CN1361766A - 具有酰氧基甲氧基羰基侧链的三环化合物 - Google Patents
具有酰氧基甲氧基羰基侧链的三环化合物 Download PDFInfo
- Publication number
- CN1361766A CN1361766A CN00810581A CN00810581A CN1361766A CN 1361766 A CN1361766 A CN 1361766A CN 00810581 A CN00810581 A CN 00810581A CN 00810581 A CN00810581 A CN 00810581A CN 1361766 A CN1361766 A CN 1361766A
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- Prior art keywords
- unsubstituted
- compound
- alkyl group
- replace
- low alkyl
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- 150000001875 compounds Chemical group 0.000 title claims abstract description 409
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 131
- -1 carbamoyloxy Chemical group 0.000 claims abstract description 118
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 64
- 239000001257 hydrogen Substances 0.000 claims abstract description 63
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 50
- 229910052727 yttrium Inorganic materials 0.000 claims abstract description 46
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 39
- 150000003839 salts Chemical class 0.000 claims abstract description 31
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 29
- 239000012453 solvate Substances 0.000 claims abstract description 24
- 125000003118 aryl group Chemical group 0.000 claims abstract description 18
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 76
- 150000002367 halogens Chemical class 0.000 claims description 75
- 125000003545 alkoxy group Chemical group 0.000 claims description 64
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 62
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 42
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 39
- 150000002431 hydrogen Chemical class 0.000 claims description 35
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 32
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 25
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 23
- 229910052799 carbon Inorganic materials 0.000 claims description 20
- 125000004414 alkyl thio group Chemical group 0.000 claims description 16
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 16
- 125000000304 alkynyl group Chemical group 0.000 claims description 15
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 14
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 13
- 125000004423 acyloxy group Chemical group 0.000 claims description 12
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 239000001301 oxygen Substances 0.000 claims description 9
- 239000000043 antiallergic agent Substances 0.000 claims description 8
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 7
- 239000003018 immunosuppressive agent Substances 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 6
- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 6
- 125000005108 alkenylthio group Chemical group 0.000 claims description 5
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 5
- 125000005110 aryl thio group Chemical group 0.000 claims description 5
- RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Natural products CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 claims description 4
- 125000001425 triazolyl group Chemical group 0.000 claims description 4
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 3
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 3
- ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 3
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 3
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 3
- VBQICASFGLMAME-UHFFFAOYSA-N C=CC(C)=C.[O] Chemical group C=CC(C)=C.[O] VBQICASFGLMAME-UHFFFAOYSA-N 0.000 claims description 2
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 abstract description 42
- 125000005115 alkyl carbamoyl group Chemical group 0.000 abstract 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 84
- 238000000034 method Methods 0.000 description 65
- 239000002585 base Substances 0.000 description 63
- 238000006243 chemical reaction Methods 0.000 description 50
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 44
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 42
- 239000000460 chlorine Substances 0.000 description 35
- 239000000243 solution Substances 0.000 description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 26
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 26
- 239000002904 solvent Substances 0.000 description 26
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 25
- 238000004458 analytical method Methods 0.000 description 23
- 238000005160 1H NMR spectroscopy Methods 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 239000000203 mixture Substances 0.000 description 18
- 239000000651 prodrug Substances 0.000 description 18
- 229940002612 prodrug Drugs 0.000 description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 17
- 125000002252 acyl group Chemical group 0.000 description 17
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 17
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 230000002194 synthesizing effect Effects 0.000 description 14
- 239000000376 reactant Substances 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 12
- 239000011734 sodium Substances 0.000 description 12
- JDVPQXZIJDEHAN-UHFFFAOYSA-N succinamic acid Chemical class NC(=O)CCC(O)=O JDVPQXZIJDEHAN-UHFFFAOYSA-N 0.000 description 12
- 238000010438 heat treatment Methods 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 238000006069 Suzuki reaction reaction Methods 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 10
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical group [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 10
- 125000001424 substituent group Chemical group 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000003513 alkali Substances 0.000 description 9
- 238000010511 deprotection reaction Methods 0.000 description 9
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 8
- 229910052796 boron Inorganic materials 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 7
- 239000003054 catalyst Substances 0.000 description 7
- 239000000543 intermediate Chemical class 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 description 7
- 210000002381 plasma Anatomy 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- 101150003085 Pdcl gene Proteins 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 230000003266 anti-allergic effect Effects 0.000 description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 6
- 229910052794 bromium Inorganic materials 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 230000001506 immunosuppresive effect Effects 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- 229910052763 palladium Inorganic materials 0.000 description 6
- 150000003254 radicals Chemical class 0.000 description 6
- 238000006467 substitution reaction Methods 0.000 description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 5
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 238000003810 ethyl acetate extraction Methods 0.000 description 5
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000011630 iodine Substances 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 5
- 230000036470 plasma concentration Effects 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 239000012312 sodium hydride Substances 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 5
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical group CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 description 4
- 108010058846 Ovalbumin Proteins 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 125000001118 alkylidene group Chemical group 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 229910000085 borane Inorganic materials 0.000 description 4
- JYWJULGYGOLCGW-UHFFFAOYSA-N chloromethyl chloroformate Chemical compound ClCOC(Cl)=O JYWJULGYGOLCGW-UHFFFAOYSA-N 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 230000000704 physical effect Effects 0.000 description 4
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 235000015320 potassium carbonate Nutrition 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 description 4
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
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- 125000000707 boryl group Chemical group B* 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 3
- 239000008116 calcium stearate Substances 0.000 description 3
- 235000013539 calcium stearate Nutrition 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000006482 condensation reaction Methods 0.000 description 3
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- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
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- 241001465754 Metazoa Species 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- OKJIRPAQVSHGFK-UHFFFAOYSA-N N-acetylglycine Chemical compound CC(=O)NCC(O)=O OKJIRPAQVSHGFK-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/70—Sulfur atoms
-
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A—HUMAN NECESSITIES
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Abstract
本发明提供由式(I)表示的化合物或其可药用盐或溶剂化物,以及包含本发明化合物的药物组合物:其中X和X′为-N(COOCR3R2OCOR1)-,-O-等,R1为由氨基甲酰基、低级烷基氨基甲酰基、氨基甲酰氧基、低级烷基氨基甲酰氧基、乙酰基氨基等取代的烷基,R2和R3为氢等,Y和Y′为低级烷基、低级链烯基等,环A、环B和环C为未取代的或取代的芳族碳环或者为未取代的或取代的杂环,W1、W2和/或W3为键等,并且V1和V2为单键等。
Description
技术领域
本发明涉及新的用作前药的化合物、包含该化合物的药物组合物及其中间体。尤其,本发明涉及新的具有酰氧基甲氧基羰基侧链的三环化合物、包含该化合物的免疫抑制剂和抗变态反应药以及新的具有免疫抑制活性和抗变态反应活性的三环化合物及其中间体。
背景技术
在很多情况下,为了改善物理性质如可结晶性、稳定性、水溶性等等、生物利用度和药理活性持续时间,研究具有药学活性物质前药的制备。尤其,为了增强可吸收性和稳定性,需要将胺化合物转化为前药,但简单的酰胺化前药不可能在活体内再转化为胺,因此要求确立转化成前药的步骤。
WO97/39999和WO98/04508中公开,对三联苯衍生物是有效的免疫抑制剂和抗变态反应药。WO98/04508中特别提到了前药并尤其描述了将羟基化合物转化为前药。
在JP-A23359/1985,JP-A18747/1986和WO96/18605中描述了通过用-COOCR1R2OCOR3(R3=烷基、羧基烷基、卤代烷基、氨基甲酰基烷基等)取代伯胺或仲胺制备前药的方法。另外,在JP-A503925/1993和“合成”(1990年12月,1159-1166)中描述了用R2SCOOCH2OCOR1(化合物A)和ClCOOCH2OCOR1(化合物B)作为中间体合成前药。然而,其中清楚地描述了按照所述方法不能从化合物A(其中R1为羟乙基或乙酰基氨基甲基并且R2为乙基)合成化合物B。
