixture of ice and water, neutralize with 5% aqueous sodium hydroxide solution then.With chloroform extraction and reclaim organic phase, dryly also be evaporated to dried.Resistates by silica gel chromatography, is used methylene dichloride: the mixture wash-out of methyl alcohol (2: 98).Obtain the 6.94g product.Yield: 58.5%.9.1.2 six hydrogen-5H-1,4-diaza -5-keto hydrochloride
With 5.5g (26.2mmol) 1-(phenmethyl)-six hydrogen-5H-1,4-diaza -5-ketone is dissolved in 100ml methyl alcohol, add 0.7g10% palladium charcoal and with reaction mixture under 0.29MPa (42 pounds/square inch) pressure in 45 ℃ of heating 3 hours.Reaction mixture is filtered, and steaming desolventizes and resistates is added in the 30ml ethanol.Heating, the filtering insolubles desolventizes with ether flushing and steaming.Obtain 2.44g cream-coloured powder shape product and it is directly used in next step reaction.9.2 1-[2-amino-5-[5-methyl isophthalic acid-(trityl)-1H-imidazol-4 yl]-1-oxo amyl group]-six hydrogen-5H-1,4-diaza -5-keto hydrochloride 9.2.1 (S)-[4-[5-methyl isophthalic acid-(trityl)-1H-imidazol-4 yl]-1-[(5-oxo-six hydrogen-5H-1,4-diaza -1-yl) carbonyl] butyl] carboxylamine 1,1-dimethyl ethyl ester
Under 0 ℃, with 2.15g (4mmol) (S)-α-[[(1,1-dimethyl oxyethyl group) carbonyl] amino]-5-methyl isophthalic acid-(trityl)-1H-imidazoles-4-valeric acid, 2.8ml (16mmol) N, N-diisopropylethylamine and 1.5g (4mmol) O-(benzotriazole-1-yl)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate join 0.6g (4mmol) six hydrogen-5H-1 successively, in the 40ml dichloromethane solution of 4-diaza -5-keto hydrochloride.The temperature of reaction mixture is risen to room temperature, under this temperature, continue to stir and spend the night, then with the reaction mixture vacuum concentration.Resistates is added in the 200ml ethyl acetate, use 3 * 30ml1N hydrochloric acid, 2 * 20ml saturated sodium bicarbonate saturated solution and the washing of 20ml saturated nacl aqueous solution successively.With organic layer with dried over mgso and concentrating under reduced pressure.Resistates by silica gel chromatography, is used methylene dichloride: the gradient elution of methyl alcohol (98: 2 to 97: 3).Obtain 1.87g micro white spumescence product.Yield=74%.9.2.2 1-[2-amino-5-[5-methyl isophthalic acid-(trityl)-1H-imidazol-4 yl]-1-oxo amyl group]-six hydrogen-5H-1,4-diaza -5-keto hydrochloride
Under 0 ℃, with 1.87g (2.94mmol) (S)-[4-[5-methyl isophthalic acid-(trityl)-1H-imidazol-4 yl]-1-[(5-oxo-six hydrogen-5H-1,4-diaza -1-yl) carbonyl] butyl] the 200ml toluene solution of carboxylamine 1,1 dimethyl ethyl ester handled for 10 seconds with hci gas flow.The temperature of mixture is risen to room temperature, then with the reaction mixture concentrating under reduced pressure.Resistates is dissolved in the methylene dichloride of minimal volumes and adds the 200ml ether.With the mixture development, filter and drying.Obtain the 1.64g product and it is directly used in next step reaction.Yield=97%.Embodiment 10 (S)-alpha-amino group-N-cyclopentyl-N, 5-dimethyl-1-(trityl)-1H-imidazoles-4-valeramide hydrochloride 10.1N-methyl cyclopentamine hydrochloride 10.1.1N-cyclopentyl methane amide
The mixture of 10g (117mmol) cyclopentamine and 10.8ml (140mmol) ethyl formate was heated 4 hours under reflux temperature, then with the reaction mixture concentrating under reduced pressure.Resistates by silica gel chromatography, is used ethyl acetate: hexanaphthene (1: 9 to 6: 4) gradient elution.Obtain 10g oily product.Yield=75%.10.1.2 cyclopentyl-methyl carboxylamine 1,1-dimethyl ethyl ester
Under 0 ℃ and the nitrogen, the tetrahydrofuran solution of 50ml (50mmol) 1M lithium aluminium hydride is added drop-wise in the 20ml anhydrous tetrahydrofuran solution of 4.37g (38mmol) N-cyclopentyl methane amide.The temperature of mixture is risen to room temperature and reaction mixture was heated 8 hours under reflux temperature.The reaction medium thing is cooled to 0 ℃ also uses the 1N hcl acidifying, pH is transferred to 8 with salt of wormwood to pH2.Drip the 40ml methanol solution of 8.6g (40mmol) two carbonic acid two (1, the 1-dimethyl ethyl) ester then.The temperature of mixture is risen to room temperature and continue stirring 15 hours under this temperature.Reaction mixture is merged with 2 * 300ml extracted with diethyl ether and with organic phase.It with the washing of 2 * 200ml1N aqueous hydrochloric acid, is washed with the 200ml saturated nacl aqueous solution then.With the organic phase dried over sodium sulfate that merges, filter and concentrating under reduced pressure.Resistates by silica gel chromatography, is used hexanaphthene: the mixture wash-out of ether (95: 5).Obtain 2.91g oily product.Yield=38%.10.1.3N-methyl cyclopentamine hydrochloride
With 2.9g (14.5mmol) cyclopentyl-methyl carboxylamine 1, the solution of 1-dimethyl ethyl ester was handled 5 minutes down at 0 ℃ with hci gas flow.This mixture was stirred 4 hours under this temperature, then concentrating under reduced pressure.Obtain 1.96g white hygroscopic powder shape product.Yield=100%.Fusing point=123-126 ℃.10.2 (S)-alpha-amino group-N-cyclopentyl-N, 5-dimethyl-1-(trityl)-1H-imidazoles-4-valeramide hydrochloride 10.2.1 (S)-[1-[(cyclopentyl-methyl amino) carbonyl]-4-[5-methyl isophthalic acid-(trityl) 1H-imidazol-4 yl] butyl] carboxylamine 1,1-dimethyl ethyl ester
Under 0 ℃ and the nitrogen, with 0.68g (5mmol) N-methyl cyclopentamine hydrochloride, 2.15ml (12.3mmol) N, N-diisopropylethylamine and 1.98g (5.24mmol) 0-(benzotriazole-1-yl)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate join successively 2.57g (4.76mmol) (S)-the 15ml dichloromethane solution of α-[[(1,1-dimethyl oxyethyl group) carbonyl] amino]-5-methyl isophthalic acid-(trityl)-1H-imidazoles-4-valeric acid in.The temperature of reaction medium is risen to room temperature, under this temperature, continue to stir 15 hours, then with the reaction mixture vacuum concentration.Resistates is added in the 150ml ethyl acetate, successively with 100ml1N aqueous hydrochloric acid, 100ml saturated sodium bicarbonate solution and the washing of 100ml saturated nacl aqueous solution.With organic layer with dried over sodium sulfate and concentrating under reduced pressure.Resistates by silica gel chromatography, is used ethyl acetate: the gradient elution of hexanaphthene (3: 7 to 8: 2).Obtain 2.26g amorphous solid product.Yield=77%.Fusing point=86-90 ℃.10.2.2 (S)-and alpha-amino group-N-cyclopentyl-N, 5-dimethyl-1-(trityl)-1H-imidazoles-4-valeramide hydrochloride
Under 0 ℃, with 2.2g (3.5mmol) (S)-[1-[(cyclopentyl-methyl amino) carbonyl]-4-[5-methyl isophthalic acid-(trityl)-1H-imidazol-4 yl] butyl] carboxylamine 1, the solution of 1-dimethyl ethyl ester was handled 5 minutes with hci gas flow.Mixture is stirred 5 hours concentrating under reduced pressure then under this temperature.Obtain the 2g product and it is directly used in next step reaction.Yield=100%.Fusing point=138-142 ℃.Embodiment 11 (S)-alpha-amino group-N, 5-dimethyl-N-tetramethyleneimine-1-base-1-(trityl)-1H-imidazoles-4-valeramide hydrochloride 11.1 N-methylpyrrolidin-1-amine hydrochlorate 11.1.1 tetramethyleneimine-1-aminocarbamic acids 1,1-dimethyl ethyl ester
1.13ml (8.15mmol) triethylamine is added drop-wise in the 8ml dichloromethane solution of 1g (8.15mmol) tetramethyleneimine-1-amine hydrochlorate and 1.62g (7.4mmol) two carbonic acid two (1, the 1-dimethyl ethyl) ester.Mixture is stirred 15 hours concentrating under reduced pressure then.Resistates is added in the 100ml ether, successively with 10ml water and the washing of 100ml saturated sodium-chloride water solution.With the organic layer dried over sodium sulfate, filter and concentrating under reduced pressure with silicon-dioxide.Obtain the 1g product.Yield=67%.Fusing point=108 ℃.11.1.2 methylpyrrolidin-1-aminocarbamic acid 1,1-dimethyl ethyl ester
Under-78 ℃ and the nitrogen, the tetrahydrofuran solution of 7.7ml (7.7mmol) 1M two (TMS) amido lithium is added drop-wise to 1.34g (7mmol) tetramethyleneimine-1-aminocarbamic acid 1, in the 3ml anhydrous tetrahydrofuran solution of 1-dimethyl ethyl ester and 1.75ml (28mmol) methyl iodide.The temperature of mixture is risen to room temperature and under this temperature, stirred 30 minutes.Add the 150ml ether, successively with 100ml water and the washing of 100ml saturated sodium-chloride water solution.With the organic layer dried over sodium sulfate, filter and concentrating under reduced pressure.Resistates by silica gel chromatography, is used hexanaphthene: ethyl acetate (9: 1) mixture wash-out.Obtain 0.75g oily product.Yield=55%.11.1.3N-methylpyrrolidin-1-amine hydrochlorate
