CN117003770A - 一种稠合嘧啶类化合物或其药学上可接受盐及其制备方法和应用 - Google Patents
一种稠合嘧啶类化合物或其药学上可接受盐及其制备方法和应用 Download PDFInfo
- Publication number
- CN117003770A CN117003770A CN202310668727.6A CN202310668727A CN117003770A CN 117003770 A CN117003770 A CN 117003770A CN 202310668727 A CN202310668727 A CN 202310668727A CN 117003770 A CN117003770 A CN 117003770A
- Authority
- CN
- China
- Prior art keywords
- preparation
- methyl
- compound
- pharmaceutically acceptable
- acceptable salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 63
- -1 pyrimidine compound Chemical class 0.000 title claims abstract description 53
- 150000003839 salts Chemical class 0.000 title claims abstract description 25
- 150000001875 compounds Chemical class 0.000 claims description 69
- 238000006243 chemical reaction Methods 0.000 claims description 43
- 239000001257 hydrogen Substances 0.000 claims description 30
- 229910052739 hydrogen Inorganic materials 0.000 claims description 30
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 24
- 230000000694 effects Effects 0.000 claims description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 230000009471 action Effects 0.000 claims description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- 239000001301 oxygen Chemical group 0.000 claims description 14
- 229910052760 oxygen Inorganic materials 0.000 claims description 14
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 12
- 239000011593 sulfur Chemical group 0.000 claims description 12
- 229910052717 sulfur Chemical group 0.000 claims description 12
- 206010028980 Neoplasm Diseases 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 125000005842 heteroatom Chemical group 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 9
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 9
- 210000004881 tumor cell Anatomy 0.000 claims description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 230000035755 proliferation Effects 0.000 claims description 8
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- UMXDBGWXIQPJKK-UHFFFAOYSA-N methyl 2-methyl-1h-indole-4-carboxylate Chemical compound COC(=O)C1=CC=CC2=C1C=C(C)N2 UMXDBGWXIQPJKK-UHFFFAOYSA-N 0.000 claims description 7
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- 230000006907 apoptotic process Effects 0.000 claims description 6
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 6
- 201000011510 cancer Diseases 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 claims description 5
- 208000034578 Multiple myelomas Diseases 0.000 claims description 4
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 4
- 239000004202 carbamide Substances 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 3
- 208000032839 leukemia Diseases 0.000 claims description 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 201000002528 pancreatic cancer Diseases 0.000 claims description 3
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 3
- 150000003230 pyrimidines Chemical class 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- XJPZKYIHCLDXST-UHFFFAOYSA-N 4,6-dichloropyrimidine Chemical compound ClC1=CC(Cl)=NC=N1 XJPZKYIHCLDXST-UHFFFAOYSA-N 0.000 claims description 2
- 208000022072 Gallbladder Neoplasms Diseases 0.000 claims description 2
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 2
- 239000004327 boric acid Substances 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 150000001735 carboxylic acids Chemical class 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 230000002357 endometrial effect Effects 0.000 claims description 2
- 201000010175 gallbladder cancer Diseases 0.000 claims description 2
- 125000001188 haloalkyl group Chemical group 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 238000003780 insertion Methods 0.000 claims description 2
- 230000037431 insertion Effects 0.000 claims description 2
- 125000001620 monocyclic carbocycle group Chemical group 0.000 claims description 2
- 229940122887 p97 inhibitor Drugs 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 125000005017 substituted alkenyl group Chemical group 0.000 claims description 2
- 125000004426 substituted alkynyl group Chemical group 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 2
- 102100037364 Craniofacial development protein 1 Human genes 0.000 claims 1
- 210000000481 breast Anatomy 0.000 claims 1
- 210000001072 colon Anatomy 0.000 claims 1
- 210000000232 gallbladder Anatomy 0.000 claims 1
- 210000003734 kidney Anatomy 0.000 claims 1
- 210000004072 lung Anatomy 0.000 claims 1
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims 1
- 230000002611 ovarian Effects 0.000 claims 1
- 210000002307 prostate Anatomy 0.000 claims 1
- 230000002381 testicular Effects 0.000 claims 1
- 210000003932 urinary bladder Anatomy 0.000 claims 1
- 230000002485 urinary effect Effects 0.000 claims 1
- 210000004027 cell Anatomy 0.000 description 35
- 239000000543 intermediate Substances 0.000 description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 30
- 102100026145 Transitional endoplasmic reticulum ATPase Human genes 0.000 description 25
- 239000012074 organic phase Substances 0.000 description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 19
- 239000000047 product Substances 0.000 description 18
- 239000007787 solid Substances 0.000 description 17
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
- 230000005764 inhibitory process Effects 0.000 description 15
- 238000005481 NMR spectroscopy Methods 0.000 description 14
- 230000002401 inhibitory effect Effects 0.000 description 14
- 239000000203 mixture Substances 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 238000002390 rotary evaporation Methods 0.000 description 12
- 239000008346 aqueous phase Substances 0.000 description 11
- 238000001819 mass spectrum Methods 0.000 description 11
- 238000010183 spectrum analysis Methods 0.000 description 11
- 230000002829 reductive effect Effects 0.000 description 10
