CN1556808A - 基于n6-取代腺嘌呤的杂环化合物,它们的制备方法,它们用于制备药物、化妆品制剂和生长调节剂的用途 ,包含这些化合物的药物制剂、化妆品制剂和生长调节剂 - Google Patents
基于n6-取代腺嘌呤的杂环化合物,它们的制备方法,它们用于制备药物、化妆品制剂和生长调节剂的用途 ,包含这些化合物的药物制剂、化妆品制剂和生长调节剂 Download PDFInfo
- Publication number
- CN1556808A CN1556808A CNA028185528A CN02818552A CN1556808A CN 1556808 A CN1556808 A CN 1556808A CN A028185528 A CNA028185528 A CN A028185528A CN 02818552 A CN02818552 A CN 02818552A CN 1556808 A CN1556808 A CN 1556808A
- Authority
- CN
- China
- Prior art keywords
- purine
- benzylamino
- amino
- benzyl
- chloro
- 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
- -1 N6-substituted adenine Chemical class 0.000 title claims abstract description 367
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 238000000034 method Methods 0.000 title claims abstract description 21
- 239000003814 drug Substances 0.000 title claims abstract description 20
- 239000003630 growth substance Substances 0.000 title claims abstract description 12
- 229940079593 drug Drugs 0.000 title abstract description 9
- 239000002537 cosmetic Substances 0.000 title abstract description 7
- 150000002391 heterocyclic compounds Chemical class 0.000 title description 2
- 239000000825 pharmaceutical preparation Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 99
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 18
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
- 230000000394 mitotic effect Effects 0.000 claims abstract description 4
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 578
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 125
- 210000004027 cell Anatomy 0.000 claims description 79
- 125000003368 amide group Chemical group 0.000 claims description 65
- 125000000217 alkyl group Chemical group 0.000 claims description 64
- 230000014509 gene expression Effects 0.000 claims description 49
- 125000003118 aryl group Chemical group 0.000 claims description 34
- 125000001072 heteroaryl group Chemical group 0.000 claims description 32
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 32
- 239000000203 mixture Substances 0.000 claims description 31
- GFFGJBXGBJISGV-UHFFFAOYSA-N adenyl group Chemical class N1=CN=C2N=CNC2=C1N GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims description 28
- 125000003545 alkoxy group Chemical group 0.000 claims description 28
- 125000004442 acylamino group Chemical group 0.000 claims description 26
- 229910052736 halogen Inorganic materials 0.000 claims description 26
- 150000002367 halogens Chemical group 0.000 claims description 26
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 26
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims description 25
- 229960000485 methotrexate Drugs 0.000 claims description 25
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 23
- 125000003282 alkyl amino group Chemical group 0.000 claims description 22
- 125000004423 acyloxy group Chemical group 0.000 claims description 20
- 125000003107 substituted aryl group Chemical group 0.000 claims description 20
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 150000001356 alkyl thiols Chemical class 0.000 claims description 17
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 17
- 241000196324 Embryophyta Species 0.000 claims description 16
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 16
- 239000000463 material Substances 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 15
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 13
- 150000002431 hydrogen Chemical group 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 11
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 125000000524 functional group Chemical group 0.000 claims description 10
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 10
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 9
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 229910052740 iodine Inorganic materials 0.000 claims description 7
- UGGBIVVLRPJYKC-UHFFFAOYSA-N n-[(2,4,6-trimethoxyphenyl)methyl]-7h-purin-6-amine Chemical compound COC1=CC(OC)=CC(OC)=C1CNC1=NC=NC2=C1NC=N2 UGGBIVVLRPJYKC-UHFFFAOYSA-N 0.000 claims description 7
- QKAZZGOALRRZIZ-UHFFFAOYSA-N 1-[3-[(7h-purin-6-ylamino)methyl]phenyl]ethanone Chemical compound CC(=O)C1=CC=CC(CNC=2C=3NC=NC=3N=CN=2)=C1 QKAZZGOALRRZIZ-UHFFFAOYSA-N 0.000 claims description 6
- CZNHDIGYWBRFEK-UHFFFAOYSA-N 2-methoxy-6-[(7h-purin-6-ylamino)methyl]phenol Chemical compound COC1=CC=CC(CNC=2C=3NC=NC=3N=CN=2)=C1O CZNHDIGYWBRFEK-UHFFFAOYSA-N 0.000 claims description 6
- FURPLLPJUBDPRU-UHFFFAOYSA-N 4-[(7h-purin-6-ylamino)methyl]benzene-1,2-diol Chemical compound C1=C(O)C(O)=CC=C1CNC1=NC=NC2=C1NC=N2 FURPLLPJUBDPRU-UHFFFAOYSA-N 0.000 claims description 6
- 241000124008 Mammalia Species 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 238000004113 cell culture Methods 0.000 claims description 6
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 6
- 238000005516 engineering process Methods 0.000 claims description 6
- 230000005764 inhibitory process Effects 0.000 claims description 6
- HTFODAFEUYNHMV-UHFFFAOYSA-N n-[(2-chloro-4-fluorophenyl)methyl]-7h-purin-6-amine Chemical compound ClC1=CC(F)=CC=C1CNC1=NC=NC2=C1NC=N2 HTFODAFEUYNHMV-UHFFFAOYSA-N 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- LFLSCGLVSMEKGW-UHFFFAOYSA-N 2-methoxy-4-[(7h-purin-6-ylamino)methyl]phenol Chemical compound C1=C(O)C(OC)=CC(CNC=2C=3NC=NC=3N=CN=2)=C1 LFLSCGLVSMEKGW-UHFFFAOYSA-N 0.000 claims description 5
- RIQYCXBBKOQNJX-UHFFFAOYSA-N 2-methoxy-5-[(7h-purin-6-ylamino)methyl]phenol Chemical compound C1=C(O)C(OC)=CC=C1CNC1=NC=NC2=C1NC=N2 RIQYCXBBKOQNJX-UHFFFAOYSA-N 0.000 claims description 5
- 230000032683 aging Effects 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 201000010099 disease Diseases 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- 125000004475 heteroaralkyl group Chemical group 0.000 claims description 5
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 5
- NMTRZECLZGTLQP-UHFFFAOYSA-N n-[(2,3,4-trifluorophenyl)methyl]-7h-purin-6-amine Chemical compound FC1=C(F)C(F)=CC=C1CNC1=NC=NC2=C1NC=N2 NMTRZECLZGTLQP-UHFFFAOYSA-N 0.000 claims description 5
- AVABYJXKHLOFKV-UHFFFAOYSA-N n-[(2,4-dichlorophenyl)methyl]-7h-purin-6-amine Chemical compound ClC1=CC(Cl)=CC=C1CNC1=NC=NC2=C1NC=N2 AVABYJXKHLOFKV-UHFFFAOYSA-N 0.000 claims description 5
- BUSZAVZMOKMTQL-UHFFFAOYSA-N n-[(2,4-difluorophenyl)methyl]-7h-purin-6-amine Chemical compound FC1=CC(F)=CC=C1CNC1=NC=NC2=C1NC=N2 BUSZAVZMOKMTQL-UHFFFAOYSA-N 0.000 claims description 5
- YKOPIHVRMLXYAK-UHFFFAOYSA-N n-[(2,4-dimethoxyphenyl)methyl]-7h-purin-6-amine Chemical compound COC1=CC(OC)=CC=C1CNC1=NC=NC2=C1NC=N2 YKOPIHVRMLXYAK-UHFFFAOYSA-N 0.000 claims description 5
- YWPFTGKKYUNEIY-UHFFFAOYSA-N n-[(2-bromophenyl)methyl]-7h-purin-6-amine Chemical compound BrC1=CC=CC=C1CNC1=NC=NC2=C1NC=N2 YWPFTGKKYUNEIY-UHFFFAOYSA-N 0.000 claims description 5
- STWJKIOLMNHFIK-UHFFFAOYSA-N n-[(2-methoxyphenyl)methyl]-7h-purin-6-amine Chemical compound COC1=CC=CC=C1CNC1=NC=NC2=C1NC=N2 STWJKIOLMNHFIK-UHFFFAOYSA-N 0.000 claims description 5
- UGNHBTDGSONRKB-UHFFFAOYSA-N n-[(2-methylphenyl)methyl]-7h-purin-6-amine Chemical compound CC1=CC=CC=C1CNC1=NC=NC2=C1NC=N2 UGNHBTDGSONRKB-UHFFFAOYSA-N 0.000 claims description 5
- JNDQVHZQBMFTTQ-UHFFFAOYSA-N n-[(3,4,5-trimethoxyphenyl)methyl]-7h-purin-6-amine Chemical compound COC1=C(OC)C(OC)=CC(CNC=2C=3NC=NC=3N=CN=2)=C1 JNDQVHZQBMFTTQ-UHFFFAOYSA-N 0.000 claims description 5
- KFCRCDSFFAMAHH-UHFFFAOYSA-N n-[(3,4-dichlorophenyl)methyl]-7h-purin-6-amine Chemical compound C1=C(Cl)C(Cl)=CC=C1CNC1=NC=NC2=C1NC=N2 KFCRCDSFFAMAHH-UHFFFAOYSA-N 0.000 claims description 5
- JLFVTVWYTKYYPS-UHFFFAOYSA-N n-[(3-methoxyphenyl)methyl]-7h-purin-6-amine Chemical compound COC1=CC=CC(CNC=2C=3NC=NC=3N=CN=2)=C1 JLFVTVWYTKYYPS-UHFFFAOYSA-N 0.000 claims description 5
- NJUGLVUMAHIRDN-UHFFFAOYSA-N n-[(3-methylphenyl)methyl]-7h-purin-6-amine Chemical compound CC1=CC=CC(CNC=2C=3NC=NC=3N=CN=2)=C1 NJUGLVUMAHIRDN-UHFFFAOYSA-N 0.000 claims description 5
- LGIAMFVFYKMPAN-UHFFFAOYSA-N n-[(4-bromophenyl)methyl]-7h-purin-6-amine Chemical compound C1=CC(Br)=CC=C1CNC1=NC=NC2=C1NC=N2 LGIAMFVFYKMPAN-UHFFFAOYSA-N 0.000 claims description 5
- JNRWSGYVASKILI-UHFFFAOYSA-N n-[(4-methoxyphenyl)methyl]-7h-purin-6-amine Chemical compound C1=CC(OC)=CC=C1CNC1=NC=NC2=C1NC=N2 JNRWSGYVASKILI-UHFFFAOYSA-N 0.000 claims description 5
