CN109305990A - 一种磷酸衍生物及制备方法和用途 - Google Patents
一种磷酸衍生物及制备方法和用途 Download PDFInfo
- Publication number
- CN109305990A CN109305990A CN201810740849.0A CN201810740849A CN109305990A CN 109305990 A CN109305990 A CN 109305990A CN 201810740849 A CN201810740849 A CN 201810740849A CN 109305990 A CN109305990 A CN 109305990A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- compound
- amino
- methyl
- ethyl
- 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.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims description 37
- 150000003013 phosphoric acid derivatives Chemical class 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 73
- 239000003814 drug Substances 0.000 claims abstract description 34
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 57
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 31
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 28
- 229940079593 drug Drugs 0.000 claims description 26
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- 229910052794 bromium Inorganic materials 0.000 claims description 17
- 229910052801 chlorine Inorganic materials 0.000 claims description 17
- 229910052731 fluorine Inorganic materials 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 229910052740 iodine Inorganic materials 0.000 claims description 16
- 125000001424 substituent group Chemical group 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 11
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 11
- 201000010099 disease Diseases 0.000 claims description 10
- 229940011871 estrogen Drugs 0.000 claims description 8
- 239000000262 estrogen Substances 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 206010002091 Anaesthesia Diseases 0.000 claims description 5
- 230000037005 anaesthesia Effects 0.000 claims description 5
- 210000003169 central nervous system Anatomy 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 230000036592 analgesia Effects 0.000 claims description 3
- 210000004556 brain Anatomy 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 231100000572 poisoning Toxicity 0.000 claims description 3
- 230000000607 poisoning effect Effects 0.000 claims description 3
- 208000002874 Acne Vulgaris Diseases 0.000 claims description 2
- 208000007848 Alcoholism Diseases 0.000 claims description 2
- 206010006187 Breast cancer Diseases 0.000 claims description 2
- 208000026310 Breast neoplasm Diseases 0.000 claims description 2
- 206010052804 Drug tolerance Diseases 0.000 claims description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 2
- 208000019695 Migraine disease Diseases 0.000 claims description 2
- 201000003793 Myelodysplastic syndrome Diseases 0.000 claims description 2
- 206010028980 Neoplasm Diseases 0.000 claims description 2
- 206010030247 Oestrogen deficiency Diseases 0.000 claims description 2
- 239000008896 Opium Substances 0.000 claims description 2
- 208000001132 Osteoporosis Diseases 0.000 claims description 2
- 206010060862 Prostate cancer Diseases 0.000 claims description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
- 206010000496 acne Diseases 0.000 claims description 2
- 201000007930 alcohol dependence Diseases 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 claims description 2
- 238000003745 diagnosis Methods 0.000 claims description 2
- 230000026781 habituation Effects 0.000 claims description 2
- 230000000147 hypnotic effect Effects 0.000 claims description 2
- 230000036512 infertility Effects 0.000 claims description 2
- 206010027599 migraine Diseases 0.000 claims description 2
- 229940124636 opioid drug Drugs 0.000 claims description 2
- 229960001027 opium Drugs 0.000 claims description 2
- 208000011580 syndromic disease Diseases 0.000 claims description 2
- 230000017260 vegetative to reproductive phase transition of meristem Effects 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 183
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 120
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 120
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 114
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 63
- 238000006243 chemical reaction Methods 0.000 description 54
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 54
- 238000003756 stirring Methods 0.000 description 51
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 49
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 46
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical class [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 45
- -1 chlorins compound Chemical class 0.000 description 43
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 30
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 28
- 238000001819 mass spectrum Methods 0.000 description 27
- 239000007791 liquid phase Substances 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- 239000000243 solution Substances 0.000 description 24
- 229910052757 nitrogen Inorganic materials 0.000 description 23
- 239000012044 organic layer Substances 0.000 description 23
- 238000005160 1H NMR spectroscopy Methods 0.000 description 22
- 238000010898 silica gel chromatography Methods 0.000 description 22
- 238000013517 stratification Methods 0.000 description 22
- 239000011259 mixed solution Substances 0.000 description 20
- YAQKNCSWDMGPOY-JEDNCBNOSA-N propan-2-yl (2s)-2-aminopropanoate;hydrochloride Chemical compound Cl.CC(C)OC(=O)[C@H](C)N YAQKNCSWDMGPOY-JEDNCBNOSA-N 0.000 description 19
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
- 238000012360 testing method Methods 0.000 description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 18
- 230000000694 effects Effects 0.000 description 16
- 229940125904 compound 1 Drugs 0.000 description 15
- 238000002347 injection Methods 0.000 description 15
- 239000007924 injection Substances 0.000 description 15
- 239000012071 phase Substances 0.000 description 15
- 238000004808 supercritical fluid chromatography Methods 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 13
- 239000000460 chlorine Substances 0.000 description 13
- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 description 13
- 229960004134 propofol Drugs 0.000 description 13
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 12
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 12
- 241000700159 Rattus Species 0.000 description 12
- 239000007787 solid Substances 0.000 description 11
- 239000000126 substance Substances 0.000 description 11
- 210000002381 plasma Anatomy 0.000 description 10
- 239000002253 acid Substances 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- 235000019198 oils Nutrition 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 229960005537 combretastatin A-4 Drugs 0.000 description 8
- HVXBOLULGPECHP-UHFFFAOYSA-N combretastatin A4 Natural products C1=C(O)C(OC)=CC=C1C=CC1=CC(OC)=C(OC)C(OC)=C1 HVXBOLULGPECHP-UHFFFAOYSA-N 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 229910052698 phosphorus Inorganic materials 0.000 description 8
- 239000011574 phosphorus Substances 0.000 description 8
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- RGPDIGOSVORSAK-STHHAXOLSA-N naloxone hydrochloride Chemical group Cl.O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C RGPDIGOSVORSAK-STHHAXOLSA-N 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 229910052708 sodium Inorganic materials 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- 241000282472 Canis lupus familiaris Species 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 6
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 6
- 229910052760 oxygen Inorganic materials 0.000 description 6
- 239000001301 oxygen Substances 0.000 description 6
- UVWBGHMUMMARAV-WNQIDUERSA-N C(=O)(OCC)Cl.N[C@@H](C)C(=O)O Chemical compound C(=O)(OCC)Cl.N[C@@H](C)C(=O)O UVWBGHMUMMARAV-WNQIDUERSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
- 238000010171 animal model Methods 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 229960001866 silicon dioxide Drugs 0.000 description 5
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 4
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- LTXREWYXXSTFRX-QGZVFWFLSA-N Linagliptin Chemical compound N=1C=2N(C)C(=O)N(CC=3N=C4C=CC=CC4=C(C)N=3)C(=O)C=2N(CC#CC)C=1N1CCC[C@@H](N)C1 LTXREWYXXSTFRX-QGZVFWFLSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
- 239000005864 Sulphur Substances 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 description 4
- NEHMKBQYUWJMIP-UHFFFAOYSA-N anhydrous methyl chloride Natural products ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 4
- JSFHKWZXTOIBLY-UWVGGRQHSA-N bis[[(2S)-1-oxo-1-propan-2-yloxypropan-2-yl]amino]phosphinic acid Chemical class CC(C)OC(=O)[C@H](C)NP(O)(=O)N[C@@H](C)C(=O)OC(C)C JSFHKWZXTOIBLY-UWVGGRQHSA-N 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 238000006482 condensation reaction Methods 0.000 description 4
- 229960005309 estradiol Drugs 0.000 description 4
- 229930182833 estradiol Natural products 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000004519 grease Substances 0.000 description 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 230000004060 metabolic process Effects 0.000 description 4
- 229960004127 naloxone Drugs 0.000 description 4
- YNPNZTXNASCQKK-UHFFFAOYSA-N phenanthrene Chemical compound C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 4
- 150000003217 pyrazoles Chemical class 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 229960004034 sitagliptin Drugs 0.000 description 4
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 description 4
- 238000010189 synthetic method Methods 0.000 description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 4
- 229960001254 vildagliptin Drugs 0.000 description 4
- SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 description 4
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 3
- 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 3
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 3
- 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 3
- 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 3
- OMAFFHIGWTVZOH-UHFFFAOYSA-O 1-methyl-2h-tetrazol-1-ium Chemical compound C[N+]1=CN=NN1 OMAFFHIGWTVZOH-UHFFFAOYSA-O 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 229940126657 Compound 17 Drugs 0.000 description 3
- 102000004243 Tubulin Human genes 0.000 description 3
- 108090000704 Tubulin Proteins 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000003146 anticoagulant agent Substances 0.000 description 3
- 229940127219 anticoagulant drug Drugs 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- JPOXNPPZZKNXOV-UHFFFAOYSA-N bromochloromethane Chemical compound ClCBr JPOXNPPZZKNXOV-UHFFFAOYSA-N 0.000 description 3
- 229940125797 compound 12 Drugs 0.000 description 3
- 229940126543 compound 14 Drugs 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 229940090124 dipeptidyl peptidase 4 (dpp-4) inhibitors for blood glucose lowering Drugs 0.000 description 3
- 150000002168 ethanoic acid esters Chemical class 0.000 description 3
- 238000010579 first pass effect Methods 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 150000002460 imidazoles Chemical class 0.000 description 3
- 229960002397 linagliptin Drugs 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- MKMPWKUAHLTIBJ-ISTRZQFTSA-N omarigliptin Chemical compound C1([C@H]2OC[C@@H](C[C@@H]2N)N2CC3=CN(N=C3C2)S(=O)(=O)C)=CC(F)=CC=C1F MKMPWKUAHLTIBJ-ISTRZQFTSA-N 0.000 description 3
