CN87100769A - 带有2-[2-[n,n-双(2-氯乙基)磷酰二氨基氧基]乙基]基团的新杂环化合物 - Google Patents
带有2-[2-[n,n-双(2-氯乙基)磷酰二氨基氧基]乙基]基团的新杂环化合物 Download PDFInfo
- Publication number
- CN87100769A CN87100769A CN198787100769A CN87100769A CN87100769A CN 87100769 A CN87100769 A CN 87100769A CN 198787100769 A CN198787100769 A CN 198787100769A CN 87100769 A CN87100769 A CN 87100769A CN 87100769 A CN87100769 A CN 87100769A
- Authority
- CN
- China
- Prior art keywords
- formula
- group
- compound
- acid
- represent
- 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
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 title claims abstract description 29
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 title description 14
- 150000002391 heterocyclic compounds Chemical class 0.000 title description 2
- SBOJXQVPLKSXOG-UHFFFAOYSA-N o-amino-hydroxylamine Chemical compound NON SBOJXQVPLKSXOG-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 79
- -1 4Be hydrogen Chemical class 0.000 claims abstract description 62
- 239000001257 hydrogen Substances 0.000 claims abstract description 46
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 46
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical class [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 27
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 23
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 18
- 125000002252 acyl group Chemical group 0.000 claims abstract description 10
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 7
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims description 45
- 239000002253 acid Substances 0.000 claims description 41
- 238000006243 chemical reaction Methods 0.000 claims description 36
- 150000003839 salts Chemical class 0.000 claims description 28
- 229910052799 carbon Inorganic materials 0.000 claims description 18
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- 150000001413 amino acids Chemical class 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 230000029936 alkylation Effects 0.000 claims description 10
- 238000005804 alkylation reaction Methods 0.000 claims description 10
- 108010016626 Dipeptides Proteins 0.000 claims description 8
- 125000004414 alkyl thio group Chemical group 0.000 claims description 7
- 125000002947 alkylene group Chemical group 0.000 claims description 7
- 230000032050 esterification Effects 0.000 claims description 6
- 238000005886 esterification reaction Methods 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- 230000008859 change Effects 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 238000005917 acylation reaction Methods 0.000 claims description 3
- 125000002228 disulfide group Chemical group 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 230000010933 acylation Effects 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims description 2
- 125000000539 amino acid group Chemical group 0.000 claims description 2
- 125000005392 carboxamide group Chemical group NC(=O)* 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 2
- 239000012059 conventional drug carrier Substances 0.000 claims 1
- 239000001301 oxygen Substances 0.000 abstract description 3
- 229910052760 oxygen Inorganic materials 0.000 abstract description 3
- 239000005864 Sulphur Substances 0.000 abstract description 2
- 230000000259 anti-tumor effect Effects 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract 1
- 125000004430 oxygen atom Chemical group O* 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 66
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 47
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 45
- 239000000243 solution Substances 0.000 description 35
- 229910052757 nitrogen Inorganic materials 0.000 description 34
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 33
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 28
- 229910052698 phosphorus Inorganic materials 0.000 description 25
- 239000011574 phosphorus Substances 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- 239000002904 solvent Substances 0.000 description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- 239000007795 chemical reaction product Substances 0.000 description 17
- 239000000203 mixture Substances 0.000 description 17
- 239000000047 product Substances 0.000 description 17
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 229940024606 amino acid Drugs 0.000 description 15
- 235000001014 amino acid Nutrition 0.000 description 15
- 239000007924 injection Substances 0.000 description 15
- 238000002347 injection Methods 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 13
- 150000002500 ions Chemical class 0.000 description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 13
- 150000003254 radicals Chemical class 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 11
- 125000003545 alkoxy group Chemical group 0.000 description 11
- 150000001721 carbon Chemical group 0.000 description 11
- 239000003795 chemical substances by application Substances 0.000 description 11
- 239000012141 concentrate Substances 0.000 description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 239000003513 alkali Substances 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 10
- 230000008569 process Effects 0.000 description 10
- 239000002994 raw material Substances 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 9
- 150000001412 amines Chemical class 0.000 description 9
- 229910052794 bromium Inorganic materials 0.000 description 9
- 239000000460 chlorine Substances 0.000 description 9
- 229910052801 chlorine Inorganic materials 0.000 description 9
- 239000003480 eluent Substances 0.000 description 9
- 238000000605 extraction Methods 0.000 description 9
- 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 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- 229910052783 alkali metal Inorganic materials 0.000 description 8
- 150000001408 amides Chemical group 0.000 description 8
- ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 8
- 235000019253 formic acid Nutrition 0.000 description 8
- 239000000499 gel Substances 0.000 description 8
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 7
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 7
- 229910052736 halogen Inorganic materials 0.000 description 7
- 150000002367 halogens Chemical class 0.000 description 7
- 229910052740 iodine Inorganic materials 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 239000011230 binding agent Substances 0.000 description 6
