CN116925088A - 二芳并四甘脲八羧酸盐及其用途 - Google Patents
二芳并四甘脲八羧酸盐及其用途 Download PDFInfo
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- CN116925088A CN116925088A CN202310899966.2A CN202310899966A CN116925088A CN 116925088 A CN116925088 A CN 116925088A CN 202310899966 A CN202310899966 A CN 202310899966A CN 116925088 A CN116925088 A CN 116925088A
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- substituted
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- alkyl
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- YCWSUKQGVSGXJO-NTUHNPAUSA-N nifuroxazide Chemical group C1=CC(O)=CC=C1C(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 YCWSUKQGVSGXJO-NTUHNPAUSA-N 0.000 title abstract description 6
- -1 aryl tetracarboxylic acid Chemical class 0.000 claims abstract description 43
- 235000019658 bitter taste Nutrition 0.000 claims abstract description 25
- 238000002360 preparation method Methods 0.000 claims abstract description 13
- VPVSTMAPERLKKM-UHFFFAOYSA-N glycoluril Chemical compound N1C(=O)NC2NC(=O)NC21 VPVSTMAPERLKKM-UHFFFAOYSA-N 0.000 claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims description 90
- 125000000217 alkyl group Chemical group 0.000 claims description 48
- 239000000203 mixture Substances 0.000 claims description 27
- 125000004432 carbon atom Chemical group C* 0.000 claims description 25
- 239000003795 chemical substances by application Substances 0.000 claims description 25
- 125000001072 heteroaryl group Chemical group 0.000 claims description 23
- 125000003118 aryl group Chemical group 0.000 claims description 22
- 150000003839 salts Chemical group 0.000 claims description 22
- 125000005842 heteroatom Chemical group 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 239000001257 hydrogen Substances 0.000 claims description 20
- 238000006467 substitution reaction Methods 0.000 claims description 20
- 229910052717 sulfur Inorganic materials 0.000 claims description 19
- 229910052760 oxygen Inorganic materials 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 16
- 125000003545 alkoxy group Chemical group 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 229940093265 berberine Drugs 0.000 claims description 13
- YBHILYKTIRIUTE-UHFFFAOYSA-N berberine Chemical compound C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 YBHILYKTIRIUTE-UHFFFAOYSA-N 0.000 claims description 13
- QISXPYZVZJBNDM-UHFFFAOYSA-N berberine Natural products COc1ccc2C=C3N(Cc2c1OC)C=Cc4cc5OCOc5cc34 QISXPYZVZJBNDM-UHFFFAOYSA-N 0.000 claims description 13
- 125000000623 heterocyclic group Chemical group 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 239000012453 solvate Substances 0.000 claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 11
- 239000004480 active ingredient Substances 0.000 claims description 10
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
- 239000006068 taste-masking agent Substances 0.000 claims description 10
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 239000013078 crystal Chemical group 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 239000001096 (4-ethenyl-1-azabicyclo[2.2.2]octan-7-yl)-(6-methoxyquinolin-4-yl)methanol hydrochloride Substances 0.000 claims description 7
- 125000006651 (C3-C20) cycloalkyl group Chemical group 0.000 claims description 7
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- 238000009472 formulation Methods 0.000 claims description 7
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 7
- 150000002431 hydrogen Chemical class 0.000 claims description 7
- 229960001811 quinine hydrochloride Drugs 0.000 claims description 7
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- 125000004474 heteroalkylene group Chemical group 0.000 claims description 5
- 238000011282 treatment Methods 0.000 claims description 5