- 238000004611 spectroscopical analysis Methods 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000004440 column chromatography Methods 0.000 description 9
- 210000001853 liver microsome Anatomy 0.000 description 9
- 238000010898 silica gel chromatography Methods 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 229940079593 drug Drugs 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- 108090000623 proteins and genes Proteins 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- 238000001228 spectrum Methods 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 239000003112 inhibitor Substances 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 239000000523 sample Substances 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- KCBAMQOKOLXLOX-BSZYMOERSA-N CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O Chemical compound CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O KCBAMQOKOLXLOX-BSZYMOERSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 6
- 229940125833 compound 23 Drugs 0.000 description 6
- 125000001072 heteroaryl group Chemical group 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- 238000004949 mass spectrometry Methods 0.000 description 6
- 235000018102 proteins Nutrition 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- MXRPXKYWAYTGJY-UHFFFAOYSA-N 4-bromo-2-methyl-1h-indole Chemical compound C1=CC=C2NC(C)=CC2=C1Br MXRPXKYWAYTGJY-UHFFFAOYSA-N 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 5
- 229940125898 compound 5 Drugs 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- IAUTTZKZEBNNIB-UHFFFAOYSA-N 1-(benzenesulfonyl)-4-bromo-2-methylindole Chemical compound CC1=CC2=C(Br)C=CC=C2N1S(=O)(=O)C1=CC=CC=C1 IAUTTZKZEBNNIB-UHFFFAOYSA-N 0.000 description 4
- HCVHHKPCZJWQCF-UHFFFAOYSA-N 1-(benzenesulfonyl)-4-bromoindole Chemical compound C1=CC=2C(Br)=CC=CC=2N1S(=O)(=O)C1=CC=CC=C1 HCVHHKPCZJWQCF-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical group [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- 102000018745 NF-KappaB Inhibitor alpha Human genes 0.000 description 4
- 108010052419 NF-KappaB Inhibitor alpha Proteins 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 235000011054 acetic acid Nutrition 0.000 description 4
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 229910002091 carbon monoxide Inorganic materials 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 239000013641 positive control Substances 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 241000894007 species Species 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- 210000003462 vein Anatomy 0.000 description 4
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 3
- JQPYINKVAWEQDQ-UHFFFAOYSA-N 1h-pyrido[2,3-d]pyrimidine-2,4-dione Chemical compound C1=CC=C2C(=O)NC(=O)NC2=N1 JQPYINKVAWEQDQ-UHFFFAOYSA-N 0.000 description 3
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 206010009944 Colon cancer Diseases 0.000 description 3
- 230000008341 ER-associated protein catabolic process Effects 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- 241000282414 Homo sapiens Species 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- 108091023040 Transcription factor Proteins 0.000 description 3
- 102000040945 Transcription factor Human genes 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 230000001028 anti-proliverative effect Effects 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 230000033228 biological regulation Effects 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 235000013877 carbamide Nutrition 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 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
- 229940126208 compound 22 Drugs 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 3
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- DDLIGBOFAVUZHB-UHFFFAOYSA-N midazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NC=C2CN=C1C1=CC=CC=C1F DDLIGBOFAVUZHB-UHFFFAOYSA-N 0.000 description 3
- 229960003793 midazolam Drugs 0.000 description 3
- 210000004940 nucleus Anatomy 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- LTZWPRXMGJIPPQ-UHFFFAOYSA-N tert-butyl 2,4-dichloro-6,7-dihydro-5h-pyrido[2,3-d]pyrimidine-8-carboxylate Chemical compound N1=C(Cl)N=C2N(C(=O)OC(C)(C)C)CCCC2=C1Cl LTZWPRXMGJIPPQ-UHFFFAOYSA-N 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- 238000003260 vortexing Methods 0.000 description 3
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 3
- SLTBMTIRYMGWLX-XMMPIXPASA-N (2r)-2-[(4-chloroanilino)carbamoylamino]-3-(1h-indol-3-yl)-n-(2-phenylethyl)propanamide Chemical compound C1=CC(Cl)=CC=C1NNC(=O)N[C@@H](C(=O)NCCC=1C=CC=CC=1)CC1=CNC2=CC=CC=C12 SLTBMTIRYMGWLX-XMMPIXPASA-N 0.000 description 2
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 2
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 2
- GCDQZEWWSOWZRG-UHFFFAOYSA-N 1-(benzenesulfonyl)-4-chloropyrrolo[3,2-c]pyridine Chemical compound C1=CC=2C(Cl)=NC=CC=2N1S(=O)(=O)C1=CC=CC=C1 GCDQZEWWSOWZRG-UHFFFAOYSA-N 0.000 description 2
- URRKQHXKXUDNGV-UHFFFAOYSA-N 1-(benzenesulfonyl)-5-oxidopyrrolo[3,2-c]pyridin-5-ium Chemical compound C1=CC2=C[N+]([O-])=CC=C2N1S(=O)(=O)C1=CC=CC=C1 URRKQHXKXUDNGV-UHFFFAOYSA-N 0.000 description 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 2
- KPRZOPQOBJRYSW-UHFFFAOYSA-N 2-(aminomethyl)phenol Chemical compound NCC1=CC=CC=C1O KPRZOPQOBJRYSW-UHFFFAOYSA-N 0.000 description 2
- KPIVDNYJNOPGBE-UHFFFAOYSA-N 2-aminonicotinic acid Chemical compound NC1=NC=CC=C1C(O)=O KPIVDNYJNOPGBE-UHFFFAOYSA-N 0.000 description 2
- JNZYADHPGVZMQK-UHFFFAOYSA-N 3-(aminomethyl)phenol Chemical compound NCC1=CC=CC(O)=C1 JNZYADHPGVZMQK-UHFFFAOYSA-N 0.000 description 2
- WHBMMWSBFZVSSR-UHFFFAOYSA-N 3-hydroxybutyric acid Chemical compound CC(O)CC(O)=O WHBMMWSBFZVSSR-UHFFFAOYSA-N 0.000 description 2
- RQJDUEKERVZLLU-UHFFFAOYSA-N 4-Hydroxybenzylamine Chemical compound NCC1=CC=C(O)C=C1 RQJDUEKERVZLLU-UHFFFAOYSA-N 0.000 description 2