- 239000011630 iodine Substances 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 229960001866 silicon dioxide Drugs 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 229910021529 ammonia Inorganic materials 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000003643 water by type Substances 0.000 description 5
- OBTZDIRUQWFRFZ-UHFFFAOYSA-N 2-(5-methylfuran-2-yl)-n-(4-methylphenyl)quinoline-4-carboxamide Chemical compound O1C(C)=CC=C1C1=CC(C(=O)NC=2C=CC(C)=CC=2)=C(C=CC=C2)C2=N1 OBTZDIRUQWFRFZ-UHFFFAOYSA-N 0.000 description 4
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 4
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- OPKOKAMJFNKNAS-UHFFFAOYSA-N N-methylethanolamine Chemical compound CNCCO OPKOKAMJFNKNAS-UHFFFAOYSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 4
- 150000003862 amino acid derivatives Chemical class 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 239000001913 cellulose Substances 0.000 description 4
- 229920002678 cellulose Polymers 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 125000004494 ethyl ester group Chemical group 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000012442 inert solvent Substances 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000007127 saponification reaction Methods 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 description 3
- YXXURDJTDAAEPH-UHFFFAOYSA-N 2-aminopropanethioic s-acid Chemical compound CC(N)C(S)=O YXXURDJTDAAEPH-UHFFFAOYSA-N 0.000 description 3
- YQTNXPUMHHTXIB-UHFFFAOYSA-N ClCC[P] Chemical compound ClCC[P] YQTNXPUMHHTXIB-UHFFFAOYSA-N 0.000 description 3
- FFFHZYDWPBMWHY-UHFFFAOYSA-N HOMOCYSTEINE Chemical compound OC(=O)C(N)CCS FFFHZYDWPBMWHY-UHFFFAOYSA-N 0.000 description 3
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 3
- 229930195722 L-methionine Natural products 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- XUYPXLNMDZIRQH-LURJTMIESA-N N-acetyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC(C)=O XUYPXLNMDZIRQH-LURJTMIESA-N 0.000 description 3
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 3
- 229920005654 Sephadex Polymers 0.000 description 3
- 239000012507 Sephadex™ Substances 0.000 description 3
- OUUQCZGPVNCOIJ-UHFFFAOYSA-M Superoxide Chemical compound [O-][O] OUUQCZGPVNCOIJ-UHFFFAOYSA-M 0.000 description 3
- 150000008065 acid anhydrides Chemical class 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 239000005030 aluminium foil Substances 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000000010 aprotic solvent Substances 0.000 description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 3
- 229910052728 basic metal Inorganic materials 0.000 description 3
- 150000003818 basic metals Chemical class 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000004587 chromatography analysis Methods 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
- 238000007796 conventional method Methods 0.000 description 3
- 150000004292 cyclic ethers Chemical class 0.000 description 3
- UFULAYFCSOUIOV-UHFFFAOYSA-O cysteaminium Chemical compound [NH3+]CCS UFULAYFCSOUIOV-UHFFFAOYSA-O 0.000 description 3
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 3
- LIWAQLJGPBVORC-UHFFFAOYSA-N ethylmethylamine Chemical compound CCNC LIWAQLJGPBVORC-UHFFFAOYSA-N 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 238000002523 gelfiltration Methods 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 3
- 125000004464 hydroxyphenyl group Chemical group 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 229960003151 mercaptamine Drugs 0.000 description 3
- 229930182817 methionine Natural products 0.000 description 3
- 150000002892 organic cations Chemical group 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 238000006385 ozonation reaction Methods 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- 150000003512 tertiary amines Chemical class 0.000 description 3
- 238000012360 testing method Methods 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
- MYRTYDVEIRVNKP-UHFFFAOYSA-N 1,2-Divinylbenzene Chemical compound C=CC1=CC=CC=C1C=C MYRTYDVEIRVNKP-UHFFFAOYSA-N 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 2
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 2
- MIJDSYMOBYNHOT-UHFFFAOYSA-N 2-(ethylamino)ethanol Chemical compound CCNCCO MIJDSYMOBYNHOT-UHFFFAOYSA-N 0.000 description 2
- WFIYPADYPQQLNN-UHFFFAOYSA-N 2-[2-(4-bromopyrazol-1-yl)ethyl]isoindole-1,3-dione Chemical compound C1=C(Br)C=NN1CCN1C(=O)C2=CC=CC=C2C1=O WFIYPADYPQQLNN-UHFFFAOYSA-N 0.000 description 2
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 2
- MNHKUCBXXMFQDM-UHFFFAOYSA-N 4-[(4-nitrophenyl)methyl]pyridine Chemical compound C1=CC([N+](=O)[O-])=CC=C1CC1=CC=NC=C1 MNHKUCBXXMFQDM-UHFFFAOYSA-N 0.000 description 2
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 2
- 206010051779 Bone marrow toxicity Diseases 0.000 description 2
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 230000005526 G1 to G0 transition Effects 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 201000008645 Joubert syndrome Diseases 0.000 description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- NSOXQYCFHDMMGV-UHFFFAOYSA-N Tetrakis(2-hydroxypropyl)ethylenediamine Chemical compound CC(O)CN(CC(C)O)CCN(CC(C)O)CC(C)O NSOXQYCFHDMMGV-UHFFFAOYSA-N 0.000 description 2
- 150000001241 acetals Chemical class 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 2
- 150000008046 alkali metal hydrides Chemical class 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 150000001447 alkali salts Chemical class 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 150000001342 alkaline earth metals Chemical class 0.000 description 2
- 239000002168 alkylating agent Substances 0.000 description 2
- 229940100198 alkylating agent Drugs 0.000 description 2
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 231100000366 bone marrow toxicity Toxicity 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 150000001767 cationic compounds Chemical class 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 description 2
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000005336 cracking Methods 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- 239000000824 cytostatic agent Substances 0.000 description 2
- 230000001085 cytostatic effect Effects 0.000 description 2
- 230000007123 defense Effects 0.000 description 2