The method that this product is described according to embodiment 10.1.3, from 0.75g (3.7mmol) methylpyrrolidin-1-aminocarbamic acid 1,1-dimethyl ethyl ester makes.Obtain 0.5g thickness oily product.Yield=100%.11.2 (S)-alpha-amino group-N, 5-dimethyl-N-tetramethyleneimine-1-base-1-(trityl)-1H-imidazoles-4-valeramide hydrochloride 11.2.1 (S)-[1-[(methylpyrrolidin-1-base is amino) carbonyl]-4-[5-methyl isophthalic acid-(trityl)-1H-imidazol-4 yl] butyl] carboxylamine 1,1-dimethyl ethyl ester
The method that this product is described according to embodiment 10.2.1, from 1.8g (3.3mmol) (S)-α-[[(1,1-dimethyl oxyethyl group) carbonyl] amino]-5-methyl isophthalic acid-(trityl)-1H-imidazoles-4-valeric acid and 0.48g (3.5mmol) N-methylpyrrolidin-1-amine hydrochlorate make.Obtain 1.8g amorphous solid shape product.Yield=88%.Fusing point=70-75 ℃.11.2.2 (S)-and alpha-amino group-N, 5-dimethyl-N-tetramethyleneimine 1 base-1-(trityl)-1H-
Imidazoles-4-valeramide hydrochloride
The method that this product is described according to embodiment 10.2.2, from 1.8g (2.8mmol) (S)-[1-[(methylpyrrolidin-1-base is amino) carbonyl]-4-[5-methyl isophthalic acid-(trityl)-1H-imidazol-4 yl] butyl] carboxylamine 1,1-dimethyl ethyl ester makes.Obtain 1.65g amorphous solid shape product.Yield=100%.Fusing point=130-135 ℃.Embodiment 12 (compound number 67) (S)-N-[3-[[[4-(5-ethyl-1H-imidazol-4 yl)-1-[(4-ethyl piperidine-1-yl) carbonyl] butyl] amino] alkylsulfonyl] [1; 1 '-phenylbenzene]-the 2-yl] propionamide hydrochloride (1: 1) 12.1 (S)-N-[3-[[[1-(4-ethyl piperidine-1-yl) carbonyl]-4-[5-ethyl-1-(trityl)-1H-imidazol-4 yl] butyl] amino] alkylsulfonyl] [1,1 '-phenylbenzene]-2-yl]-N-(1-oxo-propyl group) propionic acid amide
Under 0 ℃ and the nitrogen, with 0.48ml (3.4mmol) triethylamine be added drop-wise to 0.435g (1.25mmol) [two (1-oxo-propyl group) amino]-[1,1 '-phenylbenzene]-3-SULPHURYL CHLORIDE and 0.61g (1.04mmol) (S)-the 8ml dichloromethane solution of the mixture of 5-ethyl-α-[(4-ethyl piperidine-1-yl) carbonyl]-1-(trityl)-1H-imidazoles-4-butylamine hydrochloride in.This mixture is stirred 4 hours concentrating under reduced pressure then.Resistates is added in the 100ml ethyl acetate, successively with 50ml1N hydrochloric acid, 50ml saturated sodium bicarbonate solution and the washing of 50ml saturated nacl aqueous solution, with dried over mgso and concentrating under reduced pressure.Obtain 0.85g thickness oily product and it is directly used in next step reaction.Yield=95%.12.2 (S)-and N-[3-[[[4-(5-ethyl-1H-imidazol-4 yl)-1-[(4-ethyl piperidine-1-yl) carbonyl] butyl] amino] alkylsulfonyl] [1,1 '-phenylbenzene]-2-yl] propionamide hydrochloride (1: 1)
With 0.85g (0.95mmol) (S)-N-[3-[[[1-(4-ethyl piperidine-1-yl) carbonyl]-4-[5-ethyl-1-(trityl)-1H-imidazol-4 yl] butyl] amino] alkylsulfonyl] [1; 1 '-phenylbenzene]-the 2-yl]-N-(1-oxo-propyl group) propionic acid amide is dissolved in the mixture of 30ml acetate and 10ml water and this solution heated 16 hours under reflux temperature, then with the reaction mixture concentrating under reduced pressure.Resistates is added in the 150ml ethyl acetate, successively with 50ml saturated sodium bicarbonate solution and the washing of 50ml saturated nacl aqueous solution, with dried over sodium sulfate and concentrating under reduced pressure.Resistates by silica gel chromatography, is used methyl alcohol: the mixture wash-out of methylene dichloride (4: 96).
Obtain the product of 0.44g alkali form, add in the aqueous isopropanol of 10ml0.1N hydrogenchloride it and concentrating under reduced pressure.Resistates is separated in the enterprising circumstances in which people get things ready for a trip spectrum of RP18 post, use acetonitrile: the mixture wash-out of water (3: 7).Obtain 0.42g white powder product after the lyophilize.Yield=69%.Fusing point=132 ℃.[α]
D 20=+112 °; (c=0.2, methyl alcohol).Embodiment 13 (compound number 40) (S)-N-[3-[[[4-(5-methyl isophthalic acid H-imidazol-4 yl)-1-[[4-(trifluoromethyl) piperidines-1-yl] carbonyl] butyl] amino] alkylsulfonyl] [1; 1 '-phenylbenzene]-the 2-yl] propionamide hydrochloride (1: 1) 13.1 (S)-N-[3-[[[4-(5-methyl isophthalic acid-(trityl)-1H-imidazol-4 yl]-1-[[4-(trifluoromethyl) piperidines-1-yl] carbonyl] butyl] amino] alkylsulfonyl] [1,1 '-phenylbenzene]-2-yl]-N-(1-oxo-propyl group) propionic acid amide
Under 0 ℃ and the hydrogen, with 0.79ml (5.7mmol) triethylamine be added drop-wise to 0.65g (1.72mmol) [two (1-oxo-propyl group) amino]-[1,1 '-phenylbenzene]-3-SULPHURYL CHLORIDE and 1.05g (1.72mmol) (S)-the 20ml dichloromethane solution of the mixture of 5-methyl-α-[[4-(trifluoromethyl) piperidines-1-yl] carbonyl]-1-(trityl)-1H-imidazoles-4-butylamine hydrochloride in.The temperature of mixture is risen to room temperature, under this temperature, continue to stir 18 hours, then with the reaction mixture concentrating under reduced pressure.Resistates is added in the 100ml ethyl acetate, successively with 50ml1N aqueous hydrochloric acid, 50ml saturated sodium bicarbonate solution and the washing of 50ml saturated nacl aqueous solution, with dried over sodium sulfate and concentrating under reduced pressure.Resistates by silica gel chromatography, is used methyl alcohol: the mixture wash-out of methylene dichloride (2: 98).Obtain 1.04g thickness oily product.Yield=70%.13.2 (S)-and N-[3-[[[4-(5-methyl isophthalic acid H-imidazol-4 yl)-1-[[4-(trifluoromethyl) piperidines-1-yl] carbonyl] butyl] amino] alkylsulfonyl] [1,1 '-phenylbenzene]-2-yl] propionamide hydrochloride (1: 1)
With 1.02g (1.1mmol) (S)-N-[3-[[[4-(5-methyl isophthalic acid-(trityl)-1H-imidazol-4 yl]-1-[[4-(trifluoromethyl) piperidines-1-yl] carbonyl] butyl] amino] alkylsulfonyl] [1; 1 '-phenylbenzene]-the 2-yl]-N-(1-oxo-propyl group) propionic acid amide is dissolved in the mixture of 25ml acetate and 25ml water and this solution heated 10 hours under reflux temperature, then with the reaction mixture concentrating under reduced pressure.Resistates is added in the 100ml ethyl acetate, with the washing of 50ml saturated sodium bicarbonate solution, with dried over sodium sulfate and concentrating under reduced pressure.Resistates by silica gel chromatography, is used methyl alcohol: the mixture wash-out of methylene dichloride (5: 95).Obtain the product of 0.42g alkali form, add in the aqueous isopropanol of 12ml0.1N hydrogenchloride it and concentrating under reduced pressure.Resistates is separated in the enterprising circumstances in which people get things ready for a trip spectrum of RP18 post, use acetonitrile: the mixture wash-out of water (3: 7).Obtain the 0.33g product after the lyophilize.Yield=46%.Fusing point=146-150 ℃.[α]
D 20=+80 °; (c=0.2, methyl alcohol).Embodiment 14 (compound number 34) (S)-N-[2-[[[1-[(4-methoxyl group piperidines-1-yl) carbonyl]-4-(5-methyl isophthalic acid H-imidazol-4 yl)-butyl] amino] alkylsulfonyl]-6-thiophene-2-base phenyl]-propionamide hydrochloride (1: 1) 14.1 (S)-1-[2-(3-ethyls-1; 1-dioxo-5-thiophene-2-base-2H-1; 2,4-benzothiadiazine-2-yl)-5-[5-methyl isophthalic acid-(trityl)-1H-imidazol-4 yl]-1-oxo-amyl group]-4-methoxyl group piperidinyl-1 4.1.1 2-[(1-chlorine propylidene) amino]-3-thiophene-2-base-benzene sulfonyl chloride
Under 0 ℃, 2.86ml (33mmol) propionyl chloride is added drop-wise in the 30ml dichloromethane solution of mixture of 3.8g (15mmol) 2-amino-3-(thiophene-2-yl) Phenylsulfonic acid and 4ml (49.5mmol) pyridine.Reaction mixture is stirred 5 hours concentrating under reduced pressure then under this temperature.Resistates is added in the 40ml methylene dichloride, add 7.8g (37.5mmol) phosphorus pentachloride in batches and also this mixture was stirred 1 hour down in 0 ℃, stirring at room is 2 hours then.Add the 200ml ether to reaction mixture, filter and filtrate is used 2 * 200ml frozen water and the washing of 50ml saturated nacl aqueous solution successively, with dried over sodium sulfate and concentrating under reduced pressure.With resistates at Florisil
Last chromatographic separation is carried out purifying, with the rapid wash-out of ether.
