CN1255117A - 兴奋性氨基酸受体调节剂 - Google Patents
兴奋性氨基酸受体调节剂 Download PDFInfo
- Publication number
- CN1255117A CN1255117A CN98804992A CN98804992A CN1255117A CN 1255117 A CN1255117 A CN 1255117A CN 98804992 A CN98804992 A CN 98804992A CN 98804992 A CN98804992 A CN 98804992A CN 1255117 A CN1255117 A CN 1255117A
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- CN
- China
- Prior art keywords
- group
- alkyl
- compound
- hexane
- amino
- Prior art date
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- Granted
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- 102000018899 Glutamate Receptors Human genes 0.000 title description 8
- 108010027915 Glutamate Receptors Proteins 0.000 title description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 133
- 150000001408 amides Chemical class 0.000 claims abstract description 17
- 150000002148 esters Chemical class 0.000 claims abstract description 17
- 102000016193 Metabotropic glutamate receptors Human genes 0.000 claims abstract description 14
- 108010010914 Metabotropic glutamate receptors Proteins 0.000 claims abstract description 14
- 231100000252 nontoxic Toxicity 0.000 claims abstract description 8
- 230000003000 nontoxic effect Effects 0.000 claims abstract description 8
- -1 Methoxy, amino, azido, acetylamino, benzoylamino, methylsulfonylamino, methylaminocarbonylamino Chemical group 0.000 claims description 174
- 125000000217 alkyl group Chemical group 0.000 claims description 88
- 239000001257 hydrogen Substances 0.000 claims description 51
- 229910052739 hydrogen Inorganic materials 0.000 claims description 50
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 46
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 42
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 31
- 150000003839 salts Chemical class 0.000 claims description 26
- ANUFAWHRSIJTHW-UHFFFAOYSA-N 2-methylheptanedioic acid Chemical compound OC(=O)C(C)CCCCC(O)=O ANUFAWHRSIJTHW-UHFFFAOYSA-N 0.000 claims description 24
- 125000003545 alkoxy group Chemical group 0.000 claims description 21
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 21
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 20
- 125000003118 aryl group Chemical group 0.000 claims description 20
- 239000011737 fluorine Substances 0.000 claims description 20
- 229910052731 fluorine Inorganic materials 0.000 claims description 20
- 229910052736 halogen Inorganic materials 0.000 claims description 19
- 150000002367 halogens Chemical class 0.000 claims description 19
- 125000001072 heteroaryl group Chemical group 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 17
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 17
- 125000001424 substituent group Chemical group 0.000 claims description 15
- 125000003342 alkenyl group Chemical group 0.000 claims description 11
- 125000001589 carboacyl group Chemical group 0.000 claims description 11
- 125000003277 amino group Chemical group 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 10
- 229910006069 SO3H Inorganic materials 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 9
- 125000003107 substituted aryl group Chemical group 0.000 claims description 8
- 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 claims description 8
- 125000000304 alkynyl group Chemical group 0.000 claims description 7
- 150000002431 hydrogen Chemical class 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 125000006239 protecting group Chemical group 0.000 claims description 7
- 229910018828 PO3H2 Inorganic materials 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 5
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 5
- 239000004305 biphenyl Substances 0.000 claims description 5
- 235000010290 biphenyl Nutrition 0.000 claims description 5
- 125000006267 biphenyl group Chemical group 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 5
- 230000003301 hydrolyzing effect Effects 0.000 claims description 5
- 125000001620 monocyclic carbocycle group Chemical group 0.000 claims description 5
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 5
- XHBZYLUDOIQPFQ-RGDLXGNYSA-N (1s,2s,5r,6r)-2-amino-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid Chemical compound OC(=O)[C@]1(N)CC(=O)[C@H]2[C@H](C(O)=O)[C@@H]12 XHBZYLUDOIQPFQ-RGDLXGNYSA-N 0.000 claims description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
- 125000002837 carbocyclic group Chemical group 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- OOLBYBOPYDRLHD-JXBXBTJBSA-N (1s,2s,5r,6s)-2-amino-4-methylidenebicyclo[3.1.0]hexane-2,6-dicarboxylic acid Chemical compound OC(=O)[C@]1(N)CC(=C)[C@H]2[C@H](C(O)=O)[C@@H]12 OOLBYBOPYDRLHD-JXBXBTJBSA-N 0.000 claims description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
- 238000004590 computer program Methods 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 186
- 239000000047 product Substances 0.000 description 123
- 235000019439 ethyl acetate Nutrition 0.000 description 87
- 239000011541 reaction mixture Substances 0.000 description 83
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 78
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 76
- 239000000243 solution Substances 0.000 description 68
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 62
- 238000006243 chemical reaction Methods 0.000 description 59
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 57
- 238000000434 field desorption mass spectrometry Methods 0.000 description 55
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 52
- 229910001868 water Inorganic materials 0.000 description 52
- 238000004364 calculation method Methods 0.000 description 46
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 45
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 44
- 239000000203 mixture Substances 0.000 description 43
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 42
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 36
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 36
- 239000007787 solid Substances 0.000 description 35
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 34
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 28
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 27
- 238000002844 melting Methods 0.000 description 24
- 230000008018 melting Effects 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 22
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 22
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 22
- 235000019341 magnesium sulphate Nutrition 0.000 description 22
- 239000012267 brine Substances 0.000 description 18
- 230000002829 reductive effect Effects 0.000 description 18
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 17
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 17
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 17
- 229920006395 saturated elastomer Polymers 0.000 description 17
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 16
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 15
- 229960000583 acetic acid Drugs 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- 239000012043 crude product Substances 0.000 description 14