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 2
- GRJZJFUBQYULKL-UHFFFAOYSA-N 4-bromo-1h-indole Chemical compound BrC1=CC=CC2=C1C=CN2 GRJZJFUBQYULKL-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- JADVOEZJVRXVIF-UHFFFAOYSA-N 5,6,7,8-tetrahydro-1h-pyrido[2,3-d]pyrimidine-2,4-dione Chemical compound N1CCCC2=C1NC(=O)NC2=O JADVOEZJVRXVIF-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 241000282693 Cercopithecidae Species 0.000 description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 241000009328 Perro Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 108090000708 Proteasome Endopeptidase Complex Proteins 0.000 description 2
- 102000004245 Proteasome Endopeptidase Complex Human genes 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- 235000019438 castor oil Nutrition 0.000 description 2
- 230000033077 cellular process Effects 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 230000002860 competitive effect Effects 0.000 description 2
- 229940125961 compound 24 Drugs 0.000 description 2
- 239000013068 control sample Substances 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000000539 dimer Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 230000003228 microsomal effect Effects 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- BDJRBEYXGGNYIS-UHFFFAOYSA-N nonanedioic acid Chemical compound OC(=O)CCCCCCCC(O)=O BDJRBEYXGGNYIS-UHFFFAOYSA-N 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 2
- GPHQHTOMRSGBNZ-UHFFFAOYSA-N pyridine-4-carbonitrile Chemical compound N#CC1=CC=NC=C1 GPHQHTOMRSGBNZ-UHFFFAOYSA-N 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- NVTZLPLLMCSMLC-UHFFFAOYSA-N tert-butyl 4-(benzylamino)-2-chloro-6,7-dihydro-5H-pyrido[2,3-d]pyrimidine-8-carboxylate Chemical compound C(C1=CC=CC=C1)NC=1C2=C(N=C(N1)Cl)N(CCC2)C(=O)OC(C)(C)C NVTZLPLLMCSMLC-UHFFFAOYSA-N 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 230000004580 weight loss Effects 0.000 description 2
- UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- FRJJJAKBRKABFA-TYFAACHXSA-N (4r,6s)-6-[(e)-2-[6-chloro-4-(4-fluorophenyl)-2-propan-2-ylquinolin-3-yl]ethenyl]-4-hydroxyoxan-2-one Chemical compound C(\[C@H]1OC(=O)C[C@H](O)C1)=C/C=1C(C(C)C)=NC2=CC=C(Cl)C=C2C=1C1=CC=C(F)C=C1 FRJJJAKBRKABFA-TYFAACHXSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-bis(diphenylphosphino)propane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 description 1
- JXCHTSUBCBYZAV-UHFFFAOYSA-N 1-(benzenesulfonyl)pyrrolo[3,2-c]pyridine Chemical compound C1=CC2=CN=CC=C2N1S(=O)(=O)C1=CC=CC=C1 JXCHTSUBCBYZAV-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- LDMOEFOXLIZJOW-UHFFFAOYSA-N 1-dodecanesulfonic acid Chemical compound CCCCCCCCCCCCS(O)(=O)=O LDMOEFOXLIZJOW-UHFFFAOYSA-N 0.000 description 1
- LNETULKMXZVUST-UHFFFAOYSA-N 1-naphthoic acid Chemical compound C1=CC=C2C(C(=O)O)=CC=CC2=C1 LNETULKMXZVUST-UHFFFAOYSA-N 0.000 description 1
- VAICOOVFEQDEAG-UHFFFAOYSA-N 2,4-dichloro-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine Chemical compound C1CCNC2=NC(Cl)=NC(Cl)=C21 VAICOOVFEQDEAG-UHFFFAOYSA-N 0.000 description 1
- WOXFMYVTSLAQMO-UHFFFAOYSA-N 2-Pyridinemethanamine Chemical compound NCC1=CC=CC=N1 WOXFMYVTSLAQMO-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- 125000003469 3-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- JOFDSYLCZIHGGO-UHFFFAOYSA-N 4-[(4-cyclohexylphenyl)methyl-[2-[[5-(dimethylamino)naphthalen-1-yl]sulfonyl-methylamino]acetyl]amino]-2-hydroxybenzoic acid Chemical compound C1=CC=C2C(N(C)C)=CC=CC2=C1S(=O)(=O)N(C)CC(=O)N(C=1C=C(O)C(C(O)=O)=CC=1)CC(C=C1)=CC=C1C1CCCCC1 JOFDSYLCZIHGGO-UHFFFAOYSA-N 0.000 description 1
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- XYTHDEPHDIPOCJ-UHFFFAOYSA-N 5-bromofuran-2-sulfonamide Chemical compound NS(=O)(=O)C1=CC=C(Br)O1 XYTHDEPHDIPOCJ-UHFFFAOYSA-N 0.000 description 1
- 108010022579 ATP dependent 26S protease Proteins 0.000 description 1
- 108091006112 ATPases Proteins 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 102000057290 Adenosine Triphosphatases Human genes 0.000 description 1
- 101710101449 Alpha-centractin Proteins 0.000 description 1
- 102100025665 Angiopoietin-related protein 1 Human genes 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 208000031648 Body Weight Changes Diseases 0.000 description 1
- 241000903210 Bryconamericus alpha Species 0.000 description 1
- QUMCIHKVKQYNPA-RUZDIDTESA-N C1(CCCCC1)CN1[C@@H](C=2N(C=3C=NC(=NC1=3)NC1=C(C=C(C(=O)NC3CCN(CC3)C)C=C1)OC)C(=NN=2)C)CC Chemical compound C1(CCCCC1)CN1[C@@H](C=2N(C=3C=NC(=NC1=3)NC1=C(C=C(C(=O)NC3CCN(CC3)C)C=C1)OC)C(=NN=2)C)CC QUMCIHKVKQYNPA-RUZDIDTESA-N 0.000 description 1
- 102000011727 Caspases Human genes 0.000 description 1
- 108010076667 Caspases Proteins 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 102100032373 Coiled-coil domain-containing protein 85B Human genes 0.000 description 1
- 102000036364 Cullin Ring E3 Ligases Human genes 0.000 description 1
- 108091007045 Cullin Ring E3 Ligases Proteins 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 230000006782 ER associated degradation Effects 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- DSLZVSRJTYRBFB-UHFFFAOYSA-N Galactaric acid Natural products OC(=O)C(O)C(O)C(O)C(O)C(O)=O DSLZVSRJTYRBFB-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- LYNOGBKNFIHKLE-UHFFFAOYSA-N HET0016 Chemical compound CCCCC1=CC=C(N=CNO)C(C)=C1 LYNOGBKNFIHKLE-UHFFFAOYSA-N 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000868814 Homo sapiens Coiled-coil domain-containing protein 85B Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 208000032271 Malignant tumor of penis Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- ACFIXJIJDZMPPO-NNYOXOHSSA-N NADPH Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](OP(O)(O)=O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 ACFIXJIJDZMPPO-NNYOXOHSSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- 208000002471 Penile Neoplasms Diseases 0.000 description 1
