CN103607888A - 取代的甲基甲酰基试剂以及使用所述试剂改进化合物的物理化学性质和/或药代动力学性质的方法 - Google Patents
取代的甲基甲酰基试剂以及使用所述试剂改进化合物的物理化学性质和/或药代动力学性质的方法 Download PDFInfo
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- CN103607888A CN103607888A CN201280022913.2A CN201280022913A CN103607888A CN 103607888 A CN103607888 A CN 103607888A CN 201280022913 A CN201280022913 A CN 201280022913A CN 103607888 A CN103607888 A CN 103607888A
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- Prior art keywords
- methyl
- chloromethyl ester
- oxygen base
- acid chloromethyl
- ester
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 123
- 239000003153 chemical reaction reagent Substances 0.000 title claims abstract description 119
- 238000000034 method Methods 0.000 title claims description 68
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical group COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 title abstract 2
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 36
- 239000002585 base Substances 0.000 claims description 330
- -1 morpholino methyl carbonic acid Chemical compound 0.000 claims description 269
- 229910052760 oxygen Inorganic materials 0.000 claims description 214
- 239000001301 oxygen Substances 0.000 claims description 165
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 164
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 125
- 239000003814 drug Substances 0.000 claims description 104
- 239000000460 chlorine Substances 0.000 claims description 83
- 229910052801 chlorine Inorganic materials 0.000 claims description 83
- 239000000203 mixture Substances 0.000 claims description 73
- 229910052757 nitrogen Inorganic materials 0.000 claims description 59
- MLXKRQZNBPENEJ-UHFFFAOYSA-N chloromethyl hydrogen carbonate Chemical compound OC(=O)OCCl MLXKRQZNBPENEJ-UHFFFAOYSA-N 0.000 claims description 55
- 229910052717 sulfur Inorganic materials 0.000 claims description 50
- 125000004429 atom Chemical group 0.000 claims description 49
- 125000000217 alkyl group Chemical group 0.000 claims description 47
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 36
- 150000002148 esters Chemical class 0.000 claims description 35
- 125000003545 alkoxy group Chemical group 0.000 claims description 32
- 239000002253 acid Substances 0.000 claims description 28
- 125000003118 aryl group Chemical group 0.000 claims description 26
- 125000006202 diisopropylaminoethyl group Chemical group [H]C([H])([H])C([H])(N(C([H])([H])C([H])([H])*)C([H])(C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 claims description 23
- SMJYMSAPPGLBAR-UHFFFAOYSA-N chloromethyl acetate Chemical compound CC(=O)OCCl SMJYMSAPPGLBAR-UHFFFAOYSA-N 0.000 claims description 22
- 125000005605 benzo group Chemical group 0.000 claims description 21
- 125000001072 heteroaryl group Chemical group 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 19
- XZSTVWKWQAULJQ-UHFFFAOYSA-N CC(=O)Oc1ccccc1C([O])=O Chemical compound CC(=O)Oc1ccccc1C([O])=O XZSTVWKWQAULJQ-UHFFFAOYSA-N 0.000 claims description 17
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 17
- 238000001212 derivatisation Methods 0.000 claims description 17
- 229910052731 fluorine Inorganic materials 0.000 claims description 17
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 17
- 239000000126 substance Substances 0.000 claims description 17
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 16
- 125000000524 functional group Chemical group 0.000 claims description 16
- 229910052740 iodine Inorganic materials 0.000 claims description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- PSEJBIODJNSJNT-UHFFFAOYSA-N CCCCC([O])=O Chemical compound CCCCC([O])=O PSEJBIODJNSJNT-UHFFFAOYSA-N 0.000 claims description 15
- VXWDQYHMYFTTBQ-UHFFFAOYSA-N chloromethyl pyridine-3-carboxylate Chemical compound ClCOC(=O)C1=CC=CN=C1 VXWDQYHMYFTTBQ-UHFFFAOYSA-N 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 230000003285 pharmacodynamic effect Effects 0.000 claims description 14
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 claims description 13
- 229960001138 acetylsalicylic acid Drugs 0.000 claims description 12
- 125000002837 carbocyclic group Chemical group 0.000 claims description 12
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 claims description 12
- 229940079593 drug Drugs 0.000 claims description 12
- 125000005842 heteroatom Chemical group 0.000 claims description 12
- CXHHBNMLPJOKQD-UHFFFAOYSA-N methyl hydrogen carbonate Chemical compound COC(O)=O CXHHBNMLPJOKQD-UHFFFAOYSA-N 0.000 claims description 12
- RTFGZMKXMSDULM-UHFFFAOYSA-N chloromethyl ethyl carbonate Chemical compound CCOC(=O)OCCl RTFGZMKXMSDULM-UHFFFAOYSA-N 0.000 claims description 11
- HOBCFUWDNJPFHB-UHFFFAOYSA-N indolizine Chemical compound C1=CC=CN2C=CC=C21 HOBCFUWDNJPFHB-UHFFFAOYSA-N 0.000 claims description 11
- 239000011630 iodine Substances 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 11
- 239000012266 salt solution Substances 0.000 claims description 11
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 11
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 claims description 10
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 10
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 10
- CGLRXKACBSXHIU-UHFFFAOYSA-N chloromethyl carbamate Chemical compound NC(=O)OCCl CGLRXKACBSXHIU-UHFFFAOYSA-N 0.000 claims description 9
- 235000001968 nicotinic acid Nutrition 0.000 claims description 9
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 9
- AGEBJYJJWHBPJT-UHFFFAOYSA-N $l^{1}-oxidanylsulfonylmethane Chemical compound CS([O])(=O)=O AGEBJYJJWHBPJT-UHFFFAOYSA-N 0.000 claims description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 8
- DJMVSBAOTMOYLX-UHFFFAOYSA-N chloromethyl n-methylcarbamate Chemical compound CNC(=O)OCCl DJMVSBAOTMOYLX-UHFFFAOYSA-N 0.000 claims description 8
- BTBBPNVBJSIADI-UHFFFAOYSA-N chloromethyl propanoate Chemical compound CCC(=O)OCCl BTBBPNVBJSIADI-UHFFFAOYSA-N 0.000 claims description 8
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 8
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 8
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 7
- 229930012538 Paclitaxel Natural products 0.000 claims description 7
- GWYFCOCPABKNJV-UHFFFAOYSA-N beta-methyl-butyric acid Natural products CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 7
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 7
- ILUWVORABZTBIU-UHFFFAOYSA-N chloromethyl 2-methylpropanoate Chemical compound CC(C)C(=O)OCCl ILUWVORABZTBIU-UHFFFAOYSA-N 0.000 claims description 7
- LHXLWSDJXYETLZ-UHFFFAOYSA-N chloromethyl morpholine-4-carboxylate Chemical compound ClCOC(=O)N1CCOCC1 LHXLWSDJXYETLZ-UHFFFAOYSA-N 0.000 claims description 7
- 150000002500 ions Chemical class 0.000 claims description 7
- JNODQFNWMXFMEV-UHFFFAOYSA-N latrepirdine Chemical compound C1N(C)CCC2=C1C1=CC(C)=CC=C1N2CCC1=CC=C(C)N=C1 JNODQFNWMXFMEV-UHFFFAOYSA-N 0.000 claims description 7
- LBHIOVVIQHSOQN-UHFFFAOYSA-N nicorandil Chemical compound [O-][N+](=O)OCCNC(=O)C1=CC=CN=C1 LBHIOVVIQHSOQN-UHFFFAOYSA-N 0.000 claims description 7
- 229960002497 nicorandil Drugs 0.000 claims description 7
- 229960001592 paclitaxel Drugs 0.000 claims description 7
- 229960005489 paracetamol Drugs 0.000 claims description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- 150000003335 secondary amines Chemical class 0.000 claims description 7
- 229960003328 benzoyl peroxide Drugs 0.000 claims description 6
- 230000004071 biological effect Effects 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 230000008859 change Effects 0.000 claims description 6
- ZFYFSEXLXRFOLD-UHFFFAOYSA-N chloromethyl cyclohexanecarboxylate Chemical compound ClCOC(=O)C1CCCCC1 ZFYFSEXLXRFOLD-UHFFFAOYSA-N 0.000 claims description 6
- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 claims description 6
- LJOODBDWMQKMFB-UHFFFAOYSA-N cyclohexyl-acetic acid Natural products OC(=O)CC1CCCCC1 LJOODBDWMQKMFB-UHFFFAOYSA-N 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 6
- 150000002814 niacins Chemical class 0.000 claims description 6
- 150000003141 primary amines Chemical class 0.000 claims description 6
- QOHDTSVYCIETJO-UHFFFAOYSA-N (4-acetamidophenyl) pyridine-3-carboxylate Chemical compound C1=CC(NC(=O)C)=CC=C1OC(=O)C1=CC=CN=C1 QOHDTSVYCIETJO-UHFFFAOYSA-N 0.000 claims description 5
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical group C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims description 5
- NAPASAWYHWNTHO-UHFFFAOYSA-N C(=O)CN(C)[O] Chemical compound C(=O)CN(C)[O] NAPASAWYHWNTHO-UHFFFAOYSA-N 0.000 claims description 5
- YSRNIQSBBAUXOX-UHFFFAOYSA-N CC(C)C([O])=O Chemical compound CC(C)C([O])=O YSRNIQSBBAUXOX-UHFFFAOYSA-N 0.000 claims description 5
- 239000005517 L01XE01 - Imatinib Substances 0.000 claims description 5
- FRJZOYQRAJDROR-UHFFFAOYSA-N cyclohexyl hydrogen carbonate Chemical compound OC(=O)OC1CCCCC1 FRJZOYQRAJDROR-UHFFFAOYSA-N 0.000 claims description 5
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 claims description 5
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- 239000011664 nicotinic acid Substances 0.000 claims description 5
- GWYFCOCPABKNJV-UHFFFAOYSA-M 3-Methylbutanoic acid Natural products CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 claims description 4
- DGFQXXDHYHWWSP-UHFFFAOYSA-N CC(C)OC([O])=O Chemical compound CC(C)OC([O])=O DGFQXXDHYHWWSP-UHFFFAOYSA-N 0.000 claims description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 4
- 239000002535 acidifier Substances 0.000 claims description 4
- 230000003444 anaesthetic effect Effects 0.000 claims description 4
- 239000002269 analeptic agent Substances 0.000 claims description 4
- 239000000730 antalgic agent Substances 0.000 claims description 4
- 230000002155 anti-virotic effect Effects 0.000 claims description 4
- NJAPCAIWQRPQPY-UHFFFAOYSA-N benzyl hydrogen carbonate Chemical compound OC(=O)OCC1=CC=CC=C1 NJAPCAIWQRPQPY-UHFFFAOYSA-N 0.000 claims description 4
