WO2015161479A1 - 一种嘧啶类化合物的抗***用途 - Google Patents
一种嘧啶类化合物的抗***用途 Download PDFInfo
- Publication number
- WO2015161479A1 WO2015161479A1 PCT/CN2014/076110 CN2014076110W WO2015161479A1 WO 2015161479 A1 WO2015161479 A1 WO 2015161479A1 CN 2014076110 W CN2014076110 W CN 2014076110W WO 2015161479 A1 WO2015161479 A1 WO 2015161479A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- use according
- alkyl group
- alkyloxy
- cervical cancer
- Prior art date
Links
- 206010008342 Cervix carcinoma Diseases 0.000 title claims abstract description 33
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 title claims abstract description 33
- 201000010881 cervical cancer Diseases 0.000 title claims abstract description 33
- -1 pyrimidine compound Chemical class 0.000 title claims abstract description 20
- 241000341655 Human papillomavirus type 16 Species 0.000 claims abstract description 23
- 239000003814 drug Substances 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 229940079593 drug Drugs 0.000 claims abstract description 11
- 241000701806 Human papillomavirus Species 0.000 claims description 39
- 150000001875 compounds Chemical class 0.000 claims description 27
- 125000003277 amino group Chemical group 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 108090000623 proteins and genes Proteins 0.000 claims description 9
- 102000004169 proteins and genes Human genes 0.000 claims description 9
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 208000009608 Papillomavirus Infections Diseases 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 125000006549 C4-C10 aryl group Chemical group 0.000 claims description 4
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 208000021145 human papilloma virus infection Diseases 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims 12
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 8
- 125000004103 aminoalkyl group Chemical group 0.000 claims 8
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 4
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical group N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Substances O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 10
- 230000005764 inhibitory process Effects 0.000 abstract description 4
- 241001631646 Papillomaviridae Species 0.000 abstract description 2
- 206010028980 Neoplasm Diseases 0.000 description 12
- 230000002401 inhibitory effect Effects 0.000 description 9
- 125000003396 thiol group Chemical group [H]S* 0.000 description 9
- 201000011510 cancer Diseases 0.000 description 8
- 125000006612 decyloxy group Chemical group 0.000 description 8
- 108020004999 messenger RNA Proteins 0.000 description 6
- 241000700605 Viruses Species 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 101100540311 Human papillomavirus type 16 E6 gene Proteins 0.000 description 4
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 101000767631 Human papillomavirus type 16 Protein E7 Proteins 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 230000003902 lesion Effects 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 102000052575 Proto-Oncogene Human genes 0.000 description 2
- 108700020978 Proto-Oncogene Proteins 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 210000004392 genitalia Anatomy 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- XTEGVFVZDVNBPF-UHFFFAOYSA-N naphthalene-1,5-disulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1S(O)(=O)=O XTEGVFVZDVNBPF-UHFFFAOYSA-N 0.000 description 2
- 231100000028 nontoxic concentration Toxicity 0.000 description 2
- 125000003544 oxime group Chemical group 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- 0 *c1c(*)c(*)c(CNc2ncnc(Cl)c2C=N)c(*)c1* Chemical compound *c1c(*)c(*)c(CNc2ncnc(Cl)c2C=N)c(*)c1* 0.000 description 1
- RTBFRGCFXZNCOE-UHFFFAOYSA-N 1-methylsulfonylpiperidin-4-one Chemical compound CS(=O)(=O)N1CCC(=O)CC1 RTBFRGCFXZNCOE-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 241000238876 Acari Species 0.000 description 1
- 206010059313 Anogenital warts Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000009458 Carcinoma in Situ Diseases 0.000 description 1
- 201000006082 Chickenpox Diseases 0.000 description 1
- VWFCHDSQECPREK-LURJTMIESA-N Cidofovir Chemical compound NC=1C=CN(C[C@@H](CO)OCP(O)(O)=O)C(=O)N=1 VWFCHDSQECPREK-LURJTMIESA-N 0.000 description 1
- 108020004638 Circular DNA Proteins 0.000 description 1
- 208000000907 Condylomata Acuminata Diseases 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 208000007514 Herpes zoster Diseases 0.000 description 1
- 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 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 231100000645 Reed–Muench method Toxicity 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 206010046980 Varicella Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N anhydrous glutaric acid Natural products OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- 208000025009 anogenital human papillomavirus infection Diseases 0.000 description 1
- 201000004201 anogenital venereal wart Diseases 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 210000003679 cervix uteri Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229960000724 cidofovir Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 229940121657 clinical drug Drugs 0.000 description 1
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229960002598 fumaric acid Drugs 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 201000004933 in situ carcinoma Diseases 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 150000002506 iron compounds Chemical class 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960000448 lactic acid Drugs 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- KHPXUQMNIQBQEV-UHFFFAOYSA-N oxaloacetic acid Chemical compound OC(=O)CC(=O)C(O)=O KHPXUQMNIQBQEV-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 208000003154 papilloma Diseases 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- YQUVCSBJEUQKSH-UHFFFAOYSA-N protochatechuic acid Natural products OC(=O)C1=CC=C(O)C(O)=C1 YQUVCSBJEUQKSH-UHFFFAOYSA-N 0.000 description 1
- 238000003753 real-time PCR Methods 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 201000010153 skin papilloma Diseases 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
- 231100000816 toxic dose Toxicity 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- WKOLLVMJNQIZCI-UHFFFAOYSA-N vanillic acid Chemical compound COC1=CC(C(O)=O)=CC=C1O WKOLLVMJNQIZCI-UHFFFAOYSA-N 0.000 description 1
- TUUBOHWZSQXCSW-UHFFFAOYSA-N vanillic acid Natural products COC1=CC(O)=CC(C(O)=O)=C1 TUUBOHWZSQXCSW-UHFFFAOYSA-N 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention relates to a novel use of a pyrimidine compound against cervical cancer.
- Cervical cancer is the most common gynecologic malignant neoplasm.
- the high incidence of carcinoma in situ is 30 to 35 years old, and the invasive cancer is 45-55 years old.
- cervical cancer The widespread use of cervical cancer and precancerous lesions for early detection and treatment, the incidence and mortality of cervical cancer has been clearly
- HPV human papillomavirus
- the virus belongs to the papavirus family of papovaviridae, 52-55 nm in diameter, has no capsule, has a icosahedral structure, has 72 shells on the surface, and the viral genome is a double-stranded circular DNA molecule. It is an epithelial virus that is widely distributed in humans and ticks with high specificity. It has long been known that HPV can cause benign tumors and tendons in humans, such as humans that grow on the skin and mucous membranes near the reproductive organs. Common warts, genital warts, and papilloma that grow on the mucosa. Repeated infection with certain high-risk HPV types without symptoms may lead to precancerous lesions, even invasive cancers.
- HPV16 is a high-risk type of HPV associated with genital precancerous lesions or genital cancer.
- Patent Application No. 201310013707 1 discloses a pyrimidine compound represented by Formula 1, or a pharmaceutically acceptable salt thereof,
- the patent application also discloses that the compound has anti-chucking virus and influenza virus activity, and can treat diseases related to chickenpox, herpes zoster, influenza and the like.
- the present invention provides a use of a pyrimidine compound represented by Formula 1, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating cervical cancer,
- R is selected from a substituted or unsubstituted C4-10 aryl or heterocyclic aryl group, wherein the substituent is selected from a C1-6 fluorenyl group, a C1-4 decyloxy group, a C1-4 amidino group or a halogen. .
- the cervical cancer is a cervical cancer accompanied by a human papillomavirus infection.
- HPV is positive, but the cause of cancer may be caused by HPV, or may be caused by HPV infection. Caused by factors.
- the cervical cancer is a cervical cancer caused by human papillomavirus, and it is in cervical cancer.
- HPV is positive, but its carcinogenic cause is caused by HPV infection.
- the human papillomavirus is a high-risk human papillomavirus.
- the high-risk human papillomavirus is HPV16, HPV18, HPV31 or HPV33. Further, the high-risk human papillomavirus is HPV16.
