CN1221403A - 具有消炎和免疫抑制活性的化合物 - Google Patents
具有消炎和免疫抑制活性的化合物 Download PDFInfo
- Publication number
- CN1221403A CN1221403A CN97195410A CN97195410A CN1221403A CN 1221403 A CN1221403 A CN 1221403A CN 97195410 A CN97195410 A CN 97195410A CN 97195410 A CN97195410 A CN 97195410A CN 1221403 A CN1221403 A CN 1221403A
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- China
- Prior art keywords
- mmoles
- compound
- alkyl
- acid
- phenyl
- Prior art date
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- Granted
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 69
- 230000003110 anti-inflammatory effect Effects 0.000 title abstract description 7
- 230000000947 anti-immunosuppressive effect Effects 0.000 title abstract description 3
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 11
- 239000001257 hydrogen Substances 0.000 claims abstract description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 7
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims abstract description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 5
- 125000004423 acyloxy group Chemical group 0.000 claims abstract description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 3
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims abstract description 3
- 229910052736 halogen Inorganic materials 0.000 claims abstract 2
- 150000002367 halogens Chemical group 0.000 claims abstract 2
- -1 amino, amino Chemical group 0.000 claims description 49
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 7
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 5
- 125000005210 alkyl ammonium group Chemical group 0.000 claims description 4
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 239000003018 immunosuppressive agent Substances 0.000 claims description 4
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 3
- 230000001741 anti-phlogistic effect Effects 0.000 claims description 3
- 125000004122 cyclic group Chemical group 0.000 claims description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 2
- 125000005493 quinolyl group Chemical group 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Substances C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 claims 1
- 125000004103 aminoalkyl group Chemical group 0.000 abstract 2
- 125000004956 cyclohexylene group Chemical group 0.000 abstract 1
- 125000000623 heterocyclic group Chemical group 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 134
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 67
- 239000000243 solution Substances 0.000 description 54
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 51
- 239000002904 solvent Substances 0.000 description 36
- VDEUYMSGMPQMIK-UHFFFAOYSA-N benzhydroxamic acid Chemical compound ONC(=O)C1=CC=CC=C1 VDEUYMSGMPQMIK-UHFFFAOYSA-N 0.000 description 35
- 238000005160 1H NMR spectroscopy Methods 0.000 description 34
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 32
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
- 239000012043 crude product Substances 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 22
- 239000000203 mixture Substances 0.000 description 22
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- 238000001035 drying Methods 0.000 description 20
- 235000011121 sodium hydroxide Nutrition 0.000 description 17
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N methyl alcohol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 15
- 229940083608 sodium hydroxide Drugs 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 13
- 239000002253 acid Substances 0.000 description 13
- 239000011541 reaction mixture Substances 0.000 description 13
- 239000002158 endotoxin Substances 0.000 description 12
- 239000003999 initiator Substances 0.000 description 12
- HBFKRHROCKKBGJ-UHFFFAOYSA-N n-hydroxybenzamide;hydrochloride Chemical compound Cl.ONC(=O)C1=CC=CC=C1 HBFKRHROCKKBGJ-UHFFFAOYSA-N 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 229920006008 lipopolysaccharide Polymers 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 9
- 102000003777 Interleukin-1 beta Human genes 0.000 description 9
- 108090000193 Interleukin-1 beta Proteins 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 238000000354 decomposition reaction Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- 238000010025 steaming Methods 0.000 description 8
- 238000003810 ethyl acetate extraction Methods 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- 235000017550 sodium carbonate Nutrition 0.000 description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- JQVDAXLFBXTEQA-UHFFFAOYSA-N N-butyl-butylamine Natural products CCCCNCCCC JQVDAXLFBXTEQA-UHFFFAOYSA-N 0.000 description 5
- 235000010290 biphenyl Nutrition 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- 102000004127 Cytokines Human genes 0.000 description 4
- 108090000695 Cytokines Proteins 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 4
- 229960003957 dexamethasone Drugs 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- QQVIHTHCMHWDBS-UHFFFAOYSA-N perisophthalic acid Natural products OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 3
- PKSROMPNLONTJT-UHFFFAOYSA-N azanium;chloroform;methanol;hydroxide Chemical compound N.O.OC.ClC(Cl)Cl PKSROMPNLONTJT-UHFFFAOYSA-N 0.000 description 3
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 3
- 229940098773 bovine serum albumin Drugs 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- MHYCRLGKOZWVEF-UHFFFAOYSA-N ethyl acetate;hydrate Chemical compound O.CCOC(C)=O MHYCRLGKOZWVEF-UHFFFAOYSA-N 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000012280 lithium aluminium hydride Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 150000003222 pyridines Chemical class 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 3
- 239000012265 solid product Substances 0.000 description 3
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- NCNTUMUUBWMWIR-UHFFFAOYSA-N 2-bromopentane Chemical compound [CH2]CCC(C)Br NCNTUMUUBWMWIR-UHFFFAOYSA-N 0.000 description 2
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical group C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- VAJVDSVGBWFCLW-UHFFFAOYSA-N 3-Phenyl-1-propanol Chemical compound OCCCC1=CC=CC=C1 VAJVDSVGBWFCLW-UHFFFAOYSA-N 0.000 description 2
- XRSQZFJLEPBPOZ-UHFFFAOYSA-N 4-amino-2-methylbenzoic acid Chemical compound CC1=CC(N)=CC=C1C(O)=O XRSQZFJLEPBPOZ-UHFFFAOYSA-N 0.000 description 2
- TWBKCAGYIIDUQF-UHFFFAOYSA-N 6-(diethylcarbamoyl)naphthalene-2-carboxylic acid Chemical compound C1=C(C(O)=O)C=CC2=CC(C(=O)N(CC)CC)=CC=C21 TWBKCAGYIIDUQF-UHFFFAOYSA-N 0.000 description 2
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- 241000283707 Capra Species 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 241001354013 Salmonella enterica subsp. enterica serovar Enteritidis Species 0.000 description 2
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- 230000004913 activation Effects 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 125000005263 alkylenediamine group Chemical group 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- QCTBMLYLENLHLA-UHFFFAOYSA-N aminomethylbenzoic acid Chemical compound NCC1=CC=C(C(O)=O)C=C1 QCTBMLYLENLHLA-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
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- 230000008030 elimination Effects 0.000 description 2
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- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
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- RXOHFPCZGPKIRD-UHFFFAOYSA-N naphthalene-2,6-dicarboxylic acid Chemical class C1=C(C(O)=O)C=CC2=CC(C(=O)O)=CC=C21 RXOHFPCZGPKIRD-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
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- 238000000926 separation method Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
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- 150000003512 tertiary amines Chemical class 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
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- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
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- RKWYGYPAIKRCCI-UHFFFAOYSA-N O=C(CCCCC1=CC=CC=C1)NC(C=CC=C1)=C1C(Cl)=O Chemical compound O=C(CCCCC1=CC=CC=C1)NC(C=CC=C1)=C1C(Cl)=O RKWYGYPAIKRCCI-UHFFFAOYSA-N 0.000 description 1
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- 239000012980 RPMI-1640 medium Substances 0.000 description 1
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- 241000194017 Streptococcus Species 0.000 description 1
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- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/10—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to carbon atoms of six-membered aromatic rings
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Abstract
具有消炎和免疫抑制活性的分子式(Ⅰ)的化合物,其中R′为氢原子或烷基,A为金刚烷基或可选择地不饱和的单-,双-或三环基团,一个杂环基团和/或可被羟基,烷酰氧基,氨基,氨基烷基,卤原子,烷基,三烷基铵烷基取代的基团;(a)为含1到5个碳原子的链基,可选择地含有双键或NR′;R为氢或苯基;X为O或NR′或不存在;r和m独立地为0,1或2;B为亚苯基或亚环己基;Y为羟基或氨基烷基,可选择地被O间隔。
Description
本发明涉及新的化合物及其作为消炎和免疫抑制剂的用途。
细胞因子(例如IL-1β和α,TNFα和IL-6在发炎反应的发生中的作用是已知的(Dinarello C.A.和Wolff S.M.,New Eng.J.Med.(新英格兰医学杂志)328(2):106113,1993;Tracey K.J.和Cerami A.,Crit.CareMed.21:S415,1993;Melli M.和Parente L.,炎症中的细胞因子和脂皮质蛋白及其区别,Wiley-liss.纽约1990;Dawson M.M.淋巴因子和白细胞介素.CRC出版,Boca Raton,FL 1991)。为了寻找称作细胞因子抑制性消炎药(SAID)的化合物已经进行了大量的研究工作,这种化合物对促炎细胞因子的产生有一种抑制作用,特别是对IL-1β和TNFα(LeeJ.C.等人,自然372:739,1994;Davidsen S.K.和Summers J.B.,Exp.Opin.Ther.Patents.5(10):1087,1995),最近公开了称作非传统的非甾类的消炎药的广谱性药剂(Chiou G.C.Y.和Liu S.X.L.,Exp.Opin.Ther.Patents.6(1):41,1996)。
Tanaka等人,Chem.Pharm.Bull.(化学药物公报),31(8),2810-2819(1983)报道了作为消炎活性成分的异羟肟基团的重要性:它被说成具有如此重要的作用以至于使分子的其他部分显得不太重要,其中的基团如甲氧基可以提高炎性的效力,而其他的基团,如乙酰氨基,可导致活性降低。
现在令人惊奇的发现,含有苯基酰氨部分的异羟肟酸衍生物,相对于前面报导的技术,具有显著的消炎作用,以及免疫抑制活性。
因此本发明涉及分子式(Ⅰ)的化合物:
其中R′为氢原子或(C1-4)烷基,
A为金刚烷基或单-,双-或三环残基,其可选择性地部分或全部为不饱和的,其可以包含一个或多个选自N,S或O的杂原子,且可选择地被羟基,烷酰氧基,伯,仲或叔氨基,氨基(C1-4)烷基,单-或双-(C1-4)烷基-氨基(C1-4)烷基,卤原子,(C1-4)烷基,三(C1-4)烷基铵(C1-4)烷基取代;
R为氢或苯基;
X为氧原子或NR′基团,其中R′如上所定义或不存在;
r和m独立地为0,1或2;
B为亚苯基或亚环己基环;
Y为羟基或氨基(C1-4)烷基链,可选择地被氧原子间隔;
其条件为仅当X不为O且同时Y不为羟基时作为A所定义的三环基团是芴基,除非所说的芴基是被三(C1-4)烷基铵(C1-4)烷基基团取代的。
根据下文所述,上面定义的烷基基团为,例如:甲基,乙基,2-甲基乙基,1,3-丙基,1,4-丁基,2-乙基乙基,3-甲基丙基,1,5-戊基,2-乙基丙基,2-甲基丁基和类似的基团,而上面定义的单-,双-或三环基团可以是苯基,环己基,吡啶基,哌啶基,嘧啶基,哒嗪基,萘基,茚基,蒽基,菲基,芴基,呋喃基,吡喃基,苯并呋喃基,苯并吡喃基,呫吨基,异噻唑基,异噁唑基,吩噻嗪基,吩噁嗪,吗啡酚基,硫代苯基,苯并硫代苯基等等。卤原子可以是氯,溴或氟。最后,烷酰氧基基团为,乙酰氧基,丙酰氧基,异丙酰氧基,丁酰氧基和类似的基团。
首先优选的分子式(Ⅰ)的化合物为其中R'为氢;A选自选择性地如上取代的苯基,1-或2-萘基,环己基,1-或2-1,2,3,4-四氢化萘基,金刚烷基,喹啉基,异喹啉基,1-或2-茚基,四氢喹啉基,四氢异喹啉基;
其次优选的化合物为其中R′为氢;A为可选择地取代的苯基或1-或2-萘基,更优选地为1-或2-萘基;当A为苯基时R为苯基,或当A为1-或2-萘基时R为氢;R,B,m和r如上所定义;Y为OH,C1-3的亚烷基链如上面首先优选的化合物所定义。
A代表的基团优选地被(C1-4)-烷基氨基(C1-4)-烷基基团取代。
本发明进一步的目标涉及分子式(Ⅰ)的化合物作为消炎和免疫抑制剂的用途,以及它们的包括药物可接受的赋形剂的药物组合物。
其中R和A如上所定义,X ′为氧原子或NR′基团,其中R′为上述定义的。此化合物与碳酸反应性衍生物如二琥珀酰亚胺碳酸酯或羰基二咪唑(CDI)反应,且在叔胺存在下,如三乙胺,或芳族的,如吡啶,在惰性溶剂如乙腈,四氢呋喃(THF),二噁烷,氯化溶剂中,在室温到溶剂回流温度下反应,并且反应时间在1到48小时范围内。
得到的化合物(Ⅲ)
其中R,A和X′如上所定义,R1为咪唑基或羟基琥珀酰亚胺基团,与所需要的氨基酸在水和水-可混溶有机溶剂如四氢呋喃,乙腈或乙醇的混合物中反应,且在无机碱存在下进行,如碱金属氢氧化物,例如氢氧化钠,碱或碱土金属的碳酸盐或碳酸氢盐,例如碳酸钠,在室温下进行1到48小时。
其中R,A,X′,B,m和r如上所定义,将其活化为酰基氯的反应是通过在氯化溶剂中或用亚硫酰氯作溶剂与亚硫酰氯作用,温度范围从室温到溶剂回流温度且进行1到12小时。
然后,在分子式(Ⅰ)的化合物中Y为所要求的羟基的情况下,酰基氯与盐酸羟胺反应,或在其它情况下与合适的亚烷基二胺反应。此反应发生在水和水-可混溶有机溶剂如四氢呋喃,乙腈的混合物中,且在上步所述的无机碱的存在下,在室温下进行1到48小时,得到要求的化合物(Ⅰ)。
可供选择的,酸(Ⅳ)和盐酸羟胺或亚烷基二胺在存在缩合剂如CDI时进行反应,且存在叔胺如三乙胺,在惰性溶剂如乙腈,四氢呋喃,二噁烷,氯化的溶剂中反应,在室温下进行1到24小时,最终产物按常用的色谱法或结晶法纯化。
其中R和A如上所定义,通过在氯化的溶剂中或用亚硫酰氯作溶剂时与亚硫酰氯作用活化为酰基氯,温度在室温到溶剂的回流温度范围内变化,进行约1-12小时。酰基氯与所需要的氨基酸在水和水-可混溶有机溶剂如THF或乙腈中反应,在存在碱如碱金属氢氧化物,如氢氧化钠时,或碱金属或碱土金属碳酸盐或碳酸氢盐,如碳酸钠存在时,在室温进行1-72小时。
其中R,A,B,m和r如上所定义,可按照上面1所描述的步骤转化为所要求的化合物(Ⅰ)。
下面,对一些本发明的代表化合物的制备实施例进行说明。如果没有另外指明,在二甲亚砜(DMSO)中用1H-NMR谱与VARIAN GEMINI200分光计纪录。
实施例1
4-(5-苯基戊酰氨基)苯基异羟肟酸
A.向5-苯基戊酸(5g,28毫摩尔)的氯仿(100ml)溶液中加入亚硫酰氯(2.5ml,34毫摩尔)。反应混合物回流4小时,然后蒸干。残余物再次溶解在氯仿中且再次蒸干反复三次。所得的5-苯基戊烷酰氯再溶解在THF(50ml)中,所得溶液缓慢地加入4-氨甲基苯甲酸(3.8g,28毫摩尔)的1N氢氧化钠(56ml)溶液中。反应混合物在室温下搅拌3小时,然后在低温下蒸发THF同时水溶液用HCl酸化。将形成的沉淀物过滤,再次溶解在THF中,用无水氯化钙干燥且蒸去溶剂得到6.7g的4-(5-苯基戊酰氨基)苯甲酸(产率81%);m.p.=227-230℃。
1H-NMR d 12.5(s,1H,与D2O交换),10.3(s,1H),7.92(d,2H),7.75(d,2H),7.25(m,5H),2.63(t,2H),2.41(t,2H),1.65(m,4H)。
B.向A中所得的化合物(6.7g,22毫摩尔)的氯仿(100ml)溶液加入亚硫酰氯(3.3ml,45毫摩尔)和3滴吡啶。反应混合物在室温下搅拌5小时,然后蒸干。残余物再次溶解在氯仿中且再次蒸干反复三次。所得的4-(5-苯基戊酰氨基)苯甲酰氯溶解在THF(50ml)中,所得溶液缓慢地加入盐酸羟胺(1.9g,27毫摩尔)和碳酸氢钠(1.9g,22毫摩尔)的1N氢氧化钠(27ml,27毫摩尔)和THF(25ml)溶液中。反应混合物在室温下搅拌3小时,然后用1N HCl酸化并且在低温下蒸发THF。用乙酸乙酯萃取水相,得到的有机相用无水硫酸钠干燥后蒸去溶剂。所得的粗品用乙醚处理,过滤得到4.8g的标题化合物。(产率69%);m.p.=189-191℃。
1H-NMR d 11.12(s,1H),10.13(s,1H),8.97(s,1H),7.691(m,4H),7.33/7.13(m,5H),2.61(m,2H),2.38(m,2H),1.65/1.58(m,4H)。
实施例2
4-[2,2-(二苯基)乙氧基氨基甲酰基甲基]苯基异羟肟酸
A.将2,2-二苯基乙醇(6g,30毫摩尔),和CDI(4.9g,30毫摩尔)在THF(30ml)中的混合物,室温下搅拌2小时,然后向其中加入4-氨甲基苯甲酸(4.6g,30毫摩尔)的1N氢氧化钠(30ml)溶液。反应混合物在室温下搅拌3小时,然后用HCl酸化,低温下蒸出THF,然后水溶液用乙酸乙酯萃取。有机相用无水硫酸钠干燥后,蒸去溶剂。所得的粗品用热正己烷处理并过滤得到10g的4-[2,2-(二苯基)乙氧基氨基甲酰基-甲基]苯甲酸(产率90%);m.p.=102-105℃。
1H-NMR d12.7(s,1H,与D2O交换),7.91(d,2H),7.78(t,1H),7.50-7.20(m,12H),4.61(d,2H),4.38(t,1H),4.23(d,2H)。
B.向在步骤A中所得的化合物(4.5g,12毫摩尔)的氯仿(50ml)溶液中,加入亚硫酰氯(1.3ml,18毫摩尔)和3滴吡啶。反应混合物在室温下搅拌3小时,然后蒸干。残余物再次溶解在氯仿中且再次蒸干反复三次。所得的4-[2,2-(二苯基)乙氧基氨基甲酰基甲基]-苯甲酰氯溶解在THF(50ml)中,且将溶液缓慢地加入盐酸羟胺(1.0g,14.4毫摩尔)和碳酸氢钠(1g,12毫摩尔)的1N氢氧化钠(14.4ml,14.4毫摩尔)和THF(20ml)溶液中。反应混合物在室温下搅拌3小时,然后用1N HCl酸化,低温下蒸出THF.用热乙酸乙酯萃取水相,合并的有机相用无水硫酸钠干燥后蒸出溶剂。所得的粗品用硅胶色谱柱纯化(洗脱剂∶二氯甲烷/甲醇15∶1),将得到的产物用热乙醚处理并过滤从而得到1.5g的标题化合物.(产率32%);m.p.=164-166℃。
1H-NMR d 11.12(s,1H),9.04(s,1H),7.74(t,1H),7.72(m,2H),7.38/7.20(m,12H),4.60(d,2H),4.38(t,1H),4.20(d,2H)。
实施例3
4-[2-(金刚烷-1-基)-乙氧基氨基甲酰基]苯基异羟肟酸
A.2-(金刚烷-1-基)乙醇(2.1g,12毫摩尔),羧酸二琥珀酰亚胺(3.3g,13毫摩尔)和吡啶(0.86ml,10毫摩尔)在乙腈(50ml)中的混合物,室温下搅拌24小时,然后低温下蒸出溶剂,残余物溶解在二氯甲烷(100ml)中。溶液用水洗(50ml),再用1N HCl(50ml)和水(50ml)洗。有机相用无水硫酸钠干燥后,蒸去溶剂。将所得的3g(9毫摩尔)的2-(金刚烷基-1-基)乙基-琥珀酰亚胺碳酸酯粗品再次溶解在THF(30ml)中。所得溶液加入4-氨基苯甲酸(1.3g,9毫摩尔)和碳酸钠(0.98g,9毫摩尔)的水(30ml)溶液中,然后在室温下搅拌一夜并用HCl酸化,低温下蒸出THF,然后水相用乙酸乙酯萃取。有机相用无水硫酸钠干燥后,蒸去溶剂,所得的粗品用热正己烷处理并过滤,得到3.2g的4-[2-(金刚烷基-1-基)乙氧基氨基甲酰基]苯甲酸(产率77%);m.p.=197-200℃。
1H-NMR d 12.6(s,1H,与D2O交换),10.0(s,1H),7.89(d,2H),7.60(d,2H),4.19(t,2H),1.93(m,5H),1.75/1.40(m,12H)。
B.在步骤A中所得的化合物(3g,8.7毫摩尔)的氯仿(50ml)溶液中,加入亚硫酰氯(1.2ml,17.4毫摩尔)和3滴吡啶。反应混合物回流5小时,然后蒸干。残余物再次溶解在氯仿中且再次蒸干反复三次。所得的4-[2-(金刚烷-1-基)乙氧基氨基甲酰基]苯甲酰氯溶解在THF(50ml)中,且将溶液缓慢地加入盐酸羟胺(0.7g,10.4毫摩尔)和碳酸氢钠(0.7g,8.7毫摩尔)的1N氢氧化钠(10.4ml,10.4毫摩尔)和THF(20ml)溶液中。反应混合物在室温下搅拌8小时,然后用1N HCl酸化,低温下蒸出THF。用乙酸乙酯萃取水相,合并的有机相用无水硫酸钠干燥后蒸出溶剂。所得的粗品用热乙醚处理并过滤,得到1.5g的标题化合物。(产率48%);m.p.=198-200℃。
1H-NMR d 11.08(s,1H),9.84(s,1H),8.94(s,1H),7.70(m,2H),7.53(m,2H),4.17(m,2H),1.94(m,3H),1.73/1.37(m,14H)。
实施例4
4-[(萘-1-基)甲氧基氨基甲酰基]苯基异羟肟酸
A.萘-1-基-甲醇(5g,31毫摩尔)为起始物,接下来的步骤如实施例3A描述的,得到7g纯的4-[(萘-1-基)甲氧基氨基甲酰基]苯甲酸(产率81%)。
1H-NMR d 12.7(s,1H,与D2O交换),10.2(s,1H),8.18(d,1H),7.97(m,4H),7.61(m,6H),5.69(s,2H)。
B.在步骤A中所得的化合物(6g,19毫摩尔)为起始物,接下来的步骤如实施例3B描述的,得到1.86g的标题化合物(产率30%);m.p.=192-194℃。
1H-NMR d 11.12(s,1H),10.06(s,1H),8.98(s,1H),8.14(m,1H),8.03/7.96(m,2H),7.76/7.50(m,8H),5.67(s,2H)。
实施例5
4-[(1,2,3,4-四氢化萘-2-基)甲氧基氨基甲酰基]苯基异羟肟酸
A.(1,2,3,4-四氢化萘-2-基)甲醇(4g,24毫摩尔)为起始物,接下来的步骤如实施例3A描述的,得到5.2g纯的4-[(1,2,3,4-四氢化萘-2-基)甲氧基氨基甲酰基]苯甲酸(产率67%);m.p.=203-206℃。
1H-NMR d 12.6(s,1H,与D2O交换),10.1(s,1H),7.92(d,2H),7.63(d,2H),7.1(m,4H),4.14(d,2H),2.88(m,3H),2.54(m,1H),2.25-1.90(m,2H),1.49(m,1H)。
B.在步骤A中所得的化合物(5.2g,16毫摩尔)为起始物,接下来的步骤如实施例3B描述的,得到4.1g的标题化合物(产率75%);m.p.=184-186℃。
1H-NMR d 11.10(s,1H),9.97(s,1H),8.96(s,1H),7.72(m,2H),7.54(m,2H),7.09(s,4H),4.11(d,2H),2.92/2.75(m,3H),2.61/2.47(m,1H),2.17/1.93(m,2H),1.56/1.35(m,1H)。
实施例6
4-[(3-苯基丙氧基)氨基甲酰基]苯基异羟肟酸
A.3-苯基丙醇(5g,36毫摩尔)为起始物,接下来的步骤如实施例3A描述的,得到7.7g纯的4-[(3-苯基丙氧基)氨基甲酰基]苯甲酸(产率71%);m.p.=171-173℃。
1H-NMR d 12.6(s,1H,与D2O交换),10.1(s,1H),7.90(d,2H),7.61(d,2H),7.28(m,5H),4.13(t,2H),2.72(t,2H),1.98(m,2H)。
B.在步骤A中所得的化合物(7g,23毫摩尔)为起始物,接下来的步骤如实施例3B描述的,得到5.8g的标题化合物(产率80%);m.p.=179-181℃。
1H-NMR d 11.09(s,1H),9.94(s,1H),8.95(s,1H),7.71(m,2H),7.54(m,2H),7.36/7.15(m,5H),4.10(t,2H),2.70(m,2H),1.95(m,2H)。
实施例7
4-[(萘-2-基)甲氧基氨基甲酰基]苯基异羟肟酸
A.萘-2-基-甲醇(5g,31毫摩尔)为起始物,接下来的步骤如实施例3A描述的,得到6.6g纯的4-[(萘-2-基)甲氧基氨基甲酰基]苯甲酸(产率68%);m.p.=241-243℃。
1H-NMR d 12.7(s,1H,与D2O交换),10.2(s,1H),7.95(m,6H),7.60(m,5H),5.39(s,2H)。
B.在步骤A中所得的化合物(6g,18.6毫摩尔)为起始物,接下来的步骤如实施例3B描述的,得到4.5g的标题化合物(产率72%);m.p.=220-222℃。
1H-NMR d 11.10(s,1H),11.01(s,1H),8.95(s,1H),7.99/7.90(m,4H),7.73(m,2H),7.61/7.50(m,5H),5.36(s,2H)。
实施例8
(E)-4-[(3-苯基-丙-2-烯基)氨基甲酰基]苯基异羟肟酸
A.将1.75g(13毫摩尔)的反式-肉桂醇在氩气保护下溶解在130ml乙腈中,然后加入5g(19毫摩尔)N,N'-二琥珀酰亚胺基-羧酸并加热至完全溶解,然后将混合物冷却至20℃并加入吡啶(0.65ml,1g,12毫摩尔)。反应混合物用铝覆盖并且在室温下搅拌30小时。低温下蒸发溶剂,残余物用乙酸乙酯处理并反复用0.1N HCl洗,最后用水洗。干燥溶液,然后低温蒸干,粗品溶解在26ml二噁烷中,再加入到对-氨基苯甲酸(1.79g,13毫摩尔)的碳酸钠1.38g(13毫摩尔)水溶液26ml中。然后在室温下搅拌60小时,再加入THF和盐水。分离有机相,用0.1N HCl洗(二次)再用盐水洗,然后干燥并蒸去溶剂。所得的粗品用异丙基醚处理并过滤,得到0.7g的(E)-4-[(3-苯基-丙-2-烯基)-氨基甲酰基]苯甲酸(产率18%);m.p.=176-178℃。
1H-NMR d 12.70(s,1H,与D2O交换),10.20(s,1H),7.93(d,2H),7.61(d,2H),7.55/7.25(m,5H),6.78(d,1H),6.46(dt,1H),4.87(d,2H)。
B.在步骤A中所得的化合物(0.7g,2.3毫摩尔)溶解在8ml无水THF中并且在0℃时加入CDI(0.46g,2.8毫摩尔)。混合物在室温下搅拌一夜,然后向其中加入盐酸羟胺(0.2g,2.3毫摩尔)并且在室温下连续搅拌60小时。过滤产生的沉淀并悬浮于1N HCl中,然后搅拌一夜。真空过滤干燥,得到400mg的标题化合物(产率55.6%);m.p.=194-195℃。
1H-NMR d 11.14(s,1H,与D2O交换),10.07(s,1H),8.97(s,1H,与D2O交换),7.75(d,2H),7.65/7.25(m,7H),6.79(d,1H),6.48(dt,1H),4.85(d,2H)。
实施例9
(Z)-4-[(3-苯基-丙-2-烯基)氨基甲酰基]苯基异羟肟酸
A.顺式-肉桂醇(2.82g,20毫摩尔)为起始物,接下来的步骤如实施例8A中描述的,得到2.4g的(Z)-4-[(3-苯基-丙-2-烯基)-氨基甲酰基]苯甲酸(产率40%)。
1H-NMR d 12.72(s,1H,与D2O交换),10.20(s,1H),7.92(d,2H),7.60(d,2H),7.55/7.25(m,5H),6.73(d,1H),5.91(dt,1H),4.96(d,2H)。
B.以步骤A中所得的化合物(0.7g,2.3毫摩尔)为起始物,接下来的步骤如实施例8B中描述的,得到400mg的标题化合物(产率55.6%);m.p.=169-170℃。
1H-NMR d 11.13(s,1H,与D2O交换),10.05(s,1H),8.98(s,1H,与D2O交换),7.74(d,2H),7.55(d,2H),7.50/7.25(m,5H),6.77(d,1H),5.90(dt,1H),4.94(d,2H)。
实施例10
4-[3,3-(二苯基)丙氧基氨基甲酰基]苯基异羟肟酸
A.3,3-二苯基丙醇(3g,14毫摩尔)为起始物,接下来的步骤如实施例3A中描述的,得到4.2g的4-[3,3(二苯基)丙氧基氨基甲酰基]苯甲酸(产率80%);m.p.=156-159℃。
1H-NMR d 12.6(s,1H,与D2O交换),10.1(s,1H),7.90(d,2H),7.60(d,2H),7.40/7.15(m,10H),4.17(t,1H),4.03(t,2H),2.46(m,2H)。
B.以步骤A中所得的化合物(4.0g,10毫摩尔)为起始物,接下来的步骤如实施例3B中描述的,得到1g的标题化合物(产率26%);m.p.=196-197℃。
1H-NMR d 11.08(s,1H),9.93(s,1H),8.93(s,1H),7.70(m,2H),7.54(m,2H),7.39/7.15(m,10H),4.15(t,1H),3.99(t,2H),2.44(q,2H)。
实施例11
N-[2-氨基乙基-4-乙(芴-9-基)甲氧基-氨基甲酰基甲基]苯胺·HCl
A.将9-芴基甲基氯甲酸酯(5g,19毫摩尔)的TNF(50ml)溶液缓慢地加入4-氨基甲基苯甲酸(2.9g,19毫摩尔)溶液中。反应混合物在室温下搅拌3小时,然后用1N HCl酸化,再在低温下蒸去TNF。水相用乙酸乙酯萃取,合并的有机相用无水硫酸钠干燥后将溶剂蒸除。得到的粗品用热乙醚处理过滤,得到7g的4-[(芴-9-基)甲氧基-氨基甲酰基甲基]苯甲酸(产率98%);m.p.=232-235℃。
1H-NMR d 12.7(s,1H,与D2O交换),7.94(s,5H),7.77(d,2H),7.58/7.30(m,6H),4.42(d,2H),4.30(m,3H)。
B.向步骤A中所得的化合物(3.7g,10毫摩尔)的氯仿(100ml)溶液中加入亚硫酰氯(1.46ml,20毫摩尔),再将反应混合物回流2小时,然后蒸干。残余物溶解在氯仿中并且再次蒸发反复三次。得到的4-[(芴-9-基)甲氧基-氨基甲酰基甲基]苯甲酰氯溶解在THF(30ml)中,再将溶液缓慢地加入2-(叔-丁氧基亚氨基)乙胺(1.6g,10毫摩尔)和碳酸氢钠(0.8g,10毫摩尔)的水(20ml)和THF(30ml)溶液中。反应混合物在室温下搅拌12小时,低温下蒸去THF,水相用1N HCl酸化并且用乙酸乙酯萃取。有机相用无水硫酸钠干燥后蒸去溶剂。所得的粗品用热乙醚处理并过滤得到3.85g的N-(2-叔-丁氧基氨基甲酰基甲基)-4-(芴-9-基)甲氧基氨基甲酰基甲基]苯甲酰胺(产率75%);m.p.=167-169℃。
1H-NMR d 8.45(t,1H),7.94/7.70(m,7H),7.54/7.25(m,6H),6.96(t,1H),4.42(d,2H),4.27(m,3H),3.32(q,2H),3.13(q,2H),1.41(s,9H)。
C.将步骤B的产物(3.6g,7毫摩尔)在0℃时分批加入三氟乙酸(25ml)中。混合物在室温下搅拌4小时,然后蒸去酸并将残余物用热乙醚处理过滤后得到的产物溶解在THF和甲醇中,向其中加入HCl醚溶液。蒸去溶剂并重复此步骤4次。粗品在0℃下用水处理并过滤得到2g的标题化合物(产率65%);m.p.=182-184℃。
1H-NMR d 8.79(t,1H),8.17(s,3H),7.96/7.86(m,5H),7.72(m,2H),7.48/7.29(m,6H),4.38(m,2H),4.25(m,3H),3.55(q,2H),3.00(t,2H)。
实施例12
4-[6-(二乙基氨基甲基)萘-2-基甲氧基氨基甲酰基]苯基异羟肟酸氢氯化物
A.将1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺氢氯化物(EDCI)(22.2g,115毫摩尔)加入2,6-萘基二羧酸(25g,115毫摩尔)和羟基苯并三唑(15.6g,1/5毫摩尔)的二甲基甲酰胺(1800ml)溶液中,并且在室温下搅拌2小时,加入二乙胺(34.3ml,345毫摩尔),溶液在室温下搅拌一夜。减压蒸馏除去溶剂后将粗品用1N HCl(500ml)和乙酸乙酯(500ml)处理,过滤未溶解的化合物分离有机相和水相。有机相用5%的碳酸钠(3×200ml)萃取同时将合并得到的水溶液用浓HCl酸化并用乙酸乙酯(3×200ml)萃取。然后有机溶液用1N HCl(6×100ml)洗,用无水硫酸钠干燥后减压蒸去溶剂,产物为纯的18.5g(产率60%)6-(二乙基氨基羰基)-2-萘基羧酸;m.p.=122-124℃。
1H-NMR d 8.67(s,1H),8.25-8.00(m,4H),7.56(d,1H),3.60-3.20(m,4H),1.30-1.00(m,6H)。
B.将6-(二乙基氨基羰基)-2-萘羧酸(18g,66毫摩尔)的THF(200ml)溶液缓慢地加入在THF(500ml)中回流的氢化铝锂悬浮液(7.5g,199毫摩尔)。混合物回流1小时,然后冷却至室温并用水(3.5ml)和THF(25ml)的混合物,20%的氢氧化钠(8.5ml),最后用水(33ml)处理。过滤出白色固体并减压除去溶剂。粗品溶解在乙醚(200ml)中并且用1N HCl(3×100ml)萃取。水溶液用32%的氢氧化钠处理并用乙醚(3×100ml)萃取。有机溶液用无水硫酸钠干燥并减压除去溶剂,产物12.7g(产率79%),为纯的粘稠的油状物6-(二乙基氨基甲基)-2-萘基甲醇。
1H-NMR d 7.90-7.74(m,4H),7.49(m,2H),5.32(t,1H,与D2O交换),4.68(d,2H),3.69(s,2H),2.52(q,4H),1.01(t,6H)。
C.6-(二乙基氨基甲基)-2-萘基甲醇(12.5g,51毫摩尔)和N,N'-二琥珀酰亚胺碳酸酯-(13.2g,51毫摩尔)的乙腈(250ml)溶液在室温下搅拌3小时,然后除去溶剂并将粗品溶解在THF(110ml)中。将此溶液加入4-氨基苯甲酸(7.1g,51毫摩尔)和碳酸钠(5.5g,51毫摩尔)的水(200ml)和THF(100ml)溶液中。混合物在室温下搅拌一夜,然后减压蒸去THF并将溶液用1NHCl(102ml,102毫摩尔)处理。过滤沉淀,减压干燥,用乙醚处理三次过滤得产物为13.2g(产率64%)纯的4-[6-(二乙基氨基甲基)萘-2-基甲氧基氨基甲酰基]-苯甲酸;m.p.=201-205℃(分解)。
1H-NMR d 10.26(s,1H),8.13(s,1H),8.05-7.75(m,6H),7.63(m,3H),5.40(s,2H),4.32(s,2H),2.98(q,4H),1.24(t,6H)。
D.将4-[6-(二乙基氨基甲基)萘-2-基甲氧基氨基甲酰基]苯甲酸(13.1g,32毫摩尔)和亚硫酰氯(7ml,96毫摩尔)的氯仿(100ml)溶液回流4小时,然后蒸出溶剂和亚硫酰氯。将粗品溶解在氯仿(100ml)中,蒸干反复三次。粗品作为固体加入盐酸羟胺(2.7g,39毫摩尔)和碳酸氢钠(5.4g,64mmol)和1N氢氧化钠(39ml,39mmol)的水(150ml)和THF(50ml)溶液中。混合物在室温下搅拌一夜,然后减压蒸去THF,将水相用乙酸乙酯(3×100ml)萃取。得到的有机相用无水硫酸钠干燥后减压蒸去溶剂。粗品溶解在THF中并用1.5N HCl的醚溶液处理。过滤和干燥固体产物,得到6g纯的白色固体4-[6-(二乙基氨基甲基)萘-2-基甲氧基氨基甲酰基]-苯基异羟肟酸氢氯化物;m.p.=162-165℃(分解)。
1H-NMR d 11.24(s,1H,与D2O交换),10.88(s,1H,与D2O交换),10.16(s,1H),8.98(bs,1H,与D2O交换),8.21(s,1H),8.10-7.97(m,3H),7.89(d,1H),7.80-7.55(m,5H),5.39(s,2H),4.48(d,2H),3.09(m,4H),1.30(t,6H)。
实施例13
4-[6-(二丙基氨基甲基)萘-2-基甲氧基氨基甲酰基]苯基异羟肟酸氢氯化物
以2,6-萘二羧酸(5g)和二丙胺(9.6ml)开始反应,接下来的步骤与实施例12相同,得到1g纯的4-[6-(二丙基氨基甲基)萘-2-基甲氧基氨基甲酰基]苯基异羟肟酸氢氯化物的白色固体;m.p.=140-142℃(分解)。
1H-NMR d 11.15(s,1H,与D2O交换),10.g5(s,1H,与D2O交换),10.16(s,1H),8.20(s,1H),8.10-7.97(m,3H),7.89(d,1H),7.80-7.55(m,5H),5.40(s,2H),4.50(d,2H),2.98(m,4H),1.79(m,4H),0.88(t,6H)。
实施例14
4-[6-(二丁基氨基甲基)萘-2-基甲氧基氨基甲酰基]苯基异羟肟酸氢氯化物
以2,6-萘二羧酸(5g)和二丁基胺(11.8ml)开始反应,接下来的步骤与实施例12所述相同,得到1.2g纯的4-[6-(二丁基氨基甲基)萘-2-基甲氧基氨基甲酰基]苯基异羟肟酸氢氯化物的白色固体;m.p.=137-141℃(分解)。
1H-NMR d 11.19(s,1H,与D2O交换),10.91(s,1H,与D2O交换),10.16(s,1H),8.96(bs,1H,与D2O交换),8.21(s,1H),8.10-7.98(m,3H),7.87(d,1H),7.80-7.55(m,5H),5.38(s,2H),4.52(d,2H),3.02(m,4H),1.77(m,4H),1.30(m,4H),1.77(m,4H),1.30(m,4H),0.89(t,6H)。
实施例15
4-[4-(二乙基氨基甲基)萘-1-基甲氧基氨基甲酰基]苯基异羟肟酸氢氯化物
以1,4-萘二羧酸(5g)和二乙胺(7.3ml)开始反应,接下来的步骤与实施例12所述相同,得到1.1g纯的4-[4-(二乙基氨基甲基)萘-1-基甲氧基氨基甲酰基]苯基异羟肟酸氢氯化物的白色固体;m.p.=162-165℃(分解)。
1H-NMR d 11.24(s,1H,与D2O交换),10.48(s,1H,与D2O交换),10.13(s,1H),8.43(m,1H),8.26(m,1H),8.04(d,1H),7.82-7.70(m,5H),7.58(d,2H),5.73(s,2H),4.84(d,2H),3.17(m,4H),1.32(t,6H)。
实施例16
4-[6-(二乙基氨基甲基)萘-2-基甲氧基氨基甲酰基]苯基异羟肟酸氢氯化物
A.6-(二乙基氨基羰基)-2-萘羧酸(按照实施例12A制备)(14g,52毫摩尔)和亚硫酰氯(3.8ml,52毫摩尔)的氯仿溶液(200ml)回流3小时,然后蒸去溶剂和亚硫酰氯。粗品溶解在氯仿(100ml)中并蒸干反复三次。粗品溶解在THF(50ml)中,在0℃时加入32%的氢氧化铵(10ml)的水(50ml)和THF(50ml)溶液中。混合物在室温下搅拌一夜。然后减压蒸出THF并过滤固体干燥得到11.6g(产率81%)的6-(二乙基氨基羰基)-2-萘酰胺。其没有进一步纯化将用于下一步。
B.将6-(二乙基氨基羰基)-2-萘羧酰胺(11.6g,42毫摩尔)的THF(100ml)溶液缓慢地加入在THF(100ml)中回流氢化铝锂的悬浮液(4.9g,128毫摩尔)中。混合物回流2小时,然后冷却至室温并用THF(16ml)和用水(2.2ml)的混合物,20%的氢氧化钠(5.5ml)和用水(22ml)处理。过滤出白色固体并减压除去溶剂。粗品用硅胶色谱柱纯化(洗脱剂氯仿-甲醇-氢氧化铵15∶1∶0.1)得到8.1g(产率80%)纯的6-(二乙基氨基甲基)-2-萘甲基胺的蜡状固体。
1H-NMR d 7.78(m,4H),7.49(m,2H),3.89(s,2H),3.67(s,2H),2.50(q,4H),1.00(t,6H)。
C.6-(二乙基氨基甲基)-2-萘-甲基胺(6g,24毫摩尔)和N,N'-二琥珀酰亚胺碳酸酯(6.3g,24毫摩尔)的乙腈(200ml)溶液在室温下搅拌3小时,然后向溶液中加入4-氨基苯甲酸(3.4g,24毫摩尔)和碳酸钠(2.6g,24毫摩尔)的水(100ml)和THF(100ml)的溶液。混合物在室温下搅拌48小时,然后加入1N HCl(48ml,48毫摩尔)再减压蒸去溶剂。粗品用硅胶色谱柱纯化(洗脱剂氯仿-甲醇-氢氧化铵7∶3∶0.5)得到3.5g(产率36%)纯的4-[6-(二乙基氨基甲基)萘-2-基甲基氨基氨基甲酰基]苯甲酸;m.p.=179-183℃(分解)。
1H-NMR d 9.58(s,1H),7.95-7.78(m,6H),7.65-7.45(m,4H),7.29(t,1H),4.51(d,2H),3.81(s,2H),2.62(q,4H),1.07(t,6H)。
D.4-[6-(二乙基氨基甲基)萘-2-基-甲基氨基氨基甲酰基]苯甲酸(3.1g,7.6毫摩尔)和亚硫酰氯(1.1ml,15.2毫摩尔)在二甲基甲酰胺(30ml)的溶液在室温下搅拌一夜,然后用乙醚稀释悬浮液并且过滤和干燥固体,得到3.2g4-[6-(二乙基氨基甲基)萘-2-基甲基氨基甲酰基]苯甲酰氯粗品。将此固体化合物加入盐酸羟胺(0.6g,8.5毫摩尔)和碳酸氢钠(1.2g,14毫摩尔)和1N氢氧化钠(8.5ml,8.5毫摩尔)的水(30ml)和THF(40ml)溶液中。混合物在室温下搅拌2小时,然后将混合物用氯化钠饱和并分离有机相,水相用THF萃取。合并的有机相用无水硫酸钠干燥后减压蒸去溶剂。粗品溶于热的THF(150ml)中且过滤不溶的物质。溶液冷却至室温并用1.5N HCl的醚溶液处理。过滤和干燥固体产物,得到纯的4-[6-(二乙基氨基甲基)萘-2-基甲基氨基氨基甲酰基]-苯基异羟肟酸氢氯化物白色固体1.2g(产率38%);m.p.=167-168℃(分解)。
1H-NMR d 11.07(s,1H,与D2O交换),10.49(bs,1H,与D2O交换),9.49(s,1H),8.93(s,1H,与D2O交换),8.15(s,1H),8.05-7.87(m,3H),7.81(d,1H),7.72(d,2H),7.65-7.50(m,3H),7.27(t,1H),4.54(d,2H),4.48(s,2H),3.11(m,4H),1.30(t,6H)。
实施例17
4-[N-异丙基-1,2,3,4-四氢(异喹啉-3-基)甲氧基氨基甲酰基甲基]苯基异羟肟酸氢氯化物
A.1,2,3,4-四氢-3-异喹啉羧酸(9g,42毫摩尔),2-溴戊烷(8ml,84毫摩尔)和1N NaOH(168毫摩尔)的乙醇(170ml)溶液回流5小时,然后加入2-溴戊烷(8ml,84毫摩尔)和1N NaOH(168ml,168毫摩尔)且将混合物回流5小时。除去乙醇并将水溶液用6N盐酸处理至pH=7。过滤回收未反应的起始原料再减压蒸去溶剂。粗品溶解在乙醇中,滤去无机盐类再减压蒸出有机溶液,此步骤重复三次产出8.1g(产率87%)纯的N-(异丙基-1,2,3,4-四氢-3-异喹啉羧酸,其未进一步纯化而用于下一步。
1H-NMRδ7.13(m,4H),4.16(d,1H),3.89(d,1H),3.58(t,1H),3.43(m,1H),3.13(dd,1H),2.94(dd,1H),1.19(d,,3H),1.11(d,3H)。
B.将N-(异丙基-1,2,3,4-四氢-3-异喹啉羧酸(8.0g,36毫摩尔)的四氢呋喃(100ml)悬浮液缓慢地加入氢化铝锂(2.1g,54毫摩尔)在四氢呋喃(100ml)中的回流悬浮液中。混合物回流2小时,然后冷却至室温并用四氢呋喃(7ml)和水(0.9ml),20%氢氧化钠(2.3ml)最后用水(9.2ml)处理。过滤去白色固体并减压除去溶剂产出5.0g(产率68%)的纯的粘稠油状物N-异丙基-1,2,3,4-四氢异喹啉-3-基甲醇。
1H-NMRδ7.12(m,4H),4.54(bs,1H,与D2O交换),3.68(S,2H),3.55-3.35(m,2H),3.20-2.90(m,2H),2.79(d,2H),1.10(d,3H),1.01(d,3H)。
C.将N-异丙基-1,2,3,4-四氢异喹啉-3-基甲醇(4.6g,22.4毫摩尔)和1,1'-羰基二咪唑(3.63g,22.4毫摩尔)的四氢呋喃(50ml)溶液室温下搅拌3小时。然后将此溶液加入4-氨基甲基苯甲酸(3.38g,22.4毫摩尔)和1N氢氧化钠(22.4ml,22.4毫摩尔)的水(20ml)的溶液中。溶液在室温下搅拌一夜,然后加入1N HCl(22.4ml,22.4毫摩尔)并将溶剂减压除去。粗产品用硅胶色谱柱纯化(洗脱剂氯仿-甲醇-氢氧化铵8∶2∶0.5)得到3.1g(产率35%)的纯的4-[(N-异丙基-1,2,3,4-四氢-异喹啉-3-基)-甲氧基氨基甲酰基]苯甲酸白色固体;m.p.=93-95℃(分解)。
1H-NMRδ7.92(d,2H),7.86(t,1H),7.36(t,2H),7.14(m,4H),4.26(d,2H),4.07(dd,1H),3.73(s,2H),3.68(dd,1H),3.25(m,1H),3.02(m,1H),2.89(dd,1H),2.72(dd,1H),1.10(d,3H),1.04(d,3H)。
D.4-[(N-异丙基-1,2,3,4-四氢-异喹啉-3-基)甲氧基氨基甲酰基]苯甲酸(3.0g,7.8毫摩尔)和亚硫酰氯(1.7ml,23毫摩尔)的氯仿(100ml)溶液回流3小时,然后蒸出溶剂和亚硫酰氯。粗品溶解在氯仿(100ml)中并蒸干反复三次。将粗品溶于四氢呋喃(50ml)中且加入盐酸羟胺(0.65g,9.4毫摩尔)和碳酸氢钠(1.3g,15.7毫摩尔)和1N氢氧化钠(9.4ml,9.4毫摩尔)的水(30ml)和四氢呋喃(20ml)溶液中。混合物在室温下搅拌1小时,然后减压除去四氢呋喃并水相用乙酸乙酯萃取(3×100ml)。合并的有机相用无水硫酸钠干燥后减压蒸去溶剂。粗品溶解在四氢呋喃中并用1.5N HCl的醚溶液处理。过滤固体产物并干燥产出2.1g(产率62%)的纯的4-[(N-异丙基-1,2,3,4-四氢异喹啉-3-基)甲氧基氨基甲酰基]苯基异羟肟酸氢氯化物的白色固体;m.p.=154-157℃(分解)。
1H-NMRδ11.24(s,1H),10.75(s,1H),9.07(bs,1H),8.01(t,1H),7.70(d,2H),7.34(d,2H),7.32(m,4H),4.38(d,2H),4.26(m,4H),4.02(m,1H),3.78(m,1H),3.15(d,2H),1.42(d,3H),1.30(d,3H)。
下面的化合物可由上面报道的相似方法制备:-4-[(4-二甲基氨基甲基-萘-2-基)甲氧基氨基甲酰基]苯基异羟肟酸-4-[(4-二乙基氨基乙基-萘-2-基)甲氧基氨基甲酰基]苯基异羟肟酸-4-[(4-二甲基氨基乙基-萘-2-基)甲氧基氨基甲酰基]苯基异羟肟酸-4-[(6-二甲基氨基甲基-萘-2-基)甲氧基氨基甲酰基]苯基异羟肟酸-4-[(6-二-异-丙基氨基甲基-萘-2-基)甲氧基氨基甲酰基]苯基异羟肟酸-4-[(4-二甲基氨基甲基-萘-2-基)甲氧基氨基甲酰基]甲基苯基异羟肟酸-4-[(4-二甲基氨基甲基-萘-2-基)乙氧基氨基甲酰基]苯基异羟肟酸-4-[(5,6,7,8-四氢化萘-2-基)甲氧基氨基甲酰基]苯基异羟肟酸-4-[N-(1,2,3,4-四氢化萘-2-基)甘氨酰胺基]苯基异羟肟酸-4-[(4-二乙基氨甲基-萘-2-基)乙氧基氨基甲酰基]苯基异羟肟酸-4-[(6-二甲基氨甲基-萘-2-基)乙氧基氨基甲酰基]苯基异羟肟酸-4-[(6-二乙基氨甲基-萘-2-基)乙氧基氨基甲酰基]苯基异羟肟酸-4-[(1,2,3,4-四氢化萘-2-基)甲氧基氨基甲酰基]苯基异羟肟酸-4-[(4-二甲基氨基甲基-萘-1-基)甲氧基氨基甲酰基]苯基异羟肟酸-4-[(4-二甲基氨基乙基-萘-1-基)甲氧基氨基甲酰基]苯基异羟肟酸-4-[(5-二甲基氨基甲基-萘-1-基)甲氧基氨基甲酰基]苯基异羟肟酸-4-[(5-二乙基氨基甲基-萘-1-基)甲氧基氨基甲酰基]苯基异羟肟酸-4-[(5-二-正-丙基氨基甲基-萘-1-基)甲氧基氨基甲酰基]苯基异羟肟酸-4-[(5-二-异-丙基氨基甲基-萘-1-基)甲氧基氨基甲酰基]苯基异羟肟酸-4-[(5-二-正-丁基氨基甲基-萘-1-基)甲氧基氨基甲酰基]苯基异羟肟酸-4-[(6-二甲基氨基甲基-萘-1-基)甲氧基氨基甲酰基]苯基异羟肟酸-4-[(6-二乙基氨基甲基-萘-1-基)甲氧基氨基甲酰基]苯基异羟肟酸-4-[(6-二-正-丙基氨基甲基-萘-1-基)甲氧基氨基甲酰基]苯基异羟肟酸-4-[(6-二-异-丙基氨基甲基-萘-1-基)甲氧基氨基甲酰基]苯基异羟肟酸-4-[(6-二-正-丁基氨基甲基-萘-1-基)甲氧基氨基甲酰基]苯基异羟肟酸-4-