- 206010034299 Penile cancer Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 229940079156 Proteasome inhibitor Drugs 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 1
- 108020004459 Small interfering RNA Proteins 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical group [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000006593 Urologic Neoplasms Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 102000018709 Valosin Containing Protein Human genes 0.000 description 1
- 108010027273 Valosin Containing Protein Proteins 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 229940022663 acetate Drugs 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- IAJILQKETJEXLJ-RSJOWCBRSA-N aldehydo-D-galacturonic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-RSJOWCBRSA-N 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000004900 autophagic degradation Effects 0.000 description 1
- 239000007640 basal medium Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- UENWRTRMUIOCKN-UHFFFAOYSA-N benzyl thiol Chemical compound SCC1=CC=CC=C1 UENWRTRMUIOCKN-UHFFFAOYSA-N 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- ACFIXJIJDZMPPO-UHFFFAOYSA-N beta-NADPH Natural products C1=CCC(C(=O)N)=CN1C1C(O)C(O)C(COP(O)(=O)OP(O)(=O)OCC2C(C(OP(O)(O)=O)C(O2)N2C3=NC=NC(N)=C3N=C2)O)O1 ACFIXJIJDZMPPO-UHFFFAOYSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 230000004579 body weight change Effects 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 229940078916 carbamide peroxide Drugs 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000025084 cell cycle arrest Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000012054 celltiter-glo Methods 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 210000000172 cytosol Anatomy 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- LVTYICIALWPMFW-UHFFFAOYSA-N diisopropanolamine Chemical compound CC(O)CNCC(C)O LVTYICIALWPMFW-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- DSLZVSRJTYRBFB-DUHBMQHGSA-N galactaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O DSLZVSRJTYRBFB-DUHBMQHGSA-N 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- XNXVOSBNFZWHBV-UHFFFAOYSA-N hydron;o-methylhydroxylamine;chloride Chemical compound Cl.CON XNXVOSBNFZWHBV-UHFFFAOYSA-N 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 108091006086 inhibitor proteins Proteins 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229940070765 laurate Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000034217 membrane fusion Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 230000036963 noncompetitive effect Effects 0.000 description 1
- 210000000633 nuclear envelope Anatomy 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 238000006384 oligomerization reaction Methods 0.000 description 1
- PFGVNLZDWRZPJW-OPAMFIHVSA-N otamixaban Chemical compound C([C@@H](C(=O)OC)[C@@H](C)NC(=O)C=1C=CC(=CC=1)C=1C=C[N+]([O-])=CC=1)C1=CC=CC(C(N)=N)=C1 PFGVNLZDWRZPJW-OPAMFIHVSA-N 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 229940055726 pantothenic acid Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 230000029279 positive regulation of transcription, DNA-dependent Effects 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 229960003712 propranolol Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003207 proteasome inhibitor Substances 0.000 description 1
- 230000012846 protein folding Effects 0.000 description 1
- 229940121649 protein inhibitor Drugs 0.000 description 1
- 239000012268 protein inhibitor Substances 0.000 description 1
- 230000006920 protein precipitation Effects 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 230000007111 proteostasis Effects 0.000 description 1
- HDOUGSFASVGDCS-UHFFFAOYSA-N pyridin-3-ylmethanamine Chemical compound NCC1=CC=CN=C1 HDOUGSFASVGDCS-UHFFFAOYSA-N 0.000 description 1
- TXQWFIVRZNOPCK-UHFFFAOYSA-N pyridin-4-ylmethanamine Chemical compound NCC1=CC=NC=C1 TXQWFIVRZNOPCK-UHFFFAOYSA-N 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 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 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000022983 regulation of cell cycle Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 208000000649 small cell carcinoma Diseases 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 102000003390 tumor necrosis factor Human genes 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 230000036967 uncompetitive effect Effects 0.000 description 1
- AQLJVWUFPCUVLO-UHFFFAOYSA-N urea hydrogen peroxide Chemical compound OO.NC(N)=O AQLJVWUFPCUVLO-UHFFFAOYSA-N 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 206010046885 vaginal cancer Diseases 0.000 description 1
- 208000013139 vaginal neoplasm Diseases 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种稠合嘧啶类化合物或其药学上可接受的盐及其制备方法和应用,其中,稠合嘧啶类化合物的结构式I所示,与现有技术相比,本发明稠合嘧啶类化合物或其药学上可接受的盐是一种结构新颖的且具有抑制p97蛋白功能的化合物,它们作为p97蛋白抑制剂,能阻断肿瘤细胞增殖,诱发肿瘤细胞凋亡,从而可用于人和动物的多种疾病如恶性肿瘤的治疗和预防,效果显著。
Description
技术领域
本发明涉及一种稠合嘧啶类化合物或其药学上可接受盐及其制备方法和应用,属于药物化学技术领域。
背景技术
Cdc48(Cell Division Cycle 48)最早在1982年由Moir等人在酿酒酵母中分离鉴定出来,是一种ATP酶,因该蛋白与细胞周期阻滞密切相关而得名。后来Koller和Brownstein发现了一种哺乳动物同源物,将其命名为p97或含缬氨酸的蛋白质前体(Valosine Containing Protein,VCP)。哺乳动物p97由六个相同的亚基组成,每个亚基由N-末端结构域、D1结构域、D2结构域和C-末端延伸区组成,分子量为92KD。研究表明,D1结构域参与寡聚化和六聚体的组装,是六聚体稳定的主要因素。每个亚基的D1和D2结构域都包含有保守的ATP结合(Walker A)和水解(Walker B)序列,以及有效水解所必需的第二同源区域(SRH)。因此,p97共含有12个ATP酶活性位点。然而,在生理条件(37℃)下,D1结构域仅显示弱的ATP酶活性,而D2结构域具有较强的ATP酶活性。
P97是真核细胞质中最丰富的蛋白质之一,其参与许多细胞过程,包括泛素蛋白酶体系统(Ubiquitin-Proteasome System,UPS)介导的蛋白质降解、内质网相关降解(Endoplasmic Reticulum-Associated Degradation,ERAD)、有丝分裂完成后的核膜融合、高尔基重组、转录激活和自噬、细胞周期控制、细胞凋亡和分子伴侣活性。P97参与多种蛋白质质量控制途径,研究最多的是它在ERAD中的作用。P97将错误折叠的多泛素化蛋白从内质网腔中转移到细胞溶质中,然后将它们转运到蛋白酶体中进行降解。