- the drug is a drug that inhibits the E6 or E7 protein in HPV16.
- R is selected from a substituted or unsubstituted C4-6 aryl or heterocyclic aryl group; wherein the heterocyclic aryl group is a 0- or N-heterocyclic aromatic group.
- the substituent is selected from a thiol group of C1-4, a decyloxy group of C1-2, an aminoguanidino group of C1-2, and further, the compound is OH
- a thiol group selected from Cl-6, a methoxy group of C1-4, an amino group of C1-4, an amino group or
- a thiol group selected from C1-4, a methoxy group of C1-2, an amino group of C1-2, an amino group or
- the thiol group of C1-4 is a butyl group
- the oxime group of C1-2 is a methoxy group
- the amino group of C1-2 is an aminomethyl group.
- butyl group is a tert-butyl group.
- the compound is:
- Formula 1 R is selected from a substituted or unsubstituted C4-10 aryl or heterocyclic aryl group, wherein the substituent is selected from a C1-6 fluorenyl group, a C1-4 decyloxy group, a C1-4 amidino group or a halogen. .
- human papillomavirus is a high-risk human papillomavirus.
- high-risk human papillomavirus is HPV16, HPV18, HPV31 or HPV33 0
- the high risk human papillomavirus is HPV16.
- the drug is a drug that inhibits the E6 or E7 protein in HPV16.
- R is selected from a substituted or unsubstituted C4-6 aryl or heterocyclic aryl group; wherein the heterocyclic aryl group is a 0- or N-heterocyclic aromatic group.
- the substituent is selected from a thiol group of C1-4, a decyloxy group of C1-2, an aminoguanidino group of C1-2, an amino group or a halogen.
- an alkyl group selected from C1-6, a methoxy group of C1-4, an amino group of C1-4, an amino group or
- a thiol group selected from C1-4, a methoxy group of C1-2, an amino group of C1-2, an amino group or
- the thiol group of C1-4 is a butyl group
- the oxime group of C1-2 is a methoxy group
- the amino group of C1-2 is an aminomethyl group.
- butyl group is a tert-butyl group.
- the compound is:
- the "pharmaceutically acceptable salt” of the present invention includes a compound of the formula 1 or 2 and a salt which is non-toxic to a living organism, and comprises a compound of the invention with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, Malic acid, formic acid, maleic acid, acetic acid, malonic acid, pamoic acid, 1,5-naphthalenedisulfonic acid, cyclohexylsulfamic acid, salicylic acid, adipic acid, glutaric acid, vanillic acid, a salt formed from oxaloacetic acid, ascorbic acid, lactic acid, fumaric acid, succinic acid, tartaric acid, methanes
- the above-mentioned compound or a pharmaceutically acceptable salt thereof is also isotopically labeled, and the isotopically labeled compound means the same as the compound listed herein, but one or more of the atoms are Another atomic substitution, the atomic mass or mass of the atom is different from the atomic mass or mass number that is common in nature.
- Isotopes which may be introduced into the compound include hydrogen, carbon, nitrogen, oxygen, sulfur, ⁇ H 2 H, 3 H, 13 C, 14 C, 15 N, 17 0, 18 0, 35 S.
- the pharmaceutical use of the above-mentioned isotopes and/or other atomic isotopes, and stereoisomers thereof, as well as the pharmaceutically acceptable salts of the compounds, stereoisomers, are intended to be encompassed within the scope of the invention.
- the related pharmaceutical use of the prodrugs of the compounds should also be included in the scope of the present invention, wherein the prodrugs refer to the present invention.
- the present invention found that the pyrimidine compound can effectively fight cervical cancer and has a good inhibitory effect on E6 and E7 of HPV16, indicating that the pyrimidine compound also has a good anti-human papillomavirus effect, and provides a clinical drug. New choice. It is apparent that various other modifications, substitutions, and changes can be made in the form of the above-described embodiments of the present invention without departing from the spirit and scope of the invention.
- test compound of the present invention is in accordance with Patent Application No. 201310013707. Method preparation in 1. [Experimental method]
- Cytotoxicity Half of the toxic concentration (TC 5 ) and the maximum non-toxic concentration (TC.) were calculated by the Reed-Muench method using the MTT method.
- HPV16 E6 and E7 mRNA Cell culture was treated at the maximum non-toxic concentration for 48 hours, the culture was terminated, and total RNA was extracted from the cells. The effect of the test sample on HPV16 E6 and E7 mRNA was determined by Real-time PCR.
- test of the present invention proves that the compound has an inhibitory effect on cervical cancer cells, and the cervix The cancer cells are HPV16 positive, suggesting that the above compounds may have an inhibitory effect on HPV virus.
- CH01 inhibits HPV E6 and E7 mRNA in Caski cells.
- CH02 inhibits HPV E6 and E7 mRNA in Caski cells.
- E6 and E7 are two important proteins expressed by HPV16 virus. These two proteins can activate the protooncogene P53 in cells, which can cause cancer cells.
- Currently, a large number of literature studies have shown that the inhibition of E6 and E7 proteins of HPV16 may be The proto-oncogene P53 is inactivated to achieve an anti-tumor effect.
- the results of this experiment show that the samples CH01 and CH02 have good inhibitory activity against E6 and E7, and have higher inhibitory activity than the positive control cidofovir, indicating that the compounds provided by the present invention may be by inhibiting E6 and E7 proteins in HPV. Inhibition of viral activity to achieve anti-cervical cancer (HPV positive) effect.
- the pyrimidine compound of the present invention has good anti-cervical cancer activity, and has significant inhibitory effect on proteins closely related to cancer such as E6 and E7 of HPV16 virus, and exhibits good physiological activity. Provides new options for clinical use.
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Abstract
本发明提供了一种嘧啶类化合物或其药学上可接受的盐在制备抗***的药物中的用途。本发明研究发现,上述嘧啶类化合物能够有效对抗***,并对HPV16的E6、E7有良好的抑制作用,表明上述嘧啶类化合物也具有良好的抗人类***瘤病毒的作用,为临床用药提供了新的选择。
Description
一种嘧啶类化合物的抗***用途