具有与本发明化合物类似骨架并具有免疫抑制活性或抗变态反应活性的化合物描述于WO94/27980、WO95/13067、WO96/15123、WO95/15318、WO96/40659、WO96/40143、WO96/38412、WO96/10012、WO97/24356、WO97/27181、WO97/24324、WO97/44333、WO97/46524、WO98/04508、WO98/24766、WO98/24782、WO98/56785、FR2301250、US5593991、JP-B7368/1972、JP-A91259/1976、JP-A3163/1996、JP-A124571/1997、JP-A71564/1997、JP-A124571/1997、JP-A79993/1999,Bioorganic & Medicinal Chemistry Letters,Vol.5,No.18,p2143-2146(1995),J.Med.Chem.,1974,Vol.17,No.11,1177-1181等等。
另外,具有与本发明化合物类似骨架的液态结晶化合物公开于JP-A121225/1983、JP-A87253/1997、JP-A253065/1988、JP-A106864/1986、JP-A106871/1986、JP-A83346/1990、JP-A48760/1997、JP-A31063/1997、WO88/07992等等中,具有杀虫活性或杀螨活性的化合物公开于JP-A193067/1996,具有治疗循环疾病和精神病活性的化合物公开于EP0600717A1中并且具有治疗中枢神经疾病活性的化合物公开于WO95/15954中。
本发明公开
本发明的目的是提供新的具有免疫抑制活性和/或抗变态反应活性的化合物的前药。
本发明提供下列化合物或其可药用盐或其前药。
[1]、由式(I)表示的化合物:(下文称作化合物(I))
其中X和X′中的一个为-N(COOCR3R2OCOR1)-,另一个为-(CH2)s-(其中s为整数0-2)、-O-、-NRA-(其中RA为氢、未取代的或取代的低级烷基、低级链烯基或低级烷基羰基)、-N(COOCR3R2OCOR1)-或-S(O)p-(其中p为整数0-2),
R1为由1个或2个取代基取代的低级烷基,所述取代基选自-CONH2、-CONHCH3、-CONHC2H5、-OCONH2、-OCONHCH3、-OCONHC2H5、-(NHCOCRR′)mNHCOCH3、-(NHCOCRR′)mNHCOC2H5、-CSNH2、-(OCH2CH2)nOH、-OCH3、-(OCH2CH2)nOCH3、-COCH3、-COC2H5、-OCOCH3、-OCOC2H5、-NHOH、-NHCONH2、-NHCSNH2、-NHSO2CH3、-N(SO2CH3)2、-SO2NH2、-SOCH3、-SO2CH3、-OCH2CONH2、-OCH2CON(CH3)2、-SO2N(CH3)2、-PO(OCH3)2、-NHCSNHC2H5、-CH=NNHCONH2、-CH=NNHCSNH2或-CH=NNHSO2CH3,三唑基和四唑基(R和R′各独立地为氢或低级烷基,m为整数0-2并且n为整数1或2),
R2和R3各独立地为氢或低级烷基,
Y和Y′各独立地为氢、未取代的或取代的低级烷基、未取代的或取代的低级链烯基、未取代的或取代的低级链炔基、未取代的或取代的环烷基、未取代的或取代的环烯基、未取代的或取代的低级烷氧基羰基、未取代的或取代的氨磺酰基、未取代的或取代的氨基、未取代的或取代的芳基或者未取代的或取代的5-元或6-元杂环,
当X为-CH2-时,Y可以是未取代的或取代的低级烷氧基,
当X′为-CH2-时,Y′可以是未取代的或取代的低级烷氧基,
当X为-O-或-NRA-时,Y可以是未取代的或取代的低级烷基磺酰基或者未取代的或取代的芳基磺酰基,
当X′为-O-或-NRA-时,Y′可以是未取代的或取代的低级烷基磺酰基或者未取代的或取代的芳基磺酰基,
环A、环B和环C各独立地为未取代的或取代的芳族碳环或者为可以与苯环稠合的未取代的或取代的5-元或6-元杂环,
当环A、环B和/或环C是未取代的或取代的5-元杂环时,W1、W2和/或W3代表键,
V1和V2中的一个为单键、另一个为单键、-O-、-NH-、-OCH2-、-CH2O-、-CH=CH-、-C≡C-、-CH(ORB)-(其中RB为氢或低级烷基)、-CO-、-NHCHRc-或-CHRcNH-(其中Rc为氢或羟基),
当V1和V2都为单键时,环A、环B和环C中至少一个为未取代的或取代的芳族碳环,并且至少一个为可以与苯环稠合的未取代的或取代的5-元或6-元杂环,
[2]、由式(II)表示的化合物:(下文称作化合物(II))
其中X和X′中的一个为-N(COOCR3R2OCOR1)-,另一个为-O-、-NH-或-N(COOCR3R2OCOR1)-,
Y和Y′各自独立地为未取代的或取代的低级烷基、未取代的或取代的低级链烯基或者未取代的或取代的低级链炔基,
R1、R2和R3具有与[1]相同的含义,
环A和环C各自独立地为未取代的或取代的苯环或者未取代的或取代的包含1个或2个杂原子的6-元杂环,至少其中一个为6-元杂环。
R8、R9、R10和R11各自独立地为氢、卤素、羟基、未取代的或取代的低级烷基、未取代的或取代的低级烷氧基、未取代的或取代的低级链烯基、未取代的或取代的低级链烯氧基、未取代的或取代的环烷氧基、未取代的或取代的酰氧基、羧基、未取代的或取代的低级烷氧基羰基、未取代的或取代的低级链烯氧基羰基、未取代的或取代的低级烷硫基、未取代的或取代的低级烯硫基、未取代的或取代的氨基、未取代的或取代的氨基甲酰基、胍基、硝基、未取代的或取代的低级烷基磺酰基、未取代的或取代的低级烷基磺酰氧基、未取代的或取代的芳基磺酰基或未取代的或取代的芳基磺酰氧基,
其中X为-NH-或-N(COOCR3R2OCOR1)-,X′为-O-、-NH-或-N(COOCR3R2OCOR1)-,至少X和X′中的一个为-N(COOCR3R2OCOR1)-,
Y和Y′各独立地为未取代的或取代的低级烷基或者未取代的或取代的低级链烯基,
R1、R2和R3具有与[1]相同的含义,
R4、R5、R6、R7、R8、R9、R10和R11各独立地为氢、卤素、羟基、未取代的或取代的低级烷基、未取代的或取代的低级烷氧基、未取代的或取代的低级链烯基、未取代的或取代的低级链烯氧基、羧基、未取代的或取代的低级烷氧基羰基或者未取代的或取代的氨基,
环C为未取代的或由低级烷基取代的吡啶或嘧啶,
[4]、[1]-[3]所描述的任一化合物,其中R1为由1个或2个取代基取代的C1-C3烷基,所述取代基选自-CONH2、-OCONH2和-(NHCOCRR′)mNHCOCH3,
[5]、[3]中所描述的化合物,其中R4和R5各独立地为氢或卤素,
[6]、[3]中所描述的化合物,其中R6和R7都为氢,
[7]、[2]或[3]中所描述的化合物,其中R8和R11各独立地为氢、羟基或低级烷基,
[8]、[2]或[3]中所描述的化合物,其中R9和R10各独立地为低级烷基、低级烷氧基或低级烷氧基羰基,
[9]、[1]-[3]所描述的任一化合物,其中X′为-O-,
[10]、[3]中所描述的化合物,其中X为-NH-或-N(COOCR3R2OCOR1)-,X′为-O-、-NH-或-N(COOCR3R2OCOR1)-,至少X和X′中的一个为-N(COOCR3R2OCOR1)-,
R1为由1个或2个取代基取代的C1-C3烷基,所述取代基选自-CONH2、-OCONH2和-(NHCOCRR′)mNHCOCH3,R2和R3为氢或C1-C3烷基,
Y和Y′各独立地为未取代的或由卤代取代的低级烷基,或者未取代的或由卤素取代的低级链烯基,R4和R5各独立地为氢或卤素,R6和R7都是氢,R8和R11各独立地为氢、羟基或低级烷基,R9和R10各独立地为低级烷基、低级烷氧基或低级烷氧基羰基,并且环C为未取代的或由低级烷基取代的吡啶或嘧啶,
[11]、[1]、[2]、[3]和[10]中所描述的任一化合物,其中Y和Y′都是异戊二烯基(prenyl),
R4和R5各独立地为氢、卤素或低级烷氧基,R6和R7各独立地为氢、卤素或低级烷基,R8和R11都为低级烷基,或者其中的一个为低级烷基并且另一个为氢或低级烷氧基,R9和R10都为氢、低级烷基或低级烷氧基,并且-X-Y和-X′-Y′中的一个为-N(COOCR3R2OCOR1)-(未取代的或取代的低级烷基或者未取代的或取代的低级链烯基),并且另一个为异戊二烯氧基(prenyloxy)或异戊二烯氨基(prenylamino),
本发明另一具体实施方案提供包含[1]-[13]中所描述的任一化合物或其可药用盐或溶剂化物,特别是免疫抑制剂或抗变态反应药的药物组合物。
另外,本发明提供抑制免疫反应的方法或治疗或预防变态反应疾病的方法,所述方法包括给予化合物(I)。而且,本发明提供化合物在制备用于抑制免疫反应或者治疗或预防变态反应疾病的药物中的应用。
本发明另一实施方案提供用作化合物(I)和(II)中间体的下列化合物:
由式(VIIb′)表示的化合物或其可药用盐或溶剂化物:其中R4和R5中的一个为氢,另一个为卤素,R8和R11各独立地为氢、羟基或低级烷基,R9和R10各独立地为低级烷基、低级烷氧基或低级烷氧基羰基,L′为二羟基硼烷基、二低级烷基硼烷基或二低级烷氧基硼烷基,和
附图简述
图1显示的是当给予化合物(I-1)时血浆中母化合物(II-1)浓度的图示。
图2显示的是当给予化合物(I-163)或母化合物(II-4)时血浆中母化合物(II-1)浓度的图示。
图3显示的是当给予化合物(I-16)或母化合物(II-1)时血浆中母化合物(II-1)浓度的图示。
实施本发明的最佳方式
本文所使用的“卤素”包括氟、氯、溴和碘。尤其优选氟和氯。
“低级烷基”包括直链或支链C1-C10,优选C1-C8,更优选C1-C5,并且最优选C1-C3烷基。其实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、己基、异己基、正庚基、异庚基、正辛基、异辛基、正壬基和正癸基。最优选甲基。
“C1-C5烷基”包括直链或支链烷基,例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基和新戊基。
“C1-C3烷基”包括直链或支链烷基,例如甲基、乙基、正丙基和异丙基。
“未取代的或取代的低级烷基”中取代基的实例包括卤素;羟基;未取代的或由低级烷氧基取代的低级烷氧基;酰基;酰氧基;羧基;低级烷氧基羰基;巯基;低级烷硫基;未取代的或由羟基、低级烷基或者未取代的或取代的酰基取代的氨基,未取代的或由羟基、低级烷氧基、羧基-低级烷氧基、芳基-低级烷氧基或5-或6-元杂环取代的亚氨基;未取代的或由氨基甲酰基或低级烷氧基羰基取代的亚肼基(hydrazono);未取代的或由低级烷基或氨基取代的氨基甲酰基;未取代的或由低级烷基取代的硫代氨基甲酰基;未取代的或由低级烷基或低级烷氧基取代的环烷基;未取代的或由低级烷基取代的环烯基;氰基;未取代的或由1个或多个羟基、低级烷基、羧基、低级烷氧基羰基和低级烷氧基取代的苯基;未取代的或由低级烷基取代的并且是未稠合的或与苯环稠合的5-元或6-元杂环。在本文情况下,可以由1个或多个所述取代基取代任何部位。优选未取代的低级烷基。
“低级烷氧基”中的低级烷基部分与上述“低级烷基”中所述相同。
“未取代的或取代的低级烷氧基”中取代基的实例包括卤素;羟基;未取代的或由低级酰氧基取代的低级烷氧基;酰基;酰氧基;羧基;低级烷氧基羰基;低级烷硫基;未取代的或由低级烷基取代的氨基;未取代的或由低级烷基或低级烷氧基取代的苯基;杂环;杂环碳酰氧基。优选未取代的低级烷氧基。
“低级烷硫基”、“低级烷氧基羰基”、“低级烷基磺酰基”、“低级烷基磺酰氧基”、“低级烷基亚磺酰基”、“低级烷基氨基甲酰基”、“低级烷基氨基甲酰氧基”和“低级亚烷基二氧基”中的低级烷基部分与上述“低级烷基”中所述相同。
“未取代的或取代的低级烷氧基羰基”、“未取代的或取代的低级烷基磺酰基”、“未取代的或取代的低级烷基磺酰氧基”、“未取代的或取代的低级烷基亚磺酰基”和“未取代的或取代的低级烷硫基”中的取代基与上述“未取代的或取代的低级烷氧基”所述相同。
“低级链烯基”包括在任意部位具有一个或多个双键的直链或支链C2-C10,优选C2-C8,更优选C3-C6链烯基。尤其,其实例包括乙烯基、丙烯基、异丙烯基、丁烯基、异丁烯基、异戊二烯基(prenyl)、丁二烯基、戊烯基、异戊烯基、戊二烯基、己烯基、异己烯基、己二烯基、庚烯基、辛烯基、壬烯基和癸烯基。“未取代的或取代的低级链烯基”中的取代基与上述“未取代的或取代的低级烷氧基”所述相同。
“低级链烯氧基”、“低级链烯氧基羰基”和“低级链烯硫基”中低级链烯基部分与上述“低级链烯基”所述相同。“未取代的或取代的低级链烯氧基”、“未取代的或取代的低级链烯氧基羰基”和“未取代的或取代的低级链烯硫基”中的取代基与上述“未取代的或取代的低级烷氧基”所述相同。
“低级链炔基”包括直链或支链C2-C10,优选C2-C8并且更优选C3-C6链炔基,例如乙炔基、丙炔基(2-丙炔基等)、丁炔基(2-丁炔基等)、戊炔基、己炔基、庚炔基、辛炔基、壬炔基和癸炔基。这些炔基在任意部位具有一个或多个三键并且可能还具有双键。
“未取代的或取代的低级链炔基”中的取代基与上述“未取代的或取代的低级烷氧基”所述相同。
“酰基”包括直链或支链C1-C10,更优选C1-C6,最优选C1-C4烷基羰基,直链或支链C3-C10,更优选C3-C6,最优选C3-C4链烯基羰基,和C4-C9,优选C4-C7环烷基羰基和芳基羰基。尤其,其实例包括甲酰基、乙酰基、丙酰基、丁酰基、异丁酰基、戊酰基、新戊酰基、己酰基、丙烯酰基、丙炔酰基、异丁烯酰基、巴豆酰基、环丙基羰基、环己基羰基、环辛基羰基和苯甲酰基。尤其优选乙酰基。
“未取代的或取代的酰基”中的取代基与上述“未取代的或取代的低级烷氧基”所述相同,并且环烷基羰基和芳基羰基可以进一步还有低级烷基取代基。
“酰氧基”中的酰基部分与上述“酰基”所述相同,并且“未取代的或取代的酰氧基”中的取代基与上述“未取代的或取代的酰基”所述相同。
“环烷基”为C3-C6碳环并且包括,例如环丙基、环丁基、环戊基、环己基等等。
“未取代的或取代的环烷基”中取代基的实例包括低级烷基、卤素、羟基、羧基、低级烷氧基羰基、低级烷氧基、低级亚烷基二氧基、未取代的或由低级烷氧基、芳基和5-元或6-元杂环取代的亚氨基。可以在1个或多个任意部位取代。
“环烯基”包括在环的任意部位具有1个或多个双键的上述环烷基,例如环丙烯基、环丁烯基、环戊烯基、环己烯基和环己二烯基。
“未取代的或取代的环烯基”的取代基与上述“环烷基”所述相同。
“未取代的或取代的氨基”中取代基的实例包括未取代的或取代的低级烷基{其中取代基为低级烷氧基、环烷基、未取代的或取代的氨基(取代基为低级烷基、苯基等)、未取代的或取代的芳基(取代基为低级烷基、低级烷氧基、羧基、低级烷氧基羰基)或杂环};低级亚烷基;低级链烯基;低级链炔基;环烷基;未取代的或由低级烷基、羧基、酰基或低级烷氧基羰基取代的芳基;未取代的或由低级烷基取代的氨磺酰基;低级烷氧基羰基;低级烷基磺酰基;未取代的或由低级烷基或低级亚烷基等取代的氨基。
“未取代的或取代的亚氨基”包括取代的亚氨基和未取代的亚氨基,并且其取代基与上述“未取代的或取代的氨基”所述相同。
“未取代的或取代的氨基甲酰基”包括未取代的或由低级烷基、低级链烯基、低级链炔基等等取代的氨基甲酰基。
“未取代的或取代的氨磺酰基”包括未取代的或由低级烷基、低级链烯基、低级链炔基等等取代的氨磺酰基。
“芳族碳环”包括苯环、萘环、蒽环和菲环。尤其优选苯环。
另外,“芳族碳环”可以与另一碳环稠合,并且其实例包括2,3-二氢化茚环、茚环和二氢化萘环。
“芳基”包括苯基、萘基、蒽基和菲基。尤其优选苯基。另外,“芳基”可以与另一碳环稠合,其中键合基可以位于任何位置。其实例包括2,3-二氢化茚基、茚基、二氢化萘基等等。
“未取代的或取代的芳族碳环”和“未取代的或取代的芳基”中取代基的实例包括卤素;羟基;未取代的或由卤素或羧基取代的低级烷基;未取代的或由卤素、芳基、杂芳基或低级烷氧基取代的低级烷氧基;低级链烯基;低级链炔基;环烷基;低级链烯氧基;低级链炔氧基;环烷氧基;酰基;酰氧基;羧基;低级烷氧基羰基;低级链烯氧基羰基;低级烷硫基;低级炔硫基;未取代的或由低级烷基、环烷基-低级烷基、杂芳基-低级烷基、低级链烯基、环烷基、未取代的或由卤素取代的酰基、低级烷氧基羰基或低级烷基磺酰基取代的氨基;胍基;硝基;低级烷基磺酰基;二羟基硼烷基;未取代的或由卤素取代的低级烷基磺酰氧基;芳基磺酰基;芳基磺酰氧基;芳基;和5-或6-元杂环。可以在1个或多个任意部位由这些取代基取代。优选的是卤素;羟基;未取代的或由卤素取代的低级烷基;未取代的或由芳基或低级烷氧基取代的低级烷氧基;低级链烯氧基;酰氧基;低级烷硫基;未取代的或由低级烷基、低级链烯基、未取代的或由卤素取代的酰基、或低级烷基磺酰基取代的氨基;硝基;低级烷基磺酰基;未取代的或由卤素取代的低级烷基磺酰氧基;和芳基磺酰氧基。
“芳基磺酰基”和“芳基磺酰氧基”中的芳基部分与上述“芳基”所述相同。尤其优选苯基。“未取代的或取代的芳基磺酰基”与上述“未取代的或取代的芳基”所述相同。尤其优选未取代的。
“5-元或6-元杂环”包括在环中包含1个或多个选自O、S和N杂原子的5-元或6-元杂环,例如芳族杂环如吡咯环、咪唑环、吡唑环、吡啶环、哒嗪环、嘧啶环、吡嗪环、三唑环、三嗪环、异噁唑环、噁唑环、噁二唑环、异噻唑环、噻唑环、噻二唑环、呋喃环和噻吩环,和非芳族杂环如四氢吡喃环、二氢吡啶环、二氢哒嗪环、二氢吡嗪环、二噁烷环、氧硫杂茂烷(oxathiolane)环、thiane环、吡咯烷环、吡咯啉环、咪唑烷环、咪唑啉环、吡唑烷环、吡唑啉环、哌啶环、哌嗪环和吗啉环。
“包含1个或2个杂原子的5-元或6-元杂环”包括上述“5-元或6-元杂环”中的芳族杂环如吡咯环、咪唑环、吡唑环、吡啶环、哒嗪环、嘧啶环、吡嗪环、异噁唑环、噁唑环、异噻唑环、噻唑环、呋喃环和噻吩环,和非芳族杂环如二噁烷环、氧硫杂茂烷环、thiane环、二氢吡啶环、吡咯烷环、吡咯啉环、咪唑烷环、咪唑啉环、吡唑烷环、吡唑啉环、哌啶环、哌嗪环和吗啉环。尤其优选芳族杂环。
在环A、环B和环C中的“5-元或6-元杂环”的实例优选包括2,5-吡啶二基和2,5-嘧啶二基。
在Y中的“5-元或6-元杂环”的实例优选包括4-吡啶基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、1,2-二氢吡啶基、2,3-二氢哒嗪基、1,2-二氢吡嗪基等等。
“可以与苯环稠合的5-元或6-元杂环”的实例包括上述“5-元或6-元杂环”中所述杂环实例,以及吲哚环、异吲哚环、苯并咪唑环、吲唑环、噌啉环、酞嗪、喹唑啉环、苯并异噁唑环、苯并噁唑环、苯并噁二唑环、苯并噻唑环、苯并异噻唑环、苯并呋喃环、苯并噻吩环、苯并三唑环、异苯并呋喃环、二氢吲哚环、异二氢吲哚环和苯并吡喃环。
“未取代的或取代的5-元或6-元杂环”和“可以与苯环稠合的未取代的或取代的5-元或6-元杂环”中取代基的实例包括卤素;卤素;羟基;未取代的或由羟基或酰氧基取代的低级烷基;未取代的或由卤素、芳基或5-元或6-元杂环取代的低级烷氧基;低级链烯基;低级链烯氧基;低级链炔基;低级链炔氧基;酰氧基;羧基;低级烷氧基羰基;巯基;低级烷硫基;低级烯硫基;未取代的或由卤素、未取代的或取代的低级烷基(取代基为环烷基或5-元或6-元杂环)、未取代的或由卤素、低级链烯基、环烷基或低级烷基磺酰基取代的酰基一或二取代的氨基;未取代的或由低级烷基磺酰基取代的亚氨基;硝基;低级烷基磺酰基:芳基;5-元或6-元杂环;氧代;和氧化物。可以在1个或多个任意部位取代。
“未取代的或取代的包含的1个或2个杂原子的5-元或6-元杂环”的取代基与以上所述相同。尤其优选用低级烷基取代的杂环或未取代的杂环。
“当环A、环B和/或环C为未取代的或取代的5-元杂环时,W1、W2和/或W3代表键”是指当环A为5-元杂环时,W1代表键,并且连接到环A上的V1和X的位置如下:
本说明书中化合物(I)、化合物(II)和化合物(III)(下文称作本发明化合物)可药用盐的实例包括无机酸如盐酸、硫酸、硝酸、磷酸、氢氟酸和氢溴酸的盐;有机酸例如甲酸、乙酸、酒石酸、乳酸、柠檬酸、富马酸、马来酸和琥珀酸的盐;有机碱如铵、三甲基铵和三乙基铵的盐;碱金属如钠、钾等的盐和碱土金属如钙、镁等的盐。
本发明包括本发明化合物的溶剂化物。一分子化合物可以与任意数目适宜的溶剂或水分子配位。优选地,溶剂化物为水合物。另外,本发明包括本发明化合物的所有立体异构体(如阻转异构体)。
本发明化合物的最大特征是它可以通过用酰氧基甲氧基羰基取代由氨基取代的三环化合物的氨基转化为前药,其中所述酰氧基甲氧基羰基是由非离子和亲水基团取代的。“非离子和亲水基团”包括不能在溶液中分离成离子并且可降低母化合物的亲油性(疏水性)提高其亲水性的基团。亲水性基团包括可通过Journal of MedicinalChemistry,1973,Vol.16,No.11,1207-1216和Journal ofMedicinal Chemistry,1977,Vol.20,No.20,304-306中所描述的方法获得的具有负疏水取代基常数π的基团,优选π为-0.5或更小的基团。疏水取代基常数可通过下列方程式获得:
π=log PX-C6H5-log P苯其中PX-C6H5是由要求获得π的取代基X取代的苯在水-辛醇之间的分布系数,并且P苯是苯在水-辛醇之间的分布系数(log P苯=2.13)。
其实例包括-CONH2、-CONHCH3、-CONHC2H5、-OCONH2、-OCONHCH3、-OCONHC2H5、-(NHCOCRR′)mNHCOCH3、-(NHCOCRR′)mNHCOC2H5、-CSNH2、-(OCH2CH2)nOH、-OCH3、-(OCH2CH2)nOCH3、-COCH3、-COC2H5、-OCOCH3、-OCOC2H5、-NHOH、-NHCONH2、-NHCSNH2、-NHSO2CH3、-N(SO2CH3)2、-SO2NH2、-SOCH3、-SO2CH3、-OCH2CONH2、-OCH2CON(CH3)2、-SO2N(CH3)2、-PO(OCH3)2、-NHCSNHC2H5、-CH=NNHCONH2、-CH=NNHCSNH2、-CH=NNHSO2CH3、三唑基和四唑基(R和R′各独立地为氢或低级烷基,m为整数0-2并且n为整数1或2),
当用本发明范围之外的基团取代由氨基取代的三环化合物中的氨基时,不能获得其作为前药时足够大的效应。
例如,当简单地用酰基或烷氧基羰基取代所述氨基时,所得到的化合物是稳定的并且在活体内不能再转化为其活性形式。当用氨酰基或羧酰基取代所述氨基时,所得到的化合物具有降低的亲油性,但在活体内不能再转化为其活性形式。
另外,当用未取代的酰氧基烷氧基羰基取代所述氨基时,所得到的化合物具有高亲水性并且难以吸收到活体内。
当用羟基取代的酰氧基甲氧基羰基取代所述氨基时,所得到的化合物具有低熔点并且难以配制成制剂。
当用离子性亲水基团如羧基和二烷基氨基取代的酰氧基甲氧基羰基取代化合物中的氨基时,所得到的化合物可能获得改善的效应如亲水性,但难以在活体内再转化为其活性形式。另外,每个这样的化合物都具有产率低,不结晶并且化学稳定性较差导致难以配制成制剂的问题,因此所述化合物不能在工业上落实。
当用被离子性亲水基团例如磷酸根和磺酸根取代的酰氧甲氧基羰基取代化合物的氨基时,该化合物很难被合成,在工业生产中难以应用。
所以,本发明的特征在于将氨基取代的三联苯基化合物和用上述基团取代的酰氧基甲氧基羰基组合。