- KOGDZGJILJKQJY-UHFFFAOYSA-N n-[(4-methylphenyl)methyl]-7h-purin-6-amine Chemical compound C1=CC(C)=CC=C1CNC1=NC=NC2=C1NC=N2 KOGDZGJILJKQJY-UHFFFAOYSA-N 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 claims description 4
- QMXCKKNYBDZYHP-UHFFFAOYSA-N 1-[2-[(7h-purin-6-ylamino)methyl]phenyl]ethanone Chemical compound CC(=O)C1=CC=CC=C1CNC1=NC=NC2=C1NC=N2 QMXCKKNYBDZYHP-UHFFFAOYSA-N 0.000 claims description 4
- WYOHUQDZZVVATD-UHFFFAOYSA-N 2-[(7h-purin-6-ylamino)methyl]benzene-1,3,5-triol Chemical compound OC1=CC(O)=CC(O)=C1CNC1=NC=NC2=C1NC=N2 WYOHUQDZZVVATD-UHFFFAOYSA-N 0.000 claims description 4
- BUDWTFCZGZYQHZ-UHFFFAOYSA-N 3-[(7h-purin-6-ylamino)methyl]phenol Chemical compound OC1=CC=CC(CNC=2C=3NC=NC=3N=CN=2)=C1 BUDWTFCZGZYQHZ-UHFFFAOYSA-N 0.000 claims description 4
- PWMMSLFZXFQHQW-UHFFFAOYSA-N 4-[(7h-purin-6-ylamino)methyl]benzene-1,2,3-triol Chemical compound OC1=C(O)C(O)=CC=C1CNC1=NC=NC2=C1NC=N2 PWMMSLFZXFQHQW-UHFFFAOYSA-N 0.000 claims description 4
- 206010052779 Transplant rejections Diseases 0.000 claims description 4
- 238000010521 absorption reaction Methods 0.000 claims description 4
- 125000002837 carbocyclic group Chemical group 0.000 claims description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 230000003308 immunostimulating effect Effects 0.000 claims description 4
- ZJTRLXXRFINXKP-UHFFFAOYSA-N n-[(2-amino-6-chlorophenyl)methyl]-7h-purin-6-amine Chemical compound NC1=CC=CC(Cl)=C1CNC1=NC=NC2=C1NC=N2 ZJTRLXXRFINXKP-UHFFFAOYSA-N 0.000 claims description 4
- QTHDKRDGRLYUAG-UHFFFAOYSA-N n-[(2-chloro-3,6-difluorophenyl)methyl]-7h-purin-6-amine Chemical compound FC1=CC=C(F)C(CNC=2C=3NC=NC=3N=CN=2)=C1Cl QTHDKRDGRLYUAG-UHFFFAOYSA-N 0.000 claims description 4
- JOKWOTYVMPTGJL-UHFFFAOYSA-N n-[(2-chlorophenyl)methyl]-7h-purin-6-amine Chemical compound ClC1=CC=CC=C1CNC1=NC=NC2=C1NC=N2 JOKWOTYVMPTGJL-UHFFFAOYSA-N 0.000 claims description 4
- UIPBJXUABCBASK-UHFFFAOYSA-N n-[(3,4-dimethoxyphenyl)methyl]-7h-purin-6-amine Chemical compound C1=C(OC)C(OC)=CC=C1CNC1=NC=NC2=C1NC=N2 UIPBJXUABCBASK-UHFFFAOYSA-N 0.000 claims description 4
- CBHRFVHKMMMKPW-UHFFFAOYSA-N n-[(3,5-dimethoxyphenyl)methyl]-7h-purin-6-amine Chemical compound COC1=CC(OC)=CC(CNC=2C=3NC=NC=3N=CN=2)=C1 CBHRFVHKMMMKPW-UHFFFAOYSA-N 0.000 claims description 4
- FKSQJVJXEFKZQE-UHFFFAOYSA-N n-[(3-bromophenyl)methyl]-7h-purin-6-amine Chemical compound BrC1=CC=CC(CNC=2C=3NC=NC=3N=CN=2)=C1 FKSQJVJXEFKZQE-UHFFFAOYSA-N 0.000 claims description 4
- UTZWZZICQOYTFM-UHFFFAOYSA-N n-[(3-chloro-2,6-difluorophenyl)methyl]-7h-purin-6-amine Chemical compound FC1=CC=C(Cl)C(F)=C1CNC1=NC=NC2=C1NC=N2 UTZWZZICQOYTFM-UHFFFAOYSA-N 0.000 claims description 4
- XRBLGYUGFSEASE-UHFFFAOYSA-N n-[(3-nitrophenyl)methyl]-7h-purin-6-amine Chemical compound [O-][N+](=O)C1=CC=CC(CNC=2C=3NC=NC=3N=CN=2)=C1 XRBLGYUGFSEASE-UHFFFAOYSA-N 0.000 claims description 4
- PGPCCTUFQQKBIZ-UHFFFAOYSA-N n-[(4-ethoxyphenyl)methyl]-7h-purin-6-amine Chemical compound C1=CC(OCC)=CC=C1CNC1=NC=NC2=C1NC=N2 PGPCCTUFQQKBIZ-UHFFFAOYSA-N 0.000 claims description 4
- AXYKSADFXHVJFP-UHFFFAOYSA-N n-[(4-nitrophenyl)methyl]-7h-purin-6-amine Chemical compound C1=CC([N+](=O)[O-])=CC=C1CNC1=NC=NC2=C1NC=N2 AXYKSADFXHVJFP-UHFFFAOYSA-N 0.000 claims description 4
- QRUOJHAIQPNBLF-UHFFFAOYSA-N n-[2,4-bis(trifluoromethyl)phenyl]-7h-purin-6-amine Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC=C1NC1=NC=NC2=C1NC=N2 QRUOJHAIQPNBLF-UHFFFAOYSA-N 0.000 claims description 4
- HZKFNJWQHIMWEO-UHFFFAOYSA-N n-[[4-(trifluoromethyl)phenyl]methyl]-7h-purin-6-amine Chemical compound C1=CC(C(F)(F)F)=CC=C1CNC1=NC=NC2=C1NC=N2 HZKFNJWQHIMWEO-UHFFFAOYSA-N 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- BRNFSOIOUTVDNV-UHFFFAOYSA-N 3-chloro-6-[(7h-purin-6-ylamino)methyl]benzene-1,2-diol Chemical compound OC1=C(Cl)C=CC(CNC=2C=3NC=NC=3N=CN=2)=C1O BRNFSOIOUTVDNV-UHFFFAOYSA-N 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 230000010261 cell growth Effects 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 3
- UUXDAWLFNYUUAX-UHFFFAOYSA-N n-[(2,3,6-trichlorophenyl)methyl]-7h-purin-6-amine Chemical compound ClC1=CC=C(Cl)C(CNC=2C=3NC=NC=3N=CN=2)=C1Cl UUXDAWLFNYUUAX-UHFFFAOYSA-N 0.000 claims description 3
- IPTZAGPLYVGZBK-UHFFFAOYSA-N n-[(2-methyl-5-nitrophenyl)methyl]-7h-purin-6-amine Chemical compound CC1=CC=C([N+]([O-])=O)C=C1CNC1=NC=NC2=C1NC=N2 IPTZAGPLYVGZBK-UHFFFAOYSA-N 0.000 claims description 3
- REGPXSZEDITJKW-UHFFFAOYSA-N n-[(3-fluoro-4-methylphenyl)methyl]-7h-purin-6-amine Chemical compound C1=C(F)C(C)=CC=C1CNC1=NC=NC2=C1NC=N2 REGPXSZEDITJKW-UHFFFAOYSA-N 0.000 claims description 3
- MSXAMTDJNFBSNC-UHFFFAOYSA-N n-[2,6-dibromo-4-(trifluoromethoxy)phenyl]-7h-purin-6-amine Chemical compound BrC1=CC(OC(F)(F)F)=CC(Br)=C1NC1=NC=NC2=C1NC=N2 MSXAMTDJNFBSNC-UHFFFAOYSA-N 0.000 claims description 3
- UWMCHDDHXMFKMA-UHFFFAOYSA-N (2,5-dimethoxyphenyl)methanamine Chemical compound COC1=CC=C(OC)C(CN)=C1 UWMCHDDHXMFKMA-UHFFFAOYSA-N 0.000 claims description 2
- GVULSXIBCHPJEH-UHFFFAOYSA-N (2-chloro-6-fluorophenyl)methanamine Chemical compound NCC1=C(F)C=CC=C1Cl GVULSXIBCHPJEH-UHFFFAOYSA-N 0.000 claims description 2
- VJNGGOMRUHYAMC-UHFFFAOYSA-N (3,5-difluorophenyl)methanamine Chemical compound NCC1=CC(F)=CC(F)=C1 VJNGGOMRUHYAMC-UHFFFAOYSA-N 0.000 claims description 2
- QIEDWVJRICQSAL-UHFFFAOYSA-N (4-pentylphenyl)methanamine Chemical compound CCCCCC1=CC=C(CN)C=C1 QIEDWVJRICQSAL-UHFFFAOYSA-N 0.000 claims description 2
- QNVQQOMDSJXWBV-UHFFFAOYSA-N 1-methoxy-3-[(7h-purin-6-ylamino)methyl]cyclohexa-3,5-diene-1,2-diol Chemical compound OC1C(OC)(O)C=CC=C1CNC1=NC=NC2=C1NC=N2 QNVQQOMDSJXWBV-UHFFFAOYSA-N 0.000 claims description 2
- CZWOGDMIUCHGMQ-UHFFFAOYSA-N 2,6-dibromo-4-[(7h-purin-6-ylamino)methyl]phenol Chemical compound C1=C(Br)C(O)=C(Br)C=C1CNC1=NC=NC2=C1NC=N2 CZWOGDMIUCHGMQ-UHFFFAOYSA-N 0.000 claims description 2
- LXLNOVFJVBWOHT-UHFFFAOYSA-N 2,6-dimethyl-4-[(7h-purin-6-ylamino)methyl]phenol Chemical compound CC1=C(O)C(C)=CC(CNC=2C=3NC=NC=3N=CN=2)=C1 LXLNOVFJVBWOHT-UHFFFAOYSA-N 0.000 claims description 2
- YCWRFIYBUQBHJI-UHFFFAOYSA-N 2-(4-aminophenyl)acetonitrile Chemical group NC1=CC=C(CC#N)C=C1 YCWRFIYBUQBHJI-UHFFFAOYSA-N 0.000 claims description 2
- LKVNZRUBOOJTNN-UHFFFAOYSA-N 2-[(7h-purin-6-ylamino)methyl]benzaldehyde Chemical compound O=CC1=CC=CC=C1CNC1=NC=NC2=C1NC=N2 LKVNZRUBOOJTNN-UHFFFAOYSA-N 0.000 claims description 2
- OOEKZBZBWMVRQD-UHFFFAOYSA-N 2-[(7h-purin-6-ylamino)methyl]benzene-1,3-diol Chemical compound OC1=CC=CC(O)=C1CNC1=NC=NC2=C1NC=N2 OOEKZBZBWMVRQD-UHFFFAOYSA-N 0.000 claims description 2
- KFYXVCOVDDKZIG-UHFFFAOYSA-N 2-[(7h-purin-6-ylamino)methyl]benzene-1,4-diamine Chemical compound NC1=CC=C(N)C(CNC=2C=3NC=NC=3N=CN=2)=C1 KFYXVCOVDDKZIG-UHFFFAOYSA-N 0.000 claims description 2
- KLAFRFHICUEWKS-UHFFFAOYSA-N 2-[(7h-purin-6-ylamino)methyl]benzene-1,4-diol Chemical compound OC1=CC=C(O)C(CNC=2C=3NC=NC=3N=CN=2)=C1 KLAFRFHICUEWKS-UHFFFAOYSA-N 0.000 claims description 2
- LCHBLEPBBKHBPJ-UHFFFAOYSA-N 2-[(7h-purin-6-ylamino)methyl]benzonitrile Chemical compound N#CC1=CC=CC=C1CNC1=NC=NC2=C1NC=N2 LCHBLEPBBKHBPJ-UHFFFAOYSA-N 0.000 claims description 2
- AKOVXPNRITVXAR-UHFFFAOYSA-N 2-[(7h-purin-6-ylamino)methyl]phenol Chemical compound OC1=CC=CC=C1CNC1=NC=NC2=C1NC=N2 AKOVXPNRITVXAR-UHFFFAOYSA-N 0.000 claims description 2
- ISNQTPITAZZVGJ-UHFFFAOYSA-N 2-bromo-4-[(7h-purin-6-ylamino)methyl]phenol Chemical compound C1=C(Br)C(O)=CC=C1CNC1=NC=NC2=C1NC=N2 ISNQTPITAZZVGJ-UHFFFAOYSA-N 0.000 claims description 2
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Abstract
基于N6-取代腺嘌呤的新杂环衍生物及其制备方法,该衍生物具有对于植物、动物和人类细胞的抗癌、有丝分裂、免疫抑制和抗衰老性能。也包括药物组合物、化妆品制剂和生长调节剂,它们包含这些衍生物作为活性化合物,以及在生物技术过程、化妆品和农业中将这些衍生物用于制备药物、化妆品制剂的用途。
Description
发明领域
本发明涉及基于N6-取代腺嘌呤的新杂环衍生物及其制备方法,该衍生物具有对于植物、动物和人类细胞的抗癌、有丝分裂、免疫抑制和抗衰老性能,及其作为药物、药物组合物的用途,这些药品、医药组合物包含这些衍生物作为活性化合物,以及将这些衍生物用于药品的制备、化妆品的制备、生物技术方法、用于化妆品中和用于农业中。
背景技术
现已充分证实的植物调节化合物是植物激素。在这些植物激素中占有重要位置的是细胞分裂素。在结构上,所有的天然形成的细胞分裂素属于N6-取代腺嘌呤衍生物的同系组,它们在许多不同的发育过程中起着重要作用,这些发育过程包括细胞分裂、生长和分化,以及花和果实的发育。它们可以中断种子休眠,抑制顶端优势和刺激侧枝的生长,延迟细胞老化,增加耐应力性,影响细胞膜渗透性和引起各种代谢物在其应用位置上的积累(Letham a Palni 1983-Ann.Rev.Plant.Physiol.34:163-197,1983,Mok,D.W.S.,Mok,M.C.:细胞分裂素:化学,活性和功能。CRC Press,Boca Raton,伦敦,东京1994)。