- 150000001768 cations Chemical class 0.000 claims description 4
- 125000002993 cycloalkylene group Chemical group 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- 150000003863 ammonium salts Chemical class 0.000 claims description 2
- 229960000686 benzalkonium chloride Drugs 0.000 claims description 2
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims description 2
- NNKXWRRDHYTHFP-HZQSTTLBSA-N (r)-[(2s,4s,5r)-5-ethenyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methanol;hydron;dichloride Chemical compound Cl.Cl.C([C@H]([C@H](C1)C=C)C2)CN1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 NNKXWRRDHYTHFP-HZQSTTLBSA-N 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 24
- 229940079593 drug Drugs 0.000 abstract description 19
- 125000002091 cationic group Chemical group 0.000 abstract description 15
- 230000002209 hydrophobic effect Effects 0.000 abstract description 9
- 125000005841 biaryl group Chemical group 0.000 abstract 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 40
- 239000000243 solution Substances 0.000 description 34
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 14
- 150000005347 biaryls Chemical group 0.000 description 13
- 238000002474 experimental method Methods 0.000 description 13
- 238000004448 titration Methods 0.000 description 13
- 238000005481 NMR spectroscopy Methods 0.000 description 12
- 241000699670 Mus sp. Species 0.000 description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 9
- 229940043267 rhodamine b Drugs 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- 229910021642 ultra pure water Inorganic materials 0.000 description 9
- 239000012498 ultrapure water Substances 0.000 description 9
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 230000000873 masking effect Effects 0.000 description 8
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 235000019441 ethanol Nutrition 0.000 description 7
- 238000004896 high resolution mass spectrometry Methods 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- MPQKYZPYCSTMEI-FLZPLBAKSA-N (r)-[(2s,4s,5r)-5-ethenyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methanol;dihydrate;hydrochloride Chemical compound O.O.Cl.C([C@H]([C@H](C1)C=C)C2)CN1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 MPQKYZPYCSTMEI-FLZPLBAKSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 239000006187 pill Substances 0.000 description 6
- 150000003254 radicals Chemical class 0.000 description 6
- 239000011593 sulfur Chemical group 0.000 description 6
- DQXKOHDUMJLXKH-PHEQNACWSA-N (e)-n-[2-[2-[[(e)-oct-2-enoyl]amino]ethyldisulfanyl]ethyl]oct-2-enamide Chemical compound CCCCC\C=C\C(=O)NCCSSCCNC(=O)\C=C\CCCCC DQXKOHDUMJLXKH-PHEQNACWSA-N 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000001301 oxygen Chemical group 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 238000011740 C57BL/6 mouse Methods 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 239000011575 calcium Substances 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 125000002541 furyl group Chemical group 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 231100000053 low toxicity Toxicity 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 125000004076 pyridyl group Chemical group 0.000 description 4
- 239000012488 sample solution Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 description 3
- 125000006714 (C3-C10) heterocyclyl group Chemical group 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 238000000862 absorption spectrum Methods 0.000 description 3
- 235000010443 alginic acid Nutrition 0.000 description 3