With obtaining the 3.18g product after the pentane crystallization.Yield=61%.Fusing point=74 ℃.14.1.2 (S)-1-[2-(3-ethyl-1,1-dioxo-5-thiophene-2-base-2H-1,2,4-benzothiadiazine-2-yl)-5-[5-methyl isophthalic acid-(trityl)-1H-imidazol-4 yl]-1-oxo-amyl group]-4-methoxyl group piperidines
Under 0 ℃, 0.55ml (3.96mmol) triethylamine is added drop-wise to 0.42g (1.2mmol) 2-[(1-chlorine propylidene) amino]-3-thiophene-2-base-benzene sulfonyl chloride and 0.69g (1.2mmol) (S)-the 15ml dichloromethane solution of the mixture of α-[(4-methoxyl group piperidines-1-yl) carbonyl]-5-methyl isophthalic acid-(trityl)-1H-imidazoles-4-butylamine hydrochloride in.The temperature of mixture is risen to room temperature, under this temperature, continue to stir 18 hours, then with the reaction mixture concentrating under reduced pressure.Resistates is added in the 100ml ethyl acetate, successively with 50ml1N aqueous hydrochloric acid, 50ml saturated sodium bicarbonate solution and the washing of 50ml saturated nacl aqueous solution, with dried over sodium sulfate and concentrating under reduced pressure.Obtain 1.07g thickness oily product and it is directly used in next step reaction.Yield=100%.14.2 (S)-and N-[2-[[[1-[(4-methoxyl group piperidines-1-yl) carbonyl]-4-(5-methyl isophthalic acid H-imidazol-4 yl)-butyl] amino] alkylsulfonyl]-6-thiophene-2-base phenyl]-propionamide hydrochloride (1: 1)
With 1.07g (1.2mmol) (S)-1-[2-(3-ethyl-1,1-dioxo-5-thiophene-2-base-2H-1,2,4-benzothiadiazine-2-yl)-5-[5-methyl isophthalic acid-(trityl)-1H-imidazol-4 yl]-1-oxo amyl group]-4-methoxyl group piperidines is dissolved in the mixture of 50ml acetate and 50ml water and this solution heated 6 hours under reflux temperature, then with the reaction mixture concentrating under reduced pressure.Resistates is added in the 150ml ethyl acetate, successively with 50ml saturated sodium bicarbonate solution and the washing of 50ml saturated nacl aqueous solution, with dried over sodium sulfate and concentrating under reduced pressure.Resistates by silica gel chromatography, is used methyl alcohol: the mixture wash-out of methylene dichloride (5: 95).Obtain the product of 0.43g alkali form, add in the 12ml0.1N hydrochloric acid aqueous isopropanol it and concentrating under reduced pressure.Resistates is separated in the enterprising circumstances in which people get things ready for a trip spectrum of RP18 post, use acetonitrile: the mixture wash-out of water (3: 7).Obtain 0.34g white powder product after the lyophilize.Yield=45%.Fusing point=126 ℃.[α]
D 20=+87 °; (c=0.2, methyl alcohol).Embodiment 15 (compound number 47) (S)-N-[2-[[[4-(5-methyl isophthalic acid H-imidazol-4 yl)-1-[(4-methylenepiperidines-1-yl) carbonyl] butyl] amino] alkylsulfonyl]-6-thiophene-2-base phenyl]-propionamide hydrochloride (1: 1)
The method that this compound is described according to embodiment 14 is from (S)-5-methyl-α-[(4-methylenepiperidines-1-yl) carbonyl]-1-(trityl)-1H-imidazoles-4-butylamine hydrochloride and 2-[(1-chlorine propylidene) amino]-3-thiophene-2-base-benzene sulfonyl chloride makes.Fusing point=115-120 ℃.[α]
D 20=+54 °; (c=0.2, methyl alcohol).Embodiment 16 (compound number 45) (S)-N-[2-[[[1-[(4-cyclopropyl piperidine-1-yl) carbonyl]-4-(5-methyl isophthalic acid H-imidazol-4 yl)-butyl] amino] alkylsulfonyl]-6-thiophene-2-base phenyl]-propionamide hydrochloride (1: 1) 16.1 (S)-4-cyclopropyl-1-[2-(3-ethyls-1; 1-dioxo-5-thiophene-2-base 2H-1; 2,4-benzothiadiazine-2-yl)-5-[5-methyl isophthalic acid-(trityl)-1H-imidazoles-4-yl]-1-oxo amyl group] piperidines
Under 0 ℃, 0.5ml (3.63mmol) triethylamine is added drop-wise to 0.38g (1.1mmol) 2-[(1-chlorine propylidene) amino]-3-thiophene-2-base-benzene sulfonyl chloride and 0.64g (1.1mmol) (S)-the 20ml dichloromethane solution of the mixture of α-[(4-cyclopropyl piperidine-1-yl) carbonyl]-5-methyl isophthalic acid-(trityl)-1H-imidazoles-4-butylamine hydrochloride in.The temperature of mixture is risen to room temperature, under this temperature, continue to stir 2 hours, then with the reaction mixture concentrating under reduced pressure.Resistates is added in the 100ml ethyl acetate, successively with 50ml1N aqueous hydrochloric acid, 50ml saturated sodium bicarbonate solution and the washing of 50ml saturated nacl aqueous solution, with dried over sodium sulfate and concentrating under reduced pressure.Obtain 1.1g thickness oily product and it is directly used in next step reaction.Yield=100%.16.2 (S)-and N-[2-[[[1-[(4-cyclopropyl piperidine-1-yl) carbonyl]-4-(5-methyl isophthalic acid H-imidazol-4 yl)-butyl] amino] alkylsulfonyl]-6-thiophene-2-base phenyl]-propionamide hydrochloride (1: 1)
With 1.1g (1.1mmol) (S)-4-cyclopropyl-1-[2-(3-ethyl-1,1-dioxo-5-thiophene-2-base-2H-1,2,4-benzothiadiazine-2-yl)-5-[5-methyl isophthalic acid-(trityl)-1H-imidazol-4 yl]-1-oxo amyl group] piperidines is dissolved in the mixture of 25ml acetate and 25ml water and this solution heated 4 hours under reflux temperature, then with the reaction mixture concentrating under reduced pressure.Resistates is added in the 150ml ethyl acetate, successively with 50ml saturated sodium bicarbonate solution and the washing of 50ml saturated nacl aqueous solution, with dried over sodium sulfate and concentrating under reduced pressure.Resistates by silica gel chromatography, is used methyl alcohol: the mixture wash-out of methylene dichloride (2: 98 to 8: 92).Obtain the product of 0.528g alkali form.Yield=80%.
0.528g alkali is added in the aqueous isopropanol of 10ml0.1N hydrogenchloride and concentrating under reduced pressure.Resistates is separated in the enterprising circumstances in which people get things ready for a trip spectrum of RP18 post, use acetonitrile: the mixture wash-out of water (3: 7).Obtain 0.27g white powder product after the lyophilize.Yield=39%.Fusing point=108-110 ℃.[α]
D 20=+98 °; (c=0.2, methyl alcohol).Embodiment 17 (compound number 20) (S)-N-[3 '-(ethylamino)-3-[[[1-[(4-ethyl-piperidines-1-yl) carbonyl]-4-(5-methyl isophthalic acid H-imidazol-4 yl) butyl] amino] alkylsulfonyl]-[1; 1 '-phenylbenzene]-the 2-yl] propionamide hydrochloride (1: 2) 17.1 (S)-1-[2-[7-bromo-3-ethyl-5-(3-nitrophenyl)-1; 1-dioxo-2H-1; 2; 4-benzothiadiazine-2-yl)-5-[5-methyl isophthalic acid-(trityl)-1H-imidazoles-4-yl]-1-oxo amyl group]-4-ethyl piperidine 17.1.1 5-bromo-2-[(1-chlorine cyclopropylidene) amino]-3 '-nitro [1; 1 '-phenylbenzene]-a) 5-bromo-3 '-nitro-2-[(1-oxopropyl of 3-SULPHURYL CHLORIDE) amino] pyridinium salt of [1,1 '-phenylbenzene]-3-sulfonic acid
Under 0 ℃ and nitrogen atmosphere, 1.62ml (18.6mmol) propionyl chloride is added drop-wise in the 10ml dichloromethane solution of 3.15g (8.45mmol) 2-amino-5-bromo-3 '-nitro [1,1 '-phenylbenzene]-3-sulfonic acid and 2.4ml (29.6mmol) pyridine.The temperature of mixture is risen to room temperature and continues stirring 18 hours.With the reaction mixture concentrating under reduced pressure.Resistates is directly used in next step reaction.B) amino 5-bromo-2-[(1-chlorine cyclopropylidene)]-3 '-nitro [1,1 '-phenylbenzene]-3-SULPHURYL CHLORIDE
The above resistates that obtains is dissolved in the 20ml methylene dichloride and adds 4.6g (21.2mmol) phosphorus pentachloride under 0 ℃ and nitrogen atmosphere.The temperature of mixture is risen to room temperature and mixture is continued stirring 5 hours under this temperature.Add in the 150ml ether with the reaction mixture concentrating under reduced pressure and with resistates, filter with agglomerating glass.Filtrate is used 2 * 100ml water and the washing of 100ml saturated nacl aqueous solution successively, with dried over mgso and concentrating under reduced pressure.Obtain the transparent oily product of 3g and it is directly used in next step reaction.Yield=77%.17.1.2 (S)-and 1-[2-[7-bromo-3-ethyl-5-(3-nitrophenyl)-1,1-dioxo-2H-
1,2,4-benzothiadiazine-2-yl)-5-[5-methyl isophthalic acid-(trityl)-1H-imidazoles
-4-yl]-1-oxo-amyl group]-the 4-ethyl piperidine
Under 0 ℃, 0.42ml (3.5mmol) triethylamine is added drop-wise to 0.53g (1.15mmol) 5-bromo-2-[(1-chlorine propylidene) amino]-3 '-nitro [1,1 '-phenylbenzene]-3-SULPHURYL CHLORIDE and 0.58g (1.02mmol) (S)-the 5ml dichloromethane solution of the mixture of α-[(4-ethyl piperidine-1-yl) carbonyl]-5-methyl isophthalic acid-(trityl)-1H-imidazoles-4-butylamine hydrochloride in.The temperature of mixture is risen to room temperature, under this temperature, continue to stir 18 hours, then with the reaction mixture concentrating under reduced pressure.Resistates is added in the 100ml ethyl acetate, successively with 50ml1N aqueous hydrochloric acid, 50ml saturated sodium bicarbonate solution and the washing of 50ml saturated nacl aqueous solution, with dried over sodium sulfate and concentrating under reduced pressure.Obtain 1g thickness oily product and it is directly used in next step reaction.Yield=100%.17.2 (S)-and N-[5-bromo-3-[[[1-[(4-ethyl piperidine-1-yl) carbonyl]-4-(5-methyl-1H-imidazol-4 yl) butyl] amino] alkylsulfonyl]-3 '-nitro [1,1 '-phenylbenzene]-2 bases] propionic acid amide
With 1g (1mmol) (S)-1-[2-[7-bromo-3-ethyl-5-(3-nitrophenyl)-1,1-dioxo-2H-1,2,4-benzothiadiazine-2-yl)-5-[5-methyl isophthalic acid-(trityl)-1H-imidazol-4 yl]-1-oxo amyl group]-the 4-ethyl piperidine is dissolved in the mixture of 30ml acetate and 20ml water and this solution heated 8 hours under reflux temperature, then with the reaction mixture concentrating under reduced pressure.Resistates is added in the 100ml ethyl acetate, with the washing of 50ml saturated sodium bicarbonate solution, with dried over sodium sulfate and concentrating under reduced pressure.Resistates by silica gel chromatography, is used methyl alcohol: the mixture wash-out of methylene dichloride (5: 95).Obtain 0.42g white solid product.Yield=60%.Fusing point=215 ℃.17.3 (S)-and N-[3 ' amino-3-[[[1-[(4-ethyl piperidine-1-yl) carbonyl]-4-(5-methyl isophthalic acid H-imidazol-4 yl) butyl] amino] alkylsulfonyl] [1,1 '-phenylbenzene]-2-yl] propionic acid amide