在植物组织培养物中,它们与植物生长素的相互作用在细胞分裂的刺激和细胞分化的调节中是特别重要的(Skoog,Miller 1957)。细胞分裂素作为一组植物生长调节剂的一般定义也是基于这个效果(Skoog,F.,Armstrong,D.J.:Cytokinins.-Ann.Rev.Plant Physiol.21:359-384,1970)。6-苄基氨基嘌呤(BAP),与激动素一起,通常用作植物体外培养物的活性细胞分裂素。此化合物长时间以来被认为是纯合成的,然而,近来证实它天然存在于植物中。通常也将具有有限或不具有生物活性的化合物称为细胞分裂素(7-和9-葡糖苷,氨基酸共轭物,tRNA中的一些高改性细胞分裂素)。由此原因,结构上衍生自N6-取代腺嘌呤的化合物也在本申请中称为细胞分裂素。
由于地球上所有的生物已经在一起进化发育数百万年,可以假定植物化合物的相互调节作用如细胞分裂素存在于动物和人类中。细胞分裂素衍生的化合物可能影响动物和人体细胞中的许多不同分子机理。我们近来发现,新一代的抗炎、抗癌、免疫抑制、抗病毒和其它药物可以基于N6-取代腺嘌呤和它们的衍生物。
发明内容
本发明的目的是提供抗癌、免疫抑制、生长调节、形态形成活性和抗衰老杂环化合物,该化合物具有改进选择性和效率指数,即与迄今为止已知的类似物相比,毒性较低而更加有效。
本发明的目的是一种通式I的基于N6-取代腺嘌呤的杂环化合物及其药用盐
其中
R2是氢、卤素、羟基、烷氧基、氨基、1,2-亚肼基、巯基、甲硫基、羧基、氰基、硝基、酰氨基(amido)、磺基、磺氨基、酰基氨基(acylamino)、酰氧基、烷基氨基、二烷基氨基、烷基巯基、环烷基和氨基甲酰基,R6是烷基、取代烷基、环烷基、取代环烷基、环烷基烷基、芳基烷基、杂烷基、杂芳基烷基、杂环烷基烷基或
R6’X,其中
X是-O-、-S-、-NH-、-N(C1-6烷基)-;
R6’是氢、烷基、取代烷基、酰基、环烷基、取代环烷基、芳基、取代芳基、杂环、杂芳基、取代杂芳基、芳基烷基、杂环烷基、取代杂环烷基、杂芳基烷基、杂烷基、环烷基烷基、环杂烷基、酰氨基(amido)和磺基;
然而类属取代基具有与在此方面中定义的相应基团定义相同的意义,其中
“卤素”表示氟、溴、氯和碘原子;
“羟基”表示基团-OH;
“巯基”表示基团-SH;
“烷基”表示支化或未支化C1-C6链,该C1-C6链是饱和或不饱和的,选自例示此术语的甲基、丙基、异丙基、叔丁基、烯丙基、乙烯基、乙炔基、炔丙基、己-2-基等;
“取代烷基”表示前述烷基,其中包括1-5个取代基,例如羟基、巯基、烷巯基、卤素、烷氧基、酰氧基、氨基、酰基氨基(acylamino)、肼基、氨基甲酰基、酰氨基(amido)、羟基、磺基、酰基、胍基等,因此这些基团可以连接到烷基部分的任何碳原子上;
“烷氧基”表示基团-OR,其中R是在此定义的烷基、取代烷基、芳基、取代芳基、芳基烷基、取代芳基烷基、环烷基、取代环烷基、杂环烷基或取代杂环烷基;
“烷基巯基”表示基团-SR,其中R如对于“烷氧基”所定义;
“磺基”表示-SO3R,其中R是H、在此定义的烷基或取代烷基;
“磺酰氨基”表示-SO2NRR”,其中R和R”是H、烷基或取代烷基;
“酰基”表示-C(O)R,其中R是氢、在此定义的烷基、取代烷基、芳基、取代芳基、芳基烷基、取代芳基烷基、环烷基、取代环烷基;
“芳氧基”表示-OAr,其中Ar是在此定义的芳基、取代芳基、取代芳烷基、杂芳基或取代杂芳基;
“烷基氨基”表示基团-NRR’,其中R和R’可以独立地是氢、在此定义的烷基、取代烷基、芳基、取代芳基、杂芳基或取代杂芳基;
“酰氨基(amido)”表示基团-C(O)NRR’,其中R和R’可以独立地是氢、在此定义的烷基、取代烷基、芳基、取代芳基、杂芳基或取代杂芳基;
“羧基”表示基团-C(O)OR,其中R是氢、在此定义的烷基、取代烷基、芳基、取代芳基、杂芳基(hetaryl)或取代杂芳基(substitutedhetaryl);
“酰基氨基(acylamino)”表示基团-NHCOR,其中R是在此定义的烷基、取代烷基、杂环基团、芳基、取代芳基、杂芳基和取代杂芳基;
“氨基甲酰基氨基”表示基团NHCOOR,其中R是烷基或芳基;
“芳基”或“ar”表示含有至少一个芳族环的芳族碳环基团,如苯基或联苯或其中至少一个为环芳族的多个稠环,如1,2,3,4-四氢萘基、萘基、蒽基、或菲基;
“取代芳基”表示可选择的由1-5个官能团取代的前述芳基,该官能团是如在此定义的卤素、烷基、羟基、氨基、酰基氨基(acylamino)、氨基甲酰基氨基、肼基、巯基、烷氧基、烷基巯基、烷基氨基、酰氨基(amido)、羧基、硝基、磺基;
“杂环”表示在环中含有至少一个杂原子,如N、O或S的不饱和或芳族碳环基团;环是单环如吡喃基、吡啶基或呋喃基或多个稠合环如喹唑啉基、嘌呤基、喹啉基或苯并呋喃基,它们可以选择性地由如下基团取代或未取代:在此定义的卤素、氨基、羟基、氰基、硝基、巯基、烷氧基、烷基氨基、酰基氨基(acylamino)、氨基甲酰基氨基、酰氧基、二烷基氨基、烷巯基、羧基、酰氨基(amido)、磺基、磺酰氨基及其它类似基团;
“杂芳基”是其中至少一个杂环是芳族的杂环基团;
“取代杂芳基”表示可选择性的由1-5个官能团单或多取代的杂环,该官能团是如在此定义的卤素、氨基、羟基、氰基、硝基、巯基、烷氧基、烷基氨基、酰基氨基(acylamino)、氨基甲酰基氨基、酰氧基、二烷基氨基、烷巯基、羧基、酰氨基(amido)、磺基、磺酰氨基等;
“芳烷基”表示基团-R-Ar,其中Ar是芳基并且R是烷基或取代烷基,其中芳基可选择性地由如下基团取代或未取代:在此定义的卤素、氨基、酰基氨基(acylamino)、氨基甲酰基氨基、肼基、酰氧基、烷基、羟基、烷氧基、烷巯基、烷基氨基、酰氨基(amido)、羧基、羟基、芳基、硝基、巯基、磺基等;
“杂烷基”表示基团-R-Het,其中Het是杂环基团并且R是烷基,该杂烷基可选择性地由如下基团取代或未取代:上述在此定义的卤素、氨基、羟基、氰基、硝基、巯基、烷氧基、烷基氨基、酰基氨基(acylamino)、氨基甲酰基氨基、酰氧基、二烷基氨基、烷巯基、羧基、酰氨基(amido)、磺基、磺酰氨基等;
“杂芳烷基”表示基团-R-Het-Ar,其中HetAr是杂芳基并且R是烷基或取代烷基,而杂芳烷基可选择性地由如下基团取代或未取代:上述在此定义的卤素、烷基、取代烷基、烷氧基、烷巯基、硝基、硫羟基、磺基等;
“环烷基”表示包含3-15个碳原子的二价环状或多环烷基;
“取代环烷基”表示包括1-5个取代基的环烷基,该取代基选自上述在此定义的卤素、氨基、羟基、氰基、硝基、巯基、烷氧基、烷基氨基、酰基氨基(acylamino)、氨基甲酰基氨基、酰氧基、二烷基氨基、烷巯基、羧基、酰氨基(amido)、磺基、磺酰氨基等;
“杂环烷基”表示在此定义的环烷基,其中至少一个环亚甲基由如下基团替代:NH、OH、SH;
“取代杂环烷基”表示包含1-5个取代基的在此定义的环杂烷基,这些取代基是上述在此定义的卤素、氨基、羟基、氰基、硝基、巯基、烷氧基、烷基氨基、酰基氨基(acylamino)、氨基甲酰基氨基、酰氧基、二烷基氨基、烷基巯基、羧基、酰氨基(amido)、磺基、磺酰氨基等;
“环烷基烷基”表示表示基团-R-环烷基,其中环烷基是环烷基并且R是烷基或取代烷基,其中环烷基可选择地由如下基团取代或未取代:上述在此定义的卤素、氨基、羟基、氰基、硝基、巯基、烷氧基、烷基氨基、酰基氨基(acylamino)、氨基甲酰基氨基、酰氧基、二烷基氨基、烷巯基、羧基、酰氨基(amido)、磺基、磺酰氨基等;
“杂环烷基烷基”表示基团-R-杂环烷基,其中R是烷基或取代烷基,其中杂环烷基可选择地由如下基团取代或未取代:之前在此定义的卤素、氨基、羟基、氰基、硝基、巯基、烷氧基、烷基氨基、酰基氨基(acylamino)、氨基甲酰基氨基、酰氧基、二烷基氨基、烷巯基、羧基、酰氨基(amido)、磺基、磺酰氨基等;
及其外消旋化合物、其旋光异构体和其酸盐。
如下的衍生物是特别优选的,即:6-(2-羟基-3-氯氧苄基氨基)嘌呤、6-(2-羟基-4-氯苄基氨基)嘌呤、6-(2-羟基-5-氯苄基氨基)嘌呤、6-(2-羟基-6-氯苄基氨基)嘌呤、6-(2-羟基-3-碘苄基氨基)嘌呤、6-(2-羟基-4-碘苄基氨基)嘌呤、6-(2-羟基-5-碘苄基氨基)嘌呤、6-(2-羟基-6-碘苄基氨基)嘌呤、6-(2-羟基-3-溴苄基氨基)嘌呤、6-(2-羟基-4-溴苄基氨基)嘌呤、6-(2-羟基-5-溴苄基氨基)嘌呤、6-(2-羟基-6-溴苄基氨基)嘌呤、6-(2-羟基-3-氟苄基氨基)嘌呤、6-(2-羟基-4-氟苄基氨基)嘌呤、6-(2-羟基-5-氟苄基氨基)嘌呤、6-(2-羟基-6-氟苄基氨基)嘌呤、6-(2,3-二羟基-4-甲氧基苄基氨基)嘌呤、6-(2,5-二羟基-4-甲氧基苄基氨基)嘌呤、6-(2,6-二羟基-3-甲氧基苄基氨基)嘌呤、6-(2,3-二羟基-3-甲氧基苄基氨基)嘌呤、6-(2,5-二羟基-3-甲氧基苄基氨基)嘌呤、6-(2,6-二羟基-4-甲氧基苄基氨基)嘌呤、6-(2,3-二羟基-4-氯苄基氨基)嘌呤、6-(2,3-二羟基-4-氯苄基氨基)嘌呤、6-(2,5-二羟基-4-氯苄基氨基)嘌呤、6-(2,6-二羟基-4-氯苄基氨基)嘌呤、6-(2,6-二羟基-4-溴氧基苄基氨基)嘌呤、6-(2,6-二羟基-4-碘苄基氨基)嘌呤、6-(2,6-二羟基-3-氯苄基氨基)嘌呤、6-(2,6-二羟基-3-溴苄基氨基)嘌呤、6-(2,6-二羟基-3-碘苄基氨基)嘌呤、6-(2,6-二羟基-3-氟苄基氨基)嘌呤、6-(2,6-二羟基-3,5-二氯苄基氨基)嘌呤、6-(2,6-二羟基-3,5-二溴苄基氨基)嘌呤、6-(2,6-二羟基-3,5-二碘苄基氨基)嘌呤、6-(2,6-二羟基-3,5-二氟苄基氨基)嘌呤、6-(2-氟苄基氨基)嘌呤、6-(3-氟苄基氨基)嘌呤、6-(4-氟苄基氨基)嘌呤、6-(2-溴苄基氨基)嘌呤、6-(3-溴苄基氨基)嘌呤、6-(4-溴苄基氨基)嘌呤、6-(2-碘苄基氨基)嘌呤、6-(3-碘苄基氨基)嘌呤、6-(4-碘苄基氨基)嘌呤、6-(2-氯苄基氨基)嘌呤、6-(2-氯苄基氨基)嘌呤、6-(3-氯苄基氨基)嘌呤、6-(4-氯苄基氨基)嘌呤、6-(2-乙酰基苄基氨基)嘌呤、6-(3-乙酰基苄基氨基)嘌呤、6-(4-乙酰基苄基氨基)嘌呤、6-(3-羧基苄基氨基)嘌呤、6-(4-羧基苄基氨基)嘌呤、6-(2-乙酰氧基苄基氨基)嘌呤、6-(3-乙酰氧基苄基氨基)嘌呤、6-(4-乙酰氧基苄基氨基)嘌呤、6-(2-硝基苄基氨基)嘌呤、6-(3-硝基苄基氨基)嘌呤、6-(4-硝基苄基氨基)嘌呤、6-(2-磺基苄基氨基)嘌呤、6-(2-磺基苄基氨基)嘌呤、6-(4-磺基苄基氨基)嘌呤、6-(2-氰基苄基氨基)嘌呤、6-(3-氰基苄基氨基)嘌呤、6-(4-氰基苄基氨基)嘌呤、6-(5-硝基-2-甲基苄基氨基)嘌呤、6-(2-甲基苄基氨基)嘌呤、6-(3-甲基苄基氨基)嘌呤、6-(4-甲基苄基氨基)嘌呤、6-(4-甲基氨基苄基氨基)嘌呤、6-(2-甲氧基苄基氨基)嘌呤、6-(3-甲氧基苄基氨基)嘌呤、6-(4-甲氧基苄基氨基)嘌呤、6-(2-羟基苄基氨基)嘌呤、6-(3-羟基苄基氨基)嘌呤、6-(4-羟基苄基氨基)嘌呤、6-(4-己基苄基氨基)嘌呤、6-(4-己氧基苄基氨基)嘌呤、6-(2-甲酰基苄基氨基)嘌呤、6-(3-甲酰基苄基氨基)嘌呤、6-(4-甲酰基苄基氨基)嘌呤、6-(2-乙氧基苄基氨基)嘌呤、6-(3-乙氧基苄基氨基)嘌呤、6-(4-乙氧基苄基氨基)嘌呤、6-(4-乙基苄基氨基)嘌呤、6-(4-戊基苄基氨基)嘌呤、6-(4-戊氧基苄基氨基)嘌呤、6-(4-苯氧基苄基氨基)嘌呤、6-(4-苯基苄基氨基)嘌呤、6-(4-丙基苄基氨基)嘌呤、6-(4-丙氧基苄基氨基)嘌呤、6-(4-辛基苄基氨基)嘌呤、6-(4-辛氧基苄基氨基)嘌呤、6-(4-乙氧基苄基氨基)嘌呤、6-(3,4-二乙酰氧基苄基氨基)嘌呤、6-(3,5-二乙酰氧基苄基氨基)嘌呤、6-(2,5-二氨基苄基氨基)嘌呤、6-(3,5-二溴苄基氨基)嘌呤、6-(3,5-二溴-4-甲氧基苄基氨基)嘌呤、6-(2,3-二氯苄基氨基)嘌呤、6-(2,4-二氯苄基氨基)嘌呤、6-(2,5-二氯苄基氨基)嘌呤、6-(2,6-二氯苄基氨基)嘌呤、6-(3,4-二氯苄基氨基)嘌呤、6-(3,5-二氯苄基氨基)嘌呤、6-(2,3,4,5-四氟苄基氨基)嘌呤、6-(2-氯-3,6-二氟苄基氨基)嘌呤、6-(5-氯-2-氟苄基氨基)嘌呤、6-(2,3,4-三氟苄基氨基)嘌呤、6-(2,3,5-三氟苄基氨基)嘌呤、6-(2,4,5-三氟苄基氨基)嘌呤、6-(3,4,5-三氟苄基氨基)嘌呤、6-(2,3,6-三氟苄基氨基)嘌呤、6-(3-氯-2,6-二氟苄基氨基)嘌呤、6-(2-氯-6-氟苄基氨基)嘌呤、6-(2,6-二氟苄基氨基)嘌呤、6-(2,4-二氟苄基氨基)嘌呤、6-(3,4-二氟苄基氨基)嘌呤、6-(2,5-二氟苄基氨基)嘌呤、6-(3,5-二氟苄基氨基)嘌呤、6-(5-氟-2-(三氟甲基)苄基氨基)嘌呤、6-(4-氟-2-(三氟甲基)苄基氨基)嘌呤、6-(2-氯-5-(三氟甲基)苄基氨基)嘌呤、6-(2-(二氟甲氧基)苄基氨基)嘌呤、6-(3-(二氟甲氧基)苄基氨基)嘌呤、6-(4-(二氟甲氧基)苄基氨基)嘌呤、6-(2-氟-5-(三氟甲基)苄基氨基)嘌呤、6-(3-氟-4-(三氟甲基)苄基氨基)嘌呤、6-(2-氟-4-(三氟甲基)苄基氨基)嘌呤、6-(2-(三氟甲硫基)苄基氨基)嘌呤、6-(2-氟-3-(三氟甲基)苄基氨基)嘌呤、6-(2-氯-6-氟-3-甲基苄基氨基)嘌呤、6-(6-氯-2-氟-3-甲基苄基氨基)嘌呤、6-(3-氯-2-氟-5-(三氟甲基)苄基氨基)嘌呤、6-(3-氯-2-氟-6-(三氟甲基)苄基氨基)嘌呤、6-(2,3-二氟-4-甲基苄基氨基)嘌呤、6-(2,6-二氟-3-甲基苄基氨基)嘌呤、6-(2-氟-6-(三氟甲基)苄基氨基)嘌呤、6-(3-氯-2,6-二氟苄基氨基)嘌呤、6-(3-(三氟甲硫基)苄基氨基)嘌呤、6-(3-氟-4-甲基苄基氨基)嘌呤、6-(4-氟-3-甲基苄基氨基)嘌呤、6-(5-氟-2-甲基苄基氨基)嘌呤、6-(2-氯-3,6-二氟苄基氨基)嘌呤、6-(4-(三氟甲硫基)苄基氨基)嘌呤、6-(3-氟-5-(三氟甲基)苄基氨基)嘌呤、6-(2-氯-4-氟苄基氨基)嘌呤、6-(2-(三氟甲氧基)苄基氨基)嘌呤、6-(3-(三氟甲基)苄基氨基)嘌呤、6-(2-(三氟甲基)苄基氨基)嘌呤、6-(4-(三氟甲基)苄基氨基)嘌呤、6-(4-氯-3-(三氟甲基)苄基氨基)嘌呤、6-(4-氟-3-(三氟甲基)苄基氨基)嘌呤、6-(3,5-双(三氟甲基)苄基氨基)嘌呤、6-(3-(三氟甲氧基)苄基氨基)嘌呤、6-(4-(三氟甲氧基)苄基氨基)嘌呤、6-(4-(三氟甲基)苄基氨基)嘌呤、6-(4-二乙基氨基苄基氨基)嘌呤、6-(3,4-二羟基苄基氨基)嘌呤、6-(3,5-二羟基苄基氨基)嘌呤、6-(3,4-二羟基苄基氨基)嘌呤、6-(2,3-亚乙基二氧苄基氨基)嘌呤、6-(2,4-二羟基苄基氨基)嘌呤、6-(2,5-二羟基苄基氨基)嘌呤、6-(2,6-二羟基苄基氨基)嘌呤、6-(3,4-二甲氧基苄基氨基)嘌呤、6-(3,4-二甲氧基苄基氨基)嘌呤、6-(3,5-二甲氧基苄基氨基)嘌呤、6-(2,3-二甲氧基苄基氨基)嘌呤、6-(2,4-二甲氧基苄基氨基)嘌呤、6-(2,5-二甲氧基苄基氨基)嘌呤、6-(2,6-二甲氧基苄基氨基)嘌呤、6-(3-羟基-4-甲氧基苄基氨基)嘌呤、6-(2-羟基-3-甲氧基苄基氨基)嘌呤、6-(4-羟基-3-甲氧基苄基氨基)嘌呤、6-(2-羟基-4-甲氧基苄基氨基)嘌呤、6-(4-羟基-2-甲氧基苄基氨基)嘌呤、6-(2-羟基-5-甲氧基苄基氨基)嘌呤、6-(3-羟基-4-甲氧基苄基氨基)嘌呤、6-(4-羟基-3-甲氧基苄基氨基)嘌呤、6-(2-羟基-6-甲氧基苄基氨基)嘌呤、6-(3-羟基-5-甲氧基苄基氨基)嘌呤、6-(4,5-二甲氧基-2-硝基苄基氨基)嘌呤、6-(3,4-二甲基苄基氨基)嘌呤、6-(2,3-二甲基苄基氨基)嘌呤、6-(2,4-二甲基苄基氨基)嘌呤、6-(2,6-二甲基苄基氨基)嘌呤、6-(2,6-二甲基-4-羟基苄基氨基)嘌呤、6-(3,5-二甲基-4-羟基苄基氨基)嘌呤、6-(2-氟-4-羟基苄基氨基)嘌呤、6-(3-氟-4-羟基苄基氨基)嘌呤、6-(3,4-二硝基苄基氨基)嘌呤、6-(3,5-二硝基苄基氨基)嘌呤、6-(2-甲基-5-硝基苄基氨基)嘌呤、6-(3-甲基-4-硝基苄基氨基)嘌呤、6-(3,4-二碘-4-羟基苄基氨基)嘌呤、6-(2-氯-3,4-二甲氧基苄基氨基)嘌呤、6-(4-氯-3,5-二硝基苄基氨基)嘌呤、6-(2-氯-4-氟苄基氨基)嘌呤、6-(3-氯-4-氟苄基氨基)嘌呤、6-(2-氯-6-甲基苄基氨基)嘌呤、6-(3-氯-2-甲基苄基氨基)嘌呤、6-(3-氯-4-甲基苄基氨基)嘌呤、6-(5-氯-2-甲氧基苄基氨基)嘌呤、6-(2-氯-4-氟苄基氨基)嘌呤、6-(4-氯甲基苄基氨基)嘌呤、6-(2-氯-5-硝基苄基氨基)嘌呤、6-(2-氯-6-硝基苄基氨基)嘌呤、6-(4-氯-3-硝基苄基氨基)嘌呤、6-(5-氯-2-硝基苄基氨基)嘌呤、6-(3-溴-4-羟基苄基氨基)嘌呤、6-(3,5-二溴-4-羟基苄基氨基)嘌呤、6-(3-溴-4-甲氧基苄基氨基)嘌呤、6-(4-溴甲基苄基氨基)嘌呤、6-(4-丁氧基苄基氨基)嘌呤、6-(4-丁氧基苄基氨基)嘌呤、6-(4-/叔丁基/苄基氨基)嘌呤、6-(4-叔丁基-2,6-二甲基苄基氨基)嘌呤、6-(2-氨基苄基氨基)嘌呤、6-(3-氨基苄基氨基)嘌呤、6-(4-氨基苄基氨基)嘌呤、6-(2-氨基-6-氯苄基氨基)嘌呤、6-(3-氨基-4-氯苄基氨基)嘌呤、6-(2-氨基-3-氯苄基氨基)嘌呤、6-(2-氨基-4-氯苄基氨基)嘌呤、6-(2-氨基-6-氯苄基氨基)嘌呤、6-(2,6-二氨基-3-氯苄基氨基)嘌呤、6-(2,6-二氨基-4-氯苄基氨基)嘌呤、6-(4-氨基-3-氯苄基氨基)嘌呤、6-(4-氨基-5-二氯苄基氨基)嘌呤、6-(5-氨基-2-甲基苄基氨基)嘌呤、6-(2-氨基-3-硝基苄基氨基)嘌呤、6-(4-氨基-3-硝基苄基氨基)嘌呤、6-(4-苄氧基苄基氨基)嘌呤、6-(3-乙酰基苄基氨基)嘌呤、6-(2-乙酰基苄基氨基)嘌呤、6-(2,3,4-三甲氧基苄基氨基)嘌呤、6-(2,4,5-三甲氧基苄基氨基)嘌呤、6-(2,4,6-三甲氧基苄基氨基)嘌呤、6-(3,4,5-三甲氧基苄基氨基)嘌呤、6-(2,4,6-三甲氧基苄基氨基)嘌呤、6-(2,3,4-三羟基苄基氨基)嘌呤、6-(2,4,6-三羟基苄基氨基)嘌呤、6-(2,3,4-三羟基苄基氨基)嘌呤、6-(3,4,5-三羟基苄基氨基)嘌呤、6-(2,4,6-三羟基苄基氨基)嘌呤、6-(2,4,5-三氯苄基氨基)嘌呤、6-(2,4,5-三氯苄基氨基)嘌呤、6-(2,4,6-三氯苄基氨基)嘌呤、6-(2,3,4-三氯苄基氨基)嘌呤、6-(2,3,5-三氯苄基氨基)嘌呤、6-(2,3,6-三氯苄基氨基)嘌呤、6-(2,5,6-三氯苄基氨基)嘌呤、6-苯胺基嘌呤、6-(2,4-双(三氟甲基)苯胺基)嘌呤、6-(2,5-双(三氟甲基)苯胺基)嘌呤、6-(2,4-双(三氟甲基)苯胺基)嘌呤、6-(3,5-双(三氟甲基)苯胺基)嘌呤、6-(2-溴苯胺基)嘌呤、6-(3-溴苯胺基)嘌呤、6-(4-溴苯胺基)嘌呤、6-(4-溴-2-氯苯胺基)嘌呤、6-(4-溴-3-氯苯胺基)嘌呤、6-(2-溴-6-氯-4-(三氟甲基)苯胺基)嘌呤、6-(4-溴-5,6-二氟苯胺基)嘌呤、6-(2-溴-4,6-二氟苯胺基)嘌呤、6-(4-溴-2,6-二氟苯胺基)嘌呤、6-(4-溴-2-氟苯胺基)