- 229920000615 alginic acid Polymers 0.000 description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 150000007942 carboxylates Chemical class 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- MSBXTPRURXJCPF-DQWIULQBSA-N cucurbit[6]uril Chemical compound N1([C@@H]2[C@@H]3N(C1=O)CN1[C@@H]4[C@@H]5N(C1=O)CN1[C@@H]6[C@@H]7N(C1=O)CN1[C@@H]8[C@@H]9N(C1=O)CN([C@H]1N(C%10=O)CN9C(=O)N8CN7C(=O)N6CN5C(=O)N4CN3C(=O)N2C2)C3=O)CN4C(=O)N5[C@@H]6[C@H]4N2C(=O)N6CN%10[C@H]1N3C5 MSBXTPRURXJCPF-DQWIULQBSA-N 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 239000008367 deionised water Substances 0.000 description 3
- 229910021641 deionized water Inorganic materials 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000000168 pyrrolyl group Chemical group 0.000 description 3
- 238000002390 rotary evaporation Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000007909 solid dosage form Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
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- 239000000126 substance Substances 0.000 description 3
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- 239000012085 test solution Substances 0.000 description 3
- 125000001544 thienyl group Chemical group 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical group CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 229920000858 Cyclodextrin Polymers 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 241000206672 Gelidium Species 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 150000001204 N-oxides Chemical class 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 229940072056 alginate Drugs 0.000 description 2
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 229960001716 benzalkonium Drugs 0.000 description 2
- RBUHEOMIOUHQDN-UHFFFAOYSA-N benzene-1,3,5-tricarboxylic acid;sodium Chemical compound [Na].OC(=O)C1=CC(C(O)=O)=CC(C(O)=O)=C1 RBUHEOMIOUHQDN-UHFFFAOYSA-N 0.000 description 2
- CYDRXTMLKJDRQH-UHFFFAOYSA-N benzododecinium Chemical compound CCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 CYDRXTMLKJDRQH-UHFFFAOYSA-N 0.000 description 2
- 230000000595 bitter masking effect Effects 0.000 description 2
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000010609 cell counting kit-8 assay Methods 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000010668 complexation reaction Methods 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 229940097362 cyclodextrins Drugs 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
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- GBXQPDCOMJJCMJ-UHFFFAOYSA-M trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;bromide Chemical compound [Br-].C[N+](C)(C)CCCCCC[N+](C)(C)C GBXQPDCOMJJCMJ-UHFFFAOYSA-M 0.000 description 1
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- C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
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- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/49—Cinchonan derivatives, e.g. quinine
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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Abstract
本发明涉及一类二芳并四甘脲八羧酸盐的制备和用途。具体地,本发明提供的二芳并四甘脲八羧酸盐从芳基四羧酸和甘脲四聚体缩合制备,其疏水空穴可以特异性结合阳离子型苦味药物而遮蔽苦味,及其在药物苦味遮蔽方面的应用。
Description
技术领域
本发明属于医药领域,具体地,本发明涉及一类二芳并四甘脲八羧酸盐及其作为苦味掩蔽剂的用途。
背景技术
主客体化学是近些年来发展迅速的学科。大环化合物是研究广泛的主体化合物。水溶性的具有疏水内穴的主体分子可以通过疏水作用驱动结合客体分子。著名的例子是葡萄糖缩合形成的天然环糊精,可以结合很多疏水的药物,提高药物的稳定性和水溶性,延长药物的代谢周期,降低药物的毒性和副作用及消除药物的不良气味或异味等。受环糊精上述性能的启发,化学家近年来发展了很多非天然的大环分子,研究它们对不同分子或离子的结合。葫芦脲大环系列是其中一类重要的具有疏水性内穴的甘脲衍生物。但葫芦脲骨架具有特别刚性和难以修饰的缺点,难以实现快速的结合动力学,难以通过调节其内穴形状以实现对不同客体分子结合的构象适配性。而结合客体类型最具多样性的葫芦[8]脲,由于其水溶性极低,也限制了其作为药物和药物辅剂研发的潜力。Ma等2010年报导,在甘脲四聚体两侧引入两个苯环合成了携带四个乙酸盐基团的衍生物。Jiang等2018年又报导了类似的两侧引入两个萘环的携带四个乙酸盐基团的衍生物。这两个开环葫芦脲的水溶性、对药物的结合亲和性、生物相容性尚不明确。
许多药物分子本身味苦或含有苦味的辅料成分,口服依从性差。发展简单有效的遮蔽药物苦味的技术具有临床应用的潜力。理论上,水溶性的羧酸盐主体可以通过疏水作用和离子对静电作用驱动,特异性结合正离子型的苦味药物,形成稳定络合物,遮蔽其苦味。羧酸盐修饰的开环葫芦脲作为一类主体化合物,可能通过合理设计得到高水溶性、高生物相容性、有药物应用前景的化合物,是本领域一个研究目标。并且,在较强酸性的胃酸作用下,羧酸盐酸化为中性的羧酸导致药物的释放并在胃肠道被吸收。
综上所述,本领域亟需一种水溶性好,生物相容性高,毒性低,口服依从性好的化合物作为苦味遮蔽剂。
发明内容
本发明的一个目的是提供一种水溶性好,生物相容性高,毒性低,口服依从性好,无味的苦味遮蔽化合物。
本发明的另一个目的是提供一种苦味遮蔽化合物的制备方法。
本发明的第一方面,提供了一种式(I)所示的二芳并四甘脲八羧酸盐化合物、或其药学上可接受的盐、晶型、水合物或溶剂合物,
其中,
各个X各自独立地选自下组:取代或未取代的C1-20亚烷基、取代或未取代的含有一个或多个选自N、O和S的杂原子的C1-20亚杂烷基、取代或未取代的C3-20亚环烷基、取代或未取代的3-20元亚杂环基;
各个Y各自独立地选自下组:取代或未取代的C1-20烷基、取代或未取代的含有一个或多个选自N、O和S的杂原子的C1-20杂烷基、取代或未取代的C3-20环烷基、取代或未取代的3-20元杂环基,或两个相邻Y与其相连的碳原子共同形成取代或未取代的C3-20环烷基或3-20元杂环基;
各个Z各自独立地选自下组:氢、C1-20烷氧基、取代或未取代的C1-20烷基或C3-20环烷基,或两个相邻的Z与其相连的碳原子共同形成取代或未取代的选自下组的基团:C3-20碳环、3-20元碳杂环、C6-20芳基、5-20元杂芳基;
各个M各自独立地为药学上可接受的阳离子;
除非特别说明,否则所述的取代是指基团上的氢被一个或多个卤素、氰基、硝基、氨基、羰基、苄基、苯基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C3-7环烷基取代。
在另一优选例中,各个X各自独立地选自下组:取代或未取代的C1-10亚烷基、取代或未取代的含有一个或多个选自N、O和S的杂原子的C1-10亚杂烷基、取代或未取代的C3-10亚环烷基、取代或未取代的3-10元亚杂环基;
各个Y各自独立地选自下组:取代或未取代的C1-10烷基、取代或未取代的含有一个或多个选自N、O和S的杂原子的C1-10杂烷基、取代或未取代的C3-10环烷基、取代或未取代的3-10元杂环基,或两个相邻Y与其相连的碳原子共同形成取代或未取代的C3-10环烷基或3-10元杂环基;
各个Z各自独立地选自下组:氢、C1-10烷氧基、取代或未取代的C1-10烷基或C3-10环烷基,或两个相邻的Z与其相连的碳原子共同形成取代或未取代的选自下组的基团:C3-10环烷基、3-10元杂环基、C6-10芳基、5-10元杂芳基;
除非特别说明,否则所述的取代是指基团上的氢被一个或多个卤素、氰基、硝基、氨基、羰基、苄基、苯基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C3-7环烷基取代。
在另一优选例中,各个X各自独立地选自下组:取代或未取代的C1-6亚烷基、取代或未取代的含有一个或多个选自N、O和S的杂原子的C1-6亚杂烷基、取代或未取代的C3-7亚环烷基、取代或未取代的3-7元亚杂环基;
各个Y各自独立地选自下组:取代或未取代的C1-6烷基、取代或未取代的含有一个或多个选自N、O和S的杂原子的C1-6杂烷基、取代或未取代的C3-6环烷基、取代或未取代的3-6元杂环基,或两个相邻Y与其相连的碳原子共同形成取代或未取代的C3-7环烷基或3-7元杂环基;
各个Z各自独立地选自下组:氢、C1-6烷氧基、取代或未取代的C1-6烷基或C3-7环烷基,或两个相邻的Z与其相连的碳原子共同形成取代或未取代的选自下组的基团:C3-7环烷基、3-7元杂环基、苯基、5-7元杂芳基;
各个M各自独立地为Na+、K+、Li+、Mg2+、Ca2+、NH4 +、或一个到四个各自独立地为C1-6烷基或C6-10芳基取代的铵盐;
除非特别说明,否则所述的取代是指基团上的氢被一个或多个卤素、氰基、硝基、氨基、羰基、苄基、苯基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C3-7环烷基取代。
在另一优选例中,M为碱性阳离子。
在另一优选例中,M各自独立地为Li+、Na+、K+、Mg2+、Ca2 +、NH4 +;各个X各自独立地为-(CH2)n-,其中,n为2,3,4,5,6;Y各自独立地为C1-3烷基。
在另一优选例中,X各自独立地为亚乙基、亚丙基、亚丁基。
在另一优选例中,Y各自独立地为甲基、乙基、丙基。
在另一优选例中,各个Z各自独立地选自下组:氢、C1-6烷基,或两个相邻的Z与其相连的碳原子共同形成取代或未取代的选自下组的基团:C3-7环烷基、苯基。
在另一优选例中,各自独立地为/>其中,G为H,或一个或多个各自独立地选自下组的基团:卤素、C1-6烷基、C1-6烷氧基。
在另一优选例中,所述的化合物选自下组:
在本发明的第二方面,提供了本发明第一方面所述的二芳并四甘脲八羧酸盐、或其药学上可接受的盐、晶型、水合物或溶剂合物用作苦味遮蔽剂的用途。
在本发明的第三方面,提供了一种本发明第一方面所述的化合物的制备方法,包括如下步骤:
在TFA的存在下,式d化合物与式e化合物甘脲四聚体反应,然后加入氢氧化物MOH水解,得到式I所示的本发明第一方面所述的化合物;
式中,R为取代或未取代的C1-5烷基;其中,所述的取代是指基团上的一个或多个氢被C1-6烷基取代,各个Z,Y,X,M分别如本发明第一方面所述。
在另一优选例中,所述的氢氧化物MOH选自下组:NaOH,KOH,LiOH,Ca(OH)2,Mg(OH)2、氨水,或其组合。
在另一优选例中,所述的式d化合物的制备方法包括步骤:
(a)在碱的存在下,式a化合物和式b化合物反应,得到式c化合物;
(b)式c化合物与CH2(CO2R)反应,得到式d化合物;
式中,R为取代或未取代的C1-5烷基,其中,所述的取代是指基团上的氢被一个或多个C1-6烷基取代;各个Z,Y,X,M分别如本发明第一方面所述。
在另一优选例中,步骤(a)中,所述的碱为NaOH,KOH,LiOH,或其组合。
在另一优选例中,步骤(b)具体包括:在三乙胺的存在下,式c化合物与MsCl反应,随后加入CH2(CO2R)和碳酸钾反应,得到式d化合物,其中,R为取代或未取代的C1-5烷基。
在本发明的第四方面,提供了一种式d所示的酯基侧链芳环化合物,结构如下:
式中,R为取代或未取代的C1-5烷基,其中,所述的取代是指基团上的氢被一个或多个C1-6烷基取代。
在另一优选例中,所述的式d化合物用于制备本发明第一方面所述的化合物。
在本发明的第五方面,提供了一种药物组合物或口服制剂,包括:
(i)苦味药物活性成分;
(ii)本发明第一方面所述的二芳并四甘脲八羧酸盐、或其药学上可接受的盐、晶型、水合物或溶剂合物;和
(iii)药学上可接受的载体或赋形剂。
在另一优选例中,所述的苦味药物为阳离子型苦味药物。
在另一优选例中,所述的口服制剂选自下组:胶囊剂、片剂、丸剂、散剂和颗粒剂。
在本发明的第六方面,提供了一种药物组合物或口服制剂,包括:
(a)苦味剂:小檗碱、苦精(苯甲地那铵)和盐酸奎宁;和
(b)本发明第一方面所述的二芳并四甘脲八羧酸盐、或其药学上可接受的盐、晶型、水合物或溶剂合物;和
(c)药学上可接受的载体或赋形剂。
在另一优选例中,所述的口服制剂选自下组:胶囊剂、片剂、丸剂、散剂和颗粒剂。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
附图说明
图1为二芳并四甘脲八羧酸盐化合物I-2与阳离子型苦味剂小檗碱在溶液相中的结合模式测定的核磁滴定实验谱图;
图2为二芳并四甘脲八羧酸盐化合物I-2与阳离子型苦味剂苯甲地那铵在溶液相中的结合模式测定的核磁滴定实验谱图;
图3为二芳并四甘脲八羧酸盐化合物I-3与阳离子型苦味剂盐酸奎宁在溶液相中的结合模式测定的核磁滴定实验谱图;
图4为二芳并四甘脲八羧酸盐化合物I-1与罗丹明B结合常数测定实验。(a)紫外可见吸收滴定实验谱图和(b)拟合结果;
图5为阳离子型苦味剂小檗碱与罗丹明B@二芳并四甘脲八羧酸盐化合物I-1的竞争滴定实验。(a)紫外可见吸收滴定实验谱图和(b)拟合结果;
图6为二芳并四甘脲八羧酸盐的细胞毒性测定结果;
图7为小鼠对二芳并四甘脲八羧酸盐的双瓶偏好实验结果;
图8为小鼠对阳离子型苦味剂@二芳并四甘脲八羧酸盐的双瓶偏好实验结果。
具体实施方式
发明人经过广泛而深入地研究,首次提供了一种并入两个芳基的四甘脲八羧酸盐。本发明的二芳并四甘脲八羧酸盐具有高度水溶性、毒性低、生物相容性好,对苦味药物的结合有pH依赖性。作为苦味遮蔽剂能够有效的遮蔽小檗碱,苦精,盐酸奎宁等常见的苦味剂的苦味,提高受试者的依从性;可以广泛用于阳离子型苦味剂。基于此,发明人完成了本发明。
术语
如本文所用,“C1-20烷基”是指包括1-20个碳原子的直链或支链烷基,例如甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基等、或类似基团。
如本文所用,“C1-20烷基链”是指包括1-20个碳原子的直链或支链的烷基链(CH2)n- 1CH3(n=1~20)。
如本文所用,“C3-20环烷基”是指包含3-20个碳原子的环烷基或者带有侧链的环烷基,例如环丙基、环丁基、环戊基、环己基等。
如本文所用,“C1-20杂烷基”是指C1-20的烷基链中的一个或多个碳原子被选自氮、氧和硫的杂原子取代的基团,例如,C1-8杂烷基是指CH3-CH2-CH2-CH2-O-CH2-CH2-CH2-,或CH3-CH2-CH2-CH2-O-CH2-CH2-O-等类似基团。
如本文所用,“C2-20元杂烯基”是指C2-20的烯基链中的一个或多个碳原子被选自氮、氧和硫的杂原子取代的基团,例如,C2-7元杂烯基是指CH3-CH2-CH2-O-CH2-CH=CH-,或CH3-S-CH2-CH2-O-CH=CH-等类似基团。
如本文所用,“C2-20元杂炔基”是指C2-20的炔基链中的一个或多个碳原子被选自氮、氧和硫的杂原子取代的基团,例如,C2-7元杂炔基是指CH3-CH2-CH2-O-CH2-C≡C-,或CH3-S-CH2-CH2-O-C≡C-等类似基团。
在本发明中,术语“C1-6烷氧基”是指包含但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、正戊氧基、异戊氧基、新戊氧基、己氧基等。优选为C1-4烷氧基。
在本发明中,术语“杂环芳基”或“杂芳基”具有相同的含义,指包含一个到多个杂原子的杂芳族基团。例如“C3-10杂芳基”是指含有1-4个选自氧、硫和氮中的杂原子以及3-10个碳原子的芳香杂环。非限制性例子包括:呋喃基、噻吩基、吡啶基、吡唑基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为杂芳基环。杂芳基可以是任选取代的或未取代的。
如本文所用,术语“水合物”是指本发明化合物与水配位形成的配合物。
如本文所用,术语“溶剂合物”指本发明化合物与溶剂分子配位形成特定比例的配合物。
如本文所用,术语“芳基”是指6至20个(较佳6-14个)碳原子的单价芳香族碳环基团,它具有单环(如苯基)或稠环(如萘基或蒽基),如果连接点在芳香碳原上,稠环可能是非芳香性的(如2-苯并噁唑酮,2H-1,4-苯并噁嗪-3(4H)-酮-7-基等)。优选的芳基包括苯基和萘基。
如本文所用,术语“环烷基”是指具有3至12(优选为3至10)个碳原子的、具有单环或多环(包括稠合体系,桥环体系和螺环体系)的环状烷基。在稠环体系中,一个或多个环可以是环烷基、杂环的、芳基或杂芳基,只要连接位点是通过环烷基的环。合适的环烷基的例子包括:例如,金刚烷基、环丙基、环丁基、环戊基和环辛基。
如本文所用,术语“杂芳基”是指环内具有2至10个碳原子和1至4个选自氧、氮和硫的杂原子的芳香基团,这样的杂芳基可以是单环的(如吡啶基或呋喃基)或稠环(如吲嗪基(indolizinyl)或苯并噻吩基),其中,所述稠环可以是非芳香性的和/或含有一个杂原子,只要连接点是通过芳香性杂芳基的原子。在一实施例中,杂芳基的环原子氮和/或硫任选地被氧化为N-氧化物(N-O),亚磺酰基或磺酰基。优选地杂芳基包括吡啶基、吡咯基、吲哚基、噻吩基和呋喃基。在一实施例中,杂芳基指3-14元杂芳基,优选地为5-12元杂芳基。
如本文所用,术语“取代的杂芳基”是指被1至5个、优选1至3个、更优选1至2个的取代基所取代的杂芳基,所述取代基选自与取代的芳基所定义的相同取代基。
碳氢基团中碳原子数量的最小值和最大值通过前缀表示,例如,前缀Cm-n烷基表示任何含“m”至“n”个碳原子的烷基。因此,例如,C1-3烷基是指包含1-3个碳原子的烷基,即C1、C2、C3的烷基,例如:甲基、乙基、正丙基、异丙基。
在本发明中,术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基,或各实施例中所出现的取代基。除非特别说明,某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基,所述的取代基在各个位置上可以是相同或不同的。本领域技术人员应理解,本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。
如本文所用,术语“含有一个或多个选自N、S和O的杂原子的3-20元杂环基”是指具有3-20个原子的且其中一个或多个个(优选1-3个)原子为选自N、S和O的杂原子的饱和或部分饱和的环状基团。其可以是单环,也可以是双环形式,例如桥环或螺环形式。具体的实例可以为氧杂环丁烷、氮杂环丁烷、四氢-2H-吡喃基、哌啶基、四氢呋喃基、吗啉基和吡咯烷基等。
如本文所用,术语“5-20元杂芳基”指具有5-20个原子的且其中一个或多个(优选1-3个)原子为选自N、S和O的杂原子的环状芳香基团。其可以是单环,也可以是稠环形式。具体的实例可以为吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、(1,2,3)-三唑基以及(1,2,4)-三唑基、四唑基、呋喃基、噻吩基、异恶唑基、噻唑基、恶唑基等。
本发明所述的基团除非特别说明是“取代的或未取代的”,否则本发明的基团均可被选自下组的取代基所取代:卤素、腈基、硝基、羟基、氨基、C1-C6烷基-胺基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、卤代C1-C6烷基、卤代C2-C6烯基、卤代C2-C6炔基、卤代C1-C6烷氧基、烯丙基、苄基、C6-C12芳基、C1-C6烷氧基-C1-C6烷基、C1-C6烷氧基-羰基、苯氧羰基、C2-C6炔基-羰基、C2-C6烯基-羰基、C3-C6环烷基-羰基、C1-C6烷基-磺酰基等。
二芳并四甘脲八羧酸盐
本发明提供了一种用作苦味遮蔽剂的式I结构的二芳并四甘脲八羧酸盐、或其药学上可接受的盐、晶型、水合物或溶剂合物;
其中,各X,Y,Z,M如本发明第一方面所述。
本发明公开了一种并入两个芳基的四甘脲八羧酸盐,其在酸性条件下,羧酸盐酸化为二芳并四甘脲八羧酸,其水溶性差,不络合苦味剂;在中性或弱碱性介质中,水溶性能优异,同时八羧酸盐能够与阳离子型苦味剂有较强的结合而实现苦味遮蔽。
制备方法
本发明还提供了苦味遮蔽化合物的制备方法,具体地,首先合成侧链引入酯基的芳环中间体,再与甘脲四聚体反应。
下面更具体地描述本发明式(I)结构化合物的制备方法,但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得,这样的组合可由本发明所属领域的技术人员容易地进行。在某些情况下,可以改变执行方案的步骤顺序,以促进反应或避免不需要的副反应产物。
具体包含以下步骤:
其中,R为取代或未取代的C1-5的烷基,其中,所述的取代是指烷基上一个或多个H被C1-6烷基取代;X,Y,Z,M如本发明第一方面所述。
进一步地,所述酯基侧链芳环中间体的制备方法包括在碱性条件下,对芳基二酚引入末端羟基取代的脂肪链;将末端羟基转化为好的离去基团;再与丙二酸二酯CH2(CO2R)2反应,得到酯基侧链芳环中间体;
进一步地,所述二芳并四甘脲八羧酸盐的制备方法包括:酯基侧链芳环中间体与甘脲四聚体反应,然后在碱性条件下水解得到相应的八羧酸盐。
较佳地,本发明的各反应物之间摩尔比为芳基二酚:末端溴代脂肪醇=1:(3±0.5);二芳醚:甲磺酰氯:二酸二酯=1:(3±0.5):(3±0.5);酯基侧链芳环中间体:甘脲四聚体=(3±0.5):1。
苦味遮蔽剂
本发明还提供了式I所示的二芳并四甘脲八羧酸盐化合物、或其药学上可接受的盐、晶型、水合物或溶剂合物作为苦味遮蔽剂中的用途。
本发明的苦味遮蔽剂具有疏水空腔,苦味剂或苦味药物分子进入空腔后,苦味被掩蔽,受试者口服依从性较好。
本发明提供的化合物生物相容性好、无味毒性低,适合广泛用作苦味遮蔽剂。
通过C57BL/6小鼠试验,验证了本发明所述的二芳并四甘脲八羧酸盐对药物苦味的遮蔽作用。所述苦味掩蔽剂掩蔽的苦味剂为阳离子型苦味剂,包括但不限于小檗碱、苦精(苯甲地那铵)和盐酸奎宁。
药物组合物或口服制剂
本发明还提供了一种药物组合物,它包含安全有效量范围内的活性成分,以及药学上可接受的载体。“安全有效量”指的是:活性成分的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有1-2000mg活性成分/剂,更佳地,含有10-200mg活性成分/剂。较佳地,所述的“一剂”为一个药片。
“药学上可接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的活性成分以及它们之间相互掺和,而不明显降低活性成分的药效。
通常,优选实施例的化合物将以治疗有效量、通过具有类似作用的药剂的任意一种可接受的模式施用。优选实施例的化合物(即活性成分)的实际用量根据多个因素确定,如待治疗疾病的严重程度、患者的年龄和相对健康程度、被使用化合物的效力、施用的路径和形式,以及其他因素。该药物可一天施用多次,优选地,每天一次或两次。所有这些因素都在主治医生的考虑范围内。
优选实施例的目的,治疗有效剂量通常可以是对患者一次性施用或分次施用的每日总剂量,例如,每日约0.001至约1000毫克/公斤体重,优选地,每日约1.0至约30毫克/千克体重。单位剂量组合物(Dosage unit composition)可包含其剂量因数以形成每日剂量。剂型的选择取决于各种因素,例如给药模式和药物物质的生物利用度。通常,优选实施例的化合物可作为药物组合物通过以下任意一种路线给药:口服、全身给药(如透皮、鼻内或通过栓剂)、或肠外给药(如肌内、静脉内或皮下)。优选的给药方式为口服,可根据苦的程度调节方便的日剂量。组合物可采取的形式为片剂、丸剂、胶囊、半固体、粉剂、缓释制剂、溶液、悬浮液、酏剂、气雾剂或任何其他适当的组合物。另一种优选的施用优选实施例化合物的方式为吸入。这是一种将治疗剂直接运送给呼吸道的有效方法(参见,如美国专利号5,607,915)。
合适的药学上可接受的载体或赋形剂包括:如处理剂和药物运送改性剂和促进剂,诸如磷酸钙、硬脂酸镁、滑石、单糖、二糖、淀粉、明胶、纤维素、甲基纤维素钠、羧甲基纤维素、葡萄糖、羟丙基-B-环糊精、聚乙烯吡咯烷酮、低熔点蜡、离子交换树脂等,及其任意两种或多种的组合。液体和半固体的赋形剂可以选自甘油、丙二醇、水、乙醇和各种油,包括石油、动物油、植物油或合成来源,如花生油、豆油、矿物油、芝麻油等。优选的液体载体,特别是用于可注射溶液的载体,包括水、盐水、葡萄糖水性溶液和乙二醇。其它适宜的药学上可接受的赋形剂在《雷明顿药物科学》(Remington’s Pharmaceutical Sciences),MackPub.Co.,新泽西(1991)有描述,通过引用纳入本文。
如本文所用,术语“药学上可接受的盐”是指通式I化合物的非毒性酸或碱土金属盐。这些盐可在最终分离和纯化通式I化合物时原位制得、或分别将合适的有机或无机酸或碱与碱性或酸性官能团反应制得。代表性的盐包括,但不限于:乙酸盐、己二酸盐、藻酸盐、柠檬酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、二葡糖酸盐、环戊烷丙酸盐、十二烷基硫酸盐、乙磺酸盐、葡萄糖庚酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、富马酸盐、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、烟酸盐、2-萘基磺酸盐、草酸盐、双羟萘酸盐、果胶酸盐、硫氰酸盐、3-苯基丙酸盐、苦味酸盐、新戊酸盐、丙酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐和十一烷酸盐。此外,含氮的碱性基团可被如下试剂季铵盐化:烷基卤化物,如甲基、乙基、丙基、丁基的氯化物、溴化物和碘化物;二烷基硫酸盐,如二甲基、二乙基、二丁基和二戊基硫酸酯;长链卤化物如癸基、月桂基、肉豆蔻基和硬脂基的氯化物、溴化物和碘化物;芳烷基卤化物如苄基和苯乙基溴化物等。由此得到水溶性或油溶性或可分散产品。可被用于形成药学上可接受的酸加成盐的酸的例子包括如盐酸、硫酸、磷酸的无机酸,和如草酸、马来酸、甲磺酸、琥珀酸、柠檬酸的有机酸。碱加成盐可在最终分离和纯化通式I的化合物时原位制得、或使羧酸部分分别与合适的碱(如药学上可接受的金属阳离子的氢氧化物,碳酸盐或碳酸氢盐)或氨、或有机伯、仲或叔胺反应制得。药学上可接受的盐包括,但不限于,基于碱金属和碱土金属的阳离子,如钠、锂、钾、钙、镁、铝的盐等,以及无毒的铵、季铵和胺阳离子,包括,但不限于:铵、四甲基铵、四乙基铵、甲胺、二甲胺、三甲胺、三乙胺、乙胺等。其它代表性的用于形成碱加成盐的有机胺包括二乙胺、乙二胺、乙醇胺、二乙醇胺、哌嗪等。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药,或者与其他药学上可接受的其他化合物(如抗肿瘤药物)联合给药。
本发明治疗方法可以单独施用,或者与其它治疗手段或者治疗药物联用。
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为1~2000mg,优选50~1000mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
与现有技术相比,本发明的主要优点包括:
(a)本发明的式I所示的二芳并四甘脲八羧酸盐具有高度水溶性,生物相容性好。
(b)本发明的式I所示的二芳并四甘脲八羧酸盐具有良好的苦味遮蔽作用,能够有效的遮蔽市面上常见的苦味剂及苦味药物,受试者的依从性好。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件如Sambrook等人,分子克隆:实验室手册(New York:Cold Spring Harbor LaboratoryPress,1989)中所述的条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
除非另行定义,文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外,任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
实施例1
本发明二芳并四甘脲八羧酸盐通用制备方法,以化合物I-1为例提供,反应路线如下式所示:
具体操作为:将氢氧化钠(1.60g,40mmol)溶解在乙醇(20mL)和水(5mL)的混合物中,并投入1,4-二羟基萘1a(1.60g,10mmol)的乙醇溶液(20mL)中,搅拌活化30分钟,然后在搅拌下加入2-溴乙醇(3.75g,30mmol)并回流24小时。反应液冷却至室温后,旋转蒸发浓缩,得到红色固体,将其重新溶解在乙酸乙酯(100mL)中并用水(2×75mL)洗涤。水相进一步用乙酸乙酯(2×75mL)萃取。将合并的有机相用饱和食盐水(50mL)洗涤,经无水硫酸钠干燥后旋转蒸发除去溶剂。通过柱层析法纯化粗产物(洗脱剂乙酸乙酯:正己烷=1:1到2:1),得到灰白色粉末状固体1,4-对萘二酚二羟乙基醚1b(2.01g,81%)。M.p.123–124℃.1H NMR(400MHz,CDCl3):δ8.24–8.21(m,2H),7.54–7.51(m,2H),6.72(s,2H),4.23(t,J=4.0Hz,4H),4.09(t,J=4.0Hz,4H),1.99(bs,2H).13C NMR(100MHz,CDCl3):148.89,126.62,126.22,121.84,105.03,70.81,61.90.HR-MS(ESI):calcd for C14H16O4Na[M+Na]+:271.0941,found 271.0941。
将三乙胺(1.52g,15mmol)加入1,4-对萘二酚二羟乙基醚1b(1.24g,5mmol)的无水四氢呋喃溶液(10mL)中,然后通过冰浴将溶液冷却至0℃。将甲磺酰氯(1.72g,15mmol)分散在5mL无水四氢呋喃中并将其缓慢滴入混合物。撤去冰浴并将溶液在室温下搅拌2小时。加入30mL水淬灭反应,并用乙酸乙酯(2×50mL)进一步萃取混合物。合并的有机相用饱和食盐水(50mL)洗涤并用无水硫酸钠干燥。旋转蒸发除去溶剂并将粗产物重新溶解在N,N-二甲基甲酰胺(50mL)中,加入丙二酸二甲酯(1.98g,15mmol)和碳酸钾(2.07g,15mmol)并将混合物在100℃下搅拌24小时。待反应物冷却至室温,加入100mL水淬灭反应,并用乙酸乙酯(3×50mL)进一步萃取混合物。将合并的有机相用饱和食盐水(100mL)洗涤,经无水硫酸钠干燥。旋干溶剂,粗产品通过柱层析法(洗脱剂乙酸乙酯/正己烷=1:5)纯化粗产品,得到白色粉末状固体1,4-双(3,3-二甲氧羰基丙氧基)萘1c(1.47g,61%)。M.p.131–132℃.1H NMR(400MHz,CDCl3):δ8.17–8.15(m,2H),7.52–7.49(m,2H),6.64(s,2H),4.15(t,J=4.0Hz,4H),3.82(t,J=8.0Hz,2H),3.75(s,12H),2.53(q,J=6.0Hz,4H).13C NMR(100MHz,CDCl3):148.79,126.76,126.39,121.99,105.13,68.98,42.26.HR-MS(ESI):calcd for C24H29O10[M+H]+:477.1756,found 477.1752。
将甘脲四聚体(390mg,0.5mmol)用2毫升三氟乙酸溶解,并加入1,4-双(3,3-二甲氧羰基丙氧基)萘1c(715mg,1.5mmol)和乙酸酐(2mL),将混合物搅拌并在70℃加热反应3小时。待反应物冷却至室温后,将溶液倒入甲醇(100mL)中搅拌30分钟。滤出沉淀物并用甲醇(5mL)和水(5mL)洗涤。得到的沉淀加入氢氧化钠(160mg,4mmol)的甲醇-水溶液(10mL,体积比1:1)中,将混合物加热至60℃并搅拌2小时。将溶液冷却、过滤并浓缩至0.5mL,重新加入10mL甲醇后产生白色絮状物。将絮状物滤出并用水和甲醇(体积比1:10)重结晶,得到白色固体I-1(414mg,47%)。M.p.>320℃(分解).1H NMR(400MHz,D2O):δ7.81(s,4H),7.21(s,4H),5.53–5.21(m,14H),4.50(d,J=15.7Hz,4H),4.19(d,J=15.6Hz,4H),4.06–3.99(m,6H),3.75(d,J=6.8Hz,4H),3.31(t,J=7.6Hz,4H),2.28(d,J=6.7Hz,8H),1.76(s,6H),1.71(s,6H).13CNMR(100MHz,D2O):δ178.95,178.77,156.99,156.44,148.36,127.81,127.26,126.15,122.50,78.65,77.69,75.05,71.65,71.35,55.08,54.72,53.12,48.59,36.55,30.54,16.60,15.19.HR-MS(ESI):calcd for C70H71N16O28[M-8Na+7H]-:1583.4618,found 1583.4631。
实施例2
化合物I-2的制备以2,3-二甲基-1,4-对苯二酚二羟乙基醚2a为原料,再转化为化合物2b,然后与甘脲四聚体反应,具体步骤与化合物I-1的制备相同。化合物2b,产率67%。M.p.126–127℃.1H NMR(400MHz,CDCl3):δ6.58(s,2H),3.94(t,J=5.9Hz,4H),3.75(m,14H),2.40(q,J=5.9Hz,4H),2.13(s,6H).13C NMR(100MHz,CDCl3):169.79,151.15,127.22,109.25,66.06,52.76,48.77,29.00,12.25.HR-MS(ESI):calcd for C22H30O10Na[M+Na]+:477.1731,found 477.1731。化合物I-2,产率39%。M.p.>320℃(分解).1H NMR(400MHz,D2O):δ5.73(dd,J=15.2,5.1Hz,2H),5.62(d,J=15.8Hz,4H),5.56–5.43(m,4H),5.15(dd,J=16.1,5.5Hz,4H),4.43(d,J=16.0Hz,4H),4.29(d,J=15.7Hz,4H),4.17(d,J=15.4Hz,2H),3.91(q,J=6.6Hz,4H),3.65–3.56(m,4H),3.30(t,J=7.5Hz,4H),2.28(q,J=7.1Hz,8H),2.13(s,12H),1.85(s,6H),1.75(s,6H).13C NMR(100MHz,D2O):178.88,178.67,156.99,156.31,150.47,131.62,128.14,78.62,77.49,73.53,71.36,54.94,53.53,48.51,36.37,30.39,16.63,15.24,12.70.HR-MS(ESI):calcd for C66H75N16O28[M-8Na+7H]-:1539.4931,found 1539.4945。
实施例3
化合物I-3的制备以1,4-对苯二酚二羟乙基醚3a为原料,再转化为化合物3b,然后与甘脲四聚体反应,具体步骤与化合物I-1的制备相同。化合物3b,产率78%。M.p.119–120℃.1H NMR(400MHz,CDCl3):δ6.78(s,4H),3.96(t,J=5.9Hz,4H),3.75(s,12H),3.70(t,J=7.3Hz,2H),2.36(q,J=6.0Hz,4H).13C NMR(100MHz,CDCl3):169.75,153.10,115.62,65.87,52.76,48.66,28.83.HR-MS(ESI):calcd for C20H26O10Na[M+Na]+:449.1419,found449.1419.化合物I-3,产率52%。M.p.>320℃(分解).1H NMR(400MHz,D2O):δ7.02(s,4H),5.72(d,J=15.4Hz,2H),5.61(d,J=15.8Hz,4H),5.56–5.44(m,4H),5.31(d,J=16.3Hz,4H),4.33(dd,J=26.3,16.1Hz,8H),4.22–4.13(m,6H),4.00–3.90(m,4H),3.36(m,8H),2.22(p,J=6.3Hz,8H),1.85(s,6H),1.76(s,6H).13C NMR(100MHz,D2O):179.23,178.93,157.04,156.55,150.32,128.24,128.14,115.71,78.97,77.68,71.39,71.33,69.82,57.34,55.34,52.73,48.52,35.50,35.21,30.14,16.63,16.26,15.05.HR-MS(ESI):calcdfor C62H67N16O28[M-8Na+7H]-:1484.4316,found 1484.4308。
实施例4
通过核磁氢谱实验确定二芳并四甘脲八羧酸盐在水中的溶解度。以化合物I-1为例,具体操作为:将过量的I-1加入到1mL重水中,将混合物在室温下磁力搅拌过夜,然后离心两次(8000rpm),每次10分钟。取10μL上清液和10μL均苯三甲酸钠的重水溶液(400mmol/L)加入480μL重水中,通过I-1和均苯三甲酸钠在核磁氢谱上的信号积分面积比,计算得到化合物I-1在25℃水中的饱和溶解度为155mmol/L(273mg/mL)。类似的,化合物I-2、化合物I-3在25℃水中的饱和溶解度分别为224.2mmol/L(385mg/mL)与241mmol/L(400mg/mL)。在酸性条件下,二芳并四甘脲八羧酸盐酸化为二芳并四甘脲八羧酸,不溶于水溶液。
本发明还测试了文献中已知的引入四羧酸根负离子的二芳并四甘脲的水溶性为14mg/mL-40mg/mL。对比两者的结果可知,本发明的引入8个羧酸根负离子的二芳并四甘脲八羧酸盐的水溶性相对于引入4个羧酸根负离子的羧酸盐大幅提升,提升倍数最高达到了惊人的28倍,表明本发明的二芳并四甘脲八羧酸盐具有优异的水溶性。
实施例5
通过核磁滴定实验确定二芳并四甘脲八羧酸盐与阳离子型苦味剂在溶液相中的结合模式。以化合物I-2和小檗碱的结合为例,具体操作为:配制1.0mmol/L的小檗碱(Ber)重水溶液和10.0mol/L的化合物I-2重水溶液,向小檗碱溶液中按比例逐渐滴入化合物I-2溶液,并测定每一次滴加后溶液体系的核磁氢谱(图1)。核磁滴定实验表明,随着I-2浓度的增加,小檗碱的质子信号发生明显变化,表明其进入了化合物I-2的疏水空腔。类似的,化合物I-2和苦精(又称苯甲地那铵,DB)的滴定实验(图2)以及化合物I-3和盐酸奎宁(QHCl)的滴定实验(图3)均表明,苦味剂进入了二芳并四甘脲八羧酸盐的疏水空腔。
实施例6
通过紫外可见吸收光谱的变化确定二芳并四甘脲八羧酸盐与染料罗丹明B(RB)的结合常数。以化合物I-1为例,具体实验操作为:在25℃下在磷酸钠缓冲液(10mmol/L,pH=7)中配制10μmol/L的RB溶液,逐滴滴加I-1,测定紫外-可见吸收光谱,如图4a所示。通过1:1络合模型对波长570nm处紫外可见吸收的变化进行拟合(图4b),得到I-1与RB的结合常数为(7.67±0.04)×105M-1。
实施例7
以阳离子型苦味剂与染料@八羧酸盐的紫外可见吸收竞争滴定实验,确定二芳并四甘脲八羧酸盐与阳离子型苦味剂的结合常数。以小檗碱(Ber)和RB@I-1络合物的竞争滴定为例,具体操作为:25℃下在磷酸钠缓冲液(10mmol/L,pH=7)中配制10μmol/L的RB@I-1溶液(1:1),逐滴滴加Ber,测定紫外可见吸收光谱,如图5a所示。通过1:1竞争滴定络合模型对波长570nm处紫外可见吸收的变化进行拟合(图5b),结合实施例6测得的I-1与RB的结合常数,得到I-1与Ber的结合常数为(3.22±1.07)×105M-1。
实施例8
通过细胞计数试剂盒Cell Counting Kit-8(CCK-8)测定二芳并四甘脲八羧酸盐化合物I-1~3的细胞毒性。具体操作为,二芳并四甘脲八羧酸盐化合物I-1~3分别用1×PBS配制为溶液,利用正常肝细胞(L-02)和大鼠心肌细胞(H9C2)作为模型,研究I-1~3的体外细胞毒性。结果显示,当八羧酸盐浓度在0~500μmol/mL时,两种细胞的存活率均在80%以上(图6),说明二芳并四甘脲八羧酸盐化合物I-1~3均有较低的细胞毒性。
实施例9
通过计算C57BL/6小鼠摄取超纯水或二芳并四甘脲八羧酸盐溶液(样品溶液)的质量差的双瓶偏好测试,来判断小鼠对超纯水和样品溶液的喜好差别。以I-1为例,具体操作为:在双瓶偏好测试之前,小鼠被饲养在包含两个水瓶(装有超纯水)的笼子中,以习惯于有两个位置来喝水,两个水瓶具有相同的尖端角度的平行位置。饲养一周之后,将其中一瓶超纯水替换为I-1水溶液(以去离子水配制,浓度为500μmol/L),随后每48小时对两个水瓶进行称重。为了避免由位置引起的偏爱,每24小时后交换两个水瓶的位置。计算每只小鼠对每种测试溶液的平均每日(24小时)液体摄入量。偏好百分比通过如下公式计算:偏好(%)=平均每日测试溶液摄入量/(平均每日总摄入量(样品溶液+超纯水))×100%。计算得到小鼠对I-1溶液的偏好百分比为48.0±1.2%(图7),且根据配对t检验,小鼠对超纯水和I-1溶液没有显著偏好差异。类似的,小鼠对化合物I-2和I-3溶液的偏好百分比分别为49.3±0.5%和50.1±0.6%(图7)。结果表明,化合物I-1~3对小鼠而言没有任何特殊味道。
实施例10
二芳并四甘脲八羧酸盐的动物毒性测定。用二芳并四甘脲八羧酸盐化合物I-1~3溶液(以去离子水配制,浓度为500μmol/L)分别喂养C57BL/6小鼠两周,并在固定的时间间隔(第0、2、4、6、8、10、12和14天)记录小鼠的体重。与对照组(超纯水)相比,小鼠体重未见明显差别,证明二芳并四甘脲八羧酸盐化合物I-1~3均没有明显的动物毒性。
实施例11
通过计算C57BL/6小鼠摄取阳离子苦味剂溶液或阳离子苦味剂与二芳并四甘脲八羧酸盐络合后的溶液(样品溶液)的质量差的双瓶偏好测试,来判断二芳并四甘脲八羧酸盐对苦味剂的苦味遮蔽效果。以小檗碱(Ber)为例,具体操作为:在双瓶偏好测试之前,小鼠被饲养在包含两个水瓶(装有超纯水)的笼子中,以习惯于有两个位置来喝水,两个水瓶具有相同的尖端角度的平行位置。饲养一周之后,将一瓶超纯水分别替换为Ber、Ber@I-1、Ber@I-2或Ber@I-3溶液(以去离子水配制,浓度为500μmol/L),随后每48小时对两个水瓶进行称重。为了避免由位置引起的偏爱,每24小时后交换两个水瓶的位置。计算每只小鼠对每种测试溶液的平均每日(24小时)液体摄入量。偏好百分比通过如下公式计算: 计算得到:小鼠对Ber、Ber@I-1、Ber@I-2或Ber@I-3溶液的偏好百分比分别为13.1±0.4%、45.0±1.0%、45.0±0.3%和43.6±0.7%(图8),且根据单向方差分析,I-1、I-2或I-3的加入都导致了显著的差异(p<0.05)。结果表明,I-1、I-2、I-3的添加均有效掩蔽了Ber的苦味。
参照文献方法制备二芳并四甘脲四羧酸盐I-3-4C(J.Org.Chem.2010,75,4786–4795)。以去离子水配制配置Ber@I-3-4C溶液(浓度为500μmol/L),按照上述实验方法,测定出小鼠对Ber@I-3-4C的偏好百分比为14.2±0.8%,其值与Ber组无显著性差异,表明I-3-4C的添加没有获得掩蔽Ber苦味的功能。
从上述结果可知,本发明的二芳并四甘脲八羧酸盐具有无味、生物相容性好、水溶性高、毒性低,苦味掩蔽效果优异等特点,特别是相比于含有四个羧酸盐的二芳并四甘脲四羧酸盐,本发明的引入八羧酸盐的二芳并四甘脲八羧酸盐具备了有效的苦味掩蔽效果,同时水溶性大幅提升。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (12)
1.一种式(I)所示的二芳并四甘脲八羧酸盐化合物、或其药学上可接受的盐、晶型、水合物或溶剂合物,
其中,
各个X各自独立地选自下组:取代或未取代的C1-20亚烷基、取代或未取代的含有一个或多个选自N、O和S的杂原子的C1-20亚杂烷基、取代或未取代的C3-20亚环烷基、取代或未取代的3-20元亚杂环基;
各个Y各自独立地选自下组:取代或未取代的C1-20烷基、取代或未取代的含有一个或多个选自N、O和S的杂原子的C1-20杂烷基、取代或未取代的C3-20环烷基、取代或未取代的3-20元杂环基,或两个相邻Y与其相连的碳原子共同形成取代或未取代的C3-20环烷基或3-20元杂环基;
各个Z各自独立地选自下组:氢、C1-20烷氧基、取代或未取代的C1-20烷基或C3-20环烷基,或两个相邻的Z与其相连的碳原子共同形成取代或未取代的选自下组的基团:C3-20碳环、3-20元碳杂环、C6-20芳基、5-20元杂芳基;
各个M各自独立地为药学上可接受的阳离子;
除非特别说明,否则所述的取代是指基团上的氢被一个或多个卤素、氰基、硝基、氨基、羰基、苄基、苯基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C3-7环烷基取代。
2.如权利要求1所述的化合物,其特征在于,各个X各自独立地选自下组:取代或未取代的C1-6亚烷基、取代或未取代的含有一个或多个选自N、O和S的杂原子的C1-6亚杂烷基、取代或未取代的C3-7亚环烷基、取代或未取代的3-7元亚杂环基;
各个Y各自独立地选自下组:取代或未取代的C1-6烷基、取代或未取代的含有一个或多个选自N、O和S的杂原子的C1-6杂烷基、取代或未取代的C3-6环烷基、取代或未取代的3-6元杂环基,或两个相邻Y与其相连的碳原子共同形成取代或未取代的C3-7环烷基或3-7元杂环基;
各个Z各自独立地选自下组:氢、C1-6烷氧基、取代或未取代的C1-6烷基或C3-7环烷基,或两个相邻的Z与其相连的碳原子共同形成取代或未取代的选自下组的基团:C3-7环烷基、3-7元杂环基、苯基、5-7元杂芳基;
各个M各自独立地为Na+、K+、Li+、Mg2+、Ca2+、NH4 +、或一个到四个各自独立地为C1-6烷基或C6-10芳基取代的铵盐;
除非特别说明,否则所述的取代是指基团上的氢被一个或多个卤素、氰基、硝基、氨基、羰基、苄基、苯基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C3-7环烷基取代。
3.如权利要求1所述的化合物,其特征在于,M各自独立地为Li+、Na+、K+、Mg2+、Ca2 +、NH4 +;各个X各自独立地为-(CH2)n-,其中,n为2,3,4,5,6;Y各自独立地为C1-3烷基。
4.如权利要求1所述的化合物,其特征在于,各个Z各自独立地选自下组:氢、C1-6烷基,或两个相邻的Z与其相连的碳原子共同形成取代或未取代的选自下组的基团:C3-7环烷基、苯基。
5.如权利要求1所述的化合物,其特征在于,各自独立地为/>或其中,G为H,或一个或多个各自独立地选自下组的基团:卤素、C1-6烷基、C1-6烷氧基。
6.如权利要求1所述的化合物,其特征在于,所述的化合物选自下组:
7.权利要求1所述的二芳并四甘脲八羧酸盐、或其药学上可接受的盐、晶型、水合物或溶剂合物用作苦味遮蔽剂的用途。
8.一种如权利要求1所述的化合物的制备方法,其特征在于,包括如下步骤:
在TFA的存在下,式d化合物与式e化合物甘脲四聚体反应,然后加入氢氧化物MOH水解,得到式I所示的权利要求1所述的化合物;
式中,R为取代或未取代的C1-5烷基;其中,所述的取代是指基团上的氢被一个或多个C1-6烷基取代,各个Z,Y,X,M分别如权利要求1所述。
9.如权利要求8所述的方法,其特征在于,所述的式d化合物的制备方法包括步骤:
(a)在碱的存在下,式a化合物和式b化合物反应,得到式c化合物;
(b)式c化合物与CH2(CO2R)反应,得到式d化合物;
式中,R为取代或未取代的C1-5烷基,其中,所述的取代是指基团上的氢被一个或多个C1-6烷基取代;各个Z,Y,X,M分别如权利要求1所述。
10.一种式d所示的酯基侧链芳环化合物,其特征在于,结构如下:
式中,R为取代或未取代的C1-5烷基,其中,所述的取代是指基团上的氢被一个或多个C1-6烷基取代。
11.一种药物组合物或口服制剂,其特征在于,包括:
(i)苦味药物活性成分;
(ii)权利要求1所述的二芳并四甘脲八羧酸盐化合物、或其药学上可接受的盐、晶型、水合物或溶剂合物;和
(iii)药学上可接受的载体或赋形剂。
12.一种药物组合物或口服制剂,其特征在于,包括:
(a)苦味剂:小檗碱、苦精(苯甲地那铵)和盐酸奎宁;和
(b)权利要求1所述的二芳并四甘脲八羧酸盐化合物、或其药学上可接受的盐、晶型、水合物或溶剂合物;和
(c)药学上可接受的载体或赋形剂。
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