核转录因子Kappa B(NF-κB)是一种重要的转录因子。NF-κB参与多种基因调控并通过对炎症、凋亡和免疫反应的调节在生理病理过程中发挥重要的作用。在基础状态下,由蛋白p50和p65组成的NF-κB异二聚体与抑制蛋白I-κBα(NF-κB抑制剂α)或相关蛋白结合从而保持在非活性状态,并阻止NF-κB二聚体进入细胞核内与DNA结合。转录因子的激活需要先降解I-κBα,这一过程依赖于p97。当细胞受到细菌、病毒、炎性因子、肿瘤坏死因子、辐射以及药物等因子刺激时,作为信号级联的一部分,p65和I-κBα都被磷酸化。在磷酸化之后,Cullin-RING泛素连接酶CRL1β-TrCP泛素化I-κBα从而招募p97。p97结合多泛素化的I-κBα并使其与NF-κB解离继而被26S蛋白酶体降解。解离后的NF-κB二聚体易位到细胞核中以调节其靶基因。
研究表明,siRNA诱导的p97敲低会导致ER应激并激活UPR,通过UPS抑制和caspase激活导致细胞凋亡。在多种实体瘤和血液瘤,如非小细胞肺癌、胰腺癌、乳腺癌和白血病中,p97都高表达并且在维持细胞蛋白质稳态中起重要作用。P97抑制可以优先杀死具有高蛋白质合成负荷的癌细胞。鉴于p97在ERAD和NF-κB调控中的重要作用,相较于抑制蛋白酶体的功能,靶向抑制p97可保留大部分蛋白酶体抑制剂的功效但具有较小的毒性。然而,虽然已有多种p97抑制剂开发出来,但大都不能成药。因此,需要开发适用于抑制p97活性且具有良好成药性的化合物以用于肿瘤的治疗。
发明内容
发明目的:本发明的第一目的是提供一种稠合嘧啶类化合物或其药学上可接受盐;本发明的第二目的是提供一种该稠合嘧啶类化合物或其药学上可接受盐的制备方法,本发明的第三目的是提供该稠合嘧啶类化合物或其药学上可接受盐在制备抑制VCP蛋白药物或制备阻断肿瘤细胞增值药物中的应用。
技术方案:本发明的一种稠合嘧啶类化合物或其药学上可接受的盐,所述稠合嘧啶类化合物结构如式I所示,
其中:R选自-COORa、-CON(Ra)2、-CONHS(O)tRa,其中,每个Ra独立地为氢、羟基、烷基、卤代烷基、烷氧基、烯基、取代的烯基、炔基、取代的炔基、3-8元饱和或部分不饱和的单环碳环、苯基、具有1-2个独立地选自氮、氧或硫的杂原子的4-8元饱和或部分不饱和的单环杂环、具有1-4个独立地选自氮、氧或硫的杂原子的5-6元单环杂芳环或具有1-5个独立地选自氮、氧或硫的杂原子的8-10元双环杂芳环及他们的任意组合,每个t独立地选自1-2的整数;R1独立地为氢、羟基、氨基或硼酸;R2独立地为甲基或氘代甲基;A、B、C、X、Y、Z均独立地为碳或氮;D均独立地为-NH、氧或硫。
进一步地,R选自-COORa、-CON(Ra)2、-CSN(Ra)2、-CONHS(O)2Ra,其中,每个Ra独立地为氢、烷基、烷氧基、具有1-4个独立地选自氮、氧或硫的杂原子的5-6元单环杂芳环及他们的任意组合;R1独立地为氢或羟基;R2独立地为甲基或氘代甲基;A、B、C、X、Y、Z均独立地为碳或氮;D独立地为-NH、氧或硫。
更进一步地,所述稠合嘧啶类衍生物选自:
本发明所述稠合嘧啶类化合物或其药学上可接受盐的制备方法,包括以下步骤:
(1)制备二氯嘧啶母核
由A(2-氨基烟酸)在尿素溶液中反应,接着水解得到B(吡啶并[2,3-d]嘧啶-2,4-二醇),B在氢氧化钯催化下乙酸作溶剂还原得到C(5,6,7,8-四氢吡啶并[2,3-d]嘧啶-2,4-二醇),C转化成二氯化物D,然后在氨基上引入Boc保护基得到E(2,4-二氯-6,7-二氢吡啶并[2,3-d]嘧啶-8(5H)-羧酸叔丁酯);
(2)制备2-甲基-1H-吲哚-4-羧酸甲酯
F(4-溴-1H-吲哚)在氢化钠作用下与苯磺酰氯反应得到保护的G(吲哚),G在LDA作用下与碘甲烷反应得到H(2位甲基的吲哚),H在氢氧化钠作用下脱去苯磺酰基得到I(4-溴-2-甲基-1H-吲哚),I在催化剂的作用下与CO发生插羰反应制得J(2-甲基-1H-吲哚-4-羧酸甲酯);
(3)制备目标化合物稠合嘧啶类化合物V15
E(2,4-二氯-6,7-二氢吡啶并[2,3-d]嘧啶-8(5H)-羧酸叔丁酯)在三乙胺作碱与苄胺反应得到K,K在钯催化剂的作用下与J(2-甲基-1H-吲哚-4-羧酸甲酯)偶联得到中间体L(吲哚4位取代基羧酸甲酯),L在氢氧化锂作用下皂化得到羧酸,然后酰化得到产物N,N在三氟乙酸或HCl的作用下脱去Boc保护基得到稠合嘧啶类化合物V15。
一种药物组合物,包含本发明所述的稠合嘧啶类化合物或其药学上可接受的盐。
本发明还包括所述稠合嘧啶类化合物或其药学上可接受的盐或者本发明所述的药物组合物在制备p97抑制剂中的应用。
本发明还包括所述的稠合嘧啶类化合物或其药学上可接受的盐或者本发明所述的药物组合物在制备治疗与p97活性相关的疾病的药物中的应用。
本发明还包括所述的稠合嘧啶类化合物或其药学上可接受的盐或者本发明所述的药物组合物在制备治疗癌症药物中的应用。
进一步地,所述癌症包括但不限于前列腺癌、膀胱癌、肺癌(包括小细胞或非小细胞癌)、结肠癌、肾癌、乳腺癌、子宫颈癌、子宫内膜癌或其他子宫癌、卵巢癌、睾丸癌、阴茎癌、阴道癌、尿道癌、胆囊癌、食道癌或胰腺癌、多发性骨髓瘤、白血病。
进一步地,所述药物可阻断肿瘤细胞增殖,诱发肿瘤细胞凋亡。
进一步地,除非另外定义,前述所用的全部技术和科学术语都具有本领域的普通技术人员通常理解的相同含义。
“烷基”是指仅由碳和氢原子组成的直链或支链烃链基团,其不含不饱和度,具有一至十个碳原子(例如C1-C10烷基)。每当其在本文中出现时,如“1至10”的数值范围是指在给定范围内的每个整数。典型的烷基包括但绝不限于甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、异丁基、叔丁基、戊基、异戊基、新戊基、己基、庚基、辛基、王基、癸基等。烷基通过单键连接至分子的其余部分,例如甲基(Me)、乙基(Et)、正丙基,1ー甲基乙基(异丙基)、正丁基、正丁基、1,1ー二甲基乙基(叔丁基)、3-甲基己基、2-甲基己基等。
“烷氧基”是指基团-O-烷基,其包括1至8个呈直链、支链、环状构型及其组合的碳原子,它们通过氧连接到母体结构上。实例包括甲氧基、乙氧基、丙氧基、异丙氧基、环丙氧基、环己氧基等。“低级烷氧基”是指含有一至六个碳的烷氧基。在一些实施方案中,C1-C4烷基为包括1至4个碳原子的直链和支链烷基的烷基。
“杂芳环”是指5、6或10元芳族基(例如C5-C13杂芳基),其包括一个或多个选自氮、氧及硫的环杂原子并且其可以是单环、双环、三环或四环系统。每当它在本文中出现时,数值范围是指在给定范围内的每个整数。含N的“杂芳族”或“杂芳环”部分是指其中至少一个环骨架原子为氮原子的芳族基团。多环杂芳环可以是稠合或非稠合的。杂芳环中的杂原子任选被氧化。一个或多个氮原子(如果存在的话)任选被季铵化。杂芳环通过环的任何原子连接至分子的其余部分。
合适的药学上可接受的酸加成盐可由无机酸或由有机酸来制备。无机酸的实例包括盐酸、氢溴酸、氢碘酸、硝酸、碳酸、硫酸及磷酸。适当的有机酸可选自脂族、环脂族、芳族、劳脂族、杂环、羧酸及磺酸类的有机酸,其实例包括甲酸、乙酸、丙酸、琥珀酸、乙醇酸、葡糖酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血的、葡糖醛酸、马来酸、富马酸、丙酮酸、丁氨二酸、谷氨酸、苯甲酸、邻氨基苯甲酸、4-羟基苯甲酸、苯乙酸、扁桃酸、恩北酸(双羟萘酸)、甲磺酸、乙磺酸、苯磺酸、泛酸、三氟甲磺酸、2-羟基乙磺酸、对甲苯磺酸、磺胺酸、环己基氨基磺酸、硬脂酸、海藻酸、β-羟基丁酸、水杨酸、半乳糖二酸及半乳糖醛酸。药学上不可接受的酸加成盐的实例包括例如高氯酸盐和四氟硼酸盐。代表性盐包括氢溴酸盐、盐酸盐、硫酸盐、硫酸氢盐、磷酸盐、硝盐、乙酸盐、戊酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月桂酸盐、苯甲酸盐、乳酸盐、磷酸盐、甲苯磺酸盐、柠檬酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、萘甲酸盐、甲磺酸盐、葡萄糖酸盐、乳糖醛酸盐、月桂基磺酸盐及氨基酸盐等。
如本领域中所公知的“前药”为可向患者施用的物质,其中所述物质在患者体内在生化剂(如酶)的作用下转化成活性药物成分。前药的实例包括羧酸基的酯,其可通过如人类及其他哺乳动物的血流中所见的内源性酯酶进行水解。
如果必须为整数的变量(例如烷基中的碳原子数目或环上取代基的数目)的值被描述为一个范围,例如0-4,那么这意味着该值可以是在0与4之间的任何整数,包括端点,即0、1、2、3或4。
在不同实施方案中,如用于本发明方法中的化合物或化合物的组可以是以上所列实施方案的组合和/或亚组合的任一个。
在不同实施方案中,提供如任一实施例中所示或在示例性化合物之中的化合物。限制条件可用于任何所公开的种类或实施方案,其中任何一种或多种其他以上所公开的的实施方案或物质可从这样的种类或实施方案中排除。
在某些实施方案中,本发明涉及抑制p97的方法。用于本文所公开的方法中的本发明的稠合嘧啶化合物例如非共价地或共价地结合至p97的活性位点。在某些这类实施方案中共价键可以是可逆的或不可逆的。
本发明化合物及其药物组合物能够充当p97的“抑制剂”,这意味着它们能够阻断或降低酶的活性,例如抑制p97的各种活性。抑制剂可以竞争性、无竞争性或非竞争性抑制来起作用。抑制剂可以可逆地或不可逆地结合,且因此该术语包括自毁(suicide)酶的化合物,或其可导致在酶上别处的构象变化。
本发明化合物及其药物组合物之所以用作治疗剂是因为它们能够预防、改善、减轻和影响病症或病状,它们是指以下化合物:在统计样品中相对于未治疗的对照样品减少治疗样品中病症或病状的发生;或相对于未治疗的对照样品延迟所述病症或病状的一种或多种症状的发作或减轻其严重性。
预防、改善、减轻和影响相关病状如局部复发(例如疼痛)、疾病如癌症、复杂综合征如心力衰竭或任何其他医学病状的能力是本领域中众所周知的,并且包括施用组合物,该组合物相对于不接受所述组合物的受试者减小受试者中的医学病状症状的出现率或延迟其发作。因此,癌症的预防包括例如对比未治疗的对照群体例如以统计上或临床上著量减少治疗群体中可检测的癌生长群的数目和延迟可检测的癌生长的出现。
有益效果:与现有技术相比,本发明具有如下显著优点:
本发明稠合嘧啶类化合物或其药学上可接受的盐是一种结构新颖的且具有抑制p97蛋白功能的化合物,它们作为p97蛋白抑制剂,能阻断肿瘤细胞增殖,诱发肿瘤细胞凋亡,从而可用于人和动物的多种疾病如恶性肿瘤的治疗和预防,效果显著。与现有阳性药CB-5339相比,具有更好的大鼠口服吸收和更低的小鼠毒性。
附图说明
图1为实施例13中连续给药15天小鼠体重变化结果图。
具体实施方式
下面结合附图对本发明的技术方案作进一步说明。
实施例1中间产物5的制备
中间产物5的制备路线与合成:
具体制备过程如下:
(1)上述化合物2(吡啶并[2,3-d]嘧啶-2,4-二醇)的制备
在1L的茄形瓶中加入尿素(150g,2497mmol),然后加热到195℃使尿素溶解,搅拌下缓慢加入2-氨基烟酸(69g,499mmol)。加入完毕后继续反应1.5小时。然后将反应降到室温,加入NaOH(600mL,499mmol)水溶液,100℃反应1小时。将反应混合物降至室温,用1mol/L的盐酸调节pH至4,此时有大量白色固体析出,抽滤,水洗滤饼,60℃下真空干燥得产物吡啶并[2,3-d]嘧啶-2,4-二醇(66g,收率81%)。
对上述吡啶并[2,3-d]嘧啶-2,4-二醇进行核磁氢谱分析,结果为:1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),11.47(s,1H),8.60(dd,J=4.8,1.9Hz,1H),8.26(dd,J=7.8,1.9Hz,1H),7.25(dd,J=7.7,4.8Hz,1H).MS(ESI,m/z):164.1[M+H]+。
(2)上述化合物3(5,6,7,8-四氢吡啶并[2,3-d]嘧啶-2,4-二醇)的制备
将步骤(1)制备的吡啶并[2,3-d]嘧啶-2,4-二醇(66g,6mmol)溶于乙酸(900mL)中,再加入水(600mL)和Pd(OH)2/C(6.6g,10%wt)。反应混合物置换氢气3次,在氢气球作用下70℃反应18小时。反应完毕后趁热抽滤,然后滤液浓缩除去大部分乙酸,室温静置过夜,抽滤,水洗滤饼,60℃下真空干燥得产物5,6,7,8-四氢吡啶并[2,3-d]嘧啶-2,4-二醇(54g,粗品),直接用于下一步。
对上述5,6,7,8-四氢吡啶并[2,3-d]嘧啶-2,4-二醇进行核磁氢谱分析,结果为:1H NMR(400MHz,DMSO-d6)δ10.10(d,J=6.1Hz,2H),5.97(d,J=2.7Hz,1H),3.17(m,2H),2.17(t,J=6.2Hz,2H),1.74–1.56(m,2H).MS(ESI,m/z):168.1[M+H]+。
(3)上述化合物4(2,4-二氯-5,6,7,8-四氢吡啶并[2,3-d]嘧啶)的制备
将步骤(2)制备的5,6,7,8-四氢吡啶并[2,3-d]嘧啶-2,4-二醇(30g,179.4mmol)溶于POCl3(300mL)中,再加入PCl5(18.7g,89.7mmol)。反应混合物130℃搅拌12小时。反应完毕后降至室温,减压旋蒸除去大部分溶剂,然后加入冰水(300mL),水相EA(100mL×3)萃取。合并有机相,干燥、旋蒸后柱色谱纯化得到中间体2,4-二氯-5,6,7,8-四氢吡啶并[2,3-d]嘧啶(13.5g,收率36.8%)。
对上述2,4-二氯-5,6,7,8-四氢吡啶并[2,3-d]嘧啶进行核磁氢谱分析,结果为:1H NMR(400MHz,CDCl3)δ7.01(s,1H),3.50(m,2H),2.74(t,J=6.4Hz,2H),2.04–1.87(m,2H).MS(ESI,m/z):204.1[M+H]+。
(4)上述化合物5(2,4-二氯-6,7-二氢吡啶并[2,3-d]嘧啶-8(5H)-羧酸叔丁酯)的制备