With 0.4g (0.56mmol) (S)-N-[5-bromo-3-[[[1-[(4-ethyl piperidine-1-yl) carbonyl]-4-(5-methyl isophthalic acid H-imidazol-4 yl) butyl] amino] alkylsulfonyl]-3 '-nitro [1,1 '-phenylbenzene]-2-yl] the 20ml ethanolic soln of propionic acid amide is hydrogenation in the presence of the 0.1g10% palladium charcoal, under 0.35MPa (50 pounds/square inch) pressure and room temperature 10 hours.Reaction mixture is concentrated with diatomite filtration and with filtrate decompression.Resistates is added in the 100ml ethyl acetate, with the washing of 50ml saturated sodium bicarbonate solution, with dried over sodium sulfate and concentrating under reduced pressure.Obtain 0.33g white solid product.Yield=100%.Fusing point=160 ℃.17.4 (S)-and N-[3 '-(ethylamino)-3-[[[1-[(4-ethyl-piperidines-1-yl) carbonyl]-4-(5-methyl isophthalic acid H-imidazol-4 yl) butyl] amino] alkylsulfonyl]-[1,1 '-phenylbenzene]-2-yl] propionamide hydrochloride (1: 2)
With 0.043ml (0.78mmol) acetaldehyde and 70mg10% palladium charcoal join 0.33g (0.56mmol) (S)-N-[3 '-amino-3-[[[1-[(4-ethyl piperidine-1-yl) carbonyl]-4-(5-methyl isophthalic acid H-imidazol-4 yl) butyl] amino] alkylsulfonyl] [1,1 '-phenylbenzene]-2 bases] in the 10ml ethanolic soln of propionic acid amide and with this mixture stirring at room 8 hours under 0.35MPa (50 pounds/square inch) pressure.With the reaction mixture diatomite filtration, the aqueous isopropanol of adding 4ml0.1N hydrogenchloride and filtrate decompression is concentrated in filtrate.Resistates is separated in the enterprising circumstances in which people get things ready for a trip spectrum of RP18 post, use acetonitrile: the mixture wash-out of water (3: 7).Obtain 0.2g white powder product after the lyophilize.Yield=53%.Fusing point=163 ℃.[α]
D 20=+130 °; (c=0.2, methyl alcohol).Embodiment 18 (compound number 29) (S)-N-[3-[[[1-[(4-ethyl piperidine-1-yl) carbonyl]-4-(5-methyl isophthalic acid H-imidazol-4 yl) butyl] amino] alkylsulfonyl] [1; 1 '-phenylbenzene]-the 2-yl]-2-(2-methoxy ethoxy) acetamide hydrochloride (1: 1) 18.1 (S)-2-amino-N-[1-[(4-ethyl piperidine-1-yl) carbonyl]-4-[5-methyl isophthalic acid-(trityl)-1H-imidazol-4 yl] butyl] [1,1 '-phenylbenzene]-3-sulphonamide
Under 0 ℃ and the argon atmospher, with 0.365ml (2.61mmol) triethylamine be added drop-wise to 0.5g (0.87mmol) (S)-the 10ml dichloromethane solution of the mixture of 5-ethyl-α-[(4-ethyl piperidine-1-yl) carbonyl]-1-(trityl)-1H-imidazoles-4-butylamine hydrochloride and 0.281g (1.05mmol) 2-amino [1,1 '-phenylbenzene]-3-SULPHURYL CHLORIDE in.Mixture was stirred 1 hour under this temperature, then concentrating under reduced pressure.Resistates is added in the 50ml ethyl acetate, with 20ml1N hydrochloric acid, 20ml saturated sodium bicarbonate solution and the washing of 20ml saturated nacl aqueous solution, use dried over mgso then successively.At last, organic phase is filtered and be concentrated into dried.Resistates by silica gel chromatography, is used methyl alcohol: the mixture wash-out of methylene dichloride (1: 99 to 3: 97).Obtain 0.53g white solid product.Yield=79%.18.2 (S)-and N-[3-[[[1-[(4-ethyl piperidine-1-yl) carbonyl]-4-(5-methyl isophthalic acid H-imidazol-4 yl) butyl] amino] alkylsulfonyl] [1,1 '-phenylbenzene]-2-yl]-2-(2-methoxy ethoxy) acetamide hydrochloride (1: 1)
Under room temperature and argon atmospher, with 2g (13mmol) 2-(2-methoxy ethoxy) Acetyl Chloride 98Min. join 1g (1.3mmol) (S)-2-amino-N-[1-[(4 ethyl piperidine-1-yl) carbonyl]-4[5-methyl isophthalic acid-(trityl)-1H-imidazol-4 yl] butyl] in the solution of 10ml N,N-DIMETHYLACETAMIDE of [1,1 '-phenylbenzene]-3-sulphonamide.Reaction mixture was stirred 0.5 hour under this temperature, cool off with ice bath then.Add 100ml ethyl acetate and 100ml1N aqueous hydrochloric acid and reclaim organic phase.It is washed with 50ml saturated sodium bicarbonate solution and 50ml saturated nacl aqueous solution successively, then vacuum concentration.Resistates is added acetate: water: in the mixture of tetrahydrofuran (THF) (2: 1: 1), this mixture is heated 3 hours vacuum concentration then in 80 ℃.Resistates is added in the 100ml ethyl acetate, with 50ml1N hydrochloric acid soln, 50ml saturated sodium bicarbonate solution and the washing of 50ml saturated nacl aqueous solution, use dried over mgso then successively.At last, organic phase is filtered and vacuum concentration.Resistates by silica gel chromatography, is used methylene dichloride: the mixture wash-out of methyl alcohol (then be 90: 10 at 98: 2).Obtain the product of 0.54g alkali form.In 10ml0.1N hydrochloric acid aqueous isopropanol, prepare hydrochloride.After the lyophilize, obtain the 0.57g product.Yield=64.6%.Fusing point=98 ℃.[α]
D 20=+55.5 °; (c=0.2, methyl alcohol).Embodiment 19 (compound number 30) (S)-N-[2-cyclopentyl-6-[[[1-[(4-ethyl piperidine-1-yl) carbonyl]-4-(5-methyl isophthalic acid H-imidazol-4 yl) butyl] amino] alkylsulfonyl]-phenyl]-N '-ethyl carbamide hydrochloride (1: 1) 19.1 (S)-2-amino-3-cyclopentyl-N-[1-[(4-ethyl piperidine-1-yl) carbonyl]-4-[5-methyl isophthalic acid-(trityl)-1H-imidazol-4 yl] butyl] benzsulfamide
Under 0 ℃, with 0.95ml (6.75mmol) triethylamine be added drop-wise to 0.70g (2.7mmol) 2-amino-3-cyclopentyl benzene sulfonyl chloride and 1.54g (2.7mmol) (S)-the 6ml dichloromethane solution of the mixture of 5-methyl-α-[(4-ethyl piperidine-1-yl) carbonyl]-1-(trityl)-1H-imidazoles-4-butylamine hydrochloride in.Reaction mixture was stirred 5 hours under this temperature, then concentrating under reduced pressure.Resistates is added in the 100ml ethyl acetate, successively with 50ml1N hydrochloric acid soln, 50ml saturated sodium bicarbonate solution and the washing of 50ml saturated nacl aqueous solution, with dried over mgso and concentrating under reduced pressure.Resistates by silica gel chromatography, is used methylene dichloride: the mixture wash-out of methyl alcohol (98: 2).Obtain 1.8g thickness oily product.Yield=88%.19.2 (S)-and N-[2-cyclopentyl-6-[[[1-[(4-ethyl piperidine-1-yl) carbonyl]-4-[5-methyl isophthalic acid-(trityl)-1H-imidazol-4 yl] butyl] amino] alkylsulfonyl]-phenyl]-N '-ethyl carbamide
With 0.75g (1mmol) (S)-2-amino-3-cyclopentyl-N-[1-[(4-ethyl piperidine-1-yl) carbonyl]-4-[5-methyl isophthalic acid-(trityl)-1H-imidazol-4 yl] butyl] dimethyl formamide solution of benzsulfamide and 0.32ml (4mmol) ethyl isocyanate is in 50 ℃ of heating 38 hours, then with the reaction mixture concentrating under reduced pressure.The resistates that obtains is passed through silica gel chromatography, use methyl alcohol: the mixture wash-out of methylene dichloride (2: 98).Obtain 0.53g white solid product.Yield=65%.Fusing point=115 ℃.19.3 (S)-and N-[2-cyclopentyl-6-[[[1-[(4-ethyl piperidine-1-yl) carbonyl]-4-(5-methyl isophthalic acid H-imidazol-4 yl) butyl] amino] alkylsulfonyl] phenyl]-N '-ethyl carbamide hydrochloride (1: 1)
With 0.53g (0.64mmol) (S)-N-[2-cyclopentyl-6-[[[1-[(4-ethyl piperidine-1-yl) carbonyl]-4-[5-methyl isophthalic acid-(trityl)-1H-imidazol-4 yl] butyl] amino] alkylsulfonyl] phenyl]-mixture of N '-ethyl carbamide and 0.2g10% palladium charcoal adds in the propanol solution of 8ml0.1N hydrochloric acid and with its stirring at room 40 hours under 0.35MPa (50 pounds/square inch) pressure.Mixture is concentrated with diatomite filtration and with filtrate decompression.Resistates chromatographic separation on the RP18 post is carried out purifying, use acetonitrile: the mixture wash-out of water (4: 6).Obtain the 0.30g product after the lyophilize.Yield=77%.Fusing point=147 ℃.[α]
D 20=+86 °; (c=0.2, methyl alcohol).Embodiment 20 (compound number 70) (S)-N-[3-[[[4-(5-chloro-1H-imidazol-4 yl)-1-[(4-ethyl piperidine-1-yl) carbonyl] butyl] amino] alkylsulfonyl] [1; 1 '-phenylbenzene]-the 2-yl] propionamide hydrochloride (1: 1) 20.1 (S)-N-[3-[[[1-(4-ethyl piperidine-1-yl) carbonyl]-4-(1H-imidazol-4 yl) butyl] amino] alkylsulfonyl] [1; 1 '-phenylbenzene]-the 2-yl] propionic acid amide 20.1.1 2-[(1-chlorine propylidene) amino] [1,1 '-phenylbenzene]-3-SULPHURYL CHLORIDE
Method according to embodiment 14.1.1 describes prepares from 2-amino-[1,1 '-phenylbenzene]-3-sulfonic acid.Obtain thickness buttery product and it is directly used in next step reaction.20.1.2 (S)-N-[3-[[[1-(4-ethyl piperidine-1-yl) carbonyl]-4-(1H-imidazol-4 yl) butyl] amino] alkylsulfonyl] [1,1 '-phenylbenzene]-2-yl] propionic acid amide
Under 0 ℃ and nitrogen, 2.2ml (15.84mmol) triethylamine is added drop-wise to 1.8g (5.3mmol) 2-[(1-chlorine propylidene) amino]-[1,1 '-phenylbenzene]-3-SULPHURYL CHLORIDE and 2.7g (4.8mmol) (S)-the 30ml dichloromethane solution of the mixture of α-[(4-ethyl piperidine-1-yl) carbonyl]-1-(trityl)-1H-imidazoles-4-butylamine hydrochloride in.The temperature of mixture is risen to room temperature and continue stirring 18 hours under this temperature, then with the reaction mixture concentrating under reduced pressure.Resistates is added in the 150ml ethyl acetate, successively with 100ml1N aqueous hydrochloric acid, 50ml saturated sodium bicarbonate solution and the washing of 50ml saturated nacl aqueous solution, with dried over sodium sulfate and concentrating under reduced pressure.