- XMIIGOLPHOKFCH-UHFFFAOYSA-N beta-phenylpropanoic acid Natural products OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 claims description 4
- 210000003169 central nervous system Anatomy 0.000 claims description 4
- RJRPATMXXHZXSS-QMMMGPOBSA-N chloromethyl (2s)-2-phenylpropanoate Chemical compound ClCOC(=O)[C@@H](C)C1=CC=CC=C1 RJRPATMXXHZXSS-QMMMGPOBSA-N 0.000 claims description 4
- SWIMRRJQXRFQEP-UHFFFAOYSA-N chloromethyl azetidine-1-carboxylate Chemical compound ClCOC(=O)N1CCC1 SWIMRRJQXRFQEP-UHFFFAOYSA-N 0.000 claims description 4
- 235000019504 cigarettes Nutrition 0.000 claims description 4
- SHZIWNPUGXLXDT-UHFFFAOYSA-N ethyl hexanoate Chemical compound CCCCCC(=O)OCC SHZIWNPUGXLXDT-UHFFFAOYSA-N 0.000 claims description 4
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 claims description 4
- GPSDUZXPYCFOSQ-UHFFFAOYSA-N m-toluic acid Chemical compound CC1=CC=CC(C(O)=O)=C1 GPSDUZXPYCFOSQ-UHFFFAOYSA-N 0.000 claims description 4
- 229940095102 methyl benzoate Drugs 0.000 claims description 4
- FUZZWVXGSFPDMH-UHFFFAOYSA-N n-hexanoic acid Natural products CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 4
- KVWDHTXUZHCGIO-UHFFFAOYSA-N olanzapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 KVWDHTXUZHCGIO-UHFFFAOYSA-N 0.000 claims description 4
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- LPNBBFKOUUSUDB-UHFFFAOYSA-N p-toluic acid Chemical compound CC1=CC=C(C(O)=O)C=C1 LPNBBFKOUUSUDB-UHFFFAOYSA-N 0.000 claims description 4
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 4
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- KNWWGBNAUNTSRV-UHFFFAOYSA-N 4-methylpiperazine-1-carboxylic acid Chemical compound CN1CCN(C(O)=O)CC1 KNWWGBNAUNTSRV-UHFFFAOYSA-N 0.000 claims description 3
- FJHBVJOVLFPMQE-QFIPXVFZSA-N 7-Ethyl-10-Hydroxy-Camptothecin Chemical compound C1=C(O)C=C2C(CC)=C(CN3C(C4=C([C@@](C(=O)OC4)(O)CC)C=C33)=O)C3=NC2=C1 FJHBVJOVLFPMQE-QFIPXVFZSA-N 0.000 claims description 3
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- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
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- ISPKBNAGBUBSCZ-QMMMGPOBSA-N chloromethyl n-[(1s)-1-phenylethyl]carbamate Chemical compound ClCOC(=O)N[C@@H](C)C1=CC=CC=C1 ISPKBNAGBUBSCZ-QMMMGPOBSA-N 0.000 claims description 3
- ACOQXMCHWVXXSE-YFKPBYRVSA-N chloromethyl n-[(2s)-butan-2-yl]carbamate Chemical compound CC[C@H](C)NC(=O)OCCl ACOQXMCHWVXXSE-YFKPBYRVSA-N 0.000 claims description 3
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- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 claims description 3
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Abstract
本发明涉及合成和应用新的手性/非手性经取代甲基甲酰基试剂以修饰药用剂和/或生物活性物质从而改进由未经修饰初始药用剂得到的化合物的物理化学性质、生物学性质和/或药代动力学性质。
Description
技术领域
本发明涉及合成和应用新的手性/非手性经取代甲基甲酰基试剂来修饰药用剂和/或生物活性物质以改进由未经修饰的初始药用剂得到的化合物的物理化学性质、生物学性质和/或药代动力学性质。
背景技术
对其靶标具有强活性的化学实体是药物发现过程中的第一步骤。但是,强效化合物只在其施用后适当的量以可接受的速率输送到作用位点时有效。即使强效化合物也获益于这些方面的优化。许多强效化学实体不具有最佳的药代动力学参数,因此这些药物的药效学性质也是次优的。此外,市场中已经可以得到若干化学实体,这些化学实体具有受限的药代动力学性质,因此不能被配制为便于患者施用的方式。
可以通过向初始分子添加某些基团从而修饰该分子及其性质来控制输送入血液循环的速率和程度。分子修饰是已知的预先表征的先导化合物的化学修饰,其目的是增强该化合物作为药物的有用性。这可意味着增强该化合物对特定靶位点的特异性、提高其效力、提高其吸收速率和程度、改变活性组分在体内变为生物可用的时程(例如择时释放制剂(timerelease formulation))、降低其毒性和/或改变其物理或化学性质(例如溶解性)以优化这些方面用于特定应用。
但是,用于药物的分子修饰的部分必须使得维持和/或增强化合物的治疗效力,同时使得改进药代动力学性质。此外,经修饰化合物在施用时必须不会超出耐受程度不利地影响化学实体的安全性、毒性和效力。
前述结构在现有药品可以被施用之方式方面导致限制(一些长久存在)。例如,乙酰水杨酸(阿司匹林中的活性成分)在待静脉内施用的盐水中不充分地溶解。因此,从发现咀嚼柳树皮可以减轻发热的时间开始至首次合成阿司匹林的时间直至今日,阿司匹林最常经口施用,并且不适于静脉内施用。
这些结构还使得难以改进现有药品的药效学性质从而将它们优化用于特定用途。如果能开发可以改进药物的药代动力学性质和药效学性质而不会不利地影响药物的效力、安全性和毒性的衍生化方法,则会有助于药品的开发。
如本文所示的一些实施例所举例说明的,需要修饰可用作药物的化合物以使得所得化合物的药代动力学性质、物理性质和/或药效学性质中的一个或更多个得以改进的方法。
因此,为了解决该需要,本发明的目的在于提供可用于修饰现有化合物以改进其药代动力学性质、物理性质和/或药效学性质的新的基于经取代甲基甲酰基的试剂。本发明公开了用于修饰的试剂和使用它们来增强特定性质同时保留初始化合物的安全性、毒性和效力的方法。
优点
本发明允许实现以下中的一个或更多个:
1)提供用于化学实体的分子修饰的新的基于经取代甲基甲酰基的试剂;
2)改进经修饰实体的药代动力学性质;
3)改进经修饰实体的药效学性质;
4)保持经修饰实体的期望的安全性和毒性;
5)改善安全性和毒性;
6)使药用剂及其他生物活性物质更易溶于盐水和/或在生物可用pH范围内更易溶;
7)改进药用剂及其他生物活性物质的药代动力学性质;
8)通过修饰经取代甲基甲酰基试剂的结构或者通过在生物系统中引起因特异性和选择性而有助于影响该转化的变化来改变经修饰药用剂及其他生物活性物质转化为初始药用剂和生物活性物质的比率;和/或
9)通过修饰经取代甲基甲酰基试剂的结构或者通过在生物系统中引起因特异性和选择性而有助于影响该转化的变化来改变经修饰药用剂及其他生物活性物质转化为初始药用剂和生物活性物质的有利位点。
发明概述
本发明提供了下图1所示通式的新的甲基甲酰基衍生化试剂:
图1:
图1示出经取代甲基甲酰基试剂的结构;
其中:
X选自Cl、Br、I、OTs、OMs;
Y选自R2、OR2或N(R2)2;
R和R1可以独立地为H;C1-C8直链或支链烷基—任选地包含1至3个选自O、N、S、SO或SO2的杂原子;3至7元环烷基,其任选地包含1至3个选自O、N、S、SO或SO2的杂原子和/或低级烷基、直链或支链烷基、烷氧基;烷芳基、芳基、杂芳基或烷杂芳基;
R和R1也可以连接以形成3至7元碳环,该碳环任选地包含1至2个选自O、N、S、SO、SO2的杂原子并且还任选地被烷氧基、F或Cl取代;
R2可以独立地为H;C1-C8直链或支链烷基—任选地包含1至3个选自O、N、S、SO或SO2的杂原子;3至7元环烷基,其任选地包含1至3个选自O、N、S、SO或SO2的杂原子和/或低级烷基、直链或支链烷基、烷氧基;烷芳基、芳基、杂芳基或烷杂芳基;并且
R2也可以是3至7元环的一部分,所述3至7元环任选地包含额外的1至2个选自O、N、S、SO、SO2的杂原子并且还任选地被烷氧基、F或Cl取代。
本发明的甲基甲酰基试剂可以以对映体纯形式或者作为对映体或非对映体的混合物存在。
已发现用这些经取代甲基甲酰基试剂衍生化的化合物具有显著增强的水溶性,并且在药代动力学和药效学性质方面表现出显著且出乎意料的改进。这些衍生化试剂可用于有利地改进药物化合物的物理化学性质和药效学性质以及其他相关用途。
因此,本发明还包括使用这些新的衍生化试剂来改进药物化合物的物理化学性质和药代动力学性质以及药效学性质中的一个或更多个的方法。如本文所示实施例所证明的,本发明方法可以容易地应用于多种化合物从而以期望的方式改进其性质并且获得具有改进的性质的所得化合物。
优选实施方案详述
本发明提供了适合作为用于分子修饰(其中,经修饰实体表现出改进的性质并且适合用于药物用途)的试剂的新的经取代甲基甲酰基化合物。通过使用本发明的新试剂获得的所得经修饰化合物适合用作具有改进的药代动力学性质和/或药效学性质同时保持期望的安全性和毒性的药物和/或药用剂。本发明还提供了用于制备更易溶于盐水和/或在生物可用pH范围内更易溶的药用剂及其他生物活性物质的方法;用以影响药用剂及其他生物活性物质的药代动力学性质的方法;通过修饰经取代甲基甲酰基试剂的结构或者通过在生物系统中引起因特异性和选择性而有助于影响该转化的变化来影响经修饰药用剂及其他生物活性物质转化为初始药用剂和生物活性物质的比率的方法;以及通过修饰经取代甲基甲酰基试剂的结构或者通过在生物系统中引起因特异性和选择性而有助于影响该转化的变化来影响经修饰药用剂及其他生物活性物质转化为初始药用剂和生物活性物质的有利位点的方法。还提供了用于制备和分离经修饰化合物的方法。
A.新的经取代甲基甲酰基试剂
B.通过使式1化合物与杂环系统的官能团或杂原子共价连接来修饰化合物以获得具有改进的化学性质和生物学性质的经修饰化合物的方法;
其中在化合物(1)中:
X选自Cl、Br、I、OTs、OMs;
Y选自R2、OR2或N(R2)2;并且
R和R1独立地为H;C1-C8直链或支链烷基—任选地包含1至3个选自O、N、S、SO或SO2的杂原子;3至7元环烷基,其任选地包含1至3个选自O、N、S、SO或SO2的杂原子和/或低级烷基、直链或支链烷基、烷氧基;烷芳基、芳基、杂芳基或烷杂芳基;
R和R1也可以连接至经取代甲基甲酰基以形成3至7元碳环,该碳环任选地包含1至2个选自O、N、S、SO、SO2的杂原子并且还任选地被烷氧基、F或Cl取代;
R2独立地为H;C1-C8直链或支链烷基—任选地包含1至3个选自O、N、S、SO或SO2的杂原子;3至7元环烷基,其任选地包含1至3个选自O、N、S、SO或SO2的杂原子和/或低级烷基、直链或支链烷基、烷氧基;烷芳基、芳基、杂芳基或烷杂芳基;并且
R2独立地为3至7元环的一部分,所述3至7元环任选地包含额外的1至2个选自O、N、S、SO、SO2的杂原子并且还任选地被烷氧基、F或Cl取代。
A.1新的经取代甲基甲酰基试剂
其中:
图1示出经取代甲基甲酰基试剂的结构;
X选自Cl、Br、I、OTs、OMs;
Y选自R2、OR2或N(R2)2;
R和R1可以独立地为H;C1-C8直链或支链烷基—任选地包含1至3个选自O、N、S、SO或SO2的杂原子;3至7元环烷基,其任选地包含1至3个选自O、N、S、SO或SO2的杂原子和/或低级烷基、直链或支链烷基、烷氧基;烷芳基、芳基、杂芳基或烷杂芳基;
R和R1也可以连接至经取代甲基甲酰基以形成3至7元碳环,该碳环任选地包含1至2个选自O、N、S、SO、SO2的杂原子并且还任选地被烷氧基、F或Cl取代;
R2可以独立地为H;C1-C8直链或支链烷基—任选地包含1至3个选自O、N、S、SO或SO2的杂原子;3至7元环烷基,其任选地包含1至3个选自O、N、S、SO或SO2的杂原子和/或低级烷基、直链或支链烷基、烷氧基;烷芳基、芳基、杂芳基或烷杂芳基;并且
R2也可以是3至7元环的一部分,所述3至7元环任选地包含额外的1至2个选自O、N、S、SO、SO2的杂原子并且还任选地被烷氧基、F或Cl取代。
术语“烷”或“烷基”是指具有1至12个碳原子、优选1至8个碳原子的直链或支链烃基。表达“低级烷基”是指1至4个碳原子的烷基。
术语“烯基”是指具有至少一个双键的2至10、优选2至4个碳原子的直链或支链烃基。在烯基与氮原子相连时,优选该基团不直接通过带有双键的碳连接。
术语“炔基”是指具有至少一个三键的2至10、优选2至4个碳原子的直链或支链烃基。在炔基与氮原子相连时,优选该基团不直接通过带有三键的碳连接。
术语“亚烷基”是指通过单键连接的1至5个碳原子的直链桥(例如-(CH2)x-,其中x为1至5),其可以被1至3个低级烷基取代。
术语“亚烯基”是指通过单键连接并且可以被1至3个低级烷基取代的具有一个或两个双键的2至5个碳原子的直链桥。示例性亚烯基是-CH=CH-CH=CH-、-CH2-CH=CH-、-CH2-CH=CH-CH2-、-C(CH3)2CH=CH-和-CH(C2H5)-CH=CH-。
术语“亚炔基”是指其中具有三键的2至5个碳原子的直链桥,其通过单键连接,并且可以被1至3个低级烷基取代。示例性亚炔基是-C=C-、-CH2-C=C-、-CH(CH3)-C=C-和-C=C-CH(C2H5)CH2-。
术语“芳”或“芳基”是指包含6至14个碳原子的芳族环基团(例如6元单环、10元双环或14元三环系统)。示例性芳基包括苯基、萘基、联苯基和蒽。
术语“环烷基”和“环烯基”是指3至12个碳原子的环烃基。
术语“卤素”是指氟、氯、溴和碘。
术语“不饱和环”包括部分饱和环和芳族环。
术语“杂环”是指完全饱和的或不饱和的(包括芳族的(即“杂芳基”))环基团,例如,4至7元单环、7至11元双环或10至15元三环系统,其在含至少一个碳原子的环中具有至少一个杂原子。含杂原子的杂环基的每个环可以具有选自氮原子、氧原子和/或硫原子的1、2、3或4个杂原子,其中氮和硫杂原子可以任选地被氧化并且氮杂原子可以任选地被季铵化。
可以在环或环系统的任意杂原子或碳原子处与杂环基连接。
示例性单环杂环基包括:吡咯烷基、吡咯基、吡唑基、氧杂环丁烷基、吡唑啉基、咪唑基、咪唑啉基、咪唑烷基、噁唑基、噁唑烷基、异噁唑啉基、异噁唑基、噻唑基、噻二唑基、噻唑烷基、异噻唑基、异噻唑烷基、呋喃基、四氢呋喃基、噻吩基、噁二唑基、哌啶基、哌嗪基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、2-氧代吖庚因基、吖庚因基(azepinyl)、4-哌啶酮基、吡啶基、吡嗪基、嘧啶基、哒嗪基、四氢吡喃基、吗啉基、硫杂吗啉基、硫杂吗啉基亚砜、硫杂吗啉基砜、1,3-二氧戊环以及四氢-1,1-二氧代噻吩基、三唑基、三嗪基等。
示例性双环杂环基包括:吲哚基、苯并噻唑基、苯并唑基、苯并间二氧杂环戊烯基(benzodioxolyl)、苯并噻吩基、奎宁环基(quinuclidinyl)、喹啉基、四氢异喹啉基、异喹啉基、苯并咪唑基、苯并吡喃基、吲嗪基(indolizinyl)、苯并呋喃基、色酮基、香豆素基、苯并吡喃基、噌啉基、喹喔啉基、吲唑基、吡咯并吡啶基(pyrrolopyridyl)、呋喃并吡啶基(例如呋喃并[2,3-c]吡啶基、呋喃并[3,2-b]吡啶基]或呋喃并[2,3-b]吡啶基)、二氢异吲哚基、二氢喹唑啉基(例如3,4-二氢-4-氧代-喹唑啉基)、四氢喹啉基等。
示例性三环杂环基包括:咔唑基、苯并吲哚基、菲咯啉基、吖啶基、菲啶基、呫吨基等。
术语“杂芳基”是指芳族杂环基。
示例性杂芳基包括:吡咯基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、噻二唑基、异噻唑基、呋喃基、噻吩基、噁二唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、三唑基、三嗪基等。
本文中的术语“亚烷基”和“烷基”分别包括直链和支链的、饱和的和不饱和(即含一个双键)的二价亚烷基和一价烷基。本文中的术语“烷醇”同样包括烷醇基团的直链和支链的、饱和的和不饱和的烷基组成,其中羟基可以位于烷基部分上的任何位置处。术语“环烷醇”包括未取代的和取代的(例如甲基或乙基)环醇。
药用剂包括被认为是药品、药物或药剂的任何物质或试剂。
生物活性物质包括如本领域技术人员所理解的表现出生物活性的任何物质。
化学性质和生物学性质包括药代动力学性质和药效学性质。
在一优选实施方案中,本发明的新的经取代甲基甲酰基化合物试剂具有图1所示的结构。
在另一优选实施方案中,本发明包括使用这些新的衍生化试剂来改进药物化合物的物理化学性质和药代动力学性质以及药效学性质中的一个或更多个的方法。如本文所示实施例所证明的,本发明的方法可以容易地应用于多种化合物从而以期望的方式改进它们的性质。
图1披露了本发明衍生化试剂的一般结构。与图1相关的不同结构可以划分为三类,即,I型,其中Y=R2;II型,其中Y=(NR2)2以及III型,其中Y=OR2。
A.2用于制备新的经取代甲基甲酰基试剂的一般方法
甲基甲酰基试剂(I、II、III型)可以由各酸、胺和醇直接制备。可以使活化或未活化的酸在Lewis酸的存在下与相应的醛反应从而可以提供I型试剂。可以使醇在碱的存在下与卤代乙酸卤甲酯反应以提供III型试剂。类似地,可以使胺(伯胺或仲胺)在存在或不存在碱的条件下与卤代乙酸卤甲酯反应从而可以提供II型试剂。
A.2.2合成I型试剂的一般方法
方案1
一般方法:
可以使醛(例如多聚甲醛)和酰氯[3]在无水条件和合适的温度(通常为-10℃至60℃)下与Lewis酸(例如氯化锌(干燥))反应最多24小时的时间。可以用溶剂(例如二氯甲烷)稀释反应混合物,用水性稀碱(例如Na2HCO3溶液)洗涤。进行标准工作并纯化,得到期望的经取代甲基甲酰基试剂[4]。
方案2
一般方法:
可以在合适的温度(通常为0℃至室温)下用含溴碘甲烷的无水THF将期望的酸的金属盐(例如酸[2]的铯盐)处理16小时,并且如果需要的话进行加热。可以用溶剂(例如乙酸乙酯)稀释反应混合物,用含水稀碱(例如Na2HCO3水溶液)洗涤。进行标准工作并纯化,得到期望的经取代甲基甲酰基试剂[5]。
方案3
一般方法:
在室温下,向剧烈搅拌的酸[2]在溶剂(例如二氯甲烷)中的溶液中添加含碱(例如碳酸氢钠和四丁基硫酸氢铵)的水,然后逐滴添加氯磺酸氯甲酯在溶剂(例如二氯甲烷)中的溶液。反应完成之后,用5%Na2CO3水溶液洗涤有机层。进行标准工作并纯化,得到期望的经取代甲基甲酰基试剂[4]。
如上所举例说明的和本文所解释的,Y=R2,R4可以是连接待修饰化合物与本发明甲基甲酰基试剂的若干部分中的任一者。R2可以独立地为H;C1-C8直链或支链烷基—任选地包含1至3个选自O、N、S、SO或SO2的杂原子;3至7元环烷基,其任选地包含1至3个选自O、N、S、SO或SO2的杂原子和/或低级烷基、直链或支链烷基、烷氧基;烷芳基、芳基、杂芳基或烷杂芳基。
R2也可以是3至7元环的一部分,所述3至7元环任选地包含额外的1至2个选自O、N、S、SO、SO2的杂原子并且还任选地被烷氧基、F或Cl取代。
A.2.3合成II型试剂的一般方法
方案2
一般方法:
可以在0℃下,使相应的伯胺或仲胺与经取代或未经取代的氯甲酸氯甲酯[6]在溶剂(例如己烷或DCM)中反应。可以过滤反应混合物,然后可以用1.0N HCI洗涤滤液。可以蒸发有机相以得到期望的试剂[7]。如果需要的话,可以使用有机化学实验室中实践的任何一般纯化方法(例如沉淀或结晶或制备柱纯化)来实现进一步纯化。
如上所举例说明和本文所解释的,R和R1可以独立地为H;C1-C8直链或支链烷基—任选地包含1至3个选自O、N、S、SO或SO2的杂原子;3至7元环烷基,其任选地包含1至3个选自O、N、S、SO或SO2的杂原子和/或低级烷基、直链或支链烷基、烷氧基;烷芳基、芳基、杂芳基或烷杂芳基。
R和R1也可以连接至经取代甲基甲酰基以形成3至7元碳环,该碳环任选地包含1至2个选自O、N、S、SO、SO2的杂原子并且还任选地被烷氧基、F或Cl取代。
R2可以独立地为H;C1-C8直链或支链烷基—任选地包含1至3个选自O、N、S、SO或SO2的杂原子;3至7元环烷基,其任选地包含1至3个选自O、N、S、SO或SO2的杂原子和/或低级烷基、直链或支链烷基、烷氧基;烷芳基、芳基、杂芳基或烷杂芳基。
R2也可以是3至7元环的一部分,所述3至7元环任选地包含额外的1至2个选自O、N、S、SO、SO2的杂原子并且还任选地被烷氧基、F或Cl取代。