技术领域
本发明涉及一种嘧啶类化合物的抗***的新用途。
背景技术
***的发生是多因素作用的结果、 主要与人***瘤病毒 (human papillomavirus , HPV), 尤其是高危型 HPV16、 18型感染密切相关, 而其 它易感因素, 如早婚-
***过多等, 均是 HPV感;
作用。 经研究 997%的子***, 都是因感染 HPV所造成。 该病毒属*** 多瘤空泡病毒科 (papovaviridae)***瘤病毒属, 直径 52-55nm, 无被膜, 正 20 面体结构, 表面有 72个壳体, 病毒基因组是双链环状 DNA分子。 它是一种 嗜上皮性病毒, 在人和动犓中分布广泛 有高度的特异性, 长期以来, 已知 HPV可引起人类良性的肿瘤和疣,如生长在生殖器官附近皮肤和粘膜上的人 类寻常疣、 ***以及生长在粘膜上的***状瘤。 若反复感染某些高危险 性, 且又没有疣等症状的 HPV类型, 可能发展成为癌前病变, 甚至是侵袭 性癌症。
根据 HPV的同源性, g前已发现 130多种型别。这些 HPV病毒按危险 性分类, 可以划分为低危型(非癌相关型)和高危型 (癌相关型), 其中, 与 生殖道癌前病变或生殖道癌症相关的高危型 HPV类型主要有 HPV16、 18、
31、 33等 因此, 研制抗 HPV病毒的药物, 也有助于治疗与 HPV病毒相 中瘤类疾病。
专利申请号 201310013707 1 , 公开了一种式 1所示的嘧啶类化合物或 其药学上可接受的盐,
,ΟΗ
该专利申请中还记载了, 该类化合物具有一定抗疱瘆病毒、 流感病毒 活性, 可治疗水痘、 带状疱疹、 流感等相关感染型疾病。
目前还未见上述化合物抗其他胂瘤或病毒的报道。
发明内容
本发明的目的在于提供式 1所示嘧啶类化合物的新用途。
本发明提供了式 1所示的嘧啶类化合物或其药学上可接受的盐在制备抗 ***的药物中的用途,
.OH
R选自取代或非取代的 C4-10的芳香基或杂环芳香基, 其中, 取代基选 自 C1-6的垸基、 C1-4的垸氧基、 C1-4的氨垸基或卤素。
进一歩地, 所述***是伴有人类***瘤病毒感染的***, 此种宫颈 癌中, HPV呈阳性, 但其致癌原因可能是由 HPV所致, 也可能由除 HPV感 染外的其他因素所致。
更迸一歩地、 所述***是人类***瘤病毒所致的***, 其***中
HPV呈阳性, 但其致癌原因是由感染 HPV所致。
其中, 所述人类***瘤病毒为高危型人类***瘤病毒。
进一歩地,所述高危型人类***瘤病毒为 HPV16、HPV18、HPV31或 HPV33。 更进一歩地, 所述高危型人类***瘤病毒为 HPV16。
优选地, 所述药物是抑制 HPV16中 E6或 E7蛋白的药物。
其中, R选自取代或非取代的 C4-6的芳香基或杂环芳香基; 其中, 所述 杂环芳香基为含 0或 N杂环芳香基。
式 2
其中, 选自 Cl-6的垸基、 C1-4的垸氧基、 C1-4的氨垸基、 氨基 或
其中, 选自 C1-4的垸基、 C1-2的垸氧基、 C1-2的氨垸基、 氨基 或
进一歩地, 选自 C1-4的垸基或 C1-2的垸氧基。
更进一歩地, R2、 R4为 H; Rl、 R5为 H或 C1-2的垸氧基, 但不同时 为 H; R3为 C1-4的垸基。
其中, 所述 C1-4的垸基为丁基, C1-2的垸氧基为甲氧基, C1-2的氨垸 基为氨甲基。
进一歩地, 所述丁基为叔丁基。
优选地, 所述化合物为:
4- (4-叔丁基苄胺) -5-甲醛肟 -6-氯嘧啶、 或 4- (2-甲氧基苄胺) -5-甲酸 肟 -6-氯嘧啶。
目前已知, 99.7%的子***都是因感染 HPV所造成, 而本发明也发 现, 上述化合物或其药学上可接受的盐类能够同日 t对***中的 HPV有抑 制活性 因 本发明根据相关实验, 还提供了式 1所示的嘧啶类化合物或 其药学上可接受的盐在制备抗人类***瘤病毒的药物中的用途,
式 1
R选自取代或非取代的 C4-10的芳香基或杂环芳香基, 其中, 取代基选 自 C1-6的垸基、 C1-4的垸氧基、 C1-4的氨垸基或卤素。
进一歩地, 所述人类***瘤病毒为高危型人类***瘤病毒。
更进一歩地, 所述高危型人类***瘤病毒为 HPV16、 HPV18、 HPV31或 HPV330
优选地, 所述高危型人类***瘤病毒为 HPV16。
进一歩优选地, 所述药物是抑制 HPV16中 E6或 E7蛋白的药物。
其中, R选自取代或非取代的 C4-6的芳香基或杂环芳香基; 其中, 所述 杂环芳香基为含 0或 N杂环芳香基。
进一歩地, 取代基选自 C1-4的垸基、 C1-2的垸氧基、 C1-2的氨垸基、 氨基或卤素。
更进一歩地, 所述化合
其中, 选自 C1-4的垸基、 C1-2的垸氧基、 C1-2的氨垸基、 氨基 或
进一歩地, 选自 C1-4的垸基或 C1-2的垸氧基。
更进一歩地, R2、 R4为 H; Rl、 R5为 H或 C1-2的垸氧基, 但不同时 为 H; R3为 C1-4的垸基。
其中, 所述 C1-4的垸基为丁基, C1-2的垸氧基为甲氧基, C1-2的氨垸 基为氨甲基。
进一歩地, 所述丁基为叔丁基。
优选地, 所述化合物为:
4- (4-叔丁基苄胺) -5-甲醛肟 -6-氯嘧啶、 或 4- ( 2-甲氧基苄胺) -5-甲酸 肟 -6-氯嘧啶。
本发明所述 "药学上可接受的盐"包括通式 1或 2化合物与对活生物体 无毒性的盐, 包含有本发明化合物与盐酸、 氢溴酸、 硝酸、 硫酸、 磷酸、 柠 檬酸、 苹果酸、 甲酸、 马来酸、 乙酸、 丙二酸、 双羟萘酸、 1,5-萘二磺酸、 环己基氨基磺酸、 水杨酸、 己二酸、 戊二酸、 香草酸、 草酰乙酸、 抗坏血酸、 乳酸、 富马酸、 琥珀酸、 酒石酸、 甲磺酸或对甲苯磺酸等形成的盐类, 或, 本发明化合物与碱形成的含钠、钾、 镁、锌或铁等的盐类, 但并不局限于此。 本发明的一种实施方式中, 还包括了同位素标记的上述化合物或其药学 上可接受的盐, 所述同位素标记化合物是指与本文中所列化合物相同, 但是 其中的一个或多个原子被另一个原子取代, 该原子的原子质量或质量数不同 于自然界中常见的原子质量或质量数。 可以引入化合物中的同位素包括氢、 碳、 氮、 氧、 硫, §卩 2 H, 3 H、 13 C、 14 C、 15 N、 17 0、 18 0、 35 S。 含有 上述同位素和 / 或其它原子同位素的化合物及其立体异构体, 以及该化合 物、 立体异构体的可药用的盐的制药用途均应包含在本发明范围之内。 除本发明所述化合物及其药学上可接受的盐外, 所述化合物前体药物的 相关制药用途也应该被包括在本发明的保护范围内, 其中, 所述前体药物是 指本发明所述嘧啶类化合物经过化学结构修饰后得到的在体内经酶或非酶的 转化释放出活性成分而发挥药效的化合物。 本发明研究发现, 上述嘧啶类化合物能够有效对抗***, 并对 HPV16 的 E6、 E7有良好的抑制作用, 表明上述嘧啶类化合物也具有良好的抗人类 ***瘤病毒的作用, 为临床用药提供了新的选择。 显然, 根据本发明的上述内容, 按照本领域的普通技术知识和手段, 在 不脱离本发明上述基本技术思想前提下, 还可以做出其他多种形式的修改、 替换或变更。
以下通过具体实施例的形式, 对本发明的上述内容再做进一歩的详细说 明。 但不应将此理解为本发明上述主题的范围仅限于以下的实施例。 凡基于 本发明上述内容所实现的技术均属于本发明的范围。 具体实施方式
实施例 1 CHOI, CH02对人***细胞 Caski和 HPV16病毒的影响
【实验目的】 为研究 CH01,CH02体外抗***和 HPV16病毒作用,本试验在
人***细胞(HPV16阳性)培养中研究了上述化合物等对细胞的毒性, 对 HPV16 E6和 E
CHOI CH02
本发明受试化合物按照专利申请号 201310013707。 1 中的方法制备。 【实验方法】 一
1.细胞毒性:采用 MTT法, 以 Reed-Muench法计算半数有毒浓度 (TC5。) 和最大无毒浓度 (TC。) 为指标。
2. HPV16 E6和 E7 mRNA :以最大无毒浓度处理细胞培养 48小时后终止 培养,提取细胞内的总 RNA, 采用 Real-time PCR法, 测定待测样品对 HPV16 E6和 E7 mRNA的影响。
【实验结果】
1. ***细胞 Caski的抑制试验:
表 1
上表结果表明, 化合物对***细胞具有很好的抑制作用, 样品 CH01 的 IC5。约为 1. 5 ug/ml , 样品 CH02的 IC5。约为 0. 4 ug/ml。
另外, 本发明试验证明了化合物对此***细胞有抑制作用, 此宫颈
癌细胞为 HPV16阳性, 提示上述化合物可能对 HPV病毒具有抑制作用
2. 样品对 Caski细胞 HPV16 E6 mRNA 、 HPV16 E7 mRNA表达的抑制作用:
【实验结论】
1、 CH01对 Caski细胞中的 HPV E6和 E7 mRNA有抑制作用
2、 CH02对 Caski细胞中的 HPV E6和 E7 mRNA有抑制作用
E6、 E7为 HPV16病毒表达的两种重要的蛋白, 这两种蛋白在细胞中能 够激活原癌基因 P53 , 从而使细胞癌变, 目前有大量文献研究表明对 HPV16 的 E6、 E7蛋白的抑制可能是原癌基因 P53失活而达到抗肿瘤的效果。 本实 验结果表明样品 CH01、 CH02对 E6、 E7具有很好的抑制活性, 比阳性对照 西多夫韦的抑制活性更高, 表明本发明提供的化合物可能是通过抑制 HPV 中的 E6、 E7蛋白来抑制病毒活性, 从而达到抗*** (HPV阳性) 效果。 综合上述实验可知, 本发明所述的嘧啶类化合物具有良好的抗***活 性, 并且对 HPV16病毒的 E6、 E7等与癌症密切相关的蛋白有显著的抑制作 用, 表现出了良好的生理活性, 为临床用药提供了新的选择。
Claims
1、式 1所示的嘧啶类化合物或其药学上可接受的盐在制备抗***的药 中的用途,
ΌΗ
R选自取代或非取代的 C4-10的芳香基或杂环芳香基, 其中, 取代基选 自 C1-6的垸基、 C1-4的垸氧基、 C1-4的氨垸基或卤素。
2、 根据权利要求 1所述的用途, 其特征在于: 所述***是伴有人类 ***瘤病毒感染的***。
3、 根据权利要求 2所述的用途, 其特征在于: 所述***是人类*** 瘤病毒所致的***。
4、 根据权利要求 2或 3所述的用途, 其特征在于: 所述人类***瘤病 毒为高危型人类***瘤病毒。
5、 根据权利要求 4所述的用途, 其特征在于: 所述高危型人类***瘤 病毒为 HPV16、 HPV18、 HPV31或 HPV33。
6、 根据权利要求 5所述的用途, 其特征在于: 所述高危型人类***瘤 病毒为 HPV16。
7、 根据权利要求 6所述的用途, 其特征在于: 所述药物是抑制 HPV16 中 E6或 /和 E7蛋白的药物。
8、 根据权利要求 1所述的用途, 其特征在于: R选自取代或非取代的 C4-6的芳香基或杂环芳香基; 其中, 所述杂环芳香基为含 0或 N杂环芳香 基。
9、 根据权利要求 1或 8所述的用途, 其特征在于: 取代基选自 C1-4的 垸基、 C1-2的垸氧基、 C1-2的氨垸基、 氨基或卤素。
10、 根据权利要求 1、 8或 9所述的嘧啶类化合物, 其特征在于: 所述化 合物为
式 2
其中, 选自 C1-6的垸基、 C1-4的垸氧基、 C1-4的氨垸基、 氨基 或
11、 根据权利要求 10所述的用途, 其特征在于: 选自 C1-4的垸 基、 C1-2的垸氧基、 C1-2的氨垸基、 氨基或 H。
12、 根据权利要求 11所述的用途, 其特征在于: 选自 C1-4的垸 基或 C1-2的垸氧基。
13、 根据权利要求 12所述的用途, 其特征在于: R2、 R4为 H; Rl、 R5 为 H或 C1-2的垸氧基, 但不同时为 H; R3为 C1-4的垸基。
14、 根据权利要求 11~13任意一项所述的用途, 其特征在于: 所述 C1-4 的垸基为丁基, C1-2的垸氧基为甲氧基, C1-2的氨垸基为氨甲基。
15、 根据权利要求 14所述的用途, 其特征在于: 所述丁基为叔丁基。
16、 根据权利要求 1所述的用途, 其特征在于: 所述化合物为:
4- (4-叔丁基苄胺) -5-甲醛肟 -6-氯嘧啶、 或 4- ( 2-甲氧基苄胺) -5-甲酸 肟 -6-氯嘧啶。
17、 式 1所示的嘧啶类化合物或其药学上可接受的盐在制备抗人类*** 瘤病毒的药物中的用途,
■OH
R选自取代或非取代的 C4-10的芳香基或杂环芳香基, 其中, 取代基选 自 C1-6的垸基、 C1-4的垸氧基、 C1-4的氨垸基或卤素。
18、 根据权利要求 17所述的用途, 其特征在于: 所述人类***瘤病毒 为高危型人类***瘤病毒。