将步骤(3)制备的2,4-二氯-5,6,7,8-四氢吡啶并[2,3-d]嘧啶(13.5g,66.2mmol)溶解在DCM(150mL)中,再加入DMAP(1.6g,13.2mmol)和(Boc)2O(15.9g,72.8mmol),室温反应3小时。反应完毕后加入水(100mL),分液,水相DCM(100mL×2)萃取,合并有机相,干燥、旋蒸后柱色谱纯化得到中间体2,4-二氯-6,7-二氢吡啶并[2,3-d]嘧啶-8(5H)-羧酸叔丁酯(18g,收率89.4%)。
对上述2,4-二氯-6,7-二氢吡啶并[2,3-d]嘧啶-8(5H)-羧酸叔丁酯进行核磁氢谱分析,结果为:1H NMR(400MHz,Chloroform-d)δ3.83–3.76(m,2H),2.79(t,J=6.7Hz,2H),2.08–1.96(m,2H),1.58(s,9H).MS(ESI,m/z):305.3[M+H]+。
实施例2中间产物9c-9h的制备
中间产物9c的制备路线与合成:
具体制备过程分别如下:
(1)上述化合物7b(4-溴-1-(苯基磺酰基)-1H-吲哚)的制备
在0℃下,向6b(4-溴-1H-吲哚)(25g,127.5mmol)的THF(200mL)溶液中分批缓慢加入NaH(7.7g,191.3mmol)。将混合物冰浴继续搅拌30分钟,然后加入苯磺酰氯(27g,153mmol)。随后将反应物置于室温并再搅拌2小时,然后倒入预冷的5%NH4Cl水溶液(200mL)中。分离水相并用乙酸乙酯(100mL×3)萃取,合并的有机相干燥、旋蒸得到粗品,然后重结晶(EA,PE)得到4-溴-1-(苯基磺酰基)-1H-吲哚(7b)(38g,收率89%),为灰白色固体。
(2)上述化合物8b(4-溴-2-甲基-1-(苯基磺酰基)-1H-吲哚)的制备
在250mL的三口瓶中加入无水THF(50mL)和DIPA(5.9g,58.3mmol),降温至-50℃。随后缓慢加入n-BuLi(2.5M in THF,23.3mL,58.3mmol)。反应在-50℃下继续搅拌1h。将步骤(1)制备的4-溴-1-(苯基磺酰基)-1H-吲哚(9.8g,29.2mmol)溶于无水THF(50mL)中,然后缓慢加入三口瓶中,在-50℃下继续反应1小时。随后加入MeI(8.3g,58.3mmol)。10分钟后将反应从低温转移到室温,继续反应3小时。反应结束后将反应液倒入预冷的5% NH4Cl水溶液(100mL)中并用乙酸乙酯(100mL×3)萃取。合并有机相,干燥、旋蒸后硅胶柱层析纯化得到产物4-溴-2-甲基-1-(苯基磺酰基)-1H-吲哚(6.8g,收率66%),为白色固体。
对上述4-溴-2-甲基-1-(苯基磺酰基)-1H-吲哚进行核磁氢谱分析,结果为:1HNMR(400MHz,DMSO-d6)δ8.06(m,1H),7.93–7.89(m,2H),7.76–7.70(m,1H),7.63–7.58(m,2H),7.46(dd,J1=0.7Hz,J2=7.8Hz,1H),7.24(t,J=8.1Hz,1H),6.60(t,J=1.1Hz,1H),2.64(d,J=1.1Hz,3H)。
(3)上述化合物9b(4-溴-2-甲基-1H-吲哚)的制备
在2L的茄形瓶中加入乙醇(600mL)和步骤(2)方法制备的4-溴-2-甲基-1-(苯基磺酰基)-1H-吲哚(42.3g,117.8mmol),室温搅拌溶解后加入氢氧化钠水溶液(4M,117mL,471mmol)。然后将反应混合物在50℃下反应12小时。监测反应完全后,将反应液减压旋蒸除去乙醇,然后加入水(200mL),用乙酸乙酯(100mL×3)萃取。合并有机相,干燥、旋蒸后得到粗品4-溴-2-甲基-1H-吲哚(24g),为黄色粘稠液体,直接用于下一步。
对上述4-溴-2-甲基-1H-吲哚进行核磁氢谱分析,结果为:1H NMR(400MHz,DMSO-d6)δ7.61(m,1H),7.43(m,1H),7.13(m,1H),6.30(m,1H),2.44(s,3H).MS(ESI)m/z:210.0[M+H]+。
(4)上述化合物9c(2-甲基-1H-吲哚-4-羧酸甲酯)的制备
将步骤(3)制备的4-溴-2-甲基-1H-吲哚(24g,114.2mmol)、Pd(OAc)2(2.6g,11.4mmol),1,3-双(二苯基膦)丙烷(4.7g,11.4mmol)和TEA(23.1g,228.4mmol)溶于甲醇(200mL)中。然后将反应混合物置于高压反应釜中,在CO气氛下80℃反应24小时。反应结束后减压浓缩反应液除去甲醇,加入水(200mL),乙酸乙酯(100mL×3)萃取。合并有机相,干燥、旋蒸后硅胶柱层析纯化得到中间体2-甲基-1H-吲哚-4-羧酸甲酯(18.2g,收率84%),为棕黄色固体。
对上述2-甲基-1H-吲哚-4-羧酸甲酯进行核磁氢谱分析,结果为:1H NMR(400MHz,DMSO-d6)δ11.33(s,1H),7.66(m,1H),7.53(dd,J=7.9,1.0Hz,1H),7.08(t,J=7.8Hz,1H),6.67–6.64(m,1H),3.86(s,3H),2.42(d,J=0.9Hz,3H).MS(ESI)m/z 190.3[M+H]+。
实施例3中间产物9d-9h的制备
中间产物9d-9h的制备路线与合成:
具体制备过程分别如下:
1、中间产物9d(4-氯-2-甲基-1-(苯基磺酰基)-1H-吡咯并[3,2-c]吡啶)的制备
(1)上述化合物12(1-(苯基磺酰基)-1H-吡咯并[3,2-c]吡啶5-氧化物)的制备
其中,化合物11制备方法与实施例2中7b相同。
将1-(苯基磺酰基)-1H-吡咯并[3,2-c]吡啶(4.2g,16.1mmol)溶于二氧六环(200mL)中,然后缓慢分批加入m-CPBA(3.1g,17.7mmol),室温反应5小时。反应完毕后减压旋蒸除去二氧六环,加入Na2SO3(5%,50mL),DCM(100×3)萃取水相。合并有机相,干燥、旋蒸后硅胶柱层析纯化得到中间体1-(苯基磺酰基)-1H-吡咯并[3,2-c]吡啶5-氧化物(3g,收率68%),黄色固体。
对上述1-(苯基磺酰基)-1H-吡咯并[3,2-c]吡啶5-氧化物进行核磁氢谱分析,结果为:1H NMR(400MHz,CDCl3)δ8.52(dd,J=1.7,0.7Hz,1H),8.19(dd,J=7.2,1.8Hz,1H),7.90(m,3H),7.71–7.62(m,2H),7.55(m,2H),6.66(dd,J=3.7,0.8Hz,1H).MS(ESI,m/z):275.0[M+H]+.
(2)上述化合物13(4-氯-1-(苯基磺酰基)-1H-吡咯并[3,2-c]吡啶)的制备
将1-(苯基磺酰基)-1H-吡咯并[3,2-c]吡啶5-氧化物(3g,10.9mmol)溶于MeCN/dioxane(30/30,v/v),然后加入POCl3(1.8g,12mmol),90℃反应18小时。检测反应完全,减压旋蒸除去溶剂,加水(50mL),DCM(50×3)萃取水相。合并有机相,干燥、旋蒸后硅胶柱层析纯化得到中间体4-氯-1-(苯基磺酰基)-1H-吡咯并[3,2-c]吡啶(2.6g,收率81%),黄色固体。
对上述4-氯-1-(苯基磺酰基)-1H-吡咯并[3,2-c]吡啶进行核磁氢谱分析,结果为:1H NMR(400MHz,CDCl3)δ8.27(d,J=5.8Hz,1H),7.92(d,J=1.4Hz,1H),7.87(dd,J=5.8,0.9Hz,1H),7.68–7.60(m,2H),7.53(m,2H),6.82(dd,J=3.7,0.9Hz,1H).MS(ESI,m/z):292.0[M+H]+。
(3)上述化合物9d(4-氯-2-甲基-1-(苯基磺酰基)-1H-吡咯并[3,2-c]吡啶)的制备
对化合物14的制备过程与实施例2中的9b合成方法一致,以化合物13为原料先与碘甲烷反应然后在NaOH的作用下脱保护得到中间体14(4-氯-2-甲基-1H-吡咯并[3,2-c]吡啶)。对4-氯-2-甲基-1H-吡咯并[3,2-c]吡啶进行质谱分析,结果为:MS(ESI,m/z):167.1[M+H]+。
在25mL茄形瓶中加入4-氯-2-甲基-1H-吡咯并[3,2-c]吡啶(100mg,0.6mmol),氰化锌(78mg,0.66mmol),Pd2(dba)3(114mg,0.13mmol)、dppf(134mg,0.24mmol)和锌粉(4mg,0.06mmol),然后加入NMP(6mL),置换氩气3次,120℃反应18小时。反应完毕后加水(30mL),EA(15×3)萃取水相。合并有机相,干燥、旋蒸后硅胶柱层析纯化得到中间体4-氯-2-甲基-1-(苯基磺酰基)-1H-吡咯并[3,2-c]吡啶(50mg,收率53%)。
对4-氯-2-甲基-1-(苯基磺酰基)-1H-吡咯并[3,2-c]吡啶进行质谱分析,结果为:MS(ESI,m/z):158.1[M+H]+。
2、化合物9e(2-甲基-1H-吡咯并[2,3-c]吡啶-4-腈(9e)的制备
以15a为原料,与9b相同的方法制备得到16a。将16a(280mg,1.3mmol)溶于DMF(10mL)中,再加入水(0.3mL),超声排气。加入dppf(72mg,0.13mmol)、Pd2(dba)3(60mg,0.065mmol)和氰化锌(160mg,1.36mmol),置换氩气3次,120℃反应1.5小时,检测反应完毕后向反应中加水(50mL),EA(20×3)萃取水相。合并有机相,干燥、旋蒸后硅胶柱层析纯化得到中间体2-甲基-1H-吡咯并[2,3-c]吡啶-4-腈(160mg,收率78%)。
对2-甲基-1H-吡咯并[2,3-c]吡啶-4-腈进行质谱分析,结果为:MS(ESI,m/z):158.1[M+H]+。
3、化合物9f-9h的制备
与化合物9e的制备方法相同,以15b或17为原料,先与苯磺酰氯反应,然后与碘甲烷反应,再在NaOH的作用下脱保护得到中间体16b或18。与9e的制备方法相同,中间体16b或18与氰化锌反应得到4位氰基的产物9f或9g。
与化合物9e的制备方法相同,以19为原料,先与苯磺酰氯反应,然后与氘代碘甲烷反应,再在NaOH的作用下脱保护得到中间体9h。
实施例4中间体20a-20i的制备
中间体20a-20i的制备路线与合成:
1、化合物20a(4-(苄基氨基)-2-氯-6,7-二氢吡啶并[2,3-d]嘧啶-8(5H)-羧酸叔丁酯)的制备
将实施例1中的化合物5(3.5g,11.5mmol)溶解在异丙醇(50mL)中,然后加入苄胺(1.9g,17.3mmol)和TEA(3.5g,34.5mmol),70℃反应12小时。反应完毕后减压旋蒸除去溶剂,加入水(50mL)然后EA(50mL×3)萃取。合并有机相,干燥、旋蒸后硅胶柱层析纯化得到中间体4-(苄基氨基)-2-氯-6,7-二氢吡啶并[2,3-d]嘧啶-8(5H)-羧酸叔丁酯(27g,收率63%),白色固体。
对上述4-(苄基氨基)-2-氯-6,7-二氢吡啶并[2,3-d]嘧啶-8(5H)-羧酸叔丁酯进行核磁氢谱分析,结果为:1H NMR(400MHz,CDCl3)δ7.43–7.31(m,5H),4.81(t,J=5.4Hz,1H),4.71(d,J=5.3Hz,2H),3.78–3.69(m,2H),2.33(t,J=6.8Hz,2H),2.05–1.94(m,2H),1.57(s,9H).MS(ESI,m/z):375.1[M+H]+。
2、以与20a相同的方法,化合物5分别与2-(氨基甲基)苯酚、3-(氨基甲基)苯酚、4-(氨基甲基)苯酚、吡啶-2-基甲胺、吡啶-3-基甲胺、吡啶-4-基甲胺发生亲核取代反应制备得到20b-20g。
3、化合物20h(4-(苄氧基)-2-氯-6,7-二氢吡啶并[2,3-d]嘧啶-8(5H)-羧酸叔丁酯)的制备
将实施例1中的化合物5(200mg,0.66mmol)溶于DMF(5mL)中,加入NaH(40mg,0.99mmol)然后再加入苄醇(78mg,0.73mmol),室温反应3小时。检测反应完全后加入水(30mL),EA(20×3)萃取水相。合并有机相,干燥、旋蒸后硅胶柱层析纯化得到中间体4-(苄氧基)-2-氯-6,7-二氢吡啶并[2,3-d]嘧啶-8(5H)-羧酸叔丁酯(112mg,收率45%),白色固体。
对上述4-(苄氧基)-2-氯-6,7-二氢吡啶并[2,3-d]嘧啶-8(5H)-羧酸叔丁酯进行核磁氢谱分析,结果为:1H NMR(400MHz,Chloroform-d)δ7.55–7.33(m,5H),5.44(s,2H),3.79–3.70(m,2H),2.62(m,2H),1.98–1.89(m,2H),1.57(s,9H).MS(ESI,m/z):376.1[M+H]+。
4、化合物20i(4-(苄硫基)-2-氯-6,7-二氢吡啶并[2,3-d]嘧啶-8(5H)-羧酸叔丁酯(20i)的制备
将实施例1中的化合物5(200mg,0.66mM)溶于DMF(5mL)中,加入K2CO3(182mg,1.32mM)和苄硫醇(98mg,0.79mM),室温反应3小时。检测反应完全后加入水(30mL),EA(20×3)萃取水相。合并有机相,干燥、旋蒸后硅胶柱层析纯化得到中间体4-(苄硫基)-2-氯-6,7-二氢吡啶并[2,3-d]嘧啶-8(5H)-羧酸叔丁酯(310mg,收率79%),淡黄色固体。
对上述4-(苄硫基)-2-氯-6,7-二氢吡啶并[2,3-d]嘧啶-8(5H)-羧酸叔丁酯进行核磁氢谱分析,结果为:1H NMR(400MHz,CDCl3)δ7.46–7.43(m,2H),7.37–7.31(m,2H),7.28(s,1H),4.47(s,2H),3.80–3.68(m,2H),2.52(t,J=6.7Hz,2H),2.01–1.88(m,2H),1.57(s,9H).MS(ESI,m/z):392.1[M+H]+。