A.2.4合成III型试剂的一般方法
方案3:
一般方法:
可以向氯甲酸氯甲酯[8]在溶剂(例如己烷)中的溶液中添加吡啶在己烷中的溶液,在冰冷却下逐滴添加。可以在相同的温度下向该反应混合物中添加相应的醇。可以将反应混合物搅拌最多24小时的时间。进行标准工作和纯化,得到期望的相应碳酸酯试剂[9]。
如上所举例说明和本文所解释的,R2可以是连接待修饰化合物与本发明甲基甲酰基试剂的若干部分中的任一者。
R2可以独立地为H;C1-C8直链或支链烷基—任选地包含1至3个选自O、N、S、SO或SO2的杂原子;3至7元环烷基,其任选地包含1至3个选自O、N、S、SO或SO2的杂原子和/或低级烷基、直链或支链烷基、烷氧基;烷芳基、芳基、杂芳基或烷杂芳基。
R2也可以是3至7元环的一部分,所述3至7元环任选地包含额外的1至2个选自O、N、S、SO、SO2的杂原子并且还任选地被烷氧基、F或Cl取代。
方案4:用于卤素置换的一般合成方案
方案4.1:
一般方法:
在合适的温度(通常为40℃至80℃)下,用合适的溴化物试剂(例如溴化锂或溴化钠)处理氯甲基甲酰基试剂[4]最多24小时的时间,然后进行标准工作并纯化,得到期望的溴甲基甲酰基试剂[5]。
方案4.2:
一般方法:
在合适的温度(通常为室温至60℃)下,用试剂(例如碘化钠)处理氯甲基甲酰基试剂[4]多至24小时的时间,然后进行标准工作并纯化,得到期望的碘甲基甲酰基试剂[10]。
方案4.3
一般方法:
在合适的温度(通常为室温至60℃至90℃)下,用甲磺酸的银盐处理氯甲基甲酰基试剂[4]最多24小时的时间,然后进行标准工作并纯化,得到期望的((甲基磺酰基)氧基)甲基甲酰基试剂[11]。
方案4.4:
一般方法:
在合适的温度(通常为室温至60℃至90℃)下,用对甲基苯磺酸的银盐处理氯甲基甲酰基试剂[4]多至24小时的时间,然后进行标准工作并纯化,得到期望的((甲基磺酰基)氧基)甲基甲酰基试剂[12]。
A.3经取代甲基甲酰基试剂:
基于如A.2中所公开的方案,可以合成许多经取代甲基甲酰基试剂。可以按照上述方案合成的本发明经取代甲基甲酰基试剂的非限制性列表在本文中提供为如下并且示于图1:
I型试剂
i.异丙基碳酸氯甲酯
ii.苄基碳酸氯甲酯
iii.吗啉代甲基碳酸氯甲酯
iv.异丁基碳酸氯甲酯
v.甲基碳酸氯甲酯
vi.(S)-仲丁基碳酸氯甲酯
vii.(R)-仲丁基碳酸氯甲酯
viii.((3S,5R)-3,5-二甲基吗啉代)甲基碳酸氯甲酯
ix.2-甲基环丙基碳酸氯甲酯
x.2-甲氧基乙基碳酸氯甲酯
xi.丙基碳酸氯甲酯
xii.环丁基碳酸氯甲酯
xiii.环丙基碳酸氯甲酯
xiv.2,2-二甲基环丁基碳酸氯甲酯
xv.环戊基碳酸氯甲酯
xvi.氧杂环丁烷-3-基碳酸氯甲酯
xvii.(S)-四氢呋喃-3-基碳酸氯甲酯
xviii.环己基甲基碳酸氯甲酯
xix.3-甲氧基环己基碳酸氯甲酯
xx.(R)-四氢呋喃-3-基碳酸氯甲酯
xxi.乙氧基甲基碳酸氯甲酯
xxii.氧杂环庚烷-4-基碳酸氯甲酯
xxiii.(1R,2S,4S)-二环[2.2.1]庚-2-基碳酸氯甲酯
xxiv.2,3-二氢-1H-茚-1-基碳酸氯甲酯
xxv.苄基碳酸氯甲酯
xxvi.(S)-1-苯基乙基碳酸氯甲酯
xxvii.环己基碳酸氯甲酯
xxviii.异丁基碳酸氯甲酯
xxix.4-甲基环己基碳酸氯甲酯
xxx.2-(甲基硫代)乙基碳酸氯甲酯
xxxi.3-甲基环己基碳酸氯甲酯
xxxii.戊-2-基碳酸氯甲酯
xxxiii.新戊基碳酸氯甲酯
xxxiv.1-((氯甲氧基)羰基氧基)环丙烷羧酸甲酯
xxxv.环丙基甲基碳酸氯甲酯
xxxvi.2,2-二乙氧基乙基碳酸氯甲酯
xxxvii.环戊基甲基碳酸氯甲酯
xxxviii.2-((氯甲氧基)羰基氧基)丙酸甲酯
xxxix.(S)-2,2,4-三甲基环戊-3-烯基碳酸氯甲酯
xl.1,3-二氧戊环-2-基碳酸氯甲酯
xli.(2,6-二甲基环己基)甲基碳酸氯甲酯
xlii.2-(四氢-2H-吡喃-2-基)乙基碳酸氯甲酯
xliii.(四氢-2H-吡喃-4-基)甲基碳酸氯甲酯
xliv.四氢-2H-吡喃-4-基碳酸氯甲酯
xlv.1-甲基环戊基碳酸氯甲酯
xlvi.1-环戊基乙基碳酸氯甲酯
xlvii.3-甲基环戊基碳酸氯甲酯
xlviii.3,3-二甲基环己基碳酸氯甲酯
xlix.2,5-二甲基环己基碳酸氯甲酯
l.1-(4-甲基环己基)乙基碳酸氯甲酯
li.(3-甲基氧杂环丁烷-3-基)甲基碳酸氯甲酯
lii.(3-甲基氧杂环丁烷-3-基)甲基碳酸氯甲酯
liii.2-异丙氧基乙基碳酸氯甲酯
liv.(氯甲基碳酸)5-((3aS,4S,6aR)-2-氧代六氢-1H-噻吩并[3,4-d]咪唑-4-基)戊酸酐
lv.4-((氯甲氧基)羰基氧基)-2-羟基-4-氧代丁酸
lvi.4-甲酰基-2-甲氧基苯基碳酸氯甲酯
lvii.3-氧代丁-2-基碳酸氯甲酯
lviii.4-((氯甲氧基)羰基氧基)苯甲酸甲酯
lix.(R)-2-氨基-3-((氯甲氧基)羰基氧基)丙酸
lx.3-叔丁基-4-甲氧基苯基碳酸氯甲酯
lxi.(R)-2-氨基-3-(4-((氯甲氧基)羰基氧基)苯基)丙酸
lxii.(R)-2-氨基-4-((氯甲氧基)羰基氧基)-4-氧代丁酸
lxiii.(E)-3,7-二甲基辛-2,6-二烯基碳酸氯甲酯
lxiv.4-((氯甲氧基)羰基氧基)苯甲酸甲酯
lxv.2-(4-甲基环己-3-烯基)丙-2-基碳酸氯甲酯
lxvi.3,7-二甲基辛-1,6-二烯-3-基碳酸氯甲酯
lxvii.4-烯丙基-2-甲氧基苯基碳酸氯甲酯
lxviii.(1R,2S,5R)-2-异丙基-5-甲基环己基碳酸氯甲酯
lxix.4-((氯甲氧基)羰基氧基)苯甲酸丙酯
lxx.(E)-3,7-二甲基辛-2,6-二烯基碳酸氯甲酯
I型试剂
图1:I型试剂的一些非限制性实例
II型试剂的非限制性实例列举在下文中并且示于图2中。
II型试剂
i.环己烷羧酸氯甲酯
ii.2-环己基乙酸氯甲酯
iii.4-甲基环己烷羧酸氯甲酯
iv.1-甲基环己烷羧酸氯甲酯
v.环戊烷羧酸氯甲酯
vi.1-(三氟甲基)环戊烷羧酸氯甲酯
vii.环丁烷羧酸氯甲酯
viii.2-乙基己酸氯甲酯
ix.3-环戊基丙酸氯甲酯
x.环丙烷羧酸氯甲酯
xi.戊酸氯甲酯
xii.2-甲基戊酸氯甲酯
xiii.3,5,5-三甲基己酸氯甲酯
xiv.2,2-二甲基丁酸氯甲酯
xv.2-甲基丁酸氯甲酯
xvi.己酸氯甲酯
xvii.2-乙基丁酸氯甲酯
xviii.丁酸氯甲酯
xix.3-苯基丙酸氯甲酯
xx.2-苯基丙酸氯甲酯
xxi.(R)-2-苯基丙酸氯甲酯
xxii.(S)-2-苯基丙酸氯甲酯
xxiii.(1r,4r)-4-甲基环己烷羧酸氯甲酯
xxiv.4-甲氧基环己烷羧酸氯甲酯
xxv.4,4-二氟环己烷羧酸氯甲酯
xxvi.3-甲氧基环己烷羧酸氯甲酯
xxvii.(2R)-2-甲基环戊烷羧酸氯甲酯
xxviii.(R)-2-甲基丁酸氯甲酯
xxix.(S)-2-甲基丁酸氯甲酯
xxx.(S)-2-甲氧基-2-苯基乙酸氯甲酯
xxxi.(S)-2-苯基丙酸氯甲酯
xxxii.(S)-2-苯基丁酸氯甲酯
xxxiii.(S)-3-苯基丁酸氯甲酯
xxxiv.2,2-二甲基丙二酸双(氯甲基)酯
xxxv.草酸双(氯甲基)酯
xxxvi.2-环丙基乙酸氯甲酯
xxxvii.2-环丁基乙酸氯甲酯
xxxviii.2-环戊基乙酸氯甲酯
xxxix.2-(四氢呋喃-3-基)乙酸氯甲酯
xl.2-(四氢-2H-吡喃-4-基)乙酸氯甲酯
xli.2-甲基环丙烷羧酸氯甲酯
xlii.2-(1-甲基环丁基)乙酸氯甲酯
xliii.2-(1-甲基环丙基)乙酸氯甲酯
xliv.丙酸氯甲酯
xlv.乙酸氯甲酯
xlvi.异丁酸氯甲酯
xlvii.2-异丙基-3-甲基丁酸氯甲酯
xlviii.3,5-二甲基环己烷羧酸氯甲酯
xlix.2-丙基戊酸氯甲酯
l.4-甲氧基苯甲酸氯甲酯
li.4-甲基苯甲酸氯甲酯
lii.3-甲基苯甲酸氯甲酯
liii.2,2,2-三氟乙酸氯甲酯
liv.5,5-二甲基-3-氧代己酸氯甲酯
lv.双(氯甲基)环丙烷-1,1-二羧酸酯
lvi.1,2-二氢环丁苯-1-羧酸氯甲酯
lvii.2-环戊烯基乙酸氯甲酯
lviii.2-苯基丁酸氯甲酯
lix.2,2-二氟乙酸氯甲酯
lx.4-氟苯甲酸氯甲酯
lxi.3-环己基丙酸氯甲酯
lxii.2-环己基乙酸氯甲酯
lxiii.3-(四氢-2H-吡喃-4-基)丙酸氯甲酯
lxiv.2-(四氢-2H-吡喃-3-基)乙酸氯甲酯
lxv.3-(四氢-2H-吡喃-3-基)丙酸氯甲酯
图2:II型试剂的非限制性化合物组
属于III型的非限制性化合物组列举在下文中并且示于图3中。
III型试剂
i.异丙基氨基甲酸氯甲酯
ii.二异丙基氨基甲酸氯甲酯
iii.二甲基氨基甲酸氯甲酯
iv.异丁基氨基甲酸氯甲酯
v.甲基氨基甲酸氯甲酯
vi.乙基(异丙基)氨基甲酸氯甲酯
vii.异丁基(甲基)氨基甲酸氯甲酯
viii.(S)-仲丁基氨基甲酸氯甲酯
ix.甲基氨基甲酸氯甲酯
x.异丙基(甲基)氨基甲酸氯甲酯
xi.丙基氨基甲酸氯甲酯
xii.2-甲氧基乙基氨基甲酸氯甲酯
xiii.甲基(丙基)氨基甲酸氯甲酯
xiv.二异丁基氨基甲酸氯甲酯
xv.叔丁基(异丙基)氨基甲酸氯甲酯
xvi.二-仲丁基氨基甲酸氯甲酯
xvii.氮杂环丙烷-1-羧酸氯甲酯
xviii.2-甲基环丙基氨基甲酸氯甲酯
xix.环丙基氨基甲酸氯甲酯
xx.环丙基甲基(丙基)氨基甲酸氯甲酯
xxi.环丙基(甲基)氨基甲酸氯甲酯
xxii.氮杂环丁烷-1-羧酸氯甲酯
xxiii.环丁基氨基甲酸氯甲酯
xxiv.2,2-二甲基环丁基氨基甲酸氯甲酯
xxv.3-甲氧基氮杂环丁烷-1-羧酸氯甲酯
xxvi.环丁基(甲基)氨基甲酸氯甲酯
xxvii.氧杂环丁烷-3-基氨基甲酸氯甲酯
xxviii.(S)-2-甲基吡咯烷小羧酸氯甲酯
xxix.环戊基氨基甲酸氯甲酯
xxx.环戊基(甲基)氨基甲酸氯甲酯
xxxi.四氢呋喃-3-基氨基甲酸氯甲酯
xxxii.哌啶-1-羧酸氯甲酯
xxxiii.(2R,6S)-2,6-二甲基哌啶-1-羧酸氯甲酯
xxxiv.(R)-2-甲基哌啶-1-羧酸氯甲酯
xxxv.哌啶-1-羧酸氯甲酯
xxxvi.3-甲氧基环己基氨基甲酸氯甲酯
xxxvii.环己基甲基氨基甲酸氯甲酯
xxxviii.环己基甲基(甲基)氨基甲酸氯甲酯
xxxix.吗啉-4-羧酸氯甲酯
xl.(3S,5R)-3,5-二甲基吗啉-4-羧酸氯甲酯
xli.(3R,5S)-3,5-二甲基吗啉-4-羧酸氯甲酯
xlii.(2S,6R)-2,6-二甲基吗啉-4-羧酸氯甲酯
xliii.4-甲基哌嗪-1-羧酸氯甲酯
xliv.氮杂环庚烷-1-羧酸氯甲酯
xlv.环庚基氨基甲酸氯甲酯
xlvi.氧杂环庚烷-4-基氨基甲酸氯甲酯
xlvii.(1R,2S,4S)-二环[2.2.1]庚-2-基氨基甲酸氯甲酯
xlviii.2,3-二氢-1H-茚-1-基氨基甲酸氯甲酯
xlix.苄基氨基甲酸氯甲酯
l.(S)-1-苯基乙基氨基甲酸氯甲酯
li.2-((氯甲氧基)羰基氨基)-3-甲基丁酸乙酯
lii.2-((氯甲氧基)羰基氨基)-3-苯基丙酸乙酯
liii.(S)-2-((氯甲氧基)羰基氨基)戊二酸二乙酯
liv.((氯甲氧基)羰基氨基)丙酸乙酯
lv.2-氨基-6-((氯甲氧基)羰基氨基)己酸乙酯
lvi.2-((氯甲氧基)羰基氨基)-4-甲基戊酸乙酯
lvii.2-((氯甲氧基)羰基氨基)-3-甲基戊酸乙酯
lviii.(S)-2-((氯甲氧基)羰基氨基)琥珀酸二甲酯
lix.(S)-2-((氯甲氧基)羰基氨基)-5-胍基戊酸乙酯
lx.(S)-4-氨基-2-((氯甲氧基)羰基氨基)-4-氧代丁酸乙酯
lxi.(S)-2-氨基-5-((氯甲氧基)羰基氨基)戊酸乙酯
lxii.(S)-5-氨基-2-((氯甲氧基)羰基氨基)-5-氧代戊酸乙酯
lxiii.2-((氯甲氧基)羰基氨基)-4-(甲基硫代)丁酸乙酯
lxiv.1-氯甲基3-甲基2-甲基-5,6-二氢吡啶-1,3(2H)-二羧酸酯
lxv.(S)-(1-甲基吡咯烷-2-基)甲基碳酸氯甲酯
lxvi.(R)-(1-甲基吡咯烷-2-基)甲基碳酸氯甲酯
lxvii.(S)-(1-苄基吡咯烷-2-基)甲基碳酸氯甲酯
lxviii.1H-吡咯-1-羧酸氯甲酯
lxix.2-烟酰肼羧酸氯甲酯
lxx.(6S)-3-氯-7-((氯甲氧基)羰基氨基)-8-氧代-5-硫杂-1-氮杂双环[4.2.0]辛-2-烯-2-羧酸
lxxi.(6S)-7-((氯甲氧基)羰基氨基)-8-氧代-3-乙烯基-5-硫杂-1-氮杂双环[4.2.0]辛-2-烯-2-羧酸
lxxii.(6S)-7-((氯甲氧基)羰基氨基)-3-(甲氧基甲基)-8-氧代-5-硫杂-1-氮杂双环[4.2.0]辛-2-烯-2-羧酸
lxxiii.(6R,7R)-7-((氯甲氧基)羰基氨基)-3-甲氧基-8-氧代-5-硫杂-1-氮杂双环[4.2.0]辛-2-烯-2-羧酸
lxxiv.3-(4-氯苯基)-1H-吡唑-1-羧酸氯甲酯
lxxv.3-(4-氟苯基)-1H-吡唑-1-羧酸氯甲酯
lxxvi.3-苯基-1H-吡唑-1-羧酸氯甲酯
lxxvii.3-(4溴苯基)-1H-吡唑-1-羧酸氯甲酯
lxxviii.2-氰基-1H-吡咯-1-羧酸氯甲酯
lxxix.4-氧代哌啶-1-羧酸氯甲酯
lxxx.1-氯甲基3-乙基2-氧代哌啶-1,3-二羧酸酯
lxxxi.2,2,6,6-四甲基-4-氧代哌啶-1-羧酸氯甲酯
lxxxii.2-氧代哌啶-1-羧酸氯甲酯
图3:III型化合物的列表
C.用经取代甲基甲酰基试剂修饰化合物
本发明的新的经取代甲基甲酰基试剂用于修饰任何可用于药物、营养或其他用途的化学分子的性质。这样的修饰可以在多种底物上实施以改进若干参数。可以通过使化学分子的官能团与本发明的经取代甲基甲酰基试剂反应来实施该修饰。还可以通过使本发明的经取代甲基甲酰基试剂与杂环系统的杂原子发生化学反应来实施该修饰。
该修饰可以如下实施:转化存在于I型、II型或III型目的化学分子中的任何官能团,然后与合适的外部季铵化试剂反应,或者通过试剂与存在于目的分子上的杂原子反应以制备季铵化合物。
术语“化合物”在其范围内包括目前作为药物存在于市场中的所有分子(包括抗生素和罕见药(orphan drug))、目前经历临床试验的分子、等待许可的分子、意在用作保健物或营养物的分子、意在用于农业目的(例如农药、除草剂、杀虫剂、杀真菌剂)以及其他类似应用的分子。
术语“官能团”包括分子中负责这些分子的特征性化学反应的特定原子团和/或键,并且包括烃、含卤素基团、含氧基团、含氮基团、含硫基团、含磷基团、含硼基团。所述官能团在性质上可以是脂肪族的或芳香族的。
用于通过经取代甲基甲酰基试剂修饰的优选基团(其可被称为翻译位点)是羧基、氨基、环的杂原子、醇基、酰胺等。
“杂环系统”的杂原子可以是任何杂原子,但优选为O、N、S或P。
B.1.用于化合物之修饰的一般合成方案
在下文中通过举例说明提供了使用甲基甲酰基试剂来修饰多种官能团的一般方案。
B.1.1会氮的芳族环
方案5:用含氮的芳族环(例如吡啶、咪唑、三唑等)修饰药物/生物活性分子
R3和R4可以独立地为H;C1-C8直链或支链烷基—任选地包含1至3个选自O、N、S、SO或SO2的杂原子;3至7元环烷基,其任选地包含1至3个选自O、N、S、SO或SO2的杂原子和/或低级烷基、直链或支链烷基、烷氧基;烷芳基、芳基、杂芳基或烷杂芳基。
R3和/或R4也可以是3至7元环的一部分,所述3至7元环任选地包含额外的1至2个选自O、N、S、SO、SO2的杂原子并且还任选地被烷氧基、F或Cl取代。适当地,R3和R4可以连接以形成稠合至杂芳族环的3至8元脂肪族或芳族环。本领域技术人员会知道哪些环适当地为脂肪族以及哪些为芳族。
一般方法:
在室温于无水条件下,可以使用溶剂(例如DCM或ACN)使具有含氮芳族环的药物或生物活性分子(例如[234])与I型试剂(例如[235])反应多至24小时。可以将反应混合物蒸发至干并用醚研磨。进行标准工作,得到期望产物[236]。
可以在通常为RT至60℃的温度下使任何含芳族氮的具有生物重要性的药物或分子(例如吡啶)与期望的甲基甲酰基试剂(I型(Y=R2)或II型(Y=NR2)2)或III型(Y=OR2)在溶剂(例如ACN)中反应。反应完成之后,通过蒸发过量的有机溶剂来浓缩反应以得到期望产物,如果需要的话,可以通过在有机化学实验室中实践的任何一般纯化方法(例如沉淀或结晶或制备柱纯化)来纯化所述期望的产物。
B.1.2胺
方案6:含脂肪族叔胺的药物/生物活性分子(例如哌啶、哌嗪和三烷基胺)的修饰
R3和R4可以独立地为H;C1-C8直链或支链烷基—任选地包含1至3个选自O、N、S、SO或SO2的杂原子;3至7元环烷基,其任选地包含1至3个选自O、N、S、SO或SO2的杂原子和/或低级烷基、直链或支链烷基、烷氧基;烷芳基、芳基、杂芳基或烷杂芳基。
R3和/或R4也可以是3至7元环的一部分,所述3至7元环任选地包含额外的1至2个选自O、N、S、SO、SO2的杂原子并且还任选地被烷氧基、F或Cl取代。适当地,R3和R4可以连接以形成稠合至杂脂肪族环(hetero-alicyclic ring)的3至8元脂肪族或芳族环。本领域技术人员会知道哪些环适当地为脂肪族以及哪些为芳族。
一般方法:
可以在室温于无水条件下,使用乙腈/四氢呋喃/二氯甲烷作为溶剂使具有脂肪族叔铵的药物或生物活性分子(例如[234])与I型试剂(例如[237])反应多至24小时的时间。可以将反应混合物蒸发至干并且用醚研磨。进行标准工作,得到期望产物(例如[238])。
可以在通常为RT至60℃的温度下,使任何含脂肪族叔氮的具有生物重要性的药物或分子(例如哌啶)与期望的甲基甲酰基试剂(I型(Y=R2)或II型(Y=NR2)2)或III型(Y=OR2)在溶剂(例如ACN)中反应。反应完成之后,蒸发过量的有机溶剂将得到期望产物,如果需要的话,可以通过在有机化学中实践的任何一般纯化方法(例如沉淀或结晶或制备柱纯化)来纯化所述期望产物。
还可以如下修饰具有醇和/或酚和/或胺的药物或生物活性分子:转化为各自的甲基甲酰基试剂,然后使用胺(例如吡啶)来制备季铵阳离子,例如,烟酰胺是优选的实施方案。使用具有醇和/或酚的药物或生物活性分子的这样的转化的非限制性实例示于下文的方案中。具有伯胺或仲胺的药物或生物活性分子之这样的转化的非限制性实例示于方案7和8中。
具有脂肪族伯胺或仲胺的药物/生物活性分子的修饰
方案7:
Rx/Ry=H或烷基;
类似地,首先使用吡啶作为碱并且使用DCM作为溶剂,使含胺的药物或生物活性分子(例如[239])与氯甲酸氯甲酯(例如[8])反应。对反应混合物进行标准工作,得到中间体[240]。然后在室温下或者在加热下使该中间体进一步与碘化物合适的金属盐(例如NaI)在丙酮或乙腈中反应,接着对反应混合物进行标准工作,得到中间体[241]。在室温下,使用溶剂(例如DCM或ACN)使该中间体与季铵化试剂(例如烟酰胺[243])反应。然后,在真空下蒸发有机溶剂以得到期望的经修饰药物或生物活性分子[242]。
方案8:
其中Rx/Ry=H或烷基;
类似地,可以首先使用DCM作为溶剂,使具有伯胺基团或仲胺基团的药物或生物活性分子[239]与合适的卤代乙酰基氯化物(例如溴代乙酰基氯化物)[244]反应。对反应混合物进行标准工作,得到中间体[245]。可以在室温下,使用溶剂(例如DCM)使该中间体[245]进一步与季铵化试剂(例如烟酰胺[243])反应。可以蒸发反应混合物以得到期望的最终经修饰药物或生物活性分子[246]。
方案9:
类似地,可以在室温下使用DCM作为溶剂,使具有伯胺基团或仲胺基团的相应药物或生物活性分子(例如[239])与氯甲基烟酸[247]反应。对反应进行标准工作,得到中间体[248],可以在室温下使用DCM作为溶剂,用合适的甲基甲酰基试剂[235](Y=R2、N(R2)2或OR2)进一步处理中间体[248]。进行类似的工作,得到期望的经修饰生物活性分子[249]。
B.1.3醇
用于具有醇/酚的药物/生物活性分子之修饰的方案
方案10:
可以使含醇的药物或生物活性分子(例如[250])与氯甲酸氯甲酯[8]在碱(例如吡啶)和溶剂(例如DCM)的存在下反应。对反应混合物进行标准工作,得到中间体[251]。在期望的温度(从环境温度至加热)下,使该中间体与合适的金属盐(例如碘化钠)在溶剂(例如丙酮)中反应,然后进行标准工作,得到化合物[252]。在室温下,使用溶剂(例如DCM),使化合物[252]与合适的季铵化试剂(例如烟酰胺[243])反应,然后蒸发有机溶剂,提供期望的经修饰药物或生物活性分子[253]。
方案11:
类似地,于期望的温度(从环境温度至回流)在碱(例如吡啶)的存在下,使相应的药物或生物活性分子[250]与合适的酰氯(例如烟酰氯[254])在溶剂(例如DCM)中反应,接着进行标准工作以得到中间体[255],在期望的温度(从环境温度至回流)下,使用溶剂(例如乙腈),用合适的甲基甲酰基试剂[235](Y=R2、N(R2)2或OR2)进一步处理中间体[255],得到期望的经修饰生物活性分子[256]。
方案12:
可以首先在期望的温度下,使含醇的药物或生物活性分子(例如[250])与合适的卤代乙酰基卤化物(例如溴代乙酰基氯化物[244])在溶剂(例如DCM)中反应,接着进行标准工作,得到化合物[257]。可以在期望的温度下,使用溶剂(例如ACN)使化合物[257]与合适的季铵化试剂(例如烟酰胺[243])进一步反应。蒸发反应混合物之后得到期望的最终经修饰药物或生物活性分子[258]。
方案13:
类似地,可以在期望的温度(从环境温度至回流)下,使相应的药物或生物活性分子[250]与合适的卤代甲基试剂(例如烟酸氯甲酯[259])在溶剂(例如DCM)中反应。对反应进行标准工作,得到中间体[260],可以在室温下使用DCM作为溶剂,用合适的甲基甲酰基试剂(例如[10](Y=R2、N(R2)2或OR2))进一步处理中间体[260]。进行类似的工作,得到期望的经修饰生物活性分子[261]。
B.1.4羧酸—具有羧酸部分之药物/生物活性分子的修饰
方案14:
可以在期望的温度下,使具有羧基的药物或生物活性分子[262]与合适的卤代甲基试剂(例如烟酸氯甲酯[259])在溶剂(例如DCM)中反应。对反应进行标准工作,得到中间体[263],可以在室温下使用DCM作为溶剂,用合适的甲基甲酰基试剂[235](Y=R2、N(R2)2或OR2)进一步处理中间体[263],以得到期望的经修饰生物活性分子[264]。
方案15:
类似地,可以在-10℃至60℃的温度下,使具有羧酸基团的相应药物或生物活性分子[262]与Lewis酸(例如氯化锌)(干燥)和醛(例如多聚甲醛)反应多至20小时至24小时的时间。对反应混合物进行标准工作,得到中间体[265],可以在室温下,使用DCM或ACN作为溶剂,使中间体[265]进一步与烟酰胺[322]反应。可以蒸发反应混合物,以得到期望的最终经修饰药物或生物活性分子[266]。
方案16:
类似地,可以用碱(例如碳酸氢钠和四丁基硫酸氢铵)处理二氯甲烷中的具有羧酸基团的相应药物或生物活性分子[262],然后在溶剂(例如二氯甲烷)中逐滴添加氯磺酸氯甲酯。反应完成之后,用Na2CO3水溶液洗涤有机层,然后进行标准工作并纯化,得到经取代甲基甲酰基试剂[265]。可以使29与季铵化试剂(例如烟酰胺[243])在溶剂(例如ACN)中进一步反应。蒸发反应混合物提供经修饰药物或生物活性分子[267]。
方案17:
类似地,可以使具有羧酸基团的相应药物或生物活性分子[262]与碱(例如碳酸铯)反应,然后在溶剂(例如THF)中添加试剂(例如溴代碘甲烷)。反应完成之后,进行标准工作并纯化,得到经取代甲基甲酰基试剂[268],可以使该经取代甲基甲酰基试剂[268]与季铵化试剂(例如烟酰胺[243])在溶剂(例如ACN)中进一步反应。蒸发反应混合物得到期望产物[269]。
方案18:季铵盐上的阴离子交换
可以通过上述方法使用合适的卤代甲基甲酰基试剂(例如碘甲基甲酰基)(I型或II型或III型)来制备季铵盐(例如[273])。可以在期望的温度(环境温度至回流)下,使用溶剂(例如乙腈)中合适的金属盐(例如甲磺酸银)来处理季铵化合物[272],导致碘化银沉淀并形成期望的产物。可以过滤出不溶性卤化银以得到合理纯的期望产物[273]。
上述方法适用于具有任何卤化物(例如氯化物、溴化物或碘化物)作为反离子的所有类型的季铵盐上的阴离子交换。可以使用多种类型的银盐,例如乙酸银、甲磺酸银或甲苯磺酸银等。
B.2由经取代甲基甲酰基修饰的化合物的实例
本文中提到的经取代甲基甲酰基试剂可用于通过如上所解释的方案修饰化合物。使用本发明的方法和试剂修饰的非限制性化合物组示于表1中。该列表仅意在举例说明并且不应理解为限制本发明的范围。
C.使用经取代甲基甲酰基试剂修饰化合物以改进在体内的转化率和位点
特异性
本发明的经取代甲基甲酰基试剂用于产生新的化学实体(NCE),使得可以控制这些NCE转化为母体药物/生物活性化合物的比率和位点。由于参与NCE转化成母体药物/生物活性物质的只可(或者甚至主要地)选择性地存在于转化位点处的转化酶或其他转化参数以及试剂的存在,这可以实现。转化率可以被改变,因为被修饰药物/生物活性分子的结构或存在于转化位点处转化酶的浓度/量可以影响NCE转化为药物/生物活性化合物的比率。能够转化这些化合物的内源性酶属于国际纯粹与应用化学联合会中的四类。来自1类的酶是氧化还原酶,来自2类的酶是转移酶,来自3类的酶是水解酶,并且来自4类的酶是裂解酶。已开发了多种经修饰化合物用于递送比通过施用未修饰化合物本身可以获得的更高浓度的药物至靶标。已鉴定了如本专利所述的经修饰药物或生物活性分子可采用的四种主要递送方式:(1)靶器官中的被动药物富集;(2)转运因子介导的递送;(3)通过酶的选择性代谢活化;以及(4)抗原靶向。
本发明的申请不止实现了简单地修饰药物/生物活性分子的药代动力学性质和物理化学性质。这导致能够使用与未经修饰药物所需相比较少的总计药物/生物活性化合物。这提供若干益处,包括非期望副作用的潜在降低或甚至消除。
因此,本领域普通技术人员会理解,本发明的甲基甲酰基试剂设计为通过内源系统自他们所结合的药物裂解,所述内源系统例如在较大或较小程度上存在于人和大多数作为宠物或家畜饲养的动物中的酶。因此,不同于对有效药物进行许多其他可能的共价修饰,根据本发明的衍生化使得能够改进经修饰化合物的性质,而不会牺牲初始的未经修饰药物的安全性、效力或毒理学。基于该原理,本领域普通技术人员会容易理解,本发明方法可以与本文所公开和教导的试剂一起用于制备多种具有改进的药代动力学性质、药效学性质和物理化学性质而不降低初始药物的效力的衍生化化合物。因此,本领域普通技术人员会理解,本文所示的实例仅为本发明及其应用的举例说明,并且不以任何方式限制本发明所公开或教导的发明的范围和宽度。
表2示出了可以使用本发明所述的方法和修饰试剂修饰的现有药物/生物活性化合物的示例性但非限制性列表。第一栏提供了药物和/或生物活性化合物的编号。第二栏给出了药物和/或生物活性化合物的通用名称。第三栏给出了药物出售时的商品名(适用时)。第四栏给出了药物和/或生物活性化合物的IUPAC名称。第五栏示出了药物的化学结构。例如,dimebon[4149]具有两个可经历衍生化的官能团。一个官能团是叔胺,另一个是芳胺。在方案31和32中对这些衍生化的非限制性实例进行了举例说明。本领域普通技术人员会容易理解,本发明教导,可以通过实施本发明的方法,使用具有根据方案1、2和/或3提及的官能团中的一个或更多个的任意多种药物来形成本发明的新的衍生化化合物。
表2:可以根据本发明实施方案衍生化的药物或生物活性分子的非限制性列表
本发明的试剂可用于修饰属于以下化合物类别的药物,所述药物可以选自但不限于:中枢神经系统药物,例如CNS/呼吸兴奋剂,镇痛剂,麻醉性激动剂,麻醉性激动剂/拮抗剂,非甾体抗炎/镇痛剂,行为调节剂,镇定剂/镇静剂,麻醉剂,吸入剂,麻醉剂(narcotic),逆转剂,抗惊厥剂,骨骼肌松弛剂,平滑肌松弛剂,安乐死制剂(Smooth,Euthanasia Agent),心血管剂,正性肌力剂,抗心律失常药,抗胆碱能剂,血管舒张剂,用于治疗休克的药剂,α-肾上腺素能阻断剂,β-肾上腺素能阻断剂,呼吸药物,支气管扩张药,拟交感神经药,抗组胺剂,镇咳剂,肾和尿道,用于尿失禁/潴留的药剂,尿碱化剂,尿酸化剂,胆碱能刺激剂,用于尿石病的药剂,胃肠药,抗呕吐药,抗酸剂,H2拮抗剂,胃粘膜保护剂,质子泵抑制剂,食欲刺激剂,GI解痉药-抗胆碱能剂,GI刺激剂,轻泻剂,盐水,体积产生剂,润滑剂,表面活性剂,止泻药,激素/内分泌/生殖药,性激素,合成代谢类固醇,垂体后叶激素,肾上腺皮质类固醇,糖皮质激素,抗糖尿病药,甲状腺药,甲状腺激素,混杂的内分泌/生殖药物,前列腺素,抗感染药物,抗寄生虫药,抗球虫剂,抗生素,抗结核药,氨基环醇类,头孢菌素类,大环内酯类,青霉素类,四环素类,林可酰胺类,喹诺酮类,磺酰胺类,混杂抗细菌剂,抗真菌剂,抗病毒剂,血液调节剂,凝血剂,抗凝血剂,促红细胞生成药物,抗肿瘤剂/免疫抑制剂,烷化剂,解毒剂,骨/关节药剂,皮肤病剂(全身),维生素和矿物质/营养物,全身酸化剂,全身碱化剂,抗癌剂,抗病毒剂等。
本发明的化合物被修饰后包括但不限于:
iii.1-((异丁酰基氧基)甲基)-3-((2-(硝基氧基)乙基)氨基甲酰基)吡啶-1-碘化物;
v.1-(((乙氧基羰基)氧基)甲基)-3-((2-(硝基氧基)乙基)氨基甲酰基)吡啶-1-碘化物;
xi.2-(((二异丙基氨基甲酰基)氧基)甲基)-5-(2-(1-(((二异丙基氨基甲酰基)氧基)甲基)-6-甲基吡啶-1--3-基)乙基)-2,8-二甲基-2,3,4,5-四氢-1H-吡啶并[4,3-b]吲哚-2-二碘化物;
xii.(S)-((4,11-二乙基-4-羟基-3,14-二氧代-3,4,12,14-四氢-1H-吡喃并[3′,4′:6,7]吲嗪并[1,2-b]喹啉-9-基)氧基)甲基烟酸酯;
xiii.(S)-3-((((4,11-二乙基-4-羟基-3,14-二氧代-3,4,12,14-四氢-1H-吡喃并[3′,4′:6,7]吲嗪并[1,2-b]喹啉-9-基)氧基)甲氧基)羰基)-1-(((异丙基氨基甲酰基)氧基)甲基)吡啶-1-碘化物;
xiv.4-((1E,4Z,6E)-5-羟基-7-(4-羟基-3-甲氧基苯基)-3-氧代庚-1,4,6-三烯-1-基)-2-甲氧基苯基烟酸酯;
xv.((1E,3Z,6E)-3-羟基-5-氧代庚-1,3,6-三烯-1,7-二基)双(2-甲氧基-4,1-亚苯基)二烟酸酯;
xvi.3,3′-(((((1E,3Z,6E)-3-羟基-5-氧代庚-1,3,6-三烯-1,7-二基)双(2-甲氧基-4,1-亚苯基))双(氧基))双(羰基))双(1-(((异丙基氨基甲酰基)氧基)甲基)吡啶-1-)二碘化物;
xvii.(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-苯甲酰胺基-2-(烟酰基氧基)-3-苯基丙酰基)氧基)-12-(苯甲酰基氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二氢-1H-7,11-桥亚甲基环十[3,4]苯并[1,2-b]氧杂环丁烷-6,12b-二基二乙酸酯;
xviii.3-((((1S,2R)-1-苯甲酰胺基-3-(((2aR,4S,4aS6R,9S,11S,12S,12aR,12bS)-6,12b-二乙酰氧基-12-(苯甲酰基氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二氢-1H-7,11-桥亚甲基环十[3,4]苯并[1,2-b]氧杂环丁-9-基)氧基)-3-氧代-1-苯基丙-2-基)氧基)羰基)-1-(((异丙基氨基甲酰基)氧基)甲基)吡啶-1-碘化物;
xix.(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-苯甲酰胺基-2-(((氯甲氧基)羰基)氧基)-3-苯基丙酰基)氧基)-12-(苯甲酰基氧基)-4-(((氯甲氧基)羰基)氧基)-11-羟基-4a,8,13,13-四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二氢-1H-7,11-桥亚甲基环十[3,4]苯并[1,2-b]氧杂环丁烷-6,12b-二基二乙酸酯;
xx.(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-苯甲酰胺基-2-(((碘甲氧基)羰基)氧基)-3-苯基丙酰基)氧基)-12-(苯甲酰基氧基)-11-羟基-4-(((碘甲氧基)羰基)氧基)-4a,8,13,13-四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二氢-1H-7,11-桥亚甲基环十[3,4]苯并[1,2-b]氧杂环丁烷-6,12b-二基二乙酸酯;
xxi.单(1-((((((1S,2R)-1-苯甲酰胺基-3-(((2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-6,12b-二乙酰氧基-12-(苯甲酰基氧基)-4-((((3-(二甲基氨基甲酰基)吡啶-1--1-基)甲氧基)羰基)氧基)-11-羟基-4a,8,13,13-四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二氢-1H-7,11-桥亚甲基环十[3,4]苯并[1,2-b]氧杂环丁-9-基)氧基)-3-氧代-1-苯基丙-2-基)氧基)羰基)氧基)甲基)-3-(二甲基氨基甲酰基)吡啶-1-)二碘化物;
xxii.((2-乙酰氧基苯甲酰基)氧基)甲基烟酸酯;
D.盐和异构体以及反离子
本发明在其范围内包括盐和异构体。在某些情况下,本发明的化合物可以在被经取代甲基甲酰基试剂修饰之后形成盐,所述盐也在本发明的范围内。本文中使用的术语“盐”是指与无机和/或有机酸和碱形成的酸性盐和/或碱性盐。两性离子(内部或内在的盐)包括在本文中使用的术语“盐’’的范围内(并且可以在例如R取代基包含诸如羧基的酸部分时形成)。本文中还包括季铵盐(例如烷基铵盐)。
优选药学可接受(即无毒、生理学上可接受)的盐,但其他盐也可用于例如可以在制备期间采用的分离或纯化步骤中。可以例如通过使化合物与一定量(例如当量)的酸或碱在介质(例如盐在其中沉淀的介质或者在水性介质)中反应然后冻干来形成所述化合物的盐。
示例性酸加成盐包括:乙酸盐(例如与乙酸或三卤代乙酸(例如三氟乙酸)形成的那些)、己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、硼酸盐、丁酸盐、柠檬酸盐、樟脑酸盐、樟脑磺酸盐、环戊烷丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙磺酸盐、乳酸盐、马来酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、草酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐、水杨酸盐、琥珀酸盐、硫酸盐(例如与硫酸形成的那些)、磺酸盐(例如本文所提到的那些)、酒石酸盐、硫氰酸盐、甲苯磺酸盐、十一酸盐等。
示例性碱盐(形成的,例如,其中取代基包含诸如羧基的酸性部分)包括:铵盐、碱金属盐(例如钠盐、锂盐和钾盐)、碱土金属盐(例如钙盐和镁盐)、与有机碱(例如有机胺)(例如苄星青霉素、二环己胺、哈胺(hydrabaimes)、N-甲基-D-葡糖胺、N-甲基-D-葡糖酰胺、叔丁胺)的盐以及与氨基酸(例如精氨酸、赖氨酸等)的盐。碱性含氮基团可以被一些试剂季铵化,所述试剂例如低级烷基卤化物(例如甲基、乙基、丙基和丁基氯化物、溴化物和碘化物)、硫酸二烷基酯(例如二甲基、二乙基、二丁基和二戊基硫酸酯)、长链卤化物(例如癸基、月桂基、肉豆蔻基和硬脂基氯化物、溴化物和碘化物)、芳烷基卤化物(例如苄基和苯乙基溴化物)以及其他。
本发明化合物的溶剂化物也涵盖在本文中。式I化合物的溶剂化物优选地为水合物或任何其他药学可接受的溶剂化物。
本发明化合物的所有立体异构体(例如,由于化合物的R取代基上的不对称碳原子可存在的那些,包括对映体形式和非对映体形式)涵盖在本发明的范围内。本发明化合物的各立体异构体可以例如基本上不含其他异构体,或者可以例如混合为外消旋体或与所有其他或其他选择的立体异构体混合。本发明的手性中心可以具有S或R构型。
本发明在其范围内还设想合适的反离子的选择作用。可以通过选择药物能够在所述pH范围内离子化的解离常数来选择本发明化合物的反离子。通过评估任何化合物的离子化的和未离子化的药物浓度(使用公认的方程式(例如Henderson-Hasselbach方程式)),可以改进药物的溶解性并且因此可以改进药物的吸收。
本发明在其范围内包括氘化化合物的修饰。氘化化合物是其中所述化合物中选择性并入氘代替氢的那些。根据本文所公开的方法,可以用本发明的经取代甲基甲酰基试剂来进一步修饰氘化化合物。
E.包含本发明的经修饰实体的组合物
因此,本发明还提供如本文所定义的经修饰实体在人医或兽医中的用途。用作药物的化合物可以表示为药物制剂。
因此,在另一方面中,本发明提供了药物制剂,所述药物制剂包含本发明的经修饰化合物及其药学可接受的载体,并任选地包含其他治疗和/或预防成分。载体必须是“可接受的”,其意义是与该配方的其他成分相容并且对其接受者无害。药物制剂将合适地为合适的单位剂型。
所述药物制剂可以是任何制剂,并且包括适于经口、鼻内、眼内或肠胃外(包括肌内和静脉内)施用的那些。制剂可以(如果合适)方便地以离散剂量单位提供,并且可以通过药学领域中公知的任何方法来制备。所有方法包括以下步骤:将活性化合物与液体载体或良好分离的固体载体或二者组合在一起,然后,如果必要的话,将产物成形为期望的制剂。
出于这些目的,本发明的化合物可以通过经口、局部、鼻内、眼内、肠胃外、通过吸入喷剂或直肠以包含常规的无毒药学可接受载体、佐剂和载剂的单位剂量制剂施用。本文中使用的术语“肠胃外”包括皮下注射、静脉内注射、肌内注射或胸骨内(intrasteral)注射或输注技术。除诸如小鼠、大鼠、马、狗、猫等的温血动物的治疗以外,本发明的化合物在人的治疗中也有效。
实施例
根据上述教导,可以对本发明进行多种修改和变化。因此,应理解,在所附权利要求书的范围内,除在本文中具体地举例说明的那些以外,还可以以其他方式实施本发明。
实验
方案19:用于合成III型试剂的典型合成方法的实例
方法:
步骤(A):
在冰冷却下,向氯甲酸氯甲酯[8](7.75mmol,1当量)的己烷溶液中逐滴添加吡啶(19.3mmol,2.5当量)的己烷溶液。完成添加之后,形成了白色固体沉淀。在相同的温度下向己烷中添加叔丁醇(11.62mmol,1.5当量)。在添加叔丁醇之后,反应混合物变为澄清溶液。将所得混合物在冰冷却下搅拌2小时,然后在室温(RT)下搅拌1小时。通过TLC监测反应完成,与起始材料相比,其示出一个非极性点。对反应进行以下工作:用己烷稀释反应混合物,用饱和NaHCO3溶液洗涤,接着用2N HCl溶液洗涤,然后用饱和NaHCO3溶液进行第二洗涤,最后用水洗涤。分离有机层,经Na2SO4干燥并在减压下蒸发以得到作为无色粘性液体的试剂叔丁基(氯甲基)碳酸酯[274](0.900g,70%)。
1H NMR:[CDCl3,300MHz]:-δ5.774(s,2H),1.518(s,9H).
步骤(B):
向溶解于丙酮中的叔丁基(氯甲基)碳酸酯[274](9.87mmol,1当量)溶液中添加碘化钠(29.61mmol,3当量)。在室温下,将所得反应混合物搅拌过夜。TLC示出初始材料的消耗和与初始材料相比一个新的非极性点。对反应进行以下工作:滤出任何沉淀的固体并蒸发丙酮层。将所得固体溶于DCM中。再将溶液过滤一次以除去任何未溶于DCM中的固体。蒸发所得DCM层。通过使用100-200目大小二氧化硅和1%MeOH-DCM作为溶剂系统将粗制产物通过柱色谱,以得到作为无色液体的产物叔丁基(碘甲基)碳酸酯[275](136mg,30%)。
1H NMR[CDCl3,300MHz]:δ5.90(s,2H),1.518(s,9H).
方案20:用于合成I型试剂的典型合成方法的实例
步骤(A):
在惰性气氛下,将合适的Lewis酸(例如氯化锌)(催化量-0.50g)融合在干燥的2颈圆底烧瓶中。在室温下,向所制备的Lewis酸中添加异丁酰基氯化物[276](46.72mmol,1当量)和多聚甲醛(47.0mmol,10当量)。将反应混合物加热至60℃过夜。通过TLC监测反应。通过添加DCM停止反应,并用饱和NaHCO3洗涤,然后用盐水洗涤。分离有机层,经Na2SO4干燥并在减压下蒸发以得到作为无色油的产物异丁酸氯甲酯[277](2.0g,31%)。
1H NMR[CDCl3,300MHz]:δ5.71-5.76(d,2H),2.54-2.64(m,1H),1.17-1.21(d,6H)
步骤(B):
向异丁酸氯甲酯[277](14.6mmol,1当量)的丙酮溶液中添加碘化钠(43.9mmol,3当量)。将所得反应混合物在室温下搅拌过夜。通过TLC监测反应完成。对反应进行以下工作:滤出沉淀的固体,并在减压下蒸发过量的丙酮。获得固体并用DCM洗涤,同时使用布氏漏斗在抽滤。蒸发所得DCM层以提供粗制产物,使用硅胶柱色谱(100至200目)并且使用DCM作为洗脱剂来进一步纯化所述粗制产物。获得作为褐色液体的产物异丁酸碘甲酯[278](1.6g,50%产率)。
1H NMR[CDCl3,300MHz]:δ6.21(s,2H),2.54-2.64(m,1H),1.17-1.21(d,6H).
方案21:((甲基磺酰基)氧基)甲基3-甲基丁酸酯的合成:
方法:
[179]向乙腈(8ml)中添加甲磺酸的银盐[0.34g,1.6mmol,0.5当量],并且向其中添加3-甲基丁酸氯甲酯[279](0.5g,3.3mmol,1.0当量)。将所得溶液加热至60℃,保持5小时。通过TL(监测反应进程。完成之后,过滤反应并在真空下蒸发溶剂以得到无色油。通过硅胶柱色谱(10%EtOAc:环己烷,100-200目)纯化粗化合物,得到作为无色油的[280]((甲基磺酰基)氧基)甲基3-甲基丁酸酯[0.25g,40%]。
方案22:I型试剂(烟酸氯甲酯)
向装配有干燥冷凝器、输出器(take-off)和制动器的经烘箱干燥的三颈R.B.F中添加氯化锌(0.3g,10%),在干燥条件下使用热枪融合。冷却至室温后,添加无水DCM(60ml),然后添加多聚甲醛(5.2g,170mmol,10.0当量)和化合物[254](3.0g,17mmol,1.0当量)。在干燥条件下将反应回流两天。冷却之后,用NaHCO3饱和溶液处理反应,并用DCM萃取。将合并的有机层经Na2SO4干燥,在真空下蒸发以得到作为无色油的[281](0.6g,16.6%)。
1HNMR(300MHz;CDCl3)δ:9.28-9.27(s,1H);8.89-8.83(dd,1H);8.34-8.33(d,1H);7.47-7.42(dd,1H);5.97(s,2H).M+1=172
方案23:I型试剂(烟酸氯甲酯)之合成的改进方法
在室温下,向剧烈搅拌的烟酸[282](1.0g,10.0mmol,1.0当量)、碳酸氢钠(3.2g,40.0mmol,4.0当量)和四丁基硫酸氢铵(0.175g,0.1mmol,0.1当量)的水溶液(10ml)中,添加二氯甲烷(10ml),然后逐滴添加氯磺酸氯甲酯(0.1g,12.5mmol,1.1当量)的二氯甲烷(5ml)溶液。在室温下将反应搅拌1小时后,分离二氯甲烷层,用5%Na2CO3水溶液(1×25ml)洗涤,分离有机层,经Na2SO4干燥,然后在真空下过滤并浓缩以得到作为无色油的烟酸氯甲酯[28l](0.70g,50%)。
方案24:试剂((甲基磺酰基)氧基)甲基烟酸酯的合成
方法:
向乙腈(8ml)中添加甲磺酸的银盐[0.096g,0.47mmol,0.8当量],并且向其中添加烟酸氯甲酯[281](0.1g,0.59mmol,1.0当量)。将所得溶液加热至60℃,保持5小时。通过TLC监测反应进程。完成之后,过滤反应并在真空下蒸发溶剂以得到无色油。通过硅胶柱色谱(35%EtOAc:环己烷,100-200目)纯化粗化合物以得到作为无色油的[282]((甲基磺酰基)氧基)甲基烟酸酯[0.035g,25%]。
m/z:232
方案25:用于合成II型试剂的典型合成方法的实施例
步骤(A):
在0℃下,向氯甲酸氯甲酯[8](1.00g,7.75mmol,1.0当量)的DCM(yml)溶液中逐滴添加异丙胺(1.14g,19.30mmol,2.5当量)的DCM溶液。在添加时反应混合物中沉淀出白色固体。将所得混合物在0℃下搅拌2小时,然后在室温下搅拌1小时。通过TLC监测反应,对反应进行以下工作:用DCM稀释反应混合物,用饱和的NaHCO3溶液洗涤,然后用2N HCl溶液洗涤,再用饱和的NaHCO3溶液洗涤,最后用水洗涤。分离有机层,经Na2SO4干燥,在减压下蒸发以得到作为无色油的异丙基氨基甲酸氯甲酯[283](0.50g,44%)。
1H NMR[CDCl3,300MHz]:δ5.73(s,2H),4.73(s,-NH),3.78-3.91(m,1H),1.17-1.19(d,6H)
步骤(B):
向异丙基氨基甲酸氯甲酯[283](0.30g,1.98mmol,1.0当量)的丙酮溶液中添加碘化钠(0.89g,5.94mmol,3.0当量)。将所得反应混合物在室温下搅拌过夜。通过TLC监测反应。对反应进行以下工作:过滤出沉淀的固体,在真空下蒸发丙酮层。将所得固体溶于DCM中并过滤以除去残余固体。在减压下蒸发如此得到的DCM层以得到粗制产物,使用硅胶柱色谱(2%MeOH:DCM,100-200目)纯化所述粗制产物,得到作为无色粘性材料的纯异丙基氨基甲酸碘甲酯[284](0.12g,37%)。
1H NMR[CDCl3,300MHz]:δ5.96(s,2H),4.65(s,-NH),3.80-3.91(m,1H),1.17-1.19(d,6H).
方案26:吗啉-4-羧酸溴甲酯的合成
方法:
向丙酮(10ml)中添加吗啉-4-羧酸氯甲酯[285](0.3g,1.67mmol,1.0当量)和溴化钠(0.86g,8.3mmol,5.0当量)。将反应在60℃下回流24小时。通过TLC/1HNMR监测反应进程。过滤反应,在减压下将滤液蒸发至干,得到浅棕色凝胶,吗啉-4-羧酸溴甲酯[286](0.30g,80%)。
1H NMR(CDCl3):δppm5,92(s,2H),3.72(t,4H),3.54δ(t,4H)s
方案27:
方法:
向乙腈(10ml)中添加吗啉-4-羧酸氯甲酯[6316](0.3g,1.67mmol,1.0当量)和溴化锂(0.72g,8.3mmol,5.0当量)。将反应在90℃下回流30小时。通过TLC/1HNMR监测反应进程。过滤反应,在减压下将滤液蒸发至干,得到浅棕色凝胶,吗啉-4-羧酸溴甲酯[6327](0.30g,80%)。
1H NMR(CDCl3):δppm5.92(s,2H),3.72(t,4H),3.54δ(t,4H)
使用本文和上文中公开的合成方法,用多种经取代或未经取代的醇、酚、胺和酸合成其他甲基甲酰基试剂,以得到表3、4和5中的结构,这些结构使用光谱学技术(例如MS和/或1HNMR)进行了表征。
表3:I型试剂的实例
表4:II型试剂的实例
表5:III型试剂的实例
因此,本领域普通技术人员将从本文的教导容易地理解,可以如所公开和教导的那样来合成多种本发明的修饰试剂,包括但不限于本文提供的具体实例,包括表3、4和5中的那些。因此,本发明的一方面是调整图1所公开试剂家族的取代基,以适用于特定应用或者获得期望结果的能力。
对含有芳族氮作为杂原子的药物/生物活性化合物进行化学修饰的实施例
方案28:尼可地尔(Nicorandil)的经修饰形式的合成
向尼可地尔(2-(烟酰胺基)-乙基硝酸酯)[287](0.28mmol,1当量)的乙腈(3ml)溶液中逐滴添加异丙基氨基甲酸碘甲酯[6318](0.28mmol,1.2当量)。将所得反应混合物在室温下搅拌过夜。通过TLC监测反应完成。用Buchi旋转蒸发仪在真空下除去过量的乙腈。将所得粗制产物溶于最低量的MeOH中,用过量的醚洗涤。将该过程重复两次以得到接近纯的固体产物,1-(((异丙基氨基甲酰基)氧基)甲基)-3-((2-(硝基氧基)乙基)氨基甲酰基)吡啶-1-碘化物[288],将该固体产物在高真空下干燥以得到作为黄色粘性固体的产物(0.085g,88%)。
m/z:327(M+)
1H NMR[DMSO,300MHz]:δppm9.54(s,1H),9.43-9.46(m,1H),9.27-9.29(d,1H),9.01-9.04(d,1H),8.33-8.38(m,1H),7.86-7.88(m,1H),6.41(s,2H),4.67-4.70(t,2H),3.69-3.74(m,2H),3.52-3.63(m,1H),1.04-1.11(m,6H)
使用类似的合成方法用多种经取代甲基甲酰基试剂完成了尼可地尔的其他化学修饰以得到表6中的结构,其通过使用光谱学技术(例如MS和/或1H NMR)进行了表征。
测试了这些化合物的药代动力学参数,发现它们的活性比尼可地尔高。对应于化合物的Pk数据示于表6中。
按照如下方案测试了这些化合物的PK数据:
将雌性Sprague Dawley(SD)大鼠(每组3只)禁食过夜之后,用含伊马替尼及其经修饰药物的蒸馏水(5ml/kg)以3mg/kg的剂量水平经口(通过强饲法)施用。通过连续取血在0.16h、0.5h、1h、2h、4h、6h、8h以及24h将血液收集到肝素化试管中。将血液样品在4℃以10,000rpm离心10分钟,以获得血浆,将所得血浆吸入单独的标记试管中,并在-80℃下储存。使用400ng/ml的含维拉帕米(Verapmil)的乙腈作为药物萃取溶剂,以从血浆中萃取药物。将萃取溶剂添加到血浆中,涡旋并在振荡器中振荡10分钟,在4℃以10,000rpm离心10分钟。保留上清液用于分析。
产生乙腈和血浆校准曲线,并确定从血浆回收药物的百分比。通过使用多反应监测的液相色谱串联质谱(API3000LC-MS/MS)完成定量分析。使用Graph Pad PRISM版本5.04计算了Cmax、Tmax、AUC以及t1/2。
表6:尼可地尔的化学修饰的一些实例及其在以3mpk经口施用的Swiss
小鼠中确定的药代动力学参数(T
max
、C
max
、AUC以及t
1/2
)
因此,本领域普通技术人员将容易地从本文的教导理解,可以如所教导和公开的那样合成多种本发明修饰试剂,包括但不限于本文提供的具体实例。如本文所教导的以及本文中示例性给出的,根据本发明教导的修饰提供了改变生物活性化合物的各种药代动力学参数的容易且灵活的方法。具有脂肪族叔氮作为杂原子的药物/生物活性化合物的化学修饰的实例
方案31:Dimebon的经修饰形式(衍生物1)的合成
方法:
在室温下,向dimebon(2,8-二甲基-5-(2-(6-甲基吡啶-3-基)乙基)-2,3,4,5-四氢-1H-吡啶并[4,3-b]吲哚)[4149](0.070g,0.22mmol,1.0当量)的乙酸乙酯搅拌溶液中添加二异丙基碳酸碘甲酯[6304](0.057g,0.20mmol,0.9当量)。将反应混合物在室温下搅拌4小时至6小时。通过在抽吸下过滤收集所得沉淀,用乙酸乙酯洗涤四次,然后再用乙醚洗涤,得到浅黄色固体,在室温于真空下干燥该固体,得到期望产物2-(((二异丙基氨基甲酰基)氧基)甲基)-2,8-二甲基-5-(2-(6-甲基吡啶-3-基)乙基)-2,3,4,5-四氢-1H-吡啶并[4,3-b]吲哚-2-碘化物[292](0.020g,15%)。
m/z:477.3
方案32:Dimebon的经修饰形式(衍生物II)的合成
方法:
在室温下,向dimebon[4149](0.030g,0.094mmol,1.0当量)的乙酸乙酯搅拌溶液中添加二异丙基氨基甲酸碘甲酯[6304](0.134g,0.47mmol,5.0当量)。将反应混合物在室温下搅拌4小时至6小时。在抽滤所得沉淀,用乙酸乙酯洗涤四次,然后再用乙醚洗涤,得到浅黄色固体,在室温于真空下干燥该固体,得到期望产物2-(((二异丙基氨基甲酰基)氧基)甲基)-5-(2-(1-(((二异丙基氨基甲酰基)氧基)甲基)-6-甲基吡啶-1--3-基)乙基)-2,8-二甲基-2,3,4,5-四氢-1H-吡啶并[4,3-b]吲哚-2-二碘化物[293](0.033g,39%)。
m/z:317.8
方案33:奥氮平(Olanzapine)的经修饰形式的合成
在室温下,向奥氮平,(2-甲基-4-(4-甲基哌嗪-1-基)-10H-苯并[b]噻吩并[2,3-e][1,4]二氮杂[4134](0.025g,0.086mmol,1.0当量)的ACN搅拌溶液中添加异丙基氨基甲酸碘甲酯[6318](0.20g,0.086mmol,1.0当量)。将反应混合物在室温下搅拌4至16小时。通过TLC监测反应进程。在真空下除去溶剂以得到粗制产物。用乙醚(5ml×2)研磨所得粗制产物,得到作为黄色固体的期望产物[294],1-(((异丙基氨基甲酰基)氧基)甲基)-1-甲基-4-(2-甲基-10H-苯并[b]噻吩并[2,3-e][1,4]二氮杂-4-基)哌嗪-1-碘化物(0.013g,41%)。
方案34:西地那非(Sildenafil)的经修饰形式的合成
方法:
在室温下,向西地那非[4102](0.03g,0.063mmol,1.0当量)的ACN(3ml)搅拌溶液中添加乙酸氯甲酯[5212](0.007g,0.063mmol,1.0当量)和碘化钠(0.018g,0.063mmol,3.0当量)。将反应混合物在室温下搅拌4至48小时。通过TLC监测反应进程。在真空下除去溶剂以得到粗制产物。向粗制产物中添加DCM以沉淀出碘化钠,通过过滤分离碘化钠,并蒸发滤液以得到白色固体。在室温于真空下干燥产物,得到[295]1-(乙酰氧基甲基)-4-((4-乙氧基-3-(1-甲基-7-氧代-3-丙基-4,7-二氢-1H-吡唑并[4,3-d]嘧啶-5-基)苯基)磺酰基)-1-甲基哌嗪-1-碘化物(0.14g,42%)。
还可以以类似的方式制备西地那非的其他衍生物。西地那非的一些非限制性实例如下:
具有醇/酚作为官能团的药物/生物活性化合物的化学修饰的实例
方案35:扑热息痛的经修饰形式(衍生物I)的合成
步骤1:
在氩气氛下,向扑热息痛[4147](0.26g,1.7mmol,1.0当量)的无水THF溶液中添加TEA(1.2ml,8.6mmol,5.0当量)。在0℃下,向上述反应混合物中添加烟酰氯盐酸盐[296](1.53gm,8.6mmol,5.0当量)。将反应混合物在室温下搅拌24小时。24小时之后,在真空下蒸发有机溶剂,将残余物溶于二氯甲烷(50ml)中,用10%的NaHCO3溶液(15ml)洗涤,然后用盐水(10ml)洗涤,接着经无水硫酸钠干燥有机层。蒸发溶剂,提供白色固体,通过硅胶柱色谱(4%MeOH:DCM,100-200目二氧化硅)纯化该白色固体,得到产物4-乙酰胺基苯基烟酸酯[297](0.34g,78%)。
m/z:257
步骤2:
向4-乙酰胺基苯基烟酸酯[297](0.05g,1.95mmol,1.0当量)的乙腈(4ml)溶液中添加二异丙基氨基甲酸碘甲酯[6304](0.055g,1.95mmol,1.0当量)。将所得反应混合物在室温下搅拌过夜。通过TLC监测反应。在真空下除去乙腈,用乙醚(10ml)洗涤所得粗混合物,以得到浅黄色固体产物3-((4-乙酰胺基苯氧基)羰基)-1-(((二异丙基氨基甲酰基)氧基)甲基)吡啶-1-碘化物[298](0.086g,81%)。
m/z:414
方案36:扑热息痛的经修饰形式(衍生物II)的合成
步骤1:
在氩气氛下,向扑热息痛[4147](0.10g,0.66mmol,1.0当量)的无水THF溶液中添加TEA(0.28ml,1.98mmol,3.0当量)。在0℃下,添加溴乙酰氯[244](0.123g,0.79mmol,1.2当量)。将反应混合物在室温下搅拌24小时。24小时之后,在真空下蒸发溶剂,将残余物溶于二氯甲烷(50ml)中,用10%的NaHCO3溶液(15ml)洗涤,然后用盐水(10ml)洗涤,接着经无水硫酸钠干燥有机层。蒸发溶剂提供白色固体,通过硅胶柱色谱(0.5%MeOH:DCM,100-200目二氧化硅)纯化该白色固体,得到产物4-乙酰胺基苯基2-溴乙酸酯[299](0.05g,28%)。
m/z:272
步骤2:
向4-乙酰胺基苯基2-溴乙酸酯[299](0.05g,1.84mmol,1.0当量)的乙腈(5ml)溶液中添加碘化钠(0.083g,5.52mmol,3.0当量),接着添加二甲基烟酰胺[300](0.027g,1.84mmol,1.0当量)。将所得反应混合物在40℃下搅拌48小时。通过TLC监测反应进程。在真空下除去溶剂,得到粗制产物。将所得粗制产物溶于DCM中以沉淀过量的碘化钠和溴化钠,通过过滤除去过量的碘化钠和溴化钠,并蒸发滤液以得到黄色固体,用乙醚(10ml)洗涤该黄色固体,然后在真空下干燥,得到浅黄色固体1-(2-(4-乙酰胺基苯氧基)-2-氧代乙基)-3-(二甲基氨基甲酰基)吡啶-1-碘化物[301],(0.038g,44%)。
m/z:342
方案37:扑热息痛的经修饰形式(衍生物III)的合成
步骤1:
在0℃于氩气氛下,向氯甲酸氯甲酯(CMCF)[8](0.294g,22.8mmol,1.2当量)的无水THF(10ml)溶液中添加吡啶(0.375g,47.5mmol,2.5当量)。在0℃下,向上述反应混合物中添加扑热息痛[4147](0.30g,19.0mmol,1.0当量)的无水THF溶液。将反应混合物在室温下搅拌20小时。通过TLC监测反应进程。20小时之后,用二氯甲烷(50ml)稀释反应混合物,用水(15ml)、10%的NaHCO3溶液(15ml)、稀HCl(10ml)洗涤,然后用盐水(10ml)洗涤。经无水硫酸钠干燥有机层。在真空下蒸发溶剂得到粗制产物。通过硅胶柱色谱(2%MeOH:DCM,100-200目)纯化该粗制产物,得到灰白色产物4-乙酰胺基苯基(氯甲基)碳酸酯[302](0.33g,68%)。
m/z:244
步骤2:
向4-乙酰胺基苯基(氯甲基)碳酸酯[302](0.20g,29mmol,1.0当量)的丙酮溶液中添加碘化钠(0.454g,107mmol3.7当量)。将所得反应混合物在50℃下加热6小时。通过TLC监测反应进程。将反应混合物冷却至室温并通过二氧化硅床(100-200目)。将二氧化硅床用丙酮洗涤若干次,并收集级分,在真空下蒸发以得到期望产物4-乙酰胺基苯基(碘甲基)碳酸酯[303](0.27gm,98%)。
m/z:336
步骤2:
在氩气氛下,向4-乙酰胺基苯基(碘甲基)碳酸酯[303](0.05g,15.0mmol,1.0当量)的无水乙腈(2ml)溶液中添加二甲基烟酰胺[300](0.022g,15mmol,1.0当量)。将所得反应混合物在室温下搅拌2天。通过TLC监测反应进程。在真空下除去溶剂以得到粗制产物。用乙醚(2×10ml)研磨所得粗制产物,以得到期望产物1-((((4-乙酰胺基苯氧基)羰基)氧基)甲基)-3-(二甲基氨基甲酰基)吡啶-1-碘化物[304](0.021g,29%)。
m/z:358
方案38:SN-38的经修饰形式的合成方法
步骤1:
在0℃于N2气氛下,向SN-38((S)-4,11-二乙基-4,9-二羟基-1H-吡喃并[3′,4’:6,7]吲嗪并]1,2-b]喹啉-3,14(4H,12H)-二酮[4150])(0.20g,0.51mmol,1.0当量)的DMF(2ml)溶液中分批添加NaH(0.012g,0.51mmol,1.0当量)。再将所得反应混合物在0℃下搅拌30分钟。向反应混合物中逐滴添加溶于DMF中的烟酸氯甲酯[259](0.087g,0.51mmol,1.0当量)同时将温度保持在0℃。然后,使反应达到室温,并搅拌过夜。通过添加水淬灭反应质量。用DCM(2×100ml)萃取反应混合物。合并有机层并用盐水洗涤,经Na2SO4干燥并蒸发。在柱色谱(2%MEOH:DCM,硅胶100-200目)上纯化所得粗制产物,得到浅黄色固体(S)-((4,11-二乙基-4-羟基-3,14-二氧代-3,4,12,14-四氢-1H-吡喃并[3’,4’:6,7]吲嗪并[1,2-b]喹啉-9-基)氧基)甲基烟酸酯[305](0.036g,13%)。
m/z=528
1H NMR(DMSO,300MHz):δppm9.36(s,1H);8.95(d,1H);8.58(d,1H);8.23-8.25(dd,2H);7.84(d,1H);7.69-7.72(m,1H),7.29(d,1H);6.50-6.53(m,1H);6.01-6.04(d,1H);5.75(s,1H);5.29(s,2H);4.80-4.84(bs,1H);4.67(br,1H);4.03-4.09(bs,1H);3.31-3.33(m,2H);1.82-1.92(m,2H);1.29-1.34(t,3H);0.85-0.93(t,3H)
步骤2:
向(S)-((4,11-二乙基-4-羟基-3,14-二氧代-3,4,12,14-四氢-1H-吡喃并[3’,4’:6,7]吲嗪并[1,2-b]喹啉-9-基)氧基)甲基烟酸酯[305](0.015g,0.028mmol,1.0当量)的DCM(5ml)溶液中添加异丙基氨基甲酸碘甲酯[6318](0.007g,0.028mmol,1.0当量)。将反应混合物在室温下搅拌16小时。在减压下蒸发DCM,并用乙醚彻底洗涤,得到作为黄色固体的[306],(S)-3-((((4,11-二乙基-4-羟基-3,14-二氧代-3,4,12,14-四氢-1H-吡喃并[3′,4′:6,7]吲嗪并[1,2-b]喹啉-9-基)氧基)甲氧基)羰基)-1-(((异丙基氨基甲酰基)氧基)甲基)吡啶-1-碘化物(0.018g,85%)。
m/z:643
1H NMR(300MHz;DMSO):δ9.98(s,1H);9.39-9.46(d,1H);9.36(d,1H);8.45-8.49(t,1H);8.28-8.29(dd,2H);7.25(s,1H);6.50-6.53(m,3H);6.04-6.07(d,1H);5.39-5.42(s,2H);4.80-4.87(br,1H);4.72(br,1H);4.03-4.09(br,1H);3.36(m,1H);3.07-3.11(m,2H);1.84-1.90(m,2H);1.29-1.34(t,3H);1.06-1.11(m,6H);0.85-0.93(t,3H)
方案39:姜黄素的经修饰形式的合成
步骤1:
在0℃下,向烟酰氯盐酸盐[296](0.725g,4.0mmol,1.5当量)的THF(30ml)溶液中逐滴添加TEA(1ml,xmmol,y当量)。然后在相同的温度下添加姜黄素((1E,4Z,6E)-5-羟基-1,7-双(4-羟基-3-甲氧基苯基)庚-1,4,6-三烯-3-酮[4151](1.0g,2.7摩尔,1.0当量))和吡啶(1ml)的THF(10ml)溶液。将反应温度逐渐升高至室温。将反应混合物在室温下搅拌20小时。通过TLC监测反应。用EtOAc(200ml)稀释反应混合物,依次用饱和NaHCO3溶液(75ml)和水(100ml)洗涤。分离EtOAc层,用硫酸钠干燥并在减压下浓缩以得到粗制产物。通过采用2%MeOH:DCM,100-200目的柱色谱纯化粗制产物,以得到作为黄色固体的期望产物4-((1E,4Z,6E)-5-羟基-7-(4-羟基-3-甲氧基苯基)-3-氧代庚-1,4,6-三烯-1-基)-2-甲氧基苯基烟酸酯[307](0.30g,23%)。
m/z:579
还产生了对应于((1E,3Z,6E)-3-羟基-5-氧代庚-1,3,6-三烯-1,7-二基)双(2-甲氧基-4,1-亚苯基)二烟酸酯[308](0.03g,2.3%)的黄色固体。
m/z:474.
步骤2:
将化合物[308][((1E,3Z,6E)-3-羟基-5-氧代庚-1,3,6-三烯-1,7-二基)双(2-甲氧基-4,1-亚苯基)二烟酸酯](0.02g,0.035mmol,1.0当量)溶于溶剂ACN(1ml)中,接着在室温于搅拌下添加[6318](0.018g,0.076mmol,2.2当量)。在室温下,将所得反应混合物进一步搅拌过夜。通过TLC监测反应。在真空下蒸发过量的乙腈,以得到粗制产物,用乙酸乙酯(5ml)接着用乙醚(10ml)研磨该粗制产物,得到黄色固体3,3′-(((((1E,3Z,6E)-3-羟基-5-氧代庚-1,3,6-三烯-1,7-二基)双(2-甲氧基-4,1-亚苯基))双(氧基))双(羰基))双(1-(((异丙基氨基甲酰基)氧基)甲基)吡啶-1-)二碘化物[309](0.017g,46%)。
m/z:405.
方案40:紫杉醇的经修饰形式(衍生物I)的合成
步骤1:
在氮气氛下,向紫杉醇[4114](0.10g,0.117mmol1.0当量)的无水二氯甲烷溶液中添加4滴吡啶。在0℃下,添加烟酰基氯盐酸盐[296](0.17g,1.17mmol10.0当量)。将反应混合物在室温下搅拌24小时。24小时之后,用二氯甲烷(25ml)稀释该混合物,用10%的NaHCO3溶液(15ml)和盐水(10ml)洗涤,接着经无水硫酸钠干燥。蒸发溶剂提供残余黄色固体,通过硅胶柱色谱(30%乙酸乙酯:环己烷,100-200目二氧化硅)纯化该黄色固体,得到白色固体[310],(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-苯甲酰胺基-2-(烟酰基氧基)-3-苯基丙酰基)氧基)-12-(苯甲酰基氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二氢-1H-7,11-桥亚甲基环十[3,4]苯并[1,2-b]氧杂环丁烷-6,12b-二基二乙酸酯(0.05g,45%)。
m/z:959.2
步骤2:
在氩气氛下,向[310](0.01g,10.0mmol,1.0当量)的无水乙腈溶液中添加异丙基氨基甲酸碘甲酯[6318](0.003g,10mmol,1.0当量)。将所得反应混合物在室温下搅拌6小时。通过TLC监测反应进程。在高真空泵下蒸发溶剂以得到粗制产物。用乙醚(2×10ml)研磨所得粗制产物,得到黄色固体[311],3-((((1S,2R)-1-苯甲酰胺基-3-(((2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-6,12b-二乙酰氧基-12-(苯甲酰基氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二氢-1H-7,11-桥亚甲基环十[3,4]苯并[1,2-b]氧杂环丁-9-基)氧基)-3-氧代-1-苯基丙-2-基)氧基)羰基)-1-(((异丙基氨基甲酰基)氧基)甲基)吡啶-1-碘化物,(0.01g,90%)。
m/z:1075.2
方案41:紫杉醇的经修饰形式(衍生物II)的合成
步骤1:
在0℃于氩气氛下,向氯甲酸氯甲酯(CMCF)[8](0.02g,23.0mmol,2.0当量)的无水二氯甲烷溶液中添加吡啶(0.026g,23.0mmol,2.0当量)。在0℃下,向上述反应混合物中添加紫杉醇[4114](0.10g,11.7mmol,1.0当量)的无水二氯甲烷溶液。将反应混合物在室温下搅拌2小时。通过TLC监测反应进程。2小时之后,用二氯甲烷(25ml)稀释反应混合物,用10%的NaHCO3溶液(15ml)、盐水(10ml)洗涤,然后经无水硫酸钠干燥。在真空下蒸发溶剂,得到白色固体[312],(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-苯甲酰胺基-2-(((氯甲氧基)羰基)氧基)-3-苯基丙酰基)氧基)-12-(苯甲酰基氧基)-4-(((氯甲氧基)羰基)氧基)-11-羟基-4a,8,13,13-四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二氢-1H-7,11-桥亚甲基环十[3,4]苯并[1,2-b]氧杂环丁烷-6,12b-二基二乙酸酯(0.11g,90%)。
m/z:1038.3
步骤2:
向[312](0.03g,29.0mmol,1当量)的丙酮溶液中添加碘化钠(0.022g,145.0mmol,5当量)。将所得反应混合物在60℃下回流6小时。通过TLC监测反应进程。将反应混合物冷却至室温,并流经二氧化硅床(100-200目)。用丙酮洗涤二氧化硅床,收集丙酮并在真空下蒸发,得到白色固体[313],(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-苯甲酰胺基-2-(((碘甲氧基)羰基)氧基)-3-苯基丙酰基)氧基)-12-(苯甲酰基氧基)-11-羟基-4-(((碘甲氧基)羰基)氧基)-4a,8,13,13-四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二氢-1H-7,11-桥亚甲基环十[3,4]苯并[1,2-b]氧杂环丁烷-6,12b-二基二乙酸酯,(0.02g,70%)。
m/z:1221.7
步骤3:
在氩气氛下,向[313](0.01g,10.0mmol,x当量)的无水乙腈(y ml)溶液中添加烟酸二甲酯[300](0.003g,20.0mmol,x当量)。将所得反应混合物在室温下搅拌16小时。通过TLC监测反应进程。在高真空泵下除去溶剂以得到粗制产物。用乙醚(10ml×2)研磨所得粗制产物,得到黄色固体[314],单(1-((((((1S,2R)-1-苯甲酰胺基-3-(((2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-6,12b-二乙酰氧基-12-(苯甲酰基氧基)-4-((((3-(二甲基氨基甲酰基)吡啶-1--1-基)甲氧基)羰基)氧基)-11-羟基-4a,8,13,13-四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二氢-1H-7,11-桥亚甲基环十[3,4]苯并[l,2-b]氧杂环丁-9-基)氧基)-3-氧代-1-苯基丙-2-基)氧基)羰基)氧基)甲基)-3-(二甲基氨基甲酰基)吡啶-1-)二碘化物(0.014g,60%)。
m/z:1268
方案42:紫杉醇的经修饰形式(衍生物III)的合成
步骤1:
在0℃于氩气氛下,向氯甲酸氯甲酯(CMCF)[8](0.04g,23.0mmol,4.0当量)的无水二氯甲烷溶液中添加DIPEA(0.026g,46.0mmol,4.0当量)。在0℃下向上述反应混合物中添加紫杉醇[4114](0.10g,11.7mmol,1.0当量)的无水二氯甲烷(y ml)溶液。将反应混合物在室温下搅拌16小时。通过TLC监测反应进程。16小时之后,用二氯甲烷(25ml)稀释反应混合物,用10%的NaHCO3溶液(15ml)、盐水(10ml)洗涤,然后经无水Na2SO4干燥。在真空下蒸发溶剂,得到白色固体,(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-苯甲酰胺基-2-(((氯甲氧基)羰基)氧基)-3-苯基丙酰基)氧基)-12-(苯甲酰基氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二氢-1H-7,11-桥亚甲基环十[3,4]苯并[1,2-b]氧杂环丁烷-6,12b-二基二乙酸酯[315],(0.08g,70%)。
m/z=946
步骤2:
向[315](0.10g,0.116mmol,1.0当量)的乙腈(5ml)溶液中添加碘化钠(0.14g,0.42mmol,4.0当量),然后添加烟酰胺二甲酯[300](0.034g,0.233mmol,2.0当量)。将所得反应混合物在50℃下搅拌24小时。通过TLC监测反应进程。在真空下除去溶剂以得到粗制产物。向粗制产物中添加DCM以沉淀出碘化钠,通过过滤分离碘化钠,在真空下蒸发滤液,得到黄色油1-((((((1S,2R)-1-苯甲酰胺基-3-(((2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-6,12b-二乙酰氧基-12-(苯甲酰基氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二氢-1H-7,11-桥亚甲基环十[3,4]苯并[1,2-b]氧杂环丁-9-基)氧基)-3-氧代-1-苯基丙-2-基)氧基)羰基)氧基)甲基)-3-(二甲基氨基甲酰基)吡啶-1-碘化物2-(4-异丁基苯基)丙酸碘甲酯[316](0.012g,10%)。
m/z:1060.
还可以以类似的方式合成紫杉醇的其他衍生物,例如参见如下化合物编号9400和9405:
具有羧酸作为官能团的药物/生物活性化合物的化学修饰的实例
方案43:阿司匹林的经修饰形式(衍生物I)的合成:
衍生物I:
向阿司匹林[4154]和2-乙酰氧基苯甲酸(0.1g,0.56mmol,1.0当量)的DMF(2ml)溶液中添加TEA(0.08ml,0.68mmol,1.2当量)和甲基甲酰基试剂[259](0.1g,0.56mmol,1.0当量)。将反应混合物在45℃下加热16小时,然后冷却至室温,并用水稀释。用乙酸乙酯萃取有机材料,用水洗涤,经Na2SO4干燥,在真空下蒸发以得到粗制产物。通过硅胶柱色谱(含乙酸乙酯的环己烷,100-200目)纯化粗制产物,以得到暗色粘性产物[318],((2-乙酰氧基苯甲酰基)氧基)甲基烟酸酯,(0.09g,50%)。
m/z:316
将[318](0.09g,0.28mmol,1.0当量)溶于ACN(2ml)中,然后添加二甲基氨基甲酸碘甲酯试剂[6320](0.078g,0.34mmol,1.2当量),在室温下搅拌12小时。在真空下蒸发过量溶剂以得到粗制产物。通过使用DCM:乙醚沉淀粗制产物来纯化化合物,提供固体[319],3-((((2-乙酰氧基苯甲酰基)氧基)甲氧基)羰基)-1-(((二甲基氨基甲酰基)氧基)甲基)吡啶-1-碘化物(0.085g,71%)。
m/z:417
1H NMR[CDCl3,300MHz]:δ9.82-9.80,(d,1H);9.588,(s,1H);9.07-9.03,(d,H);8.39-8.34,(t,1H);8.11-8.06,(d,1H);7.66-7.63,(t,1H),7.38-7.33,(t,1H);7.15-7.12,(d,1H),6.26,(s,2H),3.014,(s,3H);2.89,(s,3H);2.34,(s,3H)
方案44:阿司匹林的经修饰形式(衍生物II)的合成
步骤1:
在室温下,向阿司匹林[4154](0.2g,1.11mmol,1.0当量)的剧烈搅拌的溶液中添加含碳酸氢钠(0.3g,4.1mmol,3.81当量)和四丁基硫酸氢铵(0.035g,0.11mmol,0.1当量)的水(5ml),添加二氯甲烷(5ml),然后逐滴添加氯磺酸氯甲酯[323](0.02ml,1.2mmol,1.1当量)的二氯甲烷(5ml)溶液。在室温下搅拌1小时之后,分离二氯甲烷层,用5%碳酸氢钠水溶液(1×25ml)洗涤,分离并经Na2SO4干燥,过滤并在真空下浓缩以得到无色油[320](2-乙酰氧基苯甲酸氯甲酯)(0.18mg,71%)。
m/z:229.
步骤2:
向ACN(3ml)中添加2-乙酰氧基苯甲酸氯甲酯[320](0.050g,0.21mmol,1.0当量)、碘化钠(0.098g,0.6mmol,3.0当量)和烟酰胺[322](0.026g,0.2mmol,1.0当量)。将反应混合物在室温下搅拌16小时。通过TLC监测反应进程。反应完成之后,真空除去溶剂以得到粗制产物。用乙醚(2×10ml)研磨所得粗制产物以得到期望产物[321],1-(((2-乙酰氧基苯甲酰基)氧基)-3-氨基甲酰基(carboyl)吡啶-1-碘化物(0.01g,14%)。
m/z:315
方案45:茚甲新的经修饰形式的合成
步骤1:
在室温下,将茚甲新[324](0.2g,0.56mmol,1.0当量)、DCM(1ml)、水(1ml)、碳酸氢钠(0.126g,1.78mmol,3.81当量)和四丁基硫酸氢铵(0.018g,0.056mmol,0.1当量)的混合物搅拌2分钟。逐滴添加氯磺酸氯甲酯[323](0.1ml,0.61mmol,1.1当量)的DCM(1ml)溶液。将该两相系统在室温下搅拌1小时。分离有机层,经Na2SO4干燥。在真空下蒸发溶剂,得到黄色油[325](2-(-1-(4-氯苯甲酰基)-5-甲氧基-2-甲基-1H-吲哚-3-基)乙酸氯甲酯)(0.16ml,70%)。
步骤2:
向ACN(3ml)中添加2-(-1-(4-氯苯甲酰基)-5-甲氧基-2-甲基-1H-吲哚-3基)乙酸氯甲酯[325](0.05g,0.12mmol,1.0当量)、碘化钠(0.055g,0.36mmol,3.0当量)和烟酰胺(0.015g,0.12mmol,1.0当量)。将反应混合物在室温下搅拌16小时。通过TLC监测反应进程。完成之后,在真空下除去溶剂以得到粗制产物。用乙醚(2×10ml)研磨所得粗制产物,以得到期望产物[326],3-氨基甲酰基-1-((2-(-1-(4-氯苯甲酰基)-5-甲氧基-2-甲基-1H-吲哚-3-基)乙酰氧基)甲基)吡啶-1-碘化物(0.015g,25%)。
方案46:布洛芬的经修饰形式的合成
步骤1:
将布洛芬[327](0.1g,0.48mmol,1.0当量)、DCM(2ml)、水(2ml)、碳酸氢钠(0.131g,1.8mmol,3.81当量)和四丁基硫酸氢铵(0.016g,0.05mmol,0.1当量)在25℃下搅拌2分钟。向上述反应混合物中逐滴添加氯磺酸氯甲酯[323](0.08ml,0.51mmol,1.1当量)的DCM(1ml)溶液,将该双相系统在室温下搅拌1小时。分离有机层,经无水Na2SO4干燥。在真空下蒸发溶剂,得到作为无色油的期望产物[328](2-(4-异丁基苯基)丙酸氯甲酯)(0.06ml,50%)。
步骤2:
向[328](0.06g,0.22mmol,1.0当量)的丙酮(5ml)溶液中添加碘化钠(0.14g,0.925mmol,4.0当量)。将所得反应混合物在室温下搅拌14小时。通过TLC监测反应进程。在真空下除去溶剂以得到粗制产物。然后,向该粗制产物中添加DCM,以沉淀出碘化钠,通过过滤分离碘化钠,在真空下蒸发滤液,得到黄色油[329]2-(4-异丁基苯基)丙酸碘甲酯(0.07g,86%)。
步骤3:
向ACN(3ml)中添加2-(4-异丁基苯基)丙酸碘甲酯[329](0.07g,0.23mmol,1.0当量)和烟酰胺[322](0.03g,0.22mmol,1.0当量)。将反应混合物在室温下搅拌16小时。通过TLC监测反应进程。在真空下除去溶剂以得到粗制产物。用乙醚(2×5ml)研磨所得粗制产物,得到期望产物[330],3-(二甲基氨基甲酰基)-1-(((2-(4-异丁基苯基)丙酰基)氧基)甲基)吡啶-1-碘化物(0.045g,60%)。
方案47:双氯芬酸(Diclofenac)的经修饰形式的合成
步骤1:
将双氯芬酸钠[331](0.1g,0.33mmol,1.0当量)、DCM(2ml)、水(2ml)、碳酸氢钠(0.105g,0.125mmol,3.81当量)和四丁基硫酸氢铵(0.011g,0.033mmol,0.1当量)在25℃下搅拌2分钟。逐滴添加氯磺酸氯甲酯[323](0.06g,0.363mmol,1.1当量)的DCM(1ml)溶液。将该双相系统在室温下搅拌1小时。分离有机层,经无水Na2SO4干燥。在真空下蒸发溶剂,得到作为白色固体的产物,2-(2-((2,6-二氯苯基)氨基)苯基)乙酸氯甲酯[332](0.11g,95%)。
m/z:343
步骤2:
向[332](0.11g,0.32mmol,1.0当量)的丙酮(5ml)溶液中添加碘化钠(0.192g,1.28mmol,4.0当量)。将所得反应混合物在室温下搅拌16小时。通过TLC监测反应进程。在真空下除去溶剂以得到粗制产物。向粗制产物中添加DCM以沉淀出碘化钠,通过过滤分离碘化钠,蒸发滤液,得到黄色油[333]2-(2-((2,6-二氯苯基)氨基)苯基)乙酸碘甲酯(0.1g,71%)。
m/z:436
步骤3:
向ACN(3ml)中添加2-(2-((2,6-二氯苯基)氨基)苯基)乙酸碘甲酯[333](0.1g,0.23mmol,1.0当量)和二甲基烟酰胺(0.034g,0.23mmol,1.0当量)。将反应混合物在室温下搅拌16小时。通过TLC监测反应进程。在真空下除去溶剂以得到粗制产物。用乙醚(2×5ml)研磨所得粗制产物,得到期望产物1-((2-(2-((2,6-二氯苯基)氨基)苯基)乙酰氧基)甲基)-3-(二甲基氨基甲酰基)吡啶-1-碘化物[334](0.082g,61%)。
m/z:585
方案48:HPPH的经修饰形式的合成
步骤1:
在25℃下,将HPPH[335](0.4g,0.62mmol,1.0当量)、DCM(5ml)、水(5ml)、碳酸氢钠(0.17g,2.3mmol,3.81当量)和四丁基硫酸氢铵(0.02g,0.05mmol,0.1当量)在黑暗中搅拌2分钟。逐滴添加氯磺酸氯甲酯[323](0.11ml,0.69mmol,1.1当量)的DCM(1ml)溶液。在室温下,将该双相系统在黑暗中搅拌1小时。分离有机相,经无水Na2SO4干燥。在真空下蒸发溶剂,得到作为黑色固体的期望产物[336](0.42g,80%)。
步骤2:
向ACN(3ml)中添加[336](0.05g,0.072mmol,1.0当量)、碘化钠(0.038g,0.21mmol,3.0当量)和烟酰胺[322](0.011g,0.072mmol,1.0当量)。在室温下,将反应混合物在黑暗中搅拌16小时。通过TLC监测反应进程。在真空下除去溶剂,以得到粗制产物。用乙醚(2×10ml)研磨所得粗制产物,得到作为黑色固体的期望产物[337](0.044g,75%)。
具有作为官能团之酰胺的药物/生物活性化合物的化学修饰的实例
方案49:linalidomide的经修饰形式的合成
步骤1:
在室温于N2气氛下,向3-(4-氨基-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮[338](0.2g,0.38mmol,1.0当量)的丙酮(17ml)溶液中添加K2CO3(0.105g,0.76mmol,2.0当量),并在60℃下加热30分钟,接着添加甲基甲酰基试剂[259](0.164g,0.48mmol,1.25当量)和碘化钠(0.29g,0.95mmol,2.5当量)。将所得反应混合物在60℃下回流24小时。通过TLC和质谱监测反应进程。然后,通过硅藻土床过滤反应质量,用丙酮(2×25ml)洗涤。然后,在真空下将丙酮层蒸发至干以得到棕色凝胶。在柱色谱(含2%MeOH的DCM作为洗脱剂100-200目二氧化硅)上纯化所得粗制产物,得到白色粉末(3-(4-氨基-1-氧代异吲哚啉-2-基)-2,6-二氧代哌啶-1-基)甲基烟酸酯[339](0.032g,20%)。
m/z:395
步骤2:
向(3-(4-氨基-1-氧代异吲哚啉-2-基)-2,6-二氧代哌啶-1-基)甲基烟酸酯[339](0.03g,0.028mmol,1.0当量)的DCM(5ml)溶液中添加异丙基氨基甲酸碘甲酯[6318](0.018g,0.028mmol,1.0当量)。将反应混合物在室温下搅拌16小时。在减压下蒸发DCM,并用乙醚彻底洗涤,得到黄色粉末[340],3-(((3-(4-氨基-1-氧代异吲哚啉-2-基)-2,6-二氧代哌啶-1-基)甲氧基)羰基)-1-(((异丙基氨基甲酰基)氧基)甲基)吡啶-1-碘化物,(0.015g,40%)。
m/z:510
具有作为杂原子之脂肪族叔氮的药物/生物活性化合物的化学修饰的实例
伊马替尼的经修饰形式的合成
方案50:使用I型试剂在脂肪族叔氨处的衍生化
在25ml的两颈圆底烧瓶中,将伊马替尼N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)-4-((4-甲基哌嗪-1-基)甲基)苯甲酰胺[148](0.100g,0.2mmol,1当量)溶于二氯甲烷(10ml)中,在室温下添加新戊酸碘甲酯[40](0.049g,0.2mmol,1当量)。搅拌3至4小时之后,过滤所形成的沉淀,用DCM洗涤,得到作为黄色固体的产物1-甲基-4-(4-((4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)氨基甲酰基)苄基)-1-((新戊酰基氧基)甲基)哌嗪-1-碘化物[41](0.040g,27%产率)。
m/z608.
1H NMR(DMSO):δ1.24(s,9H),2.20(s,3H),2.7(m,4H),3.10(s,3H),3.07(s,3H),3.48(br s,4H),3.71(s,2H),5.39(s,2H),7.19(d,1H),7.42-7.54(m,5H),7.9(d,2H),8.06(d,1H),8.45-8.52(m,2H),8.60(dd,1H),9.O(s,1H),9.27(d,1H),10.18(s,1H).
方案51:使用I型衍生化试剂在芳族氮和脂肪族叔胺处的衍生化
在25ml的两颈圆底烧瓶中,将伊马替尼[148](0.100g,0.2mmol,1当量)溶于DCM(10ml)中,在室温下添加新戊酸碘甲酯[40](0.185g,0.77mmol,3.8当量)同时进行搅拌。搅拌48小时之后,在真空下过滤所形成的沉淀,用DCM洗涤,得到作为黄色固体的产物1-甲基-4-(4-((4-甲基-3-((4-(1-((新戊酰基氧基)甲基)吡啶-1--3-基)嘧啶-2-基)氨基)苯基)氨基甲酰基)苄基)-1-((新戊酰基氧基)甲基)哌嗪-1-二碘化物[42](0.050g,25%产率)。
m/z=361
1H NMR(DMSO,300MHz):δ1.10(s,9H),1.24(s,9H),2.24(s,3H),2.78(m,4H),3.11(s,3H),3.48(br s,4H),3.72(s,2H),5.40(s,2H),6.50(s,2H),7.21-7.24(d,1H),7.32(d,1H),7.44(dd,1H),7.58(d,1H),7.98(d,2H),8.20(s,1H),8.36(dd,1H),8.72(d,1H),9.23(s,1H),9.28(d,1H),9.36(d,1H),9.9(s,1H),10.25(s,1H)
方案52:多西紫杉醇的修饰
在室温下,向多西紫杉醇[500](0.06g,0.074mmol,1.0当量)的DCM(5ml)溶液中添加吡啶(0.1ml)。将反应混合物冷却至-23℃,接着添加氯甲酸氯甲酯(0.054g,0.42mmol,6.0当量),在-23℃下搅拌30分钟。用稀HCl洗涤反应混合物,接着用盐水洗涤,经无水Na2SO4干燥,并在真空下除去溶剂以得到期望产物[501]。
通过1H NMR确认产物。
在室温下,向多西紫杉醇[501](0.075g,0.093mmol,1.0当量)的A(N(5ml)溶液中添加Nal(0.055g,0.372mmol,4.0当量)和N,N-二甲基烟酰胺(0.023g,0.186mmol,2.0当量)。将反应混合物在60℃下过夜。在真空下除去溶剂,将固体残余物添加到DCM中,过滤掉无机杂质,在真空下除去DCM,用醚研磨产物,过滤并真空干燥,得到产物[502]。
证实化合物之修饰的作用的实例:
通过如上所述的方法测试按照上述合成的化合物的pk,PK提供于表7中。
表7:经修饰药物的PK
Claims (27)
1.修饰化合物的方法,其通过使具有化合物1所提供之结构的修饰剂与化合物中杂环系统的官能团或杂原子共价连接以获得具有改进的化学性质和生物学性质的经修饰化合物;
其中,在化合物1中:
X选自Cl、Br、I、OTs、OMs;
Y选自R2、OR2或N(R2)2;并且
R和R1独立地为H;C1-C8直链或支链烷基—任选地包含1至3个选自O、N、S、SO或SO2的杂原子;3至7元环烷基,其任选地包含1至3个选自O、N、S、SO或SO2的杂原子和/或低级烷基、直链或支链烷基、烷氧基;烷芳基、芳基、杂芳基或烷杂芳基;
R和R1也可以连接至经取代甲基甲酰基以形成3至7元碳环,所述碳环任选地包含1至2个选自O、N、S、SO、SO2的杂原子并且还任选地被烷氧基、F或Cl取代;
R2独立地为H;C1-C8直链或支链烷基—任选地包含1至3个选自O、N、S、SO或SO2的杂原子;3至7元环烷基,其任选地包含1至3个选自O、N、S、SO或SO2的杂原子和/或低级烷基、直链或支链烷基、烷氧基;烷芳基、芳基、杂芳基或烷杂芳基;并且
R2独立地为3至7元环的—部分,所述3至7元环任选地包含额外的1至2个选自O、N、S、SO、SO2的杂原子并且还任选地被烷氧基、F或Cl取代。
2.根据权利要求1所述的方法,其中Y=R2。
3.根据权利要求2所述的方法,其中化合物1选自包含以下的组:
i.异丙基碳酸氯甲酯;
ii.苄基碳酸氯甲酯;
iii.吗啉代甲基碳酸氯甲酯;
iv.异丁基碳酸氯甲酯;
v.甲基碳酸氯甲酯;
vi.(S)-仲丁基碳酸氯甲酯;
vii.(R)-仲丁基碳酸氯甲酯;
viii.((3S,5R)-3,5-二甲基吗啉代)甲基碳酸氯甲酯;
ix.2-甲基环丙基碳酸氯甲酯;
x.2-甲氧基乙基碳酸氯甲酯;
xi.丙基碳酸氯甲酯;
xii.环丁基碳酸氯甲酯;
xiii.环丙基碳酸氯甲酯;
xiv.2,2-二甲基环丁基碳酸氯甲酯;
xv.环戊基碳酸氯甲酯;
xvi.氧杂环丁烷-3-基碳酸氯甲酯;
xvii.(S)-四氢呋喃-3-基碳酸氯甲酯;
xviii.环己基甲基碳酸氯甲酯;
xix.3-甲氧基环己基碳酸氯甲酯;
xx.(R)-四氢呋喃3-基碳酸氯甲酯;
xxi.乙氧基甲基碳酸氯甲酯;
xxii.氧杂环庚烷-4-基碳酸氯甲酯;
xxiii.(1R,2S,4S)-双环[2.2.1]庚-2-基碳酸氯甲酯;
xxiv.2,3-二氢-1H-茚-1-基碳酸氯甲酯;
xxv.苄基碳酸氯甲酯;
xxvi.(S)-1-苯基乙基碳酸氯甲酯;
xxvii.环己基碳酸氯甲酯;
xxviii.异丁基碳酸氯甲酯;
xxix.4-甲基环己基碳酸氯甲酯;
xxx.2-(甲基硫代)乙基碳酸氯甲酯;
xxxi.3-甲基环己基碳酸氯甲酯;
xxxii.戊-2-基碳酸氯甲酯;
xxxiii.新戊基碳酸氯甲酯;
xxxiv.1-((氯甲氧基)羰基氧基)环丙烷羧酸甲酯;
xxxv.环丙基甲基碳酸氯甲酯;
xxxvi.2,2-二乙氧基乙基碳酸氯甲酯;
xxxvii.环戊基甲基碳酸氯甲酯;
xxxviii.2-((氯甲氧基)羰基氧基)丙酸甲酯;
xxxix.(S)-2,2,4-三甲基环戊-3-烯基碳酸氯甲酯;
xl.1,3-二氧戊环-2-基碳酸氯甲酯;
xli.(2,6-二甲基环己基)甲基碳酸氯甲酯;
xlii.2-(四氢-2H-吡喃-2-基)乙基碳酸氯甲酯;
xliii.(四氢-2H-吡喃-4-基)甲基碳酸氯甲酯;
xliv.四氢-2H-吡喃-4-基碳酸氯甲酯;
xlv.1-甲基环戊基碳酸氯甲酯;
xlvi.1-环戊基乙基碳酸氯甲酯;
xlvii.3-甲基环戊基碳酸氯甲酯;
xlviii.3,3-二甲基环己基碳酸氯甲酯;
xlix.2,5-二甲基环己基碳酸氯甲酯;
l.1-(4-甲基环己基)乙基碳酸氯甲酯;
li.(3-甲基氧杂环丁烷-3-基)甲基碳酸氯甲酯;
lii.(3-甲基氧杂环丁烷-3-基)甲基碳酸氯甲酯;
liii.2-异丙氧基乙基碳酸氯甲酯;
liv.(氯甲基碳酸)5-((3aS,4S,6aR)-2-氧代六氢-1H-噻吩并[3,4-d]咪唑-4-基)戊酸酐;
lv.4-((氯甲氧基)羰基氧基)-2-羟基-4-氧代丁酸;
lvi.4-甲酰基-2-甲氧基苯基碳酸氯甲酯;
lvii.3-氧代丁-2-基碳酸氯甲酯;
lviii.4-((氯甲氧基)羰基氧基)苯甲酸甲酯;
lix.(R)-2-氨基-3-((氯甲氧基)羰基氧基)丙酸;
lx.3-叔丁基-4-甲氧基苯基碳酸氯甲酯;
lxi.(R)-2-氨基-3-(4-((氯甲氧基)羰基氧基)苯基)丙酸;
lxii.(R)-2-氨基-4-((氯甲氧基)羰基氧基)-4-氧代丁酸;
lxiii.(E)-3,7-二甲基辛-2,6-二烯基碳酸氯甲酯;
lxiv.4-((氯甲氧基)羰基氧基)苯甲酸甲酯;
lxv.2-(4-甲基环己-3-烯基)丙-2-基碳酸氯甲酯;
lxvi.3,7-二甲基辛-1,6-二烯-3-基碳酸氯甲酯;
lxvii.4-烯丙基-2-甲氧基苯基碳酸氯甲酯;
lxviii.(1R,2S,5R)-2-异丙基-5-甲基环己基碳酸氯甲酯;
lxix.4-((氯甲氧基)羰基氧基)苯甲酸丙酯;和
lxx.(E)-3,7-二甲基辛-2,6-二烯基碳酸氯甲酯。
4.根据权利要求2所述的方法,其中化合物1选自包含以下的组:
i.异丁酸氯甲酯;
ii.2,2-二甲基丁酸氯甲酯;
iii.3,3-二甲基丁酸氯甲酯;
iv.3-甲基丁酸氯甲酯;
v.2-甲氧基乙酸氯甲酯;
vi.异丁酸碘甲酯;
vii.2-苯基乙酸氯甲酯;
viii.烟酸氯甲酯;
ix.新戊酸碘甲酯;
x.异丁酸1-氯乙酯;
xi.异丁酸1-氯丙酯;
xii.乙酸氯甲酯;
xiii.3-甲基丁酸((甲基磺酰基)氧基)甲酯;
xiv.3-甲基丁酸(甲苯磺酰基氧基)甲酯;和
xv.烟酸((甲基磺酰基)氧基)甲酯。
5.根据权利要求1所述的方法,其中Y=NR2。
6.根据权利要求5所述的方法,其中化合物1选自包含以下的组:
i.环己烷羧酸氯甲酯;
ii.2-环己基乙酸氯甲酯;
iii.4-甲基环己烷羧酸氯甲酯;
iv.1-甲基环己烷羧酸氯甲酯;
v.环戊烷羧酸氯甲酯;
vi.1-(三氟甲基)环戊烷羧酸氯甲酯;
vii.环丁烷羧酸氯甲酯;
viii.2-乙基己酸氯甲酯;
ix.3-环戊基丙酸氯甲酯;
x.环丙烷羧酸氯甲酯;
xi.戊酸氯甲酯;
xii.2-甲基戊酸氯甲酯;
xiii.3,5,5-三甲基己酸氯甲酯;
xiv.2,2-二甲基丁酸氯甲酯;
xv.2-甲基丁酸氯甲酯;
xvi.己酸氯甲酯;
xvii.2-乙基丁酸氯甲酯;
xviii.丁酸氯甲酯;
xix.3-苯基丙酸氯甲酯;
xx.2-苯基丙酸氯甲酯;
xxi.(R)-2-苯基丙酸氯甲酯;
xxii.(S)-2-苯基丙酸氯甲酯;
xxiii.(1r,4r)-4-甲基环己烷羧酸氯甲酯;
xxiv.4-甲氧基环己烷羧酸氯甲酯;
xxv.4,4-二氟环己烷羧酸氯甲酯;
xxvi.3-甲氧基环己烷羧酸氯甲酯;
xxvii.(2R)-2-甲基环戊烷羧酸氯甲酯;
xxviii.(R)-2-甲基丁酸氯甲酯;
xxix.(S)-2-甲基丁酸氯甲酯;
xxx.(S)-2-甲氧基-2-苯基乙酸氯甲酯;
xxxi.(S)-2-苯基丙酸氯甲酯;
xxxii.(S)-2-苯基丁酸氯甲酯;
xxxiii.(S)-3-苯基丁酸氯甲酯;
xxxiv.2,2-二甲基丙二酸双(氯甲基)酯;
xxxv.草酸双(氯甲基)酯;
xxxvi.2-环丙基乙酸氯甲酯;
xxxvii.2-环丁基乙酸氯甲酯;
xxxviii.2-环戊基乙酸氯甲酯;
xxxix.2-(四氢呋喃-3-基)乙酸氯甲酯;
xl.2-(四氢-2H-吡喃-4-基)乙酸氯甲酯;
xli.2-甲基环丙烷羧酸氯甲酯;
xlii.2-(1-甲基环丁基)乙酸氯甲酯;
xliii.2-(1-甲基环丙基)乙酸氯甲酯;
xliv.丙酸氯甲酯;
xlv.乙酸氯甲酯;
xlvi.异丁酸氯甲酯;
xlvii.2-异丙基-3-甲基丁酸氯甲酯;
xlviii.3,5-二甲基环己烷羧酸氯甲酯;
xlix.2-丙基戊酸氯甲酯;
l.4-甲氧基苯甲酸氯甲酯;
li.4-甲基苯甲酸氯甲酯;
lii.3-甲基苯甲酸氯甲酯;
liii.2,2,2-三氟乙酸氯甲酯;
liv.5,5-二甲基-3-氧代己酸氯甲酯;
lv.环丙烷-1,1-二羧酸双(氯甲基)酯;
lvi.1,2-二氢环丁苯-1-羧酸氯甲酯;
lvii.2-环戊烯基乙酸氯甲酯;
lviii.2-苯基丁酸氯甲酯;
lix.2,2-二—氟乙酸氯甲酯;
lx.4-氟苯甲酸氯甲酯;
lxi.3-环己基丙酸氯甲酯;
lxii.2-环己基乙酸氯甲酯;
lxiii.3-(四氢-2H-吡喃-4-基)丙酸氯甲酯;
lxiv.2-(四氢-2H-吡喃-3-基)乙酸氯甲酯;和
lxv.3-(四氢-2H-吡喃-3-基)丙酸氯甲酯。
7.根据权利要求5所述的方法,其中化合物1选自包含以下的组:
i.苄基氨基甲酸氯甲酯;
ii.异丙基氨基甲酸氯甲酯;
iii.二异丙基氨基甲酸氯甲酯;
iv.二异丙基氨基甲酸碘甲酯;
v.苄基(甲基)氨基甲酸氯甲酯;
vi.哌啶-1-羧酸氯甲酯;
vii.(S)-(1-环己基乙基)氨基甲酸氯甲酯;
viii.(R)-(1-环己基乙基)氨基甲酸氯甲酯;
ix.(1-苯基乙基)氨基甲酸氯甲酯;
x.(S)-(1-苯基乙基)氨基甲酸氯甲酯;
xi.环己基氨基甲酸氯甲酯;
xii.(S)-(3-甲基丁-2-基)氨基甲酸氯甲酯;
xiii.(S)-仲丁基氨基甲酸氯甲酯;
xiv.2-甲基哌啶-1-羧酸氯甲酯;
xv.仲丁基氨基甲酸氯甲酯;
xvi.吗啉-4-羧酸氯甲酯;
xvii.吡咯烷-1-羧酸氯甲酯;
xviii.异丙基氨基甲酸碘甲酯;
xix.二甲基氨基甲酸氯甲酯;
xx.二甲基氨基甲酸碘甲酯;
xxi.4-甲基哌嗪-1-羧酸氯甲酯;
xxii.二异丙基氨基甲酸1-氯乙基酯;
xxiii.异丙基氨基甲酸1-氯乙基酯;
xxiv.吗啉-4-羧酸1-氯乙基酯;
xxv.哌啶-1-羧酸1-氯乙基酯;
xxvi.4-甲基哌啶-1-羧酸氯甲酯;和
xxvii.吗啉-4-羧酸溴甲酯。
8.根据权利要求1所述的方法,其中Y=OR2。
9.根据权利要求8所述的方法,其中化合物1选自包含以下的组:
i.异丙基氨基甲酸氯甲酯;
ii.二异丙基氨基甲酸氯甲酯;
iii.二甲基氨基甲酸氯甲酯;
iv.异丁基氨基甲酸氯甲酯;
v.甲基氨基甲酸氯甲酯;
vi.乙基(异丙基)氨基甲酸氯甲酯;
vii.异丁基(甲基)氨基甲酸氯甲酯;
viii.(S)-仲丁基氨基甲酸氯甲酯;
ix.甲基氨基甲酸氯甲酯;
x.异丙基(甲基)氨基甲酸氯甲酯;
xi.丙基氨基甲酸氯甲酯;
xii.2-甲氧基乙基氨基甲酸氯甲酯;
xiii.甲基(丙基)氨基甲酸氯甲酯;
xiv.二异丁基氨基甲酸氯甲酯;
xv.叔丁基(异丙基)氨基甲酸氯甲酯;
xvi.二-仲丁基氨基甲酸氯甲酯;
xvii.氮杂环丙烷-1-羧酸氯甲酯;
xviii.2-甲基环丙基氨基甲酸氯甲酯;
xix.环丙基氨基甲酸氯甲酯;
xx.环丙基甲基(丙基)氨基甲酸氯甲酯;
xxi.环丙基(甲基)氨基甲酸氯甲酯;
xxii.氮杂环丁烷-1-羧酸氯甲酯;
xxiii.环丁基氨基甲酸氯甲酯;
xxiv.2,2-二甲基环丁基氨基甲酸氯甲酯;
xxv.3-甲氧基氮杂环丁烷-1-羧酸氯甲酯;
xxvi.环丁基(甲基)氨基甲酸氯甲酯;
xxvii.氧杂环丁烷-3-基氨基甲酸氯甲酯;
xxviii.(S)-2-甲基吡咯烷-1-羧酸氯甲酯;
xxix.环戊基氨基甲酸氯甲酯;
xxx.环戊基(甲基)氨基甲酸氯甲酯;
xxxi.四氢呋喃-3-基氨基甲酸氯甲酯;
xxxii.哌啶-1-羧酸氯甲酯;
xxxiii.(2R,6S)-2,6-二甲基哌啶-1-羧酸氯甲酯;
xxxiv.(R)-2-甲基哌啶-1-羧酸氯甲酯;
xxxv.哌啶-1-羧酸氯甲酯;
xxxvi.3-甲氧基环己基氨基甲酸氯甲酯;
xxxvii.环己基甲基氨基甲酸氯甲酯;
xxxviii.环己基甲基(甲基)氨基甲酸氯甲酯;
xxxix.吗啉-4-羧酸氯甲酯;
xl.(3S,5R)-3,5-二甲基吗啉-4-羧酸氯甲酯;
xli.(3R,5S)-3,5-二甲基吗啉-4-羧酸氯甲酯;
xlii.(2S,6R)-2,6-二甲基吗啉-4-羧酸氯甲酯;
xliii.4-甲基哌嗪-1-羧酸氯甲酯;
xliv.氮杂环庚烷-1-羧酸氯甲酯;
xlv.环庚基氨基甲酸氯甲酯;
xlvi.氧杂环庚烷-4-基氨基甲酸氯甲酯;
xlvii.(1R,2S,4S)-二环[2.2.1]庚-2-基氨基甲酸氯甲酯;
xlviii.2,3-二氢-1H-茚-1-基氨基甲酸氯甲酯;
xlix.苄基氨基甲酸氯甲酯;
l.(S)-1-苯基乙基氨基甲酸氯甲酯;
li.2-((氯甲氧基)羰基氨基)-3-甲基丁酸乙酯;
lii.2-((氯甲氧基)羰基氨基)-3-苯基丙酸乙酯;
liii.(S)-2-((氯甲氧基)羰基氨基)戊二酸二乙酯;
liv.((氯甲氧基)羰基氨基)丙酸乙酯;
lv.2-氨基-6-((氯甲氧基)羰基氨基)己酸乙酯;
lvi.2-((氯甲氧基)羰基氨基)-4-甲基戊酸乙酯;
lvii.2-((氯甲氧基)羰基氨基)-3-甲基戊酸乙酯;
lviii.(S)-2-((氯甲氧基)羰基氨基)琥珀酸二甲酯;
lix.(S)-2-((氯甲氧基)羰基氨基)-5-胍基戊酸乙酯;
lx.(S)-4-氨基-2-((氯甲氧基)羰基氨基)-4-氧代丁酸乙酯;
lxi.(S)-2-氨基-5-((氯甲氧基)羰基氨基)戊酸乙酯;
lxii.(S)-5-氨基-2-((氯甲氧基)羰基氨基)-5-氧代戊酸乙酯;
lxiii.2-((氯甲氧基)羰基氨基)-4-(甲基硫代)丁酸乙酯;
lxiv.1-氯甲基3-甲基2-甲基-5,6-二氢吡啶-1,3(2H)-二羧酸酯;
lxv.(S)-(1-甲基吡咯烷-2-基)甲基碳酸氯甲酯;
lxvi.(R)-(1-甲基吡咯烷-2-基)甲基碳酸氯甲酯;
lxvii.(S)-(1-苄基吡咯烷-2-基)甲基碳酸氯甲酯;
lxviii.1H-吡咯-1-羧酸氯甲酯;
lxix.2-烟酰肼羧酸氯甲酯;
lxx.(6S)-3-氯-7-((氯甲氧基)羰基氨基)-8-氧代-5-硫杂-1-氮杂双环[4.2.0]辛-2-烯-2-羧酸;
lxxi.(6S)-7-((氯甲氧基)羰基氨基)-8-氧代-3-乙烯基-5-硫杂-1-氮杂双环[4.2.0]辛-2-烯-2-羧酸;
lxxii.(6S)-7-((氯甲氧基)羰基氨基)-3-(甲氧基甲基)-8-氧代-5-硫杂-1-氮杂双环[4.2.0]辛-2-烯-2-羧酸;
lxxiii.(6R,7R)-7-((氯甲氧基)羰基氨基)-3-甲氧基-8-氧代-5-硫杂-1-氮杂双环[4.2.0]辛-2-烯-2-羧酸;
lxxiv.3-(4-氯苯基)-1H-吡唑-1-羧酸氯甲酯;
lxxv.3-(4-氟苯基)-1H-吡唑-1-羧酸氯甲酯;
lxxvi.3-苯基-1H-吡唑-1-羧酸氯甲酯;
lxxvii.3-(4溴苯基)-1H-吡唑-1-羧酸氯甲酯;
lxxviii.2-氰基-1H-吡咯-1-羧酸氯甲酯;
lxxix.4-氧代哌啶-1-羧酸氯甲酯;
lxxx.1-氯甲基3-乙基2-氧代哌啶-1,3-二羧酸酯;
lxxxi.2,2,6,6-四甲基-4-氧代哌啶-1-羧酸氯甲酯;和
lxxxii.2-氧代哌啶-1-羧酸氯甲酯。
10.根据权利要求8所述的方法,其中化合物1选自包含以下的组:
i.叔丁基(氯甲基)碳酸酯;
ii.乙基碳酸氯甲酯;
iii.环己基碳酸氯甲酯;
iv.(1-甲基环己基)碳酸氯甲酯;
v.环戊基碳酸氯甲酯;
vi.叔戊基碳酸氯甲酯;
vii.(2,4-二甲基戊-3-基)碳酸氯甲酯;
viii.(环丙基甲基)碳酸氯甲酯;
ix.(3-甲基丁-2-基)碳酸氯甲酯;
x.(S)-仲丁基(氯甲基)碳酸酯;
xi.(R)-仲丁基(氯甲基)碳酸酯;
xii.环丁基碳酸氯甲酯;
xiii.(1-甲氧基丙-2-基)碳酸氯甲酯;
xiv.仲丁基(氯甲基)碳酸酯;
xv.(1-甲基环戊基)碳酸氯甲酯;
xvi.异丙基碳酸氯甲酯;
xvii.异丙基碳酸1-氯乙基酯;
xviii.苄基(碘甲基)碳酸酯;
xix.(S)-(1-苯基乙基)碳酸碘甲酯;和
xx.(R)-(1-苯基乙基)碳酸碘甲酯。
11.根据权利要求1所述的方法,其中所述官能团是伯胺、仲胺或叔胺。
12.根据权利要求1所述的方法,其中所述官能团是伯醇、仲醇或叔醇。
13.根据权利要求1所述的方法,其中所述官能团是羧酸。
14.根据权利要求1所述的方法,其中所述杂原子是氮。
15.根据权利要求1所述的方法,其中所述化合物是以下中的任意一种:他达拉非、西地那非、安普那韦、福沙那韦、安非他酮、度洛西汀、非那雄胺、拉坦前列素、洛匹那韦、雷洛昔芬、托吡卡胺、格尔德霉素、二甲双胍、紫杉醇、多柔比星、奈非那韦、雷帕霉素、吡罗昔康、氨来呫诺、罗索沙星、依托考昔、舒马曲坦、伐地那非、奎纳克林、阿托伐他汀、伐昔洛韦盐酸盐、阿托伐醌、二氢麦角胺、多奈哌齐、左氧氟沙星、托泊替康、雌二醇、喹硫平、奥氮平、文拉法辛、氮卓斯汀、吡格列酮、奈韦拉平、利扎曲普坦、依他普仑、氯沙坦、沙奎那韦、氟替卡松/沙美特罗、罗苏伐他汀、布地奈德/福莫特罗、孟鲁司特、对乙酰氨基酚、伊马替尼、Dimebon、SN-38、姜黄素、羟基法舒地尔、法舒地尔、阿司匹林和/或尼可地尔。
16.根据权利要求1所述的方法,其中所述化合物选自:中枢神经系统药物,例如CNS/呼吸兴奋剂,镇痛剂,麻醉性激动剂,麻醉性激动剂/拮抗剂,非甾体抗炎/镇痛剂,行为调节剂,镇定剂/镇静剂,麻醉剂,吸入剂,麻醉剂,逆转剂,抗惊厥剂,骨骼肌松弛剂,平滑肌松弛剂,安乐死制剂,心血管剂,正性肌力剂,抗心律失常药,抗胆碱能剂,血管舒张剂,用于治疗休克的药剂,α-肾上腺素能阻断剂,β-肾上腺素能阻断剂,呼吸药物,支气管扩张药,拟交感神经药,抗组胺剂,镇咳剂,肾和尿道,用于尿失禁/潴留的药剂,尿碱化剂,尿酸化剂,胆碱能刺激剂,用于尿石病的药剂,胃肠药,抗呕吐药,抗酸剂,H2拮抗剂,胃粘膜保护剂,质子泵抑制剂,食欲刺激剂,GI解痉药-抗胆碱能剂,GI刺激剂,轻泻剂,盐水,体积产生剂,润滑剂,表面活性剂,止泻药,激素/内分泌/生殖药,性激素,合成代谢类固醇,垂体后叶激素,肾上腺皮质类固醇,糖皮质激素,抗糖尿病药,甲状腺药,甲状腺激素,混杂的内分泌/生殖药物,前列腺素,抗感染药物,抗寄生虫药,抗球虫剂,抗生素,抗结核药,氨基环醇类,头孢菌素类,大环内酯类,青霉素类,四环素类,林可酰胺类,喹诺酮类,磺酰胺类,混杂抗细菌剂,抗真菌剂,抗病毒剂,血液调节剂,凝血剂,抗凝血剂,促红细胞生成药物,抗肿瘤剂/免疫抑制剂,烷化剂,解毒剂,骨/关节药剂,皮肤病剂(全身),维生素和矿物质/营养物,全身酸化剂,全身碱化剂,抗癌剂和抗病毒剂。
17.根据权利要求1所述的方法,其中所述化合物在修饰之后可以改变并转化为盐、溶剂化物、立体异构体。
18.根据权利要求1所述的方法,其中所述化合物在修饰之后作为其反离子存在。
19.根据权利要求1所述的方法,其中所述待修饰化合物是氘化的化合物。
20.根据权利要求1所述的方法,其中改变的化学性质和生物学性质中的一种或更多种包括:与初始化合物的那些性质相比,经修饰化合物的药代动力学性质和/或药效学性质。
21.通过权利要求1所述方法制备的经修饰化合物。
22.用于通过使用化合物1来修饰化合物的试剂。
23.根据权利要求21所述的化合物,其中所述化合物是:
iv.(2R,3S)-1-(((2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-12b-乙酰氧基-12-(苯甲酰基氧基)-4,6,11-三羟基-4a,8,13,13-四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二氢-1H-7,11-桥亚甲基环十[3,4]苯并[1,2-b]氧杂环丁-9-基)氧基)-3-((叔丁氧基羰基)氨基)-1-氧代-3-苯基丙-2-基烟酸酯;
v.(3-(4-氨基-1-氧代异吲哚啉-2-基)-2,6-二氧代哌啶-1-基)甲基烟酸酯;
vii.3-((((1S,2R)-1-苯甲酰胺基-3-(((2aR,4S,4aS6R,9S,11S,12S,12aR,12bS)-6,12b-二乙酰氧基-12-(苯甲酰基氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二氢-1H-7,11-桥亚甲基环十[3,4]苯并[1,2-b]氧杂环丁-9-基)氧基)-3-氧代-1-苯基丙-2-基)氧基)羰基)-1-(((异丙氧基羰基)氧基)甲基)吡啶-1-
ix.4-((4-乙氧基-3-(1-甲基-7-氧代-3-丙基-4,7-二氢-1H-吡唑并[4,3-d]嘧啶-5-基)苯基)磺酰基)-1-((异丁酰基氧基)甲基)-1-甲基哌嗪-1-
xi.1-((((((1S,2R)-1-苯甲酰胺基-3-(((2aR,4S,4aS,6R,9S11S,12S,12aR,12bS)-6,12b-二乙酰氧基-12-(苯甲酰基氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二氢-1H-7,11-桥亚甲基环十[3,4]苯并[1,2-b]氧杂环丁-9-基)氧基)-3-氧代-1-苯基丙-2-基)氧基)羰基)氧基)甲基)-3-(二甲基氨基甲酰基)吡啶-1-
xvii.(2-(1-(4-氯苯甲酰基)-5-甲氧基-2-甲基-1H-吲哚-3-基)乙酰氧基)甲基烟酸酯;
xviii.3-(((2-乙酰氧基苯甲酰基)氧基)甲基)-1H-咪唑-3-
xx.1-(((2-乙酰氧基苯甲酰基)氧基)甲基)-3-(甲基氨基甲酰基)吡啶-1-
xxi.((2-乙酰氧基苯甲酰基)氧基)甲基烟酸酯;
xxiii.化合物337号;
xxiv.1-((((((1S,2R)-1-苯甲酰胺基-3-(((2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-6,12b-二乙酰氧基-12-(苯甲酰基氧基)-4-((((3-(二甲基氨基甲酰基)吡啶-1--1-基)甲氧基)羰基)氧基)-11-羟基-4a,8,13,13-四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二氢-1H-7,11-桥亚甲基环十[3,4]苯并[1,2-b]氧杂环丁-9-基)氧基)-3-氧代-1-苯基丙-2-基)氧基)羰基)氧基)甲基)-3-(二甲基氨基甲酰基)吡啶-1-
xxxvi.5-氯-1’-(((异丙基氨基甲酰基)氧基)甲基)-6′-甲基-3-(4-(甲基磺酰基)苯基)-[2,3’-联吡啶]-1’-
xxxvii.(S)-4-(9-氟-6-(甲氧基羰基)-3-甲基-7-氧代-3,7-二氢-2H-[1,4]嗪并[2,3,4-ij]喹啉-10-基)-1-(((异丙基氨基甲酰基)氧基)甲基)-1-甲基哌嗪-1-
xxxviii.3-((((1S,2S)-1-苯甲酰胺基-3-(((2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-6,12b-二乙酰氧基-12-(苯甲酰基氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二氢-1H-7,11-桥亚甲基环十[3,4]苯并[1,2-b]氧杂环丁-9-基)氧基)-3-氧代-1-苯基丙-2-基)氧基)羰基)-1-(((二异丙基氨基甲酰基)氧基)甲基)吡啶-1-
xlv.3-(二甲基氨基甲酰基)-1-((((4-((1E,3Z,6E)-3-羟基-7-(4-羟基-3-甲氧基苯基)-5-氧代庚-1,3,6-三烯-1-基)-2-甲氧基苯氧基)羰基)氧基)甲基)吡啶-1-
xlix.3-((((1S,2R)-1-苯甲酰胺基-3-(((2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-6,12b-二乙酰氧基-12-(苯甲酰基氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二氢-1H-7,11-桥亚甲基环十[3,4]苯并[1,2-b]氧杂环丁-9-基)氧基)-3-氧代-1-苯基丙-2-基)氧基)羰基)-1-(((异丙基氨基甲酰基)氧基)甲基)吡啶-1-
l.(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-苯甲酰胺基-2-(烟酰基氧基)-3-苯基丙酰基)氧基)-12-(苯甲酰基氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二氢-1H-7,11-桥亚甲基环十[3,4]苯并[1,2-b]氧杂环丁烷-6,12b-二基二乙酸酯;
lii.3,3′-(((((1E,3Z,6E)-3-羟基-5-氧代庚-1,3,6-三烯-1,7-二基)双(2-甲氧基-4,1-亚苯基))双(氧基))双(羰基))双(1-(((异丙基氨基甲酰基)氧基)甲基)吡啶-1-);
liii.(S)-3-((((4,11-二乙基-4-羟基-3,14-二氧代-3,4,12,14-四氢-1H-吡喃并[3′,4′:6,7]吲嗪并[1,2-b]喹啉-9-基)氧基)甲氧基)羰基)-1-(((异丙基氨基甲酰基)氧基)甲基)吡啶-1-
liv.(S)-((4,11-二乙基-4-羟基-3,14-二氧代-3,4,12,14-四氢-1H-吡喃并[3’,4’:6,7]吲嗪并[1,2-b]喹啉-9-基)氧基)甲基烟酸酯;
lv.1-(((吗啉-4-羰基)氧基)甲基)-3-((2-(硝基氧基)乙基)氨基甲酰基)吡啶-1-
lvii.((6,7-双(2-甲氧基乙氧基)喹唑啉-4-基)(3-乙炔基苯基)氨基)甲基二异丙基氨基甲酸酯;
lviii.2-(((二异丙基氨基甲酰基)氧基)甲基)-5-(2-(1-(((二异丙基氨基甲酰基)氧基)甲基)-6-甲基吡啶-1--3-基)乙基)-2,8-二甲基-2,3,4,5-四氢-1H-吡啶并[4,3-b]吲哚-2-
lxix.1-((异丁酰基氧基)甲基)-3-((2-(硝基氧基)乙基)氨基甲酰基)吡啶-1-
lxxvi.化合物502,
24.权利要求1所述的经修饰化合物,及其中间体,其中所述化合物是:
ii.2-(((二异丙基氨基甲酰基)氧基)甲基)-5-(2-(1-(((二异丙基氨基甲酰基)氧基)甲基)-6-甲基吡啶-1--3-基)乙基)-2,8-二甲基-2,3,4,5-四氢-1H-吡啶并[4,3-b]吲哚-2-二碘化物;
v.4-乙酰胺基苯基烟酸酯;
vii.4-乙酰胺基苯基2-溴乙酸酯;
ix.4-乙酰胺基苯基(氯甲基)碳酸酯;
x.4-乙酰胺基苯基(碘甲基)碳酸酯;
xii.(S)-((4,11-二乙基-4-羟基-3,14-二氧代-3,4,12,14-四氢-1H-吡喃并[3’,4’:6,7]吲嗪并[1,2-b]喹啉-9-基)氧基)甲基烟酸酯;
xiii.(S)-3-((((4,11-二乙基-4-羟基-3,14-二氧代-3,4,12,14-四氢-1H-吡喃并[3’,4’:6,7]吲嗪并[1,2-b]喹啉-9-基)氧基)甲氧基)羰基)-1-(((异丙基氨基甲酰基)氧基)甲基)吡啶-1-碘化物;
xiv.4-((1E,4Z,6E)-5-羟基-7-(4-羟基-3-甲氧基苯基)-3-氧代庚-1,4,6-三烯-1-基)-2-甲氧基苯基烟酸酯;
xv.((1E,3Z,6E)-3-羟基-5-氧代庚-1,3,6-三烯-1,7-二基)双(2-甲氧基-4,1-亚苯基)二烟酸酯;
xvi.3,3’-(((((1E,3Z,6E)-3-羟基-5-氧代庚-1,3,6-三烯-1,7-二基)双(2-甲氧基-4,1-亚苯基))双(氧基))双(羰基))双(1-(((异丙基氨基甲酰基)氧基)甲基)吡啶-1-)二碘化物;
xvii.(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-苯甲酰胺基-2-(烟酰基氧基)-3-苯基丙酰基)氧基)-12-(苯甲酰基氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二氢-1H-7,11-桥亚甲基环十[3,4]苯并[1,2-b]氧杂环丁烷-6,12b-二基二乙酸酯;
xviii.3-((((1S,2R)-1-苯甲酰胺基-3-(((2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-6,12b-二乙酰氧基-12-(苯甲酰基氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二氢-1H-7,11-桥亚甲基环十[3,4]苯并[1,2-b]氧杂环丁-9-基)氧基)-3-氧代-1-苯基丙-2-基)氧基)羰基)-1-(((异丙基氨基甲酰基)氧基)甲基)吡啶-1-碘化物;
xix.(2aR,4S,4aS,6R9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-苯甲酰胺基-2-(((氯甲氧基)羰基)氧基)-3-苯基丙酰基)氧基)-12-(苯甲酰基氧基)-4-(((氯甲氧基)羰基)氧基)-11-羟基-4a,8,13,13-四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二氢-1H-7,11-桥亚甲基环十[3,4]苯并[1,2-b]氧杂环丁烷-6,12b-二基二乙酸酯;
xx.(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-苯甲酰胺基-2-(((碘甲氧基)羰基)氧基)-3-苯基丙酰基)氧基)-12-(苯甲酰基氧基)-11-羟基-4-(((碘甲氧基)羰基)氧基)-4a,8,13,13-四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二氢-1H-7,11-桥亚甲基环十[3,4]苯并[1,2-b]氧杂环丁烷-6,12b-二基二乙酸酯;
xxi.单(1-((((((1S,2R)-1-苯甲酰胺基-3-(((2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-6,12b-二乙酰氧基-12-(苯甲酰基氧基)-4-((((3-(二甲基氨基甲酰基)吡啶-1--1-基)甲氧基)羰基)氧基)-11-羟基-4a,8,13,13-四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二氢-1H-7,11-桥亚甲基环十[3,4]苯并[1,2-b]氧杂环丁-9-基)氧基)-3-氧代-1-苯基丙-2-基)氧基)羰基)氧基)甲基)-3-(二甲基氨基甲酰基)吡啶-1-)二碘化物;
xxii.(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-苯甲酰胺基-2-(((氯甲氧基)羰基)氧基)-3-苯基丙酰基)氧基)-12-(苯甲酰基氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二氢-1H-7,11-桥亚甲基环十[3,4]苯并[1,2-b]氧杂环丁烷-6,12b-二基二乙酸酯;
xxiii-1-((((((1S,2R)-1-苯甲酰胺基-3-(((2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-6,12b-二乙酰氧基-12-(苯甲酰基氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二氢-1H-7,11-桥亚甲基环十[3,4]苯并[1,2-b]氧杂环丁-9-基)氧基)-3-氧代-1-苯基丙-2-基)氧基)羰基)氧基)甲基)-3-(二甲基氨基甲酰基)吡啶-1-碘化物2-(4-异丁基苯基)丙酸碘甲酯;
xxiv.((2-乙酰氧基苯甲酰基)氧基)甲基烟酸酯;
xxvi.2-乙酰氧基苯甲酸氯甲酯;
xxviii.2-(-1-(4-氯苯甲酰基)-5-甲氧基-2-甲基-1H-吲哚-3-基)乙酸氯甲酯;
xxx.2-(4-异丁基苯基)丙酸氯甲酯;
xxxi.2-(4-异丁基苯基)丙酸碘甲酯;
xxxiii.2-(2-((2,6-二氯苯基)氨基)苯基)乙酸氯甲酯;
xxxiv.2-(2-((2,6-二氯苯基)氨基)苯基)乙酸碘甲酯;
xxxv.1-((2-(2-((2,6-二氯苯基)氨基)苯基)乙酰氧基)甲基)-3-(二甲基氨基甲酰基)吡啶-1-碘化物;
xxxvi.化合物[337]
xxxvii.(3-(4-氨基-1-氧代异吲哚啉-2-基)-2,6-二氧代哌啶-1-基)甲基烟酸酯;
xli.化合物502
25.根据权利要求21所述的化合物,其中所述经修饰化合物作为其反离子存在。
26.根据权利要求24所述的化合物,其中所述反离子是甲磺酸盐或碘化物。
27.化合物1的衍生化试剂在修饰药用剂和/或生物活性物质以改变由未经修饰初始药用剂和/或生物活性物质得到的化合物的物理化学性质、生物学性质和/或药代动力学性质中的用途:
其中:
X选自Cl、Br、I、OTs、OMs;
Y选自R2、OR2或N(R2)2;
R和R1可以独立地为H;C1-C8直链或支链烷基—任选地包含1至3个选自O、N、S、SO或SO2的杂原子;3至7元环烷基,其任选地包含1至3个选自O、N、S、SO或SO2的杂原子和/或低级烷基、直链或支链烷基、烷氧基;烷芳基、芳基、杂芳基或烷杂芳基;
R和R1也可以连接至经取代甲基甲酰基以形成3至7元碳环,所述碳环任选地包含1至2个选自O、N、S、SO、SO2的杂原子并且还任选地被烷氧基、F或Cl取代;
R2可以独立地为H;C1-C8直链或支链烷基—任选地包含1至3个选自O、N、S、SO或SO2的杂原子;3至7元环烷基,其任选地包含1至3个选自O、N、S、SO或SO2的杂原子和/或低级烷基、直链或支链烷基、烷氧基;烷芳基、芳基、杂芳基或烷杂芳基;并且
R2还可以是3至7元环的一部分,所述3至7元环任选地包含额外的1至2个选自O、N、S、SO、SO2的杂原子并且还任选地被烷氧基、F或Cl取代。
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104812388A (zh) * | 2012-10-05 | 2015-07-29 | 斯菲拉制药私人有限公司 | 新型化合物、其合成及其用途 |
CN114144178A (zh) * | 2019-03-15 | 2022-03-04 | 尤尼赛夫医疗公司 | 尼可地尔衍生物 |
CN114286811A (zh) * | 2019-04-17 | 2022-04-05 | 伊克斯切尔制药有限责任公司 | 富马酸单甲酯的前药 |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013147092A1 (ja) | 2012-03-30 | 2013-10-03 | 三菱化学株式会社 | エポキシ化合物の製造方法及びエポキシ化反応用触媒組成物 |
JP6945963B2 (ja) * | 2012-10-04 | 2021-10-06 | インヒビカーセ セラピューティクス,インコーポレーテッド | 新規な化合物、それらの調製及びそれらの使用 |
CN103086965A (zh) * | 2012-12-24 | 2013-05-08 | 金华职业技术学院 | 烟酸对乙酰氨基苯酯化合物及其合成方法 |
CA2927675A1 (en) * | 2013-10-18 | 2015-04-23 | Blanchette Rockefeller Neurosciences Institute | Halogenated esters of cyclopropanated unsaturated fatty acids for use in the treatment of neurodegenerative diseases |
CA3036235A1 (en) | 2016-09-09 | 2018-03-15 | Irisys, Inc. | Lipsomal anticancer compositions |
EP3532057B1 (en) | 2016-10-31 | 2022-12-21 | Biocryst Pharmaceuticals, Inc. | Prodrugs of kallikrein inhibitors |
WO2018199174A1 (ja) * | 2017-04-25 | 2018-11-01 | 生化学工業株式会社 | 第3級アミン化合物又はイミン化合物-ポリマーコンジュゲートとその製造方法 |
US11535600B2 (en) | 2018-12-03 | 2022-12-27 | H. Lundbeck A/S | Prodrugs of 4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazine and 4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)piperazine |
WO2023285952A1 (en) | 2021-07-10 | 2023-01-19 | Auxilius Pharma Spolka Z Ograniczona Odpowiedzialnoscia | Modified release nicorandil compound formulations |
KR20240001072A (ko) * | 2022-06-24 | 2024-01-03 | 주식회사 아이비스바이오 | 신규한 포말리도마이드 유도체 및 이의 제조방법 |
CN115959978A (zh) * | 2022-07-22 | 2023-04-14 | 北京先通国际医药科技股份有限公司 | 一种修饰长链脂肪酸型pet试剂前体的合成方法及其用途 |
WO2024151489A1 (en) | 2023-01-09 | 2024-07-18 | Unicycive Therapeutics Inc. | Pharmaceutical pyridyl compositions and methods for use |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1662501A (zh) * | 2002-05-17 | 2005-08-31 | 利奥制药有限公司 | 氰基胍前药 |
US20070082922A1 (en) * | 2005-10-06 | 2007-04-12 | Bai-Chuan Pan | Huperzine a prodrugs and uses thereof |
CN101198608A (zh) * | 2005-06-16 | 2008-06-11 | Cv医药有限公司 | A2b腺苷受体拮抗剂的前药 |
Family Cites Families (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3642920A (en) | 1968-12-12 | 1972-02-15 | Continental Oil Co | Preparation of alkyl iodide from alkyl chloride by nucleophilic substitution |
WO1993025197A1 (en) * | 1992-06-12 | 1993-12-23 | Affymax Technologies N.V. | Compositions and methods for enhanced drug delivery |
JP3108997B2 (ja) * | 1997-03-31 | 2000-11-13 | 武田薬品工業株式会社 | アゾール化合物、その製造法および用途 |
WO1998058927A1 (en) * | 1997-06-20 | 1998-12-30 | Baker Norton Pharmaceuticals, Inc. | Soluble prodrugs of paclitaxel |
US6380405B1 (en) * | 1999-09-13 | 2002-04-30 | Nobex Corporation | Taxane prodrugs |
AU2001252711A1 (en) * | 2000-04-15 | 2001-10-30 | Byung-Wook Jo | Aqueous-prodrug compound comprising moiety of paclitxel or derivatives thereof, method of preparing same and pharmaceutical composition comprising same |
AU1494702A (en) * | 2000-11-21 | 2002-06-03 | Leo Pharma As | Cyanoguanidine prodrugs |
WO2003072575A1 (en) | 2002-02-28 | 2003-09-04 | Astrazeneca Ab | 3-cyclyl-5-(nitrogen-containing 5-membered ring) methyl-oxazolidinone derivatives and their use as antibacterial agents |
BRPI0409063A (pt) * | 2003-04-03 | 2006-03-28 | Semafore Pharmaceuticals Inc | pró medicamentos de inibidor de pi-3 cinase |
US7253153B2 (en) * | 2003-04-09 | 2007-08-07 | Wyeth | Derivatives of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)alkyl] phosphonic acid and methods of use thereof |
EP1789091B1 (en) * | 2004-08-26 | 2010-08-25 | Piramal Life Sciences Limited | Prodrugs containing novel bio-cleavable linkers |
WO2007027230A2 (en) * | 2005-05-02 | 2007-03-08 | Rigel Pharmaceuticals, Inc. | Heterocyclic anti-viral compounds comprising metabolizable moieties and their uses |
JP2009511629A (ja) * | 2005-10-17 | 2009-03-19 | ニューロセラピューティクス ファーマ, インコーポレイテッド | 中枢神経系疾患の調節に有用な利尿薬様化合物類似体 |
WO2008007171A1 (en) * | 2006-07-09 | 2008-01-17 | Techfields Biochem Co. Ltd | Positively charged water-soluble prodrugs of aspirin |
AU2006346288A1 (en) * | 2006-07-18 | 2008-01-24 | Techfields Biochem Co. Ltd | Positively charged water-soluble prodrugs of ibuprofen with very fast skin penetration rate |
BRPI0720032A2 (pt) * | 2006-12-13 | 2013-12-17 | Gilead Sciences Inc | Composto e sais farmaceuticamente aceitáveis dos mesmos, processo, formulação de aerossol, método para a prevenção e tratamento de inflamação pulmonar ou broncoconstrição, e, uso de um composto. |
EP2136797A4 (en) * | 2007-04-17 | 2013-08-21 | Codman & Shurtleff | INTRANASAL ADMINISTRATION OF CURCUMINE IN A HELIUM GAS BOLUS FOR THE TREATMENT OF MORBUS ALZHEIMER |
US20090005395A1 (en) * | 2007-06-26 | 2009-01-01 | Solvay Pharmaceuticals, B.V. | Sildenafil n-oxide as prodrug |
US20090069410A1 (en) | 2007-09-09 | 2009-03-12 | Protia, Llc | Deuterium-enriched paclitaxel |
CN102149672A (zh) * | 2008-05-20 | 2011-08-10 | 纽罗吉斯克斯公司 | 水溶性对乙酰氨基酚类似物 |
AU2009297091B2 (en) * | 2008-09-23 | 2015-03-05 | Nektar Therapeutics | Compositions and methods for achieving sustained therapeutic drug concentrations in a subject |
WO2010151711A1 (en) * | 2009-06-25 | 2010-12-29 | Alkermes, Inc. | Prodrugs of nh-acidic compounds |
WO2011017634A2 (en) * | 2009-08-07 | 2011-02-10 | Sepracore Inc. | Prodrugs of fused heterocyclic inhibitors of d-amino acid oxidase |
EP2521711B1 (en) * | 2010-01-07 | 2017-08-16 | Alkermes Pharma Ireland Limited | Quaternary ammonium salt prodrugs |
-
2012
- 2012-04-09 CN CN201811274102.7A patent/CN109608436B/zh active Active
- 2012-04-09 EP EP12768375.3A patent/EP2693876B1/en active Active
- 2012-04-09 US US14/110,373 patent/US9359376B2/en active Active
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- 2012-04-09 JP JP2014503279A patent/JP2014514300A/ja active Pending
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1662501A (zh) * | 2002-05-17 | 2005-08-31 | 利奥制药有限公司 | 氰基胍前药 |
CN101198608A (zh) * | 2005-06-16 | 2008-06-11 | Cv医药有限公司 | A2b腺苷受体拮抗剂的前药 |
US20070082922A1 (en) * | 2005-10-06 | 2007-04-12 | Bai-Chuan Pan | Huperzine a prodrugs and uses thereof |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104812388A (zh) * | 2012-10-05 | 2015-07-29 | 斯菲拉制药私人有限公司 | 新型化合物、其合成及其用途 |
CN114144178A (zh) * | 2019-03-15 | 2022-03-04 | 尤尼赛夫医疗公司 | 尼可地尔衍生物 |
CN114286811A (zh) * | 2019-04-17 | 2022-04-05 | 伊克斯切尔制药有限责任公司 | 富马酸单甲酯的前药 |
CN114286811B (zh) * | 2019-04-17 | 2024-03-08 | 伊克斯切尔制药有限责任公司 | 富马酸单甲酯的前药 |
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EP2693876B1 (en) | 2020-01-15 |
EP2693876A4 (en) | 2014-09-17 |
US20140121367A1 (en) | 2014-05-01 |
CN109608436A (zh) | 2019-04-12 |
ES2779225T3 (es) | 2020-08-14 |
JP2014514300A (ja) | 2014-06-19 |
US9359376B2 (en) | 2016-06-07 |
WO2012137225A1 (en) | 2012-10-11 |
EP2693876A1 (en) | 2014-02-12 |
CN109608436B (zh) | 2022-10-11 |
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