- 235000011054 acetic acid Nutrition 0.000 description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 13
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical group OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
- 239000000460 chlorine Substances 0.000 description 12
- 239000007789 gas Substances 0.000 description 12
- 238000001953 recrystallisation Methods 0.000 description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
- 239000002585 base Substances 0.000 description 11
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- GKIRPKYJQBWNGO-OCEACIFDSA-N clomifene Chemical compound C1=CC(OCCN(CC)CC)=CC=C1C(\C=1C=CC=CC=1)=C(\Cl)C1=CC=CC=C1 GKIRPKYJQBWNGO-OCEACIFDSA-N 0.000 description 10
- 238000010828 elution Methods 0.000 description 10
- 239000011780 sodium chloride Substances 0.000 description 10
- 239000002253 acid Substances 0.000 description 9
- 238000005277 cation exchange chromatography Methods 0.000 description 9
- 230000007062 hydrolysis Effects 0.000 description 9
- 238000006460 hydrolysis reaction Methods 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 9
- 238000000746 purification Methods 0.000 description 9
- 102000005962 receptors Human genes 0.000 description 9
- 108020003175 receptors Proteins 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 8
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 8
- 229910052783 alkali metal Inorganic materials 0.000 description 8
- 238000004587 chromatography analysis Methods 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- 239000006260 foam Substances 0.000 description 8
- 230000006870 function Effects 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- 159000000000 sodium salts Chemical class 0.000 description 8
- 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 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 7
- 239000003957 anion exchange resin Substances 0.000 description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 7
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 7
- 125000005842 heteroatom Chemical group 0.000 description 7
- 229910052757 nitrogen Chemical group 0.000 description 7
- 239000001301 oxygen Substances 0.000 description 7
- 229910052760 oxygen Inorganic materials 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 229910052708 sodium Inorganic materials 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 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 6
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 6
- 229920002472 Starch Polymers 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 229940024606 amino acid Drugs 0.000 description 6
- 150000001413 amino acids Chemical class 0.000 description 6
- 239000000377 silicon dioxide Substances 0.000 description 6
- 235000019698 starch Nutrition 0.000 description 6
- 239000011593 sulfur Chemical group 0.000 description 6
- 229910052717 sulfur Inorganic materials 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 229930195712 glutamate Natural products 0.000 description 5
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Inorganic materials [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 5
- 230000000926 neurological effect Effects 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 239000008107 starch Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 239000007810 chemical reaction solvent Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 239000003257 excitatory amino acid Substances 0.000 description 4
- 230000002461 excitatory amino acid Effects 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 description 4
- 229940091173 hydantoin Drugs 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 210000002569 neuron Anatomy 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 229910052700 potassium Inorganic materials 0.000 description 4
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 4
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 4
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- WLYANNSIDDXEGE-GWGQIBMDSA-N (1s,2r,4s,5s,6s)-2-amino-4-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid Chemical compound OC(=O)[C@@]1(N)C[C@H](F)[C@@H]2[C@@H](C(O)=O)[C@H]12 WLYANNSIDDXEGE-GWGQIBMDSA-N 0.000 description 3
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 3
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 3
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 3
- 239000012346 acetyl chloride Substances 0.000 description 3
- 230000010933 acylation Effects 0.000 description 3
- 238000005917 acylation reaction Methods 0.000 description 3
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
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- 229940116362 tragacanth Drugs 0.000 description 1
- 230000018405 transmission of nerve impulse Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 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
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 229940071104 xylenesulfonate Drugs 0.000 description 1
- 229910001845 yogo sapphire Inorganic materials 0.000 description 1
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Abstract
式(Ⅰ)化合物——其中R1和R2的定义如说明书——和其无毒的代谢不稳定酯和酰胺用作代谢亲和性谷氨酸盐受体功能的调节剂。
Description
发明背景
在哺乳动物中枢神经系统(CNS)中,神经冲动的传递是通过传出神经原释放的神经递质和传入神经原上的导致该传入神经原兴奋的表面受体之间的交互作用控制的。L-谷氨酸盐是CNS中最丰富的神经递质,其调节哺乳动物体内主要的兴奋路径,被称为兴奋性氨基酸(EAA)。响应谷氨酸盐的受体称为兴奋性氨基酸受体(EAA受体)。参见 Watkins & Evans,Ann.Rev.Pharmacol.Toxicol.,21,165(1981);Monaghan,Bridges,和Cotman,Ann.Rev.Pharmacol.Toxicol.,29,365(1989);Watkins,Krogsgaard-Larsen,和Honore,Trans.Pharm.Sci.,11,25(1990)。兴奋性氨基酸在生物学上非常重要,参与各种生物学过程,诸如长期强化(学习和记忆)、突触可塑性的发育、运动原控制、呼吸、心血管调节和感觉性知觉。
兴奋性氨基酸受体分为两种常规的类型。直接与神经原细胞膜中的打开的阳离子通道偶联的受体称为“离子亲和性的”。通过选择性的兴奋剂N-甲基-D-门冬氨酸盐(NMDA)、α-氨基-3-羟基-5-甲基异噁唑-4-丙酸(AMPA)和红藻氨酸(KA)的去极化作用定义,将这类受体再分为至少三个亚型。第二类常规类型受体是连接G-蛋白或第二信使的“代谢亲和性的”兴奋性氨基酸受体。这第二种类型可与多种第二信使体系偶联,使磷酸肌醇水解加强、使磷脂酶D或C活化、使c-AMP的形成增加或减少并改变离子通道功能。Schoepp和Conn,Trends in Pharmacol.Sci.,14,13(1993)。这两种类型的受体不但调节沿着兴奋路径的常规突触传输,还在发育和整个生命期间参与突触的连接的修正。Schoepp,Bockaert,和Sladeczek,Trends in Pharmacol.Sci.,11,508(1990);McDonald和Johnson,Brain Research Reviews,15,41(1990)。
对兴奋性氨基酸受体的过度或不适当刺激会通过称为兴奋毒性的机理导致神经原细胞的损伤或损失。现假定该过程导致神经原在各种条件下的变性。这种神经原变性的药物的重要治疗目的是减轻这些神经病变过程。
代谢亲和性谷氨酸盐受体是与多种第二信使路径连接的谷氨酸盐受体家族中非常复杂的。这些受体能调整谷氨酸盐的前突触释放和神经原细胞对谷氨酸盐刺激的后突触敏感度。调整这些受体功能的化合物,特别是谷氨酸盐的促效药和拮抗药,对治疗急性或慢性神经变性以及作为抑制精神病、抗惊厥、止痛、抗焦虑、抗抑郁和止吐药物是有用的。
国际专利申请WO96/05175公开了化合物2-氨基双环[3.1.0]己烷-2,6-二羧酸及其盐和酯作为代谢亲和性谷氨酸盐受体兴奋剂。
本发明提供了式I化合物或其无毒的代谢不稳定酯或酰胺;或其药物上可接受的盐,
其中:
(a)R1表示氟、XOR3、XNR4R5、SO3H、四唑-5-基、CN或PO3R6 2和R2表示氢;或
(b)R1和R2分别表示氟;或
(c)R1和R2一起表示=O、=NOR7或=CR8R9;或
(d)R1和R2之一表示氨基,另一个表示羧基;或
(e)R1表示N3、(CH2)mCOOR3a、(CH2)mPO3R6a 2、NHCONHR3b或NHSO2R3c和R2表示氢;或
(f)R1和R2一起表示=CHCOOR3b、=CHPO3R2 6a或=CHCN;和
R3表示氢原子;(1-6C)烷基;(3-6C)链烯基;(3-6C)链炔基;任选取代的芳基;任选取代的杂芳基;非芳族碳环基;非芳族杂环基;与一个或两个单环芳族或杂芳族基团稠合的非芳族单环碳环基;与一个或两个单环芳族或杂芳族基团稠合的非芳族单环杂环基;或被1个、2个或3个独立选自任选取代的芳基、任选取代的杂芳基、非芳族碳环基、非芳族杂环基和与一个或两个单环芳族或杂芳族基团稠合的非芳族单环碳环基和与一个或两个单环芳族或杂芳族基团稠合的非芳族单环杂环基的基团取代的(1-6C)烷基、(3-6C)链烯基或(3-6C)链炔基;
R3a、R3b和R3c定义如R3;
X表示一个键、CH2或CO;
m表示1-3的整数;
R4表示COR16或定义如R3;
R5、R7、R8、R9和R10定义如R3;
R6表示氢或(1-6C)烷基;和
R6a定义如R6。
式I化合物是代谢亲和性谷氨酸盐受体功能的调节剂,特别是在代谢亲和性谷氨酸盐受体上谷氨酸盐的促效药或拮抗药。