实施例5目标产物V1-V13的制备
1、目标产物V1的合成路线如下式:
/>
V1的具体制备过程如下:
(1)化合物21b(2-(4-氰基-2-甲基-1H-吲哚-1-基)-4-((2-羟基苄基)氨基)-6,7-二氢吡啶并[2,3-d]嘧啶-8(5H)-羧酸叔丁酯)的制备
在25mL茄形瓶中加入20b(200mg,0.51mmol)、实施例2中的9a(80mg,0.51mmol)、Cs2CO3(249mg,0.76mmol),Pd2(dba)3(73mg,0.08mmol)和X-Phos(38mg,0.08mmol),然后加入dioxane(10mL)。将反应置换Ar气3次后在105℃下回流4小时。TLC监测反应完全后,反应冷却至室温。过滤并收集滤液,减压蒸干溶剂。将得到的固体溶于EA(50mL)中,用水(50mL)洗涤,水相用EA(50mL×2)萃取。合并有机相,干燥、旋蒸后硅胶柱层析纯化得到中间体2-(4-氰基-2-甲基-1H-吲哚-1-基)-4-((2-羟基苄基)氨基)-6,7-二氢吡啶并[2,3-d]嘧啶-8(5H)-羧酸叔丁酯(203mg,收率78%),棕色固体。
对2-(4-氰基-2-甲基-1H-吲哚-1-基)-4-((2-羟基苄基)氨基)-6,7-二氢吡啶并[2,3-d]嘧啶-8(5H)-羧酸叔丁酯进行质谱分析,结果为:MS(ESI,m/z):511.6[M+H]+。
(2)化合物V1(1-(4-((2-羟基苄基)氨基)-5,6,7,8-四氢吡啶并[2,3-d]嘧啶-2-基)-2-甲基-1H-吲哚-4-甲酰胺()的制备
在20mL茄形瓶中,将中间体化合物21b(203mg,0.4mmol)溶解在DMSO(6mL)中。然后将过氧化脲(184mg,2.0mmol)和K2CO3(55mg,0.4mmol)溶于水(0.6mL)中,再加入到反应瓶中,45℃搅拌4小时。反应完毕后加入水(20mL),EA(20mL×3)萃取。合并有机相,干燥、旋蒸后硅胶柱层析纯化得到中间体21(180mg,收率85%)。
对化合物21进行质谱分析,质谱结果为:MS(ESI,m/z):513.2[M+H]+。将上述中间体21(180mg,0.34mmol)溶解在DCM(5mL)中,加入TFA(1mL),室温反应4小时。反应完毕后减压旋蒸,加入EA(30mL),加水(20mL),再加入Na2CO3(5%)至pH为9。分液,水相EA(20mL×2)萃取,合并有机相,干燥、旋蒸后硅胶柱层析纯化得到目标化合物1-(4-((2-羟基苄基)氨基)-5,6,7,8-四氢吡啶并[2,3-d]嘧啶-2-基)-2-甲基-1H-吲哚-4-甲酰胺(102mg,收率70%),浅黄色固体。
对化合物V1进行核磁氢谱、核磁碳谱,高分辨质谱、质谱分析,质谱结果为:MS(ESI,m/z):429.3[M+H]+。磁氢谱、核磁碳谱,高分辨质谱的结果如表1所示。
2、与V1相同的制备方法,化合物20c-20i各自分别与9a偶联,随后将氰基水解成酰胺,最后脱去Boc保护基得到化合物V2-V8。化合物20a分别与9d-9h偶联,随后将氰基水解成酰胺,最后脱去Boc保护基得到化合物V9-V13。
对化合物V2-V13进行核磁氢谱、核磁碳谱,高分辨质谱分析,结果如表1所示。
实施例6目标产物V14的制备
目标产物V14的合成路线与制备
具体制备过程如下:
(1)化合物22(4-(苄氨基)-2-(4-(甲氧羰基)-2-甲基-1H-吲哚-1-基)-6,7-二氢吡啶并[2,3-d]嘧啶-8(5H)-羧酸叔丁酯)的制备
在25mL茄形瓶中加入实施例4中的20a(200mg,0.53mmol)、实施例2中的9c(100mg,0.53mmol)、Cs2CO3(261mg,0.8mmol),Pd2(dba)3(73mg,0.08mmol)和X-Phos(38mg,0.08mmol),然后加入dioxane(10mL)。将反应置换Ar气3次后在105℃下回流4小时。TLC监测反应完全后,反应冷却至室温。过滤并收集滤液,减压蒸干溶剂。将得到的固体溶于EA(50mL)中,用水(50mL)洗涤,水相用EA(50mL×2)萃取。合并有机相,干燥、旋蒸后硅胶柱层析纯化得到中间体4-(苄氨基)-2-(4-(甲氧羰基)-2-甲基-1H-吲哚-1-基)-6,7-二氢吡啶并[2,3-d]嘧啶-8(5H)-羧酸叔丁酯(218mg,收率78%),黄色固体。
对化合物22进行核磁氢谱分析,结果如下:1H NMR(400MHz,DMSO-d6)δ8.28(d,J=8.3Hz,1H),7.71(ddd,J=8.6,5.9,3.4Hz,2H),7.38–7.29(m,4H),7.25(td,J=6.0,2.6Hz,1H),6.99(t,J=7.9Hz,1H),6.89–6.86(m,1H),4.67(d,J=5.9Hz,2H),3.88(s,3H),3.77–3.69(m,2H),2.56(s,2H),2.54–2.54(m,3H),2.04–1.91(m,2H),1.43(s,9H).MS(ESI,m/z):528.3[M+H]+。
(2)化合物23(1-(4-(苄基氨基)-8-(叔丁氧基羰基)-5,6,7,8-四氢吡啶并[2,3-d]嘧啶-2-基)-2-甲基-1H-吲哚-4-羧酸)的制备
在250mL茄形瓶中将化合物22(5g,9.5mmol)溶于THF/MeOH(90mL/30mL)中。将LiOH·H2O(2.4g,57mmol)溶解在水中(30mL)缓慢滴加到反应瓶中,60℃反应6小时。反应完毕后,减压旋蒸除去溶剂,加水(50mL),EA(50mL×5)萃取。合并有机相,干燥、旋蒸后得到粗品1-(4-(苄基氨基)-8-(叔丁氧基羰基)-5,6,7,8-四氢吡啶并[2,3-d]嘧啶-2-基)-2-甲基-1H-吲哚-4-羧酸(23)(4.4g,收率90%),棕色固体,直接用于下一步。
对化合物23进行质谱分析,结果为:MS(ESI,m/z):514.1[M+H]+。
(3)目标产物V14(1-(4-(苄基氨基)-5,6,7,8-四氢吡啶并[2,3-d]嘧啶-2-基)-2-甲基-1H-吲哚-4-羧酸)的制备
将上述中间体化合物23(200mg,0.39mmol)溶解在DCM(5mL)中,加入TFA(1mL),室温反应4小时。反应完毕后减压旋蒸,加入EA(30mL),加水(20mL),再加入Na2CO3(5%)至pH为9。分液,水相EA(20mL×2)萃取,合并有机相,干燥、旋蒸后硅胶柱层析纯化得到目标化合物1-(4-(苄基氨基)-5,6,7,8-四氢吡啶并[2,3-d]嘧啶-2-基)-2-甲基-1H-吲哚-4-羧酸(120mg,收率75%),浅棕色固体。
对目标产物V14进行核磁氢谱、核磁碳谱,高分辨质谱、质谱分析,质谱结果为:MS(ESI,m/z):413.3[M+H]+。磁氢谱、核磁碳谱,高分辨质谱的结果如表1所示。
实施例7目标产物V15的制备
目标产物V15的合成路线如下式:
将化合物23(200mg,0.39mmol)溶于THF(10mL)中,加入甲氧基胺盐酸盐(33mg,0.39mmol),EDCI(112mg,0.59mmol),HOBt(80mg,0.59mmol)和DIPEA(202mg,1.56mmol),室温反应过夜。加入水(30mL),EA(20mL×3)萃取,合并有机相,干燥、旋蒸后硅胶柱层析纯化得到Boc保护的中间体化合物24。随后,中间体化合物24在TFA的作用下脱保护,纯化后得到目标化合物1-(4-(苄基氨基)-5,6,7,8-四氢吡啶并[2,3-d]嘧啶-2-基)-N-甲氧基-2-甲基-1H-吲哚-4-甲酰胺(80mg,收率62%),黄色粉末。
对目标产物V15进行核磁氢谱、核磁碳谱,高分辨质谱分析,结果如表1所示。
实施例8目标产物V16-V17的制备
目标产物V16的合成路线如下式:
将中间体化合物23(100mg,0.2mmol)、甲磺酰胺(37mg,0.4mmol)溶于DCM(2mL)中,再加入CMPI(60mg,0.23mmol)、DMAP(1.2mg,0.01mmol)和TEA(50mg,0.58mmol),室温反应1小时。加入水(30mL),DCM(20mL×3)萃取,合并有机相,干燥、旋蒸后硅胶柱层析纯化得到目标化合物1-(4-(苄基氨基)-5,6,7,8-四氢吡啶并[2,3-d]嘧啶-2-基)-2-甲基-N-(甲基磺酰基)-1H-吲哚-4-甲酰胺(45mg,收率62%),浅黄色粉末。
对目标产物V16进行核磁氢谱、核磁碳谱,高分辨质谱分析,结果如表1所示。
以与V16相同的方法,化合物23和5-溴呋喃-2-磺酰胺反应得到目标产物V17。对目标产物V17进行核磁氢谱、核磁碳谱,高分辨质谱分析,结果如表1所示。
目标化合物V1-V17核磁及质谱数据如表1所示。
表1合成的具体化合物V1-V17的核磁及质谱数据表。
/>
/>
/>
/>
实施例9体外p97抑制实验
P97通过水解ATP产生的化学能转化为机械能从而发挥其功能,参与一系列的细胞过程。因此抑制了p97水解ATP的能力就可以抑制其功能,从而发挥药效。本发明合成的化合物是p97的D2结构域ATP竞争性抑制剂,可竞争性地结合在D2结构域ATP结合位点上从而抑制ATP的水解。因此我们以ATP为底物,通过检测ADP的生成来筛选该系列化合物对p97的抑制活性。
1、测定方案如下:
(1)准确称量待测化合物V1-V17,加入DMSO溶解并使浓度为10mM。用DMSO稀释20倍后再用水稀释25倍得到浓度为20μM的药物溶液。以此为起始浓度,3倍稀释,共9个浓度点,第十个浓度点是空白对照组。化合物CB-5339为阳性对照,含1%DMSO的水作为溶剂对照。
(2)在384孔板中每孔加入p97六聚酶(2μL,60μg/mL),然后再分别加入稀释好的不同浓度的化合物(1μL)V1-V17或溶剂对照。室温反应10min。
(3)每孔加入ATP(1μL,100μM),涡旋混匀后在30℃下反应60min。
(4)每孔加入ADP-GloTM试剂4μL,在25℃条件下反应40min。
(5)每孔加入ADP-GloTM Max检测试剂8μL,25℃下继续反应60min。
(6)使用酶标仪检测每孔在570nm处的吸光度值,用Graph Pad Prism 8.0软件计算各化合物的IC50值。
2、体外P97抑制实验结果如表2所示。
表2目标化合物V1-V17和CB-5339对p97的抑制活性
aAll experiments were repeated three times.Data were reported as themean±SD.bNo activity.
由表2的酶抑制活性结果表明,化合物V1-V2、V12-V16表现出较好的抑制活性,与CB-5339相比,抑制活性相当或更好。
实施例10化合物对肿瘤细胞的增值抑制活性研究
根据实施例9对p97的抑制活性的实验结果,对p97抑制的IC50值小于0.2μM的化合物,进一步测试了这些化合物对结直肠癌细胞系HCT-116细胞和多发性骨髓瘤细胞系RPMI-8226细胞的增殖抑制作用。
1、测定方案如下:
HCT-116细胞系来源于ATCC,培养条件为5A(GIBCO#16600082)+10%FBS,5% CO2;A549细胞系来源于ATCC,培养条件为F-12K(GIBCO#21127022w/o HEPS)+10% FBS,5%CO2;RPMI-8226细胞系来源于ATCC,培养条件为RPMI-1640(GIBCO#11875119w/o HEPS)+10% FBS+25mM HEPES,5% CO2。
取对数生长期的HCT-116、A549以及RPMI-8226细胞混悬液加入384孔板中,每孔加入体积为18μL,每孔细胞数分别为600个/孔、400个/孔和2000个/孔,边缘用PBS或者基础培养基封边,放置在细胞培养箱中孵育24h。然后每孔分别加入2μL不同浓度的化合物,起始浓度为10μM,3倍稀释。对照孔为仅不加药,调零孔为不含细胞及药物。37℃,5%CO2的细胞培养箱孵育72h。然后每孔加入20μL的Cell Titer Glo检测试剂,孵育10分钟,用酶标仪测定每孔的发光值,按照如下公式计算细胞抑制率,用Graph Pad Prism 8.0软件计算每种化合物的IC50值。
2、肿瘤细胞的增值抑制活性研究实验结果如表3所示。
表3部分化合物对HCT-116和RPMI-8226细胞系的抗增殖活性
aAll experiments were repeated two times.Data were reported as themean±SD.bNo activity.
由表3结果表明,多个化合物对HCT-116细胞和RPMI8226细胞的IC50值低于1.0μM,均表现出良好的抑制活性。结直肠癌细胞系HCT-116细胞的增殖抑制实验结果中,化合物V2(0.7μM)和V15(0.7μM)对HCT-116细胞的增殖抑制作用与CB-5339(0.7μM)相同。而化合物V14表现出更好的抑制活性,IC50值仅为0.4μM;多发性骨髓瘤细胞系RPMI-8226细胞增殖抑制结果中,化合物V2、V14和V15表现出更好的抑制活性,IC50值分别为0.3μM,0.8μM和0.5μM,优于阳性对照CB-5339(0.9μM)。
在之后的V15的PK实验中发现其在体内会部分代谢成V14,因此进一步针对V14和V15进行了多种细胞系的活性筛选,细胞系培养条件及384孔板每孔铺板数如表4所示,化合物V14和V15对多种细胞系的抗增殖活性如表5所示。
表4不同细胞系培养条件及384孔板每孔接种细胞数
表5化合物V14和V15对多种细胞系的抗增殖活性
aAll experiments were repeated two times.Data were reported as themean±SD.bNot tested.