Resistates is added in the mixture of 60ml acetate and 40ml water, this mixture was heated 6 hours down in reflux temperature, then with the reaction mixture concentrating under reduced pressure.Resistates is added in the 200ml ethyl acetate, successively with 50ml saturated sodium bicarbonate solution and the washing of 50ml saturated nacl aqueous solution, with dried over sodium sulfate and concentrating under reduced pressure.Resistates by silica gel chromatography, is used methyl alcohol: the mixture wash-out of methylene dichloride (5: 95).Obtain 2.2g thickness oily product.Yield=81%.20.2 (S)-and N-[3-[[[4-(5-chloro-1H-imidazol-4 yl)-1-[(4-ethyl piperidine-1-yl) carbonyl] butyl] amino] alkylsulfonyl] [1,1 '-phenylbenzene]-2-yl] propionamide hydrochloride (1: 1)
With 0.56g (1mmol) (S)-N-[3-[[[1-(4-ethyl piperidine-1-yl) carbonyl]-4-(1H-imidazol-4 yl) butyl] amino] alkylsulfonyl] [1; 1 '-phenylbenzene]-the 2-yl] the 2ml dimethyl formamide solution of propionic acid amide and 0.116g (1.1mmol) N-chlorosuccinimide stirred 5 hours in 0 ℃, then with the reaction mixture concentrating under reduced pressure.Resistates by silica gel chromatography, is used methyl alcohol: the mixture wash-out of methylene dichloride (2: 98).Obtain the product of 0.3g alkali form.Yield=50%.
This alkali is added in the aqueous isopropanol of 15ml0.1N hydrochloric acid and concentrating under reduced pressure.The resistates chromatographic separation on the RP18 post that obtains is carried out purifying, use acetonitrile: the mixture wash-out of water (6: 4).Obtain the 0.30g product after the lyophilize.Yield=94%.Fusing point=100 ℃.[α]
D 20=+102 °; (c=0.2, methyl alcohol).Embodiment 21 (compound number 23) (S)-N-[2-[[[1-[(4-ethyl piperidine-1-yl) carbonyl]-4-(5-methyl isophthalic acid H-imidazol-4 yl)-butyl] amino] alkylsulfonyl]-6-pyridine-2-base phenyl]-propionamide hydrochloride (1: 2) 21.1 (S)-N-[4-bromo-[2-[[[1-[(4-ethyl piperidine-1-yl) carbonyl]-4-[5-methyl-1-(trityl)-1H-imidazol-4 yl] butyl] amino] alkylsulfonyl]-the 6-iodophenyl] propionic acid amide
Under 0 ℃, with 2.24g (4.4mmol) 2-[two (1-oxopropyl) amino]-5-bromo-3-iodobenzene SULPHURYL CHLORIDE and 1.84ml (13.2mmol) triethylamine be added drop-wise to successively 2.28g (4mmol) (S)-the 25ml dichloromethane solution of 5-methyl-α-[(4-ethyl piperidine-1-yl) carbonyl]-1-(trityl)-1H-imidazoles-4-butylamine hydrochloride in.Mixture is stirred 6 hours concentrating under reduced pressure then under this temperature.Resistates is added in the 200ml ethyl acetate, successively with 100ml1N aqueous hydrochloric acid, 100ml saturated sodium bicarbonate solution and the washing of 100ml saturated nacl aqueous solution, with dried over sodium sulfate and concentrating under reduced pressure.Resistates is added in the 150ml tetrahydrofuran (THF), in this solution, feeding ammonia 2 hours under 0 ℃, then with the mixture concentrating under reduced pressure.Resistates by silica gel chromatography, is used methylene dichloride: the mixture wash-out of methyl alcohol (98: 2).Obtain the transparent oily product of 2.64g.Yield=70%.21.2 (S)-the N-[4-bromo-[2-[[[1-[(4-ethyl piperidine-1-yl) carbonyl]-4-[5-methyl-1-(trityl)-1H-imidazol-4 yl] butyl] amino] alkylsulfonyl]-6-pyridine-2-base phenyl] propionic acid amide
With 1.9g (2mmol) (S)-N-[4-bromo-[2-[[[1-[(4-ethyl piperidine-1-yl) carbonyl]-4-[5-methyl isophthalic acid-(trityl)-1H-imidazol-4 yl] butyl] amino] alkylsulfonyl 1-6-iodophenyl] propionic acid amide; 0.883g (2.4mmol) 2-(tributyl stannyl) pyridine; 0.1g (0.17mmol) two (dibenzylidene ketone) palladiums (0); 0.033g (0.17mmol) mixture of cupric iodide and 0.98g (0.34mmol) triphenylarsine add in the 4ml dimethyl formamide and under argon atmospher in 80 ℃ of heating 5 hours.Reaction mixture is added in the 150ml ethyl acetate, use the washing of 2 * 100ml10% ammoniacal liquor and 50ml saturated nacl aqueous solution successively.With organic layer with dried over sodium sulfate and concentrating under reduced pressure.Resistates by silica gel chromatography, is used methylene dichloride: the mixture wash-out of methyl alcohol (98: 2).Obtain 1.15g thickness oily product.Yield=64%.21.3 (S)-the N-[4-bromo-[2-[[[1-[(4-ethyl piperidine-1-yl) carbonyl]-4-(5-methyl-1H-imidazol-4 yl) butyl] amino] alkylsulfonyl]-6-pyridine-2-base phenyl] propionic acid amide
With 1.14g (1.26mmol) (S)-N-[4-bromo-[2-[[[1-[(4-ethyl piperidine-1-yl) carbonyl]-4-[5-methyl isophthalic acid-(trityl)-1H-imidazol-4 yl] butyl] amino] alkylsulfonyl]-6-pyridine-2-base phenyl] propionic acid amide is dissolved in the mixture of 30ml acetate and 15ml water and with it and heated 1 hour under reflux temperature.Add in the 150ml ethyl acetate with the reaction mixture concentrating under reduced pressure and with resistates.Organic layer is washed with 50ml saturated sodium bicarbonate solution and 50ml saturated nacl aqueous solution successively, with dried over sodium sulfate and concentrating under reduced pressure.Resistates by silica gel chromatography, is used methyl alcohol: the mixture wash-out of methylene dichloride (5: 95).Obtain the transparent oily product of 0.66g.Yield=79.5%.21.4 (S)-and N-[2-[[[1-[(4-ethyl piperidine-1-yl) carbonyl]-4-(5-methyl isophthalic acid H-imidazol-4 yl)-butyl] amino] alkylsulfonyl]-6-pyridine-2-base phenyl]-propionamide hydrochloride (1: 2)
With 0.65g (0.98mmol) (S)-N-[4-bromo-[2-[[[1-[(4-ethyl piperidine-1-yl) carbonyl]-4-(5-methyl isophthalic acid H-imidazol-4 yl) butyl] amino] alkylsulfonyl]-6-pyridine-2-base phenyl] mixture of propionic acid amide, 1.24g (20mmo1) ammonium formiate and 0.065g palladium charcoal adds 10ml and contains in the methyl alcohol of 0.2ml acetate and heating 3 hours under reflux temperature, then with the reaction mixture concentrating under reduced pressure.Resistates is added in the 100ml ethyl acetate, successively with 50ml saturated sodium bicarbonate solution and the washing of 50ml saturated nacl aqueous solution, with dried over sodium sulfate and concentrating under reduced pressure.Resistates by silica gel chromatography, is used methyl alcohol: the mixture wash-out of methylene dichloride (5: 95).Obtain 0.55g thickness buttery alkali.Yield=96%.
Alkali is added in the aqueous isopropanol of 25ml0.1N hydrochloric acid and concentrating under reduced pressure.The resistates chromatographic separation on the RP18 post that obtains is carried out purifying, use acetonitrile: the mixture wash-out of water (6: 4).Obtain the 0.44g product.Yield=68%.Fusing point=138-144 ℃.[α]
D 20=+121 °; (c=0.2, methyl alcohol).Embodiment 22 (compound number 22) (S)-N-[2-[[[1-[(4-ethyl piperidine-1-yl) carbonyl]-4-(5-methyl isophthalic acid H-imidazol-4 yl)-butyl] amino] alkylsulfonyl]-4-fluoro-6-thiophene-2-base phenyl] propionamide hydrochloride (1: 1) 22.1 2-[two (1-oxopropyl) amino]-5-fluoro-3-thiophene-2-base benzene sulfonyl chloride 22.1.1 2-[two (1-oxopropyl) amino]-N of 5-fluoro-3-thiophene-2-base Phenylsulfonic acid, N-diethyl ethylamine salt
With under reflux temperature, heating 24 hours in mixture adding 77ml (600mmol) propionic anhydride of 10.92g (40mmol) 2-amino-5-fluoro-3-thiophene-2-base Phenylsulfonic acid and 5.6ml (40mmol) triethylamine and with it, then with the reaction mixture concentrating under reduced pressure.With the resistates ethyl acetate: ether mixture knot product.Obtain the 16.9g product.Yield=90%.Fusing point=239 ℃.22.1.2 2-[two (1-oxopropyl) amino]-5-fluoro-3-thiophene-2-base benzene sulfonyl chloride
Under 0 ℃ and the nitrogen atmosphere, 14.22g (68.2mmol) phosphorus pentachloride is joined 1.60g (34.1mmol) 2-[two (1-oxopropyl) amino]-5-fluoro-3-thiophene-2-base Phenylsulfonic acid N, in the 60ml dichloromethane solution of N-diethyl ethylamine salt.Mixture was stirred 5 hours under this temperature, be warming up to room temperature then and under this temperature, continue and stirred 1 hour.Add the 200ml ether, mixture is filtered and filtrate decompression is concentrated.Resistates is added in the 800ml ether, filter and concentrating under reduced pressure.With resistates at Florisil
Chromatographic separation is carried out purifying on the post, uses ether: the mixture wash-out of pentane (then be 1: 1 at 1: 9).Obtain 6.4g thickness oily product.Yield=55%.22.2 (S)-and N-[2-[[[1-[(4-ethyl piperidine-1-yl) carbonyl]-4-(5-methyl isophthalic acid H-imidazol-4 yl)-butyl] amino] alkylsulfonyl]-4-fluoro-6-thiophene-2-base phenyl] propionamide hydrochloride (1: 1)
Under 0 ℃ and nitrogen atmosphere, with 6.16g (18.1mmol) 2-[two (1-oxopropyl) amino]-5-fluoro-3-thiophene-2-base benzene sulfonyl chloride and 5.5mmol triethylamine be added drop-wise to successively 9.83g (17.2mmol) (S)-the 60ml dichloromethane solution of α-[(4-ethyl piperidine-1-yl) carbonyl]-5-methyl isophthalic acid-(trityl)-1H-imidazoles-4-butylamine hydrochloride in.The temperature of reaction mixture is slowly risen to room temperature, under this temperature, stirred 15 hours, then with the reaction mixture concentrating under reduced pressure.Resistates is added in the 300ml ethyl acetate, successively with 300ml1N aqueous hydrochloric acid, 300ml saturated sodium bicarbonate solution and the washing of 300ml saturated nacl aqueous solution.With the organic layer dried over sodium sulfate, filter and concentrating under reduced pressure.With resistates at 225ml acetate: heating 12 hours concentrating under reduced pressure then in water (2: the 1) mixture.Resistates is added in the 400ml methylene dichloride, successively with 200ml saturated sodium bicarbonate solution and the washing of 200ml saturated nacl aqueous solution.With the organic layer dried over sodium sulfate, filter and concentrating under reduced pressure.The resistates that obtains is passed through silica gel chromatography, use methylene dichloride: the mixture wash-out of methyl alcohol (96: 4).
Obtain the product of 7.7g alkali form.Yield=74%.Fusing point=145-150 ℃.
Prepare hydrochloride in aqueous isopropanol adding 2.5g (4.5mmol) alkali with 45.1ml0.1N hydrochloric acid.Obtain the product of 2.7g hydrochloride form.Fusing point=145 ℃.[α]
D 20=+112 °; (c=0.2, methyl alcohol).Embodiment 23 (compound number 53) (S)-N-[2-[[[1-[[4-(difluoro methylene)-piperidines-1-yl] carbonyl]-4-(5-methyl isophthalic acid H-imidazol-4 yl)-butyl] amino] alkylsulfonyl]-6-thiophene-2-base phenyl] propionamide hydrochloride (1: 1)
The method that this product is described according to embodiment 19, from 0.81g (1.36mmol) (S)-5-methyl-α-[[4-(difluoro methylene)-piperidines-1-yl] carbonyl]-1-(trityl)-1H-imidazoles-4-butylamine hydrochloride and 0.47g (1.36mmol) 2-[(1-chlorine propylidene) amino]-3-thiophene-2-base benzene sulfonyl chloride preparation.Obtain 0.58g white powder product.Yield=67%.Fusing point=144-145 ℃.[α]
D 20=+107.9 °; (c=0.2, methyl alcohol).Embodiment 24 (compound number 25) (S)-N-[6-cyclopentyl-2-[[[1-[(4-ethyl piperidine-1-yl) carbonyl]-4-(5-methyl isophthalic acid H-imidazol-4 yl)-butyl] amino] alkylsulfonyl] phenyl] N of propionamide hydrochloride (1: 1) 24.1 3-cyclopentyl-2-(diacetyl amino) benzene sulfonyl chloride 24.1.1 3-cyclopentyl-2-(diacetyl amino) Phenylsulfonic acid, N-diethyl ethylamine salt
With the N of 6.5g (19mmol) 2-amino-3-cyclopentyl Phenylsulfonic acid, N-diethyl ethylamine salt is dissolved in Acetyl Chloride 98Min. and this solution was heated 48 hours down in reflux temperature, then with the reaction mixture concentrating under reduced pressure.Obtain the 8.22g product and it is directly used in next step reaction.Yield=95%.Fusing point=186 ℃.24.1.2 3-cyclopentyl-2-(diacetyl amino) benzene sulfonyl chloride
This compound prepares from 8.2g (18.1mmol) 3-cyclopentyl-2-(diacetyl amino) Phenylsulfonic acid according to the method that embodiment 22.1 describes.Obtain 3.81g thickness buttery product and it is directly used in next step reaction.Yield=57%.24.2 (S)-and N-[6-cyclopentyl-2-[[[1-[(4-ethyl piperidine-1-yl) carbonyl]-4-(5-methyl isophthalic acid H-imidazol-4 yl)-butyl] amino] alkylsulfonyl] phenyl] propionamide hydrochloride (1: 1)
The method that this product is described according to embodiment 22.1, from 0.743g (2mmol) 3-cyclopentyl-2-(diacetyl amino) benzene sulfonyl chloride and 1.14g (2mmol) (S)-α-[(4-ethyl piperidine-1-yl) carbonyl]-5-methyl isophthalic acid-(trityl)-1H-imidazoles-4-butylamine hydrochloride preparation.Obtain the 0.73g product.Yield=60%.Fusing point=124 ℃.[α]
D 20=+89 °; (c=0.2, methyl alcohol).Embodiment 25 (compound number 64) (S)-N-[2-[[[4-(5-methyl isophthalic acid H-imidazol-4 yl)-1-[(5-oxo six hydrogen-1H-1,4-diaza -1-yl) carbonyl] butyl] amino] alkylsulfonyl]-6-thiophene-2-base phenyl] propionamide hydrochloride (1: 1) 25.1 1-[2-[[(2-amino-3-thiophene-2-base phenyl) alkylsulfonyl] amino]-the 5-[5-methyl
-1-(trityl)-1H-imidazol-4 yl]-1-oxo amyl group]-six hydrogen-5H-1,4-two
Azatropylidene-5-ketone
Place under the argon gas 80ml dichloromethane solution of 0.618g (2.26mmol) 2-amino-3-thiophene-2-base benzene sulfonyl chloride and adding 1.29g (2.26mmol) 1-[2-amino-5-[5-methyl isophthalic acid-(trityl)-1H-imidazol-4 yl]-1-oxo amyl group]-six hydrogen-5H-1,4-diaza -5-keto hydrochloride.This mixture is cooled to 0 ℃ and the slow 0.94ml (6.74mmol) of adding triethylamine with ice bath.The temperature of reaction mixture is risen to room temperature and under this temperature, stir and spend the night.Add the 10ml0.5N aqueous hydrochloric acid and organic phase is used the washing of 0.5N aqueous hydrochloric acid and saturated nacl aqueous solution successively, use dried over mgso then.Resistates by silica gel chromatography, is used methylene dichloride: the mixture wash-out of methyl alcohol (97.5: 2.5).Obtain the 1.33g product.Yield=76%.25.2 (S)-N-[2-[[[4-[5-methyl isophthalic acid-(trityl)-1H-imidazol-4 yl]-1-[(5-oxo six hydrogen-1H-1,4-diaza -1-yl) carbonyl] butyl] amino] alkylsulfonyl]-6-thiophene-2-base-phenyl] propionic acid amide
With 1.33g (1.72mmol) 1-[2-[[(2-amino-3-thiophene-2-base phenyl) alkylsulfonyl] amino]-5-[5-methyl isophthalic acid-(trityl)-1H-imidazol-4 yl]-1-oxo amyl group]-six hydrogen-5H-1,4-diaza -5-ketone adds in the 1.3ml N,N-DIMETHYLACETAMIDE and adds 0.3ml (3.44mmol) propionyl chloride.Mixture was stirred 2 hours, add ethyl acetate then.Being evaporated to dry doubling adds resistates in the methylene dichloride.Organic layer with 2 * 20ml1N salt acid elution, is also evaporated with dried over mgso.Obtain the 1.4g product and it is directly used in next step reaction.Yield=100%.25.3 (S)-and N-[2-[[[4-(5-methyl isophthalic acid H-imidazol-4 yl)-1-[(5-oxo six hydrogen-1H-1,4-diaza -1-yl) carbonyl] butyl] amino] alkylsulfonyl]-6-thiophene-2-base-phenyl] propionamide hydrochloride (1: 1)
With 0.25g (0.31mmol) (S)-N-[2-[[[4-[5-methyl isophthalic acid-(trityl)-1H-imidazol-4 yl]-1-[(5-oxo six hydrogen 1H-1; 4 diazas -1-yl) carbonyl] butyl] amino] alkylsulfonyl]-6-thiophene-2-base-phenyl] propionic acid amide adds in the 4ml tetrahydrofuran (THF), adds 2ml acetate and 2ml water.Mixture in 50 ℃ of heated overnight, is evaporated to dry doubling resistates is added in the 100ml methylene dichloride.This solution is washed and uses dried over mgso with sodium bicarbonate aqueous solution.Filter and with resistates by silica gel chromatography, use methylene dichloride: the mixture wash-out of methyl alcohol (90: 10).
This alkali is dissolved in the aqueous isopropanol of 0.1N hydrogenchloride and and carries out purifying, use the acetonitrile/water mixture wash-out product chromatographic separation on the RP18 silicagel column.Obtain the product of 0.026g hydrochloride form.Yield=14%.Fusing point=155 ℃.[α]
D 20=+80 °; (c=0.2, methyl alcohol).Embodiment 26 (compound number 65) (S)-N-cyclopentyl-N; 5-dimethyl-α-[[[the 2-[(1-oxopropyl) amino]-3-thiophene-2-base phenyl] alkylsulfonyl] amino]-1H-imidazoles-4-valeramide hydrochloride (1: 1) 26.1 (S)-α-[[(2-amino-3-thiophene-2-base phenyl) alkylsulfonyl] amino]]-N-cyclopentyl-N, 5-dimethyl-1-(trityl)-1H-imidazoles-4-valeramide
Under 0 ℃ and the nitrogen atmosphere, with the 5ml dichloromethane solution of 1g (3.66mmol) 2-amino-3-thiophene-2-base benzene sulfonyl chloride and 1.12ml (7.85mmol) triethylamine join successively 1.95g (3.5mmol) (S)-alpha-amino group-N-cyclopentyl-N, in the 15ml dichloromethane solution of 5-dimethyl-1-(trityl)-1H-imidazoles-4-valeramide hydrochloride.The temperature of reaction mixture is risen to room temperature and continue stirring 15 hours under this temperature.With the reaction mixture concentrating under reduced pressure.Resistates is added in the 150ml ethyl acetate, successively with 50ml1N aqueous hydrochloric acid, 50ml saturated sodium bicarbonate solution and the washing of 50ml saturated nacl aqueous solution.With the organic layer dried over sodium sulfate.Resistates by silica gel chromatography, is used methylene dichloride: the mixture wash-out of methyl alcohol (97: 3).Obtain 2.35g amorphous solid shape product.Yield=87%.Fusing point=102-107 ℃.26.2 (S)-and N-cyclopentyl-N, 5-dimethyl-α-[[[the 2-[(1-oxopropyl) amino]-3-thiophene-2-base-phenyl] alkylsulfonyl] amino]-1H-imidazoles-4-valeramide hydrochloride (1: 1)
Under the room temperature; with 0.51ml (5.9mmol) propionyl chloride be added drop-wise to 2.23g (2.94mmol) (S)-α-[[(2-amino-3-thiophene-2-base phenyl) alkylsulfonyl] amino]-N-cyclopentyl-N, in the 1.5ml dimethylacetamide solution of 5-dimethyl-1-(trityl)-1H-imidazoles-4-valeramide.This mixture was stirred 10 hours, add the 150ml ethyl acetate then.Organic layer is washed with 150ml water and 100ml saturated nacl aqueous solution successively.With the organic layer dried over sodium sulfate, filter and concentrating under reduced pressure.Resistates is added in 60ml ethyl acetate and the 30ml water, heated 2 hours down in reflux temperature then.Add the 150ml methylene dichloride and organic layer is used the washing of 100ml saturated sodium bicarbonate solution and 100ml saturated nacl aqueous solution successively.With the organic layer dried over sodium sulfate, filter and concentrating under reduced pressure.The resistates that obtains is added in the aqueous isopropanol of 40ml0.1N hydrochloric acid and concentrating under reduced pressure.Resistates by silica gel chromatography, is used acetonitrile: the mixture wash-out of water (2: 8).Obtain the 1.15g product.Yield=64%.Fusing point=140-145 ℃.[α]
D 20=+103 °; (c=0.2, methyl alcohol).Embodiment 27 (compound number 66) (S)-N; 5-methyl-α-[[[the 2-[(1-oxopropyl) amino]-3-thiophene-2-base phenyl] alkylsulfonyl] amino]-N-tetramethyleneimine-1-base-1H-imidazoles-4-valeramide hydrochloride (1: 1) 27.1 (S)-α-[[(2-amino-3-thiophene-2-base phenyl) alkylsulfonyl] amino]]-N, 5-dimethyl-N-tetramethyleneimine-1-base-1-(trityl)-1H-imidazoles-4-valeramide
The method that this compound is described according to embodiment 26.1, from 0.8g (2.94mmol) 2-amino-3-thiophene-2-base benzene sulfonyl chloride and 1.56g (2.8mmol) (S)-alpha-amino group-N, 5-dimethyl-N-tetramethyleneimine-1-base-1-(trityl)-1H-imidazoles-4-valeramide hydrochloride preparation.Obtain 1.84g amorphous solid shape product.Yield=83%.Fusing point=102-106 ℃.27.2 (S)-and N, 5-dimethyl-α-[[[the 2-[(1-oxopropyl) amino]-3-thiophene-2-base phenyl] alkylsulfonyl] amino]-N-tetramethyleneimine-1-base-1H-imidazoles-4-valeramide hydrochloride (1: 1)
The method that this compound is described according to embodiment 26.2, from 1.8g (2.37mmol) (S)-α-[[(2-amino-3-thiophene-2-base phenyl) alkylsulfonyl] amino]-N, 5-dimethyl-N-tetramethyleneimine-1-base-1-(trityl)-1H-imidazoles-4-valeramide preparation.Obtain the 1g product.Yield=69%.Fusing point=154-160 ℃.[α]
D 20=+119 °; (c=0.2, methyl alcohol).Explanation about table:
In " salt " hurdle,
" HCl " with respect to hydrochloride, the ratio in the bracket be (acid: ratio alkali),
At " [α]
D 20In the hurdle,
C=0.2, methyl alcohol, but except the following compound: compound 1 (c=0.22, methyl alcohol), compound 6 (c=0.26, methyl alcohol), compound 12 (c=0.25, methyl alcohol) and compound 51,54 and 56 (c=0.4, methyl alcohol).
Table
The pharmaceutical research that The compounds of this invention is carried out has confirmed their anti-thrombosis activity and as the superiority of therapeutic active substance.
1. measure inhibition constant (K to zymoplasm
i)
Following material is added in each hole of 96 hole titer plate: the solution of 25 μ l compound to be tested (having studied 7 kinds of concentration), 50 μ l chromogenic substrates (have used two kinds of concentration, S2238Chromogenix
TM) solution in the Tris of pH7.5 buffered soln (50mM Tris, 100mMNaCl and 0.1%BSA) and the thrombin solution of 25 μ l300U/ml.Detect the 4-N-methyl-p-nitroaniline that discharges in 405nm with plate reader.
Measure K by the Dixon method
i
The compounds of this invention is the inhibitor of zymoplasm, its K
iBetween 0.001-100 μ M.
2. the external rat plasma that causes of human thrombin solidifies
The male CD rat of body weight 150-200g is passed through intravenously, oral or subcutaneous route processing with compound to be tested or carrier.Use Nembutal then
TM(60mg/kg; 0.1ml/kg) anesthetized animal, extract blood from the posterior orbit venous sinus and be added to (1 volume/9 volume blood) on 3.8% trisodium citrate, with 3600g room temperature preparation in centrifugal 15 minutes blood plasma.Then 200 μ l blood plasma and 200 μ l human thrombin solution one are arised from 37 ℃ of insulations, the ultimate density of human thrombin is 0.75NIH unit/ml, the record clotting time.The effect of antithrombotics is so that the clotting time increases by 100% dosage represents.Compound of the present invention can suppress solidifying of rat plasma under 0.01-5mg/kg intravenous administration dosage.They can also be by oral and subcutaneous administration approach generation effect.
Compound of the present invention can be used for relating to the disease that the thrombosis complication maybe may take place thrombotic all clinical indications.
For this reason, open The compounds of this invention is made any form that is suitable for oral, parenteral or intravenous administration with suitable vehicle, for example tablet, drageeing, capsule comprise hard gelatin capsule, are used for the suspension of oral or drug administration by injection or solution etc.The contained dosage of all these formulations can be used the 1-1000mg compound to every patient by the single or multiple administration every day.
Claims (11)
1. formula I compound
R wherein
1And R '
1Represent hydrogen atom or halogen atom or (C independently of one another
1-C
4) alkyl, R
2The expression piperidines-1-base, described piperidines-1-base at 4 by one or more (C that are selected from hydroxyl, straight or branched
1-C
4) alkyl, hydroxyl (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group, (C
1-C
4) alkylthio, nitrile, a methyl fluoride, difluoromethyl, trifluoromethyl, 2-fluorine oxyethyl group, 2,2,2-trifluoro ethoxy, (C
3-C
6) cycloalkyl ,-COOR ' and-CONR ' R " group (R ' be (C
1-C
4) alkyl, R " is hydrogen atom or (C
1-C
4) alkyl) and group selectivity replace, or quilt=CYZ group [Y and Z are independently from each other hydrogen atom, halogen atom and (C
1-C
4) alkyl (optionally being replaced), cyano group by one or more halogen atoms and-COOR ' group, R ' is as defined above] or
Group (r=1-3) or=NOCH
3Group replaces; Perhaps, R
2Expression spiral shell [(C
3-C
6) cycloalkyl-1,4 '-piperidines]-the 1-base; Or at 4 by (the C of straight or branched
1-C
4) alkyl (optionally being replaced by one or more halogen atoms) or (C
3-C
6) the cycloalkyl selectivity replace 1,2,3,6-tetrahydropyridine-1-base; Or 4 by trifluoromethyl or=CF
2Hexahydro-1 H-azepines-1-base that group selectivity replaces; Or seven hydrogen azocine-1-base; Or octahydro-1H-azonine-1-base; Or
Group (A-B is-CONR " group, m=1-2, p=1-2); Or
(Q is carbon or nitrogen-atoms to group, and D is (C
1-C
4) alkyl or-CH
2CF
3Group, r=1-3); R
3(the C of expression straight or branched
1-C
5) alkyl; Or-COR
5Group, wherein R
5Be (the C of straight or branched
1-C
4) alkyl ,-(CH
2)
nOCH
3,-CH
2O (C
2H
4O)
nCH
3,-(CH
2)
nCF
3,-(CH
2)
nOH (n=1-4); Or-SO
2R
6Group; Or-CONHR
6Group; Or-SO
2N (R
6)
2Group, wherein R
6Be (the C of straight or branched
1-C
4) alkyl; R
4Expression hydrogen atom or halogen atom; A represents by one or more halogen atom, straight or branched (C of being selected from
1-C
4) alkyl, straight or branched (C
1-C
4) alkoxyl group, trifluoromethyl, trifluoromethoxy, formyl radical ,-CH
2OR
10,-CH
2OCOR
10,-CH
2OCONR
10R
11,-COOR
10,-CONR
10R
11, nitro ,-NR
10R
11, NHCOR
14With-NH (CH
2)
qOR
10The phenyl that replaces of substituting group selectivity, R wherein
10And R
11Be (the C of hydrogen atom or straight or branched independently of one another
1-C
4) alkyl, q is 0-6; Perhaps, A represents to be selected from the heterocycle of pyridyl, thienyl, furyl, pyrimidyl and thiazolyl, and described group can be substituted in the manner described above; Or ring (C
5-C
8) alkyl, the form of racemic modification or enantiomorph or mixture of enantiomers is the form of free acid or alkali or pharmaceutically acceptable additive salt.
2. the compound of claim 1 is characterized in that, R
1And R '
1Represent hydrogen atom or halogen atom or (C independently of one another
1-C
4) alkyl, R
2The expression piperidines-1-base, described piperidines-1-base at 4 by one or more (C that are selected from straight or branched
1-C
4) alkyl, hydroxyl (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group, (C
1-C
4) alkylthio, nitrile, difluoromethyl, trifluoromethyl, 2,2,2-trifluoro ethoxy and (C
3-C
6) group selectivity of cycloalkyl replaces, or quilt=CYZ group (Y and Z are independently from each other hydrogen atom, halogen atom and (C
1-C
4) alkyl) or=NOCH
3Group replaces; Perhaps, R
2Expression spiral shell [(C
3-C
6) cycloalkyl-1,4 '-piperidines]-the 1-base; Or at 4 by (the C of straight or branched
1-C
4) alkyl (optionally being replaced) selectivity by one or more halogen atoms replace 1,2,3,6 tetrahydropyridines-1-base; Or at 4 quilt=CF
2Hexahydro-1 H-azepines-1-base that group selectivity replaces; Or octahydro-1H-azonine-1-base; Or
Group (A-B is-CONR " group, m=1-2, p=1-2); Or
(Q is carbon or nitrogen-atoms to group, and D is (C
1-C
4) alkyl or-CH
2CF
3Group, r=1-3); R
3(the C of expression straight or branched
1-C
5) alkyl; Or-COR
5Group, wherein R
5Be (the C of straight or branched
1-C
4) alkyl ,-CH
2O (C
2H
4O)
nCH
3,-(CH
2)
nOH ,-(CH
2)
nOCH
3Group; Or-CONHR
6Group; A represents by one or more halogen atom, straight or branched (C of being selected from
1-C
4) alkyl, straight or branched (C
1-C
4) alkoxyl group, trifluoromethyl, trifluoromethoxy and-NR
10R
11The phenyl that replaces of substituting group selectivity, R wherein
10And R
11Be (the C of hydrogen atom or straight or branched independently of one another
1-C
4) alkyl; Perhaps, A represents pyridyl or thienyl, and described group can be substituted in the manner described above; Or ring (C
5-C
8) alkyl.
3. claim 1 or 2 described compounds is characterized in that R
1Expression (C
1-C
1) alkyl and R '
1The expression hydrogen atom, R
2Be illustrated in 4 by (the C of straight or branched
1-C
4) alkyl or=CF
2Piperidines-1-base that group replaces, R
3Expression-COR
5Group and R wherein
5Be (the C of straight or branched
1-C
4) alkyl, A represents according to thienyl or ring (C with the replacement of upper type selectivity
5-C
8) alkyl.
4. any described compound among the claim 1-3 is characterized in that the preferred configuration of center amino acid moiety is [S]
5. (I is the method for compound a) to prepare the described formula of claim 1
Wherein, R
1, R '
1, R
2, R
4With A such as claim 1 definition, R
5Be straight or branched (C
1-C
4) alkyl or-(CH
2)
nCF
3Group (n=1-4) the method is characterized in that, with the formula II compound
R wherein
1And R '
1Represent hydrogen atom or (C respectively
1-C
4) alkyl, with the reaction of formula III compound,
R wherein
4With A such as claim 1 definition, R
5Be straight or branched (C
1-C
4) alkyl or-(CH
2)
nCF
3Group (n=1-4) generates the formula IV compound,
Then the formula IV compound is handled in acidic medium.
6. (I is the method for compound a) to prepare the described formula of claim 1
Wherein, R
1, R '
1, R
2, R
4With A such as claim 1 definition, R
5Be straight or branched (C
1-C
4) alkyl ,-(CH
2)
nOCH
3,-CH
2O (C
2H
4O)
nCH
3, (CH
2)
nCF
3Or-(CH
2)
nOH group (n=1-4) the method is characterized in that, with formula II compound and the reaction of formula (V) compound
R wherein
4With A such as claim 1 definition, R
5As defined above, generate the compound of formula VI,
Then the compound of formula VI is handled in acidic medium.
7. (I is the method for compound a), it is characterized in that, with formula (VII) compound for preparation formula
Wherein, R
1, R '
1, R
2, R
4And R
5Such as claim 1 definition, with the reaction of the compound of formula (VIII), ASn (R)
3(VIII) wherein R represents (C
1-C
4) alkyl, A such as claim 1 definition, the compound of production (IX) thus,
Then with the compound of formula (IX) in acidic medium, heating under the reflux temperature.
8. the method for preparation formula (I b) compound,
Wherein, R
1, R '
1, R
2, R
4With A such as claim 1 definition, R
3Expression-COR
5Group, wherein R
5Be (the C of straight or branched
1-C
4) alkyl ,-(CH
2)
nOCH
3,-CH
2O (C
2H
4O)
nCH
3,-(CH
2)
nCF
3Or-(CH
2)
n(P is a protecting group to the OP group, n=1-4);-SO
2R
6Group;-CONHR
6Group or-SO
2N (R
6)
2Group, wherein R
6Be (the C of straight or branched
1-C
4) alkyl, the method is characterized in that, with the formula II compound
R wherein
1And R '
1Represent hydrogen atom or (C respectively
1-C
4) alkyl, with the reaction of formula (X) compound,
Wherein A and R
4Such as claim 1 definition, production (XI) compound thus,
Then with formula (XI) compound and formula R
5The acyl chlorides of COCl or formula R
6The alkyl isocyanate of NCO or formula R
6SO
2The SULPHURYL CHLORIDE of Cl or formula (R
6)
2NSO
2The compound of the sulfamic acid chloride reaction production (XII) of Cl,
Then formula (XII) compound is handled in acidic medium.
9. the method for preparation formula (I c) compound,
R wherein
12(the C of expression straight or branched
1-C
5) alkyl, the method is characterized in that, with formula II compound and the reaction of formula (X IV) compound,
R wherein
12(the C of expression straight or branched
1-C
5) alkyl, A and R
4Define as claim, the compound of production (X V) thus,
Then formula (X V) compound is handled in acidic medium.
10. medicine is characterized in that containing any described compound among the claim 1-4.
11. pharmaceutical composition is characterized in that containing any described compound and pharmaceutically acceptable vehicle among the claim 1-4.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR96/14309 | 1996-11-22 | ||
| FR9614309A FR2756285B1 (en) | 1996-11-22 | 1996-11-22 | N- (IMIDAZOLYLBUTYL) BENZENESULFONAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1238765A true CN1238765A (en) | 1999-12-15 |
Family
ID=9497920
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN97199986A Pending CN1238765A (en) | 1996-11-22 | 1997-11-19 | N-(imidazoly (butyl) benzenesulphonamide derivatives with anticoagulation active |
Country Status (20)
| Country | Link |
|---|---|
| EP (1) | EP0946517A1 (en) |
| JP (1) | JP2001504128A (en) |
| KR (1) | KR20000069063A (en) |
| CN (1) | CN1238765A (en) |
| AR (1) | AR009627A1 (en) |
| AU (1) | AU5226498A (en) |
| BG (1) | BG103414A (en) |
| BR (1) | BR9713291A (en) |
| CA (1) | CA2270478A1 (en) |
| CO (1) | CO4910158A1 (en) |
| CZ (1) | CZ178299A3 (en) |
| EE (1) | EE9900201A (en) |
| FR (1) | FR2756285B1 (en) |
| HU (1) | HUP9904599A2 (en) |
| IL (1) | IL129546A0 (en) |
| NO (1) | NO992436L (en) |
| SK (1) | SK66799A3 (en) |
| TR (1) | TR199901143T2 (en) |
| WO (1) | WO1998022443A1 (en) |
| ZA (1) | ZA9710515B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2783521B1 (en) * | 1998-09-18 | 2002-04-26 | Synthelabo | N- (ARGINYL) BENZENESULFONAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
| FR2806722B1 (en) * | 2000-03-23 | 2002-05-17 | Sanofi Synthelabo | N- (HETEROCYCLYLBUTYL) BENZENE- OR PYRIDINE SULFONAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
| CN107207403A (en) | 2014-09-29 | 2017-09-26 | 塞尔利克斯生物私人有限公司 | Composition and method for treating multiple sclerosis |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2689130B1 (en) * | 1992-03-30 | 1994-05-27 | Synthelabo | DERIVATIVES OF 1- [2 (ARYLSULFONYLAMINO) ETHYL-1-OXO] PIPERIDINE, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION. |
| FR2710066B1 (en) * | 1993-09-14 | 1995-10-20 | Synthelabo | 1- [2-amino-5- [1- (triphenylmethyl-1H-imidazol-4-yl] -1-oxopentyl] piperidine derivatives, their preparation and their use as synthesis intermediates. |
| FR2727410B1 (en) * | 1994-11-25 | 1996-12-20 | Synthelabo | SULFONYL CHLORIDES, THEIR PREPARATION AND THEIR USE AS SYNTHESIS INTERMEDIATES |
| FR2728570B1 (en) * | 1994-12-23 | 1997-04-11 | Synthelabo | 1-OXO-2- (PHENYLSULFONYLAMINO) PENTYLPIPERIDINE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
| DE19548797A1 (en) * | 1995-12-27 | 1997-07-03 | Thomae Gmbh Dr K | New amino-imidazole substituted amino acid derivatives |
-
1996
- 1996-11-22 FR FR9614309A patent/FR2756285B1/en not_active Expired - Fee Related
-
1997
- 1997-11-19 KR KR1019997004485A patent/KR20000069063A/en not_active Application Discontinuation
- 1997-11-19 TR TR1999/01143T patent/TR199901143T2/en unknown
- 1997-11-19 CZ CZ991782A patent/CZ178299A3/en unknown
- 1997-11-19 AU AU52264/98A patent/AU5226498A/en not_active Abandoned
- 1997-11-19 CA CA002270478A patent/CA2270478A1/en not_active Abandoned
- 1997-11-19 CO CO97067574A patent/CO4910158A1/en unknown
- 1997-11-19 SK SK667-99A patent/SK66799A3/en unknown
- 1997-11-19 JP JP52328498A patent/JP2001504128A/en active Pending
- 1997-11-19 EE EEP199900201A patent/EE9900201A/en unknown
- 1997-11-19 IL IL12954697A patent/IL129546A0/en unknown
- 1997-11-19 WO PCT/FR1997/002079 patent/WO1998022443A1/en not_active Application Discontinuation
- 1997-11-19 BR BR9713291-8A patent/BR9713291A/en not_active Application Discontinuation
- 1997-11-19 HU HU9904599A patent/HUP9904599A2/en unknown
- 1997-11-19 CN CN97199986A patent/CN1238765A/en active Pending
- 1997-11-19 EP EP97947089A patent/EP0946517A1/en not_active Ceased
- 1997-11-21 ZA ZA9710515A patent/ZA9710515B/en unknown
- 1997-11-21 AR ARP970105455A patent/AR009627A1/en unknown
-
1999
- 1999-05-19 BG BG103414A patent/BG103414A/en unknown
- 1999-05-20 NO NO992436A patent/NO992436L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| KR20000069063A (en) | 2000-11-25 |
| FR2756285B1 (en) | 1998-12-18 |
| BR9713291A (en) | 1999-10-26 |
| ZA9710515B (en) | 1998-06-10 |
| NO992436L (en) | 1999-07-22 |
| NO992436D0 (en) | 1999-05-20 |
| IL129546A0 (en) | 2000-02-29 |
| EP0946517A1 (en) | 1999-10-06 |
| JP2001504128A (en) | 2001-03-27 |
| AR009627A1 (en) | 2000-04-26 |
| CA2270478A1 (en) | 1998-05-28 |
| CZ178299A3 (en) | 1999-08-11 |
| EE9900201A (en) | 1999-12-15 |
| BG103414A (en) | 2000-01-31 |
| AU5226498A (en) | 1998-06-10 |
| FR2756285A1 (en) | 1998-05-29 |
| TR199901143T2 (en) | 1999-08-23 |
| HUP9904599A2 (en) | 2000-06-28 |
| SK66799A3 (en) | 2000-02-14 |
| CO4910158A1 (en) | 2000-04-24 |
| WO1998022443A1 (en) | 1998-05-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2143425C1 (en) | Derivatives of piperidine, their salts, methods of their synthesis, pharmaceutical composition based on thereof and intermediate substances | |
| TWI440636B (en) | Pyrazole derivatives | |
| EP1499589B1 (en) | Derivatives of n-phenyl(piperidin-2-yl)methyl benzamide, the preparation method thereof and application of same in therapeutics | |
| US20110053979A1 (en) | Pyridine derivatives used to treat orexin related disorders | |
| CN101472904B (en) | Diazepan derivatives modulators of chemokine receptors | |
| AU2003284984B2 (en) | Gamma-aminoamide modulators of chemokine receptor activity | |
| JP6346862B2 (en) | Substituted proline / piperidine as an orexin receptor antagonist | |
| SK16152002A3 (en) | Pharmaceutically active piperidine derivatives, in particular as modulators of chemokine receptor activity | |
| EA019192B1 (en) | Piperidinyl derivatives as modulators of chemokine receptor activity | |
| JP2012524760A (en) | 3-Azabicyclo [4.1.0] heptane used as an orexin antagonist | |
| US20080306055A1 (en) | Heterocyclic Mchr1 Antagonists And Their Use In Therapy | |
| WO2013131018A1 (en) | Biaryl inhibitors of the sodium channel | |
| AU2005213538A1 (en) | Piperidinylcarbonyl-pyrrolidines and their use as melanocortin agonists | |
| JPWO2006051826A1 (en) | Nitrogen-containing heterocyclic compound and pharmaceutical use thereof | |
| ES2541607T3 (en) | CCR2 antagonists of cyclohexane bound to 4-azetidinyl-1-heteroatom | |
| CA2615209A1 (en) | Mc4r-ag0nists for the treatment of urinary tract dysfunction | |
| CN1795186A (en) | Di-aryl substituted triazole modulators of metabotropic glutamate receptor-5 | |
| JP6553811B2 (en) | Fluoroindole derivatives as muscarinic M1 receptor positive allosteric modulators | |
| US20120149711A1 (en) | Piperidine derivatives used as orexin antagonists | |
| JP2010536736A (en) | Indole-2-one derivatives disubstituted at the 3-position, their preparation and their therapeutic use | |
| EP4076661A1 (en) | Compounds active towards nuclear receptors | |
| HU221811B1 (en) | N-acylated piperidine derivatives, process for producing them, and pharmaceutical compositions containing them | |
| JP6204983B2 (en) | CCR2 octahydro-cyclopentapyrrolyl antagonist | |
| WO1994002472A1 (en) | Thiazoline derivative | |
| US20070117847A1 (en) | N-(3-(4-Substituted-1-piperiding1)-1-phenylpropyl) substituted sulfonamides as NK-3 receptor antagonists |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |