CN86102767A - 5-嘧啶甲酰胺类衍生物的制备方法 - Google Patents
5-嘧啶甲酰胺类衍生物的制备方法 Download PDFInfo
- Publication number
- CN86102767A CN86102767A CN86102767.1A CN86102767A CN86102767A CN 86102767 A CN86102767 A CN 86102767A CN 86102767 A CN86102767 A CN 86102767A CN 86102767 A CN86102767 A CN 86102767A
- Authority
- CN
- China
- Prior art keywords
- pyrimidine
- preparation
- pyrimidine carboxamide
- hydrogen
- carboxamide
- 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.)
- Withdrawn
Links
- QDXGKRWDQCEABB-UHFFFAOYSA-N pyrimidine-5-carboxamide Chemical class NC(=O)C1=CN=CN=C1 QDXGKRWDQCEABB-UHFFFAOYSA-N 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 14
- 239000001257 hydrogen Substances 0.000 claims abstract description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 6
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 5
- 125000003147 glycosyl group Chemical group 0.000 claims abstract description 5
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 4
- 239000011737 fluorine Substances 0.000 claims abstract description 4
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 17
- 239000006185 dispersion Substances 0.000 claims description 9
- 239000007868 Raney catalyst Substances 0.000 claims description 8
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 8
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 8
- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical compound O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 6
- -1 diester malonate Chemical class 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- CNFLWARVXOHHAD-UHFFFAOYSA-N C1=CC(=CC=C1NC(=O)C2=CN=C(N=C2)S(=O)(=O)O)F Chemical compound C1=CC(=CC=C1NC(=O)C2=CN=C(N=C2)S(=O)(=O)O)F CNFLWARVXOHHAD-UHFFFAOYSA-N 0.000 claims description 3
- DRGNAZAUEKLAND-UHFFFAOYSA-N C1=C(C=NC(=N1)S(=O)(=O)O)C(=O)N Chemical compound C1=C(C=NC(=N1)S(=O)(=O)O)C(=O)N DRGNAZAUEKLAND-UHFFFAOYSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 claims description 2
- 229960003082 galactose Drugs 0.000 claims description 2
- 125000005640 glucopyranosyl group Chemical group 0.000 claims description 2
- 125000005113 hydroxyalkoxy group Chemical group 0.000 claims description 2
- 231100000252 nontoxic Toxicity 0.000 claims description 2
- 230000003000 nontoxic effect Effects 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- DUFGYCAXVIUXIP-UHFFFAOYSA-N 4,6-dihydroxypyrimidine Chemical compound OC1=CC(O)=NC=N1 DUFGYCAXVIUXIP-UHFFFAOYSA-N 0.000 claims 1