嘌呤、6-(2-溴-4-氟苯胺基)嘌呤、6-(2-溴-4-甲基苯胺基)嘌呤、6-(3-溴-2-甲基苯胺基)嘌呤、6-(4-溴-3-甲基苯胺基)嘌呤、6-(2-溴-4-(三氟甲氧基)苯胺基)嘌呤、6-(3-溴-4-(三氟甲氧基)苯胺基)嘌呤、6-(4-溴-2-(三氟甲氧基)苯胺基)嘌呤、6-(2-溴-4,5,6-三氟苯胺基)嘌呤、6-(2,4-二溴苯胺基)嘌吟、6-(2,5-二溴苯胺基)嘌呤、6-(2,4二溴-3,6-二氯苯胺基)嘌呤、6-(2,6-二溴-4-氟苯胺基)嘌呤、6-(2,6-二溴-4-(三氟甲氧基)苯胺基)嘌呤、6-(2,4-二溴-6-(三氟甲基)苯胺基)嘌呤、6-(2,6-二溴-4-(三氟甲基)苯胺基)嘌呤、6-(2,3-二氯苯胺基)嘌呤、6-(2,4-二氯苯胺基)嘌呤、6-(2,5-二氯苯胺基)嘌呤、6-(2,6-二氯苯胺基)嘌呤、6-(3,4-二氯苯胺基)嘌呤、6-(3,5-二氯苯胺基)嘌呤、6-(2,6-二氯-4-(三氟甲氧基)苯胺基)嘌呤、6-(2,4-二氯-6-(三氟甲氧基)苯胺基)嘌呤、6-(2,6-二氯-4-(三氟甲基)苯胺基)嘌呤、6-(2,3-二氟苯胺基)嘌呤、6-(2,4-二氟苯胺基)嘌呤、6-(2,5-二氟苯胺基)嘌呤、6-(2,6-二氟苯胺基)嘌呤、6-(3,4-二氟苯胺基)嘌呤、6-(3,5-二氟苯胺基)嘌呤、6-(2-二氟甲氧基苯胺基)嘌呤、6-(2-二氟甲氧基-5-硝基苯胺基)嘌呤、6-(2,3-二氟-6-硝基苯胺基)嘌呤、6-(2,4-二氟-6-硝基苯胺基)嘌呤、6-(2,4-二碘苯胺基)嘌呤、6-(2,3-二甲基苯胺基)嘌呤、6-(2,4-二甲基苯胺基)嘌呤、6-(2,3-二甲基-6-硝基苯胺基)嘌呤、6-(2,4-二甲氧基苯胺基)嘌呤、6-(2,3-二甲氧基苯胺基)嘌呤、6-(2,3-二硝基-6-甲基苯胺基)嘌呤、6-(4-羟基-2-甲基苯胺基)嘌呤、6-(2-氯苯胺基)嘌呤、6-(3-氯苯胺基)嘌呤、6-(4-氯苯胺基)嘌呤、(3-氯-2,6-二溴-4-氟苯胺基)嘌呤、6-(2-氯-4-氟苯胺基)嘌呤、6-(2-氯-5-氟苯胺基)嘌呤、6-(2-氯-6-氟苯胺基)嘌呤、6-(3-氯-2-氟苯胺基)嘌呤、6-(3-氯-4-氟苯胺基)嘌呤、6-(4-氯-2-氟苯胺基)嘌呤、6-(5-氯-2-氟苯胺基)嘌呤、6-(2-氯-4-氟-5-甲基苯胺基)嘌呤、6-(5-氯-4-氟-2-硝基苯胺基)嘌呤、6-(5-氯-2-羟基苯胺基)嘌呤、6-(4-氯-2-碘苯胺基)嘌呤、6-(2-氯-4-碘苯胺基)嘌呤、6-(2-氯-6-甲基苯胺基)嘌呤、6-(3-氯-2-甲基苯胺基)嘌呤、6-(3-氯-4-(三氟甲氧基)苯胺基)嘌呤、6-(4-氯-2-(三氟甲氧基)苯胺基)嘌呤、6-(2-氟苯胺基)嘌呤、6-(3-氟苯胺基)嘌呤、6-(4-氟苯胺基)嘌呤、6-(2-氟-4-碘苯胺基)嘌呤、6-(2-氟-5-硝基苯胺基)嘌呤、6-(2-氟-4-甲基苯胺基)嘌呤、6-(3-氟-2-甲基苯胺基)嘌呤、6-(3-氟-4-甲基苯胺基)嘌呤、6-(4-氟-2-甲基苯胺基)嘌呤、6-(3-氟-4-甲基苯胺基)嘌呤、6-(5-氟-2-甲基苯胺基)嘌呤、6-(4-氟-2-硝基苯胺基)嘌呤、6-(4-氟-3-硝基苯胺基)嘌呤、6-(2-碘苯胺基)嘌呤、6-(2-氟-4-(三氟甲基)苯胺基)嘌呤、6-(4-碘-2-甲基苯胺基)嘌呤、6-(2-甲氧基苯胺基)嘌呤、6-(3-甲氧基苯胺基)嘌呤、6-(4-甲氧基苯胺基)嘌呤、6-(2-甲氧基-5-甲基苯胺基)嘌呤、6-(2-甲氧基-6-甲基苯胺基)嘌呤、6-(4-甲氧基-2-甲基苯胺基)嘌呤、6-(5-甲氧基-2-甲基苯胺基)嘌呤、6-(4-甲氧基-3-(三氟甲基)苯胺基)嘌呤、6-(2-甲基苯胺基)嘌呤、6-(4-甲基苯胺基)嘌呤、6-(3-甲基苯胺基)嘌呤、6-(2-甲基-3-(三氟甲氧基)苯胺基)嘌呤、6-(2-甲基-4-(三氟甲氧基)苯胺基)嘌呤、6-(2-(甲硫基)苯胺基)嘌呤、6-(4-(甲硫基)苯胺基)嘌呤、6-(2-硝基苯胺基)嘌呤、6-(3-硝基苯胺基)嘌呤、6-(4-硝基苯胺基)嘌呤、6-(2-硝基-4,5,6-三氟苯胺基)嘌呤、6-(2-硝基-4-(三氟甲氧基)苯胺基)嘌呤、6-(2-硝基四氟苯胺基)嘌呤、6-(2,3,4,5,6-五溴苯胺基)嘌呤、6-(2,3,4,5,6-五氟苯胺基)嘌呤、6-(2,3,4,5-四氯苯胺基)嘌呤、6-(2,3,5,6-四氯苯胺基)嘌呤、6-(4-(1,1,2,2-四氟乙氧基)苯胺基)嘌呤、6-(2,3,4,5,-四氟苯胺基)嘌呤、6-(2,3,4,6,-四氟苯胺基)嘌呤、6-(2,3,5,6,-四氟苯胺基)嘌呤、6-(2,3,5,6-四氟-4-(三氟甲基)苯胺基)嘌呤、6-(2,4,6-三溴苯胺基)嘌呤、6-(2,4,6-三溴-3,5-二碘苯胺基)嘌呤、6-(2,3,4-三氯苯胺基)嘌呤、6-(2,4,5-三氯苯胺基)嘌呤、6-(2,4,6-三氯苯胺基)嘌呤、6-(2,4,5-三氟苯胺基)嘌呤、6-(2,3,5-三氟苯胺基)嘌呤、6-(2,3,6-三氟苯胺基)嘌吟、6-(2,3,4-三氟苯胺基)嘌呤、6-(2-三氟甲氧基苯胺基)嘌呤、6-(3-三氟甲氧基苯胺基)嘌呤、6-(4-三氟甲氧基苯胺基)嘌呤、6-(2,3,4-三氟-6-硝基苯胺基)嘌呤、6-(2,4,5-三甲基苯胺基)嘌呤、6-(2,4,6-三甲基苯胺基)嘌呤、6-(3-氯-5-氨基苯胺基)嘌呤、6-(3-氯-4-羧基苯胺基)嘌呤、6-(3-氨基-4-氯苯胺基)嘌呤、6-(3-氯-4-氨基苯胺基)嘌呤、6-(3-羧基-4-羟基苯胺基)嘌呤。
用于通式I化合物制备的开始材料是6-氯嘌呤,从次黄嘌呤(hypoxantin)使用POCl3根据文献(Davoll and Blowy,J.Am.Chem.Soc.73:2936(1957))合成6-氯嘌呤或市购6-氯嘌呤(Sigma,Aldrich,Fluka)。
用于通式I化合物制备的另一种开始材料是6-溴嘌呤,从次黄嘌呤使用亚硝酸正戊酯在三溴甲烷中合成6-溴嘌呤,或市购6-溴嘌呤。
根据本发明,基于具有通式I的N6-取代腺嘌呤的杂环化合物,其中R2和R6如本文上述所定义,可以从通式I的杂环化合物制备,其中R6表示溴、氯或甲基巯基并且R2如本文上述所定义,通过亲核取代以转化R6位置上的氯、溴、或甲基巯基为本文上述的任何其它形式的取代基R6,以获得具有通式I的化合物。
根据本发明的进一步方法是具有通式I的化合物的制备,其特征在于具有通式I的杂环衍生物,其中R2是氢并且R6表示氨基,该氨基通过与具有通式R6’-CHO的醛反应在R6位置被取代,其中R6’如本文上述,从而将R6位置上的氨基转化为本文上述的任何其它形式的取代基R6,以获得具有通式I的化合物。
本发明也涉及一种用作药剂的,基于符合通式I的N6-取代腺嘌呤的杂环化合物。
本发明进一步涉及一种用作植物、哺乳动物、微生物、酵母和真菌细胞生长调节剂的,根据权利要求1基于具有通式I的N6-取代腺嘌呤的杂环化合物。
本发明也涉及一种用作化妆品的,根据权利要求1基于具有通式I的N6-取代腺嘌呤的杂环化合物。
本发明的目的也是一种药物、化妆品或生长调节剂,它们包含具有通式I的化合物或其药学上可接受的盐,包括药物载体。
本发明的进一步目的是将根据权利要求l基于具有通式I的N6-取代腺嘌呤的杂环化合物用来制备如下物质的用途:亲合力吸收基质、用于工艺控制的固定化酶、免疫测定试剂、诊断样品、以及由14C、3H、抗生物素蛋白或生物素标记的化合物和寡核苷酸。
本发明也涉及一种使用具有通式I化合物或其药用盐,包括药物载体以制备药物组合物的方法,该药物组合物预定用作有丝分裂或抗有丝分裂化合物,特别是用于治疗癌症、牛皮癣、风湿性关节炎、狼疮、I型糖尿病、多发性硬化症、再狭窄、多囊性肾病、移植排斥、移植物抗宿主反应病和痛风、寄生虫病如由真菌或原生生物引起的那些、或阿尔茨海默氏病、或作为抗神经产生性药物、或用于抑制免疫刺激或用于增生性皮肤病的治疗。
本发明的目的进一步是将根据权利要求1基于具有通式I的N6-取代腺嘌呤的杂环化合物用于农业中作为生长调节剂,特别用于增加农产品产量和质量。
本发明也涉及具有通式I的基于N6-取代腺嘌呤的杂环化合物,用作抑制哺乳动物表皮细胞(如角化细胞或成纤维细胞)老化或衰老的化妆品。
本发明的进一步目的是使用具有通式I的基于N6-取代腺嘌呤的杂环化合物在细胞培养中作为生长调节剂以刺激增殖和形态发生。
本发明也涉及基于具有通式I的N6-取代腺嘌呤的杂环化合物,该化合物用于制备组合物及其用于植物和哺乳动物胚胎细胞和胚胎(特别是卵母细胞)的克隆的用途。
本发明也涉及根据权利要求1基于具有通式I的N6-取代腺嘌呤的杂环化合物,用于制备组合物及其在哺乳动物中用于抑制免疫刺激,如关节炎或用于移植排斥的抑制。
治疗给药
用于给药的合适途径包括口服、直肠、局部(包括皮肤、眼睛、口腔和舌下)、阴道和胃肠外(包括皮下、肌内、玻璃体内、静脉内、真皮内、膜内和硬膜外)。在临床医师已知的其它考虑因素中,优选的给药途径依赖于患者的病况、化合物的毒性和感染位置。
治疗组合物包括约1%-约95%活性成分,单一的给药剂型优选包括约20%-约90%活性成分以及不是单一剂量的给药剂型优选包括约5%-约20%的活性成分。单位剂型为,例如,糖衣片剂、片剂、安瓿剂、管形瓶、栓剂或胶囊。其它给药剂型是,例如,软膏、乳膏、糊剂、泡沫、酊剂、唇膏、滴剂、喷雾剂、分散体等。例子是包含约0.05g-约1.0g活性成分的胶囊。
本发明的药物组合物以自身已知的方式制备,例如通过常规混合,成粒,涂敷,溶解或冷冻干燥。
优选,使用活性成分的溶液,和此外也使用悬浮液或分散体,特别是等渗水溶液、分散体或悬浮液,对于这些物质可以在使用之前制备,例如在冷冻干燥组合物的情况下,该组合物包括活性成分自身或与载体如甘露糖醇一起。药物组合物可以是灭菌的和/或包括赋形剂,例如防腐剂、稳定剂、润湿剂和/或乳化剂、加溶剂、调节渗透压的盐和/或缓冲剂,它们以其已知的方式制备,例如通过常规溶解或冷冻干燥工艺。所述的溶液或悬浮液可包括粘度增加物质,如羧甲基纤维素钠、葡聚糖、聚乙烯基吡咯烷酮或明胶。
油中悬浮液的油性组分包括植物、通常用于注射目的的合成或半合成油。值得提及的油,特别地,是液体脂肪酸酯,该脂肪酸酯包含作为酸组分的含有8-22个特别是含有12-22个碳原子的长链脂肪酸,例如月桂酸、十三烷酸、十四烷酸、十五烷酸、十六烷酸、十七烷酸、硬脂酸、酸、花生四烯酸、二十二烷酸或相应的不饱和酸,例如油酸、反油酸、euric acid、brasidic acid或亚油酸,若合适可加入抗氧剂,例如维生素E、β-胡萝卜烷或3,5-二叔丁基-4-羟基甲苯。这些脂肪酸酯的醇组分含有不大于6个碳原子并且是一元或多元羟基的,例如一元醇、二元醇或三元醇,例如,甲醇、乙醇、丙醇、丁醇、或戊醇、或其异构体,但特别是甘醇和甘油。脂肪酸酯因此,例如是:油酸乙酯、十四酸异丙酯、十六酸异丙酯、“Labrafil M 2375”(购自Gattefosee,巴黎的聚氧乙烯甘油三油酸酯)、“Labrafil M 1944 CS”(由杏核油醇解制备并由甘油酯和聚乙二醇酯组成的不饱和聚乙醇化的甘油酯(poly-glycolated glycerides),购自Gattefosee,巴黎)、“Labrasol”(由TCM醇解并由甘油酯和聚乙二醇酯组成的饱和聚乙醇化的甘油酯(poly-glycolated glycerides),购自Gattefosee,巴黎)和/或“Miglyol 812”(链长度C8-C12饱和脂肪酸的三甘油酯,购自Huls AG,德国),并且特别是植物油,如棉籽油、杏仁油、橄榄油、蓖麻油、芝麻油、大豆油和,特别地花生油。
以通常的方式在无菌条件下进行注射组合物的制备,正如装瓶然后再封闭容器那样,所用的装瓶容器例如在安瓿或小瓶中。
例如,用于口腔的医药组合物可以通过将活性成分与一种或多种固体载体结合得到,若合适可将获得的混合物粒化,并且,若可取,可将混合物或颗粒加工成片剂或糖衣片剂的内核,若合适可加入另外的赋形剂。
合适的载体是,特别是,填料如糖,例如乳糖、蔗糖、甘露糖醇或山梨醇、纤维素制剂和/或磷酸钙,例如二磷酸三钙、或磷酸氢钙,以及进一步的粘结剂,如淀粉,例如玉米、小麦、稻米或马铃薯淀粉、甲基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠和/或聚乙烯基吡咯烷酮、和/或,若需要,崩解剂,如上述淀粉、和另外羧甲基淀粉、交联聚乙烯基吡咯烷酮、藻酸或其盐,如藻酸钠。另外的赋形剂是,特别地,流动调节剂和润滑剂,例如水杨酸、滑石、硬脂酸或其盐,如硬脂酸镁或硬脂酸钙、和/或聚乙二醇、或其衍生物。
糖衣片剂的核可以具有合适的糖衣,该糖衣在适当的情况下耐胃液,采用的糖衣特别是浓糖溶液,若恰当该浓糖溶液包括阿拉伯胶、滑石、聚乙烯基吡咯烷酮、聚乙二醇和/或二氧化钛,在合适有机溶剂或溶剂混合物中的包衣溶液或,对于制备耐胃液糖衣的包衣溶液的合适纤维素制剂溶液,如邻苯二甲酸乙酰基纤维素或邻苯二甲酸羟丙基甲基纤维素的溶液。可以将染料或颜料混合到片剂或糖衣片剂包衣中,例如用来识别或标志活性成分的不同剂量。
口服使用的药物组合物也是明胶的硬胶囊和明胶与增塑剂的软且密闭的胶囊,该增塑剂如甘油或山梨醇。硬胶囊可包含形式为颗粒的活性成分,并混合有填料,如玉米淀粉,粘结剂和/或润滑剂,如滑石或硬脂酸镁,以及稳定剂(若适当)。在软胶囊中,将活性成分优选溶于或悬浮于合适的液体赋形剂中,如含脂油、石蜡油或液体聚乙二醇或乙二醇或丙二醇的脂肪酸酯,同样可能加入稳定剂和清洁剂,例如聚乙烯脱水山梨醇脂肪酸酯类型。
其它的口服给药形式是,例如,以通常方式制备的糖浆,该糖浆包括活性成分,活性成分例如以悬浮形式,并以约5%-20%,优选约10%的浓度或引起适当独立剂量的相似浓度,例如,当测量5或10ml的独立剂量时。其它形式还有,例如,用于例如在奶中制备的粉状或液体浓缩物的振荡物(shakes)。这种浓缩物也可采用单位剂量数量装填。
可以直肠使用的药物组合物是,例如,包括活性成分与栓剂基质结合物的栓剂。合适的栓剂基质是,例如,天然或合成三甘油酯、石蜡烃、聚乙二醇或高级链烷醇。
适用于胃肠外给药的组合物是水溶形式的活性成分的水溶液,例如水溶性盐的水溶液,或含注射水悬浮液,该悬浮液包括粘度增加物质,例如羧甲基纤维素钠、山梨醇和/或葡聚糖,和在若适当的情况下采用的稳定剂。活性成分在此也可以冷冻干燥物的形式存在,若恰当与赋形剂一起,并在胃肠外给药之前通过加入合适的溶剂而溶解。例如用于胃肠外给药的溶液也可用作浸渍剂。优选的防腐剂是,例如,抗氧剂,如抗坏血酸、或杀微生物剂,如山梨酸或苯甲酸。
软膏是水包油乳液,它包括不大于70%,但优选20-50%水或水相。脂肪相特别地由烃,例如凡士林、石蜡油或硬石蜡组成,它优选包括合适的羟基化合物,如脂肪醇或其酯,例如十六烷醇或羊毛蜡醇,如羊毛蜡以改进与水的结合能力。乳化剂是相应的亲脂性物质,如脱水山梨醇脂肪酸酯(Spans),例如油酸脱水山梨醇酯和/或异硬脂酸脱水山梨醇酯。水相的添加剂是,例如,湿润剂,如多元醇,例如甘油、丙二醇、山梨醇和/或聚乙二醇、或防腐剂和有气味物质。
脂肪软膏是无水的,且包括,特别作为基质的烃,例如石蜡、凡士林或石蜡油,和此外天然形成或半合成的脂肪,例如氢化椰子油脂肪酸三甘油酯或优选氢化油,例如氢化花生油或蓖麻油,和此外甘油的脂肪酸部分酯,例如单和/或双硬脂酸甘油酯,和例如脂肪醇。它们也可包含提及的有关软膏的乳化剂和/或添加剂,它们增加水的吸收。
乳膏是水包油乳液,它包括大于50%的水。使用的油性基质,特别地是脂肪醇,例如月桂醇、鲸蜡醇或硬脂醇,脂肪酸,例如棕榈酸或硬脂酸、液体蜡到固体蜡,例如肉豆蔻酸异丙酯、羊毛蜡或蜂蜡、和/或烃,例如凡士木(矿脂)或石蜡油。乳化剂是具有主要亲水性能的表面活性物质,如相应的非离子乳化剂,例如多元醇的脂肪酸酯或其乙烯氧基加合产物,如聚甘油酸脂肪酸酯或聚乙烯脱水山梨醇脂肪酯(Tween),和此外聚氧乙烯脂肪醇醚或聚氧乙烯脂肪酸酯,或相应的离子乳化剂,如脂肪醇硫酸的碱金属盐,例如十二烷基硫酸钠、鲸蜡基硫酸钠或硬脂基硫酸钠,它们通常在脂肪醇如鲸蜡基硬脂醇(cetylstearyl alcohol)或硬脂醇存在下使用。水相的添加剂,尤其是,防止乳膏干燥的试剂,例如多元醇,如甘油、山梨醇、丙二醇和/或聚乙二醇,和此外的防腐剂和有气味的物质。
糊剂是含有分泌物-吸收粉末组分的乳膏和软膏,这些粉末组分如金属氧化物,如氧化钛或氧化锌,和此外滑石和/或硅酸铝,它的任务是结合存在的水分或分泌物。
从加压容器中施加泡沫,并且它们是以气溶胶泡沫存在的水包油乳液。作为泡沫推进剂气体,使用卤代烃,如多卤代烷烃,例如二氯氟甲烷和二氯四氟乙烷,或优选,非卤代气体烃、空气、N2O、或二氧化碳。使用的油性相,尤其指,以上对于软膏和乳膏提及的那些,还同样使用了那里提及的添加剂。
酊剂和溶液通常包括含水-乙醇类基质,该基质中共混有用于降低蒸发的湿润剂,如多元醇,例如甘油、二醇和/或聚乙二醇,和再加脂物质(re-oiling substances),如带有低级聚乙二醇的脂肪酸酯,即可溶于含水混合物中以用乙醇取代从皮肤除去的脂肪物质的亲脂物质,以及如果需要,其它赋形剂和添加剂。
本发明进一步提供兽医组合物,该组合物包括至少一种以上定义的活性成分及其兽医载体。兽医载体是用来施用组合物的材料,并且可以是固体、液体或气体材料,它们在兽医领域中是惰性或可接受的并与活性成分相容。这些兽医组合物可以口服、胃肠外使用或由任何其它可取的途径使用。
本发明也涉及上述疾病病况治疗的过程和方法。可以将化合物自身或以药物组合物的形式用于预防或治疗用途,优选以有效抵抗上述疾病的数量使用。对于要求这种治疗的温血动物,例如人类特别地以药物组合物的形式使用这种化合物。在此对于约70kg的体重,在此使用约O.1-约5g日剂量的本发明化合物,优选0.5g-约2g的日剂量。
附图说明
在图1中,显示由测试化合物对K562(A)和CEM(B)肿瘤细胞系生长的抑制。在钙黄绿素AM存在下确定细胞毒性。活性表示为最大活性的百分比(在抑制剂不存在的情况下)。iP:异戊烯腺嘌呤;2F BAP:6-(2-氟苄基氨基)嘌呤;2C1 BAP:6-(2-氯苄基氨基)嘌呤;2OH-3OCH3BAP:6-(2-羟基-3-甲氧基苄基氨基)嘌呤。
在图2中,显示由于β-半乳糖苷酶对底物X-gal(5-溴-4-氯-3-吲哚基-β-D-吡喃半乳糖苷)(1mg/ml)的作用,染成蓝色的人体成纤维细胞(B)(其它细胞(A))培养过程中的衰老细胞。
在图3中,显示在使用细胞分裂素6-(2-羟基-3-甲氧基苄基氨基)嘌呤之后,在肿瘤细胞MCF-7细胞系中引入的凋亡。A MCF-7,凋亡细胞:6h,12,20μM,B MCF-7,次级坏死细胞(即跟随调亡细胞之后的坏死细胞):12h,12,40μM;C MCF-7,坏死细胞:24h,12,40μM。Anexin FITC V(分子探针)和碘丙锭染色:anexin-绿色,PI-红色。
图4显示使用Anexin(绿色荧光)和Hoechstem 33285(蓝色荧光)染色的凋亡细胞检测。在用6-(2-羟基-3-甲氧基苄基氨基)嘌呤处理过MCF-7肿瘤细胞之后,使用“Olympus图象分析”分析。A,B-没有处理的对照细胞;C,D-凋亡细胞(染色质的凝聚);A,C-荧光显微术;B,D-荧光图象分析。
图5显示测试化合物在切断小麦叶尖端中保留叶绿素的效果。数值表达为在培育之前新鲜叶初始叶绿素含量的%。误差棒显示对于5次重复测定平均值的标准偏差。虚线指示没有任何细胞分裂素的对照培育,它是31,7±0.9。
图6显示测试化合物对烟草愈伤组织培养物新鲜重量收率的影响。误差棒显示对于5次重复测定平均值的标准偏差。虚线表示[没有任何细胞分裂素的对照处理数值,2,2±0.4g。
图7测试化合物对尾穗苋子叶/下胚轴外植体中β-花青苷合成的黑暗诱导的影响。误差棒显示对于5次重复测定平均值的标准偏差。虚线表示没有任何细胞分裂素的对照处理数值,0.043±0.009。数值表示在537和620nn吸收之间O.D.单位的差异。
图8显示作为培养时间函数的带有至少一个棕色叶子的外植体的相对数目(■:BA,●:mT,▲:mMeOBAP)。
图9显示相对于培养时间的死亡外植体的相对数目(■:BA,●:mT,▲:mMeOBAP)。
图10左边显示:在含BA的介质上的死玫瑰外植体;右边:在含mMeOBAP的介质上121天培育之后的旺盛玫瑰外植体。
以下实施例用于说明本发明而不限制其范围。
具体实施方式
实施例
实施例1
6-(3-氯苄基氨基)嘌呤
将3mmol的6-氯嘌呤溶于15ml丁醇。随后,加入4mmol的3-氯苄胺和5mmol的三乙胺并将混合物在90℃下加热4小时。在冷却之后,将沉淀的产物滤出,采用冷水和正丁醇洗涤并从乙醇或二甲基甲酰胺结晶。M.p.=252℃,TLC(CHCl3∶MeOH∶conc.NH4OH(8∶2∶0.2,v/v/v)):单一点;HPLC:纯度>98%。产率95%。
表1
由实施例1方法制备的化合物
R6取代基 | CHN分析计算的/发现的 | |||
%C | %H | %N | ESI-MS[M+H+] | |
2-氟苄基氨基 | 59,3/59,05 | 4,1/3,8 | 28,8/27,8 | 244 |
3-氟苄基氨基 | 59,3/59,1 | 4,1/3,9 | 28,8/27,7 | 244 |
4-氟苄基氨基 | 59,3/59,2 | 4,1/3,9 | 28,8/27,9 | 244 |
2-氯苄基氨基 | 55,5/55,7 | 3,8/4,2 | 27,0/26,0 | 260 |
3-氯苄基氨基 | 55,5/55,2 | 3,8/3,9 | 27,0/26,2 | 260 |
4-氯苄基氨基 | 55,5/55,3 | 3,8/3,8 | 27,0/26,6 | 260 |
2-溴苄基氨基 | 47,4/47,6 | 3,3/3,5 | 23,0/22,5 | 304 |
2-溴苄基氨基 | 47,4/47,1 | 3,3/3,4 | 23,0/23,1 | 304 |
2-溴苄基氨基 | 47,4/47,8 | 3,3/3,4 | 23,0/22.3 | 304 |
3-碘苄基氨基 | 41,0/41,4 | 2,8/2,8 | 20,0/19,5 | 352 |
2-甲基苄基氨基 | 65,2/64,9 | 5,5/5,8 | 29,3/29,8 | 240 |
3-甲基苄基氨基 | 65,2/64,7 | 5,5/6,0 | 29,3/29,9 | 240 |
4-甲基苄基氨基 | 65,2/65,7 | 5,5/5,4 | 29,3/27,5 | 240 |
2-甲氧基苄基氨基 | 61,2/61,0 | 5,1/5,5 | 27,4/26,6 | 256 |
3-甲氧基苄基氨基 | 61,2/61,0 | 5,1/5,3 | 27,4/27,5 | 256 |
4-甲氧基苄基氨基 | 61,2/60,7 | 5,1/5,3 | 27,4/26,7 | 256 |
3-硝基苄基氨基 | 53,3/53,1 | 3,7/3,6 | 31,1/30,8 | 271 |
4-硝基苄基氨基 | 53,3/53,0 | 3,7/3,5 | 31,1/30,8 | 271 |
2,4-二氯苄基氨基 | 49,0/49,4 | 3,1/3,1 | 23,8/23,1 | 295 |
3,4-二氯苄基氨基 | 49,0/49,1 | 3,1/3,2 | 23,8/23,0 | 295 |
2,3-二羟基苄基氨基 | 56,2/55,7 | 3,5/3,2 | 27,2/27,9 | 258 |
2,4-二羟基苄基氨基 | 56,2/55,4 | 3,5/3,4 | 27,2/27,7 | 258 |
3,4-二羟基苄基氨基 | 56,2/55,5 | 3,5/3,4 | 27,2/27,7 | 258 |
2-羟基-3-甲氧基苄基氨基 | 57,5/57,2 | 4,8/4,6 | 25,8/26,4 | 272 |
2-羟基-4-甲氧基苄基氨基 | 57,5/57,1 | 4,8/4,5 | 25,8/26,6 | 272 |
4-羟基-3-甲氧基苄基氨基 | 57,5/57,3 | 4,8/4,7 | 25,8/26,2 | 272 |
3-羟基-4-甲氧基苄基氨基 | 57,5/57,0 | 4,8/4,5 | 25,8/26,7 | 272 |
2,3-二甲氧基苄基氨基 | 58,9/59,3 | 5,3/5,48 | 24,5/24,5 | 286 |
2,4-二甲氧基苄基氨基 | 58,9/59,3 | 5,3/4,9 | 24,5/25,5 | 286 |
3,4-二甲氧基苄基氨基 | 58,9/59,7 | 5,3/5,6 | 24,5/24,8 | 286 |
3,5-甲氧基苄基氨基 | 58,9/59,7 | 5,3/5,32 | 24,5/24,4 | 286 |
2,4,6-三甲氧基苄基氨基 | 57,1/57,3 | 5,4/5,3 | 22,2/22,8 | 316 |
3,4,5-三甲氧基苄基氨基 | 57,1/57,1 | 5,4/5,2 | 22,2/22,5 | 316 |
2,4-二氟苄基氨基 | 55,2/54,5 | 3,5/3,1 | 26,8/27,2 | 262 |
3,5-二氟苄基氨基 | 55,2/54,8 | 3,5/3,3 | 26,8/27,3 | 262 |
2,3,4-三氟苄基氨基 | 51,6/51,1 | 2,9/2,7 | 25,1/25,5 | 280 |
3-氯-4-氟苄基氨基 | 51,9/50,9 | 3,3/3,4 | 25,2/25,7 | 278 |
2-(三氟甲基)苄基氨基 | 53,2/52,9 | 3,4/3,1 | 23,9/24,5 | 294 |
3-(三氟甲基)苄基氨基 | 53,2/52,9 | 3,4/3,2 | 23,9/24,6 | 294 |
4-(三氟甲基)苄基氨基 | 53,2/52,7 | 3,4/3,1 | 23,9/24,8 | 294 |
苯胺基 | 62,5/62,2 | 3,3/3,1 | 33,1/33,8 | 212 |
2-氟苯胺基 | 57,6/57.0 | 3,5/3,4 | 30,6/31,1 | 230 |
3-氟苯胺基 | 57,6/57,1 | 3,5/3,3 | 30,6/31,5 | 230 |
4-氟苯胺基 | 57,6/57,0 | 3,5/3,3 | 30,6/31,5 | 230 |
2-氯苯胺基 | 53,8/53,2 | 3,3/3,2 | 28,5/29,3 | 246 |
3-氯苯胺基 | 53,8/53,1 | 3,3/3,3 | 28,5/28,9 | 246 |
4-氯苯胺基 | 53,8/53,4 | 3,3/3,2 | 28,5/29,3 | 246 |
2-溴苯胺基 | 45,5/45,0 | 2,8/2,7 | 24,1/24,7 | 291 |
3-溴苯胺基 | 45,5/25,0 | 2,8/2,7 | 24,1/24,9 | 291 |
4-溴苯胺基 | 45,5/44,7 | 2,8/2,4 | 24,1/25,1 | 291 |
2-碘苯胺基 | 39,2/38,5 | 2,4/2,1 | 20,8/21,3 | 338 |
2-甲氧基苯胺基 | 59,7/59,4 | 4,6/4,6 | 29,0/29,4 | 242 |
3-甲氧基苯胺基 | 59,7/59,1 | 4,6/4,5 | 29,0/29,7 | 242 |
4-甲氧基苯胺基 | 59,7/59,2 | 4,6/4,5 | 29,0/29,6 | 242 |
2-甲基苯胺基 | 64,0/63,7 | 4,9/4,7 | 31,1/31,8 | 226 |
3-甲基苯胺基 | 64,0/63,7 | 4,9/4,8 | 31,1/31,9 | 226 |
4-甲基苯胺基 | 64,0/63,5 | 4,9/4,7 | 31,1/32,0 | 226 |
实施例2
将10mmol腺嘌呤,12mmol的2-甲氧基苯甲醛和5ml的98-100%甲酸回流3天。在甲酸蒸发之后,将获得的材料冷却并随后采用40ml乙醚洗涤。将固体残余物采用60ml水沸腾,滤出粗产物,并且粗产品从乙醇结晶。收率45%。
表2
由实施例2方法制备的化合物
R6取代基 | CHN分析计算的/发现的 | |||
%C | %H | %N | ESI-MS[M+H+] | |
2-氯苄基氨基 | 55,5/54,7 | 3,8/4,1 | 27,0/27,6 | 206 |
3-氯苄基氨基 | 55,5/54,8 | 3,8/3,9 | 27,0/27,2 | 260 |
4-氯苄基氨基 | 55,5/54,5 | 3,8/4,0 | 27,0/27,6 | 260 |
2-溴苄基氨基 | 47,4/46,7 | 3,3/3,5 | 23,0/23,4 | 304 |
2-溴苄基氨基 | 47,4/46,5 | 3,3/3,4 | 23,0/23,3 | 304 |
2-甲基苄基氨基 | 65,2/64,8 | 5,5/5,9 | 29,3/29,8 | 240 |
3-甲基苄基氨基 | 65,2/64,8 | 5,5/5,7 | 29,3/30,1 | 240 |
4-甲基苄基氨基 | 65,2/64,7 | 5,5/5,8 | 29,3/29,9 | 240 |
2-甲氧基苄基氨基 | 61,2/60,3 | 5,1/5,3 | 27,4/27,9 | 256 |
3-甲氧基苄基氨基 | 61,2/61,00 | 5,1/5,3 | 27,4/27,9 | 256 |
4-甲氧基苄基氨基 | 61,2/60,4 | 5,1/5,2 | 27,4/28,3 | 256 |
2,4-二氯苄基氨基 | 49,0/48,4 | 3,1/3,0 | 23,8/24,4 | 295 |
3,4-二氯苄基氨基 | 49,0/48,6 | 3,1/3,1 | 23,8/24,4 | 295 |
2,4-二甲氧基苄基氨基 | 58,9/58,8 | 5,3/5,4 | 24,5/24,7 | 286 |
2,4-二甲氧基苄基氨基 | 58,9/58,4 | 5,3/5,8 | 24,5/25,5 | 286 |
3,4-二甲氧基苄基氨基 | 58,9/58,5 | 5,3/5,6 | 24,5/25,2 | 286 |
3,5-二甲氧基苄基氨基 | 58,9/58,7 | 5,3/5,4 | 24,5/25,0 | 286 |
2,4,6-三甲氧基苄基氨基 | 57,1/57,2 | 5,4/5,4 | 22,2/22,5 | 316 |
3,4,5-三甲氧基苄基氨基 | 57,1/57,4 | 5,4/5,5 | 22,2/22,5 | 316 |
实施例3
新颖化合物的体外细胞毒素活性
用作细胞毒性测定基础的一个参数是有活力细胞的代谢活动。例如,微量滴定法测定,这种方法使用钙黄绿素AM,现在广泛用于量化细胞增殖和细胞毒性。例如,此测定用于药物筛选程序和化学敏感性测试。由于仅代谢活性的细胞分裂钙黄绿素AM,这些测定仅检测有活力的细胞。降低的钙黄绿素AM数量相应于培养物中活细胞的数目。
人类T-原始淋巴细胞白血球过多症细胞系CEM、前髓细胞HL-60和单核细胞U937白血球过多症、乳腺癌细胞系MCF-7、BT549、MDA-MB-231、胶质胚细胞瘤U87MG细胞、子宫颈癌细胞HELA、肉瘤细胞U2OS和Saos2、肝细胞瘤HepG2、鼠成纤维细胞NIH3T3、鼠永生化骨髓巨噬细胞B2.4和B10A.4、P388D1和L1210白血球过多症、B16和B16F10黑素瘤用于化合物的常规筛选。将细胞保持在Nunc/Corning 80cm2塑料组织培养烧瓶中,并且在细胞培养基(含有5g/l葡萄糖,2mM谷酰胺,100U/ml青霉素,100μg/ml链霉素,10%胎牛血清和碳酸氢钠的DMEM)中培养。
将细胞悬浮液由吸液管(80μl)加入96/池微量滴定板中,根据特定的细胞类型和希望的目标细胞密度(2.500-30.000个细胞每池,基于细胞生长特性)制备和稀释该细胞悬浮液。允许移植细胞在37℃和5%CO2下预培育24小时用于稳定。在零时间以20μl等分试样将所需测试浓度的四倍稀释液加入到微量滴定板池中。通常地,以6个4倍稀释液评价测试化合物。在通常测试中,最高的池浓度是266.7μM,但它可依赖于试剂而变化。检查所有的药物浓度两次。用测试化合物对细胞进行的培育在37℃下,5%CO2气氛和100%湿度中持续72小时。在培育时间结束时,通过使用钙黄绿素AM测定细胞。将十微升母液移入每个池并进一步培育1小时。采用Labsystem FIA Reader Fluoroscan Ascent(UK)测量荧光(FD)。使用如下公式计算肿瘤细胞存活率(GI50):TCS=(FD药物曝露池/平均FD对照池)×100%。从获得的剂量响应曲线计算GI50数值,肿瘤细胞的半数致死浓度(图1)。
在不同组织发生和种类源的细胞系的板上测试新颖化合物的细胞毒性(表3)。我们在这里显示在测试的所有肿瘤细胞系中发现相等的活性,然而,良性细胞,如NIH3T3成纤维细胞和正常人类淋巴细胞,对合成抑制剂诱导的细胞毒性具有抵抗力。如表3所示,NIH3T3成纤维细胞和正常人类淋巴细胞的GI50总是高于250μM。有效的新颖衍生物在接近10-50μM的浓度杀死肿瘤细胞。
表3
对于不同癌细胞系的新颖化合物的细胞毒性
测试的细胞系/IC50(μmol/L) | |||||||||
化合物 | HOS | K-562 | MCF7 | B16-F0 | NIH-3T3 | G-361 | CEM | HELA | HL60 |
激动素 | >166,7 | >166,7 | >166,7 | 155,1 | |||||
164,1 | |||||||||
IP | >166,7 | 146,9 | >166,7 | 92,2 | >166,7 | ||||
162,2 | |||||||||
BAP | >166,7 | 138,9 | 166,1 | >166,7 | >166,7 | ||||
>166,7 | |||||||||
顺式Z | >166,7 | >166,7 | >166,7 | >166,7 | >166,7 | ||||
>166,7 | |||||||||
乙酰基Z | >166,7 | >166,7 | >166,7 | >166,7 | >166,7 | ||||
>166,7 | |||||||||
MT | >166,7 | 128,4 | >166,7 | 90,6 | >166,7 | 90,1 | 79,2 | ||
140,2 | |||||||||
OT | >166,7 | >166,7 | >166,7 | 150 | 103,4 | 69,2 | 78 | ||
67 | |||||||||
2FBAP | >166,7 | 136,1 | >166,7 | 27,7 | 106,4 | 98 | |||
>166,7 | 70,7 | 99,5 | 126,5 | ||||||
2ClBAP | 84,9 | 101 | 164,1 | 16,9 | >166,7 | 56,6 | 58,4 | 109,6 | |
100,4 | 90,4 | 128,4 | |||||||
3ClBAP | >166,7 | >166,7 | >166,7 | 148,6 | >166,7 | >166,7 |
3FBAP | >166,7 | 105,2 | 163,2 | >166,7 | >166,7 | >166,7 | |||
4FBAP | >166,7 | >166,7 | >166,7 | >166,7 | 66,4 | 59,2 | |||
3MeOBAP | >166,7 | >166,7 | >166,7 | 41,5 | >166,7 | 124,7 | >166,7 | >166,7 | |
76,7 | 149,5 | ||||||||
4MeOBAP | >166,7 | >166,7 | >166,7 | 84,7 | >166,7 | 166,7 | >166,7 | >166,7 | |
>166,7 | 118 | >166,7 | |||||||
2MBAP | >166,7 | 156,6 | >166,7 | >166,7 | >166,7 | >166,7 | |||
3IBAP | >166,7 | 94,7 | 129,9 | >166,7 | 124,6 | 133,3 | |||
4MBAP | >166,7 | 72,8 | 82,8 | 160,4 | 72,1 | 88 | |||
4ClBAP | >166,7 | >166,7 | >166,7 | >166,7 | >166,7 | ||||
2MeOBAP | >166,7 | 115,8 | 153 | 63,4 | >166,7 | ||||
98,2 | |||||||||
3,5二MeOBAP | >166,7 | >166,7 | >166,7 | >166,7 | |||||
2,4,6三MeOBAP | >166,7 | >166,7 | >166,7 | 63,6 | 153,4 | ||||
105,3 | |||||||||
4OH3MeOBAP | >166,7 | >166,7 | >166,7 | >166,7 | >166,7 | ||||
3NO2BAP | >166,7 | >166,7 | >166,7 | >166,7 | |||||
4NO2BAP | >166,7 | >166,7 | >166,7 | >166,7 | >166,7 | ||||
2OH3MeOBAP | >166,7 | 26,6 | 69 | 41,6 | 64,3 | ||||
51 | 67,8 | ||||||||
3OH4MeOBAP | >166,7 | >166,7 | >166,7 | >166,7 | >166,7 | ||||
3,4二OH | >166,7 | >166,7 | >166,7 | >166,7 | >166,7 |
BAP | |||||||||
2F BAP | >166,7 | 136,1 | 108,7 | 130,6 | 106,4 | 135,7 | >166,7 | ||
70,7 | 128,5 | >166,7 | 98,9 | ||||||
3Me BAP | >166,7 | 102,5 | 164,1 | >166,7 | >166,7 | ||||
3Cl4F BAP | >166,7 | >166,7 | >166,7 | 135 | >166,7 | ||||
>166,7 | >166,7 | 95,8 | >166,7 | ||||||
2,3,4三FBAP | >166,7 | >166,7 | 32 | >166,7 | |||||
>166,7 | >166,7 | 67 | >166,7 | ||||||
2,4二FBAP | >166,7 | >166,7 | 139,7 | >166,7 | |||||
>166,7 | >166,7 | 145,8 | >166,7 | ||||||
玉米素 | >166,7 | >166,7 | >166,7 | >166,7 | |||||
>166,7 | >166,7 | >166,7 | >166,7 | ||||||
腺嘌呤 | >166,7 | >166,7 | >166,7 | >166,7 | |||||
>166,7 | >166,7 | >166,7 | >166,7 |
实施例4
新颖化合物诱导肿瘤细胞中的凋亡
为分析由新颖化合物引起的细胞毒性的机理,将凋亡与细胞死亡、坏死的其它主要形式区别出来很重要。首先,在组织水平上,凋亡产生较少的炎症或不产生炎症,这是由于相邻细胞,特别是巨噬细胞,会吞食细胞的萎缩部分,而不是被释放入细胞外液。相反,在坏死中,细胞内容物被释放入细胞外液,病因此对附近的细胞产生刺激效果,引起炎症。其次,在细胞水平上,凋亡细胞表现出细胞质的收缩和起泡、包括线粒体在内的细胞器结构的保存、染色质凝结和蚀边、细胞核碎裂、和凋亡体的形成,尽管不是在所有的细胞类型中都可以看到全部上述状况。第三,在分子水平上,许多生物化学过程在凋亡诱导中起重要的作用。然而,它们中的大多数不能被充分理解,并且它们会引起蛋白酶和核酸酶的活化,这最终破坏关键生物大分子-蛋白质和DNA。
为了检测细胞死亡的凋亡形式对坏死形式,采用两种独立的方法:由电子显微镜的形态评定和通过流式细胞计量方法的DNA断裂分析。
将HL-60细胞系在6-池培养板中,采用或不采用70μM浓度的新颖化合物,在37℃和5%CO2下培养3-24小时。在培育之后,将细胞制粒,在Hank缓冲盐溶液中洗涤并如下所述加工。
将细胞悬浮在2%戊二醛/PBS中,在4℃下固定过夜,制粒并在其后嵌入1%琼脂(Agar Noble,Difco)中。对包含固定细胞的琼脂块进行环氧化物聚合,超薄切片,四氧化饿后固定,乙酸铀对比并在电子显微镜下检查。
初始阶段对比显微镜检查指示处理的HL-60系表现出凋亡细胞的典型形态特征,并且这一点随后由电子显微镜确认(图2和3)。在所有采用测试新颖衍生物处理过的细胞中都识别出了调亡的典型形态特征:细胞质凝结、核碎裂、细胞质起泡、和凋亡体的形成。
实施例5
免疫抑制活性
特异性细胞免疫的重要参数之一是淋巴细胞对抗原或多克隆分裂素的增殖反应。大多数正常哺乳动物的末梢淋巴细胞包含静止细胞。抗原或非特异性多克隆分裂素具有活化淋巴细胞的能力并且这伴随着细胞内代谢(线粒体活性、蛋白质合成、核酸合成、胚细胞形成和细胞增生)的急剧变化。能够选择性地抑制淋巴细胞增殖的化合物是潜在的免疫抑制剂。已经建立了各种体外分析以测量淋巴细胞的增殖反应。最常用的是3H-胸苷引入方法。
在细胞增殖期间,必须在细胞分裂成两个子细胞之前复制DNA。在细胞增值和DNA合成两者之间的这种紧密联系对于评定细胞增殖是非常有吸引力的。如果将标记的DNA前体加入到细胞培养物中,要分裂的细胞会在它们的DNA中合并标记的核苷酸。传统上,这些测定通常涉及使用放射标记的核苷,特别地氚化胸苷([3H]-TdR)。用液体闪烁计数量化引入细胞DNA的[3H]-TdR数量。
从健康的志愿者由肘脉穿刺获得人类肝素化末梢血。将血液在PBS(1∶3)中稀释,并且在Ficoll-Hypaque密度梯度(Pharmacia,1.077g/ml)中在2200rpm下离心分离单核细胞30分钟。在离心之后,将淋巴细胞在PBS中洗涤,并在细胞培养基(RMPI 1640,2mM谷酰胺,100U/ml青霉素,100g/ml链霉素,10%胎牛血清和碳酸氢钠)中再悬浮。
将细胞稀释到1.100.000细胞/ml的目标密度,由吸液管(180μl)加入96/池微量滴定板中。将目标稀释浓度的四倍稀释液在时间零以20μl等分试样加入到微量滴定板池中。通常地,在6个4倍稀释液下评价测试化合物。在通常测试中,最高的池浓度是266.7μM。检查所有的药物浓度两次。采用50μl伴刀豆球蛋白A(25μg/ml)活化所有的池,除未刺激对照物以外。采用测试化合物的细胞培育在37℃下,在5%CO2气氛和100%湿度中持续72小时。在培育周期结束时,通过使用[3H]-TdR测定细胞:
将细胞培养物采用0.5μCi(20μl母液500μCi/ml)每池在37℃和5%CO2下培育6小时。自动化的细胞收集器用于在水中溶解细胞并将DNA吸附到微量滴定板构造中的玻璃-纤维过滤器上。将引入有[3H]-TdR的DNA保留在过滤器中,同时未引入的材料通过过滤器。将过滤器在室温下干燥过夜,并采用10-12ml的闪烁体密封入样品袋。由Betaplate液体闪烁计数器中的闪烁计数确定每个过滤器中存在的[3H]-TdR数量(以cpm计)。使用如下公式计算免疫抑制剂的有效剂量(ED):ED=(CCPM药物曝露池/平均CCPM对照池)×100%。从获得的剂量响应曲线计算ED50数值,即抑制50%淋巴细胞增殖的药物浓度。
为评价取代腺嘌呤的免疫抑制活性,分析它们抑制多克隆分裂素诱导正常人类淋巴细胞增殖的能力(表13)。我们的数据显示这些化合物仅对3H-胸苷引入具有边缘活性,但是,它们有效抑制活化淋巴细胞的增殖。在体外条件下新衍生物的有效免疫抑制剂量接近1-20μM。
表4
新颖衍生物的免疫抑制活性
R6取代基 | 人类淋巴细胞ED50(μM) |
3-氯苯胺基 | 4.7 |
3-氯-5-氨基苯胺基 | 12.4 |
2-羟基苄基氨基 | 0.5 |
3-羧基-4-氯苯胺基 | 2.1 |
3-羟基苄基氨基 | 5.6 |
4-溴苯胺基 | 4.7 |
4-氯苯胺基 | 6.2 |
3-氨基-4-氯苯胺基 | 8.3 |
3-氯-4-氨基苯胺基 | 12 |
2-羟基苄基氨基 | 11.5 |
3-羟基苄基氨基 | 8.4 |
3-氟苄基氨基 | 18.2 |
3-羧基-4-氯苯胺基 | 0.5 |
2-羟基-4-甲氧基苄基氨基 | 1.8 |
3-氯苯胺基 | 7.2 |
2-氟苄基氨基 | 2.5 |
2,3-二氟苄基氨基 | 10.7 |
实施例6
由新颖化合物的衰老抑制
在此实施例中,将人类二倍体成纤维细胞(各种传代水平的HCA细胞:传代25-称为HCA25;传代45-称为HCA45;传代80-称为HCA80)染色用于β-半乳糖苷酶活性。将用于细胞培育的培养基除去,将细胞在PNS中洗涤两次,并在2-3ml固定液中固定,该固定液由PBS中的2%甲醛和0.2%戊二醛组成。将细胞在室温下孵育5分钟,然后采用PBS洗涤两次。随后将细胞在37℃(没有CO2)下在2-3ml溶液中孵育1-16小时,该溶液包括铁氰化钾(5mM),亚铁氰化钾(5mM),MgCl2(2mM),X-gal(5-溴-4-氯-3-吲哚基-β-D-半乳吡喃糖苷)(1mg/ml),在柠檬/磷酸盐缓冲液中,pH6.0)。在此培育周期之后,观察细胞样品以检测蓝色细胞的存在,表明X-gal已经分裂(正性衰老细胞)。在此试验中,由于β-半乳糖苷酶对底物的作用,衰老细胞,而非其它细胞被染成蓝色(图4)。
表5
新颖化合物对人类成纤维细胞培养物中衰老细胞数量的影响
取代基 | 衰老细胞(%) | ||
R6 | HCA25 | HCA45 | HCA80 |
对照 | 3 | 5 | 38 |
3-氯苯胺基 | 4 | 5 | 25 |
3,4-二羟基苄基氨基 | 5 | 4 | 29 |
苯胺基 | 3 | 4 | 27 |
3-氯-5-氨基苯胺基 | 3 | 6 | 24 |
3-氯-4-羧基苯胺基 | 5 | 2 | 25 |
3-羧基-4-氯苯胺基 | 3 | 5 | 20 |
3-羧基-4-羟基苯胺基 | 4 | 2 | 26 |
4-溴苯胺基 | 5 | 3 | 25 |
4-氯苯胺基 | 5 | 5 | 26 |
3-氨基-4-氯苯胺基 | 4 | 6 | 22 |
3-氯-4-氨基苯胺基 | 5 | 5 | 24 |
2-氟苄基氨基 | 4 | 3 | 16 |
3-氟苄基氨基 | 3 | 3 | 15 |
2-羟基苄基氨基 | 3 | 4 | 17 |
3-羟基苄基氨基 | 5 | 3 | 22 |
2-乙酰氧基苄基氨基 | 6 | 5 | 32 |
3-乙酰氧基苄基氨基 | 4 | 6 | 27 |
2-乙酰基苄基氨基 | 3 | 4 | 25 |
3-乙酰基苄基氨基 | 5 | 5 | 28 |
2-羟基-3-甲氧基苄基氨基 | 4 | 3 | 20 |
2-羟基-3-甲基苄基氨基 | 5 | 2 | 18 |
2-羟基-3-氯苄基氨基 | 4 | 3 | 14 |
2,6-二羟基-4-氯苄基氨基 | 3 | 3 | 16 |
2,3-二羟基-4-甲氧基苄基氨基 | 3 | 4 | 17 |
2,5-二羟基-4-甲氧基苄基氨基 | 5 | 3 | 22 |
2,6-二羟基-4-甲氧基苄基氨基 | 4 | 3 | 13 |
2,3-二羟基-4-氯苄基氨基 | 3 | 3 | 14 |
2,5-二羟基-4-氯苄基氨基 | 5 | 4 | 23 |
2-氨基-6-氯苄基氨基 | 3 | 4 | 16 |
3-氨基-4-氯苄基氨基 | 5 | 5 | 22 |
2,3-二氨基-4-氯苄基氨基 | 4 | 3 | 17 |
如表5所示,随着传代数目的增加,染色变得更深。对于最老的细胞,仅存在从淡蓝色到几乎不透明颜色的蓝色细胞。在80次传代之后,N6-取代腺嘌呤衍生物在保持更低水平的衰老细胞中非常有效。在长期培育的情况下,处理的细胞能够比对照细胞多活30%的时间。
实施例7
新颖化合物对冬小麦叶节测试的衰老抑制效果
将冬小麦,小麦cv(triticum aestivum cv.)的种子在流动水下洗涤24小时和然后播种在由克诺卜溶液浸湿的蛭石上。将它们放入在50μmol.m-2.s-1下、采用16/8h光周期、25℃的生长室中。在7天之后,第一片叶子完全发育并且第二片叶子开始生长。将第一片叶子的尖端部分,大约35mm长,从5个秧苗上取下来并稍微修剪到加起来100mg的重量。将五个叶尖端的基部端放入微滴定器的聚苯乙烯板的池中,每个池包含150μl细胞分裂素溶液。将整个板插入由面巾纸衬里的塑料箱中,面巾纸由蒸馏水浸湿以防止叶片段出现干燥。在黑暗中在25℃下培育96h之后,取出叶子并在80℃下、在5ml的80%乙醇(v/v)中加热10min而萃取叶绿素。通过加入80%乙醇(v/v)将样品体积恢复到5ml。在665nm下记录萃取物的吸光度。此外,测量了新鲜叶子和在去离子水中孵育的叶尖端的叶绿素萃取物。从获得的数据,对于每种测试的化合物选择具有最高活性的浓度。计算在此浓度下化合物的相对活性(表6)。将对于10-4M6-苄基氨基嘌呤(BAP)获得的活性假定为100%。显示的数值是五次重复试验的平均值,并且将整个试验重复两次。将要测试的细胞分裂素溶于二甲亚砜(DMSO),并采用蒸馏水将溶液达到10-3M。将此原料在蒸馏水中进一步稀释到10-8M~10-4M的浓度。DMSO的最终浓度不超过0.2%,因此不影响使用的测定体系中的生物活性。
表6
在切断小麦叶尖端中新细胞分裂素衍生物对叶绿素保留的影响。
标准偏差是对于10次重复测定的平均值。
测试的化合物 | 具有最高活性的浓度(mol.l-1) | 活性(%)[10-4mol.l-1BAP=100%] | |
1. | 6-(2-氟苄基氨基)嘌呤 | 10-4 | 169(±20) |
2. | 6-(3-氟苄基氨基)嘌呤 | 10-4 | 200(±25) |
3. | 6-(4-氟苄基氨基)嘌呤 | 10-4 | 95,5(±3,5) |
4. | 6-(2-氯苄基氨基)嘌呤 | 10-4 | 116,5(±6,5) |
5. | 6-(3-氯苄基氨基)嘌呤 | 10-4 | 82(±2) |
6. | 6-(4-氯苄基氨基)嘌呤 | 10-4 | 64,5(±13,5) |
7. | 6-(2-溴苄基氨基)嘌呤 | 10-4 | 52(±14) |
8. | 6-(3-溴苄基氨基)嘌呤 | 10-4 | 48(±6) |
9. | 6-(4-溴苄基氨基)嘌呤 | 10-5 | 30(±15) |
10. | 6-(3-碘苄基氨基)嘌呤 | 10-4 | 83,5(±23) |
11. | 6-(2-甲基苄基氨基)嘌呤 | 10-4 | 158(±29) |
12. | 6-(3-甲基苄基氨基)嘌呤 | 10-4 | 111(±16) |
13. | 6-(4-甲基苄基氨基)嘌呤 | 10-4 | 35(±23) |
14. | 6-(2-甲氧基苄基氨基)嘌呤 | 10-4 | 269(±12) |
15. | 6-(3-甲氧基苄基氨基)嘌呤 | 10-4 | 178(±16) |
16. | 6-(4-甲氧基苄基氨基)嘌呤 | 10-4 | 79(±6) |
17. | 6-(3-硝基苄基氨基)嘌呤 | 10-4 | 60(±15) |
18. | 6-(4-硝基苄基氨基)嘌呤 | 10-4 | 83(±8) |
19. | 6-(2,4-二氯苄基氨基)嘌呤 | 10-5 | 0 |
20. | 6-(3,4-二氯苄基氨基)嘌呤 | 10-4 | 117(±22) |
21. | 6-(2,3-二甲氧基苄基氨基)嘌呤 | 10-4 | 109(±5) |
22. | 6-(2,4-二甲氧基苄基氨基)嘌呤 | 10-7 | 26(±11) |
23. | 6-(3,4-二甲氧基苄基氨基)嘌呤 | 10-4 | 43(±17) |
24. | 6-(3,5-二甲氧基苄基氨基)嘌呤 | 10-4 | 16(±1) |
25. | 2-氨基-6-(3-羟基苄基氨基)嘌呤 | 10-4 | 121(±7) |
26. | 2-氯-6-(3-羟基苄基氨基)嘌呤 | 10-4 | 140(±13) |
27. | 2-甲硫基-6-(3-羟基苄基氨基)嘌呤 | 10-4 | 50,5(±23,5) |
28. | 6-(2,4,6-三甲氧基苄基氨基)嘌呤 | 10-4 | 6(±4) |
29. | 6-(3,4,5-三甲氧基苄基氨基)嘌呤 | 10-4 | 25(±2) |
30. | 6-(2,4-二氟苄基氨基)嘌呤 | 10-5 | 139(±2) |
31. | 6-(3,5-二氟苄基氨基)嘌呤 | 10-5 | 156(±4) |
32. | 6-(2,3,4-三氟苄基氨基)嘌呤 | 10-5 | 131(±22) |
33. | 6-(3-氯-4-氟苄基氨基)嘌呤 | 10-5 | 141(±20) |
33. | 6-(2-羟基-3-甲氧基苄基氨基)嘌呤 | 10-5 | 34(±5) |
实施例8
新化合物对植物细胞分裂的刺激效果
将细胞分裂素依赖性烟草愈伤组织烟草L.cv.(Nicotiana tabacum L.cv.)Wisconsin 38在黑暗中、25℃下,在改性Murashige-Skoog培养基上保持,该培养基每1升包含:4μmol烟酸,2.4μmol维生素B6盐酸盐,1.2μmol硫胺素,26.6μmol甘氨酸,1.37μmol谷氨酰胺,1.8μmol肌醇,30g蔗糖,8g琼脂,5.37μmol α-萘基乙酸(NAA)和0.5μmol苄基氨基嘌呤(BAP)。每三周进行一次转种。在进行生物测定前的十四天,将愈伤组织转移到没有6-苄基氨基嘌呤(BAP)的培养基中。从四周培育之后新鲜愈伤组织重量的增加确定生物活性。对于每个细胞分裂素浓度制备五次重复样品并重复整个测试两次。从获得的数据,对于每种测试的化合物选择具有最高活性的浓度。计算在此浓度下化合物的相对活性(表6)。将10-4M的6-苄基氨基嘌呤(BAP)的活性假定为100%。将要测试的细胞分裂素溶于二甲亚砜(DMSO),并采用蒸馏水使溶液浓度达到10-3M。将此原料在用于生物测试的各自培养基中进一步稀释到10-8M~10-4M的浓度。DMSO的最终浓度不超过0.2%并因此不影响测定体系中使用的生物活性。
表7
新细胞分裂素衍生物对细胞分裂素依赖性烟草愈伤组织烟草L.cv.
(Nicotiana tabacum)Wisconsins 38生长的影响
测试的化合物 | 具有最高活性的浓度(mol.l-1) | 活性(%)[10-5mol.l-1BAP=100%] | |
1. | 6-(2-氟苄基氨基)嘌呤 | 10-6 | 111(±21) |
2. | 6-(3-氟苄基氨基)嘌呤 | 10-5 | 135(±8) |
3. | 6-(4-氟苄基氨基)嘌呤 | 10-6 | 122(±12) |
4. | 6-(2-氯苄基氨基)嘌呤 | 10-6 | 93(±4) |
5. | 6-(3-氯苄基氨基)嘌呤 | 10-5 | 94(±6) |
6. | 6-(4-氯苄基氨基)嘌呤 | 10-6 | 64(±8) |
7. | 6-(2-溴苄基氨基)嘌呤 | 10-5 | 102(±5) |
8. | 6-(3-溴苄基氨基)嘌呤 | 10-6 | 85(±11) |
9. | 6-(4-溴苄基氨基)嘌呤 | 10-6 | 15(±9) |
10. | 6-(3-碘苄基氨基)嘌呤 | 10-5 | 76(±8) |
11. | 6-(2-甲基苄基氨基)嘌呤 | 10-6 | 118(±3) |
12. | 6-(3-甲基苄基氨基)嘌呤 | 10-6 | 79(±5) |
13. | 6-(4-甲基苄基氨基)嘌呤 | 10-6 | 52(±8) |
14. | 6-(2-甲氧基苄基氨基)嘌呤 | 10-5 | 79(±5) |
15. | 6-(3-甲氧基苄基氨基)嘌呤 | 10-6 | 76(±20) |
16. | 6-(4-甲氧基苄基氨基)嘌呤 | 10-6 | 39(±17) |
17. | 6-(2,4-二氯苄基氨基)嘌呤 | 10-4 | 11(±3) |
18. | 6-(3,4-二氯苄基氨基)嘌呤 | 10-4 | 45(±7) |
19. | 6-(2,3-二甲氧基苄基氨基)嘌呤 | 10-5 | 8,5(±2) |
20. | 6-(2,4-二甲氧基苄基氨基)嘌呤 | 10-5 | 21(±5) |
21. | 6-(2,4,6-三甲氧基苄基氨基)嘌呤 | 10-4 | 13(±6) |
22. | 6-(3,4,5-三甲氧基苄基氨基)嘌呤 | 10-5 | 19(±3) |
23. | 6-(3,4-二羟基苄基氨基)嘌呤 | 10-5 | 4(±1) |
24. | 6-(2,4-二氟苄基氨基)嘌呤 | 10-5 | 95(±1) |
25. | 6-(3,5-二氟苄基氨基)嘌呤 | 10-5 | 97(±3) |
26. | 6-(2,3,4-三氟苄基氨基)嘌呤 | 10-5 | 76(±4) |
27. | 6-(3-氯-4-氟苄基氨基)嘌呤 | 10-5 | 90(±1) |
实施例9
在苋属生物中对新颖化合物的测试