因此,根据另一方面,本发明提供一种调节在包括人的哺乳动物体内代谢亲和性谷氨酸盐受体功能的方法,包括施加有效量的式I化合物或其无毒的代谢不稳定酯或酰胺或其药物可接受的盐。
根据再一个方面,本发明提供了上文定义的式I化合物的用途,即用于制备调节代谢亲和性谷氨酸盐受体功能的药物。
应认识到,式I化合物含有至少4个不对称碳原子;3个在环丙烷环上,1或2个在环戊烷环上。还应认识到,R1和R2一起表示=NOR7时的式I化合物可以是顺式或反式,R1和R2一起表示=CR8R9、=CHCOOR3b、=CHPO3R2 6a或=CHCN时的式I化合物可以是(E)或(Z)型。本发明包括式I化合物的所有立体构型,包括各个对映体和其混合物。
本发明还包括式I化合物的所有物理形式,包括晶态溶剂化物。
除了特别说明,本发明中使用的术语“烷基”表示直链或支链的烷基。(1-6C)烷基优选的例子包括(1-4C)烷基,诸如甲基、乙基、丙基、异丙基、丁基和异丁基。
术语(3-6C)链烯基包括(3-4C)链烯基,例如烯丙基。
术语(3-6C)链炔基包括(3-4C)链炔基,例如丙炔基。
术语杂芳基包括含有1-4个选自氧、硫和氮的杂原子的芳族5-6员环以及双环基,该双环基由与一个苯环或与一个有1-4个选自氧、硫和氮的杂原子的5-6员环稠合的有1-4个选自氧、硫和氮的杂原子的5-6员环组成。杂芳基的例子是呋喃基、苯硫基、噁唑基、异噁唑基、噻唑基、异噻唑基、咪唑基、嘧啶基、苯并呋喃基、苯并苯硫基、苯并咪唑基、苯并噁唑基、苯并噻唑基和吲哚基。
术语芳基包括苯基和多环芳族碳环,诸如1-萘基或2-萘基。
在术语“任选取代的杂芳基或芳基”中使用的术语“任选取代的”表示可存在1个、2个或多个取代基,所述的取代基选自原子和基团,当所述的取代基存在于式I化合物中时,它们不妨碍式I化合物作为代谢亲和性谷氨酸盐受体功能调节剂。
可在任选取代的杂芳族或芳族基团中存在的原子和基团的例子是氨基、羟基、硝基、卤素、(1-6C)烷基、(1-6C)烷氧基、(1-6C)烷基硫基、羧基、(1-6C)烷氧基羰基、氨基甲酰基、(1-6C)烷酰基氨基(alkanoylamino)、(1-6C)烷基磺酰基、(1-6C)烷基磺酰基氨基、(1-6C)烷酰基(alkanoyl)、苯基、苯氧基、苯硫基、苯磺酰基、苯磺酰基氨基、甲苯磺酰基氨基和(1-6C)氟代烷基。特别优选的例子是氨基、羟基、硝基、氟、氯、溴、碘、甲基、甲氧基、甲硫基、羧基、乙酰氨基、甲磺酰基、甲磺酰基氨基、乙酰基、苯基、苯氧基、苯硫基、苯磺酰基和三氟甲基。
优选的任选取代的芳基的例子是1-萘基、2-萘基、苯基、2-联苯基、3-联苯基、4-联苯基、2-羟基苯基、3-羟基苯基、4-羟基苯基、2-氟苯基、3-氟苯基、4-氟苯基、2,4-二氟苯基、3,4-二氟苯基、五氟苯基、2-氯苯基、3-氯苯基、4-氯苯基、2,4-二氯苯基、3,4-二氯苯基、3,5-二氯苯基、2-溴苯基、3-溴苯基、4-溴苯基、2-甲基苯基、3-甲基苯基、4-甲基苯基、2-甲氧基苯基、3-甲氧基苯基、4-甲氧基苯基、2,3-二甲氧基苯基、2,5-二甲氧基苯基、3,4-二甲氧基苯基、3,5-二甲氧基苯基、2-三氟甲基苯基、3-三氟甲基苯基、4-三氟甲基苯基、2-氟-3-三氟甲基苯基、3-三氟甲基-4-氟苯基、3-三氟甲基-5-氟苯基、2-氟-5-三氟甲基苯基、2-苯氧基苯基、3-苯氧基苯基、3-羧基苯基和4-羧基苯基。
术语“非芳族碳环基”包括单环基,例如(3-10C)环烷基,诸如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基或环癸基,还有稠合的多环基团,诸如1-金刚烷基或2-金刚烷基、1-萘烷基、2-萘烷基、4a-萘烷基、双环[3.3.0]辛-1-基、双环[3.3.0]辛-2-基或双环[3.3.0]辛-3-基、双环[4.3.0]壬-1-基、双环[4.3.0]壬-2-基、双环[4.3.0]壬-3-基或双环[4.3.0]壬-7-基、双环[5.3.0]癸-1-基、双环[5.3.0]癸-2-基、双环[5.3.0]癸-3-基、双环[5.3.0]癸-4-基、双环[5.3.0]癸-8-基或双环[5.3.0]癸-9-基或双环[3.3.1]壬-1-基、双环[3.3.1]壬-2-基、双环[3.3.1]壬-3-基或双环[3.3.1]壬-9-基。
术语“非芳族杂环基”包括含1个或2个选自氧、硫和氮的杂原子的4-7员环,例如氮杂环丁烷-1-基或氮杂环丁烷-2-基、吡咯烷-1-基、吡咯烷-2-基或吡咯烷-3-基、哌啶-1-基、哌啶-2-基、哌啶-3-基或哌啶-4-基、六氢吖庚因-1-基、六氢吖庚因-2-基、六氢吖庚因-3-基或六氢吖庚因-4-基、氧杂环丁烷-2-基(oxetan-2-yl)或氧杂环丁烷-3-基、四氢呋喃-2-基或四氢呋喃-3-基、四氢吡喃-2-基、四氢吡喃-3-基或四氢吡喃-4-基、六氢氧杂庚英-2-基(hexahydrooxepin-2-yl)、六氢氧杂庚英-3-基或六氢氧杂庚英-4-基、硫杂环丁烷-2-基(thietan-2-yl)或硫杂环丁烷-3-基、四氢噻吩-2-基或四氢噻吩-3-基、四氢噻喃-2-基、四氢噻喃-3-基或四氢噻喃-4-基、六氢硫杂庚英-2-基(hexahydrothiepin-2-yl)、六氢硫杂庚英-3-基或六氢硫杂庚英-4-基、哌嗪-1-基或哌嗪-2-基、吗啉-1-基、吗啉-2-基或吗啉-3-基、硫吗啉-1-基、硫吗啉-2-基或硫吗啉-3-基、四氢嘧啶-1-基、四氢嘧啶-2-基、四氢嘧啶-4-基或四氢嘧啶-5-基、咪唑啉-1-基、咪唑啉-2-基或咪唑啉-4-基、咪唑烷-1-基、咪唑烷-2-基或咪唑烷-4-基、噁唑啉-2-基、噁唑啉-3-基、噁唑啉-4-基或噁唑啉-5-基、噁唑烷-2-基、噁唑烷-3-基、噁唑烷-4-基或噁唑烷-5-基、噻唑啉-2-基、噻唑啉-3-基、噻唑啉-4-基或噻唑啉-5-基或噻唑烷-2-基、噻唑烷-3-基、噻唑烷-4-基或噻唑烷-5-基。
术语“与1个或2个单环芳基或杂芳基稠合的非芳族单环碳环基”包括与苯环或与含有1-4个选自氧、硫或氮的杂原子的芳族5-6员环稠合的(3-10C)环烷基,诸如2,3-二氢化茚基、1,2,3,4-四氢萘-1-基或1,2,3,4-四氢萘-2-基、5,6,7,8-四氢喹啉-5-基、5,6,7,8-四氢喹啉-6-基、5,6,7,8-四氢喹啉-7-基或5,6,7,8-四氢喹啉-8-基、5,6,7,8-四氢异喹啉-5-基、5,6,7,8-四氢异喹啉-6-基、5,6,7,8-四氢异喹啉-7-基或5,6,7,8-四氢异喹啉-8-基、4,5,6,7-四氢苯并噻吩-4-基、4,5,6,7-四氢苯并噻吩-5-基、4,5,6,7-四氢苯并噻吩-6-基或4,5,6,7-四氢苯并噻吩-7-基、二苯并[2,3,6,7]环庚烷-1-基或二苯并[2,3,6,7]环庚烷-4-基、二苯并[2,3,6,7]环庚-4-烯-1-基或二苯并[2,3,6,7]环庚-4-烯-4-基或9-芴基。
术语“与1个或2个单环芳基或杂芳基稠合的非芳族单环杂环基”包括含有1或2个选自氧、硫和氮的杂原子并与苯环或含有1-4个选自氧、硫和氮的杂原子的芳族5-6员环稠合的4-7员环,诸如2,3-二氢苯并吡喃-2-基、2,3-二氢苯并吡喃-3-基或2,3-二氢苯并吡喃-4-基、不吨-9-基、1,2,3,4-四氢喹啉-1-基、1,2,3,4-四氢喹啉-2-基、1,2,3,4-四氢喹啉-3-基或1,2,3,4-四氢喹啉-4-基、9,10-二氢吖啶-9-基或9,10-二氢吖啶-10-基、2,3-二氢苯并噻喃-2-基、2,3-二氢苯并噻喃-3-基或2,3-二氢苯并噻喃-4-基或二苯并噻喃-4-基。
当R3表示(1-6C)烷基时,优选的例子是甲基、乙基、丙基、异丙基、丁基和异丁基。
当R3表示(3-6C)链烯基时,优选的例子是烯丙基。
当R3表示(3-6C)链炔基时,优选的例子是丙炔基。
当R3表示任意被取代的芳基时,优选表示2-萘基或未取代的苯基或被1个或2个独立地选自卤素、(1-4C)烷基和(1-4C)烷氧基的取代基取代的苯基。
当R3表示任选被取代的芳基时,优选的例子是2-萘基、苯基、2-氟苯基、3-氟苯基、4-氟苯基、3,4-二氟苯基、五氟苯基、2-氯苯基、3-氯苯基、4-氯苯基、3,4-二氯苯基、2,5-二氯苯基、2-溴苯基、3-溴苯基、4-溴苯基、2-甲基苯基、3-甲基苯基、4-甲基苯基、2-甲氧基苯基、3-甲氧基苯基、4-甲氧基苯基、3-三氟甲基苯基和4-三氟甲基苯基。
当R3表示取代的(1-6C)烷基、(2-6C)链烯基或(2-6C)链炔基时,优选的例子是苯基(1-4C)烷基和二苯基(1-4C)烷基,其中在苯基上未取代或被1个或2个卤素、(1-4C)烷基和(1-4C)烷氧基取代,例如苄基、2-苯基乙基、2-苯基丙基和2-硫代苯基甲基。其它的例子是(3-6C)环烷基(1-4C)烷基,例如环丙基甲基。
当R3表示任选取代的杂芳基时,优选的例子是2-嘧啶基。
R3a特别优选的例子是氢和(1-6C)烷基,诸如甲基或乙基。
R3b特别优选的例子是氢和(1-6C)烷基,诸如甲基或乙基。
R3c特别优选的例子是(1-6C)烷基,诸如甲基。
R4更优选的例子是氢、诸如乙酰基的(1-6C)烷酰基、苯甲酰基、诸如甲基的(1-6C)烷基和诸如环丙基甲基的(3-6C)环烷基(1-4C)烷基。
R5更优选的例子是氢、诸如甲基的(1-6C)烷基和诸如环丙基甲基的(3-6C)环烷基(1-4C)烷基。
R6特别优选的例子是氢、甲基和乙基。
R6a特别优选的例子是氢、甲基和乙基。
R7、R8、R9和R10特别优选的例子是氢、诸如甲基的(1-6C)烷基和任选取代的芳基,诸如苯基。
根据本发明化合物中特定的化合物如下,其中
(a)R1表示氟、XOR3、XNR4R5、SO3H、四唑-5-基、CN或PO3R6 2和R2表示氢;或
(b)R1和R2分别表示氟;或
(c)R1和R2一起表示=O、=NOR7或=CR8R9;或
(d)R1和R2之一表示氨基,另一个表示羧基。
R1和R2特别优选是:
(a)R1表示氟;XOR3;XNR4R5;SO3H;四唑-5-基;CN或PO3H2;X表示一个键、CO或CH2;R3表示氢或(1-6C)烷基;未取代的苯基或被1个或2个独立地选自卤素、(1-4C)烷基和(1-4C)烷氧基的取代基取代的苯基;在苯基上未取代或被1个或2个独立选自卤素、(1-4C)烷基和(1-4C)烷氧基的取代基取代的苯基(1-4C)烷基或二苯基(1-4C)烷基;R4表示氢、(1-6C)烷酰基、苯甲酰基、(3-6C)环烷基(1-4C)烷基或(1-6C)烷基;和R5表示氢、(3-6C)环烷基(1-4C)烷基或(1-6C)烷基;和R2表示氢;或
(b)R1和R2分别表示氟;或
(c)R1和R2一起表示=O、=NOH或=CR8R9,其中R8和R9各自独立地表示氢原子、(1-6C)烷基或未取代的苯基或被1个或2个选自卤素、(1-4C)烷基和(1-4C)烷氧基的取代基取代的苯基;或
(d)R1和R2之一表示氨基,另一个表示羧基;或
(e)R1表示N3、CH2COOR3a、CH2PO3R2 6a、NHCONHR3b或NHSO2R3c;R3a表示氢和(1-6C)烷基;R3b表示(1-6C)烷基;R3c表示(1-6C)烷基;R2表示氢;和每个R6a独立地表示氢或(1-6C)烷基;或
(f)R1和R2一起表示=CHCOOH、=CHPO3H2、=CHPO3(C2H5)2或=CHCN。
在这些基团中,R1和R2特别优选是:
(a)R1表示氟、XOR3、XNR4R5、SO3H、四唑-5-基、CN或PO3H2;X表示一个键、CO或CH2;R3表示氢原子,(1-6C)烷基,未取代的苯基或被1个或2个独立地选自卤素、(1-4C)烷基和(1-4C)烷氧基的取代基取代的苯基,在苯基上未取代或被1个或2个选自卤素、(1-4C)烷基和(1-4C)烷氧基的取代基取代的苯基(1-4C)烷基或二苯基(1-4C)烷基;R4表示氢、(1-6C)烷酰基或(1-6C)烷基;和R5表示氢或(1-6C)烷基;和R2表示氢;或
(b)R1和R2分别表示氟;或
(c)R1和R2一起表示=O、=NOH或=CR8R9,其中R8和R9各自独立地表示氢原子、(1-6C)烷基或未取代的苯基或被1个或2个独立地选自卤素、(1-4C)烷基和(1-4C)烷氧基的取代基取代的苯基;或
(d)R1和R2之一表示氨基,另一个表示羧基。
优选R1表示氟、羟基、PO3H2、甲氧基、氨基、叠氮基、乙酰氨基、苯甲酰氨基、甲磺酰氨基、甲基氨基羰基氨基、N,N-二环丙基甲基、羧基、氰基或氨甲酰和R2表示氢,或R1和R2一起表示=O、=NOH、=CHCO2H、=CH2、=CHPO3(C2H5)2、=CHPO3H2或=CHCN。
式I化合物的例子包括:
2-氨基-4-羟基双环[3.1.0]己烷-2,6-二羧酸;
2-氨基-4-氟双环[3.1.0]己烷-2,6-二羧酸;
2-氨基-4,4-二氟双环[3.1.0]己烷-2,6-二羧酸;
2-氨基-4-羧基双环[3.1.0]己烷-2,6-二羧酸;
2,4-二氨基双环[3.1.0]己烷-2,6-二羧酸;
2-氨基-4-氨基甲基双环[3.1.0]己烷-2,6-二羧酸;
2-氨基-4-乙酰基氨基甲基双环[3.1.0]己烷-2,6-二羧酸;
2-氨基-4-氧代双环[3.1.0]己烷-2,6-二羧酸;
2-氨基-4-羟基亚氨基双环[3.1.0]己烷-2,6-二羧酸;
2-氨基-4-膦酰基双环[3.1.0]己烷-2,6-二羧酸;
2-氨基-4-甲氧基双环[3.1.0]己烷-2,6-二羧酸;
2-氨基-4-叠氮基双环[3.1.0]己烷-2,6-二羧酸;
2-氨基-4-苯甲酰基氨基双环[3.1.0]己烷-2,6-二羧酸;
2-氨基-4-甲磺酰基氨基双环[3.1.0]己烷-2,6-二羧酸;
2-氨基-4-甲基氨基羰基氨基双环[3.1.0]己烷-2,6-二羧酸;
2-氨基-4-(N,N-二环丙基甲基)氨基双环[3.1.0]己烷-2,6-二羧酸;
2-氨基-4-羧基亚甲基双环[3.1.0]己烷-2,6-二羧酸;
2-氨基-4-亚甲基双环[3.1.0]己烷-2,6-二羧酸;
2-氨基-4-二乙基膦酰基亚甲基双环[3.1.0]己烷-2,6-二羧酸;
2-氨基-4-膦酰基亚甲基双环[3.1.0]己烷-2,6-二羧酸;
2-氨基-4-氰基亚甲基双环[3.1.0]己烷-2,6-二羧酸;
2-氨基-4-氰基双环[3.1.0]己烷-2,6-二羧酸;和
2-氨基-4-氨甲酰双环[3.1.0]己烷-2,6-二羧酸。
特别优选的式I化合物是:
(1S*,2S*,5R*,6R*)-2-氨基-4-氧代双环[3.1.0]己烷-2,6-二羧酸;
(1S*,2S*,5R*,6R*)-2-氨基-4-[反]-肟基双环[3.1.0]己烷-2,6-二羧酸;
(1S*,2S*,5R*,6R*)-2-氨基-4-[顺]-肟基双环[3.1.0]己烷-2,6-二羧酸;
(1S*,2R*,4S*,5S*,6S*)-2-氨基-4-氟双环[3.1.0]己烷-2,6-二羧酸;
(1S*,2S*,5R*,6S*)-2-氨基-4-Z-羧基亚甲基双环[3.1.0]己烷-2,6-二羧酸和
(1S*,2S*,5R*,6S*)-2-氨基-4-亚甲基双环[3.1.0]己烷-2,6-二羧酸。已经发现这些化合物作为代谢亲和性谷氨酸盐受体调节剂有特别高的效能。
本发明包括式I化合物的药物可接受盐。这些盐可以与分子的酸性或碱性部分一起存在和可作为酸加成盐、伯铵盐、仲铵盐、叔铵盐或季铵盐、碱金属盐或碱土金属盐存在。通常,通过酸与式I化合物反应制备酸加成盐。一般通过所需金属盐的氢氧化物与式I化合物的反应制备碱金属盐和碱土金属盐。
通常用于形成这类盐的酸包括诸如盐酸、氢溴酸、氢碘酸、硫酸和磷酸的无机酸和诸如对甲苯磺酸、甲磺酸、草酸、对溴苯磺酸、碳酸、琥珀酸、柠檬酸、苯甲酸和乙酸的有机酸以及相关的无机酸和有机酸。因此这类药物上可接受的盐包括硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、磷酸盐、铵盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、氯化物、溴化物、碘化物、乙酸盐、丙酸盐、癸酸盐、辛酸盐、丙烯酸盐、甲酸盐、异丁酸盐、、癸酸盐、庚酸盐、丙炔酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、癸二酸盐、延胡索酸盐、马尿酸盐、丁炔-1,4-二醇盐、己烷-1,6-二醇盐、苯甲酸盐、氯苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、邻苯二甲酸盐、磺酸盐、二甲苯磺酸盐、苯乙酸盐、苯丙酸盐、苯丁酸盐、柠檬酸盐、乳酸盐、a-羟丁酸盐、甘醇酸盐、马来酸盐、酒石酸盐、甲磺酸盐、丙磺酸盐、萘-1-磺酸盐、萘-2-磺酸盐、扁桃酸盐、镁盐、四甲基铵盐、钾盐、三甲基铵盐、钠盐、甲基铵盐、钙盐等。
式I化合物的药物上可接受的代谢不稳定酯和酰胺是式I化合物的酯或酰胺衍生物,其在体内水解得到所述式I化合物和药物上可接受的醇或胺。代谢不稳定酯的例子包括与(1-6C)醇形成的酯,其中醇部分可任选被(1-8C)烷氧基取代,(1-6C)醇是例如甲醇、乙醇、丙醇和甲氧基乙醇。代谢不稳定酰胺的例子包括与诸如甲胺的胺形成的酰胺。
根据另一个方面,本发明提供了用于制备式I化合物的方法,包括:
(a)水解式II化合物或其盐,
其中,
R11表示氢原子或酰基,R12表示羧基或酯化的羧基;
其中,
R13表示羧基或酯化的羧基,R14和R15分别独立地表示氢原子、(2-6C)烷酰基、(1-4C)烷基、(3-4C)链烯基或苯基(1-4C)烷基,其中苯基是未取代的或被卤素、(1-4C)烷基或(1-4C)烷氧基取代;或
其中,
R18表示氢原子或氮保护基,R16和R17分别独立地表示氢原子或羧基保护基;
此后,如果需要和/或希望,
(i)将式I化合物拆分;
(ii)将式I化合物转化为其无毒性的代谢不稳定酯或酰胺;和/或
(iii)将式I化合物或其无毒性的代谢不稳定酯或酰胺转化为其药物上可接受的盐。
一般在McOmie,Protecting Groups in Organic Chemistry,Plenum Press,NY,1973和Greene and Wuts,Protecting Groupsin Organic Synthesis,2nd.Ed.,John Wiley & Sons,NY,1991中描述了羧酸基团和胺基团的保护。羧基保护基的例子包括烷基,诸如甲基、乙基、叔丁基和叔戊基;芳烷基,诸如苄基、4-硝基苄基、4-甲氧基苄基、3,4-二甲氧基苄基、2,4-二甲氧基苄基、2,4,6-三甲氧基苄基、2,4,6-三甲基苄基、二苯甲基和三苯甲游基;甲硅烷基,诸如三甲基甲硅烷基和叔丁基二甲基甲硅烷基;以及烯丙基,诸如烯丙基和1-(三甲基甲硅烷基甲基)丙-1-烯-3-基。胺保护基的例子包括酰基,诸如式RaCO的基团,其中Ra表示(1-6C)烷基、(3-10C)环烷基、苯基(1-6C)烷基、苯基、诸如叔丁氧基的(1-6C)烷氧基、苯基(1-6C)烷氧基或(3-10C)环烷氧基,其中苯基可任选被1个或2个独立地选自氨基、羟基、硝基、卤素、(1-6C)烷基、(1-6C)烷氧基、羧基、(1-6C)烷氧基羰基、氨基甲酰基、(1-6C)烷酰基氨基、(1-6C)烷基磺酰基氨基、苯基磺酰基氨基、甲苯磺酰基氨基和(1-6C)氟代烷基的取代基取代。
R11优选是氢、诸如乙酰基的(2-6C)烷酰基和叔丁氧基羰基。
当R12和R13表示酯化的羧基时,优选是(1-6C)烷氧基羰基,诸如乙氧基羰基。
优选R14和R15独立地是氢或苄基。
优选R16和R17是甲基和乙基。
优选R18是叔丁氧基羰基。
式II的化合物在酸——诸如盐酸或硫酸——或碱——诸如碱金属氢氧化物,例如氢氧化钠——存在下可方便地水解。水解在诸如水的含水溶剂中在50-200℃温度的范围内可方便地进行。
式III的化合物在碱——诸如碱金属氢氧化物,例如锂、钠或钾的氢氧化物,或碱土金属的氢氧化物,例如氢氧化钡—存在下可方便地水解。适合的反应介质包括水。温度在50-150℃范围内为宜。
可用常规的方法将式IV化合物去保护。从而,可通过水解除去烷基羧基保护基。通过在碱——例如碱金属氢氧化物,诸如锂、钠或钾的氢氧化物,或碱土金属的氢氧化物,例如氢氧化钡——或酸——诸如盐酸—存在下加热式IV化合物可方便地进行水解。水解在10-300℃范围内的温度进行为宜。通过氢化可方便地除去芳烷基羧基保护基。通过在VIII族金属催化剂——例如钯催化剂,诸如负载在碳上的钯—存在下使式IV化合物与氢反应可方便地进行氢化。适合的反应溶剂包括醇,诸如乙醇。反应在0-100℃范围内的温度进行为宜。通过水解还可将酰基——胺保护基——方便地除去,例如用除去烷基羧基保护基所采用的方法。在诸如乙酸乙酯的溶剂中用无水氯化氢可方便地除去叔丁氧基羰基。
与碱金属氰化物——诸如锂、钠或钾的氰化物——和卤化铵——诸如氯化铵——反应可制备式II化合物。已经发现在超声存在下进行反应是有利的。因此,卤化铵和碱金属氰化物在诸如乙腈的适合的稀释剂存在下与色谱级氧化铝混合是有利的。混合物然后用超声辐射,随后加入式V化合物,混合物再进行辐射。
然后生成的非对映异构的氨基腈可与酰化剂——诸如乙酰氯——在适合的碱——例如胺,诸如二异丙基乙胺——和适合的溶剂——诸如二氯甲烷——存在下反应,生成非对映异构的酰氨基腈的混合物。所需的非对映异构体可通过例如色谱法方便地从该混合物中分离。
式III混合物可通过式V化合物与碱金属氰化物——诸如锂、钠或钾的氰化物——和碳酸铵在醇的水溶液——诸如乙醇水溶液——中反应制备。反应在35-150℃范围内的温度进行为宜。如果需要,例如使用适当的式R14Cl或R14Br和/或R15Cl或R16Br化合物,可将化合物III随后烷基化或酰基化。
制备式III化合物。
因此,例如可通过式VI化合物与还原剂——诸如硼氢化钠——反应制备其中R1表示α-羟基和R2表示氢的式III化合物。
将相应的其中R1表示羟基的式II、III或IV化合物与式R3Z1化合物——其中Z1表示离去原子或基团——诸如氯、溴或碘原子或对甲苯磺酰氧基的基团——在诸如氢化钠或丁醇钾的碱存在下反应,可制备其中R1表示除羟基之外的OR3且R2表示氢的式II、III或IV化合物。反应在0-100℃范围内的温度进行为宜。适合的溶剂包括诸如二甲基甲酰胺的酰胺类、诸如二甲基亚砜的亚砜类和诸如四氢呋喃的醚类。或者,可用如Bull.Chem.Soc.Japan,40,2380,1967所述的Mitsunobu chemistry制备化合物。
将相应的其中R1和R2一起表示=O的式II、III或IV化合物分别与氟化试剂——诸如三氟化二乙基氨基硫或三氟化二甲基氨基硫———根据J.Org.Chem,50,1599,1985和Tet.Lett.,34(31),4917,1993所述的方法反应,可制备其中R1和R2都表示氟的式II、III或IV化合物。反应在诸如二氯甲烷或四氢呋喃的溶剂中在0-50℃范围内的温度进行为宜。或者,氟化剂是在有锌粉的三氟乙酸和CF2Br2中的氟化氢(J.Chem.Soc.Perk.Trans.1,3,335,1993)。或者,通过与H2SCH2CH2SH反应,随后与BF3-乙酸配合物反应(J.Org.Chem.,51,3508,1986),将其中R1和R2一起表示=O的式II、III或IV化合物转化为二硫戊环。
将相应的式II、III或IV化合物与式H2NOR6的羟胺或其酸加成盐,诸如盐酸的加成盐在诸如氢氧化钠、醋酸钠或三乙胺的碱存在下反应,可制备其中R1和R2一起表示=NOR6的式II、III或IV化合物。反应在0-50℃范围内的温度在诸如乙醇、乙醇水溶液或二甲基亚砜的极性溶剂存在下进行为宜。
将相应的其中R1和R2一起表示=NOH的式II、III或IV化合物还原,可制备其中R1表示氨基和R2表示氢的式II、III或IV化合物。适合的还原剂包括在贵金属催化剂——诸如负载在炭上的钯或阮内镍——存在下的氢、氢化锂铝、和乙酸一起使用的硼烷或锌。或者,它们可通过还原其中R1表示叠氮基和R2表示氢的式II、III或IV化合物制备。使用三苯基膦,在四氢呋喃水溶液存在下在0-100℃范围内的温度进行还原为宜。
例如通过使用式R4Z2或R5Z3的化合物进行烷基化,其中Z2和Z3表示离去原子或基团——诸如氯原子或对甲苯磺酰氧基的基团;通过使用醛或酮和诸如氰基硼氢化钠的还原剂进行还原烷基化;或通过使用酰卤或酸酐进行酰基化,将其中R1表示NH2的式II、III或IV化合物烷基化或酰基化,生成其中R1表示NR4R5的相应的式II、III或IV化合物。
将相应的其中R1表示氨基的式II、III或IV化合物与式R3b-N=C=O的异氰酸酯反应,可制备其中R1表示NHCONH3b的式II、III或IV化合物。适宜的溶剂包括二氯甲烷。
将相应的其中R1表示氨基的式II、III或IV化合物与式R3cSO2Z4的磺酰卤——其中Z4是例如氯或溴——反应可制备其中R1表示NHSO2R3c的式II、III或IV化合物。反应在诸如三乙胺的碱的存在下和诸如二氯甲烷的溶剂中进行为宜。
将相应的其中R1表示羟基和R2表示氢的式II、III或IV化合物与三氟化二甲基氨基硫或三氟化二乙基氨基硫根据Tet.Assym.4(2),161,1994所述的方法反应,可制备其中R1表示氟和R2表示氢的式II、III或IV化合物。反应在20-50℃范围内的温度在诸如二氯甲烷、甲苯或四氢呋喃的存在下进行为宜。或者,根据Syn.,3,273,1994所述的方法,在诸如三乙胺的存在下,醇与氟化铯和氟化四丁基铵反应。另一个方便的氟化试剂是聚(4-乙烯基-吡啶鎓)聚氟化氢(Syn.Lett.,5,267,1990)。
将相应的其中R1表示羟基的式II、III或IV化合物与诸如对甲苯磺酰氯或甲磺酰氯的烃基磺酰卤在例如吡啶的反应溶剂中反应,随后与诸如氰化钾的氰化物或诸如叠氮化钠的叠氮盐在例如二甲基亚砜的反应溶剂中反应,可制备其中R1表示CN或叠氮基的式II、III或IV化合物。
其中R1表示羧基的式II、III或IV化合物可通过水解相应的腈制备。如果需要,生成的羧基化合物可用常规的方法酯化或转化为式CONR4R5的酰胺。
其中R1表示CH2NR4R5的式II、III或IV化合物可通过还原相应的腈制备,例如通过在负载于炭上的钯或阮内镍存在下氢化,随后如果需要,进行上文所述的烷基化、还原烷基化或酰化。
将相应的其中R1表示CN的式III或IV化合物与诸如四丁基三叠氮化物的叠氮化物反应,可制备其中R1表示四唑基的式III或IV化合物。
与氧化剂——诸如琼斯试剂(CrO3,H2SO4)——反应,可制备式VI化合物。
与碱金属氰化物——氰化钾——和碳酸铵反应,然后如果需要,使用式R14Br或R15Br进行烷基化或酰基化,可制备式VII化合物。
将相应的其中R1和R2一起表示=O的式II、III或IV化合物通过维蒂希反应可制备其中R1和R2一起表示=CR8R9的式II、III或IV化合物,例如通过与式Ph3P=CR8R9化合物的反应,式Ph3P=CR8R9化合物可通过三苯基膦与卤代烷反应形成。
将相应的其中R1和R2一起表示=O的式II、III或IV化合物通过Wadsworth-Emmons反应可制备其中R1和R2一起表示=CHCOOR3b、=CHPO3R2 6a或=CHCN的式II、III或IV化合物,例如通过与二烷基膦酰基乙酸酯的碱金属盐——诸如二乙基膦酰基乙酸苄基酯的钠盐、与亚甲基二膦酸四烷基酯——诸如亚甲基二膦酸四烷基酯、或与膦酸氰基甲基二烷基酯的碱金属盐——诸如膦酸氰基甲基二乙酯的钠盐反应。反应在诸如无水甲苯的无水溶剂中进行为宜。通过水解,例如使用诸如三氟乙酸或盐酸水解,可除去R6a表示的烷基。
例如通过在VIII族金属催化剂—诸如炭负载的钯——存在下催化氢化,将相应的其中R1和R2一起表示=CHPO3R2 6a的式II、III或IV化合物通过还原反应可制备其中R1和R2一起表示(CH2)mPO3R2 6a的式II、III或IV化合物。
与硫醇——诸如N-乙酰基-L-半胱氨酸、碱——诸如硼酸钠和二芳基联硒化物——诸如二苯基联硒化物反应,可制备式VIII化合物。
通过式X化合物
与过氧化物——诸如叔丁基过氧化氢——反应,可制备式IX化合物。
通过式X化合物与亚磷酸三烷基酯——诸如亚磷酸三乙基酯——在苯酚存在下反应,可制备其中R1表示PO3R6 2和每个R6表示(1-6C)烷基的式V化合物。
例如使用过氧化氢和硫酸(Chem.Pharm.Bull.1971,19,2222)、硝酸(J.Org.Chem.,1961,26,82)或过氧化氢和乙酸(Helv.Chem.Acta 1968,349,323),将相应的其中R1表示SH和和R2表示氢的式III、IV或V化合物氧化可制备其中R1表示SO3H和R2表示氢的式III、IV或V化合物。
将相应的其中R1表示苄基巯基的式III、IV或V化合物通过与在液氨中的钠反应去苄基化,可制备其中R1表示SH的式III、IV或V化合物(Angew.Chem.1967,6,698;Org.Syn.,1986,65,215)。
通过式X化合物在碱——诸如三乙胺——存在下与苯硫酚(benzenethiol)反应可制备其中R1表示苄硫基的式V化合物。
可以理解的是式VIII化合物与其中R1表示羟基和R2表示氢的式V化合物相应。从式VIII化合物通过保护酮基和随后通过类似与本领域公知的方法将生成的被保护的化合物转化成式V的化合物,可制备其它的式V化合物。
与碘代三甲基硅烷在三乙胺存在下反应制备甲硅烷基烯醇酯,然后将甲硅烷基烯醇酯与乙酸钯反应,可制备式X化合物。或者,通过式XI化合物与碳酸烯丙基甲基酯在乙酸钯(II)存在下反应制备。反应在无水乙腈中进行为宜。
式XI化合物是已知的,可通过2-环戊-1-酮与羧基保护的(二甲基sulfuranylidene)乙酸酯反应制备。适合的反应溶剂包括芳烃,诸如甲苯。所需的非对映体产物可通过色谱分离。
通过保护式I化合物可制备式IV化合物,例如与诸如乙醇的醇在诸如亚硫酰氯的脱水剂存在下反应保护羧基,将生成的酯与Boc2O反应保护氨基。其中R1和R2一起表示=O的式IV化合物可通过类似本领域公知的方法转化为相应的式IV化合物。
例如通过与光学活性的酸或碱形成晶体盐,用常规的方法可将式I化合物拆分。或者可用光学活性的原料制备光学纯形式的式I化合物。
认为式II、III和IV化合物是新的,并提供了本发明的又一个方面。
根据本发明给药的化合物的具体剂量当然由病例周围的特定环境所确定,其包括给药的化合物、给药的途径、要处理的特定条件和类似的考虑。化合物可通过各种途径给药,包括口服给药、直肠给药、经眼给药、皮下给药、静脉给药、肌内给药或鼻内给药。或者,化合物可通过连续注射给药。典型的日剂量含有约0.01-100mg/kg本发明的活性化合物。优选日剂量为约0.05-50mg/kg,更优选为约0.1-25mg/kg。
已经表明,由于兴奋性氨基酸传递神经的过度或不适当的兴奋对各种生理活动造成影响。认为本发明的式I化合物能够治疗各种与此有关的哺乳动物体内的神经病症,包括急性神经病症,诸如在心脏搭桥手术和移植后的大脑功能缺陷、中风、大脑局部出血、脊髓外伤、头部外伤、产期低氧症、心动停止和低血糖神经损害。认为式I化合物能够治疗各种慢性神经病症,诸如早老性痴呆、慢性舞蹈病、肌萎缩性脊髓侧索硬化(ALS)、艾滋病导致的痴呆、眼损害和视网膜病、认知障碍和自发的和药物引起的帕金森症。本发明还提供治疗这些病症的方法,包括给需要的患者使用有效剂量的式I化合物或其药物上可接受的代谢不稳定酯或酰胺或其药物上可接受的盐。
还认为本发明的化合物能够治疗各种与谷氨酸盐机能障碍有关的哺乳动物的其它的神经病症,包括肌肉痉挛、惊厥、偏头痛、尿失禁、尼古丁戒除、精神病(诸如精神分裂症)、鸦片耐受和戒除、焦虑、呕吐、脑水肿、慢性疼痛和延迟性运动障碍。式I化合物还用作抗抑郁药和止痛剂。因此,本发明还提供了用于治疗这些病症的方法,包括给需要的患者使用有效剂量的式I化合物或其药物上可接受的代谢不稳定酯或酰胺或其药物上可接受的盐。
通过检验化合物对细胞内表达不同人代谢亲和性谷氨酸盐受体(mGluR)亚型的cAMP制备(mGluR 2,3,4,6,7或8)或磷酸肌醇的水解的(mGluR 1或5)的影响能力,可证明化合物有调整代谢亲和性谷氨酸盐受体功能的能力。(D.D.Schoepp,等人,Neuropharmacol.,1996,35,1661-1672和1997,36,1-11)。
本发明的化合物优选在使用前进行配制。因此,本发明的另一方面是一种药物制剂,包括式I化合物和药物上可接受的载体、稀释剂或赋型剂。本发明的药物制剂可使用公知的和易于获得的成分通过已知的方法制备。在制备本发明的组合物中,通常将活性组分与载体混合,或用载体稀释,或装入载体中,可以是胶囊、小药囊、纸或其它容器形式。当载体作为稀释剂时,其可以是固体、半固体或液体材料,可作为用于活性成分的载体、赋型剂或介质。组合物可以是片剂、丸剂、粉末、锭剂、小药囊、扁囊剂、酏剂、悬浮剂、乳剂、溶液、糖浆、气溶胶、含有例如至多10重量%的活性化合物的软膏、软和硬明胶胶囊、栓剂、无菌可注射溶液和无菌包装的粉末的形式。
适合的载体、赋型剂和稀释剂的一些例子包括乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、淀粉、树胶、阿拉伯胶、磷酸钙、藻酸盐、黄芪胶、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水糖浆、甲基纤维素、羟基苯甲酸甲酯和羟基苯甲酸丙酯、滑石、硬脂酸镁和矿物油。药物制剂还可包括润滑剂、湿润剂、乳化剂和悬浮剂、防腐剂、甜味剂或芳香剂。用本领域公知的方法配制本发明的组合物,使得在向患者给药后能快速、持续或延迟释放活性成分。
组合物优选配制成单位剂量形式,每剂量含有活性成分约5-500mg,更优选约含有25-300mg。术语“单位剂量”指适合作为人类或其它哺乳动物使用的实际上间隔的单一剂量,每单位剂量含有预定量的适于产生所需治疗效果的与适合的药物载体、稀释剂或赋型剂结合的活性物质。下列制剂的例子仅用于详细说明,在任何方面对本发明的范围不构成限制。
制剂1
使用下述成分制备硬胶囊:
将总计460mg的上述成分混合并填充到硬胶囊中。
用量(mg/胶囊) | |
活性组分 | 250 |
干燥淀粉 | 200 |
硬脂酸镁 | 10 |
总计 | 460mg |
制剂2
如下所述制备每片含有60mg活性组分的片剂:
活性组分 | 60mg |
淀粉 | 45mg |
微晶纤维素 | 35mg |
聚乙烯吡咯烷酮 | 4mg |
羧甲基淀粉钠 | 4.5mg |
硬脂酸镁 | 0.5mg |
滑石 | 1mg |
总计 | 150mg |
使活性组分、淀粉和纤维素通过45目美国筛网并充分混合。使得到的粉末随后通过14目美国筛网,并与聚乙烯吡咯烷酮溶液混合。将制得的颗粒在50℃干燥,并使其通过18目美国筛网。然后,将预先通过60目美国筛网的羧甲基淀粉钠、硬脂酸镁和滑石加入到颗粒中,混合后,在制片机上压制成每片重150mg的片剂。
下面通过实施例来进一步描述本发明的化合物和其合成方法。
下文中使用了下述缩写:
EtOAc,乙酸乙酯;THF,四氢呋喃;Boc,叔丁氧羰基;Boc2o,叔丁氧基羧酸酐;EtOH,乙醇;Et2O,乙醚;DBU,1,8-二氮杂双环[5.4.0]-十一碳-7-烯和FDMS,场解吸质谱法。
制备例1
溴化乙氧羰基甲基二甲基锍
在室温下搅拌溴乙酸乙酯(265g)和二甲基硫醚(114g)在丙酮(500ml)中的溶液。三天后,通过过滤反应混合物分离出标题化合物。熔点:88-90℃。
制备例2
(1S*,5R*,6S*)2-氧代双环[3.1.0]己烷-6-羧酸乙酯
用1,8-二氮杂双环[5.4.0]-十一碳-7-烯(30.2g,198.4mmol)处理溴化乙氧羰基甲基二甲基锍(45.5g,198.6mmol)的甲苯(350ml)悬浮液。在室温搅拌所得混合物。1小时后,用2-环戊烯-1-酮(19.57g,238.4mmol)处理反应混合物。再经18小时后,将反应混合物加入到1N盐酸/氯化钠溶液中。所得混合物用乙醚萃取。用硫酸镁干燥合并的醚萃取物,过滤并真空浓缩。用硅胶色谱提纯残余物,采用10%乙酸乙酯/己烷-50%乙酸乙酯/己烷的线性梯度进行洗脱,得到22.81g(68%)标题化合物。熔点:36-38℃。
FDMS:m/z=168(M+)。
C9H12O3的分析计算值:C,64.72;H,7.19。
实际值:C,64.54;H,7.11。
实施例1
(1S*,2S*,4S*,5R*,6R*)-2-氨基
(a)(1S*,5R*,6S*)-2-氧代双环[3.1.0]己-3-烯-6-羧酸乙酯。
将碘代
三甲基硅烷(50g,250mmol)滴加到2-氧代双环[3.1.0]己烷-6-羧酸乙酯(37g,220mmol)和三乙胺(67g,660mmol)的CH2Cl2(1L)的0℃的溶液中并搅拌1小时。将反应混合物用Et2O稀释,用饱和NH4Cl水溶液洗涤,用硫酸镁干燥并浓缩得到甲硅烷基烯醇醚(97%)。将Pd(OAc)2一次加入到0℃的甲硅烷基烯醇醚的CH3CN(300ml)溶液中。将所得反应混合物升温至室温,同时搅拌过夜。将反应混合物用Et2O稀释,并经硅藻土过滤,使产物吸附到250gSiO2上。将吸附的二氧化硅置于二氧化硅垫的上部,用己烷/EtOAc(4∶1)洗脱产物,用Et2O研磨所得到的粉红色固体,得到29.4g(80%,177mmol)白色固体标题化合物。熔点=78-80℃。FDMS:M+=166。C9H10O3的分析计算值:C,65.05;H,6.07;实际值:C,65.34;H,6.10。
(a1)(1S*,5R*,6S*)-2-氧代双环[3.1.0]己-3-烯-6-羧酸乙酯的另一种制备方法。向用火焰干燥的带有N2入口和回流冷凝器的3L三颈圆底烧瓶中加入由制备例2制得的产物(102g,424mmol)在425ml无水CH3CN中的溶液、碳酸烯丙基甲基酯(99g,848mmol)和Pd(OAc)2(4.6g,20mmol)。将所得反应混合物浸入到预热到70℃的热浴中。当内部反应温度达到40℃时,会剧烈释放出气体,并在30分钟后反应完成后停止。用EtOAc(2L)稀释反应混合物,通过SiO2(□250g)过滤,并减压浓缩得到80g粗产物。从10%的EtOAc/己烷中重结晶得到纯产物,纯产物与在步骤(a)中得到的产物完全相同。
(b)(1S*,3R*,4R*,5R*,6S*)-2-氧代双环[3.1.0]己-3-烯-氧化物-6-羧酸乙酯。用DBU(27.75g,182mmol)处理步骤(a)产物(10.1g,60.8mmol)的0℃THF(300ml)溶液,随后用叔丁基氢过氧化物处理。所得反应混合物在0℃搅拌1小时,用Et2O稀释,然后用1N HCl分配。产物用Et2O萃取,硫酸镁干燥,用己烷/EtOAc(9∶1)研磨得到的固体,得到9.83g(89%,54mmol)标题化合物。熔点=102-104℃。FDMS:M++1=182。C9H10O4的分析计算值:C,59.34;H,5.53;实际值:C,59.24;H,5.53。
(c)(1S*,4S*,5R*,6S*)-2-氧代-4-羟基-双环[3.1.0]己烷-6-羧酸乙酯。将步骤(b)产物的THF(250ml)溶液加入到搅拌脱气的N-乙酰基-L-半胱氨酸(25.64g,157mmol)、十水硼酸钠(59.88g,157mmol)和二苯基联硒化物(0.82g,2.62mmol)的水/EtOH(1∶1)(500ml)悬浮液中。加入完毕后,在室温搅拌过夜。反应混合物用Et2O稀释并用H2O分配。产物用Et2O萃取,用H2O洗涤,然后用盐水洗涤,并用硫酸镁干燥。产物用HPLC(己烷/EtOAc)提纯得到7.91g(82%,43mmol)标题化合物。熔点:60-62℃。FDMS:M+=184。C9H12O4的分析计算值:C,58.69;H,6.57;实际值:C,58.70;H,6.34。
(d)(1S*,2S*,4S*,5R*,6R*)-2-5’-螺乙内酰脲-4-羟基双环[3.1.0]己烷-6-羧酸乙酯。向步骤(c)产物(7.50g,40.7mmol)的EtOH/水(1∶1)(总体积100ml)搅拌溶液中先后加入NH2CONH4(9.54g,122.2mmol)和KCN(3.97g,61.1mmol)。加入完毕后,将反应混合物加热到40℃过夜。将反应混合物冷却至室温,酸化至pH=3,并真空过滤除去所得沉淀,得到1∶1非对映异构乙内酰脲。从EtOH(3X)中重结晶,得到0.79g(3.1mmol,8%)所需的非对映异构体。熔点:201-203℃。FDMS:M++1=255。C11H14N2O5·0.6H2O的分析计算值:C,49.85;H,5.78;N,10.57;实际值:C,49.60;H,5.68;N,10.38。
(e)(1S*,2S*,4S*,5R*,6R*)-2-氨基-4-羟基双环[3.1.0]己烷-2,6-二羧酸。将步骤(d)产物(0.35g,1.38mmol)的1NNaOH(15ml)溶液在回流条件下加热过夜。冷却反应混合物至室温并调节至pH=8。过滤,弃去所得固体。然后将滤液用1NNaOH再调至pH=12并置于Bio-Rad AG1-X8阴离子交换树脂上(乙酸盐转化为氢氧化物)。用3N乙酸洗脱产物,得到0.25g(90%,1.2mmol)标题化合物。mp=>275℃。FDMS:M++1=202。C8H11NO5·0.25H2O的分析计算值:C,46.72;H,5.64;N,6.81;实际值:C,46.68;H,5.72;N,6.59。
实施例2
(1S*,2S*,5R*,6R*)-2-氨基-4-氧代双环[3.1.0]己烷-2,
6-二羧酸
(a)(1S*,2S*,4S*,5R*,6R*)-2-(3’-苄基-5’-螺乙内酰脲)-4-羟基双环[3.1.0]己烷-6-羧酸乙酯。向实施例1步骤(c)产物(14.5g,78.7mmol)的EtOH/水(2∶1)(总体积150ml)的搅拌溶液中先后加入NH2CO2NH4(18.42g,236mmol)和KCN(7.68g,118mmol)。加入完毕后,将反应混合物加热到40℃保持两天。真空浓缩反应混合物,并用EtOAc/1N HCl和盐水分配。用EtOAc萃取乙内酰脲的混合物,用硫酸镁干燥并浓缩。将粗乙内酰脲重新溶解在DMF(50ml)中,在室温搅拌并先后连续加入NaHCO3(16.85g,200mmol)和苄基溴(12.6g,73.5mmol)。将反应混合物加热到100℃过夜。用EtOAc稀释反应混合物并用0.5NHCl分配。将乙内酰脲用EtOAc萃取,先后用水和盐水洗涤,硫酸镁干燥,并用HPLC(己烷/EtOAc)提纯,得到5.14g(19%,14.9mmol)标题化合物。FDMS:M+=344。C18H20N2O5的分析计算值:C,62.78;H,5.85;N,8.13;实际值:C,62.79;H,5.97;N,8.06。
(b)(1S*,2S*,5R*,6R*)-2-(3’-苄基-5’-螺乙内酰脲)-4-氧代-双环[3.1.0]己烷-6-羧酸乙酯。用琼斯试剂(~2M,7.5ml-CrO3,H2SO4,H2O)一次性处理步骤(a)产物(1.03g,3.0mmol)的0℃丙酮(20ml)溶液,并在室温搅拌2小时。加入2-丙醇(2ml)以还原氧化剂。然后将反应混合物用Et2O稀释,使其迅速通过硅藻土和二氧化硅垫,浓缩,得到0.90g(88%,2.6mmol)标题化合物。FDMS:M+=342。C18H18N2O5的分析计算值:C,63.15;H,5.30;N,8.18;实际值:C,62.87;H,5.56;N,8.26。
(c)按实施例1(e)的方法,将步骤(b)的产物水解,得到标题化合物。
实施例3
(a)(1S*,4R*,5S*,6S*)-2-氧代-4-(二乙基)膦酰基-双环[3.1.0]己烷-6-羧酸乙酯。将在4.2g苯酚中的实施例1(a)产物(1.6g,9.6mmol)和亚磷酸三乙酯(2.0g,12.0mmol)的混合物加热至100℃过夜。所得反应混合物用HPLC(己烷/EtOAc)提纯,得到2.7g(92%,8.9mmol)标题化合物。熔点=67-70℃。FDMS:M++1=305。C13H21O6P的分析计算值:C,51.32;H,6.96;实际值:C,51.11;H,6.89。
(b)(1S*,2R*,4R*,5S*,6S*)-2-氨基乙酰基-2-氰基-4-(二乙基)膦酰基双环[3.1.0]己烷-6-羧酸乙酯。在N2气氛下,在Branson 2000超声浴中将在CH3CN中的KCN(3.2g,49mmol)、NH4Cl(2.6g,49mmol)和Al2O3(25g)的混合物超声破碎1小时。然后加入步骤(a)的产物(1.5g,4.9mmol)并在45℃超声破碎72小时。将反应混合物经硅藻土过滤,并将滤液浓缩至干。将得到的氨基腈中间体溶解于CH2Cl2中,冷却至0℃,用乙酰氯(0.5g,6.4mmol)和N,N-二异丙基乙基胺(0.8g,6.4mmol)处理。在常温下进行反应1小时,然后在CH2Cl2和H2O之间分配混合物,分离出有机相,干燥(硫酸镁)、过滤并减压浓缩。用色谱(己烷/EtOAc)提纯粗产物。由此得到1.0g(55%)2-氨基乙酰基-2-氰基-4-(二乙基)膦酰基双环[3.1.0]己烷-6-羧酸乙酯(异构体A)和0.1g(5%)2-氨基乙酰基-2-氰基-4-(二乙基)膦酰基双环[3.1.0]己烷-6-羧酸乙酯(异构体B)。(异构体A):熔点=135-138℃。FDMS:M++1=373。C16H25N2O6P的分析计算值:C,51.61;H,6.77;N,7.52实际值:C,51.89;H,6.78;N,7.75。
(c)(1S*,2R*,4R*,5S*,6S*)-2-氨基双环[3.1.0]己烷-2,6-二羧基-4-膦酸一氢氯化物一水合物。通过在30ml的6N HCl中回流步骤(b)的产物(异构体A)(0.08g,0.2mmol)48小时可制得标题化合物。浓缩粗产物,使用用1N HCl洗脱的阴离子交换柱提纯。收集到0.06g(99%,0.2mmol)标题化合物。FDMS:M++1=266。C8H12NO7P·HCl·H2O的分析计算值:C,30.06;H,4.73;N,4.38。实际值:C,29.87;H,4.36;N,4.13。
实施例4
(1S*,2S*,4S*,5R*,6R*)-2-氨基
(a)(1S*,2S*,4S*,5R*,6R*)-2-N-叔丁氧基羰基-氨基-4-羟基双环[3.1.0]己烷-2,6-二羧酸二乙酯。向实施例1(c)产物(23.9g,130mmol)的乙醇/水(1∶1)(总体积500ml)搅拌溶液中先后加(NH4)2CO3(30.4g,390mmol)和KCN(12.7g,195mmol)。加入完毕后,将反应混合物加热至40℃直至完成反应。将反应混合物冷却至0℃,用浓盐酸酸化至pH=1并用EtOAc萃取非对映异构的5’-螺乙内酰脲混合物。合并所有有机相,用盐水洗涤,用硫酸镁干燥,并减压浓缩,得到粗乙内酰脲的1∶1混合物。在回流条件下,在2N NaOH(275ml)中加热粗5’-螺乙内酰脲的混合物(27.9g,110mmol)5天,直至用TLC判断反应进行完毕。将反应混合物冷却至0℃,用浓盐酸酸化至pH=1,并在真空中浓缩至干。将所得固体重新溶解在100%EtOH(500ml)中,冷却至0℃。然后,以保持反应温度为10℃的滴加速率向反应混合物中滴加SOCl2(120g,1mol)。滴加完毕后,将反应混合物加热回流过夜。真空浓缩反应混合物,并将其重新溶解在饱和碳酸氢钠水溶液∶THF为1∶1的混合物(总体积500ml)中。将Boc2O(118g,550mmol)一次加入到反应混合物中,室温搅拌过夜。将反应混合物减压至真空,用EtOAc萃取N-Boc二乙酯粗产物。合并所有的有机萃取物,先后用水和盐水洗涤,用碳酸钾干燥,浓缩,得到120g粗产物。分离两种非对映异构体,并用prep-HPLC(100%己烷-50%EtOAc/己烷)提纯,得到10.12g(26%,28mmol)泡沫状所需产物。FDMS:M++1=358。C17H27NO7的分析计算值:C,57.13;H,7.61;N,3.92。实际值:C,56.84;H,7.64;N,3.96。
(b)(1S*,2S*,4S*,5R*,6R*)-2-N-叔丁氧基羰基-氨基-4-甲氧基双环[3.1.0]己烷-2,6-二羧酸二乙酯。向步骤(a)产物(0.50g,1.4mmol)的0℃THF(30ml)溶液中一次加入NaH(0.07g,1.7mmol),然后滴加甲基碘(0.21g,1.5mmol)。将反应混合物加热至室温,同时搅拌过夜。用H2O稀释反应混合物,产物用EtOAc萃取。合并所有的有机相,用盐水洗涤,碳酸钾干燥,减压浓缩并用PC-TLC(10%EtOAc/己烷-90%EtOAc/己烷)提纯,得到0.12g(0.32mmol,23%)所需产物。FDMS:M++1=372。C18H29NO7的分析计算值:C,58.21;H,7.87;N,3.77。实际值:C,58.69;H,7.52;N,4.85。
(c)(1S*,2S*,4S*,5R*,6R*)-2-氨基-4-甲氧基双环[3.1.0]己烷-2,6-二羧酸二乙酯。用干燥的HCl气体清洗步骤(b)产物的0℃EtOAc(25ml)溶液,直至溶液达到饱和。在0℃搅拌反应混合物1小时,然后减压浓缩至干。将固体溶解在饱和的碳酸氢钠(aq)中,用EtOAc萃取产物。合并所有的有机相,用盐水洗涤,碳酸钾干燥,减压浓缩并用PC-TLC(10%EtOAc/己烷-100%EtOAc)提纯,得到0.05g(0.18mmol,61%)所需产物。FDMS:M++1=271。
1H NMR(CDCl3):δ1.25(t,J=7Hz,3H),1.29(t,J=7Hz,3H),1.61(t,J=3Hz,1H),1.80-1.95(br m 3H),2.17-2.20(m,1H),2.46-2.50(m,2H),3.27(s,3H),3.85-3.87(m,1H),4.15 q,J=7Hz,2H),4.24(q,J=7Hz,2H).13C NMR(CDCl3):δ13.96,14.11,20.82,31.90,33.96,40.17,56.00,60.69,61.26,64.63,82.14,172.14,174.85.C13H21NO5的分析计算值:C,57.55;H,7.80;N,5.16。实际值:C,56.04;H,7.70;N,5.81。
(d)(1S*,2S*,4S*,5R*,6R*)-2-氨基-4-甲氧基双环[3.1.0]己烷-2,6-二羧酸盐。在室温下,将步骤(c)产物(0.04g,0.11mmoll)在1∶1的1N NaOH/THF溶液(总体积10ml)中搅拌过夜。用6N盐酸酸化反应混合物至pH=1,浓缩至干。将所得固体重新溶解在pH=2的水中,置于Dowex 50X8-100阳离子交换树脂上,用10%吡啶/H2O洗脱,得到0.012g(37%,0.06mmol)所需产物。熔点=>275℃。FDMS:M++1=216。
1H NMR(D2O/KOD):δ1.08-1.14(m,2H),1.74-2.07(m 3H),3.05(s,3H),3.65-3.75(m,1H).C9H13NO5·0.2NaCl的分析计算值:C,47.64;H,5.78;N,6.17。实际值:C,47.75;H,5.74;N,7.49。
实施例5
(1S*,2S*,5R*,6R*)-2-氨基-4-氧代双环[3.1.0]己烷-2,
(a)(1S*,2S*,5R*,6R*)-2-N-叔丁氧基羰基氨基-4-氧代双环[3.1.0]己烷-2,6-二羧酸二乙酯。在室温下搅拌实施例4(a)产物(0.50g,1.4mmol)的CH2Cl2(15ml)溶液,同时一次加入重铬酸吡啶鎓。所得反应混合物在室温下搅拌过夜。用EtOAc稀释反应混合物,并经硅藻土过滤除去铬酸盐副产物。真空浓缩滤液并用PC-TLC(10%EtOAc/己烷-20%EtOAc/己烷)提纯,得到0.49g(1.38mmol,98%)白色泡沫状产物。FDMS:M++1=356。C17H25NO7的分析计算值:C,57.46;H,7.09;N,3.94。实际值:C,57.60;H,7.14;N,4.03。
(b)(1S*,2S*,5R*,6R*)-2-氨基-4-氧代双环[3.1.0]己烷-2,6-二羧酸。用干燥的HCl气体清洗步骤(a)产物(0.37g,1.04mmol)的0℃EtOAc(30ml)溶液,直至溶液达到饱和。在0℃搅拌反应混合物1小时,然后真空浓缩至干。将所得固体重新溶解在10ml 1N氢氧化钠中并搅拌过夜。用6N盐酸酸化反应混合物至pH=2,并置于Dowex 50X8-100阳离子交换树脂上,产物用10%吡啶/H2O洗脱,将得到的产物从H2O中重结晶,得到0.06g(31%,0.30mmol)所需产物。熔点=dec>210℃。FDMS:M++1=200。C8H9NO5的分析计算值:C,48.25;H,4.55;N,7.03。实际值:C,48.19;H,4.46;N,7.16。
实施例6
(1S*,2S*,5R*,6R*)-2-氨基-4-[反]-
肟基双环[3.1.0]己烷-2,6-二羧酸和
(1S*,2S*,5R*,6R*)-2-氨基-4-[顺]
(a)(1S*,2S*,5R*,6R*)-2-氨基-4-氧代双环[3.1.0]己烷-2,6-二羧酸二乙酯。用干燥的HCl气体清洗实施例5(a)产物(0.37g,1.04mmol)的0℃EtOAc(30ml)溶液,直至溶液达到饱和。在0℃搅拌所得反应混合物1小时,用饱和的碳酸氢钠水溶液稀释反应混合物,并用EtOAc萃取产物。合并所有的有机相,用盐水洗涤,碳酸钾干燥,真空浓缩,得到所需中间体(0.36g,1.4mmol,100%)。FDMS:M++1=256。C12H17NO5·0.2H2O的分析计算值:C,55.68;H,6.78;N,5.41。实际值:C,55.47;H,5.91;N,5.24。
(b)(1S*,2S*,4R*,6R*)-2-氨基-4-肟基双环[3.1.0]己烷-2,6-二羧酸二乙酯。向步骤(a)产物(0.36g,1.4mmol)和NaOAc(0.23g,2.8mmol)在EtOH/H2O为3∶1的混合物(总体积20ml)中的室温溶液中加入盐酸羟胺(0.15g,2.1mmol),并在80℃加热1小时。向反应混合物中加入碳酸氢钠水溶液,用EtOAc萃取产物,用盐水洗涤,碳酸钾干燥,真空浓缩,得到E异构体∶Z异构体为2∶1的混合物。用PC-TLC(10%EtOAc/己烷-67%EtOAc/己烷)提纯,得到纯产物。反式异构体:0.18g(0.67mmol,56%)。FDMS:M++1=271。C12H18N2O5·0.35CH2Cl2的分析计算值:C,49.44;H,6.28;N,9.34。实际值:C,49.62;H,5.89;N,9.39。顺式异构体;0.09g(0.33mmol,28%)。熔点=135-137℃。FDMS:M++1=271。C12H18N2O5·0.1己烷的分析计算值:C,54.26;H,7.01;N,10.04。实际值:C,54.03;H,6.71;N,10.14。
(c)(1S*,2S*,5R*,6R*)-2-氨基-4-[反]-肟基双环[3.1.0]己烷-2,6-二羧酸。在室温下,将步骤(b)的反式肟(0.13g,0.48mmol)在1N NaOH∶THF为1∶1(总体积20ml)的混合物中搅拌4天。反应混合物用水稀释,产物用EtOAc(3X)洗涤以除去有机杂质。用1N HCl调节水层至pH=10,并真空浓缩。将所得固体重新溶解在水中,用阴离子交换色谱(Bio-Rad AG1-X8:用3N AcOH洗脱)提纯。产物从H2O/2-丙醇(1∶1)中重结晶,得到0.07g(0.33mmol,68%)产物。熔点=dec>260℃。FDMS:M++1=215。C8H10N2O5·0.15H2O的分析计算值:C,44.30;H,4.79;N,12.91。实际值:C,44.53;H,4.48;N,12.51。
(d)(1S*,2S*,5R*,6R*)-2-氨基-4-[顺]-肟基双环[3.1.0]己烷-2,6-二羧酸。采用0.085g(0.31mmol)步骤(b)的顺式肟产物,反应条件、处理和分离与步骤(c)一样。得到0.04g(0.19mmol,60%)产物。熔点=dec>250℃。FDMS:M++1=215。C8H10N2O5·0.15NaCl的分析计算值:C,43.10;H,4.52;N,12.57。实际值:C,43.36;H,4.74;N,11.75。
实施例7
(1S*,2R*,4S*,5S*,6S*)-2-氨基-4-氟双环[3.1.0]己烷-2,
6-二羧酸
(a)(1S*,2R*,4S*,5S*,6S*)-2-N-叔丁氧基羰基-氨基-4-氟双环[3.1.0]己烷-2,6-二羧酸二乙酯。向实施例4(a)产物(0.50g,1.40mmol)的0℃CH2Cl2(25ml)溶液中一次加入二乙氨基三氟化硫(DAST)。将所得反应混合物加热到室温,搅拌过夜。用10%的碳酸氢钠水溶液稀释反应物,并用EtOAc萃取产物。合并所有有机相,用盐水洗涤,碳酸钾干燥,并用PC-TLC(10%EtOAc/己烷-20%EtOAc/己烷)提纯,得到0.38g(1.06mmol,74%)无色油状产物。FDMS:M++1=360。C17H26NO6的分析计算值:C,56.81;H,7.29;N,3.90。实际值:C,56.79;H,7.42;N,4.11。
(b)(1S*,2R*,4S*,5S*,6S*)-2-氨基-4-氟双环[3.1.0]己烷-2,6-二羧酸二乙酯。用干燥的HCl气体清洗步骤(a)产物(0.33g,0.92mmol)的0℃EtOAc(30ml)溶液,直至溶液达到饱和。在0℃搅拌反应混合物1小时,用饱和的碳酸氢钠水溶液稀释反应混合物,并用EtOAc萃取产物.合并所有有机相,用盐水洗涤,碳酸钾干燥,真空浓缩,得到0.23g(0.89mmol,96%)所需产物。FDMS:M++1=260。C12H17FNO4的分析计算值:C,55.59;H,7.00;N,5.40。实际值:C,55.56;H,6.79;N,5.21。
(c)(1S*,2R*,4S*,5S*,6S*)-2-氨基-4-氟双环[3.1.0]己烷-2,6-二羧酸。在室温下,将步骤(b)产物(0.12g,0.46mmol)在1N NaOH/THF(1∶1)混合物(总体积20ml)中的溶液搅拌过夜。反应混合物用6N HCl调节至pH=12,并用阴离子交换色谱(Bio-Rad AG1-X8离子交换树脂:用3N乙酸洗脱)提纯。产物从H2O/2-丙醇(1∶1)中重结晶,得到0.04g(0.20mmol,49%)所需产物。熔点=dec>260℃。FDMS:M++1=204。C8H10FNO4·0.45NaCl的分析计算值:C,41.78;H,4.39;N,6.10。实际值:C,41.91;H,4.00;N,5.76。
实施例8
(1S*,2S*,4R*,5R*,6S*)-2,4-二氨基
(a)(1S*,2S*,4S*,5R*,6R*)-2-N-叔丁氧基羰基-氨基-4-(对-甲苯磺酰氧基)双环[3.1.0]己烷-2,6-二羧酸二乙酯。将对甲苯磺酰氯(5.3g,28mmol)加入到实施例4(a)产物(5.0g,14mmol)的吡啶(25ml)溶液中,所得反应混合物在在室温下搅拌过夜。用EtOAc(100ml)稀释反应混合物,并用饱和的硫酸铜水溶液洗涤以除去吡啶。用盐水洗涤有机物,用硫酸镁干燥,减压浓缩,得到的粗产物用SiO2色谱(HPLC:10%EtOAc/己烷-50%EtOAc/己烷)提纯,得到6.55g(91%,12.8mmol)白色泡沫状所需产物。FDMS:M++1=512。C24H33NO9S的分析计算值:C,56.35;H,6.50;N,2.74。实际值:C,56.48;H,6.44;N,2.60。
(b)(1S*,2S*,4R*,5R*,6S*)-2-N-叔丁氧基羰基氨基-4-叠氮基双环[3.1.0]己烷-2,6-二羧酸二乙酯。将步骤(a)产物(6.35g,12.4mmol)和NaN3(2.42g,37.2mmol)的DMSO(15ml)的溶液在35℃加热3天。用水稀释反应混合物,用EtOAc萃取产物。合并所有的有机相,用盐水洗涤,硫酸镁干燥并减压浓缩,得到的粗叠氮化物经SiO2真空过滤(20%EtOAc/己烷-50%EtOAc/己烷)提纯,得到4.68g(98%,12.2mmol)所需的蜡状固体产物。FDMS:M++1=512。C17H26N4O6·0.1己烷的分析计算值:C,54.06;H,7.06;N,14.33。实际值:C,53.94;H,6.88;N,14.30。
(c)(1S*,2S*,4R*,5R*,6S*)-2-N-叔丁氧基羰基-4-氨基双环[3.1.0]己烷-2,6-二羧酸二乙酯。将三苯基膦(2.90g,11mmol)一次加入到步骤(b)产物(3.5g,9.2mmol)的THF/H2O(5∶1)溶液中,室温搅拌过夜。用EtOAc稀释反应混合物,并用0.5N NaOH(3X)洗涤。合并有机相,先后用水和盐水洗涤,碳酸钾干燥,减压浓缩,经SiO2色谱(HPLC:SiO2)(10%EtOAc/己烷-50%EtOAc/己烷)提纯,得到2.03g(62%,5.7mmol)泡沫状所需产物。FDMS:M++1=357。C17H28N2O6的分析计算值:C,57.30;H,7.92;N,7.86。实际值:C,57.02;H,7.73;N,7.72。
(d)(1S*,2S*,4R*,5R*,6S*)-2,4-二氨基双环[3.1.0]己烷-2,6-二羧酸。在1N HCl中,将步骤(c)的产物加热回流过夜。用1N NaOH调节反应混合物至pH=2,用阳离子交换色谱(Dowex 50X8-100:10%吡啶/H2O)提纯。将得到的产物从2-丙醇/H2O(1∶1)中重结晶,得到0.09g(45%,0.45mmol)所需的白色固体产物。熔点=>275℃。FDMS:M++1=201。C8H12N2O4·0.5H2O的分析计算值:C,45.93;H,6.26;N,13.39。实际值:C,45.66;H,7.45;N,13.32。
实施例9
(1S*,2S*,4R*,5R*,6S*)-2-氨基
将实施例8(b)产物(0.25g,0.65mmol)的EtOAc(30ml)溶液冷却至0℃,并用干燥的HCl气体清洗直至溶液达到饱和。在0℃搅拌反应混合物2小时,浓缩至干。将所得固体在1N NaON∶THF为1∶1的混合物(总体积20ml)中在室温下搅拌过夜。减压除去THF,用1N HCl调节含水混合物至pH=12,用阴离子交换色谱(Bio-Rad AG1-X8:乙酸盐转化为其氢氧化物形式,用3N乙酸洗脱)提纯,得到0.10g(0.44mmol,68%)所需产物。熔点=dec>270℃。FDMS:M++1=227。C8H10N4O4·0.2AcOH的分析计算值:C,42.36;H,4.57;N,23.52。实际值:C,41.96;H,4.54;N,23.55。
实施例10
(1S*,2S*,4R*,5R*,6S*)-2-氨基
(a)(1S*,2S*,4R*,5R*,6S*)-2-N-叔丁氧基羰基氨基-4-乙酰氨基双环[3.1.0]己烷-2,6-二羧酸二乙酯。将乙酰氯(0.09g,1.1mmol)滴加到0℃的实施例8(c)产物(0.35g,1.0mmol)和三乙胺(0.20g,2.0mmol)的CH2Cl2(20ml)溶液中,加热所得反应混合物至室温,同时搅拌过夜。用Et2O稀释反应混合物,并先后用硫酸氢钠水溶液和盐水洗涤,硫酸镁干燥,真空浓缩,得到粗乙酰胺,并用PC-TLC(10%EtOAc/己烷-67%EtOAc/己烷)提纯,得到0.35g(88%,0.88mmol)所需的白色固体产物。mp=dec 85-95℃。FDMS:M++1=399。C19H30N2O7的分析计算值:C,57.27;H,7.58;N,7.03。实际值:C,57.41;H,7.28;N,6.94。
(b)(1S*,2S*,4R*,5R*,6S*)-2-氨基-4-乙酰氨基双环[3.1.0]己烷-2,6-二羧酸。将步骤(a)产物(0.30g,0.75mmol)的EtOAc(30ml)溶液冷却至0℃,并用干燥的HCl气体清洗直至溶液达到饱和。在0℃搅拌反应混合物2小时,浓缩至干。在室温下,将所得固体在1N NaON∶THF为1∶1的混合物(总体积20ml)中搅拌过夜。减压除去THF,用1N HCl调节含水混合物至pH=2,用阳离子交换色谱(Dowex 50X8-100;用10%吡啶/H2O洗脱)提纯。将得到的产物从H2O/2-丙醇(1∶1)中重结晶,得到0.09g(0.37mmol,50%)所需产物。熔点=>275℃。FDMS:M++1=243。C10H14N2O5·0.3NaCl的分析计算值:C,46.24;H,5.43;N,10.78。实际值:C,45.93;H,5.50;N,10.88。
实施例11
(1S*,2S*,4R*,5R*,6S*)-2-氨基
(a)(1S*,2S*,4R*,5R*,6S*)-2-N-叔丁氧基羰基氨基-4-苯甲酰氨基双环[3.1.0]己烷-2,6-二羧酸二乙酯。将苯甲酰氯(0.16g,1.1mmol)滴加到0℃的实施例8(c)产物(0.35g,1.0mmol)和三乙胺(0.20g,2.0mmol)的CH2Cl2(20ml)溶液中,加热所得反应混合物至室温,同时搅拌过夜。用Et2O稀释反应混合物,并先后用硫酸氢钠水溶液和盐水洗涤,硫酸镁干燥,真空浓缩,得到粗酰胺产物,用PC-TLC(10%EtOAc/己烷-67%EtOAc/己烷)提纯,得到0.31g(67%,0.67mmol)所需的白色泡沫状产物。FDMS:M++1=461。C24H32N2O7的分析计算值:C,62.59;H,7.00;N,6.08。实际值:C,62.75;H,6.70;N,5.99。
(b)(1S*,2S*,4R*,5R*,6S*)-2-氨基-4-苯甲酰氨基双环[3.1.0]己烷-2,6-二羧酸。将步骤(a)产物(0.30g,0.75mmol)的EtOAc(30ml)溶液冷却至0℃,并用干燥的HCl气体清洗直至溶液达到饱和。在0℃搅拌反应混合物2小时,浓缩至干。在室温下,将所得固体在1N NaON∶THF为1∶1的混合物(总体积20ml)中搅拌过夜。减压除去THF,用1N HCl调节含水混合物至pH=2,用阳离子交换色谱(Dowex 50X8-100;用10%吡啶/H2O洗脱)提纯。将得到的产物从H2O/2-丙醇(1∶1)中重结晶,得到0.095g(0.31mmol,58%)所需产物。熔点=dec>275℃。FDMS:M++1=305。C15H16N2O5·0.32-丙醇的分析计算值:C,59.25;H,5.75;N,8.69。实际值:C,59.50;H,5.65;N,8.32。