- MCWXGJITAZMZEV-UHFFFAOYSA-N dimethoate Chemical compound CNC(=O)CSP(=S)(OC)OC MCWXGJITAZMZEV-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 2
- 150000002191 fatty alcohols Chemical class 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001640 fractional crystallisation Methods 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 230000002140 halogenating effect Effects 0.000 description 2
- 150000005826 halohydrocarbons Chemical class 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- KIWQWJKWBHZMDT-UHFFFAOYSA-N homocysteine thiolactone Chemical compound NC1CCSC1=O KIWQWJKWBHZMDT-UHFFFAOYSA-N 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 239000003456 ion exchange resin Substances 0.000 description 2
- 229920003303 ion-exchange polymer Polymers 0.000 description 2
- 239000000644 isotonic solution Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 229960003966 nicotinamide Drugs 0.000 description 2
- 235000005152 nicotinamide Nutrition 0.000 description 2
- 239000011570 nicotinamide Substances 0.000 description 2
- 239000012454 non-polar solvent Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 238000006053 organic reaction Methods 0.000 description 2
- 150000002923 oximes Chemical class 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 2
- 150000003053 piperidines Chemical class 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 229920005990 polystyrene resin Polymers 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- 239000012264 purified product Substances 0.000 description 2
- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 238000003797 solvolysis reaction Methods 0.000 description 2
- 238000004611 spectroscopical analysis Methods 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- 125000004079 stearyl 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])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])[H] 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 150000003555 thioacetals Chemical class 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- DZLNHFMRPBPULJ-UHFFFAOYSA-N thioproline Chemical compound OC(=O)C1CSCN1 DZLNHFMRPBPULJ-UHFFFAOYSA-N 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 125000005270 trialkylamine group Chemical group 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 229910052721 tungsten Inorganic materials 0.000 description 2
- 229910052727 yttrium Inorganic materials 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 2
- PYFNLWPQPNXHCS-VKHMYHEASA-N (2r)-2-amino-3-(methyldisulfanyl)propanoic acid Chemical compound CSSC[C@H](N)C(O)=O PYFNLWPQPNXHCS-VKHMYHEASA-N 0.000 description 1
- KYQJQGXEBNURRW-BYPYZUCNSA-N (2s)-n-hydroxypyrrolidine-2-carboxamide Chemical compound ON=C(O)[C@@H]1CCCN1 KYQJQGXEBNURRW-BYPYZUCNSA-N 0.000 description 1
- FEOHYDSNGHIXOM-WLDMJGECSA-N (3R,4R,5S,6R)-3-amino-6-(hydroxymethyl)-2-methyloxane-2,4,5-triol Chemical compound CC1(O)[C@H](N)[C@@H](O)[C@H](O)[C@H](O1)CO FEOHYDSNGHIXOM-WLDMJGECSA-N 0.000 description 1
- AVQQQNCBBIEMEU-UHFFFAOYSA-N 1,1,3,3-tetramethylurea Chemical compound CN(C)C(=O)N(C)C AVQQQNCBBIEMEU-UHFFFAOYSA-N 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 description 1
- SHGBCLVCOJGQDM-UHFFFAOYSA-N 2,6-diaminoheptanoic acid Chemical compound CC(N)CCCC(N)C(O)=O SHGBCLVCOJGQDM-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- VKPPFDPXZWFDFA-UHFFFAOYSA-N 2-chloroethanamine Chemical compound NCCCl VKPPFDPXZWFDFA-UHFFFAOYSA-N 0.000 description 1
- ONRREFWJTRBDRA-UHFFFAOYSA-N 2-chloroethanamine;hydron;chloride Chemical compound [Cl-].[NH3+]CCCl ONRREFWJTRBDRA-UHFFFAOYSA-N 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- 229940013085 2-diethylaminoethanol Drugs 0.000 description 1
- RSZVGLFPGDKTDK-UHFFFAOYSA-N 2-ethyl-1,3-thiazolidin-3-ium-4-carboxylate Chemical compound CCC1NC(C(O)=O)CS1 RSZVGLFPGDKTDK-UHFFFAOYSA-N 0.000 description 1
- AGIJRRREJXSQJR-UHFFFAOYSA-N 2h-thiazine Chemical compound N1SC=CC=C1 AGIJRRREJXSQJR-UHFFFAOYSA-N 0.000 description 1
- ASERXEZXVIJBRO-UHFFFAOYSA-N 3,3-diethoxypropan-1-ol Chemical class CCOC(CCO)OCC ASERXEZXVIJBRO-UHFFFAOYSA-N 0.000 description 1
- ALKYHXVLJMQRLQ-UHFFFAOYSA-N 3-Hydroxy-2-naphthoate Chemical compound C1=CC=C2C=C(O)C(C(=O)O)=CC2=C1 ALKYHXVLJMQRLQ-UHFFFAOYSA-N 0.000 description 1
- PVNNOLUAMRODAC-UHFFFAOYSA-N 4-(ethylamino)butan-1-ol Chemical compound CCNCCCCO PVNNOLUAMRODAC-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 1
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 1
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 description 1
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- FAYOCELKCDKZCA-UHFFFAOYSA-N 5-hydroxy-2,4-dimethylthiophen-3-one Chemical compound CC1SC(O)=C(C)C1=O FAYOCELKCDKZCA-UHFFFAOYSA-N 0.000 description 1
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- 241000432824 Asparagus densiflorus Species 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- DDFATLJPDIYBEB-UHFFFAOYSA-N Br[S](=O)=O Chemical compound Br[S](=O)=O DDFATLJPDIYBEB-UHFFFAOYSA-N 0.000 description 1
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 244000241257 Cucumis melo Species 0.000 description 1
- 235000015510 Cucumis melo subsp melo Nutrition 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- KGWDUNBJIMUFAP-KVVVOXFISA-N Ethanolamine Oleate Chemical compound NCCO.CCCCCCCC\C=C/CCCCCCCC(O)=O KGWDUNBJIMUFAP-KVVVOXFISA-N 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- 229920012753 Ethylene Ionomers Polymers 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 240000004859 Gamochaeta purpurea Species 0.000 description 1
- 229920001503 Glucan Polymers 0.000 description 1
- LCWPNYSDUJCNNF-UHFFFAOYSA-N I[S](=O)=O Chemical compound I[S](=O)=O LCWPNYSDUJCNNF-UHFFFAOYSA-N 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- OWIKHYCFFJSOEH-UHFFFAOYSA-N Isocyanic acid Chemical compound N=C=O OWIKHYCFFJSOEH-UHFFFAOYSA-N 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- VLJNHYLEOZPXFW-BYPYZUCNSA-N L-prolinamide Chemical compound NC(=O)[C@@H]1CCCN1 VLJNHYLEOZPXFW-BYPYZUCNSA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- PQNASZJZHFPQLE-LURJTMIESA-N N(6)-methyl-L-lysine Chemical compound CNCCCC[C@H](N)C(O)=O PQNASZJZHFPQLE-LURJTMIESA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- DEFJQIDDEAULHB-UHFFFAOYSA-N N-D-alanyl-D-alanine Natural products CC(N)C(=O)NC(C)C(O)=O DEFJQIDDEAULHB-UHFFFAOYSA-N 0.000 description 1
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 1
- 125000003047 N-acetyl group Chemical group 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 1