采用几项改进进行标准苋属生物测定。将尾穗苋(Amaranthuscaudatus)var.atropurpurea在10%的N-氯苯磺酰胺(w/v)中表面消毒10min,然后在去离子水中洗涤5次。将它们放入包含由去离子水饱和的面巾纸的培养皿(petri dishes)中。在25℃下、黑暗中培育72h之后,切割秧苗的根部。将由两个子叶和下胚轴组成的外植体放入5cm培养皿中位于两层滤纸上,该滤纸在1ml包含下列物质的培育介质中浸湿:10μmol NA2HPO4-KH2PO4,pH6.8,5μmol酪氨酸和要测试的细胞分裂素。每个盘有20个外植体。在绿色安全光下在黑暗中进行整个步骤。在25℃下在黑暗中培育48h之后,通过在4ml 3.33μM乙酸中冷冻外植体萃取β-花青苷。通过比较在537nm和620nm的吸光度确定β-花青的浓度如下:ΔA=A537nm-A620nm。从获得的数据,对于每种测试的化合物选择具有最高活性的浓度。计算在此浓度下的化合物相对活性(表6)。将10-4M的6-苄基氨基嘌呤(BAP)获得的活性假定为100%。表8中显示的数值是五次重复试验的平均值,并且重复整个测试两次。
将要测试的细胞分裂素溶于二甲亚砜(DMSO)并采用蒸馏水使溶液达到10-3M。将此原料在用于生物测试的各自培养基中进一步稀释到10-8M~10-4M的浓度。DMSO的最终浓度不超过0.2%并因此不影响使用的测定体系中的生物活性。
表8
新细胞分裂素衍生物对尾穗苋(Amaranthus caudatus)子叶/下胚轴
外植体中β-花青含量的影响
化合物 | 具有最高活性的浓度(mol.l-1) | 活性(%)[10-5mol.l-1BAP |
=100%] | ||||
1. | 6-(2-氟苄基氨基)嘌呤 | 10-4 | 116(±3) | |
2. | 6-(3-氟苄基氨基)嘌呤 | 10-4 | 140(±5) | |
3. | 6-(4-氟苄基氨基)嘌呤 | 10-5 | 44(±4) | |
4. | 6-(2-氯苄基氨基)嘌呤 | 10-5 | 109(±8) | |
5. | 6-(3-氯苄基氨基)嘌呤 | 10-5 | 96(±5) | |
6. | 6-(4-氯苄基氨基)嘌呤 | 10-5 | 35(±7) | |
7. | 6-(2-溴苄基氨基)嘌呤 | 10-4 | 94(±6) | |
8. | 6-(3-溴苄基氨基)嘌呤 | 10-4 | 71(±5) | |
9. | 6-(4-溴苄基氨基)嘌呤 | 10-5 | 17(±7) | |
10. | 6-(3-碘苄基氨基)嘌呤 | 10-5 | 79(±3) | |
11. | 6-(2-甲基苄基氨基)嘌呤 | 10-5 | 98(±22) | |
12. | 6-(3-甲基苄基氨基)嘌呤 | 10-5 | 84(±14) | |
13. | 6-(4-甲基苄基氨基)嘌呤 | 10-5 | 26(±10) | |
14. | 6-(2-甲氧基苄基氨基)嘌呤 | 10-5 | 77(±5) | |
15. | 6-(3-甲氧基苄基氨基)嘌呤 | 10-4 | 90(±16) | |
16. | 6-(4-甲氧基苄基氨基)嘌呤 | 10-4 | 23(±2) | |
17. | 6-(3-硝基苄基氨基)嘌呤 | 10-4 | 66(±7) | |
18. | 6-(4-硝基苄基氨基)嘌呤 | 10-4 | 25(±2) | |
19. | 6-(2,4-二氯苄基氨基)嘌呤 | 10-4 | 19(±8) | |
20. | 6-(3,4-二氯苄基氨基)嘌呤 | 10-4 | 63(±10) | |
21. | 6-(2,3-二甲氧基苄基氨基)嘌呤 | 10-4 | 22(±3) | |
22. | 6-(2,4-二甲氧基苄基氨基)嘌呤 | 10-5 | 12(±2) | |
23. | 6-(3,4-二甲氧基苄基氨基)嘌呤 | 10-4 | 27(±6) | |
24. | 6-(3,5-二甲氧基苄基氨基)嘌呤 | 10-4 | 1,5(±1) | |
25. | 6-(2,4,6-三甲氧基苄基氨基)嘌呤 | 10-4 | 3(±3) | |
26. | 6-(3,4,5-三甲氧基苄基氨基)嘌呤 | 10-4 | 2(±2) | |
27. | 6-(3,4-二羟基苄基氨基)嘌呤 | 10-4 | 8(±3) | |
28. | 6-(2,4-二氟苄基氨基)嘌呤 | 10-4 | 88(±7) | |
29. | 6-(3,5-二氟苄基氨基)嘌呤 | 10-4 | 108(±2) |
30. | 6-(2,3,4-三氟苄基氨基)嘌呤 | 10-4 | 94(±3) |
31. | 6-(3-氯-4-氟苄基氨基)嘌呤 | 10-4 | 91(±7) |
32. | 6-(2-羟基-3-甲氧基苄基氨基)嘌呤 | 10-4 | 19(±3) |
33. | 6-(3-羟基-4-甲氧基苄基氨基)嘌呤 | 10-4 | 24(±1) |
34. | 6-(4-羟基-3-甲氧基苄基氨基)嘌呤 | 10-4 | 10(±2) |
实施例10
新衍生物对玫瑰(多花蔷薇Rosa multiflora)体外和体外后培养(post vitro)培殖和生根的影响。
此试验的目的是测试新化合物是否在组织培养实施中具有实际用途。调查了繁殖率并检验了根部的体外后培养效果。杂交玫瑰(盆玫瑰栽培变种)在350ml容器中培养,容器的聚碳酸酯盖上有螺纹。每个培养容器包含100ml高压灭菌的培养基(120℃,20min)。将培养物在23±2℃、16h光周期、40μMm-2s-1PAR下维持。基底培养基(BMR)包含Murashige和Skoog(1962)常量元素、微量元素和维生素、95μMNaFeEDTA、555μM肌醇,111mM蔗糖,1.332mM甘氨酸,684μML-谷氨酰胺和7g/l琼脂。向此培养基补充10μM BA、mT、oMeOBAP或mMeOBAP(分别为化合物no.14和15)。对照培养不包含任何细胞分裂素。在8周的培养周期之后,确定每个外植体产生的枝条的数目,还确定根数目/外植体和总根长度/外植体。除去根并将外植体(枝条簇)种植在未施肥的泥炭中。在雾单元中水土适应四周之后,确定根数目和根长度。
如期望的那样,无细胞分裂素的培养基几乎不产生新苗。原始枝条外植体长出了良好质量的单枝条,并且生根很好。BAP得到高枝条培殖率,但枝条生根差。当与BAP本身比较时,测试的新BAP衍生物,产生了新枝条的生成并且生根显著较好(表9)。
表9
细胞分裂素对Rosa multiflora中体外和体外后培养的
枝条培殖和生根的影响
细胞分裂素 | 体外 | 体外培养前 | ||||
每个外植体的新枝条数目 | 每个外植体的花数目 | 每个外植体的根数目 | 每个外植体的总根长度(cm) | 每个外植体的根数目 | 每个外植体的总根长度(cm) | |
0 | 0.2 | 0.03 | 0.8 | 1.2 | 4.6 | 17.1 |
BA* | 3.8 | 0.00 | 0.0 | 0.0 | 0.6 | 1.1 |
MOHBAP | 2.1 | 0.16 | 0.0 | 0.0 | 1.4 | 3.8 |
OmeOBAP | 1.0 | 0.29 | 0.0 | 0.0 | 2.5 | 8.5 |
MmeOBAP | 4.3 | 0.03 | 0.0 | 0.0 | 1.7 | 4.1 |
*BA=苄基氨基
实施例11
组织培养玫瑰(杂交玫瑰)的早期枝条衰老抑制
组织培养玫瑰出现衰老症状。叶子开始变棕色并在几周之后,在容器中的所有外植体死掉。当换气受到限制时症状开始得更早,例如由塑料箔的容器的。这表明涉及乙烯我们的其它气体组分。施加到培养基的细胞分裂素产生乙烯,因此在此体系上测试有希望的新细胞分裂素似乎是有价值的。
将杂交玫瑰′Pailin′(切割玫瑰)在350ml容器中培养,容器在聚碳酸酯盖上有螺纹。每个培养容器包含100ml高压灭菌的培养基(120℃,20min)。将培养物在23±2℃、16h光周期、40μMm-2s-1PAR下维持。基底培养基(BMR)包含Murashige和Skoog(1962)常量元素、微量元素和维生素、36.7mg/l NaFeEDTA、50mg/l NaFeEDDHA、100mg/lμM肌醇,30g/l蔗糖,100mg/l甘氨酸,50mg/l泛酸钙,100mg/l L-谷氨酰胺和7g/l琼脂-琼脂(agar-agar)。向此培养基补充10μM BA、mT、和mMeOBAP。将最后2种细胞分裂素过滤器消毒,并在高压灭菌容器中的培养基之后加入。对照培养基不包含任何细胞分裂素。在6周的培养周期之后,划痕衰老症状开始出现。对于每种植物记录第一片棕色叶子出现的日子(图8),以及整个外植体完全死亡的日子(图9,10)。
在含有BA的培养基上,死植物的相对数目看来象S形曲线,表明了自催化衰老的效果,可能由乙烯引起。测量顶部空间的乙烯浓度可能是件有趣的工作。对mT和mMeOBAP,情况有所改进。mMeOBAP确定是最好的化合物。甚至在121天之后,几乎所有的植物仍然活着。尽管在含有mMeOBAP的培养基上不可避免的产生一些棕色叶,但这些植物可轻易地用于下一次的培养。mMeOBAP的使用是玫瑰(杂交玫瑰)微组织繁殖中的一项显著改进。
实施例12
干燥胶囊
5000个胶囊,每个胶囊包含0.25g在先前或以下实施例中提及的具有通式I、II和III的一种化合物作为活性成分,其制备方法如下:
组合物
活性成分 1250g
滑石 180g
小麦淀粉 120g
硬脂酸镁 80g
乳糖 20g
制备工艺:将提及的粉状物质通过目宽度0.6mm的筛网压挤。借助于胶囊填充机,将混合物的0.33g的小部分转移到明胶胶囊。
实施例13
软胶囊
5000个软明胶胶囊,每个胶囊包含0.05g在先前或以下实施例中提及的具有通式I、II和III的一种化合物作为活性成分,其制备方法如下:
组合物
活性成分 250g
Lauroglycol 2升
制备工艺:将粉状活性成分悬浮于Lauroglycol(月桂酸丙二醇酯,GattefosséS.A.,Saint Priest,法国)中,并在湿粉碎机中研磨到约1-3μm的粒度。然后通过胶囊填充机,在每种情况下将混合物的0.419g的小部分转移到软明胶胶囊。
实施例14
软胶囊
5000个明胶胶囊,每个胶囊包含0.05g在先前或以下实施例中提及的具有通式I、II和III的一种化合物作为活性成分,制备如下:
组合物
活性成分 250g
PEG400 1升
Tween 1升
制备工艺:将粉状活性成分悬浮于PEG 400(Mw为380-约420的聚乙二醇,Sigma,Fluka,Aldrich,USA)和Tweens80(聚氧乙烯失水山梨糖醇单月桂酸酯,Atlas Chem.Inc.,Inc.,USA,由Sigma,Fluka,Aldrich,USA提供)并在湿粉碎机中研磨到约1-3mm的粒度。然后通过胶囊填充机,在每种情况下将混合物的0.43g的小部分转移到软明胶胶囊。
工业实用性
根据本发明基于N6-取代腺嘌呤的新杂环化合物适用于诊断和治疗方法,特别是药物工业、化妆品、生物技术和农业等领域。
Claims (15)
1.一种通式I的基于N6-取代腺嘌呤的杂环化合物
及其药用盐,其中
R2是氢、卤素、羟基、烷氧基、氨基、1,2-亚肼基、巯基、羧基、氰基、硝基、酰氨基、磺基、磺酰氨基、酰氨基、酰氧基、烷基氨基、二烷基氨基、烷基巯基、环烷基和氨基甲酰基,
R6是烷基、取代烷基、环烷基、取代环烷基、环烷基烷基、芳基烷基、杂烷基、杂芳基烷基、环杂烷基烷基或R6’-X,
其中X是-O-、-S-、-NH-、-N(C1-6烷基)-;
R6’是氢、烷基、取代烷基、酰基、环烷基、取代环烷基、芳基、取代芳基、杂环、杂芳基、取代杂芳基、芳烷基、环杂烷基、取代环杂烷基、杂芳烷基、杂烷基、环烷基烷基、环杂烷基、酰氨基和磺基;
然而类属取代基具有与在此方面中定义的相应基团定义相同的意义,其中
“卤素”表示氟、溴、氯和碘原子;
“羟基”表示基团-OH;
“巯基”表示基团-SH;
“烷基”表示支化或未支化C1-C6链,该C1-C6链是饱和或不饱和的,选自例示此术语的甲基、丙基、异丙基、叔丁基、烯丙基、乙烯基、乙炔基、炔丙基、己-2-基等;
“取代烷基”表示包括1-5个取代基的刚刚所述烷基,取代基如羟基、巯基、烷基巯基、卤素、烷氧基、酰氧基、氨基、酰氨基、肼基、氨基甲酰基、酰氨基、羧基、磺基、酰基、胍基等,因此这些基团可以连接到烷基部分的任何碳原子上;
“烷氧基”表示基团-OR,其中R是在此定义的烷基、取代烷基、芳基、取代芳基、芳烷基、取代芳烷基、环烷基、取代环烷基、环杂烷基或取代环杂烷基;
“烷基巯基”表示基团-SR,其中R如对于“烷氧基”所定义;
“磺基”表示基团-SO3R,其中R是H、在此定义的烷基或取代烷基;
“磺酰氨基”表示基团-SO2NRR”,其中R和R”是H、烷基或取代烷基;
“酰基”表示-C(O)R,其中R是氢、在此定义的烷基、取代烷基、芳基、取代芳基、芳烷基、取代芳烷基、环烷基、取代环烷基;
“芳氧基”表示-OAr,其中Ar是在此定义的芳基、取代芳基、杂芳基或取代杂芳基官能团;
“烷基氨基”表示基团-NRR’,其中R和R’可以独立地是氢、在此定义的烷基、取代烷基、芳基、取代芳基、杂芳基或取代杂芳基;
“酰氨基”表示基团-C(O)NRR’,其中R和R’可以独立地是氢、在此定义的烷基、取代烷基、芳基、取代芳基、杂芳基或取代杂芳基;
“羧基”表示基团-C(O)OR,其中R是氢、在此定义的烷基、取代烷基、芳基、取代芳基、杂芳基(hetaryl)或取代杂芳基(substitutedhetaryl);
“酰氨基”表示基团-NHCOR,其中R是在此定义的烷基、取代烷基、杂环烷基、芳基、取代芳基、杂芳基和取代杂芳基;
“氨基甲酰基氨基”表示基团NHCOOR,其中R是烷基或芳基;
“芳基”或“ar”表示含有至少一个芳族环的芳族碳环基团,如苯基或联苯或多个稠环,其中至少一个环是芳族的如1,2,3,4-四氢萘基、萘基、蒽基、或菲基;
“取代芳基”表示可选择地由1-5个官能团取代的刚刚所述的芳基,该官能团是如在此定义的卤素、烷基、羟基、氨基、酰氨基、氨基甲酰基氨基、肼基、巯基、烷氧基、烷基巯基、烷基氨基、酰氨基、羧基、硝基、磺基;
“杂环”表示在环中含有至少一个杂原子,如N、O或S的不饱和或芳族碳环基团;环是单环如吡喃基、吡啶基或呋喃基或多个稠环如喹唑啉基、嘌呤基、喹啉基或苯并呋喃基,它们可选择是未取代的或由如下基团取代:在此定义的卤素、氨基、羟基、氰基、硝基、巯基、烷氧基、烷基氨基、酰氨基、氨基甲酰基氨基、酰氧基、二烷基氨基、烷基巯基、羧基、酰氨基、磺基、磺酰氨基等;
“杂芳基”是其中至少一个杂环是芳族的杂环基团;
“取代杂芳基”表示可选择地由1-5个官能团单或多取代的杂环,该官能团是如在此定义的卤素、氨基、羟基、氰基、硝基、巯基、烷氧基、烷基氨基、酰氨基、氨基甲酰基氨基、酰氧基、二烷基氨基、烷基巯基、羧基、酰氨基、磺基、磺酰氨基等;
“芳烷基”表示基团-R-Ar,其中Ar是芳基和R是烷基或取代烷基,其中芳基可选择为未取代的或由如下基团取代:在此定义的卤素、氨基、酰氨基、氨基甲酰基氨基、肼基、酰氧基、烷基、羟基、烷氧基、烷基巯基、烷基氨基、酰氨基、羧基、羟基、芳基、硝基、巯基、磺基等;
“杂烷基”表示基团-R-Het,其中Het是杂环基团而R是烷基,该杂烷基官能团可选择为未取代的或由如下基团取代:之前在此定义的卤素、氨基、羟基、氰基、硝基、巯基、烷氧基、烷基氨基、酰基氨基、氨基甲酰基氨基、酰氧基、二烷基氨基、烷基巯基、羧基、酰氨基、磺基、磺酰氨基等;
“杂芳烷基”表示基团-R-Het-Ar,其中HetAr是杂芳基和R是烷基或取代烷基,而杂芳烷基可选择为未取代的或由如下基团取代:之前在此定义的卤素、烷基、取代烷基、烷氧基、烷基巯基、硝基、硫氢基、磺基等;
“环烷基”表示包含3-15个碳原子的二价环状或多环烷基;
“取代环烷基”表示包括1-5个取代基的环烷基,该取代基选自之前在此定义的卤素、氨基、羟基、氰基、硝基、巯基、烷氧基、烷基氨基、酰基氨基、氨基甲酰基氨基、酰氧基、二烷基氨基、烷基巯基、羧基、酰氨基、磺基、磺酰氨基等;
“环杂烷基”表示在此定义的环烷基,其中至少一个环亚甲基由选自如下的基团替代:NH、OH、SH;
“取代环杂烷基”指的是在此定义的环杂烷基,其中包含1-5个取代基,取代基是如之前在此定义的卤素、氨基、羟基、氰基、硝基、巯基、烷氧基、烷基氨基、酰氨基、氨基甲酰基氨基、酰氧基、二烷基氨基、烷基巯基、羧基、酰氨基、磺基、磺酰氨基等;
“环烷基烷基”表示基团-R-环烷基,其中环烷基是一个环烷基基团而R是烷基或取代烷基,其中环烷基可选择为未取代的或由如下基团取代:之前在此定义的卤素、氨基、羟基、氰基、硝基、巯基、烷氧基、烷基氨基、酰氨基、氨基甲酰基氨基、酰氧基、二烷基氨基、烷基巯基、羧基、酰氨基、磺基、磺酰氨基等;
“环杂烷基烷基”表示基团-R-环杂烷基,其中R是烷基或取代烷基,其中环杂烷基可选择为未取代的或由如下基团取代:之前在此定义的卤素、氨基、羟基、氰基、硝基、巯基、烷氧基、烷基氨基、酰氨基、氨基甲酰基氨基、酰氧基、二烷基氨基、烷基巯基、羧基、酰氨基、磺基、磺酰氨基等;
及其外消旋化合物、旋光异构体和酸盐。
2.根据权利要求1所述的具有通式I的N6-取代腺嘌呤的杂环化合物,其中化合物选自6-(2-羟基-3-氯氧苄基氨基)嘌呤、6-(2-羟基-4-氯苄基氨基)嘌呤、6-(2-羟基-5-氯苄基氨基)嘌呤、6-(2-羟基-6-氯苄基氨基)嘌呤、6-(2-羟基-3-碘苄基氨基)嘌呤、6-(2-羟基-4-碘苄基氨基)嘌呤、6-(2-羟基-5-碘苄基氨基)嘌呤、6-(2-羟基-6-碘苄基氨基)嘌呤、6-(2-羟基-3-溴苄基氨基)嘌呤、6-(2-羟基-4-溴苄基氨基)嘌呤、6-(2-羟基-5-溴苄基氨基)嘌呤、6-(2-羟基-6-溴苄基氨基)嘌呤、6-(2-羟基-3-氟苄基氨基)嘌呤、6-(2-羟基-4-氟苄基氨基)嘌呤、6-(2-羟基-5-氟苄基氨基)嘌呤、6-(2-羟基-6-氟苄基氨基)嘌呤、6-(2,3-二羟基-4-甲氧基苄基氨基)嘌呤、6-(2,5-二羟基-4-甲氧基苄基氨基)嘌呤、6-(2,6-二羟基-3-甲氧基苄基氨基)嘌呤、6-(2,3-二羟基-3-甲氧基苄基氨基)嘌呤、6-(2,5-二羟基-3-甲氧基苄基氨基)嘌呤、6-(2,6-二羟基-4-甲氧基苄基氨基)嘌呤、6-(2,3-二羟基-4-氯苄基氨基)嘌呤、6-(2,3-二羟基-4-氯苄基氨基)嘌呤、6-(2,5-二羟基-4-氯苄基氨基)嘌呤、6-(2,6-二羟基-4-氯苄基氨基)嘌呤、6-(2,6-二羟基-4-溴氧基苄基氨基)嘌呤、6-(2,6-二羟基-4-碘苄基氨基)嘌呤、6-(2,6-二羟基-3-氯苄基氨基)嘌呤、6-(2,6-二羟基-3-溴苄基氨基)嘌呤、6-(2,6-二羟基-3-碘苄基氨基)嘌呤、6-(2,6-二羟基-3-氟苄基氨基)嘌呤、6-(2,6-二羟基-3,5-二氯苄基氨基)嘌呤、6-(2,6-二羟基-3,5-二溴苄基氨基)嘌呤、6-(2,6-二羟基-3,5-二碘苄基氨基)嘌呤、6-(2,6-二羟基-3,5-二氟苄基氨基)嘌呤、6-(2-氟苄基氨基)嘌呤、6-(3-氟苄基氨基)嘌呤、6-(4-氟苄基氨基)嘌呤、6-(2-溴苄基氨基)嘌呤、6-(3-溴苄基氨基)嘌呤、6-(4-溴苄基氨基)嘌呤、6-(2-碘苄基氨基)嘌呤、6-(3-碘苄基氨基)嘌呤、6-(4-碘苄基氨基)嘌呤、6-(2-氯苄基氨基)嘌呤、6-(2-氯苄基氨基)嘌呤、6-(3-氯苄基氨基)嘌呤、6-(4-氯苄基氨基)嘌呤、6-(2-乙酰基苄基氨基)嘌呤、6-(3-乙酰基苄基氨基)嘌呤、6-(4-乙酰基苄基氨基)嘌呤、6-(3-羧基苄基氨基)嘌呤、6-(4-羧基苄基氨基)嘌呤、6-(2-乙酰氧基苄基氨基)嘌呤、6-(3-乙酰氧基苄基氨基)嘌呤、6-(4-乙酰氧基苄基氨基)嘌呤、6-(2-硝基苄基氨基)嘌呤、6-(3-硝基苄基氨基)嘌呤、6-(4-硝基苄基氨基)嘌呤、6-(2-磺基苄基氨基)嘌呤、6-(3-磺基苄基氨基)嘌呤、6-(4-磺基苄基氨基)嘌呤、6-(2-氰基苄基氨基)嘌呤、6-(3-氰基苄基氨基)嘌呤、6-(4-氰基苄基氨基)嘌呤、6-(5-硝基-2-甲基苄基氨基)嘌呤、6-(2-甲基苄基氨基)嘌呤、6-(3-甲基苄基氨基)嘌呤、6-(4-甲基苄基氨基)嘌呤、6-(4-甲基氨基苄基氨基)嘌呤、6-(2-甲氧基苄基氨基)嘌呤、6-(3-甲氧基苄基氨基)嘌呤、6-(4-甲氧基苄基氨基)嘌呤、6-(2-羟基苄基氨基)嘌呤、6-(3-羟基苄基氨基)嘌呤、6-(4-羟基苄基氨基)嘌呤、6-(4-己基苄基氨基)嘌呤、6-(4-己氧基苄基氨基)嘌呤、6-(2-甲酰基苄基氨基)嘌呤、6-(3-甲酰基苄基氨基)嘌呤、6-(4-甲酰基苄基氨基)嘌呤、6-(2-乙氧基苄基氨基)嘌呤、6-(3-乙氧基苄基氨基)嘌呤、6-(4-乙氧基苄基氨基)嘌呤、6-(4-乙基苄基氨基)嘌呤、6-(4-戊基苄基氨基)嘌呤、6-(4-戊氧基苄基氨基)嘌呤、6-(4-苯氧基苄基氨基)嘌呤、6-(4-苯基苄基氨基)嘌呤、6-(4-丙基苄基氨基)嘌呤、6-(4-丙氧基苄基氨基)嘌呤、6-(4-辛基苄基氨基)嘌呤、6-(4-辛氧基苄基氨基)嘌呤、6-(4-乙氧基苄基氨基)嘌呤、6-(3,4-二乙酰氧基苄基氨基)嘌呤、6-(3,5-二乙酰氧基苄基氨基)嘌呤、6-(2,5-二氨基苄基氨基)嘌呤、6-(3,5-二溴苄基氨基)嘌呤、6-(3,5-二溴-4-甲氧基苄基氨基)嘌呤、6-(2,3-二氯苄基氨基)嘌呤、6-(2,4-二氯苄基氨基)嘌呤、6-(2,5-二氯苄基氨基)嘌呤、6-(2,6-二氯苄基氨基)嘌呤、6-(3,4-二氯苄基氨基)嘌呤、6-(3,5-二氯苄基氨基)嘌呤、6-(2,3,4,5-四氟苄基氨基)嘌呤、6-(2-氯-3,6-二氟苄基氨基)嘌呤、6-(5-氯-2-氟苄基氨基)嘌呤、6-(2,3,4-三氟苄基氨基)嘌呤、6-(2,3,5-三氟苄基氨基)嘌呤、6-(2,4,5-三氟苄基氨基)嘌呤、6-(3,4,5-三氟苄基氨基)嘌呤、6-(2,3,6-三氟苄基氨基)嘌呤、6-(3-氯-2,6-二氟苄基氨基)嘌呤、6-(2-氯-6-氟苄基氨基)嘌呤、6-(2,6-二氟苄基氨基)嘌呤、6-(2,4-二氟苄基氨基)嘌呤、6-(3,4-二氟苄基氨基)嘌呤、6-(2,5-二氟苄基氨基)嘌呤、6-(3,5-二氟苄基氨基)嘌呤、6-(5-氟-2-(三氟甲基)苄基氨基)嘌呤、6-(4-氟-2-(三氟甲基)苄基氨基)嘌呤、6-(2-氯-5-(三氟甲基)苄基氨基)嘌呤、6-(2-(二氟甲氧基)苄基氨基)嘌呤、6-(3-(二氟甲氧基)苄基氨基)嘌呤、6-(4-(二氟甲氧基)苄基氨基)嘌呤、6-(2-氟-5-(三氟甲基)苄基氨基)嘌呤、6-(3-氟-4-(三氟甲基)苄基氨基)嘌呤、6-(2-氟-4-(三氟甲基)苄基氨基)嘌呤、6-(2-(三氟甲硫基)苄基氨基)嘌呤、6-(2-氟-3-(三氟甲基)苄基氨基)嘌呤、6-(2-氯-6-氟-3-甲基苄基氨基)嘌呤、6-(6-氯-2-氟-3-甲基苄基氨基)嘌呤、6-(3-氯-2-氟-5-(三氟甲基)苄基氨基)嘌呤、6-(3-氯-2-氟-6-(三氟甲基)苄基氨基)嘌呤、6-(2,3-二氟-4-甲基苄基氨基)嘌呤、6-(2,6-二氟-3-甲基苄基氨基)嘌呤、6-(2-氟-6-(三氟甲基)苄基氨基)嘌呤、6-(3-氯-2,6-二氟苄基氨基)嘌呤、6-(3-(三氟甲硫基)苄基氨基)嘌呤、6-(3-氟-4-甲基苄基氨基)嘌呤、6-(4-氟-3-甲基苄基氨基)嘌呤、6-(5-氟-2-甲基苄基氨基)嘌呤、6-(2-氯-3,6-二氟苄基氨基)嘌呤、6-(4-(三氟甲硫基)苄基氨基)嘌呤、6-(3-氟-5-(三氟甲基)苄基氨基)嘌呤、6-(2-氯-4-氟苄基氨基)嘌呤、6-(2-(三氟甲氧基)苄基氨基)嘌呤、6-(3-(三氟甲基)苄基氨基)嘌呤、6-(2-(三氟甲基)苄基氨基)嘌呤、6-(4-(三氟甲基)苄基氨基)嘌呤、6-(4-氯-3-(三氟甲基)苄基氨基)嘌呤、6-(4-氟-3-(三氟甲基)苄基氨基)嘌呤、6-(3,5-双(三氟甲基)苄基氨基)嘌呤、6-(3-(三氟甲氧基)苄基氨基)嘌呤、6-(4-(三氟甲氧基)苄基氨基)嘌呤、6-(4-(三氟甲基)苄基氨基)嘌呤、6-(4-二乙基氨基苄基氨基)嘌呤、6-(3,4-二羟基苄基氨基)嘌呤、6-(3,5-二羟基苄基氨基)嘌呤、6-(3,4-二羟基苄基氨基)嘌呤、6-(2,3-亚乙基二氧苄基氨基)嘌呤、6-(2,4-二羟基苄基氨基)嘌呤、6-(2,5-二羟基苄基氨基)嘌呤、6-(2,6-二羟基苄基氨基)嘌呤、6-(3,4-二甲氧基苄基氨基)嘌呤、6-(3,4-二甲氧基苄基氨基)嘌呤、6-(3,5-二甲氧基苄基氨基)嘌呤、6-(2,3-二甲氧基苄基氨基)嘌呤、6-(2,4-二甲氧基苄基氨基)嘌呤、6-(2,5-二甲氧基苄基氨基)嘌呤、6-(2,6-二甲氧基苄基氨基)嘌呤、6-(3-羟基-4-甲氧基苄基氨基)嘌呤、6-(2-羟基-3-甲氧基苄基氨基)嘌呤、6-(4-羟基-3-甲氧基苄基氨基)嘌呤、6-(2-羟基-4-甲氧基苄基氨基)嘌呤、6-(4-羟基-2-甲氧基苄基氨基)嘌呤、6-(2-羟基-5-甲氧基苄基氨基)嘌呤、6-(3-羟基-4-甲氧基苄基氨基)嘌呤、6-(4-羟基-3-甲氧基苄基氨基)嘌呤、6-(2-羟基-6-甲氧基苄基氨基)嘌呤、6-(3-羟基-5-甲氧基苄基氨基)嘌呤、6-(4,5-二甲氧基-2-硝基苄基氨基)嘌呤、6-(3,4-二甲基苄基氨基)嘌呤、6-(2,3-二甲基苄基氨基)嘌呤、6-(2,4-二甲基苄基氨基)嘌呤、6-(2,6-二甲基苄基氨基)嘌呤、6-(2,6-二甲基-4-羟基苄基氨基)嘌呤、6-(3,5-二甲基-4-羟基苄基氨基)嘌呤、6-(2-氟-4-羟基苄基氨基)嘌呤、6-(3-氟-4-甲基苄基氨基)嘌呤、6-(3,4-二硝基苄基氨基)嘌呤、6-(3,5-二硝基苄基氨基)嘌呤、6-(2-甲基-5-硝基苄基氨基)嘌呤、6-(3-甲基-4-硝基苄基氨基)嘌呤、6-(3,4-二碘-4-羟基苄基氨基)嘌呤、6-(2-氯-3,4-二甲氧基苄基氨基)嘌呤、6-(4-氯-3,5-二硝基苄基氨基)嘌呤、6-(2-氯-4-氟苄基氨基)嘌呤、6-(3-氯-4-氟苄基氨基)嘌呤、6-(2-氯-6-甲基苄基氨基)嘌呤、6-(3-氯-2-甲基苄基氨基)嘌呤、6-(3-氯-4-甲基苄基氨基)嘌呤、6-(5-氯-2-甲氧基苄基氨基)嘌呤、6-(2-氯-4-氟苄基氨基)嘌呤、6-(4-氯甲基苄基氨基)嘌呤、6-(2-氯-5-硝基苄基氨基)嘌呤、6-(2-氯-6-硝基苄基氨基)嘌呤、6-(4-氯-3-硝基苄基氨基)嘌呤、6-(5-氯-2-硝基苄基氨基)嘌呤、6-(3-溴-4-羟基苄基氨基)嘌呤、6-(3,5-二溴-4-羟基苄基氨基)嘌呤、6-(3-溴-4-甲氧基苄基氨基)嘌呤、6-(4-溴甲基苄基氨基)嘌呤、6-(4-丁氧基苄基氨基)嘌呤、6-(4-丁氧基苄基氨基)嘌呤、6-(4-/叔丁基/苄基氨基)嘌呤、6-(4-叔丁基-2,6-二甲基苄基氨基)嘌呤、6-(2-氨基苄基氨基)嘌呤、6-(3-氨基苄基氨基)嘌呤、6-(4-氨基苄基氨基)嘌呤、6-(2-氨基-6-氯苄基氨基)嘌呤、6-(3-氨基-4-氯苄基氨基)嘌呤、6-(2-氨基-3-氯苄基氨基)嘌呤、6-(2-氨基-4-氯苄基氨基)嘌呤、6-(2-氨基-6-氯苄基氨基)嘌呤、6-(2,6-二氨基-3-氯苄基氨基)嘌呤、6-(2,6-二氨基-4-氯苄基氨基)嘌呤、6-(4-氨基-3-氯苄基氨基)嘌呤、6-(4-氨基-5-二氯苄基氨基)嘌呤、6-(5-氨基-2-甲基苄基氨基)嘌呤、6-(2-氨基-3-硝基苄基氨基)嘌呤、6-(4-氨基-3-硝基苄基氨基)嘌呤、6-(4-苄氧基苄基氨基)嘌呤、6-(3-乙酰基苄基氨基)嘌呤、6-(2-乙酰基苄基氨基)嘌呤、6-(2,3,4-三甲氧基苄基氨基)嘌呤、6-(2,4,5-三甲氧基苄基氨基)嘌呤、6-(2,4,6-三甲氧基苄基氨基)嘌呤、6-(3,4,5-三甲氧基苄基氨基)嘌呤、6-(2,4,6-三甲氧基苄基氨基)嘌呤、6-(2,3,4-三羟基苄基氨基)嘌呤、6-(2,4,6-三羟基苄基氨基)嘌呤、6-(2,3,4-三羟基苄基氨基)嘌呤、6-(3,4,5-三羟基苄基氨基)嘌呤、6-(2,4,6-三羟基苄基氨基)嘌呤、6-(2,4,5-三氯苄基氨基)嘌呤、6-(2,4,5-三氯苄基氨基)嘌呤、6-(2,4,6-三氯苄基氨基)嘌呤、6-(2,3,4-三氯苄基氨基)嘌呤、6-(2,3,5-三氯苄基氨基)嘌呤、6-(2,3,6-三氯苄基氨基)嘌呤、6-(2,5,6-三氯苄基氨基)嘌呤、6-苯胺基嘌呤、6-(2,4-双(三氟甲基)苯胺基)嘌呤、6-(2,5-双(三氟甲基)苯胺基)嘌呤、6-(2,4-双(三氟甲基)苯胺基)嘌呤、6-(3,5-双(三氟甲基)苯胺基)嘌呤、6-(2-溴苯胺基)嘌呤、6-(3-溴苯胺基)嘌呤、6-(4-溴苯胺基)嘌呤、6-(4-溴-2-氯苯胺基)嘌呤、6-(4-溴-3-氯苯胺基)嘌呤、6-(2-溴-6-氯-4-(三氟甲基)苯胺基)嘌呤、6-(4-溴-5,6-二氟苯胺基)嘌呤、6-(2-溴-4,6-二氟苯胺基)嘌呤、6-(4-溴-2,6-二氟苯胺基)嘌呤、6-(4-溴-2-氟苯胺基)嘌呤、6-(2-溴4-氟苯胺基)嘌呤、6-(2-溴-4-甲基苯胺基)嘌呤、6-(3-溴-2-甲基苯胺基)嘌呤、6-(4-溴-3-甲基苯胺基)嘌呤、6-(2-溴-4-(三氟甲氧基)苯胺基)嘌呤、6-(3-溴-4-(三氟甲氧基)苯胺基)嘌呤、6-(4-溴-2-(三氟甲氧基)苯胺基)嘌呤、6-(2-溴-4,5,6-三氟苯胺基)嘌呤、6-(2,4-二溴苯胺基)嘌呤、6-(2,5-二溴苯胺基)嘌呤、6-(2,4-二溴-3,6-二氯苯胺基)嘌呤、6-(2,6-二溴-4-氟苯胺基)嘌呤、6-(2,6-二溴-4-(三氟甲氧基)苯胺基)嘌呤、6-(2,4-二溴-6-(三氟甲氧基)苯胺基)嘌呤、6-(2,6-二溴-4-(三氟甲氧基)苯胺基)嘌呤、6-(2,3-二氯苯胺基)嘌呤、6-(2,4-二氯苯胺基)嘌呤、6-(2,5-二氯苯胺基)嘌呤、6-(2,6-二氯苯胺基)嘌呤、6-(3,4-二氯苯胺基)嘌呤、6-(3,5-二氯苯胺基)嘌呤、6-(2,6-二氯-4-(三氟甲氧基)苯胺基)嘌呤、6-(2,4-二氯-6-(三氟甲氧基)苯胺基)嘌呤、6-(2,6-二氯-4-(三氟甲基)苯胺基)嘌呤、6-(2,3-二氟苯胺基)嘌呤、6-(2,4-二氟苯胺基)嘌呤、6-(2,5-二氟苯胺基)嘌呤、6-(2,6-二氟苯胺基)嘌呤、6-(3,4-二氟苯胺基)嘌呤、6-(3,5-二氟苯胺基)嘌呤、6-(2-二氟甲氧基苯胺基)嘌呤、6-(2-二氟甲氧基-5-硝基苯胺基)嘌呤、6-(2,3-二氟-6-硝基苯胺基)嘌呤、6-(2,4-二氟-6-硝基苯胺基)嘌呤、6-(2,4-二碘苯胺基)嘌呤、6-(2,3-二甲基苯胺基)嘌呤、6-(2,4-二甲基苯胺基)嘌呤、6-(2,3-二甲基-6-硝基苯胺基)嘌呤、6-(2,4-二甲氧基苯胺基)嘌呤、6-(2,3-二甲氧基苯胺基)嘌呤、6-(2,3-二硝基-6-甲基苯胺基)嘌呤、6-(4-羟基-2-甲基苯胺基)嘌呤、6-(2-氯苯胺基)嘌呤、6-(3-氯苯胺基)嘌呤、6-(4-氯苯胺基)嘌呤、6-(3-氯-2,6-二溴-4-氟苯胺基)嘌呤、6-(2-氯-4-氟苯胺基)嘌呤、6-(2-氯-5-氟苯胺基)嘌呤、6-(2-氯-6-氟苯胺基)嘌呤、6-(3-氯-2-氟苯胺基)嘌呤、6-(3-氯-4-氟苯胺基)嘌呤、6-(4-氯-2-氟苯胺基)嘌呤、6-(5-氯-2-氟苯胺基)嘌呤、6-(2-氯-4-氟-5-甲基苯胺基)嘌呤、6-(5-氯-4-氟-2-硝基苯胺基)嘌呤、6-(5-氯-2-羟基苯胺基)嘌呤、6-(4-氯-2-碘苯胺基)嘌呤、6-(2-氯-4-碘苯胺基)嘌呤、6-(2-氯-6-甲基苯胺基)嘌呤、6-(3-氯-2-甲基苯胺基)嘌呤、6-(3-氯-4-(三氟甲氧基)苯胺基)嘌呤、6-(4-氯-2-(三氟甲氧基)苯胺基)嘌呤、6-(2-氟苯胺基)嘌呤、6-(3-氟苯胺基)嘌呤、6-(4-氟苯胺基)嘌呤、6-(2-氟-4-碘苯胺基)嘌呤、6-(2-氟-5-硝基苯胺基)嘌呤、6-(2-氟-4-甲基苯胺基)嘌呤、6-(3-氟-2-甲基苯胺基)嘌呤、6-(3-氟-4-甲基苯胺基)嘌呤、6-(4-氟-2-甲基苯胺基)嘌呤、6-(3-氟-4-甲基苯胺基)嘌呤、6-(5-氟-2-甲基苯胺基)嘌呤、6-(4-氟-2-硝基苯胺基)嘌呤、6-(4-氟-3-硝基苯胺基)嘌呤、6-(2-碘苯胺基)嘌呤、6-(2-氟-4-(三氟甲基)苯胺基)嘌呤、6-(4-碘-2-甲基苯胺基)嘌呤、6-(2-甲氧基苯胺基)嘌呤、6-(3-甲氧基苯胺基)嘌呤、6-(4-甲氧基苯胺基)嘌呤、6-(2-甲氧基-5-甲基苯胺基)嘌呤、6-(2-甲氧基-6-甲基苯胺基)嘌呤、6-(4-甲氧基-2-甲基苯胺基)嘌呤、6-(5-甲氧基-2-甲基苯胺基)嘌呤、6-(4-甲氧基-3-(三氟甲基)苯胺基)嘌呤、6-(2-甲基苯胺基)嘌呤、6-(4-甲基苯胺基)嘌呤、6-(3-甲基苯胺基)嘌呤、6-(2-甲基-3-(三氟甲氧基)苯胺基)嘌呤、6-(2-甲基-4-(三氟甲氧基)苯胺基)嘌呤、6-(2-(甲硫基)苯胺基)嘌呤、6-(4-(甲硫基)苯胺基)嘌呤、6-(2-硝基苯胺基)嘌呤、6-(3-硝基苯胺基)嘌呤、6-(4-硝基苯胺基)嘌呤、6-(2-硝基-4,5,6-三氟苯胺基)嘌呤、6-(2-硝基-4-(三氟甲氧基)苯胺基)嘌呤、6-(2-硝基四氟苯胺基)嘌呤、6-(2,3,4,5,6-五溴苯胺基)嘌呤、6-(2,3,4,5,6-五氟苯胺基)嘌呤、6-(2,3,4,5-四氯苯胺基)嘌呤、6-(2,3,5,6-四氯苯胺基)嘌呤、6-(4-(1,1,2,2-四氟乙氧基)苯胺基)嘌呤、6-(2,3,4,5,-四氟苯胺基)嘌呤、6-(2,3,4,6-四氟苯胺基)嘌呤、6-(2,3,5,6-四氟苯胺基)嘌呤、6-(2,3,5,6-四氟-4-(三氟甲基)苯胺基)嘌呤、6-(2,4,6-四溴苯胺基)嘌呤、6-(2,4,6-三溴-3,5-二碘苯胺基)嘌呤、6-(2,3,4-三氯苯胺基)嘌呤、6-(2,4,5-三氯苯胺基)嘌呤、6-(2,4,6-三氯苯胺基)嘌呤、6-(2,4,5-三氟苯胺基)嘌呤、6-(2,3,5-三氟苯胺基)嘌呤、6-(2,3,6-三氟苯胺基)嘌呤、6-(2,3,4-三氟苯胺基)嘌呤、6-(2-三氟甲氧基苯胺基)嘌呤、6-(3-三氟甲氧基苯胺基)嘌呤、6-(4-三氟甲氧基苯胺基)嘌呤、6-(2,3,4-三氟-6-硝基苯胺基)嘌呤、6-(2,4,5-三甲基苯胺基)嘌呤、6-(2,4,6-三甲基苯胺基)嘌呤、6-(3-氯-5-氨基苯胺基)嘌呤、6-(3-氯-4-羧基苯胺基)嘌呤、6-(3-氨基-4-氯苯胺基)嘌呤、6-(3-氯-4-氨基苯胺基)嘌呤、6-(3-羧基-4-羟基苯胺基)嘌呤。
3.一种根据权利要求1,具有通式I的衍生自N6-取代腺嘌呤组合物物质的杂环化合物的制备方法,其中R2和R6如权利要求1所定义,该方法包括亲核取代以将R6位置的氯、溴、或甲基巯基转化成为在此所述的取代基R6表示的任何其它官能团,以获得具有通式I的化合物。
4.一种从具有通式I的杂环衍生物,其中R2是氢和R6表示氨基,制备根据权利要求1具有通式I的化合物、组合物物质的方法,其中R2和R6如权利要求1定义,该杂环衍生物通过与具有通式R6,-CHO的醛的反应在R6位置被取代,其中R6’如之前在此所述,以将R6位置的氨基转化到之前在此所述的取代基R6表示的任何其它官能团,从而获得具有通式I的化合物,其中R2和R6如权利要求1所定义。
5.一种用作药剂,根据权利要求1具有通式I的基于N6-取代腺嘌呤的杂环化合物及其医药上可接受的盐。
6.一种用作植物、哺乳动物、微生物、酵母和真菌细胞生长调节剂,根据权利要求1具有通式I的基于N6-取代腺嘌呤的杂环化合物。
7.一种用作化妆品,根据权利要求1具有通式I的基于N6-取代腺嘌呤的杂环化合物。
8.一种包括具有通式I的化合物或其医药上可接受的盐,包括一种药物载体的药物、化妆品或生长调节剂。
9.一种使用具有通式I的化合物用于制备如下物质的方法:由14C、3H、卵白素或生物素标记的亲合力吸收基质、用于工艺控制的固定化酶、免疫测定试剂、诊断样品、以及化合物和寡核苷酸。
10.一种使用包括药物载体的具有通式I化合物或它们的药用盐用于制备药物组合物的方法,该药物组合物预定用作有丝分裂或抗有丝分裂化合物,特别是用于治疗癌症、牛皮癣、类风湿性关节炎、狼疮、I型糖尿病、多发性硬化症、再狭窄、多囊性肾病、移植物排斥、移植物抗宿主反应病和痛风、寄生虫病如由真菌或原生生物引起的那些、或阿尔茨海默氏病、或作为抗神经产生性药物、或用于抑制免疫刺激或用于增生性皮肤病的治疗。
11.一种在农业中用作生长调节剂,特别用于增加农产品产量和质量,根据权利要求1具有通式I的基于N6-取代腺嘌呤的杂环化合物。
12.一种用作抑制哺乳动物表皮细胞,如角质化细胞或成纤维细胞老化或衰老,根据权利要求1具有通式I的基于N6-取代腺嘌呤的杂环化合物。
13.一种在细胞培养中用作生长调节剂用于增殖刺激和形态形成,根据权利要求1具有通式I的基于N6-取代腺嘌呤的杂环化合物。
14.根据权利要求1具有通式I的基于N6-取代腺嘌呤的杂环化合物用于制备产物的用途,该产物预定用于植物或哺乳动物胚细胞,优选卵母细胞的克隆。
15.根据权利要求1具有通式I的基于N6-取代腺嘌呤的杂环化合物用于制备药物的用途,该药物预定用于哺乳动物中免疫刺激如关节炎的抑制或用于移植排斥的抑制。
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CZ20012818A CZ294535B6 (cs) | 2001-08-02 | 2001-08-02 | Heterocyklické sloučeniny na bázi N6-substituovaného adeninu, způsoby jejich přípravy, jejich použití pro přípravu léčiv, kosmetických přípravků a růstových regulátorů, farmaceutické přípravky, kosmetické přípravky a růstové regulátory tyto sloučeniny obsahující |
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PCT/CZ2002/000045 WO2003040144A2 (en) | 2001-08-02 | 2002-08-01 | Heterocyclic compound based on n6-substituted adenine, methods of their preparation, their use for preparation of drugs, cosmetic preparations and growth regulators, pharmaceutical preparations, cosmetic preparations and growth regulators containing these compounds |
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