每个化合物(I)都是具有免疫抑制和/或抗变态反应活性的化合物的前药并且下列化合物是特别优选的。
1)、化合物,其中X和X′中的一个为-N(COOCR3R2OCOR1)-并且另一个为-O-、-NH-或-N(COOCR3R2OCOR1)-,并且R1、R2和R3具有与[1]相同的含义(下文将X和X′称作X1),
化合物,其中X为-NH-或-N(COOCR3R2OCOR1)-,X′为-O-或-N(COOCR3R2OCOR1)-,至少其中的一个为-N(COOCR3R2OCOR1)-,并且R1、R2和R3具有与[1]相同的含义(下文将X和X′称作X2),
化合物,其中X为-N(COOCR3R2OCOR1)-,X′为-O-或-N(COOCR3R2OCOR1)-,R1为由1个或2个取代基取代的低级烷基,所述取代基选自-CONH2、-CONHCH3、-CONHC2H5、-OCONH2、-OCONHCH3、-OCONHC2H5、-NHCOCH3、-NHCOCH2NHCOCH3、-(NHCOCH2)2NHCOCH3和-NHCOCH(Me)NHCOCH3,并且R2和R3各独立地为氢或低级烷基(下文将X和X′称作X3),
化合物,其中X为-N(COOCR3R2OCOR1)-,X′为-O-,R1为由1个或2个取代基取代的低级烷基,所述取代基选自-CONH2、-OCONH2、-NHCOCH3和-NHCOCH2NHCOCH3,并且R2和R3都为氢(下文将X和R′称作X4),
化合物,其中X为-N(COOCR3R2OCOR1)-,X′为-O-,R1为(i)、由-CONH2和/或-NHCOCH3取代的C1-C3烷基或(ii)、由NHCOCH2NHCOCH3取代的C1-C3烷基,并且R2和R3都为氢(下文将X和X′称作X5),
2)、化合物,其中Y和Y′各独立地为未取代的或取代的低级烷基、未取代的或取代的低级链烯基或未取代的或取代的低级链炔基(下文将Y和Y′称作Y1),
化合物,其中Y和Y′各独立地为未取代的或取代的低级烷基、未取代的或取代的低级链烯基或者未取代的或取代的低级链炔基(其中取代基为卤素;羟基;低级烷氧基;酰基;酰氧基;羧基;低级烷氧基羰基;低级烷硫基;未取代的或由羟基、低级烷基或酰基取代的氨基;未取代的或由低级烷基或氨基取代的氨基甲酰基;未取代的或由低级烷基或低级烷氧基取代的环烷基;未取代的或由低级烷基取代的环烯基;氰基;未取代的或由1个或多个羟基、低级烷基、羧基、低级烷氧基羰基或低级烷氧基取代的苯基;未取代的或由低级烷基取代的5-元或6-元杂环)(下文将Y和Y′称作Y2),
化合物,其中Y和Y′各独立地为未取代的或取代的低级烷基或未取代的或取代的低级链烯基(其中取代基为卤素;羟基;低级烷氧基;酰基;羧基;低级烷氧基羰基;未取代的或由低级烷基取代的氨基;未取代的或由低级烷基取代的氨基甲酰基;环烷基;苯基;5-元或6-元杂环)(下文将Y和Y′称作Y3),
化合物,其中Y和Y′各独立地为低级烷基或低级链烯基(下文将Y和Y′称作Y4),
化合物,其中Y和Y′各独立地为低级链烯基(下文将Y和Y′称作Y5),
3)、化合物,其中环A为未取代的或取代的苯环或未取代的或取代的6-元杂环(下文将环A称作A1),
化合物,其中环A为未取代的或取代的苯环或包含1个或2个杂原子的6-元杂环(下文将环A称作A2),
化合物,其中环A为未取代的或取代的苯环(下文将环A称作A3),
化合物,其中环A为R4、R5、R6和R7各独立地为氢、卤素、羟基、未取代的或取代的低级烷基、未取代的或取代的低级烷氧基、未取代的或取代的低级链烯基、未取代的或取代的低级链烯氧基、羧基、未取代的或取代的低级烷氧基羰基或未取代的或取代的氨基(下文将环A称作A4),
4)、化合物,其中环B为苯环(下文将环B称作B1),
化合物,其中环B为R8、R9、R10和R11各独立地为氢、卤素、羟基、未取代的或取代的低级烷基、未取代的或取代的低级烷氧基、未取代的或取代的低级链烯基、未取代的或取代的低级链烯氧基、羧基、未取代的或取代的低级烷氧基羰基或未取代的或取代的氨基(下文将环B称作B2),
化合物,其中环B为R8和R11各独立地为氢、羟基或低级烷基,R9和R10各独立地为低级烷基、低级烷氧基或低级烷氧基羰基(下文将环B称作B5),
化合物,其中环B为R8和R11都为低级烷基,或者其中的一个为低级烷基并且另一个为氢或低级烷氧基,并且R9和R10都为氢、低级烷基或低级烷氧基(下文将环B称作B6),
5)、化合物,其中环C为未取代的或取代的苯环或者未取代的或取代的6-元杂环(下文将环C称作C1),
化合物,其中环C为未取代的或取代的苯环或者包含1个或2个杂原子的未取代的或取代的6-元杂环(下文将环C称作C2),
化合物,其中环C为包含1个或2个N原子的未取代的或取代的6-元杂环(下文将环C称作C3),
化合物,其中环C为未取代的或由取代基取代的6-元杂环,所述取代基选自卤素、羟基、未取代的或取代的低级烷基、未取代的或取代的低级烷氧基、未取代的或取代的低级链烯基、未取代的或取代的低级链烯氧基、羧基、未取代的或取代的低级烷氧基羰基或者包含1个或2个N原子的可以由未取代的或取代的氨基取代的6-元杂环(下文将环C称作C4),
化合物,其中环C为未取代的或各自由卤素、羟基、低级烷基、低级烷氧基或低级烷氧基羰基取代的吡啶或嘧啶(下文将环C称作C5),
化合物,其中环C为未取代的或各自由低级烷基取代的吡啶或嘧啶(下文将环C称作C6),
化合物,其中环C为未取代的吡啶(下文将环C称作C7),
6)、化合物,其中V1和V2都为单键,
7)、化合物,其中X和X’、Y和Y’、环A、环B和环C的组合如下,并且V1和V2都为单键,(X2,Y3,A3,B2,C3),(X2,Y3,A3,B2,C5),(X2,Y3,A3,B2,C6),(X2,Y3,A3,B3,C3),(X2,Y3,A3,B3,C5),(X2,Y3,A3,B3,C6),(X2,Y3,A3,B5,C3),(X2,Y3,A3,B5,C5),(X2,Y3,A3,B6,C5),(X2,Y3,A3,B7,C5),(X2,Y3,A3,B5,C6),(X2,Y3,A3,B5,C7),(X2,Y3,A5,B2,C3),(X2,Y3,A5,B2,C5),(X2,Y3,A5,B2,C6),(X2,Y3,A5,B3,C3),(X2,Y3,A5,B3,C5),(X2,Y3,A5,B3,C6),(X2,Y3,A5,B5,C3),(X2,Y3,A5,B5,C5),(X2,Y3,A5,B6,C5),(X2,Y3,A5,B7,C5),(X2,Y3,A5,B5,C6),(X2,Y3,A5,B5,C7),(X2,Y3,A7,B2,C3),(X2,Y3,A7,B2,C5),(X2,Y3,A7,B2,C6),(X2,Y3,A7,B3,C3),(X2,Y3,A7,B3,C5),(X2,Y3,A7,B3,C6),(X2,Y3,A7,B5,C3),(X2,Y3,A7,B5,C5),(X2,Y3,A7,B6,C5),(X2,Y3,A7,B7,C5),(X2,Y3,A7,B5,C6),(X2,Y3,A7,B5,C7),(X2,Y4,A3,B2,C3),(X2,Y4,A3,B2,C5),(X2,Y4,A3,B2,C6),(X2,Y4,A3,B3,C3),(X2,Y4,A3,B3,C5),(X2,Y4,A3,B3,C6),(X2,Y4,A3,B5,C3),(X2,Y4,A3,B5,C5),(X2,Y4,A3,B6,C5),(X2,Y4,A3,B7,C5),(X2,Y4,A3,B5,C6),(X2,Y4,A3,B5,C7),(X2,Y4,A5,B2,C3),(X2,Y4,A5,B2,C5),(X2,Y4,A5,B2,C6),(X2,Y4,A5,B3,C3),(X2,Y4,A5,B3,C5),(X2,Y4,A5,B3,C6),(X2,Y4,A5,B5,C3),(X2,Y4,A5,B5,C5),(X2,Y4,A5,B6,C5),(X2,Y4,A5,B7,C5),(X2,Y4,A5,B5,C6),(X2,Y4,A5,B5,C7),(X2,Y4,A7,B2,C3),(X2,Y4,A7,B2,C5),(X2,Y4,A7,B2,C6),(X2,Y4,A7,B3,C3),(X2,Y4,A7,B3,C5),(X2,Y4,A7,B3,C6),(X2,Y4,A7,B5,C3),(X2,Y4,A7,B5,C5),(X2,Y4,A7,B6,C5),(X2,Y4,A7,B7,C5),(X2,Y4,A7,B5,C6),(X2,Y4,A7,B5,C7),(X3,Y3,A3,B2,C3),(X3,Y3,A3,B2,C5),(X3,Y3,A3,B2,C6),(X3,Y3,A3,B3,C3),(X3,Y3,A3,B3,C5),(X3,Y3,A3,B3,C6),(X3,Y3,A3,B5,C3),(X3,Y3,A3,B5,C5),(X3,Y3,A3,B6,C5),(X3,Y3,A3,B7,C5),(X3,Y3,A3,B5,C6),(X3,Y3,A3,B5,C7),(X3,Y3,A5,B2,C3),(X3,Y3,A5,B2,C5),(X3,Y3,A5,B2,C6),(X3,Y3,A5,B3,C3),(X3,Y3,A5,B3,C5),(X3,Y3,A5,B3,C6),(X3,Y3,A5,B5,C3),(X3,Y3,A5,B5,C5),(X3,Y3,A5,B6,C5),(X3,Y3,A5,B7,C5),(X3,Y3,A5,B5,C6),(X3,Y3,A5,B5,C7),(X3,Y3,A7,B2,C3),(X3,Y3,A7,B2,C5),(X3,Y3,A7,B2,C6),(X3,Y3,A7,B3,C3),(X3,Y3,A7,B3,C5),(X3,Y3,A7,B3,C6),(X3,Y3,A7,B5,C3),(X3,Y3,A7,B5,C5),(X3,Y3,A7,B6,C5),(X3,Y3,A7,B7,C5),(X3,Y3,A7,B5,C6),(X3,Y3,A7,B5,C7),(X3,Y4,A3,B2,C3),(X3,Y4,A3,B2,C5),(X3,Y4,A3,B2,C6),(X3,Y4,A3,B3,C3),(X3,Y4,A3,B3,C5),(X3,Y4,A3,B3,C6),(X3,Y4,A3,B5,C3),(X3,Y4,A3,B5,C5),(X3,Y4,A3,B6,C5),(X3,Y4,A3,B7,C5),(X3,Y4,A3,B5,C6),(X3,Y4,A3,B5,C7),(X3,Y4,A5,B2,C3),(X3,Y4,A5,B2,C5),(X3,Y4,A5,B2,C6),(X3,Y4,A5,B3,C3),(X3,Y4,A5,B3,C5),(X3,Y4,A5,B3,C6),(X3,Y4,A5,B5,C3),(X3,Y4,A5,B5,C5),(X3,Y4,A5,B6,C5),(X3,Y4,A5,B7,C5),(X3,Y4,A5,B5,C6),(X3,Y4,A5,B5,C7),(X3,Y4,A7,B2,C3),(X3,Y4,A7,B2,C5),(X3,Y4,A7,B2,C6),(X3,Y4,A7,B3,C3),(X3,Y4,A7,B3,C5),(X3,Y4,A7,B3,C6),(X3,Y4,A7,B5,C3),(X3,Y4,A7,B5,C5),(X3,Y4,A7,B6,C5),(X3,Y4,A7,B7,C5),(X3,Y4,A7,B5,C6),(X3,Y4,A7,B5,C7),(X4,Y3,A3,B2,C3),(X4,Y3,A3,B2,C5),(X4,Y3,A3,B2,C6),(X4,Y3,A3,B3,C3),(X4,Y3,A3,B3,C5),(X4,Y3,A3,B3,C6),(X4,Y3,A3,B5,C3),(X4,Y3,A3,B5,C5),(X4,Y3,A3,B6,C5),(X4,Y3,A3,B7,C5),(X4,Y3,A3,B5,C6),(X4,Y3,A3,B5,C7),(X4,Y3,A5,B2,C3),(X4,Y3,A5,B2,C5),(X4,Y3,A5,B2,C6),(X4,Y3,A5,B3,C3),(X4,Y3,A5,B3,C5),(X4,Y3,A5,B3,C6),(X4,Y3,A5,B5,C3),(X4,Y3,A5,B5,C5),(X4,Y3,A5,B6,C5),(X4,Y3,A5,B7,C5),(X4,Y3,A5,B5,C6),(X4,Y3,A5,B5,C7),(X4,Y3,A7,B2,C3),(X4,Y3,A7,B2,C5),(X4,Y3,A7,B2,C6),(X4,Y3,A7,B3,C3),(X4,Y3,A7,B3,C5),(X4,Y3,A7,B3,C6),(X4,Y3,A7,B5,C3),(X4,Y3,A7,B5,C5),(X4,Y3,A7,B6,C5),(X4,Y3,A7,B7,C5),(X4,Y3,A7,B5,C6),(X4,Y3,A7,B5,C7),(X4,Y4,A3,B2,C3),(X4,Y4,A3,B2,C5),(X4,Y4,A3,B2,C6),(X4,Y4,A3,B3,C3),(X4,Y4,A3,B3,C5),(X4,Y4,A3,B3,C6),(X4,Y4,A3,B5,C3),(X4,Y4,A3,B5,C5),(X4,Y4,A3,B6,C5),(X4,Y4,A3,B7,C5),(X4,Y4,A3,B5,C6),(X4,Y4,A3,B5,C7),(X4,Y4,A5,B2,C3),(X4,Y4,A5,B2,C5),(X4,Y4,A5,B2,C6),(X4,Y4,A5,B3,C3),(X4,Y4,A5,B3,C5),(X4,Y4,A5,B3,C6),(X4,Y4,A5,B5,C3),(X4,Y4,A5,B5,C5),(X4,Y4,A5,B6,C5),(X4,Y4,A5,B7,C5),(X4,Y4,A5,B5,C6),(X4,Y4,A5,B5,C7),(X4,Y4,A7,B2,C3),(X4,Y4,A7,B2,C5),(X4,Y4,A7,B2,C6),(X4,Y4,A7,B3,C3),(X4,Y4,A7,B3,C5),(X4,Y4,A7,B3,C6),(X4,Y4,A7,B5,C3),(X4,Y4,A7,B5,C5),(X4,Y4,A7,B6,C5)(X4,Y4,A7,B7,C5),(X4,Y4,A7,B5,C6),(X4,Y4,A7,B5,C7),(X5,Y5,A3,B2,C3),(X5,Y5,A3,B2,C5),(X5,Y5,A3,B2,C6),(X5,Y5,A3,B2,C7),(X5,Y5,A3,B2,C8),(X5,Y5,A3,B3,C3),(X5,Y5,A3,B3,C5),(X5,Y5,A3,B3,C6),(X5,Y5,A3,B3,C7),(X5,Y5,A3,B3,C8),(X5,Y5,A3,B5,C3),(X5,Y5,A3,B5,C5),(X5,Y5,A3,B5,C6),(X5,Y5,A3,B5,C7),(X5,Y5,A3,B5,C8),(X5,Y5,A3,B6,C3),(X5,Y5,A3,B6,C5),(X5,Y5,A3,B6,C6),(X5,Y5,A3,B6,C7),(X5,Y5,A3,B6,C8),(X5,Y5,A3,B7,C3),(X5,Y5,A3,B7,C5),(X5,Y5,A3,B7,C6),(X5,Y5,A3,B7,C7),(X5,Y5,A3,B7,C8),(X5,Y5,A3,B8,C3),(X5,Y5,A3,B8,C5),(X5,Y5,A3,B8,C6),(X5,Y5,A3,B8,C7),(X5,Y5,A3,B8,C8),(X5,Y5,A5,B2,C3),(X5,Y5,A5,B2,C5),(X5,Y5,A5,B2,C6),(X5,Y5,A5,B2,C7),(X5,Y5,A5,B2,C8),(X5,Y5,A5,B3,C3),(X5,Y5,A5,B3,C5),(X5,Y5,A5,B3,C6),(X5,Y5,A5,B3,C7),(X5,Y5,A5,B3,C8),(X5,Y5,A5,B5,C3),(X5,Y5,A5,B5,C5),(X5,Y5,A5,B5,C6),(X5,Y5,A5,B5,C7),(X5,Y5,A5,B5,C8),(X5,Y5,A5,B6,C3),(X5,Y5,A5,B6,C5),(X5,Y5,A5,B6,C6),(X5,Y5,A5,B6,C7),(X5,Y5,A5,B6,C8),(X5,Y5,A5,B7,C3),(X5,Y5,A5,B7,C5),(X5,Y5,A5,B7,C6),(X5,Y5,A5,B7,C7),(X5,Y5,A5,B7,C8),(X5,Y5,A5,B8,C3),(X5,Y5,A5,B8,C5),(X5,Y5,A5,B8,C6),(X5,Y5,A5,B8,C7),(X5,Y5,A5,B8,C8),(X5,Y5,A7,B2,C3),(X5,Y5,A7,B2,C5),(X5,Y5,A7,B2,C6),(X5,Y5,A7,B2,C7),(X5,Y5,A7,B2,C8),(X5,Y5,A7,B3,C3),(X5,Y5,A7,B3,C5),(X5,Y5,A7,B3,C6),(X5,Y5,A7,B3,C7),(X5,Y5,A7,B3,C8),(X5,Y5,A7,B5,C3),(X5,Y5,A7,B5,C5),(X5,Y5,A7,B5,C6),(X5,Y5,A7,B5,C7),(X5,Y5,A7,B5,C8),(X5,Y5,A7,B6,C3),(X5,Y5,A7,B6,C5),(X5,Y5,A7,B6,C6),(X5,Y5,A7,B6,C7),(X5,Y5,A7,B6,C8),(X5,Y5,A7,B7,C3),(X5,Y5,A7,B7,C5),(X5,Y5,A7,B7,C6),(X5,Y5,A7,B7,C7),(X5,Y5,A7,B7,C8),(X5,Y5,A7,B8,C3),(X5,Y5,A7,B8,C5),(X5,Y5,A7,B8,C6),(X5,Y5,A7,B8,C7),(X5,Y5,A7,B8,C8),(X5,Y5,A8,B2,C3),(X5,Y5,A8,B2,C5),(X5,Y5,A8,B2,C6),(X5,Y5,A8,B2,C7),(X5,Y5,A8,B2,C8),(X5,Y5,A8,B3,C3),(X5,Y5,A8,B3,C5),(X5,Y5,A8,B3,C6),(X5,Y5,A8,B3,C7),(X5,Y5,A8,B3,C8),(X5,Y5,A8,B5,C3),(X5,Y5,A8,B5,C5),(X5,Y5,A8,B5,C6),(X5,Y5,A8,B5,C7),(X5,Y5,A8,B5,C8),(X5,Y5,A8,B6,C3),(X5,Y5,A8,B6,C5),(X5,Y5,A8,B6,C6),(X5,Y5,A8,B6,C7),(X5,Y5,A8,B6,C8),(X5,Y5,A8,B7,C3),(X5,Y5,A8,B7,C5),(X5,Y5,A8,B7,C6),(X5,Y5,A8,B7,C7),(X5,Y5,A8,B7,C8),(X5,Y5,AB,B8,C3),(X5,Y5,A8,B8,C5),(X5,Y5,A8,B8,C6),(X5,Y5,A8,B8,C7)或(X5,Y5,A8,B8,C8)。
下文将解释制备化合物(I)的方法。(制备化合物(I)的方法)
可通过将由式(IV)表示的化合物(下文称作化合物(IV))的-NH-进行α-卤代烷氧基碳化:其中X和X′中的一个为-NH-,另一个为-(CH2)s-(其中s为整数0-2)、-O-、-NRA-(其中RA为卤素、未取代的或取代的低级烷基、低级链烯基或低级烷基羰基)或-S(O)p-(其中p为整数0-2),并且其它符号具有以上所述符号相同的含义,然后,将碳化的化合物与适宜的羧酸在适宜的条件下反应合成化合物(I)。所述合成酰氧基烷基氨基甲酸酯的方法可通过WO96/18605等等所描述的方法进行。(在其中X=NH的化合物(IV)情况下)(其中各符号具有与以上所描述的符号相同的含义)
更具体地说,将化合物(IV)与氯甲酸α-卤代烷基酯在惰性溶剂如乙醚、四氢呋喃、1,4-二噁烷、乙酸乙酯或甲苯中,在碱如三乙胺或N-甲基吗啉存在下,在0℃至室温下反应,定量得到由上述式(V)表示的中间体化合物(下文称作化合物(V))。
然后,将化合物(V)与具有取代基R1的羧酸化合物的盐(如碱金属盐、碱土金属盐、银盐、汞盐等)在溶剂如N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲基亚砜、环丁砜等等中,在室温至加热下反应数小时至数天,得到化合物(I)。或者,在碱金属、碱土金属、银等的碳酸盐或碳酸氢盐存在下可使用游离羧酸,得到目标化合物。可在KBr或NaI存在下进行本反应以便用活性更强的Br或I取代化合物(V)的Cl。
如上所述,也可以在其中X′为-NH-的化合物(IV)情况下得到目标化合物。另外,在其中X和/或X′都为-NH-的情况下,可通过调整所加入氯甲酸α-卤代烷基酯的量获得其中X和/或X′被修饰的为前药的化合物。
也可以通过US4,760,057中所描述的使用对硝基苯基酰氧基烷基碳酸酯(p-NO2C6H4OCOOC(RA)(RB)OCOR1)的方法将仲胺化合物(IV)转化为化合物(I)。
此外,作为合成化合物(I)的方法,已知JP-A18747/1986中所描述了使用酰氧基烷基氯碳酸酯(acyloxyalkyl carbochloridate)(R1COOC(RA)(RB)OCOCl)的方法。
上述反应中所使用的化合物(IV)可通过WO97/39999或WO98/04508中所描述的方法或下列方法合成。(制备化合物(IV′)的方法)
由下式(IV′)表示的化合物(下文称作化合物(IV′))可通过将由式(VIa)表示的化合物(下文称作化合物(VIa))与由式(VIIa)表示的二环化合物(下文称作化合物(VIIa))反应,或者通过将由式(VIb)表示的化合物(下文称作化合物(VIb))与由式(VIIb)表示的二环化合物(下文称作化合物(VIIb))反应制备,其中L和Z中的一个二羟基硼烷基、二低级烷基硼烷基或二低级烷氧基硼烷基,另一个为卤素或-OSO2(CqF2q+1)(其中q为整数0-4),并且其它符号具有与上述符号相同的含义。
将化合物(VIa)和化合物(VIIa)或化合物(VIb)和化合物(VIIb)在适宜的溶剂(如苯、甲苯、N,N-二甲基甲酰胺、二甲氧基乙烷、四氢呋喃、二噁烷、乙醇或甲醇)和水的混合系统或者非水系统中,在钯催化剂(如Pd(PPh3)4、PdCl2(PPh3)2、PdCl2(OAc)2和PdCl2(CH3CN)2,优选Pd(PPh3)4)存在下,在碱(所述碱的实例如K3PO4、NaHCO3、NaOEt、Na2CO3、Et4NCl、Ba(OH)2、Cs2CO3、CsF、NaOH和Ag2CO3)和室温至加热条件下反应10小时,得到化合物(IV′)。
在彼此反应的化合物中,取代基L和Z中的一个就其可能用于Suzuki反应来说可以是任何硼烷基(Chemical Communication 1979,866,Journal of Synthetic Organic Chemistry,Japan,1993,vol.51,No.11,p91-100)。优选地,它是二羟基硼烷基。另一个就其可能用于Suzuki反应来说可以是任何离去基团。例如可使用卤素或-OSO2(CqF2q+1)(其中q为整数0-4)。尤其,卤素和三氟甲磺酰氧基(OTf)是优选的,并且溴、碘和OTf是最优选的。
像其它取代基一样,对于化合物(VIa)、(VIIa)、(VIb)和(VIIb)中环A、环B和环C的-X-Y和-X′-Y′来说,优选对Suzuki反应没有任何不良影响的基团,例如除卤素和-OSO2(CqF2q+2)(其中q为整数0-4)以外的基团。