- 229950000074 omarigliptin Drugs 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- 229960004937 saxagliptin Drugs 0.000 description 3
- QGJUIPDUBHWZPV-SGTAVMJGSA-N saxagliptin Chemical compound C1C(C2)CC(C3)CC2(O)CC13[C@H](N)C(=O)N1[C@H](C#N)C[C@@H]2C[C@@H]21 QGJUIPDUBHWZPV-SGTAVMJGSA-N 0.000 description 3
- 108010033693 saxagliptin Proteins 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 2
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 2
- JVKUCNQGESRUCL-UHFFFAOYSA-N 2-Hydroxyethyl 12-hydroxyoctadecanoate Chemical compound CCCCCCC(O)CCCCCCCCCCC(=O)OCCO JVKUCNQGESRUCL-UHFFFAOYSA-N 0.000 description 2
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 2
- PUQIMFNUYLGNFF-RIYIOVJFSA-N CC(C)C(C=CC=C1C(C)C)=C1OCOP(N[C@@H](C)C(O)=O)(N[C@@H](C)C(OC(C)C)=O)=O Chemical compound CC(C)C(C=CC=C1C(C)C)=C1OCOP(N[C@@H](C)C(O)=O)(N[C@@H](C)C(OC(C)C)=O)=O PUQIMFNUYLGNFF-RIYIOVJFSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- HVXBOLULGPECHP-WAYWQWQTSA-N Combretastatin A4 Chemical compound C1=C(O)C(OC)=CC=C1\C=C/C1=CC(OC)=C(OC)C(OC)=C1 HVXBOLULGPECHP-WAYWQWQTSA-N 0.000 description 2
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 2
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- DNXHEGUUPJUMQT-CBZIJGRNSA-N Estrone Chemical compound OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 DNXHEGUUPJUMQT-CBZIJGRNSA-N 0.000 description 2
- BFPYWIDHMRZLRN-SLHNCBLASA-N Ethinyl estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 BFPYWIDHMRZLRN-SLHNCBLASA-N 0.000 description 2
- ZWPRRQZNBDYKLH-VIFPVBQESA-N Gemigliptin Chemical compound C([C@@H](N)CC(=O)N1CC2=C(C(=NC(=N2)C(F)(F)F)C(F)(F)F)CC1)N1CC(F)(F)CCC1=O ZWPRRQZNBDYKLH-VIFPVBQESA-N 0.000 description 2
- 102000051325 Glucagon Human genes 0.000 description 2
- 108060003199 Glucagon Proteins 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 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 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 2
- 229920001304 Solutol HS 15 Polymers 0.000 description 2
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 2
- WREOTYWODABZMH-DTZQCDIJSA-N [[(2r,3s,4r,5r)-3,4-dihydroxy-5-[2-oxo-4-(2-phenylethoxyamino)pyrimidin-1-yl]oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O[C@H]1N(C=C\1)C(=O)NC/1=N\OCCC1=CC=CC=C1 WREOTYWODABZMH-DTZQCDIJSA-N 0.000 description 2
- 229960001667 alogliptin Drugs 0.000 description 2
- ZSBOMTDTBDDKMP-OAHLLOKOSA-N alogliptin Chemical compound C=1C=CC=C(C#N)C=1CN1C(=O)N(C)C(=O)C=C1N1CCC[C@@H](N)C1 ZSBOMTDTBDDKMP-OAHLLOKOSA-N 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- 230000008499 blood brain barrier function Effects 0.000 description 2
- 238000010241 blood sampling Methods 0.000 description 2
- 210000001218 blood-brain barrier Anatomy 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940125758 compound 15 Drugs 0.000 description 2
- 229940126142 compound 16 Drugs 0.000 description 2
- 229940125810 compound 20 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- MCWXGJITAZMZEV-UHFFFAOYSA-N dimethoate Chemical compound CNC(=O)CSP(=S)(OC)OC MCWXGJITAZMZEV-UHFFFAOYSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000003651 drinking water Substances 0.000 description 2
- 235000020188 drinking water Nutrition 0.000 description 2
- 229960002568 ethinylestradiol Drugs 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 230000009246 food effect Effects 0.000 description 2
- 235000021471 food effect Nutrition 0.000 description 2
- 229960002458 gemigliptin Drugs 0.000 description 2
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 2
- 229960004666 glucagon Drugs 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 229960002897 heparin Drugs 0.000 description 2
- 229920000669 heparin Polymers 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 230000002779 inactivation Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- 229960005250 naloxone hydrochloride Drugs 0.000 description 2
- 229940005483 opioid analgesics Drugs 0.000 description 2
- 210000004279 orbit Anatomy 0.000 description 2
- 230000036407 pain Effects 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 230000035479 physiological effects, processes and functions Effects 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- WGRQANOPCQRCME-PMACEKPBSA-N teneligliptin Chemical compound O=C([C@H]1NC[C@H](C1)N1CCN(CC1)C1=CC(=NN1C=1C=CC=CC=1)C)N1CCSC1 WGRQANOPCQRCME-PMACEKPBSA-N 0.000 description 2
- 229950000034 teneligliptin Drugs 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- IWYJYHUNXVAVAA-OAHLLOKOSA-N trelagliptin Chemical compound C=1C(F)=CC=C(C#N)C=1CN1C(=O)N(C)C(=O)C=C1N1CCC[C@@H](N)C1 IWYJYHUNXVAVAA-OAHLLOKOSA-N 0.000 description 2
- 229950010728 trelagliptin Drugs 0.000 description 2
- DNXHEGUUPJUMQT-UHFFFAOYSA-N (+)-estrone Natural products OC1=CC=C2C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 DNXHEGUUPJUMQT-UHFFFAOYSA-N 0.000 description 1
- PROQIPRRNZUXQM-UHFFFAOYSA-N (16alpha,17betaOH)-Estra-1,3,5(10)-triene-3,16,17-triol Natural products OC1=CC=C2C3CCC(C)(C(C(O)C4)O)C4C3CCC2=C1 PROQIPRRNZUXQM-UHFFFAOYSA-N 0.000 description 1
- TXTWXQXDMWILOF-UHFFFAOYSA-N (2-ethoxy-2-oxoethyl)azanium;chloride Chemical compound [Cl-].CCOC(=O)C[NH3+] TXTWXQXDMWILOF-UHFFFAOYSA-N 0.000 description 1
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 1
- QUGUFLJIAFISSW-UHFFFAOYSA-N 1,4-difluorobenzene Chemical class FC1=CC=C(F)C=C1 QUGUFLJIAFISSW-UHFFFAOYSA-N 0.000 description 1
- UZGKAASZIMOAMU-UHFFFAOYSA-N 124177-85-1 Chemical group NP(=O)=O UZGKAASZIMOAMU-UHFFFAOYSA-N 0.000 description 1
- XYMTUFXXCMZHCU-UHFFFAOYSA-N 2-(chloromethoxy)-1,3-di(propan-2-yl)benzene Chemical compound CC(C)C1=CC=CC(C(C)C)=C1OCCl XYMTUFXXCMZHCU-UHFFFAOYSA-N 0.000 description 1
- BUJWKBIFOTURDW-UHFFFAOYSA-N 2-methylsulfonyl-5,6-dihydro-4h-pyrrolo[3,4-c]pyrazole Chemical class C1NCC2=NN(S(=O)(=O)C)C=C21 BUJWKBIFOTURDW-UHFFFAOYSA-N 0.000 description 1
- JWEOEZZCZCCPJL-UHFFFAOYSA-N 4-methylquinazoline Chemical compound C1=CC=C2C(C)=NC=NC2=C1 JWEOEZZCZCCPJL-UHFFFAOYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical group CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OBMZMSLWNNWEJA-XNCRXQDQSA-N C1=CC=2C(C[C@@H]3NC(=O)[C@@H](NC(=O)[C@H](NC(=O)N(CC#CCN(CCCC[C@H](NC(=O)[C@@H](CC4=CC=CC=C4)NC3=O)C(=O)N)CC=C)NC(=O)[C@@H](N)C)CC3=CNC4=C3C=CC=C4)C)=CNC=2C=C1 Chemical compound C1=CC=2C(C[C@@H]3NC(=O)[C@@H](NC(=O)[C@H](NC(=O)N(CC#CCN(CCCC[C@H](NC(=O)[C@@H](CC4=CC=CC=C4)NC3=O)C(=O)N)CC=C)NC(=O)[C@@H](N)C)CC3=CNC4=C3C=CC=C4)C)=CNC=2C=C1 OBMZMSLWNNWEJA-XNCRXQDQSA-N 0.000 description 1
- NCSZKAFGAQGUST-UHFFFAOYSA-N CC(C)C(C=CC=C1C(C)C)=C1OP(NCC(O)=O)(NCC(OC(C)C)=O)=O Chemical compound CC(C)C(C=CC=C1C(C)C)=C1OP(NCC(O)=O)(NCC(OC(C)C)=O)=O NCSZKAFGAQGUST-UHFFFAOYSA-N 0.000 description 1
- NZFXHSUDPDVGNA-KKWUZJKMSA-N CC(C)OC([C@H](C)NP(N[C@@H](C)C(O)=O)(OC(C=C(/C=C\C(C=C1OC)=CC(OC)=C1OC)C=C1)=C1OC)=O)=O Chemical compound CC(C)OC([C@H](C)NP(N[C@@H](C)C(O)=O)(OC(C=C(/C=C\C(C=C1OC)=CC(OC)=C1OC)C=C1)=C1OC)=O)=O NZFXHSUDPDVGNA-KKWUZJKMSA-N 0.000 description 1
- HVKXGZLGUNPSIA-HCDOGKATSA-N CC(C)OC([C@H](C)NP(N[C@@H](C)C(O)=O)(OCC1=CC=CC=C1)=O)=O Chemical compound CC(C)OC([C@H](C)NP(N[C@@H](C)C(O)=O)(OCC1=CC=CC=C1)=O)=O HVKXGZLGUNPSIA-HCDOGKATSA-N 0.000 description 1
- WXNUMOJVSOEFML-STWLZBDKSA-N CC(C)OC([C@H](C)NP(N[C@@H](C)C(OC(C)C)=O)(N[C@H](CCC1)CN1C(N(CC(C=C(C=C1)F)=C1C#N)C(N1C)=O)=CC1=O)=O)=O Chemical compound CC(C)OC([C@H](C)NP(N[C@@H](C)C(OC(C)C)=O)(N[C@H](CCC1)CN1C(N(CC(C=C(C=C1)F)=C1C#N)C(N1C)=O)=CC1=O)=O)=O WXNUMOJVSOEFML-STWLZBDKSA-N 0.000 description 1
- IRFGDHLSGKNOPD-UHFFFAOYSA-N CCOC(=O)CNP(=O)(NCC(=O)OCC)OC1=C(C=CC=C1C(C)C)C(C)C Chemical compound CCOC(=O)CNP(=O)(NCC(=O)OCC)OC1=C(C=CC=C1C(C)C)C(C)C IRFGDHLSGKNOPD-UHFFFAOYSA-N 0.000 description 1
- BEJLRZAICLLJMF-QUIWEDSDSA-N CCOC(=O)[C@H](C)NP(=O)(N[C@@H](C)C(=O)O)OCC1=CC=CC=C1 Chemical compound CCOC(=O)[C@H](C)NP(=O)(N[C@@H](C)C(=O)O)OCC1=CC=CC=C1 BEJLRZAICLLJMF-QUIWEDSDSA-N 0.000 description 1
- LIAPRXDFHGWUPE-DOZYCSFHSA-N CCOC([C@H](C)NP(N[C@@H](C)C(O)=O)(OCOC1=C(C(C)C)C=CC=C1C(C)C)=O)=O Chemical compound CCOC([C@H](C)NP(N[C@@H](C)C(O)=O)(OCOC1=C(C(C)C)C=CC=C1C(C)C)=O)=O LIAPRXDFHGWUPE-DOZYCSFHSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 241000375691 Combretum caffrum Species 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 101100114697 Danio rerio cpeb1 gene Proteins 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 1
- 108090000194 Dipeptidyl-peptidases and tripeptidyl-peptidases Proteins 0.000 description 1
- 102000003779 Dipeptidyl-peptidases and tripeptidyl-peptidases Human genes 0.000 description 1
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- LCDDAGSJHKEABN-MLGOLLRUSA-N Evogliptin Chemical compound C1CNC(=O)[C@@H](COC(C)(C)C)N1C(=O)C[C@H](N)CC1=CC(F)=C(F)C=C1F LCDDAGSJHKEABN-MLGOLLRUSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 102000027484 GABAA receptors Human genes 0.000 description 1
- 108091008681 GABAA receptors Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 108090000604 Hydrolases Proteins 0.000 description 1
- 102000004157 Hydrolases Human genes 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241001024304 Mino Species 0.000 description 1
- 102000003840 Opioid Receptors Human genes 0.000 description 1
- 108090000137 Opioid Receptors Proteins 0.000 description 1
- 101710176384 Peptide 1 Proteins 0.000 description 1
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 description 1
- 241000720974 Protium Species 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 210000004404 adrenal cortex Anatomy 0.000 description 1
- 230000008484 agonism Effects 0.000 description 1
- LDXYBEHACFJIEL-HNNXBMFYSA-N anagliptin Chemical compound C=1N2N=C(C)C=C2N=CC=1C(=O)NCC(C)(C)NCC(=O)N1CCC[C@H]1C#N LDXYBEHACFJIEL-HNNXBMFYSA-N 0.000 description 1
- 229950009977 anagliptin Drugs 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- UDWFQJJTHGCIEE-YUMQZZPRSA-N bis[[(2S)-1-ethoxy-1-oxopropan-2-yl]amino]phosphinic acid Chemical compound CCOC(=O)[C@H](C)NP(O)(=O)N[C@@H](C)C(=O)OCC UDWFQJJTHGCIEE-YUMQZZPRSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940126678 chinese medicines Drugs 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- HCSDJECSMANTCX-UHFFFAOYSA-N dichloro(methoxy)phosphane Chemical compound COP(Cl)Cl HCSDJECSMANTCX-UHFFFAOYSA-N 0.000 description 1
- 229960000452 diethylstilbestrol Drugs 0.000 description 1
- RGLYKWWBQGJZGM-ISLYRVAYSA-N diethylstilbestrol Chemical compound C=1C=C(O)C=CC=1C(/CC)=C(\CC)C1=CC=C(O)C=C1 RGLYKWWBQGJZGM-ISLYRVAYSA-N 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002159 estradiols Chemical class 0.000 description 1
- 229960001348 estriol Drugs 0.000 description 1
- PROQIPRRNZUXQM-ZXXIGWHRSA-N estriol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H]([C@H](O)C4)O)[C@@H]4[C@@H]3CCC2=C1 PROQIPRRNZUXQM-ZXXIGWHRSA-N 0.000 description 1
- 229960003399 estrone Drugs 0.000 description 1
- SBODZSZCXVNMCN-GWAZLAOXSA-N ethyl (2S)-2-[[[[(3R)-1-[3-[(2-cyano-5-fluorophenyl)methyl]-1-methyl-2,6-dioxopyrimidin-4-yl]piperidin-3-yl]amino]-(methoxymethyl)phosphoryl]amino]propanoate Chemical compound CCOC([C@H](C)NP(COC)(N[C@H](CCC1)CN1C(N(CC(C=C(C=C1)F)=C1C#N)C(N1C)=O)=CC1=O)=O)=O SBODZSZCXVNMCN-GWAZLAOXSA-N 0.000 description 1
- 230000005496 eutectics Effects 0.000 description 1
- 229950011259 evogliptin Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000002695 general anesthesia Methods 0.000 description 1
- 239000003163 gonadal steroid hormone Substances 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 238000010438 heat treatment Methods 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
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 125000000336 imidazol-5-yl group Chemical group [H]N1C([H])=NC([H])=C1[*] 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 239000002869 intravenous anesthetic agent Substances 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 231100000682 maximum tolerated dose Toxicity 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229940127234 oral contraceptive Drugs 0.000 description 1
- 239000003539 oral contraceptive agent Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 230000004783 oxidative metabolism Effects 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 210000002826 placenta Anatomy 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- JSHSWRRVCOAIJO-FVQFIUHVSA-N propan-2-yl (2S)-2-[[[[(3R)-1-[7-but-2-ynyl-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]-2,6-dioxopurin-8-yl]piperidin-3-yl]amino]-(methoxymethyl)phosphoryl]amino]propanoate Chemical compound CC(C)OC([C@H](C)NP(COC)(N[C@H](CCC1)CN1C1=NC(N(C)C(N(CC2=NC3=CC=CC=C3C(C)=N2)C2=O)=O)=C2N1CC#CC)=O)=O JSHSWRRVCOAIJO-FVQFIUHVSA-N 0.000 description 1
- UBKCIXXGQRZHRO-UHFFFAOYSA-N propan-2-yl 2-aminoacetate;hydrochloride Chemical compound Cl.CC(C)OC(=O)CN UBKCIXXGQRZHRO-UHFFFAOYSA-N 0.000 description 1
- 150000003151 propanoic acid esters Chemical class 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000004885 tandem mass spectrometry Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- 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
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/22—Amides of acids of phosphorus
- C07F9/24—Esteramides
- C07F9/2404—Esteramides the ester moiety containing a substituent or a structure which is considered as characteristic
- C07F9/242—Esteramides the ester moiety containing a substituent or a structure which is considered as characteristic of hydroxyaryl compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/10—Anti-acne agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- 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
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/30—Oestrogens
-
- 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
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/22—Amides of acids of phosphorus
- C07F9/24—Esteramides
- C07F9/2404—Esteramides the ester moiety containing a substituent or a structure which is considered as characteristic
-
- 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
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/22—Amides of acids of phosphorus
- C07F9/24—Esteramides
- C07F9/2454—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic
- C07F9/2458—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic of aliphatic amines
-
- 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
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
-
- 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
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero 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
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0051—Estrane derivatives
- C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
- C07J1/007—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0051—Estrane derivatives
- C07J1/0081—Substituted in position 17 alfa and 17 beta
- C07J1/0088—Substituted in position 17 alfa and 17 beta the substituent in position 17 alfa being an unsaturated hydrocarbon group
- C07J1/0096—Alkynyl derivatives
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Diabetes (AREA)
- Neurosurgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Endocrinology (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Dermatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Anesthesiology (AREA)
- Hematology (AREA)
- Toxicology (AREA)
- Obesity (AREA)
- Emergency Medicine (AREA)
- Addiction (AREA)
- Psychiatry (AREA)
- Reproductive Health (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种通式(I)所示化合物及其立体异构体或药学上可接受的盐,以及医药中的应用,通式(I)化合物的结构为Q‑L‑R1,其基团定义与说明书定义一致。
Description
技术领域
本发明涉及一种磷酸衍生物及其中间体和制备方法,以及在制备药物中的用途。
背景技术
目前上市或研究的药物中,一些药物存在某些理化和生物学性质的缺陷,例如,溶解度差、稳定性低、容易吸湿、气味不佳、不适宜制备制剂、难以透过血脑屏障、不能口服、肝首过效应明显、口服生物利用度低、给药剂量和给药频率高、体内分布不能满足治疗需要、食物影响大、安全性窗口小、肠胃刺激大、组织刺激性大、非靶器官分布造成毒性反应、代谢过快或长期滞留等问题。因此需要开发新的技术,以达到改善药物的理化性质和消除不良气味、改善药物在体内的吸收、分布、转运与代谢过程、提高生物利用度、提高药物对靶部位作用的选择性、降低药物的毒副作用、延长作用时间等的技术效果。
微管蛋白抑制剂是一类作用于微管蛋白从而阻止细胞增殖的抗癌药物。CA-4(Combretastatin A-4)是从南非树木CombretumCaffrum中分离出来的一系列具有抑制微管蛋白聚合的活性化合物活性成分中活性最强的风车子抑素类化合物,其化学结构与抗有丝分裂药物秋水仙碱(4)相似,对微管蛋白上的秋水仙碱结合位点有较高的亲和力。顺式CA-4具有极高的广谱抗肿瘤活性,起效剂量低于最大耐受剂量的十分之一,而反式CA-4的活性则大大降低。然而顺式CA-4水溶性差,生物利用度很低(J.Med.Chem.1998,41,3022-3032),临床上使用具有很大的局限性。
丙泊酚可激活多种GABAA受体亚型,是一个临床上成熟的静脉麻醉药,广泛用于全身麻醉的诱导和维持。丙泊酚的显著药代动力学和药效学性质是起效快,维持时间短和快速可逆。静脉给药后,丙泊酚迅速从血液进入心、肺和肝等高灌注区,高脂溶性使丙泊酚容易跨越血脑屏障进入大脑发挥全身麻醉作用。然而,丙泊酚也有显而易见的局限性和缺点。据报道,约 70%的病人在注射丙泊酚时有一定程度的疼痛或不适(Pascale Picard(2000).Anesthesia& Analgesia,90,963-969),有报道认为是脂质乳剂水相中的丙泊酚导致的注射疼痛(Klement W 等,1991,Br J Anaesth 67,281)。另外,丙泊酚的生物利用度低,不适合口服。
雌激素是雌性脊椎动物的性激素,由卵巢分泌的发情激素具有促进第二性征出现的作用。天然雌激素主要为雌二醇(E2)、雌酮(E)及雌三醇(E3),由卵巢、胎盘及肾上腺皮质分泌。临床上多用雌二醇(E2),生物活性极强,治疗剂量极小,口服后在肝脏迅速代谢失活,作用时间短(17β-OH氧化代谢),不易口服,临床上常用剂型为注射剂或贴片等。炔雌醇为半合成雌激素,一种雌二醇类似物,由甾体雌激素衍生而来,常用作口服避孕药,如炔雌醇,其效力为雌二醇的7-8倍,为已烯雌酚的20倍。口服后迅速在胃肠道被吸收,肝首过效应约为60%。
纳洛酮结构类似吗啡,为一特异性类阿片拮抗剂,通过竞争阿片受体(依次为μ,κ,δ) 而起作用;同时伴有激动作用,即激动-拮抗的结合作用。能解除类阿片药物过量中毒和术后持续的呼吸抑制,还可对吸毒者进行鉴别诊断。纳洛酮口服后虽可被吸收,但由于广泛的首过代谢,其所发挥的作用仅及静脉注射给药的1/100。静脉注射纳洛酮后2min即可显效,但维持作用很短(30~60min)。
DPP-4抑制剂(二肽基肽酶4抑制剂),是一类治疗2型糖尿病的药物,该类药物能够抑制胰高血糖素样肽-1(GLP-1)和葡萄糖依赖性促胰岛素分泌多肽(GIP)的灭活,提高内源性GLP-1 和GIP的水平,促进胰岛β细胞释放胰岛素,同时抑制胰岛α细胞分泌胰高血糖素,从而提高胰岛素水平,降低血糖,且不易诱发低血糖和增加体重。迄今,世界范围内已上市多种DPP-4 抑制剂:西格列汀(sitagliptin)、维格列汀(vildagliptin)、沙格列汀(saxagliptin)、阿格列汀 (alogliptin)、利格列汀(linagliptin)、吉格列汀(gemigliptin)、替格列汀(teneligliptin)、曲格列汀 (trelagliptin)和奥格列汀(Omarigliptin)等。
因此需要开发新的技术,以达到改善药物在体内的吸收、分布、转运与代谢过程、提高生物利用度、提高药物对靶部位作用的选择性、降低药物的毒副作用、延长作用时间、降低食物影响等的技术效果。
发明内容
本发明发现磷酰胺的引入可以通过磷酰胺基团改变药物的物理化学性质,如药物的性状、稳定性、脂溶性、P-gp底物性质等,进而改变体内吸收代谢分布的特征。磷酰修饰的药物进入体内后,在体内水解酶作用下水解释放出原药。通过控制磷酰胺药物水解速率可以延长药物体内的存在时间,也可以通过水解酶的分布等特点达到提高药物对靶部位的特异性作用给药的目的。
本发明的目的之一在于提供一种新颖的、可口服的磷酸衍生物。
本发明的目的之一在于提供一种新颖的、生物利用高的、半衰期更长的、消除时间更长或作用时间更长的磷酸衍生物。
本发明的目的之一在于提供一种制备磷酸衍生物的中间体及其制备方法。
本发明提供一种通式(I)所示化合物及其立体异构体或药学上可接受的盐,
Q-L-R1 (I)
其中:
当Q选自时;
R1选自
R1a、R1c各自独立的选自H或C1-4烷基,所述的烷基任选进一步被0至4个选自H、F、Cl、Br、I、C1-4烷基或C1-4烷氧基的取代基所取代;
R1b、R1d各自独立的选自C1-4烷基;所述的烷基任选进一步被0至4个选自H、F、Cl、Br、I、C1-4烷基或C1-4烷氧基的取代基所取代;
L选自键;
当Q选自时;
R1选自
R1a、R1c各自独立的选自H或C1-4烷基,所述的烷基任选进一步被0至4个选自H、F、Cl、Br、I、C1-4烷基或C1-4烷氧基的取代基所取代;
R1b、R1d各自独立的选自C1-4烷基;所述的烷基任选进一步被0至4个选自H、F、Cl、Br、I、C1-4烷基或C1-4烷氧基的取代基所取代;
L选自键或CH2O,其中L的左边与Q连接,右边与R1连接;
当Q选自 时;
L选自键;
R选自
Ra、Rc、Re各自独立的选自H或C1-6烷基,所述的烷基任选进一步被0至4个选自F、Cl、Br、I、C1-4烷基或C1-4烷氧基的取代基所取代;
Rb、Rd、Rf各自独立的选自C1-6烷基,所述的烷基任选进一步被0至4个选自F、Cl、Br、I、C1-4烷基或C1-4烷氧基的取代基所取代。
本发明优选方案,一种通式(I)所示化合物及其立体异构体或药学上可接受的盐,其中
R1a、R1c各自独立的选自H或C1-4烷基,优选H、甲基、乙基、丙基或异丙基;
R1b、R1d各自独立的选自C1-4烷基,优选甲基、乙基、丙基或异丙基;
Ra、Rc、Re各自独立的选自H、甲基、乙基或异丙基;
Rb、Rd、Rf各自独立的选自甲基、乙基、丙基或异丙基。
本发明优选方案,一种通式(I)所述的化合物及其立体异构体或药学上可接受的盐,其中该化合物选自如下结构之一:
本申请涉及一种通式(N)所示的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药:
D-R (N)
R选自
Ra、Rc、Re各自独立的选自H或C1-6烷基,所述的烷基任选进一步被0至4个选自F、Cl、Br、I、C1-4烷基或C1-4烷氧基的取代基所取代;优选H、甲基、乙基或异丙基;
Rb、Rd、Rf各自独立的选自C1-6烷基,所述的烷基任选进一步被0至4个选自F、Cl、Br、I、C1-4烷基或C1-4烷氧基的取代基所取代;优选甲基、乙基、丙基或异丙基;
D选自
本发明还涉及一种药物组合物,所述药物组合物含有治疗有效剂量的本发明所述的化合物或其立体异构体或药学上可接受的盐,以及药学上可接受的载体和赋形剂。
本发明还涉及本发明所述的化合物及其立体异构体或药学上可接受的盐,及其本发明所述化合物的组合物在制备治疗和预防癌症、骨髓增生异常综合征、中枢神经系统相关疾病、雌激素相关疾病、酒精中毒、阿片类药物过量中毒、阿片药成瘾的诊断相关药物或糖尿病的药物中的应用。
本发明优选方案,其中中枢神经系统相关疾病选自麻醉、镇痛、偏头痛、催眠或脑保护,雌激素相关疾病选自补充雌激素不足、前列腺癌、乳腺癌、骨质疏松、痤疮、白细胞减少症、不育症、皮肤瘙痒、绝经期综合症或避孕
除非有相反的陈述,在说明书和权利要求书中使用的术语具有下述含义。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素均包括它们的同位素,及本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素任选进一步被一个或多个它们对应的同位素所替代,其中碳的同位素包括12C、13C和14C,氢的同位素包括氕(H)、氘(D,又称为重氢)、氚(T,又称为超重氢),氧的同位素包括16O、17O和18O,硫的同位素包括32S、33S、34S和36S,氮的同位素包括14N和15N,氟的同位素19F,氯的同位素包括35Cl和37Cl,溴的同位素包括79Br和81Br。
“任选”或“任选地”是指随后所描述的事件或环境可以但不必须发生,该说明包括该事件或环境发生或不发生的场合。如:“任选被F取代的烷基”指烷基可以但不必须被F取代,说明包括烷基被F取代的情形和烷基不被F取代的情形。
“药物组合物”表示一种或多种文本所述化合物或其生理学/药学上可接受的盐与其他组成成分的混合物,其中其它组分包含生理学/药学上可接受的载体和赋形剂。
“载体”指的是不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的载体或稀释剂。
“赋形剂”指的是加入到药物组合物中以进一步依赖于化合物给药的惰性物质。赋形剂的实例包括但不限于碳酸钙、磷酸钙、各种糖和不同类型的淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂、崩解剂等。
“前药”是指可以在生理条件下或通过溶剂解转化为具有生物活性的本发明化合物的化合物。本发明的前药通过修饰本发明化合物中的功能基团来制备,该修饰可以通过常规的操作或者在体内被除去,而得到母体化合物。
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体,包括顺反异构体、对映异构体和构象异构体。
“有效剂量”指引起组织、系统或受试者生理或医学反应的化合物的量,此量是所寻求的,包括在受治疗者身上施用时足以预防受治疗的疾患或病症的一种或几种症状发生或使其减轻至某种程度的化合物的量。
合成方法一:
Q-H与三氯氧磷反应得到(I-A)化合物;
(I-A)化合物与通式(I-B)化合物或其盐得到通式(I)化合物;
其中,Q、L、R1、R1d或R1c的定义与权利要求1定义一致。
合成方法二:
通式(I-C)与通式(I-B)化合物或其盐反应得到通式(I-D)化合物;
通式(I-D)化合物脱去G基团得到通式(I-D)化合物;
Q-H与BrCH2Cl反应得到通式(I-F)化合物;
通式(I-F)化合物与通式(I-H)化合物得到通式(I)化合物;
G为易离去基团,优选苄基;
其中,Q、L、R1、R1a、R1b、R1c或R1d的定义与权利要求1定义一致。
合成方法三:
D-H选自DPP4抑制剂,优选曲格列汀(trelagliptin)、阿格列汀(alogliptin)、西塔列汀 (Sitagliptin)、维格列汀(vildagliptin)、吉格列汀(gemigliptin)、沙格列汀(saxagliptin)、奥格列汀(Omarigliptin)瑞格列汀、利格列汀(linagliptin)、Anagliptin、Evogliptin、Teneligliptin、
D优选
Ra选自H或C1-6烷基,所述的烷基任选进一步被0至4个选自F、Cl、Br、I、C1-4烷基或C1-4烷氧基的取代基所取代;
R1b选自C1-6烷基,所述的烷基任选进一步被0至4个选自F、Cl、Br、I、C1-4烷基或C1-4烷氧基的取代基所取代,优选甲基、乙基、丙基、异丙基、丁基、叔丁基、戊基或己基。
D-H通过缩合反应转化为通式(I-A-1)化合物;通式(I-A-1)化合物通过缩合反应得到通式 (I-1)化合物。
合成方法四:
D-H、D、Ra和R1b的定义与方案一一致;
D-H通过缩合反应转化为通式(II-A)化合物;通式(II-A)化合物通过缩合反应得到通式(II) 化合物。
具体实施方式
以下通过具体实施例详细说明本发明的实施过程和产生的有益效果,旨在帮助阅读者更好地理解本发明的实质和特点,不作为对本案可实施范围的限定。
化合物的结构是通过核磁共振(NMR)和/或质谱(MS)来确定的,超临界流体色谱法(SFC)拆分手性结构。
NMR位移(δ)以10-6(ppm)的单位给出。
NMR的测定是用(Bruker ADVANCE III 400)核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d6),氘代氯仿(CDCl3),氘代甲醇(CD3OD),内标为四甲基硅烷(TMS),1HNMR信息以下列格式来列表:化学位移(多重峰(s,单峰;d,双重峰;t,三重峰;q,四重峰;m,多重峰),质子数)。
MS的测定用(Agilent 6120B(ESI))。
HPLC的测定使用安捷伦1260DAD高压液相色谱仪(Zorba x SB-C18 100x 4.6mm)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm~0.20mm,薄层层析分离纯化产品采用的规格是0.4mm~0.5mm。
柱层析一般使用烟台黄海硅胶200~300目硅胶为载体。
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成,或购买于成都科龙化工,成都西陇化工,成都效佳,安耐吉化学,成都叮当化学,爱斯特(成都)医药技术有限公司,韶远化学科技(上海)有限公司,国药集团药业股份有限公司,百灵威科技有限公司等公司。
实施例1:异丙基(2S)-2-[[[(3R)-1-[3-[(2-氰基-5-氟-苯基)甲基]-1-甲基-2,6-二氧代-嘧啶-4- 基]-3-哌啶基]氨基]-(甲氧基甲基)磷酰基]氨基]丙酸酯(化合物1)的合成
isopropyl
(2S)-2-[[[[(3R)-1-[3-[(2-cyano-5-fluoro-phenyl)methyl]-1-methyl-2,6-dioxo-pyrimidin-4-yl]-3-piperi dyl]amino]-(methoxymethyl)phosphoryl]amino]propanoate
氮气保护下,将二氯甲烷(10mL)加入反应瓶中,搅拌下加入(甲氧基甲基)二氯化磷 (1B)(0.51g,3.15mmol),冷却至-10℃~-5℃。缓慢滴入曲格列汀(1A)(1.07g,3mmol)、三乙胺(0.30g,3mmol)和二氯甲烷(5mL)的混合溶液,加完后-10℃~-5℃反应1h。接着依次加入 L-丙氨酸异丙酯盐酸盐(1C)(0.53g,3.15mmol)的二氯甲烷(5mL)溶液和三乙胺(0.64g,6.3 mmol)加完后升至室温搅拌反应3h,然后加入二氯甲烷(30mL)和水(50mL),搅拌5min,静置分层。有机层用无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析分离提纯(二氯甲烷 /甲醇=(v/v)50/1~20/1),所得粗品通过制备液相进一步分离纯化(液相制备条件:仪器:Thar 80 preparative SFC;色谱柱:ChiralPak AS-20u,250×50mmI.D.;流动相:A:CO2,B:甲醇;梯度:B 35%;流量:70mL/min;背压:100bar;柱温:38℃;波长:220nm;周期:12min;样品制备:化合物1溶解于甲醇中制得15mg/ml;注射:1.5ml/针),得到异丙基(2S)-2-[[[(3R)-1-[3-[(2- 氰基-5-氟-苯基)甲基]-1-甲基-2,6-二氧代-嘧啶-4-基]-3-哌啶基]氨基]-(甲氧基甲基)磷酰基]氨基] 丙酸酯(化合物1),白色泡状固体0.41g,收率:23.66%。
MS m/z(ESI):579.3[M+H]+.
1H NMR(400MHz,CDCl3)δ7.68(dd,1H),7.14–7.01(m,1H),6.95(dd,1H),5.39(s,1H), 5.35–5.17(m,2H),5.07–4.91(m,1H),4.02–3.88(m,1H),3.59(d,2H),3.43(br,1H),3.38(s, 3H),3.29(s,3H),3.25–3.16(m,1H),3.15–3.03(m,1H),2.92–2.79(m,1H),2.65(br,2H),2.04 –1.75(m,3H),1.71–1.56(m,1H),1.48–1.30(m,4H),1.30–1.18(m,6H).
实施例2:异丙基(2S)-2-[[[[(2R,3S,5R)-2-(2,5-二氟苯基)-5-(2-甲基磺酰基-4,6-二氢吡咯并 [3,4-c]吡唑-5-基)四氢吡喃-3-基]氨基]-(甲氧基甲基)磷酰基]氨基]丙酸酯(化合物2)的合成
isopropyl(2S)-2-[[[[(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6- dihydropyrrolo[3,4-c]pyrazol-5-yl)tetrahydropyran-3-yl]amino]-(methoxymethyl)phosphoryl]amino] propanoate
氮气保护下,将四氢呋喃(10mL)加入反应瓶中,搅拌下加入(甲氧基甲基)二氯化磷 (1B)(0.34g,2.1mmol),冷却至-10℃~-5℃。缓慢滴入奥格列汀(Omarigliptin,2A)(0.80g,2mmol)、三乙胺(0.20g,2mmol)和四氢呋喃(5mL)的混合溶液,加完后-10℃~-5℃反应1h。然后依次加入L-丙氨酸异丙酯盐酸盐(1C)(0.35g,2.1mmol)的二氯甲烷(10mL)溶液和三乙胺(0.43g, 4.2mmol)加完后升至室温搅拌反应3h,然后加入二氯甲烷(50mL)和水(50mL),搅拌5min,静置分层。有机层用无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析分离提纯(二氯甲烷/甲醇=(v/v)50/1~20/1),所得粗品通过制备液相进一步分离纯化(液相制备条件:仪器: Thar 80 preparative SFC;色谱柱:ChiralPak AS-20u,250×50mmI.D.;流动相:A:CO2,B:甲醇;梯度:B 35%;流量:70mL/min;背压:100bar;柱温:38℃;波长:220nm;周期:12min;样品制备:化合物1溶解于甲醇中制得15mg/ml;注射:1.5ml/针),得到异丙基 (2S)-2-[[[[(2R,3S,5R)-2-(2,5-二氟苯基)-5-(2-甲基磺酰基-4,6-二氢吡咯并[3,4-c]吡唑-5-基)四氢吡喃-3-基]氨基]-(甲氧基甲基)磷酰基]氨基]丙酸酯(化合物2),黄白色泡状固体0.41g,收率: 32.95%。
MS m/z(ESI):620.2[M+H]+.
1H NMR(400MHz,CDCl3)δ7.71(s,1H),7.25–7.16(m,1H),7.10–6.95(m,2H),5.07–4.88(m,1H),4.40–4.17(m,2H),3.97–3.63(m,5H),3.55–3.32(m,5H),3.29(s,3H),3..11–2.87(m,2H),2.82–2.72(m,1H),2.70–2.56(m,1H),1.73–1.49(m,2H),1.40–1.08(m,10H).
实施例3:异丙基(2S)-2-[[甲氧基甲基-[[(1R)-3-氧代-3-[3-(三氟甲基)-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡嗪-7-基]-1-[(2,4,5-三氟苯基)甲基]丙基]氨基]磷酰基]氨基]丙酸酯(化合物3)的合成
isopropyl(2S)-2-[[methoxymethyl-[[(1R)-3-oxo-3-[3-(trifluoromethyl)-6,8-dihydro -5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-1-[(2,4,5-trifluorophenyl)methyl]propyl]amino]phosphoryl]a mino]propanoate
氮气保护下,将四氢呋喃(5mL)加入反应瓶中,搅拌下加入(甲氧基甲基)二氯化磷(1B)(0.44 g,2.70mmol),冰水冷却。缓慢滴入西他列汀(Sitagliptin,3A)(1.00g,2.16mmol)、三乙胺(1.24 g,12.28mmol)和四氢呋喃(5mL)的混合溶液,加完后45℃加热反应20min。冰水冷却,然后加入L-丙氨酸异丙酯盐酸盐(1C)(0.62g,3.68mmol)的二氯甲烷(5mL)溶液加完后升至室温搅拌反应2h,然后加入甲醇(10mL),搅拌5min,反应液减压浓缩干。残留物溶于乙酸乙酯(40 mL),饱和氯化钠溶液(50mL)洗涤。有机层用无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析分离提纯(二氯甲烷/甲醇=(v/v)30/1),所得粗品通过制备液相进一步分离纯化(液相制备条件:仪器:Thar 80 preparative SFC;色谱柱:ChiralPak AS-20u,250×50mmI.D.;流动相:A: CO2,B:甲醇;梯度:B 35%;流量:70mL/min;背压:100bar;柱温:38℃;波长:220nm;周期:12min;样品制备:化合物1溶解于甲醇中制得15mg/ml;注射:1.5ml/针),得到异丙基 (2S)-2-[[甲氧基甲基-[[(1R)-3-氧代-3-[3-(三氟甲基)-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡嗪-7- 基]-1-[(2,4,5-三氟苯基)甲基]丙基]氨基]磷酰基]氨基]丙酸酯(化合物3),黄色固体0.25g,收率:16.20%。
MS m/z(ESI):[M+H]+.
1H NMR(400MHz,CDCl3)δ7.23–7.06(m,1H),6.99–6.77(m,1H),5.21–4.82(m,3H),4.22(m,2H),4.13–3.61(m,4H),3.58–3.47(m,1H),3.47–3.22(m,4H),3.07–2.83(m,2H),2.75 –2.48(m,2H),1.76(s,2H),1.31–1.13(m,9H).
实施例4:异丙基(2S)-2-[[[(3R)-1-[7-丁-2-炔基-3-甲基-1-[(4-甲基喹唑啉-2-基)甲基]-2,6-二氧代嘌呤-8-基]-3-哌啶基]氨基]-(甲氧基甲基)磷酰基]氨基]丙酸酯(化合物4)的合成
isopropyl(2S)-2-[[[[(3R)-1-[7-but-2-ynyl-3-methyl-1-[(4-methylquinazolin-2-yl) methyl]-2,6-dioxo-purin-8-yl]-3-piperidyl]amino]-(methoxymethyl)phosphoryl]amino]propanoate
氮气保护下,将二氯甲烷(10mL)加入反应瓶中,搅拌下加入(甲氧基甲基)二氯化磷 (1B)(0.34g,2.1mmol),冷却至-10℃~-5℃。缓慢滴入利拉列汀(4A)(0.94g,2mmol)、三乙胺 (0.20g,2mmol)和二氯甲烷(5mL)的混合溶液,加完后-10℃~-5℃反应1h。然后依次加入L- 丙氨酸异丙酯盐酸盐(1C)(0.35g,2.1mmol)的二氯甲烷(5mL)溶液和三乙胺(0.43g,4.2mmol) 加完后升至室温搅拌反应3h,然后加入二氯甲烷(30mL)和水(50mL),搅拌5min,静置分层。有机层用无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析分离提纯(二氯甲烷/甲醇= (v/v)50/1~20/1),得到异丙基(2S)-2-[[[(3R)-1-[7-丁-2-炔基-3-甲基-1[(4-甲基喹唑啉-2-基)甲基]-2,6-二氧代嘌呤-8-基]-3-哌啶基]氨基]-(甲氧基甲基)磷酰基]氨基]丙酸酯(化合物4),黄白色泡状固体0.92g,收率:65.21%。
MS m/z(ESI):694.3[M+H]+.
1H NMR(400MHz,CDCl3)δ8.01(d,1H),7.88(d,1H),7.76(t,1H),7.52(t,1H),5.57(s,2H), 5.09–4.84(m,3H),4.13–3.94(m,1H),3.76–3.50(m,7H),3.49–3.31(m,5H),3.31–3.08(m, 3H),2.88(s,3H),2.07–1.85(m,2H),1.84–1.68(m,4H),1.66–1.53(m,1H),1.46–1.35(m,3H), 1.28–1.21(m,6H).
实施例5:异丙基(2S)-2-[[[[(2R,3S,5R,6S)-2-(2,5-二氟苯基)-5-(2-甲基磺酰基-4,6-二氢吡咯并[3,4-c]吡唑-5-基)-6-(三氟甲基)四氢吡喃-3-基]氨基]-(甲氧基甲基)磷酰基]氨基]丙酸酯(化合物5)的合成
isopropyl(2S)-2-[[[[(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6- dihydropyrrolo[3,4-c]pyrazol-5-yl)-6-(trifluoromethyl)tetrahydropyran-3-yl]amino]-(methoxymethyl )phosphoryl]amino]propanoate
氮气保护下,将二氯甲烷(10mL)加入反应瓶中,搅拌下加入(甲氧基甲基)二氯化磷 (1B)(0.34g,2.1mmol),冷却至-10℃~-5℃。缓慢滴入(2R,3S,5R,6S)-2-(2,5-二氟苯基)-5-(2- 甲基磺酰基-4,6-二氢吡咯并[3,4-c]吡唑-5-基)-6-(三氟基)四氢吡喃-3-胺(5A)(0.93g,2mmol)、三乙胺(0.20g,2mmol)和二氯甲烷(5mL)的混合溶液,加完后-10℃~-5℃反应1h。然后依次加入L-丙氨酸异丙酯盐酸盐(1C)(0.35g,2.1mmol)的二氯甲烷(5mL)溶液和三乙胺(0.43g,4.2 mmol)加完后升至室温搅拌反应3h,然后加入二氯甲烷(30mL)和水(50mL),搅拌5min,静置分层。有机层用无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析分离提纯(二氯甲烷/甲醇=(v/v)50/1~20/1),所得粗品通过制备液相进一步分离纯化(液相制备条件:仪器:Thar 80 preparative SFC;色谱柱:ChiralPak AS-20u,250×50mmI.D.;流动相:A:CO2,B:甲醇;梯度:B 35%;流量:70mL/min;背压:100bar;柱温:38℃;波长:220nm;周期:12min;样品制备:化合物1溶解于甲醇中制得15mg/ml;注射:1.5ml/针),得到异丙基 (2S)-2-[[[[(2R,3S,5R,6S)-2-(2,5-二氟苯基)-5-(2-甲基磺酰基-4,6-二氢吡咯并[3,4-c]吡唑-5- 基)-6-(三氟甲基)四氢吡喃-3-基]氨基]-(甲氧基甲基)磷酰基]氨基]丙酸酯(化合物5),白色泡状固体0.42g,收率:30.63%。
MS m/z(ESI):688.2[M+H]+.
H NMR(400MHz,CDCl3)δ7.71(s,1H),7.25–7.16(m,1H),7.11–6.97(m,2H),5.11–4.87(m,1H),4.75–4.65(m,1H),4.49–4.36(m,1H),4.09–3.98(m,2H),3.92–3.79(m,3H),3.56–3.43(m,3H),3.40(s,1H),3.30(s,3H),3.21(s,2H),3.13–2.71(m,2H),2.61–2.50(m,1H), 2.17–1.59(m,2H),1.39–1.10(m,9H).
实施例6:异丙基(2S)-2-[[[[(2R,3S,5R)-2-(2,5-二氟苯基)-5-[3-甲基-2-(1-甲基四唑-5-基)-4,6 二氢吡咯并[3,4-d]咪唑-5-基]四氢吡喃-3-基]氨基]-(甲氧基甲基)磷酰基]氨基]丙酸酯(化合物6) 的合成
isopropyl(2S)-2-[[[[(2R,3S,5R)-2-(2,5-difluorophenyl)-5-[3-methyl-2-(1-methyl tetrazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-yl]tetrahydropyran-3-yl]amino]-(methoxymethyl) phosphoryl]amino]propanoate
氮气保护下,将四氢呋喃(10mL)加入反应瓶中,搅拌下加入(甲氧基甲基)二氯化磷 (1B)(0.34g,2.1mmol),冷却至-10℃~-5℃。缓慢滴入(2R,3S,5R)-2-(2,5-二氟苯基)-5-[3-甲基-2-(1-甲基四唑-5-基)-4,6-二氢吡咯并[3,4-d]咪唑-5-基]四氢吡喃-3-胺(6A)(0.83g,2mmol)、三乙胺(0.20g,2mmol)和四氢呋喃(5mL)的混合溶液,加完后-10℃~-5℃反应1h。然后依次加入L-丙氨酸异丙酯盐酸盐(1C)(0.35g,2.1mmol)的二氯甲烷(5mL)溶液和三乙胺(0.43g,4.2 mmol)加完后升至室温搅拌反应3h,然后加入二氯甲烷(30mL)和水(50mL),搅拌5min,静置分层。有机层用无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析分离提纯(二氯甲烷/甲醇=(v/v)50/1~20/1),所得粗品通过制备液相进一步分离纯化(液相制备条件:仪器:Thar 80 preparative SFC;色谱柱:ChiralPak AS-20u,250×50mmI.D.;流动相:A:CO2,B:甲醇;梯度:B 35%;流量:70mL/min;背压:100bar;柱温:38℃;波长:220nm;周期:12min;样品制备:化合物1溶解于甲醇中制得15mg/ml;注射:1.5ml/针),得到异丙基 (2S)-2-[[[[(2R,3S,5R)-2-(2,5-二氟苯基)-5-[3-甲基-2-(1-甲基四唑-5-基)-4,6二氢吡咯并[3,4-d]咪唑-5-基]四氢吡喃-3-基]氨基]-(甲氧基甲基)磷酰基]氨基]丙酸酯(化合物6),灰白色泡状固体 0.42g,收率:30.63%。
MS m/z(ESI):638.2[M+H]+.
1H NMR(400MHz,CDCl3)δ7.26–7.18(m,1H),7.12–6.94(m,2H),4.93(dt,1H),4.42(s, 3H),4.36–4.24(m,2H),4.09–3.82(m,7H),3.77–3.61(m,1H),3.55–3.42(m,3H),3.41–3.28 (m,4H),3.19–3.03(m,1H),2.99–2.81(m,1H),2.74–2.62(m,1H),1.73–1.48(m,2H),1.23– 1.17(m,6H),1.16–1.10(m,3H).
实施例7:乙基(2S)-2-[[[(3R)-1-[3-[(2-氰基-5-氟-苯基)甲基]-1-甲基-2,6-二氧代-嘧啶-4- 基]-3-哌啶基]氨基]-(甲氧基甲基)磷酰基]氨基]丙酸酯(化合物7)的合成
ethyl(2S)-2-[[[[(3R)-1-[3-[(2-cyano-5-fluoro-phenyl)methyl]-1-methyl-2,6-dioxo- pyrimidin-4-yl]-3-piperidyl]amino]-(methoxymethyl)phosphoryl]amino]propanoate
氮气保护下,将二氯甲烷(10mL)加入反应瓶中,搅拌下加入(甲氧基甲基)二氯化磷 (1B)(0.51g,3.15mmol),冷却至-10℃~-5℃。缓慢滴入曲格列汀(1A)(1.07g,3mmol)、三乙胺(0.30g,3mmol)和二氯甲烷(5mL)的混合溶液,加完后-10℃~-5℃反应1h。然后依次加入 L-丙氨酸乙酯盐酸盐(7A)(0.48g,3.15mmol)的二氯甲烷(5mL)溶液和三乙胺(0.64g,6.3mmol) 加完后升至室温搅拌反应3h,然后加入二氯甲烷(30mL)和水(50mL),搅拌5min,静置分层。有机层用无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析分离提纯(二氯甲烷/甲醇= (v/v)50/1~20/1),所得粗品通过制备液相进一步分离纯化(液相制备条件:仪器:Thar 80 preparative SFC;色谱柱:ChiralPak AS-20u,250×50mmI.D.;流动相:A:CO2,B:甲醇;梯度:B 35%;流量:70mL/min;背压:100bar;柱温:38℃;波长:220nm;周期:12min;样品制备:化合物1溶解于甲醇中制得15mg/ml;注射:1.5ml/针),得到乙基(2S)-2-[[[(3R)-1-[3-[(2-氰基-5-氟-苯基)甲基]-1-甲基-2,6-二氧代-嘧啶-4-基]-3-哌啶基]氨基]-(甲氧基甲基)磷酰基]氨基]丙酸酯(化合物7),白色泡状固体0.64g,收率:37.86%。
MS m/z(ESI):565.3[M+H]+.
1H NMR(400MHz,CDCl3)δ7.68(dd,,1H),7.13–7.03(m,1H),7.02–6.81(m,1H),5.39(d, 1H),5.34–5.17(m,2H),4.25–4.11(m,2H),4.07–3.90(m,1H),3.60(d,2H),3.50–3.34(m,4H), 3.34–3.26(m,3H),3.26–3.05(m,2H),2.94–2.80(m,1H),2.74–2.42(m,2H),2.06–1.73(m, 3H),1.70–1.55(m,1H),1.42–1.35(m,3H),1.31–1.19(m,4H).
实施例8:异丙基(2S)-2-[[[(3R)-1-[3-[(2-氰基-5-氟-苯基)甲基]-1-甲基-2,6-二氧代-嘧啶-4- 基]-3-哌啶基]氨基]-[[(1S)-2-异丙氧基-1-甲基-2-氧代-乙基]氨基]磷酰基]氨基]丙酸酯(化合物8) 的合成
isopropyl(2S)-2-[[[[(3R)-1-[3-[(2-cyano-5-fluoro-phenyl)methyl]-1-methyl-2,6- dioxo-pyrimidin-4-yl]-3-piperidyl]amino]-[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]phosph oryl]amino]propanoate
氮气保护下,将二氯甲烷(20mL)加入反应瓶中,搅拌下加入三氯氧磷(8A)(0.50g,3.26 mmol),冷却至-78℃。缓慢滴入曲格列汀(1A)(1.07g,3mmol)、三乙胺(0.30g,3mmol)和二氯甲烷(5mL)的混合溶液,加完后-78℃反应1h。然后依次加入L-丙氨酸异丙酯盐酸盐(1C)(1.08 g,6.46mmol)的二氯甲烷(5mL)溶液和三乙胺(1.48g,14.6mmol)加完后升至室温搅拌反应5h,然后加入二氯甲烷(30mL)和水(50mL),搅拌5min,静置分层。有机层用无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析分离提纯(二氯甲烷/甲醇=(v/v)50/1~20/1),所得粗品通过制备液相进一步分离纯化(液相制备条件:仪器:Thar 80preparative SFC;色谱柱: ChiralPak AS-20u,250×50mmI.D.;流动相:A:CO2,B:甲醇;梯度:B 35%;流量:70mL/min;背压:100bar;柱温:38℃;波长:220nm;周期:12min;样品制备:化合物1溶解于甲醇中制得 15mg/ml;注射:1.5ml/针),得到异丙基(2S)-2-[[[(3R)-1-[3-[(2-氰基-5-氟-苯基)甲基]-1-甲基-2,6- 二氧代-嘧啶-4-基]-3-哌啶基]氨基]-[[(1S)-2-异丙氧基-1-甲基-2-氧代-乙基]氨基]磷酰基]氨基]丙酸酯(化合物8),白色泡状固体0.41g,收率:20.60%。
MS m/z(ESI):664.3[M+H]+.
1H NMR(400MHz,CDCl3)δ7.68(dd,1H),7.08(td,1H),6.93(dd,1H),5.37(s,1H),5.31– 5.25(m,2H),5.12–4.87(m,2H),4.04–3.78(m,2H),3.45–3.22(m,5H),3.11–2.76(m,4H), 2.73–2.35(m,2H),2.04–1.90(m,1H),1.85–1.69(m,1H),1.66–1.49(m,1H),1.40–1.33(m, 6H),1.28–1.18(m,13H).
实施例9:乙基(2S)-2-[[[(3R)-1-[3-[(2-氰基-5-氟-苯基)甲基]-1-甲基-2,6-二氧代-嘧啶-4- 基]-3-哌啶基]氨基]-[[(1S)-2-乙氧基-1-甲基-2-氧代-乙基]氨基]磷酰基]氨基]丙酸酯(化合物9)的合成
ethyl(2S)-2-[[[[(3R)-1-[3-[(2-cyano-5-fluoro-phenyl)methyl]-1-methyl-2,6-dioxo- pyrimidin-4-yl]-3-piperidyl]amino]-[[(1S)-2-ethoxy-1-methyl-2-oxo-ethyl]amino]phosphoryl]amino] propanoate
氮气保护下,将二氯甲烷(20mL)加入反应瓶中,搅拌下加入三氯氧磷(0.50g,3.26mmol),冷却至-78℃。缓慢滴入曲格列汀(1.07g,3mmol)、三乙胺(0.30g,3mmol)和二氯甲烷(5mL) 的混合溶液,加完后-78℃反应1h。然后依次加入L-丙氨酸乙酯盐酸盐(7A)(0.99g,6.46mmol) 的二氯甲烷(5mL)溶液和三乙胺(1.48g,14.6mmol)加完后升至室温搅拌反应5h,然后加入二氯甲烷(30mL)和水(50mL),搅拌5min,静置分层。有机层用无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析分离提纯(二氯甲烷/甲醇=(v/v)50/1~20/1),所得粗品通过制备液相进一步分离纯化(液相制备条件:仪器:Thar 80 preparativeSFC;色谱柱:ChiralPak AS-20u, 250×50mmI.D.;流动相:A:CO2,B:甲醇;梯度:B 35%;流量:70mL/min;背压:100bar;柱温:38℃;波长:220nm;周期:12min;样品制备:化合物1溶解于甲醇中制得15mg/ml;注射:1.5ml/针),得到乙基(2S)-2-[[[(3R)-1-[3-[(2-氰基-5-氟-苯基)甲基]-1-甲基-2,6-二氧代-嘧啶-4- 基]-3-哌啶基]氨基]-[[(1S)-2-乙氧基-1-甲基-2-氧代-乙基]氨基]磷酰基]氨基]丙酸酯(化合物9),白色泡状固体0.33g,收率:17.34%。
MS m/z(ESI):[M+H]+.
1H NMR(400MHz,CDCl3)δ7.68(dd,1H),7.08(td,1H),6.93(dd,1H),5.38(s,1H),5.34– 5.18(m,2H),4.28–4.06(m,4H),4.02–3.86(m,2H),3.46–3.19(m,5H),2.84(s,2H),2.70– 2.38(m,4H),2.04–1.88(m,1H),1.83–1.70(m,1H),1.64–1.50(m,1H),1.42–1.33(m,6H), 1.31–1.20(m,7H).
实施例10
异丙基(2S)-2-[[[[(1S)-2-异丙氧基-1-甲基-2-氧代-乙基]氨基]-[2-甲氧基-5-[(Z)-2-(3,4,5- 三甲氧基苯基)乙烯基]苯氧基]磷酰基]氨基]丙酸酯(化合物10)
isopropyl
(2S)-2-[[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-[2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyp henyl)vinyl]phenoxy]phosphoryl]amino]propanoate
氮气保护下,将四氢呋喃(20mL)加入反应瓶中,搅拌下加入三氯氧磷(0.58g,3.79mmol),冷却至-78℃。缓慢滴入顺式CA-4(1.00g,3.16mmol)、三乙胺(0.32g,3.16mmol)和四氢呋喃(5mL)的混合溶液,加完后-78℃反应1h。然后依次加入L-丙氨酸异丙酯盐酸盐(1.66 g,12.6mmol)的二氯甲烷(10mL)溶液和三乙胺(2.88g,28.4mmol)加完后升至室温搅拌反应5h,然后加入乙酸乙酯(50mL)和水(50mL),搅拌5min,静置分层。有机层用无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析分离提纯(石油醚/乙酸乙酯=(v/v) 1/1),得到异丙基(2S)-2-[[[(1S)-2-异丙氧基-1-甲基-2-氧代-乙基]氨基]-[2-甲氧基-5-[(Z)-2-(3,4, 5-三甲氧基苯基)乙烯基]苯氧基]磷酰基]氨基]丙酸酯(化合物10),淡黄色油状物0.90g,收率:45.7%。
MS m/z(ESI):623.2[M+H]+。
1H NMR(400MHz,CDCl3)δ7.20(t,1H),7.09–7.01(m,1H),6.77(d,1H),6.50(s,2H),6.43 (s,2H),5.09–4.89(m,2H),4.08–3.95(m,2H),3.86(s,3H),3.84(s,3H),3.77–3.64(m,8H), 1.41–1.30(m,6H),1.26–1.21(m,12H)。
实施例11
异丙基(2S)-2-[[(2,6-二异丙基苯氧基)-[[(1S)-2-异丙氧基-1-甲基-2-氧代-乙基]氨基]磷酰基] 氨基]丙酸酯(化合物11)
isopropyl
(2S)-2-[[(2,6-diisopropylphenoxy)-[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]phosphoryl]am ino]propanoate
氮气保护下,将四氢呋喃(20mL)加入反应瓶中,搅拌下加入三氯氧磷(0.52g,3.37mmol),冷却至-78℃。缓慢滴入丙泊酚(0.50g,2.80mmol)、三乙胺(0.34g,3.36mmol)和四氢呋喃(5mL)的混合溶液,加完后-78℃反应1h。然后依次加入L-丙氨酸异丙酯盐酸盐(1.08g, 6.46mmol)的二氯甲烷(5mL)溶液和三乙胺(1.48g,14.6mmol)加完后升至室温搅拌反应5h,然后加入二氯甲烷(50mL)和水(50mL),搅拌5min,静置分层。有机层用无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析分离提纯(石油醚/乙酸乙酯=(v/v)1/1),所得化合物通过制备液相进一步分离纯化(液相制备条件:仪器:Thar 80 preparative SFC;色谱柱:ChiralPak AS-20u,250×50mmI.D.;流动相:A:CO2,B:甲醇;梯度:B 35%;流量:70mL /min;背压:100bar;柱温:38℃;波长:220nm;周期:12min;样品制备:化合物1溶解于甲醇中制得15mg/ml;注射:1.5ml/针),得到异丙基(2S)-2-[[(2,6-二异丙基苯氧基)-[[(1S)-2-异丙氧基-1-甲基-2-氧代-乙基]氨基]磷酰基]氨基]丙酸酯(化合物11),无色透明油状物0.52g,收率: 38.3%。
MS m/z(ESI):485.3[M+H]+
1H NMR(400MHz,CDCl3)δ7.10(m,3H),5.01(m,2H),4.08–3.90(m,2H),3.59–3.16(m,4H),1.41–1.20(m,30H)。
实施例12
乙基(2S)-2-[[(2,6-二异丙基苯氧基)-[[(1S)-2-乙氧基-1-甲基-2-氧代-乙基]氨基]磷酰基]氨基]丙酸酯(化合物12)
ethyl
(2S)-2-[[(2,6-diisopropylphenoxy)-[[(1S)-2-ethoxy-1-methyl-2-oxo-ethyl]amino]phosphoryl]amino] propanoate
氮气保护下,将二氯甲烷(20mL)加入反应瓶中,搅拌下加入三氯氧磷(0.52g,3.37mmol),冷却至-78℃。缓慢滴入丙泊酚(0.50g,2.80mmol)、三乙胺(0.34g,3.36mmol)和二氯甲烷(5mL)的混合溶液,加完后-78℃反应1h。然后依次加入L-丙氨酸异丙酯盐酸盐(1.08g, 6.46mmol)的二氯甲烷(5mL)溶液和三乙胺(1.48g,14.6mmol)加完后升至室温搅拌反应5h,然后加入二氯甲烷(50mL)和水(50mL),搅拌5min,静置分层。有机层用无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析分离提纯(石油醚/乙酸乙酯=(v/v)1/1),所得化合物通过制备液相进一步分离纯化(液相制备条件:仪器:Thar 80 preparative SFC;色谱柱:ChiralPak AS-20u,250×50mmI.D.;流动相:A:CO2,B:甲醇;梯度:B 35%;流量:70mL /min;背压:100bar;柱温:38℃;波长:220nm;周期:12min;样品制备:化合物1溶解于甲醇中制得15mg/ml;注射:1.5ml/针),得到乙基(2S)-2-[[(2,6-二异丙基苯氧基)-[[(1S)-2-乙氧基-1- 甲基-2-氧代-乙基]氨基]磷酰基]氨基]丙酸酯(化合物12),无色透明油状物0.45g,收率:35.6%。
MS m/z(ESI):457.2[M+H]+。
1H NMR(400MHz,CDCl3)δ7.11(m,3H),4.25–4.10(m,4H),4.08–3.96(m,2H),3.61–3.39(m,3H),3.39–3.26(s,1H),1.40–1.20(m,24H)。
实施例13
异丙基(2S)-2-[[(2,6-二异丙基苯氧基)甲氧基-[[(1S)-2-异丙氧基-1-甲基-2-氧代-乙基]氨基] 磷酰基]氨基]丙酸酯(化合物13)
isopropyl
(2S)-2-[[(2,6-diisopropylphenoxy)methoxy-[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]phosp horyl]amino]propanoate
第一步:异丙基(2S)-2-[[苄氧基-[[(1S)-2-异丙氧基-1-甲基-2-氧代-乙基]氨基]磷酰基]氨基] 丙酸酯(13A)
isopropyl
(2S)-2-[[benzyloxy-[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]phosphoryl]amino]propanoate
氮气保护下,将二氯甲烷(40mL)加入反应瓶中,搅拌下加入三氯氧磷(3.37g,22mmol),冷却至-78℃。缓慢滴入苯甲醇(2.16g,20mmol)、三乙胺(2.02g,20mmol)和二氯甲烷(10 mL)的混合溶液,加完后-78℃反应1h。然后依次加入L-丙氨酸异丙酯盐酸盐(7.71g,46mmol) 的二氯甲烷(20mL)溶液和三乙胺(10.12g,100mmol)加完后升至室温搅拌反应5h,然后加入二氯甲烷(100mL)和水(100mL),搅拌5min,静置分层。有机层用无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析分离提纯(石油醚/乙酸乙酯=(v/v)1/1),得到异丙基(2S)-2-[[苄氧基-[[(1S)-2-异丙氧基-1-甲基-2-氧代-乙基]氨基]磷酰基]氨基]丙酸乙酯 (13A),淡黄色油状物,2.12g,收率:25.6%。
MS m/z(ESI):415.2[M+H]+。
1H NMR(400MHz,CDCl3)δ7.43–7.22(m,5H),5.12–4.87(m,4H),4.02–3.81(m,2H),3.22(s,2H),1.41–1.30(m,6H),1.25–1.18(m,12H).
第二步:双[[(1S)-2-异丙氧基-1-甲基-2-氧代-乙基]氨基]次膦酸(13B)
bis[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]phosphinic acid
将甲醇(20mL)和异丙基(2S)-2-[[苄氧基-[[(1S)-2-异丙氧基-1-甲基-2-氧代-乙基]氨基] 磷酰基]氨基]丙酸乙酯(13A,2.00g,4.83mmol)加入反应瓶中,搅拌下加入10%Pd/C(0.20 g);氢气换气三次,氢化反应3h。过滤,减压浓缩干,得到双[[(1S)-2-异丙氧基-1-甲基-2-氧代-乙基]氨基]次膦酸(13B),淡黄色油状物1.22g,收率:65.9%。
MS m/z(ESI):325.1[M+H]+。
第三步:2-(氯甲氧基)-1,3-二异丙基-苯(13C)
2-(chloromethoxy)-1,3-diisopropyl-benzene
将丙泊酚(5.34g,30mmol)、氯溴甲烷(77.74g,600mmol)、四氢呋喃(50mL) 和氢氧化钠(1.60g,45mmol)加入反应瓶中,加热至回流反应2h。冷却至室温,加入石油醚(100mL)和水(100mL),搅拌5min,静置分层。有机层用无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析分离提纯(石油醚),得到2-(氯甲氧基)-1,3-二异丙基-苯(13C),无色透明油状物5.24g,收率:77.2%。
1H NMR(400MHz,CDCl3)δ7.22–7.05(m,3H),5.74(s,2H),3.50–3.24(m,2H),1.26–1.14(m,12H)。
第四步:异丙基(2S)-2-[[(2,6-二异丙基苯氧基)甲氧基-[[(1S)-2-异丙氧基-1-甲基-2-氧代-乙基]氨基]磷酰基]氨基]丙酸酯(化合物13)的合成
isopropyl
(2S)-2-[[(2,6-diisopropylphenoxy)methoxy-[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]phosp horyl]amino]propanoate
将双[[(1S)-2-异丙氧基-1-甲基-2-氧代-乙基]氨基]次膦酸(13B,0.93g,3mmol)、2-(氯甲氧基)-1,3-二异丙基-苯(13C,0.79g,3.5mmol)和乙腈(20mL)加入反应瓶中,搅拌下加入三乙胺(0.45g,4.5mmol),加热至回流反应6h。减压浓缩干,加入乙酸乙酯(50mL) 和水(50mL),搅拌5min,静置分层。有机层用无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析分离提纯(石油醚/乙酸乙酯=(v/v)2/1),所得化合物通过制备液相进一步分离纯化(液相制备条件:仪器:Thar 80 preparative SFC;色谱柱:ChiralPak AS-20u,250×50mmI.D.;流动相:A:CO2,B:甲醇;梯度:B 35%;流量:70mL/min;背压:100bar;柱温:38℃;波长:220nm;周期:12min;样品制备:化合物1溶解于甲醇中制得15mg/ml;注射:1.5ml/针),得到异丙基(2S)-2-[[(2,6-二异丙基苯氧基)甲氧基-[[(1S)-2-异丙氧基-1-甲基-2-氧代-乙基]氨基] 磷酰基]氨基]丙酸酯(化合物13),淡黄色油状物0.49g,收率:27.3%。
MS m/z(ESI):515.3[M+H]+。
1H NMR(400MHz,CDCl3)δ7.20–7.04(m,3H),5.50–5.35(m,2H),5.14–4.92(m,2H),4.01–3.80(m,2H),3.56–2.88(m,4H),1.40–1.28(m,6H),1.26–1.17(m,24H)。
实施例14
乙基(2S)-2-[[(2,6-二异丙基苯氧基)甲氧基-[[(1S)-2-乙氧基-1-甲基-2-氧代-乙基]氨基]磷酰基]氨基]丙酸酯(化合物14)
ethyl
(2S)-2-[[(2,6-diisopropylphenoxy)methoxy-[[(1S)-2-ethoxy-1-methyl-2-oxo-ethyl]amino]phosphoryl ]amino]propanoate
第一步:乙基(2S)-2-[[苄氧基-[[(1S)-2-乙氧基-1-甲基-2-氧代-乙基]氨基]磷酰基]氨基]丙酸酯(14A)
ethyl
(2S)-2-[[benzyloxy-[[(1S)-2-ethoxy-1-methyl-2-oxo-ethyl]amino]phosphoryl]amino]propanoate
氮气保护下,将二氯甲烷(60mL)加入反应瓶中,搅拌下加入三氯氧磷(5.06g,33mmol),冷却至-78℃。缓慢滴入苯甲醇(3.24g,30mmol)、三乙胺(3.03g,30mmol)和二氯甲烷(5 mL)的混合溶液,加完后-78℃反应1h。然后依次加入L-丙氨酸乙酯盐酸盐(10.59g,69mmol) 和三乙胺(15.15g,150mmol)加完后升至室温搅拌反应5h,然后加入二氯甲烷(100mL) 和水(100mL),搅拌5min,静置分层。有机层用无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析分离提纯(石油醚/乙酸乙酯=(v/v)1/1),得到乙基(2S)-2-[[苄氧基-[[(1S)-2-乙氧基-1-甲基-2-氧代-乙基]氨基]磷酰基]氨基]丙酸酯(14A),淡黄色油状物,3.26g,收率:28.2%
MS m/z(ESI):387.1[M+H]+。
第二步:双[[(1S)-2-乙氧基-1-甲基-2-氧代-乙基]氨基]次膦酸(14B)
bis[[(1S)-2-ethoxy-1-methyl-2-oxo-ethyl]amino]phosphinic acid
将甲醇(30mL)和乙基(2S)-2-[[苄氧基-[[(1S)-2-乙氧基-1-甲基-2-氧代-乙基]氨基]磷酰基] 氨基]丙酸酯(14A,1.90g,4.92mmol)加入反应瓶中,搅拌下加入10%Pd/C(0.40g);氢气换气三次,室温下氢化反应2h。过滤,减压浓缩干,得到双[[(1S)-2-乙氧基-1-甲基-2-氧代-乙基]氨基]次膦酸(14B),淡黄色油状物1.41g,收率:96.8%。
MS m/z(ESI):297.2[M+H]+。
第三步:乙基(2S)-2-[[(2,6-二异丙基苯氧基)甲氧基-[[(1S)-2-乙氧基-1-甲基-2-氧代-乙基] 氨基]磷酰基]氨基]丙酸酯(化合物14)
将双[[(1S)-2-乙氧基-1-甲基-2-氧代-乙基]氨基]次膦酸(14B,1.41g,4.76mmol)、2-(氯甲氧基)-1,3-二异丙基-苯(3C,0.91g,4mmol)和乙腈(20mL)加入反应瓶中,搅拌下加入三乙胺(0.61g,6mmol),加热至回流反应6h。减压浓缩干,加入乙酸乙酯(100mL)和水(100 mL),搅拌5min,静置分层。有机层用无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析分离提纯(石油醚/乙酸乙酯=(v/v)3/1~2/1),所得化合物通过制备液相进一步分离纯化(液相制备条件:仪器:Thar 80 preparative SFC;色谱柱:ChiralPakAS-20u,250×50mmI.D.;流动相:A:CO2,B:甲醇;梯度:B 35%;流量:70mL/min;背压:100bar;柱温:38℃;波长:220nm;周期:12min;样品制备:化合物1溶解于甲醇中制得15mg/ml;注射:1.5ml/针),得到乙基 (2S)-2-[[(2,6-二异丙基苯氧基)甲氧基-[[(1S)-2-乙氧基-1-甲基-2-氧代-乙基]氨基]磷酰基]氨基] 丙酸酯(化合物14),淡黄色油状物0.86g,收率:43.9%。
MS m/z(ESI):487.3[M+H]+
1H NMR(400MHz,CDCl3)δ7.17–7.08(m,3H),5.48–5.36(m,2H),4.22–4.12(m,4H),4.00–3.87(m,2H),3.48–3.15(m,4H),1.39–1.32(m,6H),1.27–1.20(m,18H).
实施例15
异丙基2-[[(2,6-二异丙基苯氧基)-[(2-异丙氧基-2-氧代)-乙基]氨基]磷酰基]氨基]乙酸酯(化合物15)
isopropyl
2-[[(2,6-diisopropylphenoxy)-[(2-isopropoxy-2-oxo-ethyl)amino]phosphoryl]amino]acetate
氮气保护下,将二氯甲烷20mL加入反应瓶中,搅拌下加入三氯氧磷(0.84g,5.5mmol),冷却至-78℃。缓慢滴入丙泊酚(0.90g,5mmol)、三乙胺(0.51g,5mmol)和二氯甲烷(10 mL)的混合溶液,加完后-78℃反应1h。然后依次加入甘氨酸异丙酯盐酸盐(1.77g,11.5mmol) 和三乙胺(2.53g,25mmol)加完后室温搅拌反应5h,加入二氯甲烷(50mL)和水(50mL),搅拌5min,静置分层。有机层用无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析分离提纯(石油醚/乙酸乙酯=(v/v)1/1),得到目标化合物异丙基(2S)-2-[[[(3R)-1-[3-[(2-氰基-5- 氟-苯基)甲基]-1-甲基-2,6-二氧代-嘧啶-4-基]-3-哌啶基]氨基]-[[(1S)-2-异丙氧基-1-甲基-2-氧代- 乙基]氨基]磷酰基]氨基]丙酸酯(化合物15),淡黄色油状物0.53g,收率:23.0%。
MS m/z(ESI):457.3[M+H]+。
1H NMR(400MHz,CDCl3)δ7.11(s,3H),5.14–4.99(m,2H),3.91–3.63(m,4H),3.52–3.37(m,2H),1.27–1.22(m,26H)。
实施例16
乙基2-[[(2,6-二异丙基苯氧基)-[(2-乙氧基-2-氧代-乙基)氨基]磷酰基]氨基]乙酸酯(化合物 16)
ethyl 2-[[(2,6-diisopropylphenoxy)-[(2-ethoxy-2-oxo-ethyl)amino]phosphoryl]amino]acetate
氮气保护下,将二氯甲烷50mL加入反应瓶中,搅拌下加入三氯氧磷(1.68g,11mmol),冷却至-78℃。缓慢滴入丙泊酚(1.80g,10mmol)、三乙胺(1.02g,10mmol)和二氯甲烷(10 mL)的混合溶液,加完后-78℃反应1h。然后依次加入甘氨酸乙酯盐酸盐(3.21g,23mmol) 和三乙胺(5.06g,50mmol)加完后室温搅拌反应5h,加入二氯甲烷(100mL)和水(100mL),搅拌5min,静置分层。有机层用无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析分离提纯(石油醚/乙酸乙酯=(v/v)1/1),得到目标化合物乙基2-[[(2,6-二异丙基苯氧基)-[(2-乙氧基-2-氧代-乙基)氨基]磷酰基]氨基]乙酸酯(化合物16),淡黄色油状物1.52g,收率:35.1%。
MS m/z(ESI):429.2[M+H]+。
1H NMR(400MHz,CDCl3)δ7.11(s,3H),4.28–4.15(m,4H),3.96–3.80(m,2H),3.80–3.66(m,2H),3.59–3.26(m,4H),1.29–1.22(m,18H)。
实施例17
异丙基(2S)-2-[[[(8R,9S,13S,14S,17R)-17-乙炔基-17-羟基-13-甲基-7,8,9,11,12,14,15,16-八氢 -6H-环戊二烯并[a]菲-3-基]氧基-[[(1S)-2-异丙氧基-1-甲基-2-氧代-乙基]氨基]磷酰基]氨基]丙酸酯(化合物17)
isopropyl
(2S)-2-[[[(8R,9S,13S,14S,17R)-17-ethynyl-17-hydroxy-13-methyl-7,8,9,11,12,14,15,16-octahydro-6 H-cyclopenta[a]phenanthren-3-yl]oxy-[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]phosphoryl] amino]propanoate
氮气保护下,将四氢呋喃(20mL)加入反应瓶中,搅拌下加入三氯氧磷(0.57g,3.71mmol),冷却至-78℃。缓慢滴入雌炔醇(1.00g,3.37mmol)、三乙胺(0.34g,3.37mmol)和四氢呋喃(5mL)的混合溶液,加完后-78℃反应1h。然后依次加入L-丙氨酸异丙酯盐酸盐(1.13g, 6.75mmol)的二氯甲烷(10mL)溶液和三乙胺(1.70g,16.85mmol)加完后升至室温搅拌反应5h,然后加入乙酸乙酯(50mL)和水(50mL),搅拌5min,静置分层。有机层用无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析分离提纯(石油醚/乙酸乙酯=(v/v)1/1),得到异丙基(2S)-2-[[[(8R,9S,13S,14S,17R)-17-乙炔基-17-羟基-13-甲基-7,8,9,11,12,14,15,16- 八氢-6H-环戊二烯并[a]菲-3-基]氧基-[[(1S)-2-异丙氧基-1-甲基-2-氧代-乙基]氨基]磷酰基]氨基] 丙酸酯(化合物17),白色泡状固体0.70g,收率:20.60%。
MS m/z(ESI):603.3[M+H]+。
1H NMR(400MHz,CDCl3)δ7.20(d,1H),7.00–6.88(m,2H),5.09–4.94(m,2H),4.07–3.93(m,2H),3.48(s,1H),2.90–2.78(m,2H),2.60(s,1H),2.40–2.27(m,2H),2.26–2.16(m,1H),2.08–1.97(m,2H),1.96–1.62(m,6H),1.53–1.31(m,10H),1.27–1.20(m,12H),0.87(s,3H)。
实施例18
异丙基(2S)-2-[[[(8R,9S,13S,14S,17S)-17-羟基-13-甲基-6,7,8,9,11,12,14,15,16,17-十氢[a]菲-3-基]氧基-[[(1S)-2-异丙氧基-1-甲基-2-氧代-乙基]氨基]磷酰基]氨基]丙酸酯(化合物18)
isopropyl
(2S)-2-[[[(8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopen ta[a]phenanthren-3-yl]oxy-[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]phosphoryl]amino]prop anoate
氮气保护下,将四氢呋喃(20mL)加入反应瓶中,搅拌下加入三氯氧磷(0.67g,4.36mmol),冷却至-78℃。缓慢滴入雌二醇(1.08g,3.96mmol)、三乙胺(0.40g,3.96mmol) 和四氢呋喃(5mL)的混合溶液,加完后-78℃反应1h。然后依次加入L-丙氨酸异丙酯盐酸盐(1.53g,9.12mmol)的二氯甲烷(10mL)溶液和三乙胺(2.00g,19.8mmol)加完后升至室温搅拌反应5h,然后加入乙酸乙酯(50mL)和水(50mL),搅拌5min,静置分层。有机层用无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析分离提纯(石油醚/乙酸乙酯=(v/v)1/1),所得化合物通过制备液相进一步分离纯化,得到异丙基 (2S)-2-[[[(8R,9S,13S,14S,17S)-17-羟基-13-甲基-6,7,8,9,11,12,14,15,16,17-十氢[a]菲-3-基]氧基 -[[(1S)-2-异丙氧基-1-甲基-2-氧代-乙基]氨基]磷酰基]氨基]丙酸酯(化合物18),白色泡状固体0.30g,收率:13.1%。
1H NMR(400MHz,CDCl3)δ7.19(d,1H),7.00–6.83(m,2H),5.13–4.88(m,2H),4.12–3.92(m,2H),3.72(t,1H),3.43(s,1H),2.93–2.73(m,2H),2.35–2.24(m,1H),2.22–1.80(m,5H),1.78–1.59(m,1H),1.57–1.10(m,26H),0.77(s,3H)。
实施例19
异丙基(2S)-2-[[[(4R,4aS,7aR,12bS)-3-烯丙基-4a-羟基-7-氧代-2,4,5,6,7a,13-六氢-1H-4,12- 亚甲基苯并呋喃[3,2-e]异喹啉-9-基]氧基-[[(1S)-2-异丙氧基-1-甲基-2-氧代-乙基]氨基]磷酰基] 氨基]丙酸酯(化合物19)
isopropyl
(2S)-2-[[[(4R,4aS,7aR,12bS)-3-allyl-4a-hydroxy-7-oxo-2,4,5,6,7a,13-hexahydro-1H-4,12-methanob enzofuro[3,2-e]isoquinoline-9-yl]oxy-[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]phosphoryl] amino]propanoate
氮气保护下,将四氢呋喃(20mL)加入反应瓶中,搅拌下加入三氯氧磷(1.01g,6.60mmol),冷却至-78℃。缓慢滴入纳洛酮盐酸盐(2.00g,5.50mmol)、三乙胺(0.55g,5.50mmol)和四氢呋喃(5mL)的混合溶液,加完后-78℃反应1h。然后依次加入L-丙氨酸异丙酯盐酸盐(1.73g,13.2mmol)的二氯甲烷(10mL)溶液和三乙胺(2.78g,27.5mmol) 加完后升至室温搅拌反应5h,然后加入乙酸乙酯(50mL)和水(50mL),搅拌5min,静置分层。有机层用无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析分离提纯(石油醚 /乙酸乙酯=(v/v)1/1),得到异丙基(2S)-2-[[[(4R,4aS,7aR,12bS)-3-烯丙基-4a-羟基-7-氧代 -2,4,5,6,7a,13-六氢-1H-4,12-亚甲基苯并呋喃[3,2-e]异喹啉-9-基]氧基-[[(1S)-2-异丙氧基-1-甲基 -2-氧代-乙基]氨基]磷酰基]氨基]丙酸酯(化合物19),淡黄色油状物0.55g,收率:15.8%。
MS m/z(ESI):634.3[M+H]+。
1H NMR(400MHz,CDCl3)δ7.07(dd,1H),6.67(d,1H),5.96–5.75(m,1H),5.31–5.16(m, 2H),5.09–4.93(m,2H),4.73(s,1H),4.20–3.94(m,3H),3.89–3.76(m,1H),3.26–2.96(m, 5H),2.72–2.54(m,2H),2.52–2.36(m,1H),2.32–2.20(m,1H),2.20–2.07(m,1H),2.00–1.81 (m,1H),1.64–1.50(m,2H),1.44(d,3H),1.33–1.17(m,16H)。
实施例20
乙基(2S)-2-[[[(4R,4As,7aR,12bS)-3-烯丙基-4a-羟基-7-氧代-2,4,5,6,7a,13-六氢-1H-4,12- 亚甲基苯并呋喃[3,2-e]异喹啉-9-基]氧基-[[(1S)-2-乙氧基-1-甲基-2-氧代-乙基]氨基]磷酰基]氨基]丙酸酯(化合物20)
ethyl
(2S)-2-[[[(4R,4aS,7aR,12bS)-3-allyl-4a-hydroxy-7-oxo-2,4,5,6,7a,13-hexahydro-1H-4,12-methanob enzofuro[3,2-e]isoquinoline-9-yl]oxy-[[(1S)-2-ethoxy-1-methyl-2-oxo-ethyl]amino]phosphoryl]amin o]propanoate
氮气保护下,将四氢呋喃(20mL)加入反应瓶中,搅拌下加入三氯氧磷(0.50g,3.27mmol),冷却至-78℃。缓慢滴入纳洛酮盐酸盐(1.08g,2.97mmol)、三乙胺(0.30g,2.97mmol)和四氢呋喃(5mL)的混合溶液,加完后-78℃反应1h。然后依次加入L-丙氨酸异丙酯盐酸盐(1.05g, 6.83mmol)的二氯甲烷(10mL)溶液和三乙胺(1.50g,14.85mmol)加完后升至室温搅拌反应5h,然后加入乙酸乙酯(50mL)和水(50mL),搅拌5min,静置分层。有机层用无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析分离提纯(石油醚/乙酸乙酯=(v/v)1/1),所得化合物通过制备液相进一步分离纯化(液相制备条件:仪器:Thar 80preparative SFC;色谱柱: ChiralPak AS-20u,250×50mmI.D.;流动相:A:CO2,B:甲醇;梯度:B 35%;流量:70mL/min;背压:100bar;柱温:38℃;波长:220nm;周期:12min;样品制备:化合物1溶解于甲醇中制得15mg/ml;注射:1.5ml/针),得到乙基(2S)-2-[[[(4R,4As,7aR,12bS)-3-烯丙基-4a-羟基-7-氧代 -2,4,5,6,7a,13-六氢-1H-4,12-亚甲基苯并呋喃[3,2-e]异喹啉-9-基]氧基-[[(1S)-2-乙氧基-1-甲基-2- 氧代-乙基]氨基]磷酰基]氨基]丙酸酯(化合物20),淡黄色油状物0.52g,收率:30.9%。
MS m/z(ESI):606.2[M+H]+。
1H NMR(400MHz,CDCl3)δ7.10–7.02(m,1H),6.68(d,1H),5.85(s,1H),5.35–5.15(m, 2H),4.74(s,1H),4.23–4.09(m,6H),4.09–3.96(m,1H),3.88–3.72(m,1H),3.32–2.92(m,5H), 2.73–2.36(m,3H),2.33–2.23(m,1H),2.22–2.05(m,1H),2.01–1.81(m,1H),1.66–1.50(m, 2H),1.49–1.40(m,3H),1.34–1.18(m,10H)。
生物测试例
测试例1:大鼠血浆DPP-IV酶学筛选实验
实验动物为SD大鼠,8周龄,雄性,购自北京维通利华实验动物技术有限公司,动物生产合格证号:SCXK(京)2012-0001。将禁食后的大鼠按体重分组。大鼠采用眼眶取血,EDTA-2Na 抗凝受试组口服受试化合物,剂量为3.0mg/kg;对照组口服空白试剂。分别于给药后不同时间点处取血。将血液样本于2500rpm离心15min,取出血浆,于-20℃保存。酶活测试,每个受试样取40μl血浆,加入10μl H-Ala-Pro-AFC底物(0.2mM),反应15min后用酶标仪测值(激发波长Excitation=405nM;发射波长Emission=535nM),使用Origin 7.5进行统计分析,计算测试化合物对血浆DPP-IV酶活抑制率≥70%所持续的时间,结果见表1.
表1
化合物 | 给药方式/剂量 | >70%抑制率时间(h) |
化合物3A | IV 3mg/kg | 12.31 |
化合物3A | PO 6mg/kg | 12.46 |
化合物3 | PO 9.26mg/kg | 17.24 |
测试例2:大鼠药代动力学测试
试验动物:雄性SD大鼠,180~220g左右,6~8周龄,购于成都达硕实验动物有限公司。动物饲养于SPF环境中,温度20-22℃,相对湿度:51-55%,12h/12h明暗光照,自由饮食饮水,适应性观察3天后开始试验。
药物配制:准确称取一定量受试化合物,DMSO溶解,加入solutol HS-15增溶,再加入生理盐水,旋涡混合即可。DMSO终浓度为5%,solutolHS-15终浓度为5%。所有受试化合物均临用前新鲜配制。
给药及检测:试验当天,12只SD大鼠按体重随机分为4组,每组3只。给药前1天禁食不禁水12~14h,给药后4h给食。大鼠分别口服给予不同受试化合物,给药体积为5mL/kg或10mL/kg。于给药前及给药后异氟烷麻醉经眼眶取血0.20ml,采血时间点选取0min,5min,10min,15min,30min,1h,1.5h,2h,4h,6h,8h,24h,30h,48h中的某些时间,肝素抗凝,3500rpm或6000rpm,4℃离心10min,收集血浆。所有血浆样品分析前存于-80℃。采用 HPLC-MS/MS对血浆样品中的原型药物进行检测,结果见下述的表:
表2:大鼠药代动力学参数
备注:每个化合物检测的为其对应的原药。
结论:本发明化合物具有较长的半衰期和良好的生物利用度。
表3大鼠药代动力学测试结果
结论:与顺式CA-4相比,本发明化合物10具有更长的半衰期,更高的生物利用度,约为顺式CA-4的5~6倍。
表4大鼠药代动力学测试结果
结果:化合物11具有口服性。
表5大鼠药代动力学测试结果
结论:口服化合物17后,表现出良好的Cmax与AUC0-t,具有口服性。
表6比格犬药代动力学测试结果
结论:与纳洛酮相比,本发明化合物19、20均具有更高的生物利用度,约为纳洛酮的2 倍。
3、比格犬药代动力学测试
试验动物:雄性Beagle犬,5~7kg左右,购于成都达硕实验动物有限公司。动物饲养于 SPF环境中,温度20-22℃,相对湿度:51-55%,12h/12h明暗光照,自由饮食饮水,适应性观察3天后开始试验。
药物配制:准确称取一定量受试化合物,DMSO溶解,加入solutol HS-15增溶,再加入生理盐水,旋涡混合即可。DMSO终浓度为5%,solutolHS-15终浓度为5%。所有受试化合物均临用前新鲜配制。
给药及检测:试验当天,比格犬按体重随机分组,每组3只。给药前1天禁食不禁水12~14h,给药后4h给食。比格犬分别口服给予不同受试化合物,给药体积为5mL/kg。于给药前及给药后经四肢静脉取血1.5ml左右,采血时间点选取0min,5min,10min,15min,30min,1h,1.5h,2h,4h,6h,8h,24h,30h,48h中的某些时间,肝素抗凝,3500rpm,4℃离心10min,收集血浆。所有血浆样品分析前存于-80℃。采用HPLC-MS/MS对血浆样品中的原型药物进行检测,结果如表7所示:
表7比格犬药代动力学测试结果
结论:口服化合物12后具有较好的生物利用度。
Claims (7)
1.一种通式(I)所示化合物及其立体异构体或药学上可接受的盐,
Q-L-R1 (I)
其中:
当Q选自时;
R1选自
R1a、R1c各自独立的选自H或C1-4烷基,所述的烷基任选进一步被0至4个选自H、F、Cl、Br、I、C1-4烷基或C1-4烷氧基的取代基所取代;
R1b、R1d各自独立的选自C1-4烷基,所述的烷基任选进一步被0至4个选自H、F、Cl、Br、I、C1-4烷基或C1-4烷氧基的取代基所取代;
L选自键;
当Q选自时;
R1选自
R1a、R1c各自独立的选自H或C1-4烷基,所述的烷基任选进一步被0至4个选自H、F、Cl、Br、I、C1-4烷基或C1-4烷氧基的取代基所取代;
R1b、R1d各自独立的选自C1-4烷基;,所述的烷基任选进一步被0至4个选自H、F、Cl、Br、I、C1-4烷基或C1-4烷氧基的取代基所取代;
L选自键或CH2O,其中L的左边与Q连接,右边与R1连接;
当Q选自
时;
L选自键;
R选自
Ra、Rc、Re各自独立的选自H或C1-6烷基,所述的烷基任选进一步被0至4个选自F、Cl、Br、I、C1-4烷基或C1-4烷氧基的取代基所取代;
Rb、Rd、Rf各自独立的选自C1-6烷基,所述的烷基任选进一步被0至4个选自F、Cl、Br、I、C1-4烷基或C1-4烷氧基的取代基所取代。
2.根据权利要求1所述所述的化合物及其立体异构体或药学上可接受的盐,其中
R1a、R1c各自独立的选自H或C1-4烷基;
R1b、R1d各自独立的选自C1-4烷基。
3.根据权利要求2所述所述的化合物及其立体异构体或药学上可接受的盐,其中
R1a、R1c各自独立的选自H、甲基、乙基、丙基或异丙基;
R1b、R1d各自独立的选自甲基、乙基、丙基或异丙基;
Ra、Rc、Re各自独立的选自H、甲基、乙基或异丙基;
Rb、Rd、Rf各自独立的选自甲基、乙基、丙基或异丙基。
4.根据权利要求1所述的化合物及其立体异构体或药学上可接受的盐,其中该化合物选自如下结构之一:
5.一种药物组合物,所述药物组合物含有治疗有效剂量的权利要求1~4中任意一项所述的化合物或其立体异构体或药学上可接受的盐,以及药学上可接受的载体和赋形剂。
6.权利要求1~4中任意一项所述的化合物及其立体异构体或药学上可接受的盐,以及权利要求5所述的组合物在制备治疗和预防癌症、骨髓增生异常综合征、中枢神经系统相关疾病、雌激素相关疾病、酒精中毒、阿片类药物过量中毒、阿片药成瘾的诊断相关药物或糖尿病的药物中的应用。
7.权利要求6所述的应用,其中中枢神经系统相关疾病选自麻醉、镇痛、偏头痛、催眠或脑保护,雌激素相关疾病选自补充雌激素不足、前列腺癌、乳腺癌、骨质疏松、痤疮、白细胞减少症、不育症、皮肤瘙痒、绝经期综合症或避孕。
Applications Claiming Priority (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2017106299237 | 2017-07-28 | ||
CN201710629867 | 2017-07-28 | ||
CN201710624505 | 2017-07-28 | ||
CN201710629923 | 2017-07-28 | ||
CN201710626904 | 2017-07-28 | ||
CN201710629961 | 2017-07-28 | ||
CN2017106298677 | 2017-07-28 | ||
CN2017106245059 | 2017-07-28 | ||
CN2017106269049 | 2017-07-28 | ||
CN2017106299612 | 2017-07-28 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN109305990A true CN109305990A (zh) | 2019-02-05 |
CN109305990B CN109305990B (zh) | 2021-02-26 |
Family
ID=65225900
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201810740849.0A Expired - Fee Related CN109305990B (zh) | 2017-07-28 | 2018-07-09 | 一种磷酸衍生物及制备方法和用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN109305990B (zh) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109400645A (zh) * | 2017-08-18 | 2019-03-01 | 四川海思科制药有限公司 | 一种磷酸衍生物及制备方法和用途 |
CN111675747A (zh) * | 2020-07-30 | 2020-09-18 | 中国医学科学院医药生物技术研究所 | 抗肿瘤药物和用途 |
CN112390821A (zh) * | 2019-08-15 | 2021-02-23 | 四川夏派森医药科技有限公司 | 一种丙泊酚磷酰胺衍生物、其制备方法及其在医药上的用途 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005064008A1 (en) * | 2003-12-22 | 2005-07-14 | Gilead Sciences, Inc. | Method and compositions for identifying anti-hiv therapeutic compounds |
CN1726212A (zh) * | 2002-10-16 | 2006-01-25 | 吉里德科学公司 | 预组织的三环整合酶抑制剂化合物 |
CN101041669A (zh) * | 2002-04-26 | 2007-09-26 | 吉里德科学公司 | 非核苷逆转录酶抑制剂 |
-
2018
- 2018-07-09 CN CN201810740849.0A patent/CN109305990B/zh not_active Expired - Fee Related
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101041669A (zh) * | 2002-04-26 | 2007-09-26 | 吉里德科学公司 | 非核苷逆转录酶抑制剂 |
CN1726212A (zh) * | 2002-10-16 | 2006-01-25 | 吉里德科学公司 | 预组织的三环整合酶抑制剂化合物 |
CN100374438C (zh) * | 2002-10-16 | 2008-03-12 | 吉里德科学公司 | 预组织的三环整合酶抑制剂化合物 |
WO2005064008A1 (en) * | 2003-12-22 | 2005-07-14 | Gilead Sciences, Inc. | Method and compositions for identifying anti-hiv therapeutic compounds |
Non-Patent Citations (1)
Title |
---|
H. M. ALI ET AL.: "Quantitative Structure-Activity Relationships (QSAR) of Two Series of O-Aryl or N-Aryl O-Ethyl Phosphoramidate and Phosphorodiamidate Fungicides Incorporating Amino Acid Ethyl Esters", 《BULL. ENVIRON. CONTAM. TOXICOL.》 * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109400645A (zh) * | 2017-08-18 | 2019-03-01 | 四川海思科制药有限公司 | 一种磷酸衍生物及制备方法和用途 |
CN112390821A (zh) * | 2019-08-15 | 2021-02-23 | 四川夏派森医药科技有限公司 | 一种丙泊酚磷酰胺衍生物、其制备方法及其在医药上的用途 |
CN112390821B (zh) * | 2019-08-15 | 2021-11-02 | 四川夏派森医药科技有限公司 | 一种丙泊酚磷酰胺衍生物、其制备方法及其在医药上的用途 |
CN111675747A (zh) * | 2020-07-30 | 2020-09-18 | 中国医学科学院医药生物技术研究所 | 抗肿瘤药物和用途 |
CN111675747B (zh) * | 2020-07-30 | 2021-04-27 | 中国医学科学院医药生物技术研究所 | 抗肿瘤药物和用途 |
Also Published As
Publication number | Publication date |
---|---|
CN109305990B (zh) | 2021-02-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN102197037B (zh) | 吗啡喃(morphinan)化合物 | |
CN109305990A (zh) | 一种磷酸衍生物及制备方法和用途 | |
CN110627773B (zh) | 氘代mgl-3196化合物及其用途 | |
CA2977109A1 (en) | Deuterated chenodeoxycholic acid derivative and pharmaceutical composition comprising compound thereof | |
CN105541847A (zh) | 3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-3-环戊基丙腈的羟基衍生物、酮基衍生物和葡糖苷酸衍生物 | |
AU2014373186B2 (en) | N-substituted imidazole carboxylic ester chiral compound containing ether side chain, preparation method and application | |
CN109400645A (zh) | 一种磷酸衍生物及制备方法和用途 | |
JP2021521237A (ja) | P300及び/又はcbpの調節因子を調製するための方法 | |
EP3394063A1 (fr) | Ligands macrocycliques avec groupement(s) picolinate(s), leurs complexes ainsi que leurs utilisations médicales | |
CN107382870A (zh) | N‑取代咪唑羧酸酯类化合物及其制备方法和在医药上的用途 | |
WO2020259626A1 (zh) | 作为irak4抑制剂的咪唑并吡啶类化合物 | |
CN109503590B (zh) | 一种以7-脱氮腺嘌呤碱基为母核的18f-pet/ct示踪剂及其制备方法 | |
Livni et al. | Synthesis and biodistribution of 18F-labeled fleroxacin | |
US20240116959A1 (en) | Vitamin d3 phosphate and pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising the compound and methods for preparing the compound | |
Naik et al. | Development of a radioligand for imaging V1a vasopressin receptors with PET | |
CN113651662B (zh) | 一种靶向fgfr的新型肿瘤pet分子探针及其制备方法 | |
CN114075167B (zh) | 靶向转位蛋白tspo的新型正电子药物[18f]tpo1开发 | |
WO2006012643A2 (en) | Agents with selective k-opioid receptor affinity | |
CN102675329A (zh) | 一种正电子发射断层显像剂及其制备方法 | |
CN108358958B (zh) | 中间体、中间体合成方法及应用 | |
CN114644673B (zh) | 一种雌二醇衍生物、其制备方法及其在医药上的用途 | |
CN110016052B (zh) | N-去乙基舒尼替尼的磷酰胺衍生物及其制备方法 | |
CN102659796B (zh) | 氟-18标记的螺环哌啶类sigma-1受体化合物及制备方法和应用 | |
CN115260212B (zh) | 3,5-双(亚苄基)-4-哌啶酮衍生物及其制备方法和应用 | |
CN115974925A (zh) | 一种甲状腺激素受体β激动剂及其应用 |
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 | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20210226 |