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- FUXJMHXHGDAHPD-UHFFFAOYSA-N pyrimidine-2-carboxamide Chemical compound NC(=O)C1=NC=CC=N1 FUXJMHXHGDAHPD-UHFFFAOYSA-N 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 35
- 208000032839 leukemia Diseases 0.000 abstract description 8
- 238000011161 development Methods 0.000 abstract description 3
- 238000012360 testing method Methods 0.000 description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 230000000694 effects Effects 0.000 description 16
- 241001465754 Metazoa Species 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 13
- 206010028980 Neoplasm Diseases 0.000 description 11
- 239000000203 mixture Substances 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 230000037396 body weight Effects 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 6
- 230000003203 everyday effect Effects 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000002512 chemotherapy Methods 0.000 description 5
- 239000011248 coating agent Substances 0.000 description 5
- 238000000576 coating method Methods 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- 230000000996 additive effect Effects 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000000470 constituent Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 238000007912 intraperitoneal administration Methods 0.000 description 4
- 210000003734 kidney Anatomy 0.000 description 4
- 238000001819 mass spectrum Methods 0.000 description 4
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 3
- 208000026310 Breast neoplasm Diseases 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 3
- 239000002612 dispersion medium Substances 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 230000010354 integration Effects 0.000 description 3
- 239000007928 intraperitoneal injection Substances 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 239000003182 parenteral nutrition solution Substances 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- LDRKHQOYFHSVGZ-UHFFFAOYSA-N 4-hydroxy-6-oxo-n-phenyl-1h-pyrimidine-5-carboxamide Chemical group N1=CNC(=O)C(C(=O)NC=2C=CC=CC=2)=C1O LDRKHQOYFHSVGZ-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 206010003445 Ascites Diseases 0.000 description 2
- 238000011765 DBA/2 mouse Methods 0.000 description 2
- UMYLUVCVHHSAQH-UHFFFAOYSA-N N-(2-fluorophenyl)-4-hydroxy-6-oxo-1H-pyrimidine-5-carboxamide Chemical compound FC1=C(C=CC=C1)NC(=O)C=1C(NC=NC1O)=O UMYLUVCVHHSAQH-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 239000007943 implant Substances 0.000 description 2
- 239000007951 isotonicity adjuster Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 231100000167 toxic agent Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 239000003440 toxic substance Substances 0.000 description 2
- LDDMACCNBZAMSG-BDVNFPICSA-N (2r,3r,4s,5r)-3,4,5,6-tetrahydroxy-2-(methylamino)hexanal Chemical compound CN[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO LDDMACCNBZAMSG-BDVNFPICSA-N 0.000 description 1
- VNBFUGOVQMFIRN-UHFFFAOYSA-N 1-chlorobutan-2-ol Chemical compound CCC(O)CCl VNBFUGOVQMFIRN-UHFFFAOYSA-N 0.000 description 1
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 208000031648 Body Weight Changes Diseases 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 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
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 241000009328 Perro Species 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 1
- 230000004579 body weight change Effects 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000001767 cationic compounds Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000001207 fluorophenyl group Chemical group 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910001411 inorganic cation Inorganic materials 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- BWSOSTPVYAGLPG-UHFFFAOYSA-N n-(4-fluorophenyl)-4-hydroxy-6-oxo-1h-pyrimidine-5-carboxamide Chemical compound N1=CNC(=O)C(C(=O)NC=2C=CC(F)=CC=2)=C1O BWSOSTPVYAGLPG-UHFFFAOYSA-N 0.000 description 1
- SPIFDSWFDKNERT-UHFFFAOYSA-N nickel;hydrate Chemical compound O.[Ni] SPIFDSWFDKNERT-UHFFFAOYSA-N 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002718 pyrimidine nucleoside Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000011146 sterile filtration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 238000005987 sulfurization reaction Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 235000013311 vegetables Nutrition 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
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- 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
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/60—Three or more oxygen or sulfur atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
用于缓解或抑制白血病发展的新的5-嘧啶甲酰胺,化合物具有下列通式:式中,R1为氢或含1-4个碳原子的烷氧基;R2为氢或糖基;R3和R4为氢或当R1为氢时,R3或R4之一可为氟;及其药物学上可接受的加成盐类。
Description
本发明涉及新的5-嘧啶甲酰胺类,及其药物学上可接受的加成盐类与核苷类。更具体地说,本发明涉及具有抗白学病活性的5-嘧啶甲酰胺衍生物,涉及含此类衍生物作为治疗有效组份的药物组合物,涉及用这类衍生物导致哺乳动物白血病缓解的方法。
本发明新的取代的5-嘧啶甲酰胺类具有以下通式:
式中,R1为氢或含1-4个碳原子的烷氧基;
R2为氢或糖基;
R3和R4为氢,或当R1为氢时,R3或R4之一可为氟;及其药物学上可接受的加成盐类。
可用各种各样的药物学上可接受的有机与无机的成盐试剂形成的加成盐。实用的加成盐可由有机酸与一个当量的碱混合制成,碱例如有机胺,如三乙胺或N-甲基葡糖胺,和无机阳离子,如钠、钾等。本发明有机酸的加成盐一般是在极性和非极性溶剂中都较难溶解的晶态固体。这里所说的极性溶剂如水、甲醇、乙醇,非极性有机溶剂如乙醚、苯、甲苯等。上述加成盐在质子惰性溶剂如二甲基甲酰胺和二甲基亚砜中稍溶。
另一方面,当R2为糖基时,它可为呋喃糖基(如呋喃核糖苷)、吡喃糖基(如阿糖吡喃糖基、吡喃葡萄糖基、吡喃半乳糖基)、它们的脱氧衍生物,或其脂肪族类似物(如在每个烷氧基与烷基中含2-12个碳原子的羟基烷氧基烷基或多羟基烷基,如2-羟基乙氧基甲基或2,3-二羟基丙基)。这里用的“糖基”一词,是指那些形成嘧啶核苷类或假核苷类的环状的与非环状的基团,例如上文规定的含环状与非环状基团的那些物质。
本发明的5-甲酰胺类既能以上述通式的形式存在也能以其任一互变异构形式而存在。为了便于理解,本发明的化合物在这里只以上述通式的形式加以说明,但这应理解为包含其互变异构体或互变异构体的混合物。
本发明5-嘧啶甲酰胺的一般制备方法是:使4,6-二羟基嘧啶或适当的4,6-二羟基-2-烷氧基嘧啶与异氰酸苯酯或适当取代的异氰酸苯酯,在溶剂或分散介质存在下进行反应。这里用的溶剂或分散介质如二甲基亚砜、吡啶、二甲基甲酰胺、N-甲基-吡咯烷酮、二甲基乙酰胺、四氢噻吩砜、四氢噻吩氧化物、乙腈、或是叔胺,如三乙胺。嘧啶与异氰酸苯酯反应物的摩尔比约为2∶1到1∶2,最好是约1.1∶1到1∶1.1就能满足需要。反应可在温度范围约为0℃到200℃下进行,通常约为24℃到160℃。在多数情况下,反应在约80℃到100℃下进行得相当好。反应时间约在0.5到6小时之间,通常在约2-4小时内5-甲酰胺的生成能基本完全。
另一方面,可参考共同审查中的美国专利申请号699,776,1985年2月8日(5933K ON1A)中所描述的方法,用阮内镍还原相应的2-硫代-5-嘧啶甲酰胺来制备5-嘧啶甲酰胺。尤其是,氟代苯基取代的5-嘧啶甲酰胺可按此法从相应的N-(2-氟代苯基)-或N-(4-氟苯基)-取代的2-硫代-5-嘧啶甲酰胺而制得。
2-烷氧基-5-嘧啶甲酰胺类也可由氧-烷基假脲与适当的取代的2-芳酰基氨基丙二酸二酯(由丙二酸二酯与适当的取代或未取代的异氰酸芳酯反应而制得)反应来制备,例如,[(苯基氨基)羰基]丙二酸二乙酯,并分离与回收所得的产物。
本发明新的化合物属于细胞毒药剂,可导致血液恶性肿瘤,如白血病的缓解。这些化合物既可单独使用,也可与其它为此目的有效的化疗药合并使用。这里的“缓解”与“抑制”,是指与未经治疗的病程相比,能阻止或延缓恶性肿瘤或其它病症的发展。
业已发现,新的取代5-甲酰胺对小鼠的用药剂量约为10-200毫克/千克体重,最好是约25-100毫克/千克体重,对缓解白血病有效。Freireich,E.J.等在Cancer Chemotherapy,Reg,50,NO,4,219-244,1966年3月上描述了其它大小与种类的哺乳类动物的剂量的互相关系,抗癌药剂对小鼠、大鼠、仓鼠、狗、猴和人的毒性的定量比较。
为了达到最佳的治疗反应,剂量标准当然可加以调整。例如可将每日服用剂量分成几次服用,或根据治疗情况的变化,剂量可按比例减少。
活性化合物适合于非肠道给药、静脉注射或口服。活性化合物可制成水溶液或水分散液,与表面活性剂,如羟丙基纤维素混合比较合适。也可在甘油、液态聚乙二醇及其混合物和油类中制成分散液。在普通的储存和使用条件下,这些制剂含有防腐剂以制止微生物的生长。
适于注射用的药物形式包括无菌水溶液或无菌水分散液,和为临时制备无菌注射液或分散液用的无菌粉剂。这种应用形式须经灭菌,并须有足够的流动性以保持灌注性能。在制备与储存条件下应当稳定,对微生物,如细菌与真菌的污染应当能防护。
载体可为溶剂或分散介质,包括如水、乙醇、多元醇(如甘油、丙烯醇和液态聚乙烯醇等)、及其适当的混合物和植物油。借助诸如卵磷脂之类的涂层,分散体所需的颗粒直径的保持,或借助表面活性剂可以保持合适的流动性。可用不同的抗细菌和抗真菌药剂,如对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸、硫柳汞等来阻止微生物的作用。许多情况下最好包含剂量形式的等渗剂,如蔗糖或氯化钠等。使在注射配方中掺入延迟吸收剂,如单硬脂酸铝与明胶,可延长注射剂的吸收作用。
无菌注射液的制备方法是将活性化合物与适当的溶剂混合,混入上列其它各种组份,必要时再进行过滤灭菌。一般说来,分散液的制法是将灭菌的活性组份与含分散剂及其它必要组份的无菌载体混合。另一方面,当用无菌粉剂来制备无菌注射液时,则所需组份的无菌过滤的溶液须真空干燥或冷冻干燥后,得到含活性组份及其它必要组份的粉剂。
这里用的“药物学可接受的,实质上指无毒的载体或赋形剂”包括溶剂、分散剂、涂层、抗菌剂和抗真菌剂、等渗剂与吸收延缓剂等。上述介质与药剂是本行业熟知的。与活性组份不相容或有毒的载体或赋形剂除外,用于本发明治疗配方中的载体或赋形剂是经认真研究过的。在治疗用的组合物中也可加入补加的活性组份。