例如,Y和Y′可以是未取代的或取代的低级烷基、未取代的或取代的低级链烯基、未取代的或取代的低级链炔基、未取代的或取代的环烷基、未取代的或取代的环烯基、未取代的或取代的芳基或者未取代的或取代的5-元或6-元杂环。另外,当X为-CH2-时,Y可以是未取代的或取代的低级烷氧基,并且当X′为-CH2-时,Y′可以是未取代的或取代的低级烷氧基。另外,当X为-O-或-NRA-时,Y可以是未取代的或取代的低级烷氧基羰基、未取代的或取代的低级烷基磺酰基或者未取代的或取代的芳基磺酰基,并且当X′为-O-或-NRA-时,Y′可以是未取代的或取代的低级烷氧基羰基、未取代的或取代的低级烷基磺酰基或者未取代的或取代的芳基磺酰基。
甚至当环A、环B和环C中的任何取代基为卤素时,如果取代基L和取代基Z之间的反应性高于卤素和取代基L和Z之一,那么本反应可以毫无问题地进行。
甚至当环A、环B和环C中的任何取代基-X-Y或X乙Y′为羟基时可进行上述反应。在所述情况下,优选地,所述取代基在与通常使用的羟基保护基(如甲氧基甲基、苄基、叔丁基二甲基甲硅烷基、甲磺酰基和对甲苯磺酰基)反应后进行上述反应,然后进行正常的脱保护反应。尽管作为合成化合物(IV′)的方法,优选利用上述Suzuki反应获得最佳功效并且更简单,但是可通过使用硅、锌、锡等代替上述合成方案中的硼烷基进行反应。
例如,当A和Z中的一个为-SiRD 3-r(Hal)x时(其中RD可以是各不相同的并且为低级烷基,Hal为卤素,并且r为整数1-3),另一个为卤素或-OSO2(CqF2q+1)(其中q为整数0-4)时,利用通常使用的钯催化剂(Synlett(1991)845-853,J.Org.Chem.1996,61,7232-7233)进行偶联反应。优选的钯催化剂的实例包括(i-Pr3P)2PdCl2、[(dcpe)PdCl2](dcpe=1,2-双(二环己基膦)乙烷]和(3η-C3H5PdCl)2。
另外,甚至当L和Z中的一个为-SnRE 3时(其中RE可以是各不相同的并且为低级烷基),并且另一个为卤素、乙酰氧基或-OSO2(CqF2q+1)(其中q为整数0-4)时,可利用通常使用的钯催化剂(优选Pd(PPh3)4等)(Anfew.Chem.Int.Ed.Engl.25(1986)508-524)获得靶化合物。
甚至当其中L和Z中的一个为-Zn(Hal)(其中Hal为卤素)并且另一个为卤素的化合物进行反应时,可以合成靶化合物(Acc.Chem.Res.1982,15,340-348)。任何钯催化剂就其通常使用情况来说都可能使用。优选的实例包括Pd(PPh3)4、PdCl2(dppf)(dppf=1,1′-双(二苯基膦)二茂铁)、PdCl2(PPh3)4、PdCl2(P(O-甲苯基3)2和Pd(OAc)2。
这些反应可以在适宜的溶剂(如N,N-二甲基甲酰胺、四氢呋喃等)中,在室温至加热下进行10分钟至10小时。(制备化合物(VIIa)和(VIIb)的方法)
像在上述反应式中的化合物(VIIa)和(VIIb)一样,可以使用已知的化合物,或者可以使用通过已知的方法或下列方法合成的、通过由下式(IXa)表示的化合物衍生的化合物(下文称作化合物(IXa))或由下式(IXb)表示的化合物(下文称作化合物IXb),其可通过已知方法合成或通过下述方法合成:其中D为对L和Z的Suzuki反应没有影响的基团,并且当由式(VIIIa)或式(VIIIb)表示的化合物是对称化合物时,它可以是相同的基团如L,并且其它符号具有与上述符号相同的含义。
首先像上述步骤一样,将化合物(VIb)和化合物(VIIIa)或者化合物(VIa)和化合物(VIIIb)反应,得到化合物(IXa)或(IXb)。当化合物(VIIIa)或(VIIIb)不是对称化合物时,优选地,D为对L和Z的Suzuki反应没有影响并且可以简单地衍生为L的基团,在L和Z的反应可如上所述通过使用硅、锌或锡代替硼烷基进行。
然后,将D转化为可用于Suzuki反应的取代基L。
例如,当D为羟基时,将D与三氟甲磺酰化剂(如三氟甲磺酸酐、三氟甲磺酸酰氯和N-苯基三氟甲磺酰亚胺)在适宜的溶剂(如二氯甲烷、氯仿、四氢呋喃、苯和甲苯)中,在碱(如氢化钠、吡啶、三乙胺和碳酸钾)存在下,在-20℃至加热下反应10分钟至10小时,得到其中L为OTf的靶化合物。
另外,当D为氢时,将它与卤化剂(如氯、溴、碘和N-溴琥珀酰亚胺)在适宜的溶剂(如乙酸、二氯甲烷、氯仿、四氯化碳、N,N-二甲基甲酰胺和水)中,在-20℃至加热下反应10分钟至10小时,得到其中L为卤素的靶化合物。
当D为甲酰基时,将其通过标准方法进行Baeyer-Villiger-氧化成为甲酰氧基,再进一步水解为羟基。然后,可按照与上述方法相同的方法获得其中L为OTf的化合物。
当D为硝基时,可将其还原为进行Sandmeyer反应的氨基,得到其中L为卤素的化合物。
在化合物(VIIb)中,由下式(VIIb′)表示的化合物是特别优选的;其中R4和R5中的一个为氢并且另一个为卤素,R8和R11各独立地为氢、羟基或低级烷基,R9和R10各独立地为低级烷基、低级烷氧基或低级烷氧基羰基,L′为二羟基硼烷基、、二低级烷基硼烷基或二低级烷氧基硼烷基。最优选的L′为二羟基硼烷基。通过使用该中间体,它可以不经过麻烦的保护和脱保护反应而直接进行Suzuki反应,合成靶化合物(IV′)。
首先,将已知的化合物(IXc)或通过标准方法获得的化合物(IXc)和3-甲基-2-丁烯醛与还原剂如硼氢化钠、氰基三氢硼氢化钠、三乙酰氧基硼氢化钠、三甲氧基硼氢化钠和二异丙氧基硼氯化物在适宜的溶剂如二氯甲烷、二氯乙烷、四氢呋喃、二甲氧基乙烷、二噁烷、甲苯或苯中,在中性至酸性化合物,优选酸性化合物如乙酸存在下,在0℃至加热下反应10分钟至10小时,得到化合物(IXd)。将所得到的化合物与正丁基锂、仲丁基锂、苯基锂等在适宜的溶剂如四氢呋喃、乙醚、二甲氧基乙烷等中,在-100℃至室温下反应得到锂盐,该锂盐可以与硼酸酯如硼酸三异丙酯、硼酸三甲酯、硼酸三丁酯等反应得到化合物(VIIb′)。(制备化合物(IV”)的方法)
由下式(IV”)表示的化合物(下文称作化合物(IV”))可通过由下式(X)表示的化合物(下文称作化合物(X))与由下式(VIa)表示的化合物(下文称作化合物(VIa))或由下式(XI)表示的化合物(下文称作化合物(XI))和由下式(XII)表示的化合物(下文称作化合物(XII))的缩合物进行Suzuki反应来制备:其中M和Q中的一个为羟基或氨基并且另一个为卤素、低级烷基磺酰氧基、芳基磺酰氧基、低级烷基磺酰基或芳基磺酰基或者含有取代基的甲基,或者其中的一个为锂或Mg(Hal)(其中Hal为卤素)并且另一个为羧基、低级烷氧基羰基、氨基甲酰基或甲酰基,或者其中的一个为甲酰基并且另一个为卤代甲基,或者其中的一个为乙炔基并且另一个为卤素,其它符号具有与上述符号相同的含义。
化合物(X)与化合物(VIa)反应的各种条件与制备化合物(IV′)时相同。
在化合物(XI)与化合物(XII)的反应中,当靶化合物中的V2为-O-、-NH-、-OCH2-、-CH2O-或-NHCH2-时,取代基M和Q中的一个为羟基或氨基,并且另一个为离去基团如卤素、低级烷基磺酰氧基、芳基磺酰氧基、低级烷基磺酰基和芳基磺酰基或以这些离去基团为取代基的甲基。这两个化合物在适宜的溶剂(如苯、甲苯、丙酮、乙腈、N,N-二甲基甲酰胺、二甲基亚砜、吡啶、甲醇和乙醇)中,在碱(如氢化钠、吡啶、三乙胺、碳酸钾、氢氧化钠和氢氧化钾)存在下,并且如果需要,通过加入铜催化剂(如铜粉、CuCl和CuO),在0℃至加热下反应10分钟至10小时,得到靶化合物。
在化合物(XI)与化合物(XII)的反应中,当靶化合物中的V2为-CO-、-CH(OH)-时,取代基M和Q中的一个为有机碱金属如锂或Mg(Hal)(其中Hal为卤素),并且另一个为羧基、低级烷氧基羰基、氨基甲酰基或甲酰基。这两个化合物在适宜的溶剂(如乙醚、四氢呋喃、二甲氧基乙烷和二噁烷)中,在-78℃至加热下反应10分钟至10小时,得到靶化合物。
当靶化合物中的V2为-CH(OH)-(其中R为低级烷基)时,首先得到其中V2为-CH(OH)-的化合物,然后将其烷基化。
另外, 靶化合物中V2为-CO-的化合物也可以通过将其中V2为-CH(OH)-的化合物与氧化剂如铬酸酐和Jones试剂在溶剂如叔丁醇和丙酮中,在0℃至加热下反应数小时得到。靶化合物中V2为-CH(OH)-的化合物也可以通过将其中V2为-CO-的化合物在适宜的溶剂(如乙醚、四氢呋喃、二甲氧基乙烷、二噁烷、甲醇和乙醇)中用硼氢化钠或氢化锂铝还原来制备。
当靶化合物中的V2为-CH=CH-时,取代基M和Q中的一个为甲酰基并且另一个为卤代甲基(例如,其中卤素为氯、溴或碘)。在该情况下,靶化合物可通过Wittig反应得到(Organic Reaction,1965,vol.14,p270)。
当靶化合物中的V2为-CH≡CH-时,取代基M和Q中的一个为乙炔基并且另一个为卤素(优选溴或碘)。靶化合物可通过用常用的钯催化剂进行偶联反应合成(Synthesis(1980)627,Tetrahedron,1982,38,631)。
其它取代基如在化合物(X)、(VIa)、(XI)和(XII)中环A、环B和环C的-X-Y-和-X′-Y′可以是对L和Z的Suzuki反应或M和Q的缩合反应没有任何不良影响的任何基团。然而,在化合物(X)和化合物(VIa)的反应中,甚至当任一取代基为卤素时,如果取代基L和取代基Z的反应性高于卤素和取代基L或Z的反应性时,进行本反应是没有任何问题的。甚至当任一取代基为羟基时,可进行上述反应。在该情况下,优选预先保护羟基并且,在上述反应后,进行正常的脱保护反应。
作为在上述反应式中的化合物(X),可使用已知的化合物,或用式(XIV)表示的化合物(下文称作化合物(XIV))通过已知方法合成的化合物,或者可使用下列方法合成化合物(X):其中D′为对M和Q的缩合反应没有任何不良影响的基团,当由式(XIII)表示的化合物为对称化合物时,D′可以为相同的基团如Q,并且其它符号具有与上述符号相同的含义。
当化合物(XIII)不是对称化合物时,更具体地,D′优选地为对M和Q的缩合反应没有任何不良影响并且可以简单地衍生为L的基团。其实例包括氢、甲酰基和保护的羟基和硝基。保护羟基的基团的实例包括苄基、叔丁基二甲基甲硅烷基和甲氧基甲基。将D′转化为L的方法与将D转化为L的方法相同。其它各种条件与化合物(XI)和化合物(XII)反应的条件相同。(制备化合物(IV”’)的方法)
作为合成化合物(IV)的另一方法,可通过首先构造三环化合物,然后引入侧链-X′-Y′得到靶化合物(IV)。如下解释化合物(IV′)的实例:其中T为NH2,或对Suzuki反应没有任何不良影响并且可通过正常的方法转化为U的基团(如未保护的或保护的羟基、低级烷硫基和芳硫基),U为离去基团(如卤素、低级烷基磺酰基、芳基磺酰基、低级烷基磺酰氧基和芳基磺酰氧基),s为整数0-2,并且其它符号具有与上述符号相同的含义。
首先,将由式(VIIa′)表示的化合物(下文称作化合物(VIIa′))和化合物(VIa),或者将化合物(VIIb)和由式(VIb′)表示的化合物(下文称作化合物(VIb′))按照上述Suzuki反应进行反应,得到化合物(IV)。本反应可按照上述化合物(VIa)和化合物(VIIa)或者化合物(VIb)和化合物(VIIb)的反应进行。
然后,将所得到的化合物(IV)中的T按照常规方法转化为U。
例如,当T为羟基时,它可在正常条件下转化为卤素,或者可通过使用适宜的磺化剂(如甲磺酰氯、对甲苯磺酰氯和三氟甲磺酸酐)得到磺酰基化合物。当T为预先用保护基如苄基、叔丁基甲基甲硅烷基和甲氧基甲基保护的羟基时,被保护的羟基通过正常的方法脱保护为羟基并且,从那以后的上述步骤可得到靶化合物。
另外,当T为低级烷硫基或者未取代的或取代的芳硫基时它可以通过使用适宜的氧化剂(如过氧化氢、过乙酸、间氯过苯甲酸和OXON(单过硫酸盐化合物))转化为相应的磺酰基化合物。
然后,将化合物(IV″)进行取代反应得到化合物(IV′)。例如,醇(Y′-OH)或胺(Y′-NHRA)和其中S=O的化合物在适宜的溶剂如四氢呋喃、N,N-二甲基甲酰胺、二噁烷和乙醚中,在将如氢化钠、甲醇钠和丁醇钠等碱存在下,在室温至加热下反应10分钟至10小时,得到其中X′为O或NRA的化合物(IV′)。另外,,为了得到其中X为(CH2)s的化合物(IV′),可将具有取代基Y′的亲核化合物和其中s=1或2的化合物(IV”)在类似的条件下反应。(制备化合物(VIb′)的方法)
例如,可通过下列方法合成在上述合成方案中由式(VIb′)表示的化合物(下文称作化合物(VIb′))。
1)、在该情况下,其中Z=卤素、二羟基硼烷基、二低级烷基硼烷基或二低级烷氧基硼烷基其中Hal1和Hal2为卤素,Z′为二羟基硼烷基、二低级烷基硼烷基或二低级烷氧基硼烷基,并且其它符号具有与上述符号相同的含义。
首先,将已知的化合物或通过常规方法得到的由式(VIb″)表示的化合物(下文称作化合物(VIb′))进行正常的取代反应,得到化合物(VIb′:Z=卤素)。所得到的化合物可与硼酸酯如硼酸三异丙酯、硼酸三甲酯、硼酸三丁酯和二异丙氧基硼烷氯化物(diisopropoxyboranchloride)在溶剂如四氢呋喃、二噁烷和己烷中,在碱如正丁基锂和仲丁基锂存在下反应,得到化合物(VIb′:Z=Z′)。
2)、在该情况下,Z为OSO2(CqF2q+1)
在上述化合物(VIb’)中,特别是其中环C为未取代的或由低级烷基取代的吡啶环或者未取代的或由低级烷基取代的嘧啶环,T为保护的羟基、低级烷硫基或芳硫基并且Z’为二羟基硼烷基、二低级烷基硼烷基或二低级烷氧基硼烷基的化合物优选地是化合物(IV)和化合物(I)的中间体。更优选的化合物是其中T为低级烷硫基或苯硫基,Z’为二羟基硼烷基并且s为O的化合物。
迄今为止,因为吡啶硼酸的水溶性太高,所以非常难合成(特别是分离和纯化)。然而,通过引入取代基T-(CH2)s-,合成变得容易了,因此允许制备高产率的吡啶硼酸。另外,当将T转化为离去基团时,可以用各种亲核试剂进行取代反应,得到有用的中间体,用于合成药物、农用化学品和具有2,5-二取代吡啶和嘧啶骨架作为部分结构的液晶化合物。
对于具有干扰上述反应取代基的化合物,所述基团可以预先用适宜的保护基保护,并且所述保护基可以通过常规方法在适宜的步骤脱保护。例如,当羟基干扰所述反应时,可以用保护基如甲氧基甲基、甲磺酰基、苄基、三氟甲磺酰基或叔丁基二甲基甲硅烷基保护并且,当氨基干扰所述反应时,可以用保护基如低级烷氧基羰基、低级链烯氧基羰基、卤代烷氧基羰基或芳烷氧基羰基保护,并且适宜的保护基可以在适宜的步骤除去。
例如,当用甲磺酰基保护羟基时,羟基可以与甲磺酰氯在溶剂如二氯甲烷、氯仿或四氯化碳中,在碱如三乙胺或吡啶存在下,在冰冷却至室温下反应几小时。当被保护的羟基进行脱保护反应时,可以通过加入1-4N的氢氧化钠、氢氧化钾、其水溶液,在溶剂如二甲基亚砜、N,N-二甲基甲酰胺、四氢呋喃、二噁烷和二甲氧基乙烷中的甲醇钠或溴化乙基镁,在室温至加热下反应10分钟至10小时进行。
当甲氧基甲基用作保护羟基的基团时,羟基可以与氯甲基=甲基=醚在溶剂如四氢呋喃、二噁烷和二甲氧基乙烷中,在氢化钠、二异丙基乙胺存在下反应,得到保护的羟基。当被保护的羟基脱保护时,可以在适宜的溶剂如甲醇、四氢呋喃和乙酸中,用盐酸或硫酸进行正常的脱保护反应。
当叔丁基二甲基甲硅烷基用作保护基时,羟基可以与叔丁基二甲基甲硅烷基氯或叔丁基二甲基甲硅烷基三氟磺酸酯(triflate)在溶剂如N,N-二甲基甲酰胺、乙腈、四氢呋喃和二氯甲烷中,在咪唑、三乙胺或2,6-二甲基吡啶存在下反应。当通过在溶剂如四氢呋喃中与氟化四丁基铵反应进行脱保护反应时,可除去保护基。
化合物(I)在活体内降解并且可能转化为活性形式的化合物(IV)。因为与化合物(IV)相比,化合物(I)在非禁食或禁食下显示相当好的口服可吸收性,因此可得到较高的药理学作用并且因此,化合物(I)可用作前药。另外,化合物(I)具有熔点高和不产生静电的物理优势并因此可简单地配制成制剂。
化合物(IV)抑制促细胞分裂剂反应和/或细胞因子反应,并且显示出较强的免疫抑制活性和抗变态反应活性。尤其,所述活性化合物具有非常强的抑制T和B细胞生长的活性,和/或抑制IgE、IgG等产生抗体的活性。因此,本化合物可作为药物给予,用于抑制免疫反应或者治疗或预防动物包括人变态反应性疾病。
包含本化合物的免疫抑制剂或抗变态反应药用于预防或治疗器官或组织移植的排斥反应和由骨髓移植以及变态反应性疾病如类风湿性关节炎、系统性红斑狼疮、哮喘、炎性结肠炎、局部缺血-再灌注损伤、变应性鼻炎、变应性结膜炎、特应性、荨麻疹和牛皮癣引起的移植物-宿主反应。
当给予包含本化合物的免疫抑制剂和/或抗变态反应药时,可通过口服或非肠道途径给药。口服给药可通过按照常规方法制备成常用的剂型如片剂、颗粒剂、粉剂、胶囊剂、丸剂、溶液剂、糖浆剂、口腔片或舌下片进行。非肠道给药可通过任何常用的剂型如(肌肉内或静脉内)、栓剂、经皮吸收剂和吸入剂适当地进行。尤其,口服给药是优选的。
如果需要,可将各种适用于所述剂型的药用添加剂如赋形剂、粘合剂、润湿剂、崩解剂、润滑剂和稀释剂与适宜量的本化合物混合得到药物制剂。在注射剂情况下,本化合物可以与适宜的载体一起灭菌得到制剂。
更具体地,赋形剂包括乳糖、蔗糖、葡萄糖、淀粉、碳酸钙和结晶纤维素,粘合剂包括甲基纤维素、羧甲基纤维素、羟丙基纤维素、明胶或聚乙烯吡咯烷酮,崩解剂包括羧甲基纤维素、羧甲基纤维素钠、淀粉、藻酸钠、琼脂粉和十二烷基硫酸钠,并且润滑剂包括滑石粉、硬脂酸镁和macrogol。作为栓剂的基质,可使用可可脂、macrogol和甲基纤维素。此外,当制备成溶液剂或者乳化或悬浮注射剂时,可适当地加入常用的增溶剂、悬浮剂、乳化剂、稳定剂、防腐剂和等渗剂,当通过口服给药时,可加入甜味剂和矫味剂。包含本化合物的免疫抑制剂和抗变态反应药的剂量要求根据病人的年龄和体重、疾病的类型和程度以及给药途径来确定并且,对于成年人来说,当口服给药时,给药剂量通常为0.05-100mg/kg/天,优选0.1-10mg/kg/天。当非肠道给药时,给药剂量明显地依赖于给药途径改变并且通常为0.005-10mg/kg/天,优选0.01-1mg/kg/天。该剂量可为每天一次或几次给予。
将硼烷酸(boronic acid)(2)(22.88g,0.1mol)和碳酸钠(31.8g,0.3mol)的水溶液(150ml)加到化合物(1)(23.7g,0.1mol)的二甲氧基乙烷(300ml)-乙醇(150ml)溶液中,排除反应物溶液中的气体。加入Tetrakis(三苯基膦)钯(3.47g,3mmol),将该混合物在氮环境下加热回流2小时。用水稀释后,反应物用乙酸乙酯提取。将提取液用饱和盐水洗涤,干燥,浓缩,所得到的残渣在己烷中结晶,得到化合物(3)(24.92g;产率84%)。(第二步)
按照与第一步相同的方法,将化合物(3)(20.0g,68.0mmol)和硼烷酸(VIb′-1)(14.94g,88.3mmol)反应18小时,提取液残渣通过硅胶色谱层析(己烷-乙酸乙酯2∶1)纯化,得到化合物(4)(19.24g;产率84%)。(第三步)
将吡啶(6.6ml,81.2mmol)和三氟乙酸酐(10.6ml,75.0mmol)在冰冷却下加到化合物(4)(21.15g,62.5mmol)的二氯甲烷(200ml)溶液中,将该混合物在室温下搅拌1小时。将反应物溶液用乙酸乙酯稀释。有机层相继用水、1N盐酸、5%碳酸氢钠水溶液和饱和盐水洗涤,干燥并浓缩,得到化合物(5)(22.80g;产率84%)。(第四步)
将间氯过苯甲酸(14.46g,83.8mmol)在冰冷却下加到化合物(5)(14.0g,32.2mmol)的二氯甲烷(300ml)溶液中,并将该混合物在室温下搅拌3小时。将硫代硫酸钠的水溶液加到该反应物溶液中后,该混合物用乙酸乙酯提取。有机层用饱和碳酸氢钠水溶液洗涤两次,干燥并浓缩。残渣用己烷洗涤,得到化合物(6)(12.97g;产率86%)。(第五步)
将碳酸钾(6.67g,48.2mmol)和溴化异戊二烯(prenylbromide)(4.81ml,41.8mmol)加到化合物(6)(15.0g,32.2mmol)的N,N-二甲基甲酰胺(65ml)溶液中,并将该混合物在室温下搅拌18小时。将反应物溶液用乙酸乙酯稀释,相继用水和饱和盐水洗涤,干燥,浓缩,残渣溶解在四氢呋喃(150ml)中。在冰冷却下加入通过将氢化钠(60%矿物油,3.85g,96.5mmol)加到异戊烯醇(9.8ml,96.5mmol)的四氢呋喃(150ml)溶液中制备的反应溶液,并将该混合物在室温下再搅拌2小时。反应混合物用乙酸乙酯稀释后,有机层相继用水和饱和盐水洗涤,干燥并浓缩。残渣通过硅胶色谱层析(己烷-乙酸乙酯7∶1)纯化,得到化合物II-1(12.5g;产率87%)。Mp:87-88℃1H NMR(CDCl3)δH1.74(s,3H),1.78(s,3H),1.79(s,3H),1.80(s,3H),2.22(s,3H),2.26(s,3H),3.71(d,J=6.9Hz,2H),4.87(d,J=7.2Hz,2H),5.32-5.37(m,1H),5.55-5.60(m,1H),6.35-6.47(m,2H),6.81(dd,J=0.6,8.4Hz,1H),7.02-7.13(m,3H),7.59(dd,J=2.4,8.4Hz,1H),8.16(dd,J=0.9,5.7Hz,1H).IR(Nujol):3330,2923,2853,1627,1606,1564,1527,1481,1471,1395,1376,1357,1337,1284,1240,1178,1116,990cm-1参考实施例2 化合物(2)的合成
将1,4-二溴-2,5-二甲基苯(154g,583mmol)的四氢呋喃(1.3L)溶液冷却至-78℃,并在30分钟内加入1.53M丁基锂-己烷溶液(400ml,612mmol)。将反应物溶液在相同的温度下再搅拌1小时,立即加入硼酸三异丙酯(170ml,734mmol),并将该混合物再搅拌1小时同时除去冷却浴,反应温度逐渐升高。加入水(300ml)和1N盐酸(650ml)后,将该混合物用乙酸乙酯提取。提取液用水和饱和盐水洗涤,干燥并浓缩。结晶残渣用己烷洗涤并过滤,得到化合物(2)(115g;产率86%)。实施例1 二羟基-(2-甲硫基-5-吡啶基)硼烷(VIb’-1)(第一步)5-溴-2-甲硫基-吡啶(8)的合成
将2,5-二溴吡啶(7)(1100g,4.64mol)、溴化四丁基铵(55g,0.037当量)和15%硫代甲醇钠(sodium thiomethoxide)水溶液(2387g,1.1当量)的混合物在85-90℃下加热3.5小时。反应混合物冷却至10℃后,将所得到的固体过滤掉。有机层用冷却水(1L)洗涤并浓缩,得到粗品(8)(985g,产率104%)。将粗品(8)(908g)通过在2-丙醇(2.1L)和水(4.2L)中重结晶纯化,得到化合物(8)的结晶(831g,产率91.5%)。Mp:39-40℃1H-NMR(CDCl3)δ2.54(s,3H),7.07(dd,1H,J=0.7,8.6Hz),7.58(dd,1H,J=2.4,8.6Hz),8.49(dd,1H,J=0.7,2.4Hz).C6H6NSBr的元素分析:
计算值:C,35.31;H,2.96;N,6.86;s,15.71;Br,39.15.
实测值:C,35.18;H,3.03;N,6.95;s,15.56;Br,39.17;H2O<0.2。
HPLC{柱:Cosmosil 5C18-AR 4.6×150mm,流动相:H2O-CH3CN-TFA=40-60-0.1,流速:1.0ml/min,检测(UV):245nm}。tR5.4min,(7)tR 4.3min。(第二步)化合物VIb′-1的合成
将1.53M丁基锂-己烷(500ml,765mmol)的四氢呋喃(1.28L)溶液冷却至-78℃并在40分钟内滴加在第一步中得到的化合物(8)的四氢呋喃(400ml)溶液。将反应物溶液在室温下搅拌30分钟,并在30分钟内滴加硼酸三异丙基酯(195ml,834mmol)。将该混合物搅拌30分钟同时除去冷却浴,反应温度逐渐升高。加入水(320ml)后,将该混合物减压浓缩,残渣用水(710ml)和异丙酯(210ml)稀释。滴加3N盐酸(675ml)同时将反应物溶液在室温下搅拌。过滤沉淀的结晶,用水和异丙酯洗涤并干燥,得到化合物VIb′-1(111g;产率95%)。
Mp:151-154℃。
C6H8BNO2S的元素分析:
计算值:C,42.64;H,4.77;N,8.29;S,18.97
实测值:C,42.56;H,4.88;N,8.14;S,18.79。1H-NMR(DMSO-d6)δ2.51(s,3H),7.25(dd,J=0.9,8.1,1H),7.93(dd,J=2.1,8.1,1H),8.73(dd,J=0.9,2.1,1H)HPLC{柱:Cosmosil 5C18-AR 4.6×150mm,流动相:H2O-CH3CN-TFA=60-40-0.1,流速:1.0ml/min,检测(UV):245nm}。tR 1.6min,(8)tR 14.9min,(VIb′-1)tR 2.8min。实施例2 VIIb-1的合成(第一步)化合物(10)的合成
向化合物(9)(4.41g,15.0mmol)的二氯甲烷(45ml)溶液中相继加入3-甲基-3-丁烯醛(1.74ml,18.0mmol)、乙酸(1.8g,30.0mmol)和三乙酰氧基硼氢化钠(6.36g,30.0mmol),并将反应溶液搅拌15小时。将该反应溶液倾入水中后,用乙酸乙酯提取。提取液用碳酸氢钠水溶液和饱和盐水洗涤,干燥并浓缩。残渣通过硅胶色谱层析(己烷-乙酸乙酯9∶1)纯化,得到化合物(10)(4.09g;产率75%)。(第二步)化合物VIIb-1的合成
将化合物(10)(2.4g,6.62mmol)的四氢呋喃(24mL)溶液冷却至-78℃并在30分钟内滴加1.53M丁基锂(10.4ml,15.9mmol)。将反应溶液再搅拌2小时,加入硼酸三异丙酯(5.5ml,23.8mmol),将该混合物搅拌30分钟同时除去冷却浴,反应温度逐渐升至室温。将反应溶液倾入水中后,混合物用乙酸乙酯提取。提取液用氯化铵水溶液和饱和盐水洗涤,干燥并浓缩。结晶残渣用己烷洗涤并过滤,得到化合物VIIb-1(1.82;产率87%)。1H-NMR(DMSO-d6)δ1.70(s,3H),1.72(s,3H),2.12(s,3H),2.63(s,3H),3.63(br t,2H),5.28(br t,1H),6.01(br t,1H),6.37(dd,J=2.1,13.2,1H),6.46(dd,J=2.1,8.4,1H),6.92(s,1H),6.97(t,J=8.4,1H),7.77(s,1H)参考实施例3 化合物II-10的合成(第一步)
将5-溴-2-肼基吡啶(Journal of Heterocyclic Chemistry,1986(23)1071)(376mg,2.0mmol)在丙酮(1ml)和乙醇(4ml)中加热回流15分钟。将反应溶液浓缩,得到化合物(11)(456mg,定量的)的结晶残渣。(第二步)
按照参考实施例1相同的方法,从第一步中所得到的化合物(11)(175mg,0.75mmol)和硼酸(VIIb-1)(245mg,0.75mmol)得到化合物II-10(268mg,产率83%)。参考实施例4 {2-氟-2’,5’-二甲基-4’-[6-(3-甲基-丁-2-烯氧基)-吡啶-3-基]-二苯基-4-基}-(3-甲基-丁-2-烯基)-氨基甲酸氯甲酯(V-1)的合成
将参考实施例1合成的化合物II-1(444mg,1mmol)溶解在无水乙醚(40ml)中并冰冷却,在氮环境下相继加入氯甲酸氯甲酯(194mg,1.5mmol)和三乙胺(210μl,1.5mmol)同时搅拌,除去冰浴并将混合物连续搅拌4小时。将反应物中的沉淀过滤掉。有机层用水洗涤,用无水硫酸钠干燥,并减压蒸馏掉溶剂,得到化合物V-1(540mg)的油状物。
C31H34N2O3FCl的元素分析:
计算值:C,69.33;H,6.38;N,5.22;F,3.54;Cl,6.60。
实测值:C,68.85;H,6.42;N,5.21;F,3.58;Cl,7.06。参考实施例5 (3-甲基-丁-2-烯基)-(5-[2,3,5,6-四甲基-4-[6-(3-甲基-丁-2-烯氧基)-吡啶-3-基]-苯基]-吡啶-2-基)-氨基甲酸氯甲酯(V-2)的合成
将按照参考实施例1相同的方法合成的化合物II-2(300mg,0.658mmol)溶解在无水乙醚(30ml)中并冰冷却,在氮环境下相继加入氯甲酸氯甲酯(127mg,0.987mmol)和三乙胺(128μl,0.921mmol)同时搅拌,除去冰浴并将混合物连续搅拌4小时。将反应物中的沉淀过滤掉。有机层用水洗涤,用无水硫酸钠干燥,并减压蒸馏掉溶剂,得到化合物V-2(360mg)的油状物。1H NMR(CDCl3):δH 1.67(3H,s),1.71(3H,s),1.8(3H,s),1.83(3H,s),1.97(6H,s),1.99(6H,s),4.65(2H,d,J=6.9Hz),4.89(2H,d,J=6.9Hz),5.36(1H,bt,J=6.9Hz),5.59(1H,bt,J=6.9Hz),5.88,(2H,s),6.86(1H,d,J=8.4Hz),7.4(1H,ddd,J=8.7Hz,3.3Hz,2.7Hz),7.52(1H,ddd,J=8.4Hz,5.4Hz,2.4Hz),7.66(1H,d,J=8.1Hz),7.97(1H,t,J=2.7Hz),8.26(1H,dd,J=3Hz,2.4Hz).C32H38N3O3Cl的元素分析:
计算值:C,70.12;H,6.99;N,7.67;Cl,6.47。
实测值:C,69.72;H,7.39;N,7.42;Cl,7。参考实施例6 {2-氟-2’,5’-二甲基-4’-[6-(3-甲基-丁-2-烯氧基)-吡啶-3-基]-二苯基-4-基}-异丙基-氨基甲酸氯甲酯(V-3)的合成
按照参考实施例4相同的方法,从化合物II-9(220mg,0.525mmol)和氯甲酸甲酯(101mg,0.788mmol)得到化合物V-3(271mg)。1H NMR(CDCl3):δH 1.22(6H,d,J=6.6Hz),1.79(3H,s),1.82(3H,s),2.23(3H,s),2.29(3H,s),4.63(1H,sep,J=6.6Hz),4.88(2H,d,J=7.2Hz),5.58(1H,bt,J=7.2Hz),5.76(2H,bs),6.83(1H,d,J=8.4Hz),6.92-7.3(5H,m),7.61(1H,dd,J=8.4Hz,2.4Hz),8.19(1H,d,J=2.4Hz).C29H32N2O3FCl的元素分析:
计算值:C,68.16;H,6.31;N,5.48;F,3.72;Cl,6.94。
实测值:C,66.81;H,6.36;N,5.44;F,3.51;Cl,7.82。参考实施例7 {3’-甲氧基-2’,5’,6’-三甲基-4’-[6-(3-甲基(metyl)-丁-2-烯氧基)-吡啶-3-基]-二苯基-4-基}-(3-甲基-丁-2-烯基)-氨基甲酸氯甲酯(V-4)的合成
按照参考实施例4相同的方法,从化合物II-4(220mg,0.467mmol)和氯甲酸甲酯(90mg,0.7mmol)得到化合物V-4(258mg)。1H NMR(CDCl3):δH 1.52(3H,s),1.72(3H,s),1.80(3H,s),1.83(3H,s),1.96(6H,s),2.07(3H,s),3.34(3H,s),4.32(2H,d,J=7.2Hz),4.89(2H,d,J=6.9Hz),5.34(1H,bt,J=7.2Hz),5.59(1H,bt,J=6.9Hz),5.81(2H,bs),6.84(1H,d,J=8.7Hz),7.14-7.29(4H,m),7.55(1H,dd,J=8.4Hz,2.4Hz),8.11(1H,d,J=2.4Hz).C33H39N2O4Cl的元素分析:
计算值:C,70.38;H,6.98;N,4.97;Cl,6.3。
实测值:C,69.76;H,6.95;N,5;Cl,6.48。参考实施例8 {5-[3’-氟-2,5-二甲氧基-3,6-二甲基-4’-(3-甲基-丁-2-烯基氨基)-二苯基-4-基]-吡啶-2-基}-(3-甲基-丁-2-烯基)-氨基甲酸氯甲酯(V-6)的合成
将按照参考实施例1的方法合成的化合物II-3(504mg,1mmol)溶解在无水乙醚(100ml)中并冰冷却,在氮环境下相继加入氯甲酸氯甲酯(154mg,1.2mmol)和三乙胺(140μl,1mmol)同时搅拌至反应6小时。反应物如参考实施例4进行处理,粗品通过硅胶色谱层析(展开剂:己烷-乙酸乙酯(1∶2))纯化,得到化合物V-6(490mg)。1H NMR(CDCl3):δH 1.67(3H,s),1.7(3H,s),1.76(3H,s),1.79(3H,s),2.06(3H,s),2.07(3H,s),3.32(3H,s),3.35(3H,s),3.78(2H,d,J=6.6Hz),3.88(1H,bs,),4.65(2H,d,J=7.2Hz),5.36(1H,bt,J=6.6Hz),5.4(1H,bt,J=6.9Hz),5.88(2H,s),6.77(1H,t,J=8.1Hz),6.9-7(2H,m),7.66(2H,s),8.39(1H,s).C33H39N3O4FCl的元素分析:
计算值:C,66.49;H,6.59;N,7.05;F,3.19;Cl,5.59.
实测值:C,66.24;H,6.66;N,7.13;F,3.11;Cl,6.28。参考实施例9 (5-{4’-[氯甲氧基羰基-(3-甲基-丁-2-烯基)-氨基]-3’-氟-2,5-二甲氧基-3,6二甲基-二甲基-二苯基-4-基}-吡啶-2-基)-(3-甲基-丁-2-烯基)-氨基甲酸氯甲酯(V-7)的合成
将化合物II-3(50mg,0.1mmol)在氮环境下溶解在无水乙醚(15ml)中,并相继加入氯甲酸氯甲酯(51mg,0.5mmol)和三乙胺(66μl,0.475mmol),在室温下搅拌24小时。反应物如参考实施例4进行处理,得到化合物V-7(58mg)。
1H NMR(CDCl3):δH 1.51(3H,s),1.68(6H,s),1.7(3H,s),
2.05(3H,s),2.07(3H,s),3.33(3H,s),3.36(3H,s),4.32
(2H,d,J=6.9Hz),4.7(2H,d,J=6.6Hz),5.3(1H,bt,
J=6.6Hz),5.36(1H,bt,J=6.6Hz),5.85(2H,bs),5.89(2
H,s),7.06-7.3(3H,m),7.68(2H,s),8.4(1H,s).C35H40N3O6FCl2的元素分析:
计算值:C,61.05;H,5.85;N,6.1。
实测值:C,60.98;H,5.68;N,6.09。实施例3 琥珀酰胺酸-[{2-氟-2’,5’-二甲基-4’-[6-(3-甲基-丁-2-烯氧基)-吡啶-3-基]-二苯基-4-基]}-(3-甲基-丁-2-烯基)-氨基甲酰氧基]-甲酯(I-1)的合成
将琥珀酰胺酸(105mg,0.9mmol)和碳酸钾(62mg,0.45mmol)的N,N-二甲基甲酰胺(2ml)的悬浮液在室温下搅拌10分钟。然后,相继加入化合物V-1(161mg,0.3mmol)和溴化钾(36ngl,0.3mmol),在氩环境下充分搅拌20小时。将反应混合物用乙醚(20ml)稀释并将不溶性物质过滤掉。有机层用水洗涤,用无水硫酸钠干燥,并将溶剂减压蒸馏掉,并将所得到的物质通过硅胶色谱层析(己烷-乙酸乙酯(4∶1→1∶2))纯化,得到化合物I-1(116mg,63%)。
所得到化合物具有比母化合物II-1高的熔点并且观察到物理性质的改善。Mp:107-109℃1H NMR(CDCl3):δH 1.59(3H,s),1.73(3H,s),1.79(3H,s),1.82(3H,s),2.2(3H,s),2.29(3H,s),2.55(2H,t,J=6.6Hz),2.76(2H,t,J=6.6Hz),4.30(2H,d,J=7.2Hz),4.88(2H,d,J=7.2Hz),5.31(1H,bt,J=7.2Hz),5.59(2H,bt,J=7.2Hz),5.81(2H,bs),6.82(1H,d,J=8.1Hz),6.97-7.30(5H,m),7.6(1H,dd,J=8.1Hz,2.4Hz),8.19(1H,d,J=2.4Hz).C35H40N3O6F的元素分析:
计算值:C,68.05;H,6.53;N,6.8;F,3.08。
实测值:C,67.92;H,6.49;N,6.96;F,3.13。LSIMS:m/z 618[M+H]+。实施例4 氨基甲酰氧基乙酸[{2-氟-2’,5’-二甲基-4’-[6-(3-甲基-丁-2-烯氧基)-吡啶-3-基]-二苯基-4-基]}-(3-甲基-丁-2-烯基)-氨基甲酰氧基]-甲酯(I-3)的合成
按照实施例3相同的方法,将化合物V-1(161mg,0.3mmol)和氨基甲酰氧基乙酸(179mg,1.5mmol)反应,得到化合物I-1(98mg,53%)。1H NMR(CDCl3):δH 1.58(3H,s),1.73(3H,s),1.79(3H,s),1.82(3H,s),2.2(3H,s),2.28(3H,s),4.3(2H,d,J=7.2Hz),4.66(2H,s),4.79(2H,bs),4.88(2H,d,J=6.9Hz),5.31(1H,bt,J=7.2Hz),5.57(1H,bt,J=6.9Hz),5.87(2H,bs),6.82(1H,d,J=8.7Hz),7-7.30(5H,m),7.59(1H,dd,J=8.4,2.4Hz),8.18(1H,d,J=2.4Hz).C34H38N3O7F的元素分析:
计算值:C,65.9;H,6.18;N,6.78;F,3.07。
实测值:C,65.14;H,6.47;N,6.39;F,2.93。
LSIMS:m/z 620[M+H]+,642[M+Na]+。实施例5 乙酰基氨基-乙酸[{2-氟-2’,5’-二甲基-4’-[6-(3-甲基-丁-2-烯氧基)-吡啶-3-基]-二苯基-4-基}-(3-甲基-丁-2-烯基)-氨基甲酰氧基]-甲酯(I-5)的合成
按照实施例3相同的方法,从化合物V-1(380mg,0.707mmol)和N-乙酰基甘氨酸(410mg,3.5mmol)得到化合物I-5(305mg,70%)。1H NMR(CDCl3):δH 1.57(3H,s),1.73(3H,s),1.79(3H,s),1.82(3H,s),2.05(3H,s),2.2(3H,s),2.28(3H,s),4.12(2H,d,J=5.4Hz),4.38(2H,d,J=7.2Hz),4.88(2H,d,J=6.9Hz),5.3(1H,bt,J=7.2Hz),5.57(1H,bt,J=7.2Hz),5.86(2H,bs),5.93(1H,bs),6.82(1H,d,J=8.1Hz),7-7.3(5H,m),7.59(1H,dd,J=8.4,2.4Hz),8.17(1H,d,J=2.1Hz).C35H40N3O6F的元素分析:
计算值:C,68.06H,6.53;N,6.8;F,3.08.
实测值:C,67.91;H,6.58;N,7;F,2.91。LSIMS:m/z 617M+,640[M+Na]+。
实施例6 4-乙酰基氨基-4-氨基甲酰基-丁酸[{2-氟-2’,5’-二甲基-4’-[6-(3-甲基-丁-2-烯氧基)-吡啶-3-基]-二苯基-4-基}-二苯基-4-基}-(3-甲基-丁-2-烯基)-氨基甲酰氧基]-甲酯(I-6)的合成
按照实施例3相同的方法,从化合物V-1(269mg,0.5mmol)和N-乙酰基-L-异谷氨酰胺(470mg,2.5mmol)得到化合物I-6(225mg,65%)。
Mp:85-87C
1H NMR(CDCl3):δH 1.57(3H,s),1.73(3H,s),1.8(3H,s),
1.83(3H,s),1.95(1H,m),2.02(3H,s),2.19(1H,M),2.2
(3H,s),2.28(3H,s),2.49(1H,m),2.63(1H,m),4.12(2
H,d,J=5.4Hz),4.3(2H,d,J=7.2Hz),4.54(1H,td,J=
8.1Hz,5.1Hz),4.89(2H,d,J=7.2Hz),5.31(1H,bt,J=
7.2Hz),5.33(1H,bs),5.58(1H,bt,J=7.2Hz),5.8(2H,
bs),6.35(1H,d,J=5.1Hz),6.37(1H,bs),6.84(1H,d,
J=8.4Hz),7.03-7.3(5H,m),7.62(1H,dd,J=8.4,2.4Hz),
8.18(1H,d,J=2.4Hz).C38H45N4O7F的元素分析:
计算值:C,66.26;H,6.59;N,8.13;F,2.76。
实测值:C,65.99;H,6.59;N,8.18;F,2.71.LSIMS:m/z 688 M+,611[M+Na]+。实施例7 琥珀酰胺酸[(3-甲基-丁-2-烯基)-(5-{2,3,5,6-四甲基-4-[6-(3-甲基-丁-2-烯氧基)-吡啶-3-基]-苯基}-吡啶-2-基)-氨基甲酰氧基]-甲酯(I-13)的合成
按照实施例3相同的方法,从化合物V-2(250mg,0.456mmol)和琥珀酰胺酸(267mg,2.28mmol)得到化合物I-13(211mg,74%)。Mp:124-126℃1H NMR(CDCl3):δH 1.67(3H,s),1.7(3H,s),1.8(3H,s),1.83(3H,s),1.97(6H,s),1.99(6H,s),2.56(2H,t,J=6.6Hz),2.77(2H,t,J=6.6Hz),4.63(2H,d,J=6.9Hz),4.89(2H,d,J=6.9Hz),5.31(1H,bt,J=7.2Hz),5.35(1H,bt,J=6.6Hz),5.37(1H,bs),5.59(1H,bt,J=6.9Hz),5.61(1H,bs),5.89(2H,b),6.86(1H,d,J=8.7Hz),7.37-7.67(3H,m),7.97(1H,s),8.25(1H,bs).C36H44N4O6的元素分析:
计算值:C,68.77;H,7.05;N,8.41。
实测值:C,68.52;H,7.04;N,8.79。实施例8 琥珀酰胺酸[{5-[3’-氟-2,5-二甲氧基-3,6-二甲基-4’-(3-甲基-丁-2-烯基氨基)-二苯基-4-基]-吡啶-2-基}-(3-甲基-丁-2-烯基)-氨基甲酰氧基]-甲酯(I-25)的合成
按照实施例3相同的方法,从化合物V-6(375mg,0.63mmol)和琥珀酰胺酸(368mg,3.15mmol)得到化合物I-25(295mg,69%)。Mp:136-138℃1H NMR(CDCl3):δH 1.66(3H,s),1.69(3H,s),1.75(3H,s),1.79(3H,s),2.06(3H,s),2.07(3H,s),2.55(2H,t,J=6.6Hz),2.76(2H,t,J=6.6Hz),3.31(3H,s),3.35(3H,s),3.78(2H,d,J=6.6Hz),4.63(2H,d,J=6.9Hz),5.34(1H,bt,J=6.6Hz),5.35(1H,bs),5.4(1H,bt,J=6.6Hz),5.61(1H,bs),5.88(2H,s),6.78(1H,t,J=8.4Hz),6.93-6.97(2H,m),7.65(2H,bs),8.38(1H,bs).C37H45N4O7F的元素分析:
计算值:C,65.66;H,6.7;N,8.28;F,2.81。
实测值:C,65.39;H,6.7;N,8.07;F,2.75。实施例9 琥珀酰胺酸[(5-{4’-[(3-氨基甲酰基-丙酰氧基甲氧基羰基)-(3-甲基-丁-2-烯基)氨基]-3’-氟-3,6-二甲氧基-2,5-二甲基-二苯基-4-基}-吡啶-2-基)-(3-甲基-丁-2-烯基)-氨基甲酰氧基]-甲酯(I-37)的合成
按照实施例3相同的方法,从化合物V-7(55mg,0.08mmol)和琥珀酰胺酸(94mg,0.8mmol)得到化合物I-37(52mg,76%)。1H NMR(CDCl3):δH 1.5(3H,s),1.67(3H,s),1.69(3H,s),1.7(3H,s),2.05(3H,s),2.06(3H,s),2.58(4H,m),2.77(2H,m),3.32(3H,s),3.35(3H,s),4.29(2H,d,J=6.9Hz),4.64(2H,d,J=6.9Hz),5.32(2H,m),5.4(2H,bs),5.68(2H,bs),5.75(2H,bs),5.89(2H,s),7.05-7.25(3H,m),7.67(2H,s),8.38(1H,s).C43H52N5O12F的元素分析:
计算值:C,60.77;H,6.17;N,8.24;F,2.24。
实测值:C,59.57;H,6.18;N,7.98;F,2.18。实施例10 琥珀酰胺酸[{3’-甲氧基-2’,5’,6’,-三甲基-4’-[6-(3-甲基-丁-2-烯氧基)-吡啶-3-基]-二苯基-4-基}-(3-甲基-丁-2-烯基)-氨基甲酰氧基]-甲酯(I-109)的合成
按照实施例3相同的方法,从化合物V-4(243mg,0.432mmol)和琥珀酰胺酸(253mg,2.16mmol)得到化合物I-109(218mg,78%)Mp:107-108C1H NMR(CDCl3):δH 1.53(3H,s),1.71(3H,s),1.83(3H,s),1.95(6H,s),2.06(3H,s),2.54(2H,t,J=6.3Hz),2.75(2H,t,J=6.3Hz),3.33(3H,s),4.3(2H,d,J=6.6Hz),4.88(2H,d,J=6.9Hz),5.32(1H,bt,J=6.6Hz),5.35(1H,bs),5.59(1H,bt,J=6.9Hz),5,6(1H,bs),5.82(2H,bs),6.84(1H,d,J=8.7Hz),7.13-7.3(4H,m),7.55(1H,dd,J=8.7Hz,2.4Hz),8.11(1H,d,J=2.4Hz).C37H45N3O7的元素分析:
计算值:C,69.03;H,7.05;N,6.53。
实测值:C,68.95;H,7.02;N,6.57。实施例11 琥珀酰胺酸({2-氟-2’,5’-二甲基-4’-[6-(3-甲基-丁-2-烯氧基)-吡啶-3-基]二苯基-4-基}-异丙基-氨基甲酰氧基)-甲酯(I-121)的合成
按照实施例3相同的方法,从化合物V-3(250mg,0.489mmol)和琥珀酰胺酸(286mg,2.45mmol)得到化合物I-121(122mg,42%)。1H NMR(CDCl3):δH 1.21(6H,d,J=6.6Hz),1.79(3H,s),1.82(3H,s),2.22(3H,s),2.29(3H,s),2.54(2H,t,J=6.3Hz),2.74(2H,t,J=6.3Hz),4.6(1H,sep,J=6.6Hz),4.88(2H,d,J=7.2Hz),5.58(1H,bt,J=7.2Hz),5.35(1H,bs),5.6(1H,bs),5.76(2H,bs),6.82(1H,d,J=8.4Hz),6.9-7.32(5H,m),7.6(1H,dd,J=8.4Hz,2.4Hz),8.19(1H,d,J=2.4Hz).C33H38N3O6F的元素分析:
计算值:C,66.99;H,6.47;N,7.1;F,3.21。
实测值:C,66.2;H,6.58;N,7;F,3.05。实施例12 2-乙酰基氨基-琥珀酰胺酸[{2-氟-2’,5’-二甲基-4’-[6-(3-甲基-丁-2-烯氧基)-吡啶-3-基]-二苯基-4-基}-((E)-3-甲基-丁-2-烯基)-氨基甲酰氧基]-甲酯(I-13)的合成
按照实施例3相同的方法,从化合物V-1(322mg,0.6mmol)和N-乙酰基-L-天门冬氨酸(523mg,3mmol)得到化合物I-13(201mg,50%)。Mp:130-133C1H-NMR(CDCl3):δH 1.58(3H,s),1.74(3H,s),1.79(3H,s),1.83(3H,s),2.05(3H,s),2.21(3H,s),2.28(3H,s),2.77(1H,dd,J=15.9,4.2Hz),3.01(1H,dd,J=15.9,4.5Hz),4.3(2H,d,J=6.6Hz),4.86(1H,t,J=4.2Hz),4.88(2H,d,J=6.9Hz),5.31(1H,bt,J=6.6Hz),5.48(1H,bs),5.58(1H,bt,J=6.9Hz),5.75-5.92(3H,bm),6.8(1H,d,J=7.5Hz),6.83(1H,d,J=8.7Hz),7.05-7.3(5H,m),7.61(1H,dd,J=8.7,2.1Hz),8.18(1H,d,J=2.1Hz).C37H43N4O7F的元素分析:
计算值:C,65.86;H,6.42;N,8.3;F,2.82。
实测值:C,65.57;H,6.42;N,8.27;F,2.75。ESIMS:m/z 675[M+H]+,697[M+Na]+,713[M+K]+。实施例13 3-乙酰基氨基-琥珀酰胺酸[{2-氟-2’,5’-二甲基-4’-[6-(3-甲基-丁-2-烯氧基)-吡啶-3-基]-二苯基-4-基}-((E)-3-甲基-丁-2-烯基)-氨基甲酰氧基]-甲酯(I-14)的合成
按照实施例3相同的方法,从化合物V-1(300mg,0.56mmol)和N-乙酰基-L-异天门冬酰胺(117mg,0.67mmol)得到化合物I-14(255mg,67%)。Mp:137-140C1H-NMR(CDCl3):δH 1.58(3H,s),1.73(3H,s),1.79(3H,s),1.82(3H,s),2.03(3H,s),2.2(3H,s),2.28(3H,s),2.69(1H,dd,J=17.1,6.9Hz),3.05(1H,dd,J=17.1,4.5Hz),4.3(2H,d,J=7.2Hz),4.85(1H,t,J=4.2Hz),4.88(2H,d,J=6.9Hz),5.31(1H,bt,J=7.2Hz),5.55(1H,bs),5.57(1H,bt,J=6.9Hz),5.8(1H,bs),5.82(1H,bs),6.55(1H,bs),6.82(1H,d,J=8.4Hz),6.88(1H,d,J=7.5Hz),7.01-7.3(5H,m),7.6(1H,dd,J=8.4,2.4Hz),8.17(1H,d,J=2.4Hz).C37H43N4O7F的元素分析:
计算值:C,65.86;H,6.42;N,8.3;F,2.82。
实测值:C,65.57;H,6.4;N,8.54;F,2.74。ESIMS:m/z 674[M]+,675[M+H]+,697[M+Na]+。实施例14 2-乙酰基氨基-4-氨基甲酰基-丁酸[{2-氟-2’,5’-二甲基-4’-[6-(3-甲基-丁-2-烯氧基)-吡啶-3-基]-二苯基-4-基}-((E)-3-甲基-丁-2-烯基)-氨基甲酰氧基]-甲酯(I-15)的合成
按照实施例6相同的方法,从化合物V-1(200mg,0.372mmol)和N-乙酰基-L-谷氨酰胺(351mg,1.86mmol)得到化合物I-15(156mg,61%)。Mp:110-113℃.PMR(CDCl3):δH 1.58(3H,s),1.74(3H,s),1.8(3H,s),1.83(3H,s),2.04(3H,s),2.2(3H,s),2.01-2.4(4H,m),4.29(2H,d,J=7.2Hz),4.62(1H,td,J=8.1Hz,5.1Hz),4.88(2H,d,J=7.2Hz),5.3(1H,bt,J=7.2Hz),5.36(1H,bs),5.58(1H,bt,J=7.2Hz),5.78(1H,bs),5.91(1H,bs),6.1(1H,bs),6.81(1H,d,J=8.4Hz),7.01-7.3(5H,m),7.6(1H,dd,J=8.4,2.4Hz),8.18(1H,d,J=2.4Hz).C38H45N4O7F的元素分析:
计算值:C,66.26;H,6.59;N,8.13;F,2.76。
实测值:C,66.03;H,6.62;N,8.09;F,2.7。ESIMS:m/z 688[M]+,689[M+H]+。实施例15 (2-乙酰基氨基-乙酰基氨基)-乙酸[{2-氟-2’,5’-二甲基-4’-[6-(3-甲基-丁-2-烯氧基)-吡啶-3-基]-二苯基-4-基]}-((E)-3-甲基-丁-2-烯基)-氨基甲酰氧基]-甲酯(I-16)的合成
按照实施例3相同的方法,从化合物V-1(322mg,0.6mmol)和N-乙酰基-甘氨酰基甘氨酸(523mg,3mmol)得到化合物I-16(255mg,63%)。
本发明化合物具有比母化合物II-1高的熔点并且观察到物理性质的改善。另外,本发明化合物的优势在于因为它不产生静电,因此可以简单地配制成制剂。Mp:103-106C.1H-NMR(CDCl3):δH 1.58(3H,s),1.73(3H,s),1.79(3H,s),1.82(3H,s),2.05(3H,s),2.2(3H,s),2.28(3H,s),3.98(2H,d,J=5.4Hz),4.12(2H,d,J=5.4Hz),4.29(2H,d,J=7.5Hz),4.88(2H,d,6.6Hz),5.3(1H,bt,J=7.5Hz),5.57(1H,bt,J=6.6Hz),5.85(2H,bs),6.3(1H,b),6.62(1H,b),6.83(1H,d,J=8.4Hz),6.95-7.3(5H,m),7.61(1H,dd,J=8.4,2.4Hz),8.18(1H,d,J=2.4Hz).C37H43N4O7F的元素分析:
计算值:C,65.86;H,6.42;N,8.3;F,2.82。
实测值:C,65.5;H,6.39;N,8.22;F,2.76。ESIMS:m/z 675[M+H]+,697[M+Na]+,713[M+K]+。实施例16 2-(2-乙酰基氨基-丙酰基氨基-乙酸[{2-氟-2’,5’-二甲基-4’-[6-(3-甲基-丁-2-烯氧基)-吡啶-3-基]-二苯基-4-基}-((E)-3-甲基-丁-2-烯基)-氨基甲酰氧基]-甲酯(I-17)的合成
按照实施例3相同的方法,从化合物V-1(269mg,0.5mmol)和N-乙酰基-DL-丙氨酰基甘氨酸(108mg,0.6mmol)得到化合物I-17(262mg,76%)。Mp:79-82℃.1H-NMR(CDCl3):δH 1.38(3H,d,J=7.2Hz),1.58(3H,s),1.74(3H,s),1.79(3H,s),1.82(3H,s),2.02(3H,s),2.2(3H,s),2.28(3H,s),4.05(1H,dd,J=18.3,4.5Hz),4.15(1H,dd,J=18.3,4.5Hz),4.3(2H,d,J=7.2Hz),4.55(1H,dq,J=7.5,7.2Hz),4.88(2H,d,7.2Hz),5.3(1H,bt,J=7.2Hz),5.58(1H,bt,J=7.2Hz),5.83(2H,bs),6.1(1H,d,J=7.5Hz),6.72(1H,t,J=4.5Hz),6.82(1H,d,J=8.7Hz),7.02-7.3(5H,m),7.61(1H,dd,J=8.7,1.8Hz),8.17(1H,d,J=1.8Hz).C38H45N4O7F的元素分析:
计算值:C,66.26;H,6.59;N,8.13;F,2.76。
实测值:C,66.44;H,6.73;N,8.06;F,2.6。ESIMS:m/z 689[M+H]+,711[M+Na]+,727[M+K]+。实施例17 [2-(2-乙酰基氨基-乙酰基氨基)-乙酰基氨基]-乙酸[{2-氟-2’,5’-二甲基-4’-[6-(3-甲基-丁-2-烯氧基)-吡啶-3-基]-二苯基-4-基}-((E)-3-甲基-丁-2-烯基)-氨基甲酰氧基]-甲酯(I-18)的合成
按照实施例3相同的方法,从化合物V-1(301mg,0.56mmol)和N-乙酰基-甘氨酰基甘氨酰基甘氨酸(259mg,1.1mmol)得到化合物I-18(314mg,77%)。
Mp:171-173℃.
1H-NMR(CDCl3):δH 1.58(3H,s),1.74(3H,s),1.79(3H,s),
1.83(3H,s),2.04(3H,s),2.2(3H,s),2.28(3H,s),3.94
(2H,d,J=5.7Hz),4.01(2H,d,J=6Hz),4.11(2H,d,J
=5.7Hz),4.29(2H,d,J=6.9Hz),4.88(2H,d,7.2Hz),5.3
(1H,bt,J=6.9Hz),5.57(1H,bt,J=7.2Hz),5.82(2H,
bs),6.4(1H,b),6.83(1H,d,J=8.4Hz),6.85(1H,b),7.01-7.3
(5H,m),7.6(1H,dd,J=8.4,2.4Hz),8.18(1H,d,J=2.4
Hz).C39H46N5O8F的元素分析:
计算值:C,64.01;H,6.34;N,9.57;F,2.6。
实测值:C,63.88;H,6.32;N,9.74;F,2.52。ESIMS:m/z 732[M+H]+,754[M+Na]+。
下面按照相同的方法合成化合物(I)。中间体化合物(II)和(V)以及本发明化合物(I)的结构式显示如下。表中的各符合的含义如下:Me:甲基Et:乙基Ac:乙酰基nPr:正丙基iPr:异丙基表1 表2 II-7...1.75(3H,s),1.78(3H,s),1.79(3H,s),1.80(3H,s),1.98(3H,s),2.18(6H,s),2.28(3H,s),
3.75(2H,d,J=6.9),4.91(2H,d,J=6.9),5.38(1H,m),5.58(1H,m),6.69(2H,d,J=
8.4),6.87(1H,s),7.15(1H,s),7.21(2H,d,J=8.4)II-10...泡沫物;1H-NMRδ1.74(s,3H),1.78(s,3H),1.93(s,3H),2.08(s,3H),2.22(s,3H),
2.27(s,3H),3.72(br d,J=5.4,2H),3.77(br s,1H),5.35(m,1H),6.38(dd,J=2.4,
12.3,1H),6.45(dd,J=2.4,8.4,1H),7.06(t,J=8.4,1H),7.12(s,1H),7.13(s,1H),
7.27(d,J=8.4,1H),7.61(dd,J=2.1,8.4,1H),7.68(br s,1H),8.13(d,J=2.1,1H)表3 表4
表5
表6
表7
表8
表9
表10
表11
表12
表13
表14
表15
表16
表17
表18
试验实施例1抗-卵清蛋白(OVA)IgE抗体产生的抑制作用
No | R2 | R3 | R4 | R5 | R6 | R7 | R8 | R9 | R10 | R11 | X |
V-6 | H | H | F | H | H | H | Me | MeO | MeO | Me | NH |
V-7 | H | H | F | H | H | H | Me | MeO | MeO | Me | NCOOCH2Cl |
No | R1 | R2 | R3 |
I-1 | CH2CH2CONH2 | H | H |
I-2 | CH2CH2CONHMe | H | H |
I-3 | CH2OCONH2 | H | H |
I-4 | CH2OCONHEt | H | H |
I-5 | CH2NHAc | H | H |
I-6 | CH2CH2CH(CONH2)NHAc | H | H |
I-7 | CH2CH(Me)CONH2 | H | H |
I-8 | CH2CH2CONHMe | Me | H |
I-9 | CH(Me)OCONH2 | H | H |
I-10 | CH2OCONHEt | Me | Me |
I-11 | CH2NHAc | Et | H |
I-12 | CH(Me)CH2CH(CONH2)NHAc | Me | H |
I-13 | CH(NHAc)CH2CONH2 | H | H |
I-14 | CH2CH(NHAc)CONH2 | H | H |
I-15 | CH(NHAc)(CH2)2CONH2 | H | H |
I-16 | CH2NHCOCH2NHAc | H | H |
I-17 | CH2NHCOCH(Me)NHAc | H | H |
I-18 | CH2(NHCOCH2)2NHAc | H | H |
No | R1 | R2 | R3 |
I-19 | CH2CH2CONH2 | H | H |
I-20 | CH2CH2CONHMe | H | H |
I-21 | CH2OCONH2 | H | H |
I-22 | CH2OCONHEt | H | H |
I-23 | CH2NHAc | H | H |
I-24 | CH2CH2CH(CONH2)NHAc | H | H |
I-25 | CH2CH(Me)CONH2 | H | H |
I-26 | CH2CH2CONHMe | Me | H |
I-27 | CH(Me)OCONH2 | H | H |
I-28 | CH2OCONHEt | Me | Me |
I-29 | CH2NHAc | Et | H |
I-30 | CH(Me)CH2CH(CONH2)NHAc | Me | H |
I-31 | CH(NHAc)CH2CONH2 | H | H |
I-32 | CH2CH(NHAc)CONH2 | H | H |
I-33 | CH(NHAc)(CH2)2CONH2 | H | H |
I-34 | CH2NHCOCH2NHAc | H | H |
I-35 | CH2NHCOCH(Me)NHAc | H | H |
I-36 | CH2(NHCOCH2)2NHAc | H | H |
No | R1 | R2 | R3 | X |
I-37 | CH2CH2CONH2 | H | H | NH |
I-38 | CH2CH2CONHEt | H | H | NH |
I-39 | CH2OCONH2 | H | H | NH |
I-40 | CH2OCONHMe | H | H | NH |
I-41 | CH2NHAc | H | H | NH |
I-42 | CH2CH2CH(CONH2)NHAc | H | H | NH |
I-43 | CH2CH(Me)CONH2 | H | H | NH |
I-44 | CH2CH2CONHMe | Me | H | NH |
I-45 | CH(Me)OCONH2 | H | H | NH |
I-46 | CH2OCONHEt | Me | Me | NH |
I-47 | CH2NHAc | Et | H | NH |
I-48 | CH(Me)CH2CH(CONH2)NHAc | Me | H | NH |
I-49 | CH(NHAc)CH2CONH2 | H | H | NH |
I-50 | CH2CH(NHAc)CONH2 | H | H | NH |
I-51 | CH(NHAc)(CH2)2CONH2 | H | H | NH |
I-52 | CH2NHCOCH2NHAc | H | H | NH |
I-53 | CH2NHCOCH(Me)NHAc | H | H | NH |
I-54 | CH2(NHCOCH2)2NHAc | H | H | NH |
No | R1 | R2 | R3 | X |
I-55 | CH2CH2CONH2 | H | H | NCOOCH2OCOCH2CH2CONH2 |
I-56 | CH2CH2CONHEt | H | H | NCOOCH2OCOCH2CH2CONHEt |
I-57 | CH2OCONH2 | H | H | NCOOCH2OCOCH2OCONH2 |
I-58 | CH2OCONMe | H | H | NCOOCH2OCOCH2OCONHMe |
I-59 | CH2NHAc | H | H | NCOOCH2OCOCH2NHAc |
I-50 | CH2CH2CH(CONH2)NHAc | H | H | NCOOCH2OCOCH2CH2CH(CONH2)NHAc |
I-61 | CH2CH(Me)CONH2 | H | H | NCOOCH2OCOCH2CH(Me)CONH2 |
I-52 | CH2CH2CONHMe | Me | H | NCOOCH2OCOCH2CH2CONHMe |
I-63 | CH(Me)OCONH2 | H | H | NCOOCH2OCOCH(Me)OCONH2 |
I-64 | CH2OCONHEt | Me | Me | NCOOCH2OCOCH2OCONHEt |
I-65 | CH2NHAc | Et | H | NCOOCH2OCOCH2NHAc |
I-66 | CH(Me)CH2CH(CONH2)NHAc | Me | H | NCOOCH2OCOCH(Me)CH2CH(CONH2)NHAc |
I-67 | CH(NHAc)CH2CONH2 | H | H | NCOOCH2OCOCH(NHCOCH3)CH2CONH2 |
I-68 | CH2CH(NHAc)CONH2 | H | H | NCOOCH2OCOCH2CH(NHCOCH3)CONH2 |
I-69 | CH(NHAc)(CH2)2CONH2 | H | H | NCOOCH2OCOCH(NHCOCH3)(CH2)2CONH2 |
I-70 | CH2NHCOCH2NHAc | H | H | NCOOCH2OCOCH2NHCOCH2NHCOCH3 |
I-71 | CH2NHCOCH(Me)NHAc | H | H | NCOOCH2OCOCH2NHCOCH(Me)NHCOCH3 |
I-72 | CH2(NHCOCH2)2NHAc | H | H | NCOOCH2OCOCH2(NHCOCH2)2NHCOCH3 |
No | R1 | R2 | R3 |
I-73 | CH2CH2CONH2 | H | H |
I-74 | CH2CH2CONHMe | H | H |
I-75 | CH2OCONH2 | H | H |
I-76 | CH2OCONHEt | H | H |
I-77 | CH2NHAc | H | H |
I-78 | CH2CH2CH(CONH2)NHAc | H | H |
I-79 | CH2CH(Me)CONH2 | H | H |
I-80 | CH2CH2CONHMe | Me | H |
I-81 | CH(Me)OCONH2 | H | H |
I-82 | CH2OCONHEt | Me | Me |
I-83 | CH2NHAc | Et | H |
I-84 | CH(Me)CH2CH(CONH2)NHAc | Me | H |
I-85 | CH(NHAc)CH2CONH2 | H | H |
I-86 | CH2CH(NHAc)CONH2 | H | H |
I-87 | CH(NHAc)(CH2)2CONH2 | H | H |
I-88 | CH2NHCOCH2NHAc | H | H |
I-89 | CH2NHCOCH(Me)NHAc | H | H |
I-90 | CH2(NHCOCH2)2NHAc | H | H |
No | R1 | R2 | R3 |
I-91 | CH2CH2CONH2 | H | H |
I-92 | CH2CH2CONHMe | H | H |
I-93 | CH2OCONH2 | H | H |
I-94 | CH2OCONHEt | H | H |
I-95 | CH2NHAc | H | H |
I-96 | CH2CH2CH(CONH2)NHAc | H | H |
I-97 | CH2CH(Me)CONH2 | H | H |
I-98 | CH2CH2CONHMe | Me | H |
I-99 | CH(Me)OCONH2 | H | H |
I-100 | CH2OCONHEt | Me | Me |
I-101 | CH2NHAc | Et | H |
I-102 | CH(Me)CH2CH(CONH2)NHAc | Me | H |
I-103 | CH(NHAc)CH2CONH2 | H | H |
I-104 | CH2CH(NHAc)CONH2 | H | H |
I-105 | CH(NHAc)(CH2)2CONH2 | H | H |
I-106 | CH2NHCOCH2NHAc | H | H |
I-107 | CH2NHCOCH(Me)NHAc | H | H |
I-108 | CH2(NHCOCH2)2NHAc | H | H |
No | R1 | R2 | R3 |
I-109 | CH2CH2CONH2 | H | H |
I-110 | CH2CH2CONHMe | H | H |
I-111 | CH2OCONH2 | H | H |
I-112 | CH2OCONHEt | H | H |
I-113 | CH2NHAc | H | H |
I-114 | CH2CH2CH(CONH2)NHAc | H | H |
I-115 | CH2CH(Me)CONH2 | H | H |
I-116 | CH2CH2CONHMe | Me | H |
I-117 | CH(Me)OCONH2 | H | H |
I-118 | CH2OCONHEt | Me | Me |
I-119 | CH2NHAc | Et | H |
I-120 | CH(Me)CH2CH(CONH2)NHAc | Me | H |
I-121 | CH(NHAc)CH2CONH2 | H | H |
I-122 | CH2CH(NHAc)CONH2 | H | H |
I-123 | CH(NHAc)(CH2)2CONH2 | H | H |
I-124 | CH2NHCOCH2NHAc | H | H |
I-125 | CH2NHCOCH(Me)NHAc | H | H |
I-126 | CH2(NHCOCH2)2NHAc | H | H |
No | R1 | R2 | R3 |
I-127 | CH2CH2CONH2 | H | H |
I-128 | CH2CH2CONHMe | H | H |
I-129 | CH2OCONH2 | H | H |
I-130 | CH2OCONHEt | H | H |
I-131 | CH2NHAc | H | H |
I-132 | CH2CH2CH(CONH2)NHAc | H | H |
I-133 | CH2CH(Me)CONH2 | H | H |
I-134 | CH2CH2CONHMe | Me | H |
I-135 | CH(Me)OCONH2 | H | H |
I-136 | CH2OCONHEt | Me | Me |
I-137 | CH2NHAc | Et | H |
I-138 | CH(Me)CH2CH(CONH2)NHAc | Me | H |
I-139 | CH(NHAc)CH2CONH2 | H | H |
I-140 | CH2CH(NHAc)CONH2 | H | H |
I-141 | CH(NHAc)(CH2)2CONH2 | H | H |
I-142 | CH2NHCOCH2NHAc | H | H |
I-143 | CH2NHCOCH(Me)NHAc | H | H |
I-144 | CH2(NHCOCH2)2NHAc | H | H |
No | R1 | R2 | R3 |
I-145 | CH2CH2CONH2 | H | H |
I-146 | CH2CH2CONHMe | H | H |
I-147 | CH2OCONH2 | H | H |
I-148 | CH2OCONHEt | H | H |
I-149 | CH2NHAc | H | H |
I-150 | CH2CH2CH(CONH2)NHAc | H | H |
I-151 | CH2CH(Me)CONH2 | H | H |
I-152 | CH2CH2CONHMe | Me | H |
I-153 | CH(Me)OCONH2 | H | H |
I-154 | CH2OCONHEt | Me | Me |
I-155 | CH2NHAc | Et | H |
I-156 | CH(Me)CH2CH(CONH2)NHAc | Me | H |
I-157 | CH(NHAc)CH2CONH2 | H | H |
I-158 | CH2CH(NHAc)CONH2 | H | H |
I-159 | CH(NHAc)(CH2)2CONH2 | H | H |
I-160 | CH2NHCOCH2NHAc | H | H |
I-161 | CH2NHCOCH(Me)NHAc | H | H |
I-162 | CH2(NHCOCH2)2NHAc | H | H |
No | R1 | R2 | R3 |
I-163 | CH2CH2CONH2 | H | H |
I-164 | CH2CH2CONHMe | H | H |
I-165 | CH2OCONH2 | H | H |
I-166 | CH2OCONHEt | H | H |
I-167 | CH2NHAc | H | H |
I-168 | CH2CH2CH(CONH2)NHAc | H | H |
I-169 | CH2CH(Me)CONH2 | H | H |
I-170 | CH2CH2CONHMe | Me | H |
I-171 | CH(Me)OCONH2 | H | H |
I-172 | CH2OCONHEt | Me | Me |
I-173 | CH2NHAc | Et | H |
I-174 | CH(Me)CH2CH(CONH2)NHAc | Me | H |
I-175 | CH(NHAc)CH2CONH2 | H | H |
I-176 | CH2CH(NHAc)CONH2 | H | H |
I-177 | CH(NHAc)(CH2)2CONH2 | H | H |
I-178 | CH2NHCOCH2NHAc | H | H |
I-179 | CH2NHCOCH(Me)NHAc | H | H |
I-180 | CH2(NHCOCH2)2NHAc | H | H |
No | R1 | R4 | R5 | R8 | R9 | R10 | R11 | Y |
I-181 | CH2CH2CONH2 | H | F | H | Me | Me | H | iPr |
I-182 | CH2CH2CONH2 | F | H | Me | COOMe | Me | Me | CH2CH=CMe2 |
I-183 | CH2CH2CONH2 | H | H | H | Et | Et | H | CH2CH=CMe2 |
I-184 | CH2CH2CONH2 | H | Cl | H | OEt | OEt | H | CH2CH=CMe2 |
I-185 | CH2CH2CONH2 | Cl | H | H | COOMe | Me | H | iPr |
I-186 | CH2CH2CONH2 | H | H | Et | OMe | OMe | Et | CH2CH=CMe2 |
I-187 | CH2CH2CONH2 | H | F | Et | Et | Et | H | CH2CH=CMe2 |
I-188 | CH2CH2CONH2 | F | H | Me | Me | OMe | Me | CH2CH=CMe2 |
I-189 | CH2CH2CONH2 | H | H | Me | Me | COOMe | Me | CH2CH=CMe2 |
I-190 | CH2CH2CONH2 | H | Cl | H | OMe | OMe | OH | CH2CH=CMe2 |
I-191 | CH2CH2CONH2 | Cl | H | Me | Me | Me | OH | CH2CH=CMe2 |
I-192 | CH2CH2CONH2 | H | H | Me | Me | OH | Me | CH2CH=CMe2 |
I-193 | CH2CH2CONHMe | H | F | H | OMe | OMe | H | iPr |
I-194 | CH2CH2CONHMe | F | H | Me | COOMe | Me | Me | CH2CH=CMe2 |
I-195 | CH2CH2CONHMe | H | H | H | Et | Et | H | CH2CH=CMe2 |
I-196 | CH2CH2CONHMe | H | Cl | H | OEt | OEt | H | CH2CH=CMe2 |
I-197 | CH2CH2CONHMe | Cl | H | H | COOMe | Me | H | CH2CH=CMe2 |
I-198 | CH2CH2CONHMe | H | H | Et | OMe | OMe | Et | CH2CH=CMe2 |
I-199 | CH2CH2CONHMe | H | F | Et | Et | Et | H | CH2CH=CMe2 |
I-200 | CH2CH2CONHMe | F | H | Me | Me | OMe | Me | CH2CH=CMe2 |
I-201 | CH2CH2CONHMe | H | H | Me | Me | COOMe | Me | iPr |
I-202 | CH2CH2CONHMe | H | Cl | H | OMe | OMe | OH | CH2CH=CMe2 |
I-203 | CH2CH2CONHMe | Cl | H | Me | Me | Me | OH | CH2CH=CMe2 |
I-204 | CH2CH2CONHMe | H | H | Me | Me | OH | Me | CH2CH=CMe2 |
No | R1 | R4 | R5 | R8 | R9 | R10 | R11 |
I-205 | CH2OCONH2 | H | F | H | OMe | OMe | H |
I-206 | CH2OCONH2 | F | H | Me | COOMe | Me | Me |
I-207 | CH2OCONH2 | H | H | H | Et | Et | H |
I-208 | CH2OCONH2 | H | Cl | H | OEt | OEt | H |
I-209 | CH2OCONH2 | Cl | H | H | COOMe | Me | H |
I-210 | CH2OCONH2 | H | H | Et | OMe | OMe | Et |
I-211 | CH2OCONH2 | H | F | Et | Et | Et | H |
I-212 | CH2OCONH2 | F | H | Me | Me | OMe | Me |
I-213 | CH2OCONH2 | H | H | Me | Me | COOMe | Me |
I-214 | CH2OCONH2 | H | Cl | H | OMe | OMe | OH |
I-215 | CH2OCONH2 | Cl | H | Me | Me | Me | OH |
I-216 | CH2OCONH2 | H | H | Me | Me | OH | Me |
I-217 | CH2NHAc | H | F | H | OMe | OMe | H |
I-218 | CH2NHAc | F | H | Me | COOMe | Me | Me |
I-219 | CH2NHAc | H | H | H | Et | Et | H |
I-220 | CH2NHAc | H | Cl | H | OEt | OEt | H |
I-221 | CH2NHAc | Cl | H | H | COOMe | Me | H |
I-222 | CH2NHAc | H | H | Et | OMe | OMe | Et |
I-223 | CH2NHAc | H | F | Et | Et | Et | H |
I-224 | CH2NHAc | F | H | Me | Me | OMe | Me |
I-225 | CH2NHAc | H | H | Me | Me | COOMe | Me |
I-226 | CH2NHAc | H | Cl | H | OMe | OMe | OH |
I-227 | CH2NHAc | Cl | H | Me | Me | Me | OH |
I-228 | CH2NHAc | H | H | Me | Me | OH | Me |
No | R1 | R4 | R5 | R8 | R9 | R10 | R11 |
I-229 | CH2NHCOC2H5 | H | F | H | OMe | OMe | H |
I-230 | CH2CSNH2 | F | H | Me | COOMe | Me | Me |
I-231 | CH2OCH2CH2OH | H | H | H | Et | Et | H |
I-232 | CH2OMe | H | F | H | OEt | OEt | H |
I-233 | CH2OCH2CH2OMe | F | H | H | COOMe | Me | H |
I-234 | CH2COCH3 | H | H | Et | OMe | OMe | Et |
I-235 | CH2COC2H5 | H | F | Et | Et | Et | H |
I-236 | CH2OCOCH3 | F | H | Me | Me | OMe | Me |
I-237 | CH2OCOC2H5 | H | H | Me | Me | COOMe | Me |
I-238 | CH2NHOH | H | F | H | OMe | OMe | OH |
I-239 | CH2NHCONH2 | F | H | Me | Me | Me | OH |
I-240 | CH2NHCSNH2 | H | H | Me | Me | OH | Me |
I-241 | CH2NHSO2Me | H | F | H | OMe | OMe | H |
I-242 | CH2N(SO2Me)2 | F | H | Me | COOMe | Me | Me |
I-243 | CH2SO2NH2 | H | H | H | Et | Et | H |
I-244 | CH2SOMe | H | F | H | OEt | OEt | H |
I-245 | CH2SO2Me | F | H | H | COOMe | Me | H |
I-246 | CH2OCH2CONH2 | H | H | Et | OMe | OMe | Et |
I-247 | CH2OCH2CONMe2 | H | F | Et | Et | Et | H |
I-248 | CH2SO2NMe2 | F | H | Me | Me | OMe | Me |
I-249 | CH2PO(OMe)2 | H | H | Me | Me | COOMe | Me |
I-250 | CH2NHCSNHEt | H | F | H | OMe | OMe | OH |
I-251 | CH2CH=NNHCONH2 | F | H | Me | Me | Me | OH |
I-252 | CH2CH=NNHCSNH2 | H | H | Me | Me | OH | Me |
I-253 | CH2CH=NNHSO2Me | H | F | H | OMe | OMe | H |
I-254 | CH2-1,2,3-三唑-5-基 | F | H | Me | COOMe | Me | Me |
I-255 | CH2-四唑-1-基 | H | H | H | Et | Et | H |
No | R1 | R4 | R5 | R8 | R9 | R10 | R11 |
I-256 | CH2NHCOC2H5 | H | F | H | Me | Me | H |
I-257 | CH2CSNH2 | F | H | Me | COOMe | Me | Me |
I-258 | CH2OCH2CH2OH | H | H | H | Et | Et | H |
I-259 | CH2OMe | H | F | H | OEt | OEt | H |
I-26O | CH2OCH2CH2OMe | F | H | H | COOMe | Me | H |
I-261 | CH2COCH3 | H | H | Et | OMe | OMe | Et |
I-262 | CH2COC2H5 | H | F | Et | Et | Et | H |
I-263 | CH2OCOCH3 | F | H | Me | Me | OMe | Me |
I-264 | CH2OCOC2H5 | H | H | Me | Me | COOMe | Me |
I-265 | CH2NHOH | H | F | H | OMe | OMe | OH |
I-266 | CH2NHCONH2 | F | H | Me | Me | Me | OH |
I-267 | CH2NHCSNH2 | H | H | Me | Me | OH | Me |
I-268 | CH2NHSO2Me | H | F | H | OMe | OMe | H |
I-269 | CH2N(SO2Me)2 | F | H | Me | COOMe | Me | Me |
I-270 | CH2SO2NH2 | H | H | H | Et | Et | H |
I-271 | CH2SOMe | H | F | H | OEt | OEt | H |
I-272 | CH2SO2Me | F | H | H | COOMe | Me | H |
I-273 | CH2OCH2CONH2 | H | H | Et | OMe | OMe | Et |
I-274 | CH2OCH2CONMe2 | H | F | Et | Et | Et | H |
I-275 | CH2SO2NMe2 | F | H | Me | Me | OMe | Me |
I-276 | CH2PO(OMe)2 | H | H | Me | Me | COOMe | Me |
I-277 | CH2NHCSNHEt | H | F | H | OMe | OMe | OH |
I-278 | CH2CH=NNHCONH2 | F | H | Me | Me | Me | OH |
I-279 | CH2CH=NNHCSNH2 | H | H | Me | Me | OH | Me |
I-280 | CH2CH=NNHSO2Me | H | F | H | OMe | OMe | H |
I-281 | CH2CH2-1,2,3-三唑-5-基 | F | H | Me | COOMe | Me | Me |
I-282 | CH2CH2-四唑-1-基 | H | H | H | Et | Et | H |
1)、动物
使用购于日本SLC(Shizuoka)的BALB/c小鼠(雌性,8-10周)和Wistar大鼠(雌性,8-10周)。
2)、免疫方法
通过将2μg卵清蛋白(OVA)和2mg氢氧化铝凝胶悬浮在生理盐水中得到溶液,将0.2ml该溶液通过腹膜内注射给予BALB/c鼠使之免疫。10天后,从心脏采血,分离出血清并在-40℃下贮存直至测定IgE抗体的效价。
3)、化合物
将本发明化合物及其母化合物(II-1)溶解在或悬浮在甲基纤维素中并用中性油Migriol 812稀释20倍得到溶液,以每只小鼠0.1ml的量口服给药(剂量10,40mg/kg)。从免疫当日至采血前一日连续给药10天。
4)、抗-OVA的IgE抗体效价(PCA效价)的测定
将所得到的小鼠血清用生理盐水制备成2倍稀释系列,预先去毛的Wistar大鼠经背部皮内注射该系列各50μl。24小时后,静脉内注射0.5ml含1mg OVA和5mg伊凡斯蓝色素的生理盐水引起阳性皮肤过敏反应(PCA)。30分钟后,最大稀释率的血清显示出具有5mm或更大直径的PCA阳性反应色素点,用稀释率的log2作为PCA效价。例如,当血清稀释至27倍出现PCA反应阳性时,该鼠的抗-OVA IgE抗体效价为7。结果显示于表19。
表19
3mg/Kg | 10mg/Kg | 40mg/Kg | |
II-1 | - | 6.7 | 0.8 |
I-1 | 7.0 | 0.8 | - |
I-6 | - | 1.8 | - |
I-13 | - | <0 | - |
I-15 | - | 0 | - |
I-16 | - | <0 | - |
与化合物(II-1)相比,本化合物显示出更高的活性,并且本化合物实际上发挥前药作用。试验实施例2口服吸收试验
将本化合物(I-1)用玛瑙乳钵研磨,用0.5%的甲基纤维素溶液作溶媒制备成浓度为10mg/ml的含水悬浮液。以20mg/kg的速度口服给予Jcl:SD雄性大鼠(10周,禁食18小时)作为母化合物的各化合物。给药后0.5、1、2、4、6、8和24小时,通过预先植入鼠颈静脉中的插管采血0.3ml。血样离心得到血浆。将0.5ml甲醇和乙腈(1/1(w/w))的混合溶液加到0.1ml该血浆中,除去其中的蛋白质,然后离心。上清液用作HPLC样品。化合物的HPLC条件显示于表20。
表20
柱 | Develosil ODS-UG-5(4.6×150mm) |
流动相 | 0.1M NaClO4∶MeOH=12∶88 |
流速(ml/min) | 1.0ml/min |
检测 | UV:255nm |
滞留时间(min) | 15.5min |
Cmax为2.50μg/ml,并且AUC为32.03μg·hr/ml。口服给药后的血浆浓度时间曲线显示于图1。
在口服给予(I-1)的鼠累积血浆中没有检测到本化合物(I-1),并且只观察到母化合物(II-1),显示高血浆浓度。化合物(I-1)的口服可吸收性高,并且这一点在其用作前药时可见。此外,如上所述,化合物的熔点升高并且其物理性质得到改善。使用实施例3口服吸收试验
如试验实施例2所述测定本化合物(I-163)及其母化合物(II-4)的口服可吸收性。HPLC条件显示于表21。
表21
I-163 | II-4 | |
柱 | Develosil ODS-UG-5(2.0×150mm) | Develosil ODS-UG-5(2.0×150mm) |
流动相 | H2O∶MeOH=12∶88 | H2O∶MeOH=12∶88 |
流速(ml/min) | 0.2ml/min | 1.0ml/min |
检测 | UV:255nm | UV:255nm |
滞留时间(min) | 14.5min | 6.6min |
母化合物(II-4)的Cmax为0.11μg/ml,并且AUC为1.64μg·hr/ml。本化合物(I-163)的Cmax为1.08μg/ml,并且AUC为12.38μg·hr/ml。口服给药后的血浆浓度时间曲线显示于图2。与母化合物相比,本化合物显示出相当高的口服可吸收性。试验实施例4口服吸收试验
如试验实施例2所述,用非禁食大鼠测定本化合物(I-16)及其母化合物(II-1)的口服可吸收性。HPLC条件显示于表22。
表22
I-16 | II-1 | |
柱 | Develosil ODS-UG-5(2.0×150mm) | Develosil ODS-UG-5(2.0×150mm) |
流动相 | H2O∶MeOH=12∶88 | H2O∶MeOH=12∶88 |
流速(ml/min) | 0.2ml/min | 0.2ml/min |
检测 | UV:255nm | UV:255nm |
滞留时间(min) | 6.7min | 16.0min |
在口服给予本化合物(I-16)的鼠累积血浆中没有检测到化合物(I-16),只观察到母化合物(II-1),显示高血浆浓度。(II-1)的Cmax为6.13μg/ml,并且AUC为57.31μg·hr/ml。(I-16)的Cmax为16.02μg/ml,并且AUC为165.52μg·hr/ml。口服给药后的血浆浓度时间曲线显示于图3。制备实施例1片剂
化合物(I) 15mg
淀粉 15mg
乳糖 15mg
结晶纤维素 19mg
聚乙烯醇 3mg
蒸馏水 30ml
硬脂酸钙 3mg
除硬脂酸钙外,将其它组分混合均匀,研磨并制粒,干燥并制成适宜大小的颗粒。然后加入硬脂酸钙,压模后得到片剂。
工业实用性
化合物(I)显示出较高的口服可吸收性并且其活性形式化合物(II)显示出较强的免疫抑制活性和/或抗变态反应活性。因此,本化合物是非常有用的免疫押制剂和/或抗变态反应药。
Claims (18)
1、由式(I)表示的化合物或其可药用盐或溶剂化物:其中X和X′中的一个为-N(COOCR3R2OCOR1)-,另一个为-(CH2)s-(其中s为整数0-2)、-O-、-NRA-(其中RA为氢、未取代的或取代的低级烷基、低级链烯基或低级烷基羰基)、-N(COOCR3R2OCOR1)-或-S(O)p-(其中p为整数0-2),
R1为由1个或2个取代基取代的低级烷基,所述取代基为-CONH2、-CONHCH3、-CONHC2H5、-OCONH2、-OCONHCH3、-OCONHC2H5、-(NHCOCRR′)mNHCOCH3、-(NHCOCRR′)mNHCOC2H5、-CSNH2、-(OCH2CH2)nOH、-OCH3、-(OCH2CH2)nOCH3、-COCH3、-COC2H5、-OCOCH3、-OCOC2H5、-NHOH、-NHCONH2、-NHCSNH2、-NHSO2CH3、-N(SO2CH3)2、-SO2NH2、-SOCH3、-SO2CH3、-OCH2CONH2、-OCH2CON(CH3)2、-SO2N(CH3)2、-PO(OCH3)2、-NHCSNHC2H5、-CH=NNHCONH2、-CH=NNHCSNH2或-CH=NNHSO2CH3,三唑基和四唑基(R和R′各独立地为氢或低级烷基,m为整数0-2并且n为整数1或2),
R2和R3各独立地为氢或低级烷基,
Y和Y′各独立地为氢、未取代的或取代的低级烷基、未取代的或取代的低级链烯基、未取代的或取代的低级链炔基、未取代的或取代的环烷基、未取代的或取代的环烯基、未取代的或取代的低级烷氧基羰基、未取代的或取代的氨磺酰基、未取代的或取代的氨基、未取代的或取代的芳基或者未取代的或取代的5-元或6-元杂环,
当X为-CH2-时,Y可以是未取代的或取代的低级烷氧基,
当X′为-CH2-时,Y′可以是未取代的或取代的低级烷氧基,
当X为-O-或-NRA-时,Y可以是未取代的或取代的低级烷基磺酰基或者未取代的或取代的芳基磺酰基,
当X′为-O-或-NRA-时,Y′可以是未取代的或取代的低级烷基磺酰基或者未取代的或取代的芳基磺酰基,
环A、环B和环C各独立地为未取代的或取代的芳族碳环或者为可以与苯环稠合的未取代的或取代的5-元或6-元杂环,
当环A、环B和/或环C是未取代的或取代的5-元杂环时,W1、W2和/或W3代表键,
V1和V2中的一个为单键、另一个为单键、-O-、-NH-、-OCH2-、-CH2O-、-CH=CH-、-C≡C-、-CH(ORB)-(其中RB为氢或低级烷基)、-CO-、-NHCHRc-或-CHRcNH-(其中Rc为氢或羟基),
当V1和V2都为单键时,环A、环B和环C中至少一个为未取代的或取代的芳族碳环,并且至少一个为可以与苯环稠合的未取代的或取代的5-元或6-元杂环。
Y和Y′各独立地为未取代的或取代的低级烷基、未取代的或取代的低级链烯基或者未取代的或取代的低级链炔基,
R1、R2和R3具有与权利要求1相同的含义,
环A和环C各独立地为未取代的或取代的苯环或者未取代的或取代的包含1个或2个杂原子的6-元杂环,至少其中一个为6-元杂环。
R8、R9、R10和R11各独立地为氢、卤素、羟基、未取代的或取代的低级烷基、未取代的或取代的低级烷氧基、未取代的或取代的低级链烯基、未取代的或取代的低级链烯氧基、未取代的或取代的环烷氧基、未取代的或取代的酰氧基、羧基、未取代的或取代的低级烷氧基羰基、未取代的或取代的低级链烯氧基羰基、未取代的或取代的低级烷硫基、未取代的或取代的低级烯硫基、未取代的或取代的氨基、未取代的或取代的氨基甲酰基、胍基、硝基、未取代的或取代的低级烷基磺酰基、未取代的或取代的低级烷基磺酰氧基、未取代的或取代的芳基磺酰基或未取代的或取代的芳基磺酰氧基。
3、由式(III)表示的化合物或其可药用盐或溶剂化物:其中X为-NH-或-N(COOCR3R2OCOR1)-,X′为-O-、-NH-或-N(COOCR3R2OCOR1)-,至少X和X′中的一个为-N(COOCR3R2OCOR1)-,
Y和Y′各独立地为未取代的或取代的低级烷基或者未取代的或取代的低级链烯基,
R1、R2和R3具有与权利要求1相同的含义,
R4、R5、R6、R7、R8、R9、R10和R11各独立地为氢、卤素、羟基、未取代的或取代的低级烷基、未取代的或取代的低级烷氧基、未取代的或取代的低级链烯基、未取代的或取代的低级链烯氧基、羧基、未取代的或取代的低级烷氧基羰基或者未取代的或取代的氨基,
环C为未取代的或由低级烷基取代的吡啶或嘧啶。
4、权利要求1-3的任一化合物或其可药用盐或溶剂化物,其中R1为由1个或2个取代基取代的C1-C3烷基,所述取代基选自-CONH2、-OCONH2和-(NHCOCRR′)mNHCOCH3。
5、权利要求3的化合物或其可药用盐或溶剂化物,其中R4和R5各独立地为氢或卤素。
6、权利要求3的化合物或其可药用盐或溶剂化物,其中R6和R7都为氢。
7、权利要求2或3的化合物或其可药用盐或溶剂化物,其中R8和R11各独立地为氢、羟基或低级烷基。
8、权利要求2或3的化合物或其可药用盐或溶剂化物,其中R9和R10各独立地为低级烷基、低级烷氧基或低级烷氧基羰基。
9、权利要求1-3的任一化合物或其可药用盐或溶剂化物,其中X′为-O-。
10、权利要求3的化合物或其可药用盐或溶剂化物,其中X为-NH-或-N(COOCR3R2OCOR1)-,X′为-O-、-NH-或-N(COOCR3R2OCOR1)-,至少X和X′中的一个为-N(COOCR3R2OCOR1)-,
R1为由1个或2个取代基取代的C1-C3烷基,所述取代基选自-CONH2、-OCONH2和-(NHCOCRR′)mNHCOCH3,R2和R3为氢或C1-C3烷基,
Y和Y′各独立地为未取代的或由卤素取代的低级烷基或者未取代的或由卤素取代的低级链烯基,R4和R5各独立地为氢或卤素,R6和R7都是氢,R8和R11各独立地为氢、羟基或低级烷基,R9和R10各独立地为低级烷基、低级烷氧基或低级烷氧基羰基,并且环C为未取代的或由低级烷基取代的吡啶或嘧啶。
11、权利要求1、2、3和10的任一化合物或其可药用盐或溶剂化物,其中Y和Y′都是异戊二烯基(prenyl)。
14、一种药物组合物,它包含权利要求1-13的任一化合物或其可药用盐或溶剂化物。
15、一种免疫抑制剂,它包含权利要求1-13的任一化合物或其可药用盐或溶剂化物。
16、一种抗变态反应药,它包含权利要求1-13的任一化合物或其可药用盐或溶剂化物。
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EP3674289B9 (en) * | 2017-08-25 | 2023-12-13 | Guangzhou Henovcom Bioscience Co., Ltd | Long-acting rasagiline prodrug, preparation method and use thereof |
TW201932470A (zh) | 2017-11-29 | 2019-08-16 | 愛爾蘭商健生科學愛爾蘭無限公司 | 具有抗rsv活性之吡唑并嘧啶 |
EA202091835A1 (ru) | 2018-01-31 | 2020-10-20 | Янссен Сайенсиз Айрлэнд Анлимитед Компани | Замещенные циклоалкилом пиразолопиримидины, обладающие активностью против rsv |
ES2957316T3 (es) | 2018-04-23 | 2024-01-17 | Janssen Sciences Ireland Unlimited Co | Compuestos heteroaromáticos que tienen actividad contra VSR |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4760057A (en) | 1983-06-23 | 1988-07-26 | Merck & Co., Inc. | (Acyloxyalkoxy)carbonyl derivatives as bioreversible prodrug moieties for primary and secondary amine functions in drugs |
DE3475065D1 (en) | 1983-06-23 | 1988-12-15 | Merck & Co Inc | (acyloxyalkoxy) carbonyl derivatives as bioreversible prodrug moieties for primary and secondary amine functions in drugs, their preparation and pharmaceutical compositions containing said derivatives |
US4916230A (en) | 1984-07-02 | 1990-04-10 | Merck & Co., Inc. | Process for preparing novel N-(acyloxy-alkoxy)carbonyl derivatives useful as bioreversible prodrug moieties for primary and secondary amine functions in drugs |
US4728670A (en) | 1986-06-04 | 1988-03-01 | E. R. Squibb & Sons, Inc. | Biphenyl hydroxamic acids |
GB9001405D0 (en) | 1990-01-22 | 1990-03-21 | Leo Pharm Prod Ltd | New intermediates,their production and use |
GB9226537D0 (en) | 1992-12-21 | 1993-02-17 | Smithkline Beecham Plc | Compounds |
US5684018A (en) | 1994-12-13 | 1997-11-04 | Merck & Co., Inc. | Acyloxyisopropyl carbamates as prodrugs for amine drugs |
DE69704057T2 (de) | 1996-04-22 | 2001-09-13 | Shionogi & Co., Ltd. | Terphenylverbindungen und sie enthaltende arzneimittel |
PL341984A1 (en) * | 1998-01-28 | 2001-05-07 | Shionogi & Co | Novel tricycle compounds |
WO2001007032A1 (fr) * | 1999-07-23 | 2001-02-01 | Shionogi & Co., Ltd. | Inhibiteurs de differenciation th2 |
-
2000
- 2000-07-14 AU AU60158/00A patent/AU6015800A/en not_active Abandoned
- 2000-07-14 CN CN00810581A patent/CN1361766A/zh active Pending
- 2000-07-14 US US09/980,474 patent/US6765096B1/en not_active Expired - Fee Related
- 2000-07-14 KR KR1020027000777A patent/KR20020063837A/ko not_active Application Discontinuation
- 2000-07-14 CA CA002375909A patent/CA2375909A1/en not_active Abandoned
- 2000-07-14 EP EP00946315A patent/EP1219606A4/en not_active Withdrawn
- 2000-07-14 WO PCT/JP2000/004724 patent/WO2001005768A1/ja not_active Application Discontinuation
- 2000-07-15 TW TW089114186A patent/TW589302B/zh active
Also Published As
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US6765096B1 (en) | 2004-07-20 |
AU6015800A (en) | 2001-02-05 |
TW589302B (en) | 2004-06-01 |
WO2001005768A1 (fr) | 2001-01-25 |
KR20020063837A (ko) | 2002-08-05 |
EP1219606A1 (en) | 2002-07-03 |
CA2375909A1 (en) | 2001-01-25 |
EP1219606A4 (en) | 2005-08-31 |
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