实施例12
(1S*,2S*,4R*,5R*,6S*)-2-氨基
-4-(甲磺酰氨基)-双环[3.1.0]己烷-2,6-二羧酸
(a)(1S*,2S*,4R*,5R*,6S*)-2-N-叔丁氧羰基氨基-4-(甲磺酰氨基)-双环[3.1.0]己烷-2,6-二羧酸二乙酯。将甲磺酰氯(0.13g,1.1mmol)滴加到0℃的实施例8(c)产物(0.35g,1.0mmol)和三乙胺(0.21g,2.0mm0l)的CH2Cl2(25ml)溶液中,并在0℃搅拌所得反应混合物1小时。用EtOAc稀释反应混合物,并先后用硫酸氢钠水溶液和盐水洗涤,硫酸镁干燥,真空浓缩,得到粗甲磺酰胺,用PC-TLC(10%EtOAc/己烷-67%EtOAc/己烷)提纯,得到0.44g(99%,1.0mmol)所需的白色泡沫状产物。FDMS:M++1=435。C18H30N2O8S的分析计算值:C,49.76;H,6.96;N,6.45;S,7.38。实际值:C,50.04;H,6.68;N,6.21;S,7.38。
(b)(1S*,2S*,4R*,5R*,6S*)-2-氨基-4-(甲磺酰氨基)-双环[3.1.0]己烷-2,6-二羧酸。将步骤(a)产物(0.40g,0.92mmol)的EtOAc(30ml)溶液冷却至0℃,并用干燥的HCl气体清洗直至溶液达到饱和。在0℃搅拌反应混合物2小时,浓缩至干。在室温下,将所得固体在1N NaON∶THF为1∶1的混合物(总体积20ml)中搅拌过夜。减压除去THF,用1N HCl调节含水混合物至pH=2,用阳离子交换色谱(Dowex 50X8-100;用10%吡啶/H2O洗脱)提纯。将得到的产物从H2O/2-丙醇(1∶1)中重结晶,得到0.13g(0.46mmol,50%)所需产物。熔点=>275℃。FDMS:M++1=279。C9H14N2O6S的分析计算值:C,38.84;H,5.07;N,10.07。实际值:C,39.01;H,5.21;N,10.07。
实施例13
(1S*,2S*,4R*,5R*,6S*)-2-氨基
(a)(1S*,2S*,4R*,5R*,6S*)-2-N-叔丁氧基羰基氨基-4-(甲基氨基羰基氨基)-双环[3.1.0]己烷-2,6-二羧酸二乙酯。将异氰酸甲酯(0.07g,1.2mmol)滴加到0℃的实施例8(c)产物(0.35g,1.0mmol)的CH2Cl2(25ml)溶液中,加热反应混合物至室温并搅拌过夜。用EtOAc稀释反应混合物,并先后用硫酸氢钠水溶液和盐水洗涤,硫酸镁干燥,真空浓缩,得到粗甲基脲,用PC-TLC(10%EtOAc/己烷-50%EtOAc/己烷)提纯,得到0.35g(85%,0.85mmol)所需的白色泡沫状产物。FDMS:M++1=414。C19H31N3O7·0.5H2O的分析计算值:C,54.01;H,7.63;N,9.95。实际值:C,53.81;H,7.52;N,10.64。
(b)(1S*,2S*,4R*,5R*,6S*)-2-氨基-4-(甲基氨基羰基氨基)-双环[3.1.0]己烷-2,6-二羧酸。将步骤(a)产物(0.30g,0.72mmol)的EtOAc(30ml)溶液冷却至0℃,并用干燥的HCl气体清洗直至溶液达到饱和。在0℃搅拌反应混合物1小时,浓缩至干。在室温下,将所得固体在1N NaON∶THF为1∶1的混合物(总体积20ml)中搅拌过夜。减压除去THF,用1N HCl调节含水混合物至pH=2,用阳离子交换色谱(Dowex 50X8-100,10%吡啶/H2O洗脱)提纯。将得到的产物从H2O/2-丙醇(1∶1)中重结晶,得到0.12g(0.46mmol,64%)所需产物。熔点=>275℃。FDMS:M++1=258。C10H15N3O5·0.1H2O的分析计算值:C,46.37;H,5.91;N,16.22。实际值:C,46.03;H,6.01;N,16.12。
实施例14
(1S*,2S*,4R*,5R*,6S*)-2-氨基
(a)(1S*,2S*,4R*,5R*,6S*)-2-N-叔丁氧羰基氨基-4-(N,N-二环丙基甲基氨基)-双环[3.1.0]己烷-2,6-二羧酸二乙酯。将环丙基甲基溴(0.27g,2.0mmol)滴加到实施例8(c)产物(0.32g,0.90mmol)和三乙胺(0.30g,3.0mmol)的CH3CN(25ml)的室温溶液中,将生成的反应混合物搅拌过夜。真空浓缩反应混合物,用PC-TLC(10%EtOAc/己烷-67%EtOAc/己烷)提纯,得到0.33g(78%,0.70mmol)所需的淡黄色油状产物。FDMS:M++1=465。C25H40N2O6的分析计算值:C,64.63;H,8.68;N,6.03。实际值:C,64.38;H,8.60;N,5.93。
(b)(1S*,2S*,4R*,5R*,6S*)-2-氨基-4-(N,N-二环丙基甲基氨基)-双环[3.1.0]己烷-2,6-二羧酸。将步骤(a)产物(0.28g,0.61mmol)的EtOAc(30ml)溶液冷却至0℃,并用干燥的HCl气体清洗直至溶液达到饱和。在0℃搅拌反应混合物4小时,浓缩至干。在室温下,将所得固体在1N NaON∶THF为1∶1的混合物(总体积20ml)中搅拌过夜。减压除去THF,用1N HCl调节含水混合物至pH=2,用阳离子交换色谱(Dowex 50X8-100;用10%吡啶/H2O洗脱)提纯。将得到的产物从H2O/2-丙醇(1∶1)中重结晶,得到0.15g(0.49mmol,80%)所需产物。熔点=dec>270℃。FDMS:M++1=309。C16H24N2O4·0.6H2O的分析计算值:C,60.21;H,7.96;N,8.78。实际值:C,59.92;H,7.99;N,8.93。
实施例15
(1S*,2S*,5R*,6S*)-2-氨基-
4-Z-羧基亚甲基双环[3.1.0]己烷-2,6-二羧酸
(1S*,2S*,5R*,6S*)-2-氨基-
(a)(1S*,2S*,5R*,6S*)-2-(N-叔丁氧基羰基)氨基-4-(苄氧基羰基)亚甲基双环[3.1.0]己烷-2,6-二羧酸二乙酯,异构体A和B。通过在0℃向二乙基膦酰基乙酸苄酯(1.2g,2.8mmol)的无水甲苯溶液中加入双(三甲硅烷基)氨基化钠(4.2mmol)制备二乙基膦酰基乙酸苄酯的钠盐。在0℃,将该钠盐迅速加入到实施例5(a)产物(1.0g,2.8mmol)的无水甲苯溶液中,搅拌15分钟。使反应混合物升温至室温并搅拌直至通过TLC断定反应进行完毕。加入1N HCl,用乙酸乙酯萃取反应混合物。合并有机层,用NaCl水溶液洗涤,硫酸镁干燥。浓缩有机化合物,用HPLC(EtOAc/己烷)提纯粗产物,得到1.3g(94%)两种异构体的混合物。FDMS:M+-1=486。C26H33N1O8的分析计算值:C,64.05;H,6.82;N,2.87。实际值:C,64.04;H,6.87;N,2.96。
(b)(1S*,2S*,5R*,6S*)-2-氨基-4-E-(苄氧基羰基)亚甲基双环[3.1.0]己烷-2,6-二羧酸二乙酯异构体A和(1S*,2S*,5R*,6S*)-2-氨基-4-Z-(苄氧基羰基)亚甲基双环[3.1.0]己烷-2,6-二羧酸二乙酯异构体B。在0℃,使无水HCl(g)鼓泡通入步骤(a)产物(0.4g,0.82mmol)的EtOAc溶液中。将其加热到室温并搅拌直至通过TLC断定反应进行完毕。在碳酸氢钠水溶液中分配有机物,用碳酸钾干燥,并真空浓缩,用HPLC(EtOAc/己烷)提纯,得到0.154g(48%)异构体A和0.13g(41%)异构体B。异构体A:FDMS:M++1=388。C21H25N1O6的分析计算值:C,65.01;H,6.50;N,3.62。实际值:C,64.91;H,6.40;N,3.83。异构体B:FDMS:M++1=388。C21H25N1O6+0.5当量CH2Cl2的分析计算值:C,60.07;H,6.10;N,3.26。实际值:C,60.33;H,6.05;N,3.43。
(c)(1S*,2S*,5R*,6S*)-2-氨基-4-E-羧基亚甲基双环[3.1.0]己烷-2,6-二羧酸。在5ml 2N NaOH和2ml THF中搅拌步骤(b)的产物,异构体A(0.134g,0.35mmol)5小时。用1N HCl调节反应物至pH=7,并浓缩至干。将所得固体重新溶解在pH=10的水中,并置于阴离子交换树脂(Bio-Rad AG1-X8,用2N乙酸洗脱)上,得到0.038g(45%)所需产物。FDMS:M++1=242。C10H11NO6+0.14当量NaCl的分析计算值:C,48.16;H,4.44;N,5.62。实际值:C,48.15;H,4.29;N,5.36。
(d)(1S*,2S*,5R*,6S*)-2-氨基-4-Z-羧基亚甲基双环[3.1.0]己烷-2,6-二羧酸。在5ml 2N NaOH和2ml THF中搅拌步骤(b)的产物,异构体B(0.107g,0.28mmol)5小时。用1N HCl调节反应至pH=7,并浓缩至干。将所得固体重新溶解在pH=10的水中,并置于阴离子交换树脂(Bio-Rad AG1-X8,用2N乙酸洗脱)上,得到0.050g(75%)所需产物。FDMS:M++1=242。C10H11NO6+1.0当量H2O的分析计算值:C,46.34;H,5.06;N,5.40。实际值:C,46.43;H,5.04;N,5.45。
实施例16
(1S*,2S*,5R*,6S*)-2-氨基-
(a)(1S*,2S*,5R*,6S*)-2-(N-叔丁氧基羰基)氨基-4-亚甲基双环[3.1.0]己烷-2,6-二羧酸二乙酯。在0℃将双(三甲硅烷基)氨基化钠(4.2mmol)加入到溴化甲基三苯基鏻(1.5g,4.2mmol)的无水THF淤浆中。将实施例5(a)产物(0.75g,2.1mmol)的无水THF溶液加入到反应容器中并在0℃搅拌过夜。加入1N HCl,用乙酸乙酯萃取反应混合物。合并的有机层用NaCl水溶液洗涤,用硫酸镁干燥。浓缩有机物,用HPLC(EtOAc/己烷)提纯粗产物,得到0.52g(70%)所需产物。FDMS:M++1=354。
(b)(1S*,2S*,5R*,6S*)-2-氨基-4-亚甲基双环[3.1.0]己烷-2,6-二羧酸。在1ml TFA中搅拌步骤(a)的产物(0.36g,1.0mmol)1小时,浓缩并溶解在5ml THF中。用1N NaOH调节反应物至pH=13-14,搅拌2小时。浓缩反应混合物,用1N HCl调节至pH=10,将所得物料置于阴离子交换树脂(Bio-Rad AG1-X8,用1N乙酸洗脱)上,得到0.061g(31%)所需产物。FDMS:M++1=198。C9H11NO4+0.25当量H2O的分析计算值:C,53.60;H,5.75;N,6.94。实际值:C,53.65;H,5.64;N,6.85。
实施例17
(1S*,2S*,5R*,6S*)-2-氨基-4-(Z)-(二乙基膦酰基亚甲基)-双环[3.1.0]己烷-2,6-二羧酸
(a)(1S*,2S*,5R*,6S*)-2-(N-叔丁氧基羰基)-氨基-4-((E和Z)-二乙基膦酰基亚甲基)双环[3.1.0]己烷-2,6-二羧酸二乙酯,异构体A和B。通过在0℃向亚甲基-二膦酸四乙酯(0.6g,2.1mmol)的无水甲苯溶液中加入双(三甲硅烷基)氨基化钠(2.1mmol)制备亚甲基二膦酸四乙酯的钠盐。在0℃,迅速将该钠盐加入到实施例5(a)产物(0.5g,1.4mmol)的无水甲苯溶液中,并搅拌15分钟。将反应混合物加热至室温并搅拌,直至经TCL断定反应结束。加入1N HCl,用乙酸乙酯萃取反应混合物。合并的有机层用NaCl水溶液洗涤,用硫酸镁干燥,浓缩有机物,用HPLC(EtOAc/己烷)提纯粗产物,得到0.190g(28%)的异构体A和0.119g(17%)异构体B。异构体A(E异构体):FDMS:M++1=490。C22H36NO9P的精确计算的分子量:490.2206。实际值:490.2202。异构体B(Z异构体):FDMS:M++1=490。
(b)(1S*,2S*,5R*,6S*)-2-氨基-4-(Z)-二乙基膦酰基亚甲基双环[3.1.0]己烷-2,6-二羧酸。在2ml TFA中,搅拌步骤(a)的产物异构体A(0.15g,0.31mmol)1小时,浓缩并将其溶解在5ml THF中。然后用2ml 1N NaOH处理反应混合物5小时。浓缩反应混合物,用1N HCl调节至pH=10。将所得物料置于阴离子交换树脂(Bio-Rad AG1-X8)上,用1N乙酸洗脱,并在H2O中重结晶,得到0.03g(27%)所需产物。FDMS:M++1=334。C13H20NO7P+2.6当量HCl的分析计算值:C,36.48;H,5.32;N,3.27。实际值:C,36.33;H,5.50;N,3.72。
分别从异构体B或异构体C开始,可用类似的方法制备其它两种标题化合物。
实施例18
(1S*,2S*,5R*,6S*)-2-氨基
(a)(1S*,2S*,5R*,6S*)-2-氨基-4-膦酰基亚甲基双环[3.1.0]己烷-2,6-二羧酸。在2ml TFA中,搅拌实施例17(a)的产物异构体A(0.15g,0.31mmol)1小时并浓缩。用6N HCl回流处理所得反应物料过夜,浓缩,并将所得产物在H2O和IPA中研磨,得到0.005g(5%)所需产物。FDMS:M++1=278。
实施例19
(1S*,2S*,5R*,6S*)-2-氨基
-4-(Z)-氰基亚甲基双环[3.1.0]己烷-2,6-二羧酸
(1S*,2S*,5R*,6S*)-2-氨基
-4-(E)-氰基亚甲基双环[3.1.0]己烷-2,6-二羧酸
(a)(1S*,2S*,5R*,6S*)-2-(N-叔丁氧基羰基)氨基-4-氰基亚甲基双环[3.1.0]己烷-2,6-二羧酸二乙酯,异构体A和B。通过在0℃向氰基甲基膦酸二乙酯(0.45g,2.6mol)的无水甲苯溶液中加入双(三甲硅烷基)氨基化钾(2.6mmol)制备氰基甲基膦酸二乙酯的钠盐。在0℃,迅速将该钠盐加入到实施例5(a)的产物(0.6g,1.7mmol)中,并搅拌15分钟。加热反应物至室温并搅拌直至经TLC断定反应结束。加入1N HCl,用乙酸乙酯萃取反应混合物。合并的有机层用NaCl水溶液洗涤,用硫酸镁干燥,浓缩有机物,用HPLC(EtOAc/己烷)提纯粗产物,得到0.525g(82%)两种异构体的混合物。用HPLC(EtOAc/己烷)分离异构体A和异构体B。
异构体A:M++1=379。C19H26N2O6(+H)的精确计算的分子量:379.1869。实际值:379.1879。
异构体B:M+=378。
(b)(1S*,2S*,5R*,6S*)-2-氨基-4-氰基亚甲基双环[3.1.0]己烷-2,6-二羧酸。在5ml TFA中,搅拌步骤(a)的产物异构体A(0.15g,0.39mmol)1小时,浓缩并将其溶解在5ml THF中。然后用5ml 1N NaOH处理反应5小时。反应用1N HCl调节至pH=7,浓缩至干。将所得固体重新溶解在水中,调节至pH=10,并将其置于阴离子交换树脂上(Bio-Rad AG1-X8),用2N乙酸洗脱,得到0.032g(36%)所需产物。FDMS:M++1=223。C10H10N2O4+0.3当量H2O的分析计算值:C,52.77;H,4.69;N,12.31。实际值:C,52.53;H,4.76;N,12.17。
实施例20
(1S*,2S*,4R*,5S*,6S*)-2-氨基
(a)(1S*,2S*,4R*,5S*,6S*)-2-(N-叔丁氧基羰基)氨基-4-氰基双环[3.1.0]己烷-2,6-二羧酸二乙酯。向实施例8(a)产物(1.45g,2.84mmol)的无水二甲亚砜(20ml)溶液中加入氰化钠(700mg,5当量),在40℃搅拌反应混合物48小时。
冷却反应混合物,将其注入到水(200ml)中。用乙醚萃取水相三次,用水洗涤合并的乙醚萃取物,用硫酸镁干燥。真空过滤和蒸发,得到黄色泡沫状产物(880mg)。用硅胶色谱(洗脱液为乙醚25%己烷)提纯该粗产物,得到所需的无色胶状腈(670mg)。1H NMR(300MHz,CDCl3,δppm):1.30(6H,t,CO2CH2CH2 X2),1.42(9H,s,t-Butyl),1.58(1H,dd,C3-H),2.10(1H,dd,C6-H),2.30(2H,m,C1-H+C5-H),3.05(1H,dd,C3-H),3.55(1H,m,C4-H),4.20(4H,m,-CO2CH2CH3 X2),5.40(1H,s,NH).