[(4-二甲基氨基甲基-萘-1-基)甲氧基氨基甲酰基]甲基苯基异羟肟酸-4-[(4-二甲基氨基甲基-萘1-基)乙氧基氨基甲酰基]苯基异羟肟酸-4-[(4-二乙基氨基甲基-萘-1-基)乙氧基氨基甲酰基]苯基异羟肟酸-4-[(5-二甲基氨基甲基-萘-1-基)乙氧基氨基甲酰基]苯基异羟肟酸-4-[(5-二乙基氨基甲基-萘-1-基)乙氧基氨基甲酰基]苯基异羟肟酸-4-[(6-二甲基氨基甲基-萘-1-基)乙氧基氨基甲酰基]苯基异羟肟酸-4-[(6-二乙基氨基甲基-萘-1-基)乙氧基氨基甲酰基]苯基异羟肟酸-4-[N-(萘-1-基-甲基)甘氨酰胺基]苯基异羟肟酸-4-[N-(萘-2-基-甲基)甘氨酰胺基]苯基异羟肟酸-4-[N-甲基-1,2,3,4-四氢异喹啉-5-基)甲氧基氨基甲酰基]苯基异羟肟酸-4-[N-乙基-1,2,3,4-四氢异喹啉-5-基)甲氧基氨基甲酰基]苯基异羟肟酸-4-[(异喹啉-5-基)甲氧基氨基甲酰基]苯基异羟肟酸-4-[N-甲基-1,2,3,4-四氢异喹啉-6-基)甲氧基氨基甲酰基]苯基异羟肟酸-4-[N-乙基-1,2,3,4-四氢异喹啉-6-基)甲氧基氨基甲酰基]苯基异羟肟酸-4-[(异喹啉-6-基)甲氧基氨基甲酰基]苯基异羟肟酸-4-[N-甲基-1,2,3,4-四氢异喹啉-1-基)甲氧基氨基甲酰基]苯基异羟肟酸-4-[N-乙基-1,2,3,4-四氢异喹啉-1-基)甲氧基氨基甲酰基]苯基异羟肟酸-4-[(异喹啉-1-基)甲氧基氨基甲酰基]苯基异羟肟酸-4-[N-甲基-1,2,3,4-四氢异喹啉-3-基)甲氧基氨基甲酰基]苯基异羟肟酸-4-[N-乙基-1,2,3,4-四氢异喹啉-3-基)甲氧基氨基甲酰基]苯基异羟肟酸-4-[(异喹啉-3-基)甲氧基氨基甲酰基]苯基异羟肟酸-4-[(N-甲基-1,2,3,4-四氢异喹啉-3-基)甲氧基氨基甲酰基]苯基异羟肟酸-4-[(N-乙基-1,2,3,4-四氢异喹啉-3-基)甲氧基氨基甲酰基]苯基异羟肟酸-4-[(异喹啉-4-基)甲氧基氨基甲酰基]苯基异羟肟酸-4-[3-(1,2,3,4-四氢异喹啉-2-基)丙酰氨基]苯基异羟肟酸-4-[(苯并噻吩-4-基)甲氧基氨基甲酰基]苯基异羟肟酸-4-[(苯并噻吩-5-基)甲氧基氨基甲酰基]苯基异羟肟酸-4-[(苯并呋喃-4-基)甲氧基氨基甲酰基]苯基异羟肟酸-4-[(苯并呋喃-5-基)甲氧基氨基甲酰基]苯基异羟肟酸-4-[4-(二乙基氨基丙基)萘-1-基甲氧基氨基甲酰基]苯基异羟肟酸氢氯化物-4-[3-(二乙基氨基甲基)萘-1-基甲氧基氨基甲酰基]苯基异羟肟酸氢氯化物-4-[3-(二乙基氨基乙基)萘-1-基甲氧基氨基甲酰基]苯基异羟肟酸氢氯化物-4-[3-(二乙基氨基丙基)萘-1-基甲氧基氨基甲酰基]苯基异羟肟酸氢氯化物-4-[4-(二乙基氨基丙基)萘-1-基甲基氨基氨基甲酰基]苯基异羟肟酸氢氯化物-4-[3-(二乙基氨基甲基)萘-1-基甲基氨基氨基甲酰基]苯基异羟肟酸氢氯化物-4-[3-(二乙基氨基乙基)萘-1-基甲基氨基氨基甲酰基]苯基异羟肟酸氢氯化物-4-[3-(二乙基氨基丙基)萘-1-基甲基氨基氨基甲酰基]苯基异羟肟酸氢氯化物-4-[6-(二丙基氨基甲基)萘-2-基甲基氨基氨基甲酰基]苯基异羟肟酸氢氯化物-4-[6-(二丁基氨基甲基)萘-2-基甲基氨基氨基甲酰基]苯基异羟肟酸氢氯化物-4-[4-(二乙基氨基甲基)萘-1-基甲基氨基氨基甲酰基]苯基异羟肟酸氢氯化物-4-[4-(二丙基氨基甲基)萘-1-基甲基氨基氨基甲酰基]苯基异羟肟酸氢氯化物-4-[4-(二乙基氨基乙基)萘-1-基甲基氨基氨基甲酰基]苯基异羟肟酸氢氯化物
药理学活性
在体内和体外测试了本发明化合物的消炎及免疫抑制性能。
1.体外细胞因子的产生试验
将本发明的化合物在特定的人IL-1β的产生中进行测试,单核细胞(PBMC)从健康的捐赠者的外周血液(血块黄层)经过密度梯度离心Ficoll-Hypaque(Biochrom KG,柏林,德国)得到。细胞(2.5×106/毫升)在37℃含5%二氧化碳的湿空气最终体积为200微升的96孔板中培养。培养介质为含低内毒素的RPMI 1640 N-乙酰基-L-丙氨酰-L-谷氨酰胺(低内毒素,Biochrom KG)并加入1%的牛胚胎血清(Hyclone实验公司,Logan,犹他州),100UI/毫升的青霉素及100微克/毫升的链霉素。通过用10ng/毫升的LPS(脂多糖)(得自大肠杆菌血清型055:B5(Sigma化学品公司,圣路易斯,密苏里州))刺激细胞的方法引起细胞因子产生。细胞用溶于二甲基亚砜的本发明化合物(最终浓度0.05%)预处理60分钟。在20小时的培养中存在化合物和脂多糖。并使用未被刺激的细胞进行阴性对照。在测试的最后,收集上层液并用特定的酶联免疫吸附测定法(三明治型的抗原捕集,R & D System,Minneapolis,MN。所有实验均一式二份,测定IL-1β的产生。用对人IL-1β特异的,亲合纯化的山羊多克隆血清覆盖96孔的微量滴定板(Nunc)。洗涤后,孔在含3%的牛血清白蛋白(BSA)的缓冲盐水中恒温2小时。每次测试的标准曲线由重组的人IL-1β得到,上层样品用PBS+0.1% BSA稀释到1/20及1/80。然后该板在4℃下恒温一夜。经过洗涤,加入第二种抗体-即抗人IL-1β的鼠的单克隆抗体。恒温、洗涤后,加入山羊的抗鼠Ig-G多克隆抗体缀合的过氧化物酶(Zymed)及显色剂二氯-N-四甲基联苯胺。反应被4N的硫酸终止,用自动的分光光度计(Perkin-Elmer)测量450纳米处的吸收。本发明化合物的抑制活性用IC50(即与对照培养物相比抑制50%IL-1β产生的产品浓度)来表示。
表1
化合物 IC50(nM)
样品1 305
样品2 163
样品3 531
样品4 28
样品5 137
样品6 43
样品7 12
样品8 29
样品9 72
样品10 101
样品11 96
样品12 166
样品13 382
样品14 14
样品15 10
样品16 21
样品17 575
2.体内LPS-诱导的TNFα的产生
雄性的BALB/c鼠(18-20克)从Harlan-Nossan(Correzzana,意大利)得到。来自肠炎链球菌(S.enteritidis)(编码L-6011)的脂多糖(LPS)从Sigma公司(圣路易斯,密苏里州)得到。地塞米松(Soldesam)来源于Laboratorio Farmacologico Milanese(Caronno P.,意大利)。
老鼠用脂多糖(S.enteritidis,7.5毫克/千克)进行处理。在腹膜内给药LPS30分钟以前,使用地塞米松,LPS给药90分钟前口服给予化合物。LPS给药两小时后,处死已麻醉的动物,对其心脏穿刺收集血液并使之凝固。根据制造商的指导,血清TNF由ELISA用“小鼠试剂盒”(Genzyme,Cambridge,MA)测量。用小鼠重组TNFα作为标准。
表2实施例12化合物对LPS诱导的血清TNFα的产生的影响
处理 TNF(pg/ml) 抑制率(%)
盐水(对照) <0.1LPS
LPS 1140
化合物12(0.5毫克/千克) 514 55.0
化合物12(5.0毫克/千克) 407 64.3
地塞米松(30毫克/千克) 112 90.2
结果表明被测试的化合物对抑制IL-1β和TNFα的产生都是有效的。达到或超过了地塞米松(一种对照化合物,非常著名的消炎剂)的活性。
此外,本发明涉及分子式(1)的化合物作为消炎和免疫抑制剂的用途以及所有与其相关的工业应用,包括药物组合物。这种药物组合物可以是片剂、糖衣药丸、乳膏、软膏及针剂,后者适合于口服,肌肉注射或静脉注射。它们可以只包括活性组分也可以与传统的药学中可接受的载体和赋形剂相混合。
根据治疗的需要,取决于不同类型的化合物,每日一次或多次给药,活性组分的剂量可以在比较宽的范围内变化。
Claims (6)
其中R'为氢或(C1-4)烷基;
A为金刚烷基或单-,双-或三-环残基,其可选择性地部分或全部为不饱和的,其可以含有一个或多个选自N,S或O的杂原子,并且可选择地被羟基,烷酰氧基,伯,仲或叔氨基,氨基(C1-4)烷基,单-或双(C1-4)烷基-氨基(C1-4)烷基,卤素,(C1-4)烷基,三(C1-4)烷基铵(C1-4)烷基取代;
为1到5个碳原子的链,其可选择地含有双键或NR'基团,其中R'如上所定义;
R为氢或苯基;
X为氧原子或NR′基团,其中R′如上所定义或不存在;
r和m独立地为0,1,或2;
B为亚苯基或亚环己基环;
Y为羟基或氨基(C1-4)烷基链,可选择地被氧原子间隔;
其条件为:仅当X不为O且同时Y不为羟基时作为A所定义的三环基团是芴基,除非所说的芴基是被三(C1-4)烷基铵(C1-4)烷基基团取代的。
3.权利要求1的化合物,其中R′为氢;
A可选择地为被取代的苯基或1-,2-萘基;
当A为苯基时,R为苯基,或当A为1-或2-萘基时R为氢;
R,B,m,r如权利要求1所定义的;Y为羟基且C1-5烷基链如权利要求2所定义。
4.权利要求1中的化合物用于制备适于作为消炎剂的药物的用途。
5.权利要求1中的化合物用于制备适于作为免疫抑制剂的药物的用途。
6.药物组合物,其中包含至少一种权利要求1中的化合物作为活性组分及药学上可接受的赋形剂。
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CN102665712A (zh) * | 2010-01-28 | 2012-09-12 | 凯米股份公司 | (4-羟基氨基甲酰基-苯基)-氨基甲酸(6-二甲基氨基甲基-2-萘基)酯的盐酸盐的新多晶型物 |
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ITMI20011733A1 (it) * | 2001-08-07 | 2003-02-07 | Italfarmaco Spa | Derivati dell'acido idrossamico inibitori degli enzimi istone deacetilasi, quali nuovi farmaci antiinfiammatori inibenti la sintesi di citoc |
PE20030701A1 (es) * | 2001-12-20 | 2003-08-21 | Schering Corp | Compuestos para el tratamiento de trastornos inflamatorios |
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ITMI20030064A1 (it) * | 2003-01-17 | 2004-07-18 | Italfarmaco Spa | Uso dei derivati dell'acido idrossamico per la preparazione |
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US7291744B2 (en) | 2003-11-13 | 2007-11-06 | Bristol-Myers Squibb Company | N-ureidoalkyl-amino compounds as modulators of chemokine receptor activity |
AU2004296764B2 (en) * | 2003-12-02 | 2011-04-28 | The Ohio State University Research Foundation | Zn2+ -chelating motif-tethered short -chain fatty acids as a novel class of histone deacetylase inhibitors |
EP1768662A2 (en) | 2004-06-24 | 2007-04-04 | Novartis Vaccines and Diagnostics, Inc. | Small molecule immunopotentiators and assays for their detection |
ITMI20041347A1 (it) * | 2004-07-05 | 2004-10-05 | Italfarmaco Spa | Derivati di alfa-amminoacidi ad attivita'antiinfiammatoria |
US20100152188A1 (en) * | 2005-08-05 | 2010-06-17 | Akella Satya Surya Visweswara Srinivas | Novel Heterocyclic Compounds |
IT1392908B1 (it) | 2008-09-29 | 2012-04-02 | Italfarmaco Spa | Uso degli inibitori delle istone-deacetilasi per la cura di sindromi mieloproliferative philadelphia-negative |
CA2740559C (en) | 2008-10-15 | 2016-02-16 | Generics [Uk] Limited | Improved process |
NZ593585A (en) | 2008-11-26 | 2012-12-21 | Generics Uk Ltd | Crystalline forms of vorinostat (suberoylanilide hydroxamic acid) |
KR101168801B1 (ko) | 2009-03-27 | 2012-07-25 | 주식회사종근당 | 신규한 하이드록사메이트 유도체, 이의 제조방법, 및 이를 함유하는 약제학적 조성물 |
IT1396915B1 (it) | 2009-10-23 | 2012-12-20 | Italfarmaco Spa | Dietil-[6-(4-idrossicarbamoil-fenil-carbamoilossimetil)-naftalen-2-il-metil]-ammonio cloruro ed altri derivati della n-idrossi-benzammide per l'uso nel trattamento di infezioni da hiv. |
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- 1997-05-12 CZ CZ19983667A patent/CZ293233B6/cs not_active IP Right Cessation
- 1997-05-12 ES ES97923053T patent/ES2151267T3/es not_active Expired - Lifetime
- 1997-05-12 DK DK97923053T patent/DK0901465T3/da active
- 1997-05-12 AU AU28964/97A patent/AU713300B2/en not_active Expired
- 1997-05-12 HU HU9902818A patent/HUP9902818A3/hu unknown
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- 1997-05-12 PL PL97329873A patent/PL187527B1/pl unknown
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- 1997-05-12 HU HU9902818D patent/HU225650B1/hu unknown
- 1997-05-12 WO PCT/EP1997/002407 patent/WO1997043251A1/en active IP Right Grant
- 1997-05-12 PT PT97923053T patent/PT901465E/pt unknown
- 1997-05-12 JP JP54050597A patent/JP4108127B2/ja not_active Expired - Lifetime
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102665712A (zh) * | 2010-01-28 | 2012-09-12 | 凯米股份公司 | (4-羟基氨基甲酰基-苯基)-氨基甲酸(6-二甲基氨基甲基-2-萘基)酯的盐酸盐的新多晶型物 |
CN102665712B (zh) * | 2010-01-28 | 2013-10-16 | 凯米股份公司 | (4-羟基氨基甲酰基-苯基)-氨基甲酸(6-二甲基氨基甲基-2-萘基)酯的盐酸盐的新多晶型物 |
CN113614066A (zh) * | 2019-03-06 | 2021-11-05 | 意大发马克股份公司 | 制备高纯度[4-(羟基氨基甲酰基)苯基]氨基甲酸{6-[(二乙基氨基)甲基]萘-2-基}甲酯的方法 |
CN113614066B (zh) * | 2019-03-06 | 2023-08-29 | 意大发马克股份公司 | 制备高纯度[4-(羟基氨基甲酰基)苯基]氨基甲酸{6-[(二乙基氨基)甲基]萘-2-基}甲酯的方法 |
Also Published As
Publication number | Publication date |
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DK0901465T3 (da) | 2000-12-18 |
PL329873A1 (en) | 1999-04-12 |
ITMI960968A0 (zh) | 1996-05-14 |
BR9709234B1 (pt) | 2009-01-13 |
AU713300B2 (en) | 1999-11-25 |
DE69703207D1 (de) | 2000-11-02 |
CN1105100C (zh) | 2003-04-09 |
CA2254066A1 (en) | 1997-11-20 |
HUP9902818A3 (en) | 2001-10-29 |
ITMI960968A1 (it) | 1997-11-14 |
WO1997043251A1 (en) | 1997-11-20 |
SK157998A3 (en) | 1999-04-13 |
CZ366798A3 (cs) | 1999-06-16 |
GR3035128T3 (en) | 2001-04-30 |
IT1283637B1 (it) | 1998-04-23 |
PL187527B1 (pl) | 2004-07-30 |
CZ293233B6 (cs) | 2004-03-17 |
PT901465E (pt) | 2001-01-31 |
BR9709234A (pt) | 1999-08-10 |
EP0901465A1 (en) | 1999-03-17 |
DE69703207T2 (de) | 2001-02-01 |
BR9709234B8 (pt) | 2014-04-15 |
EP0901465B1 (en) | 2000-09-27 |
CA2254066C (en) | 2007-09-11 |
SK282174B6 (sk) | 2001-11-06 |
ES2151267T3 (es) | 2000-12-16 |
AU2896497A (en) | 1997-12-05 |
US6034096A (en) | 2000-03-07 |
JP2000510472A (ja) | 2000-08-15 |
RU2177473C2 (ru) | 2001-12-27 |
HU225650B1 (en) | 2007-05-29 |
JP4108127B2 (ja) | 2008-06-25 |
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