- ZIPLHLLDHUOMHV-UHFFFAOYSA-N O1C=NC=C1.P Chemical class O1C=NC=C1.P ZIPLHLLDHUOMHV-UHFFFAOYSA-N 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- 229920000265 Polyparaphenylene Polymers 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- HCBIBCJNVBAKAB-UHFFFAOYSA-N Procaine hydrochloride Chemical compound Cl.CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 HCBIBCJNVBAKAB-UHFFFAOYSA-N 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- FJJCIZWZNKZHII-UHFFFAOYSA-N [4,6-bis(cyanoamino)-1,3,5-triazin-2-yl]cyanamide Chemical compound N#CNC1=NC(NC#N)=NC(NC#N)=N1 FJJCIZWZNKZHII-UHFFFAOYSA-N 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 229960004308 acetylcysteine Drugs 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000001339 alkali metal compounds Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 150000001347 alkyl bromides Chemical class 0.000 description 1
- 150000001348 alkyl chlorides Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 150000001351 alkyl iodides Chemical class 0.000 description 1
- 125000000337 alpha-glutamyl group Chemical group 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229960004909 aminosalicylic acid Drugs 0.000 description 1
- 150000008064 anhydrides Chemical group 0.000 description 1
- XLJMAIOERFSOGZ-UHFFFAOYSA-N anhydrous cyanic acid Natural products OC#N XLJMAIOERFSOGZ-UHFFFAOYSA-N 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- CUBCNYWQJHBXIY-UHFFFAOYSA-N benzoic acid;2-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1O CUBCNYWQJHBXIY-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
- 229910001451 bismuth ion Inorganic materials 0.000 description 1
- 201000011281 bladder sarcoma Diseases 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- RRKTZKIUPZVBMF-IBTVXLQLSA-N brucine Chemical compound O([C@@H]1[C@H]([C@H]2C3)[C@@H]4N(C(C1)=O)C=1C=C(C(=CC=11)OC)OC)CC=C2CN2[C@@H]3[C@]41CC2 RRKTZKIUPZVBMF-IBTVXLQLSA-N 0.000 description 1
- RRKTZKIUPZVBMF-UHFFFAOYSA-N brucine Natural products C1=2C=C(OC)C(OC)=CC=2N(C(C2)=O)C3C(C4C5)C2OCC=C4CN2C5C31CC2 RRKTZKIUPZVBMF-UHFFFAOYSA-N 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
- 229960001948 caffeine Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- KMPWYEUPVWOPIM-UHFFFAOYSA-N cinchonidine Natural products C1=CC=C2C(C(C3N4CCC(C(C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-UHFFFAOYSA-N 0.000 description 1
- KMPWYEUPVWOPIM-LSOMNZGLSA-N cinchonine Chemical compound C1=CC=C2C([C@@H]([C@H]3N4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-LSOMNZGLSA-N 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 235000021438 curry Nutrition 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 description 1
- RDXABLXNTVBVML-UHFFFAOYSA-N diethoxyphosphanyl diethyl phosphite Chemical compound CCOP(OCC)OP(OCC)OCC RDXABLXNTVBVML-UHFFFAOYSA-N 0.000 description 1
- HMNXRLQSCJJMBT-UHFFFAOYSA-N diethyl 2-aminobutanedioate Chemical compound CCOC(=O)CC(N)C(=O)OCC HMNXRLQSCJJMBT-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- RXKJFZQQPQGTFL-UHFFFAOYSA-N dihydroxyacetone Chemical compound OCC(=O)CO RXKJFZQQPQGTFL-UHFFFAOYSA-N 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- UWYVPFMHMJIBHE-UPHRSURJSA-N enol-oxaloacetic acid Chemical compound OC(=O)\C=C(/O)C(O)=O UWYVPFMHMJIBHE-UPHRSURJSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- 150000002169 ethanolamines Chemical class 0.000 description 1
- OTXKQKKLEDBPAD-LURJTMIESA-N ethyl (2s)-2,5-diaminopentanoate Chemical compound CCOC(=O)[C@@H](N)CCCN OTXKQKKLEDBPAD-LURJTMIESA-N 0.000 description 1
- JNTDLWHHJMGLGD-UHNVWZDZSA-N ethyl (2s,3r)-2-amino-3-hydroxybutanoate Chemical compound CCOC(=O)[C@@H](N)[C@@H](C)O JNTDLWHHJMGLGD-UHNVWZDZSA-N 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 239000011094 fiberboard Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000002642 gamma-glutamyl group Chemical group 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- JMANVNJQNLATNU-UHFFFAOYSA-N glycolonitrile Natural products N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 1
- 150000002337 glycosamines Chemical class 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 150000001261 hydroxy acids Chemical group 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910001411 inorganic cation Inorganic materials 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 201000006512 mast cell neoplasm Diseases 0.000 description 1
- 208000006971 mastocytoma Diseases 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- CEMZBWPSKYISTN-YFKPBYRVSA-N methyl (2s)-2-amino-3-methylbutanoate Chemical compound COC(=O)[C@@H](N)C(C)C CEMZBWPSKYISTN-YFKPBYRVSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000002715 modification method Methods 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- DAZXVJBJRMWXJP-UHFFFAOYSA-N n,n-dimethylethylamine Chemical compound CCN(C)C DAZXVJBJRMWXJP-UHFFFAOYSA-N 0.000 description 1
- HAUWHFROJHPKIL-UHFFFAOYSA-N n-[amino(3,3-diethoxypropoxy)phosphoryl]-2-chloro-n-(2-chloroethyl)ethanamine Chemical compound CCOC(OCC)CCOP(N)(=O)N(CCCl)CCCl HAUWHFROJHPKIL-UHFFFAOYSA-N 0.000 description 1
- GNVRJGIVDSQCOP-UHFFFAOYSA-N n-ethyl-n-methylethanamine Chemical compound CCN(C)CC GNVRJGIVDSQCOP-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000005011 phenolic resin Substances 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 125000004437 phosphorous atom Chemical group 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 229940072033 potash Drugs 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012063 pure reaction product Substances 0.000 description 1
- WRHZVMBBRYBTKZ-UHFFFAOYSA-N pyrrole-2-carboxylic acid Chemical compound OC(=O)C1=CC=CN1 WRHZVMBBRYBTKZ-UHFFFAOYSA-N 0.000 description 1
- JHHZLHWJQPUNKB-UHFFFAOYSA-N pyrrolidin-3-ol Chemical compound OC1CCNC1 JHHZLHWJQPUNKB-UHFFFAOYSA-N 0.000 description 1
- 229940107700 pyruvic acid Drugs 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
- 229960001404 quinidine Drugs 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000005201 scrubbing Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 150000003388 sodium compounds Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- QMGVPVSNSZLJIA-FVWCLLPLSA-N strychnine Chemical compound O([C@H]1CC(N([C@H]2[C@H]1[C@H]1C3)C=4C5=CC=CC=4)=O)CC=C1CN1[C@@H]3[C@]25CC1 QMGVPVSNSZLJIA-FVWCLLPLSA-N 0.000 description 1
- 229960005453 strychnine Drugs 0.000 description 1
- 231100000456 subacute toxicity Toxicity 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 150000003461 sulfonyl halides Chemical class 0.000 description 1
- XTHPWXDJESJLNJ-UHFFFAOYSA-N sulfurochloridic acid Chemical compound OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- JBQYATWDVHIOAR-UHFFFAOYSA-N tellanylidenegermanium Chemical compound [Te]=[Ge] JBQYATWDVHIOAR-UHFFFAOYSA-N 0.000 description 1
- 150000005621 tetraalkylammonium salts Chemical class 0.000 description 1
- YAPQBXQYLJRXSA-UHFFFAOYSA-N theobromine Chemical compound CN1C(=O)NC(=O)C2=C1N=CN2C YAPQBXQYLJRXSA-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 239000012745 toughening agent Substances 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 150000003628 tricarboxylic acids Chemical class 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
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6503—Five-membered rings
- C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6509—Six-membered rings
- C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and oxygen atoms as the only ring hetero atoms
- C07F9/653—Five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and oxygen atoms as the only ring hetero atoms
- C07F9/6533—Six-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
- C07F9/6539—Five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
- C07F9/6544—Six-membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Biochemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Peptides Or Proteins (AREA)
Abstract
本发明涉及式(I)化合物及其生产过程。式中R1、R2、R3、R4为氢、C1-C4烷基、2-氯乙基、2-溴乙基、或2-C1-C4烷磺酰氧乙基、R8为氢、C1_6烷基或酰基,R6和R7为氢或一起代表氧原子,或R6为氢,R7为羧基、C1_6烷氧羰基、氨羰基或烷氨羰基,Z为硫、氧、-S-C(R5)2、-O-C-(R5)2-或-NR5-C(R5)2,R5为氢或C1_6烷基。式(I)化合物有抗肿瘤活性。
Description
本发明涉及通式Ⅰ的化合物及其与生理上可接受的酸或阳离子形成的盐、它们的生产方法和以式Ⅰ化合物作为活性成分的药物,
式中,基团R1、R2、R3和R4相同或不同并代表氢、C1-C4烷基、2-氯乙基、2-溴乙基或2-C1-C4烷磺酰氧乙基且这些基团中至少有两个代表2-氯乙基、2-溴乙基或2-C1-C4烷磺酰氧乙基,R8代表氢、C1-C6烷基、C1-C6烷氧羰基、C2-C6链烷酰基、天然氨基酸或天然二肽的残基,其中游离羧基可被C1-C6烷基酯化,或者式中R8代表氨基羰基或氮原子上带有一个或两个C1-C6烷基的氨基羰基,R6和R7代表氢或合在一起代表一个氧原子,或者式中R6代表氢时,R7代表一个羰基、C1-C6烷氧羰基、氨基羰基、C1-C6烷氨羰基、二-C1-C6烷氨羰基或一个羧酰胺基,其中酰胺部分是天然氨基酸残基或天然二肽残基或它们的C1-C6烷基酯,Z代表一个硫原子、氧原子、基团
NR5、基团-S-C(R5)2-、-O-C(R5)2-或-NR5C(R5)2-,其中各R5基团相同或不同并代表氢或C1-C6烷基。
本发明的化合物是活性很高的细胞抑制剂;其全身性毒性和局部毒性(例如急性和亚急性毒性)都很低。特别是,本发明化合物对人肿瘤细胞的细胞毒性选择性较高,同时其骨髓毒性较低(即与骨髓毒性相比较)。因此,它们与已知的细胞抑制剂“环磷酰胺”相比,例如,其治疗范围要大得多(3-4倍)。另外,本发明化合物例如在体表或腔内都是有效的。而且,本发明化合物还可以用来治疗艾兹病。
本发明化合物的抗肿瘤活性是通过例如下述模型显示的:雌性无毛小鼠(nu/nu mice)的膀胱肉瘤、S180腹水瘤/小鼠、Yoshida腹水瘤/大鼠、小鼠P815肥大细胞瘤、人类肿瘤细胞体外培养试验。
和“环磷酰胺”及其它有细胞抑制活性的噁唑膦类化合物(oxazophosphorins)截然相反,本发明化合物中烷化剂的释放速率出人意料地低。
此外,本发明化合物能加强免疫防御系统(因而它后可作为生物反应增强剂)。只需很低剂量(例如0.05-5毫克/公斤体重)就可以产生这种增强免疫防御系统的效果。
即使式Ⅰ中的基团R1、R2、R3和R4中至少有两个代表2-氯乙基、2-溴乙基或2-C1-C4烷磺酰氧乙基,在每种情况下这些基团也可以是相同或不同的,亦即,举例来说,R3可以是2-氯乙基,R1可以是2-甲磺酰氧基乙基(R2和R4=氢)。
如果R1、R2、R3、R4、R5和R8代表C1-C6烷基,它们最好都是甲基。式Ⅰ中出现的烷基、烷氧基及链烷酰基可以是直链或支链形状的。如R8代表一个C2-C6链烷酰基,它代表的主要是乙酰基。这种链烷酰基还可以含有另一个羧基和(或)氨基,其中该羧基最好位于此链烷酰基的末端碳原子(即ω位)上,而氨基则出现在例如此羧基的邻位或CO基团的邻位。上述链烷酰基的例子有:α或γ谷氨酰基。当R7和(或)R8代表C1-C6烷氧羰基时,该烷氧基最好具有1或2个碳原子。如果R7代表一个C1-C6烷氨羰基,并且如果此基团另外含有一个羧基,那么这个羧基最好位于烷基的1位。式Ⅰ中的氨基羰基上的各个烷基最好具有1或2个碳原子。
Z为一个硫原子或代表基团-S-C(R5)2-(尤其当R5代表氢时)的式Ⅰ化合物活性特别高。
如果R7代表一个羧酰胺基团,而该酰胺部分代表一种天然氨基酸或一种天然二肽的残基,那末这种天然氨基酸或肽是通过该氨基酸的一个氨基或氨基官能团(最好是通过α-氨基)与该羧酸残基相连。在这种情况下,R7可以特别代表-CO-NH-CH(R18)-CO-R19这一结构,其中R19代表OH、C1-C6烷氧基或基团NH-CH(R18)-COR20,而R18代表氢、一个C1-C10烷基或一个被下述基团所取代的C1-C10烷基:一个羟基、C1-C6烷氧基、巯基、C1-C10烷硫基、苯基、羟苯基、氨基-C1-C6烷硫基、氨基-C1-C6烷氧基、氨基、氨基羰基、脲基(H2NCONH-)、胍基、羧基羧基或C1-C6烷氧羰基,或者R18与结构部分-NH-CH2-CO-R19一起构成2-羧基吡咯烷-1-基(脯氨酸-(1)-基)或4-羟基脯氨酸-(1)-基。R20代表OH或C1-C6烷氧基。
R8代表一种天然氨基酸或一种天然多肽的残基时,此基团或该肽是通过羧基与式Ⅰ中杂环的3位氮原子相连。特别是,R8代表基团-CO-CH(R21)-NHR22,其中R21代表氢、C1-C10烷基或可被下述基团所取代的C1-C10烷基:羟基、C1-C6烷氧基、巯基、C1-C6烷硫基、苯基、羟苯基、氨基-C1-C6烷硫基、氨基-C1-C6烷氧基、氨基、氨基羰基、脲基(H2NCONH-)、胍基、羧基或C1-C6烷基氧羰基,或者其中R21代表残基-CO-(CH2)n-CH(NHR22)-CO-OR23,此处R22代表氢、基团-CO-CH(R21)NH2或基团-CO-(CH2)n-CH(NH2)-CO-OR23,R23代表氢或C1-C6烷基,而n代表整数1、2或3。
特别适宜的这种天然氨基酸或二肽(外消旋体、左-和右旋体)的残基是从下列氨基酸衍生而来的残基:甘氨酸、脯氨酸、苯丙氨酸、酪氨酸。
R7代表一个羧基时,本发明的式Ⅰ化合物亦可以其与生理上可接受的无机或有机阳离子形成的相应盐的形式存在。可以采用的无机阳离子包括,例如:NH+ 4、碱金属(Na,K)阳离子、碱土金属(Ca,Mg)阳离子、铋离子、铝离子或铁离子。可以采用的有机阳离子包括例如下列胺的阳离子:伯、仲或叔C1-C6烷基胺类。这类胺还可以含有第二个氨基(例如乙二胺、N,N′-二苄基乙二胺);乙醇胺类(例如乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、胆碱、普鲁卡因);环胺类(例如C5-C6环烷基胺类,如环己基胺);胍;哌啶;N-乙基哌啶;哌嗪;吗啉;N-乙基吗啉;烟酰胺;葡糖胺;甲基葡糖胺;可可碱;咖啡因;嘌呤;咪唑。此外,适宜的有机阳离子还有高半胱氨基酸硫代内酯的阳离子、α-氨基-ε-己内酰胺的阳离子或式Ⅳ的碱性化合物的阳离子。在式Ⅳ中,R13
代表一个羟基、氨基或C1-C6烷氧基,R14代表氢或二氟甲基,R15代表氢、吲哚基-(3)-甲基、咪唑基-(4)-甲基、C1-C10烷基或被下列基团取代的C1-C10烷基:羟基、C1-C6烷氧基、巯基、C1-C6烷硫基、苯基、羟苯基、氨基-C1-C6烷硫基、氨基-C1-C6烷氧基、氨基、氨基羰基、脲基(H2NCONH-)、胍基、羧基或C1-C6烷氧羰基,或者R15与结构部分CR14(NR16R17)一起构成吡咯烷基-(2)、4-羟基吡咯烷基-(2)或2-氧代-3-氨基-3-二氟甲基哌啶基,而基团R16和R17代表氢或C1-C6烷基。
特别适宜的碱性盐组分是满足下述条件的式Ⅳ化合物:其中R13代表羧基,基团R14、R16和R17为氢,而R15代表氢或C1-C4烷基,后者也可以被氨基或胍基所取代(最好在γ位或δ位取代)。
式Ⅳ中出现的烷基、烷氧基或烷硫基可以是直链或支链的。C1-C10烷基最好含有1-6个碳原子。而烷氧基和烷硫基最好含有1-4个,特别是1-2个碳原子;同样的优选条件对基团R16和R17也适用,当它们表示烷基的时候。如果式Ⅳ中的R15为一个含有一个氨基-C1-C6烷基硫(或者氨基-C1-C6烷氧基)的烷基,那么这些基团最好是H2N-CH2-CH2-S-CH2-或H2N-CH2-CH2-O-CH2-。
式Ⅳ化合物较好是满足:R13代表羟基,R14、R16和R17为氢,而R15尤其具有下文所给出的含义。
较好的式Ⅳ碱性化合物满足,例如:R13代表羟基,R14代表氢或二氟甲基,R15代表一个咪唑基-(4)-甲基、吲哚基-(3)-甲基或C1-C10烷基-特别是有下述基团取代的C1-C6烷基:一个氨基(最好是取代在该C1-C6烷基的2、3、4、5或6位,尤其是3或4位;位置总是从该烷基与分子残体相连的位置开始算起)、氨基-C2-C4烷硫基、氨基-C2-C4烷氧基或胍基,而R16和R17代表氢或C1-C4烷基;或者,较好的式Ⅳ碱性化合物是满足下述条件的式Ⅳ的氨基酸衍生物:其中的R13代表一个氨基或C1-C4烷氧基,R14代表氢,R15代表氢、苯甲基、4-羟基苯甲基或C1-C6烷基,此C1-C6烷基(最好在2、3、4、5或6位)具有一个羟基、巯基、C1-C4烷硫基、氨基羰基、C1-C4烷氧羰基或脲基,而R16和R17代表氢或C1-C4烷基。
对于上述的氨基酸或氨基酸衍生物,相应的盐是例如由1摩尔化合物Ⅰ与1摩尔化合物Ⅳ所生成的。
此外,式Ⅳ的碱性化合物可以是例如满足以下条件的那些化合物:R代表一个氨基或C1-C4烷氧基,R14代表氢或二氟甲基,R15代表一个咪唑基-(4)-甲基、吲哚基-(3)-甲基或者C1-C10烷基-尤其是(最好在2、3、4或ω位)含有一个氨基、氨基-C2-C4烷硫基、氨基-C2-C4烷氧基或胍基的C1-C6烷基,而R16和R17代表氢或C1-C4烷基。
对于上面最后提到的氨基酸衍生物,相应的盐是例如由2摩尔化合物Ⅰ与1摩尔式Ⅳ的氨基酸衍生物所成的盐。
式Ⅳ化合物的各个例子可以举出:天冬氨二酰胺(DL型)、天冬氨酸二乙酯(L型)、瓜氨酰胺[H2N-CO-NH-(CH2)3-CH(NH2)-CONH2,L型]、鸟氨酸乙酯(L型)、精氨酸、精氨酰氨(L型)、4-硫杂赖氨酸(H2N-CH2-CH2-S-CH2-CH(NH2)-COOH)、2,6-二氨基庚酸(ε-甲基赖氨酸)、4-氧杂赖氨酸(H2N-CH2-CH2-O-CH2-CH(NH2)-COOH)、甘氨酰胺、N,N-二甲基甘氨酰胺以及相应的甲酯或乙酯、脯氨酰胺、羟基脯氨酰胺、苯丙氨酰胺、丙氨酸或苯丙氨酸的甲酯或乙酯、高半胱氨酸硫代内酯(DL型)、α-氨基-ε-己内酰胺(D(+)型)、赖氨酸(尤其是L-赖氨酸)、二氟甲基鸟氨酸(DL或L型)、缬氨酸甲酯(L型)、苏氨酸乙酯、组氨酸、组氨酸甲酯、组氨酰胺、丙氨酰胺、鸟氨酸。
在盐中,当化合物Ⅳ中R13代表一个氨基,或代表一个烷氧基但还有一个碱性基团存在时,或当R13为一个羟基并且有两个碱性基团存在时,化合物Ⅰ(酸性部分)与化合物Ⅳ(碱性部分)的比例实际上为1∶1(当碱性部分为高半胱氨酸硫代内酯或α-氨基-ε-己内酰胺时,情况也是如此)。在另一方面,如果碱性部分Ⅳ中的R13为一个氨基或一个烷氧基,并且如果此碱性部分Ⅳ中除α位上的氨基外还有另外一个碱性基团,那么化合物Ⅰ与化合物Ⅳ的比例通常是2∶1。本发明的盐是中性盐。这类盐的pH值在例如6-9范围内,尤其是在6-8范围内。
其它可考虑使用的盐成分包括,例如:式为NR′R″R′″的胺类,其中基团R′、R″和R″′相同或不同,代表氢或C1-C4烷基,此烷基中亦可含有一个羟基(例如羟乙基)。这类胺的个别例子有:甲胺、乙胺、丙胺、异丙胺、二甲胺、二乙胺、三乙胺、三甲胺、三丙胺、甲基乙基胺、二甲基乙基胺、二乙基甲基胺、2-羟基乙胺、双(2-羟乙基)胺、三(2-羟乙基)胺、(2-羟乙基)甲基胺、(2-羟乙基)二甲基胺、双(2-羟乙基)甲基胺、(2-羟乙基)乙基胺、(2-羟乙基)二乙基胺、双(2-羟乙基)乙基胺、(2-羟乙基)甲基乙基胺。可使用的环胺类的例子有:吗啉、哌啶、吡咯烷或哌嗪;而二胺类的例子有乙二胺或烟酰胺。
本发明的式Ⅰ化合物亦可以其与生理上可接受的酸形成的盐的形式存在。这种酸可以是,例如:氢卤酸、硫酸,属于脂族、脂环族、芳族或杂环系的有机单、双或三羧酸以及各种磺酸。
上述酸的例子有:甲酸、乙酸、丙酸、丁二酸、乙醇酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、马来酸、富马酸、羟基富马酸或丙酮酸;苯乙酸、苯甲酸、对氨基苯甲酸、邻氨基苯甲酸、对羟基苯甲酸、水杨酸或对氨基水杨酸、3-羟基-2-萘甲酸、甲磺酸、乙磺酸、羟基乙磺酸、亚乙基磺酸;卤代磺酸、甲苯磺酸、萘磺酸或对氨基苯磺酸,也可以是8-氯-1,3-二甲基黄嘌呤。
依赖于制备条件和原料,制得的式Ⅰ最终产品可以游离形式(即碱性化合物形式)、酸或它们的盐的形式存在。最终产品的形式为盐时,可采用常规的方法,例如使用碱、酸或离子交换剂将其分别再转变为相应的碱或化合物Ⅰ。以后者为原料,通过使其与有机酸或无机酸或相应的碱性化合物反应,尤其是与那些能够形成治疗上可接受的盐的那些化合物反应,就可以制得各种盐。
例如,可以在0-20℃,在水溶液内,用一种碱,最好是用碳酸氢钠将已与化合物Ⅰ成盐的羧酸中和,然后冷冻干燥所得溶液。
与氨基酸所成的盐,例如与赖氨酸和精氨酸所成的盐可以这样制得:把等当量的游离氨基酸加入到化合物Ⅰ的水溶液内,该水溶液室温下的初始pH值为4-5,然后进行冷冻干燥。
将化合物Ⅰ的盐中的碱性部分换成其它碱性部分的另一方法是使用载有一种碱性化合物Ⅳ的酸性离子交换剂。例如,可以采用的离子交换剂包括其基体上具有磺酸或羧酸基团的各种聚合物。这种离子交换剂的基质例如可由聚苯乙烯树脂或酚树脂所构成,这种聚苯乙烯树脂可以含有2-16%,最好是4-8%(皆为重量比)的二乙烯基苯单体。聚苯基乙烯离子交换剂最好是凝胶状体。用例如下述方法可以把上述碱性部分负载到该离子交换剂上:将150毫升交换能力为1.2毫克当量/毫升(mval/ml)*的离子交换树脂装在带有冷却套管、直径约4厘米的柱子中用盐酸再生,然后用蒸馏水将其洗至中性并且不含氯离子为止,再用该碱性化合物Ⅳ(220毫摩尔)的10%水溶液进行处理,随后用蒸馏水洗至中性。
*离子交换剂制造商把离子交换剂的交换能力(即官能团如-SO3H、-CO2H等的数目)表示为毫当量/毫升离子交换树脂或当量/克离子交换树脂。
制备方法:本发明的另一个方面是提供制备式Ⅰ化合物的方法,该方法包括,使通式Ⅱ的一种化合物与通式Ⅲ的一种化合物反应,
式Ⅱ中,R1、R2、R3、R4和R5的含义同上述,X和Y可以各代表一个C1-C6烷氧基或C1-C6烷硫基或X和Y一起代表一个氧原子、一个具有1-5个碳原子的饱和亚烷二氧基环、一个具有1-5个碳原子的饱和亚烷二硫基环,或者X与基团R4一起代表一个单键,由此形成一个六员环,此时Y代表一个羟基、一个C1-C6烷氧基或基团S-alk-SO3Z,其中alk代表一个C2-C6亚烷基桥,而Z代表氢或一个阳离子,或者Y代表可被一个羧基、羟基或C1-C6烷氧羰基所取代的C1-C10烷硫基、C1-C6链烷酰硫基或苄硫基,式Ⅲ中Z、R5、R6、R7和R8的含义同上,并且可以采用烷基化或酰基化方法,在R8代表氢而其它符号含义同上的式Ⅰ化合物中引入含义同上述但氢除外的基团R8,可由以将R8脱除,还可以在Z代表基团
NH或-NH-C(R5)2-时,通过烷基化方法在Z中引入一个C1-C6烷基,还可以把式Ⅰ化合物中的R7基团(条件是R7不代表氢原子)转变成其它可能的基团,还可以把所得到的各个化合物转变为其与生理上可接受的阳离子或阴离子所形成的盐。制备过程是在溶剂中,在下述温度下完成的:-70~+100℃,最好是5~60℃;也就是说,按照需要,制备可以在冷却、室温或加热条件下进行。原料化合物Ⅱ的X和Y代表烷氧基或一起构成一个亚烷二氧基时,该化合物与其它的原料组分Ⅱ的反应适宜于在有一种酸催化剂存在下进行,例如在下述酸存在下进行:一种无机或有机酸,如三氯乙酸、对甲苯磺酸、甲酸、盐酸、三氟甲磺酸。X与R4相连而形成一个六员环[噁唑磷己环(oxazophosphorinane)]并且Y代表羟基、烷氧基、烷硫基或基团-S-alk-SO3Z时,则要用碱金属氢氧化物(如Na OH)将pH值调整到有利于反应进行的范围,例如调整到pH5-12,特别是pH7-9。可采用的溶剂包括,例如:水、醇类(尤其是含1-6个碳原子的链烷醇,如甲醇、乙醇、正丙醇、异丙醇或异丁醇)、各含有1-4个碳原子的烷酮类(尤其是丙酮、甲乙酮)、质子惰性溶剂(例如二甲亚砜、乙腈、N-甲基吡咯烷酮、二甲基甲酰胺、六甲基磷酰胺)、具有1~3个碳原子的卤代烷(例如氯仿、二氯甲烷)、饱和环醚(例如四氢呋喃、二氧杂环己烷)、饱和低级脂肪醚(如乙醚)或者类似的溶剂或上述几种溶剂的混合物。
根据制备本发明化合物的方法,通过酰化方法引入基团R8的反应是采用下述酸来进行的:异氰酸、C1-C6烷基异氰酸,或由式R-OH代表的一种酸,其中R为一个烷氧羰基、氨基羰基、C1-C6烷氨羰基、二-C1-C6烷基氨基羰基或C2~C6烷链酰基,或为一种天然氨基酸或天然二肽的残基,而这种氨基酸或二钛最好是已经活化的。这种活化的酸用于酰化时,它们最好是通式R-W的化合物,其中R的含义同上述,而W代表卤素(例如氯或溴),但也可以代表例如式-OR′、OR′的一种基团,或代表式为-OSO3H或-OCO-R″的基团,其中R″代表C1-C6烷基,也可以代表一个苯基或由硝基、C1-C4烷氧基、C1-C4烷基或囟原子(如氯、氟、溴)所取代的苯基,或者代表一个氰甲基或羟甲基,而R″代表一个直链或支链的C1-C6烷基、C1-C6烷氧基、苯氧基或苄氧基;R还可以代表基团COCl,条件是W代表的是卤素,并且在此情况下,下一步要按常规方法进行与NH3、一种C1-C6烷基胺或二-C1-C6烷基胺的反应。W代表卤素原子时,最好是代表氯、溴或碘;R′或R″代表一个烷基、卤代烷基或烷氧基时,这些基团最好是低“分子量”的基团,其含碳数以1~4为宜。通常,尤其是当W代表一个卤原子或基团-OCOR″时,宜有一种酸结合剂存在,如碱金属氢氧化物、碱金属碳酸盐、碱金属碳酸氢盐、碱金属乙酸盐、碱金属碳酸盐、叔胺类(三烷基胺类如三乙胺、吡啶),还有碱金属氢化物以及类似化合物。这里的酸结合剂既可以单独使用,也可以与其它作为溶剂的常规物质(例如吡啶)一同使用。
使用式为R-OH的游离酸时,需有缩合剂存在以将其活化;缩合剂例如有:二环己基碳二亚胺、四乙基焦亚磷酸酯、5-(3′-磺基苯基)乙基异噁唑[5-(3′-sulfonophenyl)ethylisooxazole]、亚硫酰双烷基酰胺(例如SO[N(CH3)2]3)、N,N′-羰基二咪唑等(Organic Reactions,Vol.12,1962,pages 205 and 239)。
R8代表一个C1-C6烷基时,通过烷基化方法可将此基团引入R8代表氢的式Ⅰ化合物中。与此相似,对于Z为基团NH或-NH-C(R5)-的式Ⅰ化合物,可通过烷基化方法用一个C1-C6烷基将此碱性氮原子上的氢取而代之。
上述烷基化过程可以例如通过与式为C1-C6-烷基-hal、Ar SO2O-C1-C6烷基以及SO2(O-C1-C6-烷基)2的化合物的反应来进行,其中hal可以是一个卤原子(尤其是氯、溴或碘),而Ar为一个芳基(例如可以被一个或多个低级烷基所取代的苯基或萘基)。这些化合物的例子有:对甲苯磺酸C1-C6烷基酯、硫酸二-C1-C6烷基酯、C1-C6-烷基卤等等。该烷基化反应最好在有常规的酸结合剂存在下进行。此外,可以使用的酸结合剂例如可以是酰化时所用的同样的酸结合剂。
酰化或烷基化例如可以在-60和200℃之间,最好是在-20和150℃之间,尤其是在+20和100℃之间的温度下,在惰性溶剂或混剂中进行。可采用的溶剂或分散剂包括,例如:芳烃,例如苯、甲苯、二甲苯;脂肪酮,例如丙酮、甲乙酮;卤代烃,例如氯仿、四氯化碳、氯苯、二氯甲烷;脂肪醚,例如丁基醚;环醚,例如四氢呋喃、二氧杂环己烷;砜类,例如二甲亚砜;叔酰胺(tertiary acid amides),例如二甲基甲酰胺、N-甲基吡咯烷酮、六甲基磷酰胺;脂肪醇,例如甲醇、乙醇、异丙醇、戊醇、叔丁醇;脂环烃,例如环己烷等。也可以使用含水的上述溶剂的混合物。反应常在所用溶剂或分散剂的沸腾温度下进行。烷基化反应剂的用量常是过量的。烷基化反应亦可在一种质子惰性溶剂中,或也可以在氯仿或二氯甲烷中,在有四烷基铵盐(尤其是卤化物)及碱金属氢氧化物存在下进行,反应温度在0和100℃之间,最好是在20和80℃之间。可采用的质子惰性溶剂尤其是包括:叔酰胺类(二甲基甲酰胺、N-甲基吡咯烷酮、六甲基磷酰胺)、二甲亚砜、乙腈、二甲氧基乙烷、丙酮、四氢呋喃。在进行酰化和烷基化操作时,还可以先把待进行酰化反应的化合物制成一种碱金属化合物,方法是使该化合物与一种碱金属、碱金属氢化物或氨基碱金属(尤其是金属钠或钠化合物)或丁基锂反应,反应在惰性溶剂,如二氧杂环己烷、二甲基甲酰胺、苯或甲苯中进行,反应温度在0和150℃之间,然后,例如,加入酰化或烷基化剂(化合物R-W,W=卤素)。
还可以用化学上常用的其它等效试剂来代替上面列出的烷基化和酰化试剂(可以参考:L.F.and Mary Fieser“Reagents for Organic Synthesis”,John Wiley and Sons,Inc.,New York,1967,Vol.1,pages 1303-4 and Vol.2,page 471)。
另一方面,可以将式Ⅰ化合物的酰基溶剂解离,得到相应的R8代表氢的式Ⅰ化合物。这种溶剂解离是在10和150℃之间,尤其是在20和100℃之间的温度下,使用稀酸或碱性物质(钾碱、苏打、碱水溶液、NH3)皂化进行的。
所以,把基团R7转变成其定义中的其它可能基团可以通过下述反应进行:
a)皂化
皂化是将R7为一个C1-C6烷氧羰基、氨基羰基或烷氨基或二烷氨基羰基(这些情况下烷基都具有1~6个碳原子)的式Ⅰ化合物转变成R7为羧基的式Ⅰ化合物。皂化例如可用水、烯碱水溶液、碱的醇溶液,或也可以用无机酸如盐酸或硫酸的醇或醇水溶液,在20和200℃,最好是在20~100℃之间的温度下进行,或也可采用Na Cl/二甲亚砜来进行。也可以使用其它惰性溶剂,如二氧杂环己烷、四氢呋喃、二甲基甲酰胺、二甲基乙酰胺等。
b)酯化
酯化的方法例如有:使式Ⅰ化合物(R7=CO2H)的羧酸盐,尤其是碱金属盐或银盐,与C1-C6烷基卤(烷基氯、烷基溴、烷基碘)反应;或在有下述酸性物质存在下使游离酸与C1-C6重氮烷或C1-C6脂肪醇反应:盐酸或硫酸、氯磺酸、芳族磺酸(对甲苯磺酸)或者络合物形成物质(如三氟化硼或氯化锌);或者使相应的式Ⅰ的酰卤(R7=COHal;Hal=Cl、Br、I)或式Ⅰ的酸酐(R7=C2-C6链烷酰氧羰基)与C1-C6醇类反应,此反应最好是在下述碱性物质存在下进行:吡啶、三乙胺,碱金属或碱土金属的氢氧化物、醇化物、碳酸盐或乙酸盐。这个酯化过程可以用或不用溶剂,在20~250℃,尤其是在60~100℃的温度下进行。可考虑采用的溶剂例如有:芳烃(如苯、甲苯)、低级脂肪醇、二甲基甲酰胺、环醚类、二甲亚砜、N-甲基吡咯烷酮、环丁砜、氯仿、四甲基脲。
上述的酰卤(R7=COHal)例如可以通过与卤化剂的反应来制得,所用的卤化剂包括:三卤化磷和五卤化磷(其中的卤素为氯、溴、碘)、亚硫酰卤(其中卤素为氯、溴、碘)、磷酰囟(其中卤素为氯、溴)、硫酰卤(硫酰氯、硫酰溴、硫酰碘)或光气。该反应可以用或不用溶剂,在20~150℃,最好在30~100℃的温度下进行。可考虑采用的溶剂是惰性试剂,如二氧杂环己烷、四氢呋喃、芳烃(苯、甲苯)、卤代烃(氯仿、二氯甲烷)。通常,宜使用相应酸(R7=CO2H)的碱金属盐(钠盐、钾盐,也可以是银盐)进行上述反应。
c)酰胺的制法是,使R7为羧基或C1-C6烷氧羰基的式Ⅰ化合物(可以通过合适的酰囟或酸酐形式)与氨、C1-C6烷基胺、二-C1-C6烷基胺反应;或按照肽化学中常用的方法,使其与相应的氨基酸或二肽,或与相应的保护氨基酸或二肽反应。反应例如可以在一种常规的溶剂或悬浮物质中进行,可以考虑使用的溶剂和前面所述的相同。还可以用水作为溶剂。使用R7代表基团-COHal的式Ⅰ化合物作原料时,反应还可以在酸结合物质存在下进行,或者也可以在过量的氨或胺存在下进行;所用的酸结合物质例如有:碱金属氢氧化物、碱金属碳酸盐、碱金属碳酸氢盐、碱金属乙酸盐、碱金属碳酸盐、三烷基胺、吡啶等等。在这种情况下,酸结合剂既可以单独使用,也可以与作为溶剂的其它常用试剂(例如吡啶)混用。以R7为羧基的式Ⅰ化合物作为原料时,需要在缩合剂存在下将其活化;所用的缩合剂有:二环己基碳化二亚胺、亚硫酸双链烷酰胺(例如SO[N(CH3)2]2)、N,N′-羰基二咪唑等等(Organic Reactions Vol.,12,1962,pages 205 and 239)。
通过酸酐制备上述酰胺时,所用酸酐是由R7为羧基的式Ⅰ化合物的盐(碱金属盐、银盐)与相应的C2-C6链烷酰卤(这里卤素为氯、溴、碘)反应,或是由R7为-COCl、-COBr或COI的式Ⅰ化合物与相应的C2-C6链烷羧酸的碱金属盐或银盐反应而制得。这些反应例如是在溶剂悬浮剂中,在20~250℃的温度下进行。
式Ⅲ的原料化合物的R7为一羧基时,该化合物亦可以相应的普通盐形式使用。以后在需要时,可以把反应产物中的阳离子换为生理上可接受的阳离子。
X与R4一起表示一个单键,且R为一羟基的原料化合物Ⅱ(例如4-羟基环磷酰胺),可以由Y为氢的相应化合物(例如环磷酰胺)经常规的臭氧化处理(例如,在水、含水四氢呋喃或含水醇中进行臭氧化处理)而制得,然后可以直接进一步与化合物Ⅲ反应。臭氧化处理适宜于在无过氧化氢存在的条件下进行。
本过程产物的分离最好用色谱过程来实现,特别是用硅胶或葡聚糖凝胶(Sephadex)色谱法(见实施例1,c))。
本过程产物可通过与具有游离巯基(SH)的硫醇,如半胱氨酸、半胱胺、2-巯基乙醇相结合使之稳定化。这种稳定,可通过如将式(Ⅰ)的化合物溶于硫醇化合物的水溶液中,然后将混合物冷冻干燥来实现。此过程每1摩尔式(Ⅰ)化合物可用0.02-0.05摩尔硫醇化合物。
通式(Ⅱ)的起始原料,其中X和Y各自表示烷氧基或亚烷二氧基环,部分已见于如日本专利申请71/25140(公开号4738928),或可用类似于该专利所述的方法制得,或可按下法制备:将三氯氧磷与具下式结构:
HOC(R5)2-C(R5)2-CR5XY(X,Y=C1-C6烷氧基或O-(CH2)n-O,n=1-5)的相应缩醛在惰性溶剂中,在有叔胺存在下于低温(如-20到+10℃)下进行反应,所得产物可在叔胺存在下于-20至15℃间经一步或两步过程与胺类HNR1R2、HNR3R4或NH3进行下一步反应。按此类推,通式(Ⅱ)的起始原料,式中X和Y各自表示烷硫基或一起构成亚烷二硫基环,可通过将三氯氧磷与通式如HO(CR5)2-C(R5)2CR5XY(X,Y=C1-C6烷硫基或S-(CH2)n-S,n=1-5)的相应硫缩醛反应,接着用一至两步与胺类HNR1R2、HNR3R4或NH3反应制得。
通式Ⅱ的起始原料,其中X和Y一起表示氧原子,例如可从相应羟基化合物(X=OH,Y=H)用已知的氧化法制得[如,类似于笛·斯维,《有机化学》(D.Swern,J.Org.Chem.),43,1978,2480页;安·默勒等,《四面体通讯》(A.Myles et al,Tetrahedron Letters),1977,2475页;笛·斯维,《合成》(D.Swern,Synthesis),1981,-165页;吉·皮卡特勒等,《合成》(G.Piancatelli et al,Synthesis),1982,245页中的方法]。
此外,此类起始原料亦可从相应硫缩醛(X和Y=烷硫基或S-(CH2)n-S)用已知的方法经硫醚裂解制得[见如,类似于依·杰·柯里,《有机化学》(E.J.Corey,J.Org.Chem.),36,3553(1971)中的方法],或从相应的肟(X和Y=
N-OH)用已知的方法经肟裂解制得[见如类似于杰·赫·波依耳,《化学评论》(J.H.Boyer,Chem.Rev.),80,541(1980);皮·杰·马丁里等,《有机化学》(P.J.Mattingly el al,J.Org.Chem.),45,410(1980)以及《合成》(Synthesis),1976,808.中的方法]。
通式(Ⅱ)的新起始化合物可按常规方法制备。例如,具通式(Ⅱ)羧酸的酯化是通过羧酸与相应醇在盐酸介质中反应制得。N-乙酰基化合物是通过乙酰氯或乙酸酐与氨基化合物作用制得。例如以N-乙酰半胱胺酸为例,是用乙酰氯将半胱胺酸转化为N,N′-二乙酰基半胱胺酸,反应混合物然后在50至60℃下用锌(Zn)还原制得。N-烷基化合物例如通过相应噻唑烷化合物的还原来制备。由此,N-甲基半胱胺酸可通过噻唑烷-4-羧酸在液氨中与金属钠作用,反应产物用酸水解制得。
具通式(Ⅰ)的本过程产物是指所有可能的立体异构体及其混合物。它们分别为在磷原子上或在杂环系的碳原子上有不同构型的化合物。
用已知方法例如分级结晶或制备和分析高压液相色谱法可将非对映异构混合物拆分。按照常规的外消旋体拆分方法,例如对非对映异构的盐类进行分级结晶,可以得到各个单纯的对映体。
可考虑用例如有光学活性的碱如1-苯基乙胺、二甲氧基马钱子碱、奎尼定、盐酸马钱子碱和辛可宁拆分外消旋物,也可用其它碱或方法拆分外消旋物。所说的其它碱和方法见于美国利伸达光学拆分情报中心(The Optical Resolution Information Center in Rioerdale,U.S.A)出版的保尔·牛曼所著“化合物的光学析分法”第二卷(1981)[“Optical Resolution Procedures for Chemical Compouuds”,vol2,Paul Newman,1981]。为此,例如用已述方法将本发明的一外消旋盐转变为含上述光学活性碱的盐,并用已知方法拆分成各对映异构体。
实施例1
2-{2-[N,N-双(2-氯乙基)二酰氨基磷酰氧基]乙基}噻唑烷-4-羧酸
a)由通式(Ⅱ)化合物制备(其中X与R4一起表示一单键,Y表示羟基):
将5.0克(18毫摩尔)4-羟基环磷酰胺及2.4克(20毫摩尔)L-半胱胺酸溶于12毫升蒸馏水中与20毫克1N氢氧化钠溶液混合。反应混合物在氮气下搅拌3小时,高真空低温下浓缩,残留物用甲醇/二氯甲烷(3∶2)处理,减压抽滤除去不溶物,溶液在硅胶上用甲醇/二氯甲烷(3∶2)洗脱数次。
将Rf=0.38(游离羧酸)的纯部分减压浓缩,残留物用干燥乙醚处理两次,经高真空干燥得一玻璃状粉末,收率:4.0克(58%理论收率)。
钠盐可按下法制备,例如:
将1克羧酸,即2-{2-[N,N-双(2-氯乙基)二酰氨基磷酰氧基]乙基}噻唑烷-4-羧酸,下面有时称作D18038,用少量水溶解,与等摩尔量碳酸氢钠相混,冷冻干燥成粉末,收率:1.1克(100%理论值)。
除非另有陈述,Rf值是在室温下饱和槽内进行测定的。固定相:纤维素包裹铝箔;纤维素含萤光指示剂。
物质用量:约5微升10毫克/毫升甲醇溶液
洗脱剂:水-乙腈(1∶2)
溶剂展开距:10厘米
用下述特殊着色剂进行鉴别:
4-(4-硝基-苄基)吡啶(烷基化基团试剂)和茚三酮显色试验。
b)由通式(Ⅱ)化合物制备[其中X与R4一起表示一单键,Y为C2烷氧基(乙氧基)]:
于4.6克(15毫摩尔)4-乙氧基环磷酰胺的10毫升乙醇溶液中加入1.9克(16.5毫摩尔)L-半胱胺酸的24毫升蒸馏水溶液及16毫升1N氢氧化钠。三小时后按上述方法处理。
收率:2.8克(48%理论值)
Rf=0.38(游离酸)
c)从通式(Ⅱ)化合物制备,其中X和Y均为乙氧基:
将1.05克(3毫摩尔)O-(3,3-二乙氧基丙基)[N,N-双(2-氯乙基)]磷二酰胺悬浮于544毫克(4.5毫摩尔)L-半胱胺酸的约20毫升0.01NHCl溶液中,加热至60℃直至形成-澄清溶液(约75分钟)。用NaOH调节pH值至7。反应液用葡聚糖凝胶(Sephadex)G-10柱凝胶过滤分离,用0.07M磷酸盐缓冲液洗脱[葡聚糖凝胶(Sephadex)是一种用于在极性介质水溶液中进行凝胶过滤的改性葡聚糖]。
收集含反应产物的部分,并通过葡聚糖凝胶G-10柱以水洗脱使其从盐中游离出来,得到色谱纯的反应产物D18038的水溶液:若在-20℃下冷冻,该产物可保存数天。
溶液中烷类的浓度可用NBP试验进行测定[NBP=4-(4-硝基苄基)吡啶,均值为5毫克/毫升,相当于每批含反应产物D18038总量为约400毫克(收率为35%理论值)。
以下是另一种制备方式,通过添加半胱胺酸使之稳定化:
将3毫摩尔(1050毫克)O-(3,3-二乙氧基丙基)[N,N-双(2-氯乙基)]磷二酰胺[即磷酰胺二乙基缩醛(aldophosphamide diethyl acetal)]与4.5毫摩尔(544毫克)L-半胱胺酸一起溶于25毫升0.01N甲酸中,57℃下反应55分钟后,用25毫升氯仿振摇三次。氯仿用水泵除尽(15分钟),水溶液冷冻,并冷冻干燥过夜,约得1克冷冻干燥品,用60毫升无过氧化物的四氢呋喃(使用前通过氧化铝柱滤清)在4℃(冷室)下提取(振摇1分钟,然后超声浴1分钟)。
离心分离[索尔氏尔RC5C离心机(Sorvall RC5 Cceutrifuge),40,000克,15分钟,4℃]并将四氢呋喃上清液浓缩至干,残留物溶于含0.32毫克/毫升半胱胺酸的水溶液中,L-半胱胺酸溶液的用量要使化合物(Ⅰ)的浓度达20毫克/毫升,将其冷冻干燥。所得产物含5摩尔%L-半胱胺酸。得约200毫克D18 038(收率约18%,按所用磷酰胺二乙基缩醛计算)。
按照a)-c)法所得反应产物为非对映异构体混合物沉淀物。
在方法实例c)用作起始原料的O-(3,3-二乙氧基丙基)[N,N-双(2-氯乙基)]磷二酰胺可按下述过程制得,例如:
于3.6克(23毫摩尔)三氯氧磷的25毫升干燥二氯甲烷的溶液中在0至5℃2小时内搅拌并滴入3.4克(23毫摩尔)3-羟基丙醛缩二乙醇的10毫升二氯甲烷及3.3毫升三乙胺的溶液。0℃下继续搅拌1小时,然后加入4.2克双(2-氯乙基)胺盐酸盐,并于5-10℃下滴加7毫升三乙胺的10毫升二氯甲烷溶液。反应混合物于5℃下搅拌1小时,于4℃放置。次日于搅拌下滴加2.8克该液氮的5毫升二氯甲烷溶液,升温至20℃,继续搅拌3小时,产物用水洗,有机相用硫酸钠干燥,浓缩。残留物用硅胶色谱法纯化[用氯仿/甲醇(10∶1)洗脱]。产量为3.9克;Rf值:0.6;(洗脱液:苯/氯仿/甲醇=2∶1∶1,槽内饱和,展开距为15厘米,碘蒸气显色,在室温下展开)。
赖氨酸盐的制备:
加入足量赖氨酸以便形成盐,其量为D18 038浓缩物的等摩尔量,溶液在冷冻干燥器内冷冻干燥。无色冷冻干燥物吸湿性强,但与D18038游离物不同,它可在+4℃下除湿贮藏几星期不变。赖氨酸盐仍含有少量溶剂(水)并为一非对映体混合物。
赖氨酸盐的薄层色谱(当盐进行薄层色谱分析时,该盐分离为L-赖氨酸及D18038,因此按此法所得的为这两个成份的Rf(值):纤维素-包裹的铝箔(薄层厚度:0.1毫米);
洗脱剂水/乙腈 1∶2;
D18038:Rf=0.68;L-赖氨酸:Rf=0.08。
稳定性:
赖氨酸盐在-20℃下即使放置数星期在色谱板上也未发现有什么变化。
注射溶液的制备:
2-{2-[N,N-双(2-氯乙基)二酰氨基磷酰氧基]乙基}噻唑烷-4-羧酸的溶液在使用前,通过在37℃下将4-羟基环磷酰胺用10%过量的L-半胱胺酸的0.07M、pH7的磷酸缓冲液中保温45分钟来制备。
实施例2
2-{2-[N,N-双(2-氯乙基)-二酰氨基磷酰基氧]乙基}-噻唑烷-4-羧酸乙酯
a)从通式(Ⅱ)化合物制备(其中X与R4一起表示一个单键,Y表示羟基):
5.0克(18毫摩尔)4-羟基环磷酰胺和3.4克(18毫摩尔)乙基L-半胱胺酸盐酸盐在氮气下于18毫升水及18毫升1N氢氧化钠溶液中搅拌4小时,反应液用二氯甲烷振摇,有机层用少量0.1N硫酸洗涤并用水洗三次,用硫酸钠干燥,浓缩。残留物用干燥乙醚处理,高真空浓缩得一薄层色谱分析均匀的油。
Rf值=0.83(条件与实施例1同)
收率:4.8克(65%理论值)
b)从X和Y均为乙氧基的化合物制备:
10毫克O-(3,3-二乙氧基丙基)[N,N-双{2-氯乙基)]磷二酰胺及8毫克半胱胺酸乙酯盐酸盐在1毫升0.01NHCl中加热至56℃,60分钟后缩醛完全消失,在薄层色谱板上出现一个新峰(Rf值:0.83),反应液的处理法与a)法相同。
按a)或b)法所得反应产物均为非对映异构体混合物。
实施例3
3-N-乙酰基-2-{2-[N,N-双(2-氯乙基)二酰氨基磷酰氧基]乙基}噻唑烷-4-羧酸
将10毫克O-(3,3-二乙氧基丙基)[N,N-双{2-氯乙基)]磷二酰胺和7.5毫克L-N-乙酰基胱胺酸在56℃下于0.01NHCl中加热。产物用二氯甲烷提取,二氯甲烷层用硫酸钠干燥,除去二氯甲烷后,残留物用甲醇处理,用葡聚糖凝胶LH20柱进行色谱分离,甲醇为洗脱剂。(葡聚糖凝胶LH是一种与具有羟丙基基团的表氯醇三维交联的葡聚糖,用于有机溶剂中的凝胶过滤)。
实施例4
2-{2-[N,N-双(2-氯乙基)二酰氨基磷酰氧基]乙基}噻唑烷-4-羧酸甲酯
1克(~3毫摩尔)O-(3,3-二乙氧基丙基)[N,N-双{2-氯乙基)]磷二酰胺和770毫克(~4.5毫摩尔)L-半胱胺酸甲酯盐酸盐于20毫升0.01N盐酸盐中与56℃下加热75分钟。反应产物用氢氧化钠中和。用二氯甲烷提取(3×50毫升),合并有机层,用硫酸钠干燥,有机相浓缩所得黄色油状物用水/甲醇(1∶1)溶解,用葡聚糖凝胶G-10柱及0.07M、pH7的磷酸缓冲液进行分离。
含有反应产物的洗脱液用二氯甲烷提取(3×250毫升),浓缩二氯甲烷层。残剩物用甲醇溶解,在葡聚糖凝胶LH20上进行色谱法分离(用甲醇为洗脱剂)。含反应产物的部分浓缩,高真空干燥,得色谱纯黄色油状物,该油状物易溶于极性有机溶剂,不易溶于非极性溶剂和水。产物为一非对映异构体混合物。
Rf=0.7
收率:200毫克(17%理论值)
实施例5
2-{2-[N,N-双(2-氯乙基)二酰氨基磷酰氧基]乙基}-4-氧代噻唑烷
1克(~3毫摩尔)O-(3,3-二乙氧基丙基)[N,N-双{2-氯乙基)]磷二酰胺和730毫克(4.5毫摩尔)N-(2-巯基丙酰基)甘氨酸在20毫升0.01N盐酸中于56℃下加热60分钟。反应产物用二氯甲烷提取(3×50毫升),合并有机相,用硫酸钠干燥,有机相浓缩后的残余物用甲醇溶解,在葡聚糖凝胶LH20柱上进行色谱法分离,用甲醇洗脱。得一部分显示两个新形成的有高UV-活性的峰。洗脱液浓缩后的一黄色油,难溶于水和非极性溶剂,反应产物为一非对映异构体混合物。
Rf=0.75
收率:230毫克(19%理论值)
实施例6
3N-L-γ-谷氨酰基-2-{2-[N,N-双(2-氯乙基)-二酰氨基磷酰氧基]乙基}噻唑烷-4-羧酸-(羧甲基酰胺)
3毫摩尔(1.09克)O-(3,3-二乙氧基丙基)[N,N-双{2-氯乙基)]磷二酰胺与4.5毫摩尔(1.4克)L-谷胱甘肽、25毫升0.01N甲酸于56℃加热60分钟。随后,反应液用氯仿提取(3×25毫升),冷冻干燥,经硅胶柱分离,该硅胶含十八烷基基团(C18-反相柱),用此法,谷胱甘肽与水首先被分离出来。随后用甲醇洗脱,得谷胱甘肽-噻唑烷酮衍生物。
除去甲醇后反应产物从水/乙醇(1∶1)中沉淀析出。
产量:约200毫克;Rf:0.48。
实施例7
2-{1,1-二甲基-1-[N,N-双(2-氯乙基)二酰氨基磷酰氧基]乙基}噻唑烷-4-羧酸
将3克(8.5毫摩尔)O-[(3,3-二乙氧基-2,2-二甲基丙基-(1)][N,N-双(2-氯乙基)]磷二酰胺混悬于1.6克(13毫摩尔)L-半胱胺酸的50毫升0.01N甲酸溶液中。于80℃下保温30分钟,产物用50毫升氯仿提取三次,减压蒸除氯仿,产物冷冻干燥。得基本上只含噻唑烷反应产物及L-半胱胺酸的无色固体。为了分离反应产物,冷冻干燥物用无水四氢呋喃提取两次,每次30毫升。从四氢呋喃提取液得相对纯的反应产物1.35克(>95%),相当于38%理论值。最后用反相柱纯化产物(例如,用带十八烷基基团的硅胶),该柱可先用水冲洗,但不洗出待提的噻唑烷反应产物。然后用甲醇-水(至少含20%甲醇)或甲醇分出纯的产物。按此方法纯化的产物的分析数据如下:
元素分析:
C H N
计算值:35.29 5.88 10.29
实验值:34.99 5.74 10.01
高压液相色谱:
柱C18诺佛-帕克(Novo-Pak)
洗脱剂:甲醇/0.02N磷酸缓冲液,pH=7(36∶65)
约15分钟后出现第一个峰
薄层色谱:
纤维素-铝箔
洗脱剂:乙腈/水(2∶1)
Rf=0.89
实施例8
2-{2-[N,N-双(2-氯乙基)二酰氨基磷酰氧基]乙基}高噻唑烷-4-羧酸
将1.05克(3毫摩尔)O-[(3,3-二乙氧基丙基)[N,N-双(2-氯乙基)]磷二酰胺和4.5毫摩尔(0.61克)DL-高半胱胺酸在25毫升0.01N甲酸中于56℃加热60分钟。反应液然后进行冷冻干燥。冷冻干燥物用25毫升四氢呋喃分散。将所得悬浮液离心分离,真空浓缩。残留物用四氢呋喃溶解并与等摩尔浓盐酸混合。加乙醚后于-20℃结晶出反应产物(DL-型)为盐酸盐。熔点:136-138℃(分解)。
Rf值:0.83(纤维素固定相)
实施例9
2-{2-[N,N′-双(2-氯乙基)二酰氨基磷酰氧基]乙基}噻唑烷-4-羧酸
将4.2克(12毫摩尔)N,N′-双(2-氯乙基)磷二酰胺-3,3-二乙氧基丙酯与1.5倍摩尔数的L-半胱胺酸的100毫升0.01N甲酸溶液在60℃下保温1小时。
反应液用氯仿提取并在冷冻干燥器内浓缩。含等量噻唑烷化合物及L-半胱胺酸的无色粉末用无过氧化物的四氢呋喃提取(约100毫升四氢呋喃/1克噻唑烷化合物)。离心除去残留物,四氢呋喃溶液浓缩后得无色粉末状噻唑烷化合物。
纤维板薄层色谱:
洗脱剂:CH3CN/H2O(2∶1)
Rf=0.86
起始原料N,N′-双(2-氯乙基)磷二酰胺-3,3-二乙氧基丙酸乙酯可按下法制得:
将氯乙胺盐酸盐制成悬浮液。于0℃下将4当量(1摩尔磷酸-3,3-二乙氧基丙酯·盐酸盐)三乙胺滴加入二氯甲烷中,于约5℃及搅拌下放置16小时,用冰水振摇除去沉淀的盐酸盐,有机层用硫酸钠干燥,用活性炭提取。可通过短硅胶柱进一步纯化产品,洗脱剂:二氯甲烷。
实施例10
2-{2-[N,N′-双(2-氯乙基)二酰氨基磷酰氧基]乙基}-1,5-全氢噻嗪(高噻唑烷)-4-羧酸
4.2克(12毫摩尔)N,N′-双(2-氯乙基)磷二酰胺-1,3-二乙氧基丙酯与1.5倍摩尔数的DL-高半胱胺酸的100毫升0.01N甲酸溶液在60℃下保温1小时。反应混合液用氯仿提取,冷冻干燥浓缩。含有等量的全氢噻嗪基化合物和DL-高半胱胺酸的无色粉末用除去过氧化物的四氢呋喃提取(约100毫升四氢呋喃/1克反应产物)。
离心除去残渣并将四氢呋喃浓缩后得全氢噻嗪基化合物,为一无色粉末。
纤维素板薄层色谱:
洗脱剂:CH3CN/H2O(2∶1)
Rf=0.86
制剂实施例
实施例1化合物的冷冻干燥物
在通氮及避光下将100克实施例1化合物及160克甘露醇溶于4升注射用水中,溶液在无菌条件下用合适的膜式过滤器过滤,滤液在灭菌条件下充入50毫升注射瓶中,每份20毫升,注射瓶盖上冷冻干燥塞进行冷冻干燥。随后于冷冻干燥装置中通入氮气,在装置内将注射瓶封闭。冷冻干燥物的残余水含量不可超过0.5%。为了制备注射溶液,将瓶中内容物溶于20毫升注射用水中。注射液为等渗液,1毫升该溶液含25毫克活性物质。
含5摩尔%胱胺酸的实施1化合物的冷冻干燥物。
通氮及避光下将100克实施例1化合物、1.6克半胱胺酸和160克甘露醇溶于4升注射用水中,溶液在无菌条件下用合适的膜式过滤器过滤,滤液于无菌条件下充入50毫升灭菌注射瓶中,每份20毫升,注射瓶盖上冷冻干燥用塞子进行冷冻干燥。随后于冷冻干燥装置中通入氮气,注射瓶在装置内将封闭。冷冻干燥物的残余水含量不可超过0.5%。为制备注射溶液将瓶中内容物溶于20毫升注射用水中,注射液为等渗液,1毫升该溶液含25毫克活性物质。
Claims (3)
1、制备通式如下的化合物及其与生理上可接受的酸或阳离子所形成的盐的方法:
式中,基团R1、R2、R3和R4相同或不同并代表氢、C1-C4烷基、2-氯乙基、2-溴乙基或2-C1-C4烷磺酰氧乙基且这些基团中至少有两个代表2-氯乙基、2-溴乙基或2-C1-C4烷磺酰氧乙基,R8代表氢、C1-C6烷基、C1-C6烷氧羰基、C2-C6链烷酰基、天然氨基酸或天然二肽的残基,其中游离羧基可被C1-C6烷基酯化,或者式中R8代表氨基羰基或氮原子上带有一个或两个C1-C6烷基的氨基羰基,R6和R7代表氢或合在一起代表一个氧原子,或者式中R6代表氢时,R7代表一个羰基、C1-C6烷氧羰基、氨基羰基、C1-C6烷氨羰基、二-C1-C6烷氨羰基或一个羧酰胺基,其中酰胺部分是天然氨基酸残基或天然二肽残基或它们的C1-C6烷基酯,Z代表一个硫原子、氧原子、基团
NR5、基团-S-C(R5)2-、-O-C(R5)2-或-NR5C(R5)2-,其中各R5基团相同或不同并代表氢或C1-C6烷基,其特征在于,使通式Ⅱ的一种化合物与通式Ⅲ的一种化合物反应,
式Ⅱ中,R1、R2、R3、R4和R5的含义同上述,X和Y可以各代表一个C1-C6烷氧基或C1-C6烷硫基或X和Y一起代表一个氧原子、一个具有1-5个碳原子的饱和亚烷二氧基环、一个具有1-5个碳原子的饱和亚烷二硫基环,或者X与基团R4一起代表一个单键,由此形成一个六员环,此时Y代表一个羟基、一个C1-C6烷氧基或基团S-alk-SO3Z,其中alk代表一个C2-C6亚烷基桥,而Z代表氢或一个阳离子,或者Y代表可被一个羧基、羟基或C1-C6烷氧羰基所取代的C1-C10烷硫基、C1-C6链烷酰硫基或苄硫基,式Ⅲ中Z、R5、R6、R7和R8的含义同上,并且可以采用烷基化或酰基化方法,在R8代表氢而其它符号含义同上述的式Ⅰ化合物中引入含义同上述但氢除外的基团R8,也可以将R8脱除,还可以在Z代表基团
NH或-NH-C(R5)2-时,通过烷基化方法在Z中引入一个C1-C6烷基,还可以把R7不代表氢的式Ⅰ化合物中的R7基团转变成其它可能的基团,还可以把所得到的各个化合物转变为其与生理上可接受的阳离子或阴离子所形成的盐。
2、制备一种药物的方法,其特征在于,将通式Ⅰ的一种化合物与常规的药物载体和(或)稀释剂或其它辅助剂混在一起制成治疗上可接受的剂型,从而得到各种药物配方或一种治疗上可接受的配方。
3、通式Ⅰ的化合物在治药方面的用途。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE3605847 | 1986-02-22 | ||
DEP3605847.5 | 1986-02-22 | ||
DE3613639 | 1986-04-23 | ||
DEP3613639.5 | 1986-04-23 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN87100769A true CN87100769A (zh) | 1987-09-02 |
Family
ID=25841267
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN198787100769A Pending CN87100769A (zh) | 1986-02-22 | 1987-02-21 | 带有2-[2-[n,n-双(2-氯乙基)磷酰二氨基氧基]乙基]基团的新杂环化合物 |
Country Status (9)
Country | Link |
---|---|
US (1) | US4997822A (zh) |
EP (1) | EP0235661A3 (zh) |
CN (1) | CN87100769A (zh) |
AU (1) | AU6910787A (zh) |
DK (1) | DK86587A (zh) |
FI (1) | FI870721A (zh) |
HU (1) | HUT43862A (zh) |
NO (1) | NO870682L (zh) |
PT (1) | PT84327B (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5306727A (en) * | 1993-04-30 | 1994-04-26 | Research Corporation Technologies, Inc. | Phosphoramidates useful as antitumor agents |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE1645921C3 (de) * | 1966-07-11 | 1978-10-12 | Asta-Werke Ag Chemische Fabrik, 4800 Bielefeld | 2-Oxo-13,2-osazaphosphorinane, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Präparate |
US3732340A (en) * | 1966-07-11 | 1973-05-08 | Asta Werke Ag Chem Fab | N',o-propylene phosphoric acid ester diamides |
US3794730A (en) * | 1970-08-03 | 1974-02-26 | Exxon Research Engineering Co | Control of insects with certain phosphorus-containing thiomorpholinones |
DE3020897A1 (de) * | 1980-06-02 | 1981-12-17 | Basf Ag, 6700 Ludwigshafen | Phosphorsaeureester, ihre herstellung und ihre verwendung zur bekaempfung von schaedlingen |
-
1987
- 1987-02-16 EP EP87102177A patent/EP0235661A3/de not_active Withdrawn
- 1987-02-20 AU AU69107/87A patent/AU6910787A/en not_active Abandoned
- 1987-02-20 NO NO870682A patent/NO870682L/no unknown
- 1987-02-20 HU HU87673A patent/HUT43862A/hu unknown
- 1987-02-20 FI FI870721A patent/FI870721A/fi not_active IP Right Cessation
- 1987-02-20 US US07/016,915 patent/US4997822A/en not_active Expired - Fee Related
- 1987-02-20 PT PT84327A patent/PT84327B/pt not_active IP Right Cessation
- 1987-02-20 DK DK086587A patent/DK86587A/da not_active Application Discontinuation
- 1987-02-21 CN CN198787100769A patent/CN87100769A/zh active Pending
Also Published As
Publication number | Publication date |
---|---|
US4997822A (en) | 1991-03-05 |
AU6910787A (en) | 1987-08-27 |
DK86587D0 (da) | 1987-02-20 |
FI870721A (fi) | 1987-08-23 |
NO870682D0 (no) | 1987-02-20 |
HUT43862A (en) | 1987-12-28 |
PT84327A (de) | 1987-03-01 |
FI870721A0 (fi) | 1987-02-20 |
EP0235661A2 (de) | 1987-09-09 |
DK86587A (da) | 1987-08-23 |
NO870682L (no) | 1987-08-24 |
PT84327B (pt) | 1989-09-14 |
EP0235661A3 (de) | 1989-01-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10160787B2 (en) | Conformationally-preorganized, miniPEG-containing gamma-peptide nucleic acids | |
Barlos et al. | Efficient" one-pot" synthesis of N-tritylamino acids | |
EP2873677B1 (en) | Method of producing self-assembling peptide derivative | |
DE69632324T2 (de) | Pna-dna-chimäre und pna-synthone zu deren herstellung | |
CN1045089C (zh) | 2-(2-氨基-1,6-二氢-6-氧代-嘌呤-9-基)甲氧基-1,3-丙二醇衍生物 | |
US7910726B2 (en) | Amidite for synthesizing modified nucleic acid and method for synthesizing modified nucleic acid | |
CN1169145A (zh) | 新的法呢基转移酶抑制剂、其制法及其药物组合物 | |
HUE029538T2 (en) | Procedures for the preparation of amoxin building elements and amoxynins | |
US20140046022A1 (en) | Fluorene compound | |
WO2021002408A1 (ja) | ペプチド及びその製造方法 | |
JP5789254B2 (ja) | リシン化合物並びにペプチド及びタンパク質の部位選択的及び官能基選択的修飾におけるそれらの使用 | |
JPH02221294A (ja) | ペプチド合成法 | |
WO2019231760A1 (en) | Method for solution-phase peptide synthesis and protecting strategies therefore | |
CN1283178A (zh) | β-卤代-α-氨基-羧酸和苯基半胱氨酸衍生物及其中间体的制备方法 | |
US20160340359A1 (en) | A process for preparation of (2s,5r)-6-sulphooxy-7-oxo-2-[((3r)-piperidine-3-carbonyl)-hydrazinocarbonyl]-1,6-diaza-bicyclo[3.2.1] octane | |
CN1347419A (zh) | 吡咯烷羰基氨基环状二硫化物 | |
CN87100769A (zh) | 带有2-[2-[n,n-双(2-氯乙基)磷酰二氨基氧基]乙基]基团的新杂环化合物 | |
CN106565771B (zh) | 一种含有双氨基的磷酰胆碱化合物Lys-PC及其制备方法 | |
EP0665229B1 (en) | Process for the production of nucleic acid base derivatives | |
JPH01226868A (ja) | スルホニウム化合物及びアシル化剤 | |
WO2007020620A1 (en) | Novel coupling agent and uses thereof | |
JP7444363B2 (ja) | 2-(2-オキソ-4-置換ピペラジニル)シクロアルキルカルバメート化合物又はその塩、当該化合物を用いる鏡像異性体の分析方法 | |
US20240287131A1 (en) | Peptide | |
CN109705007B (zh) | 一种用于二泛素合成的新型辅基连接臂及其合成方法和应用 | |
SU715572A1 (ru) | Способ выделени -изолейцина из смеси солей аминокислот |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
WD01 | Invention patent application deemed withdrawn after publication |