(b)(1S*,2S*,4R*,5S*,6S*)-2-氨基双环[3.1.0]己烷-2,4,6-三羧酸。在密封容器中在90℃加热步骤(a)产物(64mg,0.175mmol)与2M盐酸(2ml)的混合物48小时。
冷却后,真空蒸发反应混合物,得到白色固体(80mg),将白色固体溶解在最少量水中,用阳离子交换色谱(Dowex 50X8-100;柱依次用H2O、H2O/THF(1∶1)和H2O洗脱,最后用H2O/吡啶(9∶1)洗脱氨基酸)提纯。真空除去吡啶,将残余固体重新溶解在水中并冷冻干燥,得到所需的松散的白色固体氨基酸(38mg)。熔点>300℃。1H NMR(300MHz,D2O,δppm):1.35(1H,dd,C3-H),1.65(1H,dd,C6-H),1.90(1H,m,C5-H),2.00(2H,m,C1-H+C3-H),3.18(1H,m,C4-H).
实施例21
(1S*,2S*,4R*,5S*,6S*)-2-氨基-4-氰基
-双环[3.1.0]己烷-2,6-二羧酸
(a)(1S*,2S*,4R*,5S*,6S*)-2-(N-叔丁氧基羰基)氨基-4-氰基双环[3.1.0]己烷-2,6-二羧酸。向实施例20(a)产物(200mg,0.55mmol)的四氢呋喃(2ml)溶液中加入1M氢氧化锂溶液(1.2ml),在室温搅拌混合物8小时。
用水稀释反应混合物,用1M盐酸酸化,用乙酸乙酯萃取3次。用饱和氯化钠溶液洗涤合并的有机萃取物,用硫酸镁干燥,真空过滤并蒸发,得到白色玻璃状产物(180mg)。
用硅胶色谱(洗脱液为乙酸乙酯5%冰醋酸)提纯粗产物,得到所需的白色固体二羧酸(120mg)。1H NMR(300MHz,DMSO-d6,δppm):1.38(9H,s,t-butyl),1.58(1H,dd,C3-H),1.82(1H,dd,C6-H),2.22(1H,m,C5-H),2.36(1H,m,C1-H),2.60(1H,dd,C3-H),3.40(1H,m,C4-H),7.30(1H,s,NH).
(b)(1S*,2S*,4R*,5S*,6S*)-2-氨基-4-氰基双环[3.1.0]己烷-2,6-二羧酸。将步骤(a)的产物(120mg,0.38mmol)溶解在三氟乙酸(5ml)中,并在室温搅拌2小时。
真空蒸发反应混合物,将残余物重新溶解在水中并真空共沸得到白色固体(62mg)。将粗产物固体重新溶解在最少量水中,用阳离子交换色谱(Dowex 50X8-100;柱依次用H2O、H2O/THF(1∶1)和H2O洗脱,最后用H2O/吡啶(9∶1)洗脱氨基酸)提纯。真空除去吡啶,将残余固体重新溶解在水中并冷冻干燥,得到所需的松散的白色固体氨基酸(35mg)。熔点:240-242℃。1H NMR(300MHz,D2O,δppm):1.85(1H,dd,C3-H),2.21(1H,t,C6-H),2.42(1H,dd,C1-H),2.60(2H,m,C3-H+C5-H),3.83(1H,m,C4-H).
实施例22
(1S*,2S*,4R*,5S*,6S*)-2-氨基
(a)(1S*,2S*,4R*,5S*,6S*)-2-(N-叔丁氧基羰基)氨基-4-氨甲酰双环[3.1.0]己烷-2,6-二羧酸.在0-5℃,向实施例20
(a)产物(145mg,0.40mmol)的无水乙醇(1ml)溶液中加入(1)30%过氧化氢(0.175ml)(2)6M氢氧化钠(0.2ml)。当用更多水(4ml)稀释时,将反应混合物加热至室温并再搅拌4小时。
72小时后,用2M盐酸酸化反应混合物,用乙酸乙酯萃取3次。用饱和氯化钠溶液洗涤合并的有机萃取物,用硫酸镁干燥,真空过滤并蒸发,得到白色固体(84mg)。用硅胶色谱(洗脱液为乙酸乙酯5%冰醋酸)提纯粗产物,得到所需的白色固体(34mg)。1H NMR(300MHz,DMSO-d6,δppm):1.42(9H,s,t-butyl),1.65(1H,dd,C3-H),1.75(1H,broad s,C6-H),2.08(2H,m,C1-H+C3-H),2.14(1H,m,C5-H),3.10(1H,m,C4-H),6.90(1H,s,NH),7.44(1H,s,NH),7.64(1H,s,NH),12.35(2H,broadhump,2XCO2H).
(b)(1S*,2S*,4R*,5S*,6S*)-2-氨基-4-氨甲酰双环[3.1.0]己烷-2,6-二羧酸。在室温搅拌步骤(a)产物(34mg,0.1mmol)的三氟乙酸(5ml)溶液2小时。
真空蒸发反应混合物至干,将残余物重新溶解在水中,在70℃真空共沸。将固体粗产物溶解在最少量水中,用阳离子交换色谱(Dowex50X8-100;柱依次用H2O、H2O/THF(1∶1)和H2O洗脱,最后用H2O/吡啶(9∶1)洗脱氨基酸)提纯。真空除去吡啶,将残余固体重新溶解在水中并冷冻干燥,得到所需的松散的白色固体氨基酸(12mg)。熔点:260-262℃(分解)。1H NMR(300MHz,D2O,δppm):1.95(1H,dd,C3-H),2.30(1H,d,C6-H),2.42-2.64(3H,m,C1-H+C3-H+C5-H),3.78(1H,m,C4-H).
实施例23
(1S*,2S*,4R*,5R*,6R*)-2-氨基
-4-羟基双环[3.1.0]己烷-2,6-二羧酸
(a)(1S*,2S*,4R*,5R*,6R*)-2-N-叔丁氧基羰基氨基-4-羟基双环[3.1.0]己烷-2,6-二羧酸二乙酯。将超氧化钾(0.52g,7.4mmol)一次加入到0℃的实施例8(a)产物(1.90g,3.7mmol)的无水DMSO(20ml)溶液中。加入完毕后,移去冷却浴,将反应混合物加热至室温,同时搅拌2小时。用EtOAc稀释反应混合物,用饱和的Na2S2O3水溶液洗涤,用硫酸镁干燥,减压浓缩,得到粗甲醇(carbinol),用PC-TLC(4mm SiO2 rotor-10%EtOAc/己烷-50%EtOAc/己烷)提纯,得到0.29g(22%,0.81mmol)所需的白色泡沫状产物。FDMS:M++1=258。C17H27NO7·0.75H2O的分析计算值:C,55.05;H,7.74;N,3.78。实际值:C,55.39;H,7.63;N,3.38。
(b)将步骤(a)产物(0.24g,0.67mmol)的EtOAc(30ml)溶液冷却至0℃,用无水HCl气体清洗直至溶液饱和。移去冷却浴,在室温搅拌反应混合物2小时,浓缩至干,在室温下,在1N NaOH∶THF为1∶1的混合物(总体积20ml)中,将所得固体搅拌过夜。用1N HCl调节使反应pH=7,减压浓缩。将所得固体重新溶解在水中,用1N NaOH调节至pH=12,用阴离子交换树脂(Bio-Rad AG1-X8:乙酸盐转化为其氢氧化物形式,用3N乙酸洗脱)提纯,得到0.12g(0.58mmol,86%)所需产物。熔点=dec>270℃。FDMS:M++1=202。C8H11NO5的分析计算值:C,47.76;H,5.51;N,6.96。实际值:C,47.51;H,5.80;N,6.72。
Claims (12)
其中
(a)R1表示氟、XOR3、XNR4R5、SO3H、四唑-5-基、CN或PO3R6 2和R2表示氢;或
(b)R1和R2分别表示氟;或
(c)R1和R2一起表示=O、=NOR7或=CR8R9;或
(d)R1和R2之一表示氨基,另一个表示羧基;或
(e)R1表示N3、(CH2)mCOOR3a、(CH2)mPO3R2 6a、NHCONHR3b或NHSO2R3c和R2表示氢;或
(f)R1和R2一起表示=CHCOOR3b、=CHPO3R2 6a或=CHCN;和
R3表示氢原子;(1-6C)烷基;(3-6C)链烯基;(3-6C)链炔基;任选取代的芳基;任选取代的杂芳基;非芳族碳环基;非芳族杂环基;与一个或两个单环芳族或杂芳族基团稠合的非芳族单环碳环基;与一个或两个单环芳族或杂芳族基团稠合的非芳族单环杂环基;或被1个、2个或3个独立选自任选取代的芳基、任选取代的杂芳基、非芳族碳环基、非芳族杂环基、与一个或两个单环芳族或杂芳族基团稠合的非芳族单环碳环基和与一个或两个单环芳族或杂芳族基团稠合的非芳族单环杂环基的基团取代的(1-6C)烷基、(3-6C)链烯基或(3-6C)链炔基;
R3a、R3b和R3c定义如R3;
X表示一个键、CH2或CO;
m表示1-3的整数;
R4表示COR10或定义如R3;
R5、R7、R8、R9和R10定义如R3;
R6表示氢或(1-6C)烷基;和
R6a定义如R6。
2.权利要求1要求保护的化合物,其中
(a)R1表示氟、XOR3、XNR4R5、SO3H、四唑-5-基、CN或PO3R6 2和R2表示氢;或
(b)R1和R2分别表示氟;或
(c)R1和R2一起表示=O、=NOR7或=CR8R9;或
(d)R1和R2之一表示氨基,另一个表示羧基。
3.权利要求1要求保护的化合物,其中
(a)R1表示氟;XOR3;XNR4R5;SO3H;四唑-5-基;CN或PO3H2;X表示一个键、CO或CH2;R3表示氢或(1-6C)烷基;未取代的苯基或被1个或2个独立地选自卤素、(1-4C)烷基和(1-4C)烷氧基的取代基取代的苯基;在苯基上未取代或被1个或2个独立选自卤素、(1-4C)烷基和(1-4C)烷氧基的取代基取代的苯基(1-4C)烷基或二苯基(1-4C)烷基;R4表示氢、(1-6C)烷酰基、苯甲酰基、(3-6C)环烷基(1-4C)烷基或(1-6C)烷基;和R5表示氢、(3-6C)环烷基(1-4C)烷基或(1-6C)烷基;和R2表示氢;或
(b)R1和R2分别表示氟;或
(c)R1和R2一起表示=O、=NOH或=CR8R9,其中R8和R9各自独立地表示氢原子、(1-6C)烷基或未取代的苯基或被1个或2个选自卤素、(1-4C)烷基和(1-4C)烷氧基的取代基取代的苯基;或
(d)R1和R2之一表示氨基,另一个表示羧基;或
(e)R1表示N3、CH2COOR3a、CH2PO3R2 6a、NHCONHR3b或NHSO2R3c;R3a表示氢和(1-6C)烷基;R3b表示(1-6C)烷基;R3c表示(1-6C)烷基;R2表示氢;和每个R6a独立地表示氢或(1-6C)烷基;或
(f)R1和R2一起表示=CHCOOH、=CHPO3H2、=CHPO3(C2H5)2或=CHCN。
4.权利要求2要求保护的化合物,其中
(a)R1表示氟、XOR3、XNR4R5、SO3H、四唑-5-基、CN或PO3H2;X表示一个键、CO或CH2;R3表示氢原子,(1-6C)烷基,未取代的苯基或被1个或2个独立地选自卤素、(1-4C)烷基和(1-4C)烷氧基的取代基取代的苯基,在苯基上未取代或被1个或2个选自卤素、(1-4C)烷基和(1-4C)烷氧基的取代基取代的苯基(1-4C)烷基或二苯基(1-4C)烷基;R4表示氢、(1-6C)烷酰基或(1-6C)烷基;和R5表示氢或(1-6C)烷基;和R2表示氢;或
(b)R1和R2分别表示氟;或
(c)R1和R2一起表示=O、=NOH或=CR8R9,其中R8和R9各自独立地表示氢原子、(1-6C)烷基或未取代的苯基或被1个或2个独立地选自卤素、(1-4C)烷基和(1-4C)烷氧基的取代基取代的苯基;或
(d)R1和R2之一表示氨基,另一个表示羧基。
5.权利要求1要求保护的化合物,其中R1表示氟、羟基、PO3H2、甲氧基、氨基、叠氮基、乙酰氨基、苯甲酰氨基、甲磺酰氨基、甲基氨基羰基氨基、N,N-二环丙基甲基、羧基、氰基或氨甲酰和R2表示氢,或R1和R2一起表示=O、=NOH、=CHCO2H、=CH2、=CHPO3(C2H5)2、=CHPO3H2或=CHCN。
6.权利要求1要求保护的化合物,其选自
(1S*,2S*,5R*,6R*)-2-氨基-4-氧代双环[3.1.0]己烷-2,6-二羧酸;
(1S*,2S*,5R*,6R*)-2-氨基-4-[反]-肟基双环[3.1.0]己烷-2,6-二羧酸;
(1S*,2S*,5R*,6R*)-2-氨基-4-[顺]-肟基双环[3.1.0]己烷-2,6-二羧酸;
(1S*,2S*,4S*,5S*,6S*)-2-氨基-4-氟双环[3.1.0]己烷-2,6-二羧酸;
(1S*,2S*,5S*,6S*)-2-氨基-4-Z-羧基亚甲基双环[3.1.0]己烷-2,6-二羧酸和
(1S*,2S*,5R*,6S*)-2-氨基-4-亚甲基双环[3.1.0]己烷-2,6-二羧酸。
7.制备权利要求1-6中任一项定义的化合物的方法,其包括
(a)水解式II化合物或其盐,
其中,
R11表示氢原子或酰基,R12表示羧基或酯化的羧基;
其中,
R13表示羧基或酯化的羧基,R14和R15分别独立地表示氢原子、(2-6C)烷酰基、(1-4C)烷基、(3-4C)链烯基或苯基(1-4C)烷基,其中苯基是未取代的或被卤素、(1-4C)烷基或(1-4C)烷氧基取代;或
其中,
R18表示氢原子或氮保护基,R16和R17分别独立地表示氢原子或羧基保护基;
此后,如果需要和/或希望,
(i)将式I化合物拆分;
(ii)将式I化合物转化为其无毒性的代谢不稳定酯或酰胺;和/或
(iii)将式I化合物或其无毒性的代谢不稳定酯或酰胺转化为其药物上可接受的盐。
8.一种药物制剂,其包括权利要求1-6中任一项所要求保护的化合物和药物上可接受的载体、稀释剂或赋型剂。
9.权利要求1要求保护的化合物,其用于制备调节代谢亲和性谷氨酸盐受体功能的药物中的用途。
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NO (1) | NO995480L (zh) |
NZ (1) | NZ500954A (zh) |
PE (1) | PE73599A1 (zh) |
PL (1) | PL336793A1 (zh) |
PT (1) | PT878463E (zh) |
SI (1) | SI0878463T1 (zh) |
SV (1) | SV1998000056A (zh) |
TR (1) | TR199902777T2 (zh) |
TW (1) | TW505623B (zh) |
WO (1) | WO1998051655A1 (zh) |
ZA (1) | ZA983930B (zh) |
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