由表5细胞增殖抑制活性结果表明CB-5339除ARP1和KMS-11两种细胞系IC50值为1.3μM外,其他7种细胞系的IC50均小于1μM。化合物V14除了SW620细胞系IC50值为2.1μM外,在其他8种细胞系中IC50值均小于1μM,并且在多个细胞系中表现出优于CB-5339的细胞活性。化合物V15在H929、MV-4-11和MOLM16三种细胞系上和CB-5339活性相当。
实施例11肝微粒体稳定性研究
1、测定方案如下:
(1)称量一定量的待测化合物,将其溶于DMSO,使其浓度为10mM,然后加入Acetonitrile/H2O(1:1,v:v)得到浓度为100μM的工作溶液。
(2)从-80℃冰箱中取出肝微粒体(20mg蛋白/mL),置于37℃水浴恒温振荡器上预温孵3min,融化待用。
(3)按照表6制备反应体系混合液(不含β-NADPH)。
(4)对照组(不含β-NADPH):取75μL步骤(3)所述反应体系混合液,加入25μL PBS,涡旋混匀后在37℃恒温振荡器中进行孵育。分别在0min和60min取样。
(5)样品组:取75μL步骤(3)所述反应体系混合液,加入25μLβ-NADPH溶液(4mM),涡旋混匀后在37℃恒温振荡器中进行孵育。分别在0min、5min、15min、30min、60min取样。
(6)在各个时间点取出样品管,分别加入300μL预冷的乙腈(含咪达唑仑),终止反应。
(7)涡旋5min后离心(5500g,10min),取上清液150μL加入150μL水,涡旋混匀。通过LC-MS/MS分析样品。其中阳性对照物咪达唑仑的孵育条件同上。
表6微粒体稳定性温孵体系的构成
2、肝微粒体稳定性研究实验结果如表7所示。
表7化合物V14、V15和CB-5339在不同种属肝微粒体中的稳定性
由表7可见,化合物V15在五个种属肝微粒体中均代谢较快,在人肝微粒体中的T1/2仅为13.3min,在小鼠、狗和猴肝微粒体中T1/2甚至小于10min。而化合物V14在人、狗和猴肝微粒体中的T1/2均大于120min,表现出良好的稳定性。这些结果表明药物代谢动力学实验中大鼠血浆中的V14很可能是V15在肝微粒体中代谢产生的。
实施例12药代动力学研究
1、测定方案如下:
药物溶液的制备方法为:分别精密称取一定量的V14、V15和CB-5339至玻璃瓶中,将其溶于一定体积DMSO和聚氧乙烯蓖麻油中,溶清后加入生理盐水(DMSO:蓖麻油:生理盐水=5:5:90,v:v)并调pH=4,超声溶解,使其终浓度为0.5mg/mL(用于注射)和2mg/mL(用于口服)。SD雄性大鼠6只,体重220±20g,随机分为两组,分别按1.00mg/kg剂量尾静脉注射和10mg/kg灌胃给予化合物V14、V15和CB-5339。血样采集分别于给药前及给药后2min、15min、30min、1h、2h、4h、8h和24h,由眼眶采血约0.20mL,置于装有肝素的离心管中,4℃离心(6800g,6min)。离心完成后取20μL血浆样品,再加入200μL含有10ng/mL的普萘洛尔/格列本脲-乙腈溶液进行蛋白沉淀,涡旋5min后,再将上述样品置于离心机中用5500g离心10min。从中取出150μL上清液,再向其中加入150μL水进行稀释,涡旋后进样20μL。通过LC/MS/MS分析样品,使用Winonlin软件计算药代动力学参数。剩余血浆样品保存在-80℃冰箱内。
2、药代动力学研究实验结果如表8所示。
表8单剂量口服和尾静脉注射化合物V15和CB-5339后SD大鼠的PK结果
由表8结果表明,化合物CB-5339的口服和尾静脉的消除相半衰期分别为1.23h和0.38h。单剂量口服10mg/kg的CB-5339后,血浆中的Cmax和AUC0-inf值分别为444ng/mL和796ng·h/mL,其口服生物利用度为20%。口服或尾静脉注射V15后,V15在体内迅速代谢成V14。血浆中V14的口服半衰期为3.52h,尾静脉半衰期为3.83h,远高于CB-5339。而血浆中V14的Tmax为0.25h,是CB-5339的一半,口服吸收速度更快。单剂量口服10mg/kg的V15后,血浆中V14的Cmax和AUC0-inf值分别为1070ng/mL和1412ng·h/mL,远高于CB-5339的血浆药物浓度。单纯以V14的结果计算V15的口服生物利用度为29.7%。
实施例13体内毒性研究
1、实验方案如下:
称取一定量的化合物V15,超声分散在含0.3%CMC-Na的氯化钠注射液中,V15配制浓度为10mg/mL,CB-5339配制浓度为5mg/mL。
每组小鼠每天灌胃给药(ig),分别为对照组(空白溶剂)、V15(50mg/kg)、V15(100mg/kg)、CB-5339(50mg/kg)、CB-5339(100mg/kg)。给药体积为0.1mL/10g动物体重,连续给药15天。用游标卡尺测量肿瘤的大小。肿瘤体积(TV)计算为:V=(长×宽2)/2。
连续给药后小鼠体重变化结果如图1所示。结果表明在体内实验期间,化合物CB-5339在50mg/kg剂量下也没有观察到明显的毒副作用。然而,当CB-5339的剂量为100mg/kg时,第4天观察到显著的体重减轻和其他副作用,第8天全部死亡。而化合物V15的剂量为50mg/kg和100mg/kg时,连续给药15天,均未观察到明显的体重减轻和其他副作用,表明化合物V15在100mg/kg剂量下无明显毒性,表现出良好的安全性。
Claims (10)
1.一种稠合嘧啶类化合物或其药学上可接受的盐,所述稠合嘧啶类化合物结构如式I所示,
其中:R选自-COORa、-CON(Ra)2、-CONHS(O)tRa,其中,每个Ra独立地为氢、羟基、烷基、卤代烷基、烷氧基、烯基、取代的烯基、炔基、取代的炔基、3-8元饱和或部分不饱和的单环碳环、苯基、具有1-2个独立地选自氮、氧或硫的杂原子的4-8元饱和或部分不饱和的单环杂环、具有1-4个独立地选自氮、氧或硫的杂原子的5-6元单环杂芳环或具有1-5个独立地选自氮、氧或硫的杂原子的8-10元双环杂芳环及他们的任意组合,每个t独立地选自1-2的整数;R1独立地为氢、羟基、氨基或硼酸;R2独立地为甲基或氘代甲基;A、B、C、X、Y、Z均独立地为碳或氮;D均独立地为-NH、氧或硫。
2.根据权利要求1所述稠合嘧啶类化合物或其药学上可接受盐,其特征在于,R选自-COORa、-CON(Ra)2、-CSN(Ra)2、-CONHS(O)2Ra,其中,每个Ra独立地为氢、烷基、烷氧基、具有1-4个独立地选自氮、氧或硫的杂原子的5-6元单环杂芳环及他们的任意组合;R1独立地为氢或羟基;R2独立地为甲基或氘代甲基;A、B、C、X、Y、Z均独立地为碳或氮;D独立地为-NH、氧或硫。
3.根据权利要求1所述稠合嘧啶类化合物或其药学上可接受盐,其特征在于,所述稠合嘧啶类衍生物选自:
4.权利要求1-3任一项所述稠合嘧啶类化合物或其药学上可接受盐的制备方法,其特征在于,包括以下步骤:
(1)制备二氯嘧啶母核
由A在尿素溶液中反应,接着水解得到B,B在氢氧化钯催化下乙酸作溶剂还原得到C,C转化成二氯化物D,然后在氨基上引入Boc保护基得到E;
(2)制备2-甲基-1H-吲哚-4-羧酸甲酯
F在氢化钠作用下与苯磺酰氯反应得到保护的G,G随后在LDA作用下与碘甲烷反应得到H,H在氢氧化钠作用下脱去苯磺酰基得到I,I在催化剂的作用下与CO发生插羰反应制得到J;
(3)制备目标化合物稠合嘧啶类化合物V15
E在三乙胺作碱与苄胺反应得到K,K在钯催化剂的作用下与J偶联,得到中间体L,L在氢氧化锂作用下皂化得到羧酸,然后酰化得到N,N在三氟乙酸或HCl的作用下脱去Boc保护基得到稠合嘧啶类化合物V15。
5.一种药物组合物,其特征在于,保护权利要求1-3任一项所述的稠合嘧啶类化合物或其药学上可接受的盐。
6.权利要求1-3任一项所述的稠合嘧啶类化合物或其药学上可接受的盐或者根据权利要求5所述的药物组合物在制备p97抑制剂中的应用。
7.权利要求1-3任一项所述的稠合嘧啶类化合物或其药学上可接受的盐或者根据权利要求5所述的药物组合物在制备治疗与p97活性相关的疾病的药物中的应用。
8.权利要求1-3任一项所述的稠合嘧啶类化合物或其药学上可接受的盐或者根据权利要求5所述的药物组合物在制备治疗癌症药物中的应用。
9.根据权利要求8所述的应用,其特征在于,所述癌症包括前列腺癌、膀胱癌、肺癌、结肠癌、肾癌、乳腺癌、子宫颈癌、子宫内膜癌或其他子宫癌、卵巢癌、睾丸癌、阴茎癌、阴道癌、尿道癌、胆囊癌、食道癌或胰腺癌、多发性骨髓瘤、白血病。
10.根据权利要求8所述的应用,其特征在于,所述药物可阻断肿瘤细胞增殖,诱发肿瘤细胞凋亡。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202310668727.6A CN117003770A (zh) | 2023-06-07 | 2023-06-07 | 一种稠合嘧啶类化合物或其药学上可接受盐及其制备方法和应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202310668727.6A CN117003770A (zh) | 2023-06-07 | 2023-06-07 | 一种稠合嘧啶类化合物或其药学上可接受盐及其制备方法和应用 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN117003770A true CN117003770A (zh) | 2023-11-07 |
Family
ID=88573572
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202310668727.6A Pending CN117003770A (zh) | 2023-06-07 | 2023-06-07 | 一种稠合嘧啶类化合物或其药学上可接受盐及其制备方法和应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN117003770A (zh) |
-
2023
- 2023-06-07 CN CN202310668727.6A patent/CN117003770A/zh active Pending
Similar Documents
Publication | Publication Date | Title |
---|---|---|
KR100816945B1 (ko) | 선택적인 사이클린 의존성 키나제 4 억제제로서의이세싸이오네이트 염 | |
CN109983016B (zh) | 嘧啶并[5,4-b]吲嗪或嘧啶并[5,4-b]吡呤化合物、其制备方法及用途 | |
WO2017092635A1 (zh) | 一种蛋白激酶抑制剂及其制备方法和医药用途 | |
CN101323591A (zh) | 一类5-位或6-位取代的萘酰亚胺化合物及抗肿瘤应用 | |
JP5820080B2 (ja) | 三環系PI3K及び/又はmTOR抑制剤 | |
JP7041821B2 (ja) | アミノ置換窒素含有縮合環化合物、その調製方法及び使用 | |
WO2019113523A1 (en) | Compounds and therapeutic uses thereof | |
Chen et al. | Water-soluble derivatives of evodiamine: Discovery of evodiamine-10-phosphate as an orally active antitumor lead compound | |
WO2013178021A1 (zh) | 吡咯并[2,1—f][1,2,4]三嗪衍生物及其抗肿瘤用途 | |
CN112300153A (zh) | 一种杂环化合物、药物组合物和用途 | |
WO2021023016A1 (zh) | 乐伐替尼酸的噻唑酮衍生物及其应用 | |
CN114805357A (zh) | 一种靶向setdb1-ttd的小分子抑制剂及其制药用途 | |
CN117003770A (zh) | 一种稠合嘧啶类化合物或其药学上可接受盐及其制备方法和应用 | |
CN111247143B (zh) | 可用作蛋白激酶抑制剂的吡啶并喹唑啉衍生物 | |
CN112125908B (zh) | Cdk激酶抑制剂、其制备方法、药物组合物和应用 | |
US9499552B2 (en) | Pyrazolo[1,5-A]pyrimidine derivative and use of anti-tumor thereof | |
CN109369676B (zh) | 一种双-氟喹诺酮噁二唑脲类n-乙酰诺氟沙星衍生物及其制备方法和应用 | |
CZ2000711A3 (cs) | Opticky čisté analogy kamptothecinu, meziprodukty syntézy a způsob přípravy | |
CN102731516A (zh) | 一类具有抗肿瘤活性的喜树碱衍生物 | |
CN113024557A (zh) | 一种Peganumine A生物碱结构简化物及其应用 | |
CN105503865A (zh) | 新型吡唑并吡啶类抗肿瘤化合物 | |
CN113493469A (zh) | 可作为免疫调节剂的化合物、其制备方法和应用 | |
WO2019056376A1 (zh) | 酸敏感的吉非替尼-氟硼二吡咯衍生物及其制备方法和在医药上的应用 | |
CN112679470B (zh) | (e)-1-苯基4-烯基-1h-吡唑类化合物及其医药用途 | |
WO2023142754A1 (zh) | Ezh1/2抑制剂及其制备和抗肿瘤治疗中的应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |