CN107698639A - The weary oxygen activation prodrug of N formic acid esters of a kind of gemcitabine phosphate and its application - Google Patents
The weary oxygen activation prodrug of N formic acid esters of a kind of gemcitabine phosphate and its application Download PDFInfo
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- CN107698639A CN107698639A CN201710794969.4A CN201710794969A CN107698639A CN 107698639 A CN107698639 A CN 107698639A CN 201710794969 A CN201710794969 A CN 201710794969A CN 107698639 A CN107698639 A CN 107698639A
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- gemcitabine
- weary oxygen
- formic acid
- acid esters
- medicine
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 title claims abstract description 42
- 239000001301 oxygen Substances 0.000 title claims abstract description 39
- 229910052760 oxygen Inorganic materials 0.000 title claims abstract description 39
- 229960005277 gemcitabine Drugs 0.000 title claims abstract description 38
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 title claims abstract description 37
- 229910019142 PO4 Inorganic materials 0.000 title claims abstract description 21
- 239000010452 phosphate Substances 0.000 title claims abstract description 21
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 title claims abstract description 20
- 229940002612 prodrug Drugs 0.000 title claims abstract description 20
- 239000000651 prodrug Substances 0.000 title claims abstract description 20
- 230000004913 activation Effects 0.000 title claims abstract description 17
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical class OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 title abstract 2
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 25
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims abstract description 3
- 125000006178 methyl benzyl group Chemical group 0.000 claims abstract description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 33
- 150000003839 salts Chemical class 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 32
- 102100026846 Cytidine deaminase Human genes 0.000 abstract description 9
- 108010031325 Cytidine deaminase Proteins 0.000 abstract description 9
- 231100000135 cytotoxicity Toxicity 0.000 abstract description 9
- 230000003013 cytotoxicity Effects 0.000 abstract description 9
- 230000004060 metabolic process Effects 0.000 abstract description 9
- 238000002360 preparation method Methods 0.000 abstract description 3
- 150000004712 monophosphates Chemical class 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 210000004185 liver Anatomy 0.000 description 12
- 230000000694 effects Effects 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- NHTKGYOMICWFQZ-BBOXMAMFSA-N fosgemcitabine palabenamide Chemical compound C[C@H](N[P@](=O)(OC[C@H]1O[C@@H](N2C=CC(N)=NC2=O)C(F)(F)[C@@H]1O)OC1=CC=CC=C1)C(=O)OCC1=CC=CC=C1 NHTKGYOMICWFQZ-BBOXMAMFSA-N 0.000 description 8
- 238000011580 nude mouse model Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 230000000259 anti-tumor effect Effects 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 230000000118 anti-neoplastic effect Effects 0.000 description 5
- 231100000331 toxic Toxicity 0.000 description 5
- 230000002588 toxic effect Effects 0.000 description 5
- 206010021143 Hypoxia Diseases 0.000 description 4
- 241000699660 Mus musculus Species 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- KNTREFQOVSMROS-QPPQHZFASA-N [(2r,3r,5r)-5-(4-amino-2-oxopyrimidin-1-yl)-4,4-difluoro-3-hydroxyoxolan-2-yl]methyl dihydrogen phosphate Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](COP(O)(O)=O)O1 KNTREFQOVSMROS-QPPQHZFASA-N 0.000 description 4
- 230000004663 cell proliferation Effects 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000003111 delayed effect Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L magnesium chloride Substances [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 3
- 229910001629 magnesium chloride Inorganic materials 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 125000003835 nucleoside group Chemical group 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 206010002660 Anoxia Diseases 0.000 description 2
- 241000976983 Anoxia Species 0.000 description 2
- UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 description 2
- SAMRUMKYXPVKPA-VFKOLLTISA-N Enocitabine Chemical compound O=C1N=C(NC(=O)CCCCCCCCCCCCCCCCCCCCC)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 SAMRUMKYXPVKPA-VFKOLLTISA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- REAYFGLASQTHKB-UHFFFAOYSA-N [2-[3-(1H-pyrazol-4-yl)phenoxy]-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound N1N=CC(=C1)C=1C=C(OC2=NC(=CC(=C2)CN)C(F)(F)F)C=CC=1 REAYFGLASQTHKB-UHFFFAOYSA-N 0.000 description 2
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 2
- 230000007953 anoxia Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 description 2
- 229950011487 enocitabine Drugs 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 230000009036 growth inhibition Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000000703 high-speed centrifugation Methods 0.000 description 2
- 230000007954 hypoxia Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 2
- 0 *CC(*C(C([C@]1F)N2C=CC(NC(*)=O)=NC2O)C=C)[C@]1O Chemical compound *CC(*C(C([C@]1F)N2C=CC(NC(*)=O)=NC2O)C=C)[C@]1O 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 1
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 1
- 102100034343 Integrase Human genes 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- NHTKGYOMICWFQZ-KKQYNPQSSA-N benzyl (2s)-2-[[[(2r,3r,5r)-5-(4-amino-2-oxopyrimidin-1-yl)-4,4-difluoro-3-hydroxyoxolan-2-yl]methoxy-phenoxyphosphoryl]amino]propanoate Chemical compound N1([C@@H]2O[C@@H]([C@H](C2(F)F)O)COP(=O)(N[C@@H](C)C(=O)OCC=2C=CC=CC=2)OC=2C=CC=CC=2)C=CC(N)=NC1=O NHTKGYOMICWFQZ-KKQYNPQSSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- -1 gemcitabine phosphate derivative Chemical class 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 231100000225 lethality Toxicity 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 210000005170 neoplastic cell Anatomy 0.000 description 1
- 230000037360 nucleotide metabolism Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000003044 randomized block design Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 1
- OBHLNVXMRZXIII-BTVCFUMJSA-M sodium;[(2r,3r,4s,5r)-2,3,4,5-tetrahydroxy-6-oxohexyl] hydrogen phosphate Chemical compound [Na+].OP(=O)([O-])OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O OBHLNVXMRZXIII-BTVCFUMJSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- 229940048102 triphosphoric acid Drugs 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The weary oxygen activation prodrug of N formic acid esters of a kind of gemcitabine phosphate and its application, structure meet formula (I)Wherein：R is：A isR ' is isopropyl or benzyl, and Ar is phenyl or adjacent methyl-benzyl.Such medicine can delay medicine to be deoxidized the metabolism of cytidine deaminase, and have stronger cytotoxicity, the preparation available for tumor under the conditions of weary oxygen.
Description
Technical field
The invention belongs to pharmaceutical field, there is provided the weary oxygen activation prodrug of N- formic acid esters of a kind of gemcitabine phosphate and its should
With.
Background technology
Gemcitabine is a kind of nucleosides series antineoplastic medicament, and the mechanism of action of such medicine is antagonism nucleotide metabolism,
In vivo after intracellular triphosphoric acid, in synthesis, incorporation DNA or the RNA molecule by suppressing deoxynucleoside triphosphate (dNTPs)
Interference cell duplication, Reverse transcriptase archaeal dna polymerase etc. act on, the metabolism of specific RNA, prevent cell division and
Breeding, ultimately results in death of neoplastic cells.After gemcitabine enters in vivo, cytidine deaminase is deoxidized in liver, kidney, blood
With it is quick in its hetero-organization and be metabolized completely, be converted into inactive metabolite Gemcitabine.
By the aminoacylates of nucleosides series antineoplastic medicament, medicine can be delayed to be deoxidized the metabolism of cytidine deaminase, such as Ah
The derivative enocitabine (Enocitabine) that the aminoacylates of sugared cytidine (Cytarabine) obtain, antitumor action compare Ah
Sugared cytidine is strong and lasting.But aminoacylates can not reduce the toxic side effect of medicine normal tissue.
Resistance easily occurs for nucleosides series antineoplastic medicament, and its phosphate prodrugs can reduce resistance, has well
Antitumor action, wherein gemcitabine phosphate prodrugs NUC-1031 come into clinical research (Journal of
Medicinal Chemistry 2014,57,1531-1542).But gemcitabine phosphate prodrugs can not delay it to be deoxidized
The metabolism of cytidine deaminase, toxic side effect of the medicine to nonneoplastic tissue can not be reduced.Gemcitabine phosphate prodrugs amino
Acylated (WO2015/134334) can delay medicine to be deoxidized the metabolism of cytidine deaminase, still can not reduce medicine to non-swollen
The toxic side effect of tumor tissue.
With the fast-growth of tumour, Partial tumors tissue is more and more remote from nearest blood vessel, and oxygen is insufficient, causes to swell
The weary oxygen of knurl (Nature review cancer 2002,2:38-47).Traditional antineoplastic has to the tumour of near vessels
Good lethality, but it is limited to the function of tumor in weary oxygen region.Tumor hypoxia activated prodrugs can be specifically weary in tumour
Oxygen region discharge anti-tumor active ingredient, so as to kill weary oxygen region tumour (Chinese Journal of Cancer 2014,
33:80-86).Weary oxygen activation prodrug has tumor-targeting, so as to have more preferable security, joins with traditional antineoplastic
It is outstanding to close antitumous effect when using.Wherein TH302 comes into clinical research, has good treatment to cancer of pancreas etc.
Act on (Journal of Clinical Oncology 2015,33,1475-1482).
Chinese invention 201610649914.X discloses the weary oxygen activation prodrugs of gemcitabine ProTide and its application, in Ji
Weary oxygen activation group is introduced on the side chain of his western shore phosphate, medicine is produced weary oxygen activation selectivity, reduces normal tissue
Toxic side effect.But medicine still can not be delayed to be deoxidized the metabolism of cytidine deaminase.
The weary oxygen activation prodrug of N- formic acid esters for the gemcitabine phosphate that the present invention obtains, by gemcitabine phosphate amino
It is acylated, medicine can be delayed to be deoxidized the metabolism of cytidine deaminase, increase drug treating time, reduce drug dose.And ammonia
Weary oxygen activation group is introduced in base acylation process, there is less cytotoxicity under normal oxygen conditions, under the conditions of weary oxygen,
With larger cytotoxicity, antitumor action, reduction pair are played therefore, it is possible to the specific tumour to tumor hypoxia region
The toxic side effect of its hetero-organization, there is excellent antitumaous effect and good security to tumour, tumour is treated available for preparing
Medicine.
The content of the invention
The technical problem of solution：Before the present invention provides the weary oxygen activation of N- formic acid esters of a kind of gemcitabine phosphate derivative
Medicine and its application.Such medicine can delay medicine to be deoxidized the metabolism of cytidine deaminase, increase drug treating time, reduce medicine
Agent amount, and there is less cytotoxicity under normal oxygen conditions, there is stronger cytotoxicity under the conditions of weary oxygen, can
For preparing the medicine for the treatment of tumour.
Technical scheme：The weary oxygen activation prodrug of N- formic acid esters of a kind of gemcitabine phosphate, structure meet formula (I)
Wherein：R is：A is
Wherein R ' is isopropyl or benzyl, and Ar is phenyl or adjacent methyl-benzyl.
The weary oxygen activation prodrug of N- formic acid esters of a kind of gemcitabine phosphate, particular chemical is as shown in following formula 1-6：
The application of above-claimed cpd or its pharmaceutically acceptable salt in tumor is prepared.
Tumor, active ingredient are above-claimed cpd or its pharmaceutically acceptable salt.
Cell growth inhibition test is shown, compared with gemcitabine phosphate prodrugs NUC-1031, the change shown in the present invention
Compound has than relatively low cytotoxicity.Liver homogenate study on the stability experiment display, with gemcitabine phosphate prodrugs NUC-
1031 gemcitabine phosphate prodrugs NUC-1031 are compared, and under normoxic conditions, invent activity caused by shown compound
Composition gemcitabine monophosphate concentration is relatively low, prompts in the speed that under normoxic conditions, the compound shown in the present invention is metabolized
Spend relatively low.And under the conditions of weary oxygen, active component gemcitabine monophosphate concentration caused by the compound shown in the present invention is higher,
Prompting can produce bigger cytotoxicity under the conditions of weary oxygen.
It is important to note that the connected mode of weary oxygen groups and gemcitabine phosphate is selected the weary oxygen of holding medicine
Property tool have a significant impact, if the amino of weary oxygen groups and gemcitabine phosphate be otherwise coupled to, medicine can not be kept
The weary oxygen selective of thing.By taking compound 7 as an example, liver homogenate study on the stability experiment display, under normoxic conditions or weary oxygen
Under the conditions of, can not caused active component gemcitabine monophosphate.If the methyl missing on weary oxygen groups side chain, medicine are weary
Oxygen selective, which has, to be remarkably decreased.By taking compound 8 as an example, liver homogenate study on the stability experiment display, under normoxic conditions or
Under the conditions of the weary oxygen of person, the significant difference of caused active component gemcitabine monophosphate concentration declines.
Beneficial effect：Such medicine can delay medicine to be deoxidized the metabolism of cytidine deaminase, increase drug treating time,
Reduce drug dose, and there is less cytotoxicity under normal oxygen conditions, there is stronger cell under the conditions of weary oxygen
Toxicity, there is excellent antitumor action and good security, the preparation available for tumor.
Brief description of the drawings
Growth inhibition effect figure of Fig. 1 target compounds 6 to people's BxPC-3 nude mouse subcutaneous transplantation knurls.
Embodiment
The following examples can make those skilled in the art to be fully understood by the present invention, but not limit this in any way
Invention.
Embodiment 1：Target compound 1- marks the synthesis of compound 6：
The synthesis of compound 1
Synthetic route:
At -78 DEG C, triphosgene (0.178g, 0.6mmol) is dissolved with 4mL toluene, addition pyridine (0.047g,
1mL toluene solutions 0.6mmol), it is then slowly added into 1- (4- nitrobenzene) ethanol (0.72g, 0.4mmol) and is dissolved in 40mL's
Toluene solution, 24h is stirred at room temperature.After the completion of reaction, it is evaporated under reduced pressure and removes toluene, obtained residue is dissolved in N, N- diformazans
Base formamide (2.5mL), at 4 DEG C, add gemcitabine phosphate prodrugs 1a (0.14g, 0.27mmol), pyridine (61 μ L,
0.75mmol), 24h is stirred at room temperature, is evaporated under reduced pressure and removes solvent, is dissolved with ethyl acetate (30mL), washing, organic layer nothing
Aqueous sodium persulfate is dried, and silica gel column chromatography obtains white solid (1,97mg).
The method of reference compound 1, compound 2- compounds 6 are synthesized.
The primary raw material of the embodiment compound of table 1 and1H NMR
Embodiment 2：Target compound is studied tumor cell proliferation In-vitro Inhibitory Effect
Take the logarithm growth period tumour cell, 0.25% pancreatin digestion 3min is added, with containing 10% calf serum RPMI-1640
Suspension cell, count, it is 1 × 10 to adjust cell concentration5Individual/mL, it is inoculated in the special 96 hole cells of Top-count with 100 μ L/ holes and trains
Support in plate, 37 DEG C, 5%CO2It is incubated 24h.Then cell is divided into experimental group and control group, it is molten that experimental group adds target compound
Liquid (0.1nM, 1nM, 10nM, 100nM), each concentration are four multiple holes, and supply 200 μ L per pore volume.After each group sample-adding
Continue to cultivate 72h respectively, before culture terminates, be separately added into per hole3H-TdR 3×105Bq, each hole is determined with Top-count
CPM (count per minute) value.Calculate the half-inhibition concentration (median of each experimental group medicine cell proliferation
Inhibition concentration, IC50)。
Half-inhibition concentration (IC of the target compound of table 1 to tumor cell proliferation (72 hours)50, nM)
Above experimental result is shown：Embodiments of the invention compound (1-6) is to tumor cell proliferation In-vitro Inhibitory Effect
Substantially less than gemcitabine, NUC-1031, prompt embodiments of the invention Compound Cytotoxicity smaller.
Embodiment 3：The investigation of generation active metabolite monophosphate gemcitabine concentration of the target compound in liver homogenate
It is prepared by NADPH activation systems：Precision weighs NADPNa2, G-6-P-Na, G-6-PDH and MgCl2In right amount, it is dissolved in water
And constant volume, system contain 2mmolL-1NADPNa2, 40mmolL-1G-6-P-Na, 4UL-1G-6-PDH, 40mmolL- 1MgCl2, -20 DEG C of preservations.
Sample preparation：Appropriate sample methanol solution is added in EP pipes first, water-bath volatilizes solvent, adds Tris bufferings
Solution, rat liver homogenate, it is vortexed and mixes.37 DEG C of pre-temperatures of constant temperature oscillation tank incubate 5min.Add the μ L of NADPH activation systems 200, whirlpool
Rotation is well mixed to be reacted with starting.Reaction final volume is 400 μ L, containing 1.0mmolL-1 1NADPNa2, 20mmolL-1G-6-
P-Na, 2UL-1G-6-PDH, 20mmolL-1MgCl2, liver homogenate albumen quality concentration is 2.0mgmL-1, Final substrate concentrations
For 0.5 μm of oLL-1.37 DEG C of water-bath temperature are incubated.Acetonitrile 0.4mL terminating reactions are separately added into after temperature incubates 60min.Parallel 5 parts.
Sample treatment：After acetonitrile terminating reaction, it is vortexed and ultrasonic 5min makes to be well mixed, high speed centrifugation (13000r
min-1, 20min, 4 DEG C), supernatant is taken, is volatilized under 37 DEG C of water-bath nitrogen streams.Residue is redissolved with 400 μ L methanol, and ultrasound makes dissolving complete
Entirely, high speed centrifugation (13 000rmin-1, 20min, 4 DEG C), supernatant is analyzed for HPLC, determines the concentration of monophosphate gemcitabine,
And compared with the concentration of monophosphate gemcitabine caused by NUC-1031.
The concentration of monophosphate gemcitabine of the target compound of table 2 in liver homogenate compares
| Compound number | The concentration (relative value %) of monophosphate gemcitabine |
| 1 | 6 |
| 2 | 7 |
| 4 | 5 |
| 5 | 6 |
| 6 | 5 |
| 7 | 0 |
| 8 | 82 |
| NUC-1031 | 100 |
Above experimental result is shown：Compared with NUC-1031, caused monophosphates of the target compound 1-6 in liver homogenate
The concentration of gemcitabine is significant lower, and target compound 7 fails to measure monophosphate gemcitabine, and caused by target compound 8
The concentration of monophosphate gemcitabine is slightly less than NUC-1031.
Embodiment 4：Study on the stability under target compound anoxia state in liver homogenate
Operate reference implementation example 3, during sample incubation, solution first uses nitrogen treatment 20 minutes before sample is added, and is adding
It is incubated under a nitrogen 60 minutes after entering sample.Centrifugate is cut down dense for Buddhist nun with HPLC measure target compounds and O- demethyls pleasure
Degree.
The concentration of monophosphate gemcitabine under the conditions of the weary oxygen of the target compound of table 3 in liver homogenate
Above experimental result is shown：Caused monophosphate Ji Xi under target compound 1-6 anoxia states in liver homogenate
The concentration of his shore is apparently higher than normal oxygen condition.Target compound 7 fails to measure monophosphate gemcitabine, prompts compound 7 to exist
Still monophosphate gemcitabine can not be effectively discharged under the conditions of weary oxygen.And monophosphate gemcitabine caused by target compound 8
The a little higher than normal oxygen condition of concentration, prompt compound 8 without weary oxygen selective.
Embodiment 5：Growth inhibition effect of the target compound 6 to people's BxPC-3 nude mouse subcutaneous transplantation knurls
Take the logarithm the BxPC-3 human pancreatic cancer cells in growth period, with 5 × 106Individual cell 0.2mL-1Only-1Concentration,
Be inoculated in nude mice dorsal sc, after transplanted tumor in nude mice major diameter >=5mm after, with the transplantable tumor line of apsides calculate knurl body phase apparent size.
Carry out in-line arrangement by the size of gross tumor volume, nude mice is divided into 5 groups with RANDOMIZED BLOCK DESIGN distribution method.
Dosage regimen:Animal pattern 40, it is divided into negative control group, low dose group (compound 6,0.15mmol/ at random
Kg), high dose group (compound 6,0.6mmol/kg), gemcitabine hydrochloride group (0.2mmol/kg), are administered to through abdominal cavity respectively
Medicine (2 times/weekly), continue 3 weeks, nude mice is put to death after being discontinued one week.Determine the weight of animals simultaneously.
Inhibition and changes of weight are shown in Fig. 1：After administration, each group shows that the significant tumour growth that suppresses acts on, institute
There is test group nude mouse body weight there is no a notable difference, but respectively less than control group.High dose group is shown more than gemcitabine group
Good therapeutic action and security.
Claims (4)
1. the weary oxygen activation prodrug of the N- formic acid esters of a kind of gemcitabine phosphate, it is characterised in that structure meets formula (I)Wherein：R is：Wherein
R ' is isopropyl or benzyl, and Ar is phenyl or adjacent methyl-benzyl.
2. the weary oxygen activation prodrug of N- formic acid esters of a kind of gemcitabine phosphate according to claim 1, it is characterised in that
Particular chemical is as shown in following formula 1-6：
3. any compounds of claim 1-2 or its pharmaceutically acceptable salt answering in tumor is prepared
With.
4. tumor, it is characterised in that active ingredient is any compounds of claim 1-2 or it pharmaceutically may be used
The salt of receiving.
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| WO2021098379A1 (en) * | 2019-11-21 | 2021-05-27 | 广东中科药物研究有限公司 | Phenylalanine-amidated nucleotide derivative, preparation method therefor and application thereof |
| CN114031657A (en) * | 2021-12-06 | 2022-02-11 | 中国海洋大学 | Gemcitabine cyclic phosphate prodrug and preparation method and application thereof |
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| CN1791591A (en) * | 2003-03-26 | 2006-06-21 | 安吉奥金尼药品有限公司 | Bioreductively-activated prodrugs |
| CN101044150A (en) * | 2004-09-24 | 2007-09-26 | 安吉奥金尼药品有限公司 | Bioreductively-activated prodrugs |
| CN106146583A (en) * | 2014-11-17 | 2016-11-23 | 常州方圆制药有限公司 | Novel cytidine derivatives and application thereof |
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| WO2021098379A1 (en) * | 2019-11-21 | 2021-05-27 | 广东中科药物研究有限公司 | Phenylalanine-amidated nucleotide derivative, preparation method therefor and application thereof |
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| CN114031657B (en) * | 2021-12-06 | 2023-08-15 | 中国海洋大学 | Gemcitabine cyclic phosphate prodrug, and preparation method and application thereof |
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