19、 根据权利要求 18所述的用途, 其特征在于: 所述高危型人类*** 瘤病毒为 HPV16、 HPV18、 HPV31或 HPV33。
20、 根据权利要求 19所述的用途, 其特征在于: 所述高危型人类*** 瘤病毒为 HPV16。
21、 根据权利要求 20所述的用途, 其特征在于: 所述药物是抑制 HPV16 中 E6或 E7蛋白的药物。
22、根据权利要求 17所述的用途, 其特征在于: R选自取代或非取代的 C4-6的芳香基或杂环芳香基; 其中, 所述杂环芳香基为含 0或 N杂环芳香 基。
23、 根据权利要求 17或 22所述的用途, 其特征在于: 取代基选自 C1-4 的垸基、 C1-2的垸氧基、 C1-2的氨垸基、 氨基或卤素。
24、 根据权利要求 17、 22或 23所述的用途, 其特征在于: 所述化合物 为
其中, 选自 C1-6的垸基、 C1-4的垸氧基、 C1-4的氨垸基、 氨基 或
25、 根据权利要求 24所述的用途, 其特征在于: 选自 C1-4的垸 基、 C1-2的垸氧基、 C1-2的氨垸基、 氨基或 Η。
26、 根据权利要求 25所述的用途, 其特征在于: 选自 C1-4的垸 基或 C1-2的垸氧基。
27、 根据权利要求 26所述的用途, 其特征在于: R2、 R4为 H; Rl、 R5 为 H或 C1-2的垸氧基, 但不同时为 H; R3为 C1-4的垸基。
28、 根据权利要求 25~27任意一项所述的用途, 其特征在于: 所述 C1-4 的垸基为丁基, C1-2的垸氧基为甲氧基, C1-2的氨垸基为氨甲基。
29、 根据权利要求 28所述的用途, 其特征在于: 所述丁基为叔丁基。
30、 根据权利要求 17所述的用途, 其特征在于: 所述化合物为: 4- (4-叔丁基苄胺) -5-甲醛肟 -6-氯嘧啶、 或 4- (2-甲氧基苄胺) -5-甲酸 肟 -6-氯嘧啶。
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JPH08134044A (ja) * | 1994-11-09 | 1996-05-28 | Nippon Shoji Kk | 新規ピリミジン化合物、中間体及びそれらの製造法 |
JPH10212235A (ja) * | 1997-01-29 | 1998-08-11 | Nippon Shoji Kk | 抗腫瘍剤 |
TW200800919A (en) * | 2005-12-21 | 2008-01-01 | Janssen Pharmaceutica Nv | Substituted pyrimidinyl oxime kinase inhibitors |
CN103058935A (zh) * | 2013-01-15 | 2013-04-24 | 四川大学 | 一种嘧啶类化合物及其制备方法和用途 |
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JPH08134044A (ja) * | 1994-11-09 | 1996-05-28 | Nippon Shoji Kk | 新規ピリミジン化合物、中間体及びそれらの製造法 |
JPH10212235A (ja) * | 1997-01-29 | 1998-08-11 | Nippon Shoji Kk | 抗腫瘍剤 |
TW200800919A (en) * | 2005-12-21 | 2008-01-01 | Janssen Pharmaceutica Nv | Substituted pyrimidinyl oxime kinase inhibitors |
CN103058935A (zh) * | 2013-01-15 | 2013-04-24 | 四川大学 | 一种嘧啶类化合物及其制备方法和用途 |
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CN114053392A (zh) * | 2020-07-30 | 2022-02-18 | 广州朗圣药业有限公司 | 新型化合物在制备预防和/或治疗hpv感染的药物中的应用 |
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