为了易于服用与剂量均一性,按本发明的组合物配制成单位剂量形式更为有利。这里所用的单位剂量形式是指物质上连续的单位,用作对所治疗的哺乳类动物的单位剂量。每一单位内含有预定量的活性物质(这一预定量是根据所需产生的治疗效果计算出来的),与所需要药物适宜的载体结合。单位剂量形式的规格按下列因素直接取决于下列因素:(a)活性物质的特性及预期达到的特定疗效,(b)为治疗在疾病条件下活体的病症而又无严重的细胞毒付反应,要配制这样一种活性物有其技术上雇有的局限性。
白血病的缓解可以达到如应用日剂量5-10天或更长时间,多种剂量或任何所需周期的剂量也可应用。这样给药的结果治疗活性组份在药量上对帮助缓解与抑制白血病的进一步发展是充分的,同时不致有严重的细胞毒性质的副作用。
5-甲酰胺类中最好的是3,4-二氢-6-羟基-4-氧代-N-苯基-5-嘧啶甲酰胺:3,4-二氢-6-羟基-2-甲氧基-4-氧代-N-苯基-5-甲酰胺;N-(4-氟代苯基-3,4-二氢-6-羟基-4-氧代-5-嘧啶甲酰胺;N-(2-氟代苯基)-3,4-二氢-6-羟基-4-氧代-5-嘧啶甲酰胺。
实施例1
3,4-二氢-6-羟基-4-氧代-N-苯基-5-嘧啶甲酰胺
于浓氢氧化铵水溶液(400毫升)和水(400毫升)中加入1,2,3,4-四氢-6-羟基-4-氧代-N-苯基-2-硫代-5-嘧啶甲酰胺(13.2克)此化合物是根据前述共同审查中的美国专利申请号699,766的实施例1中描述的方法制备的)。使嘧啶溶解,于此溶液中加入阮内镍水浆(50克),悬浮液在搅拌下缓缓回流4小时。冷却,用稀盐酸处理由产物与无机物组成的固体,过滤,固体用二当量浓度的氢氧化钠溶液萃取所得的固体并过滤。然后用稀盐酸酸化滤液,所得沉淀再溶解于氢氧化铵水溶液中,用活性炭和硅藻土纯化,用稀酸使之再沉淀。收集固体,水洗并干燥。产量5.8克,熔点200~208℃。质谱231,计算值231;核磁共振谱(DMSO),6.8-7.7δ(芳香族峰);8.28δ(2-H原子;11.8δ(可交换的质子)。
实施例2
3,4-二氢-6-羟基-2-甲氧基-4-氧代-N-苯基-5-嘧啶甲酰胺
于4,6-二羟基-2-甲氧基-嘧啶(6克)的干燥二甲基亚砜溶液中加入三乙胺(5.9毫升)。溶液加热到60℃后加入异氰酸苯酯(5克);溶液在80-90℃下保持两小时。冷却后缓缓加入水使之发生沉淀。
得到米色的固体产物,熔点164~168℃,分析:C H N O的计算值C,55.17%;H,4.21%;N,16.09%;
实测值C,54.84%;H,4.21%;N,5.85%;
质谱,计算值261,实测值261。核磁共振谱(DMSO):3.93δ(单峰,积分3);7.1-7.7δ(复杂单峰,积分6);14.2δ(单峰,积分1)。
实施例3
N-(2-氟代苯基)-3,4-二氢-6-羟基-4-氧代-5-嘧啶甲酰胺
于浓氨水(200毫升)与水(200毫升)的混合物中加入7.2克的原料N-(2-氟代苯基)-1,2,3,4-四氢-6-羟基-4-氧代-2-硫代-5-嘧啶甲酰胺(此原料是根据前述共同审查中的美国专利申请号669,776的实施例1中描述的类似化合物同样的方法制备的),于所得混合物中加入阮内镍(26克)。悬浮液缓缓加热(至80-90℃)6小时,然后冷却。加入浓盐酸直到反应混合物完全酸化,阮内镍开始溶解为止。当不再放出氢气时,收集固体,用水与乙醇洗涤滤饼,然后重新悬浮在乙醇(50毫升)中。悬浮液加热接近沸腾。收集固体,用少量乙醇和乙醚洗涤,然后干燥。产物为4.2克的灰色粉末,无明显熔点,在≥240℃时分解。核磁共振谱和质谱与预期的结果符合。
实施例4
N-(4-氟代苯基)-3,4-二氢-6-羟基-4-氧代-5-嘧啶甲酰胺
于浓氨水(200毫升)与水(200毫升)的混合物中加入7.2克的原料N-(4-氟代苯基)-1,2,3,4-四氢-6-羟基-4-氧代-2-硫代-5-嘧啶甲酰胺(此原料是根据美国专利申请号669,776的实施例1中所描述的类似化合物同样的方法制备的)。在所得混合物中加入阮内镍(26克)。悬浮液缓缓加热(至80-70℃)6小时,然后冷却。加入浓盐酸直到反应混合物完全酸化,阮内镍开始溶解为止。当不再放出氢气时,收集固体,用水与乙醇在滤饼上洗涤,然后重新悬浮在乙醇(50毫升)中。悬浮液加热到接近沸腾。收集固体,用少量乙醇和乙醚洗涤,然后干燥。产物为4.2克的灰色粉末,无明显熔点,在≥240℃时分解。核磁共振谱和质谱与预期的结构符合。
实施例1-4的化合物的抗白血病活性
与其它5-嘧啶-甲酰胺在缓解腹腔(i.p)内植入淋巴白血病L1210的作用比较。
在实施例1-4的试验化合物的样品与其它类似结构的取代的5-嘧啶甲酰胺类的试样,根据国家癌症研究所试验议定书3LE31(NCI议定书1.100,癌症化疗报告第3部分第3卷第二期,1972年9月)进行体内试验,以测定这些化合物对腹腔内植入的L1210白血病(J.Nat′l.Cancer Inst.13(5):1328,1953)的作用。每项试验包括向6只DBA/2小鼠植入白血病细胞,每次实验一种性别的动物,雄性小鼠体重最小为18克,雌性小鼠体重最小为17克,全部试验动物的体重变化范围在3克之内。试验化合物在肿瘤植入一天之后,在0.1毫升剂量的稀释的腹水液(每剂量105个细胞)中用腹腔注射法给药,每日给药连续9天。
在30天的试验期间,每天称重试验动物并记录残存者。治疗动物与对照动物生存时间的比值(T/C)以百分率的形式求出。
按每个试验化合物所得到的结果,以不同的剂量标准来进行上述试验。在3LE31试验系统中,业已统计地测出初始T/C值应至少等于125%,才能显示试验化合物的活性,重复的T/C等于或大于125%,有必要进一步加以研究。重复的T/C值达到150%或更高时,就看作有明显的活性。
试验结果概括在表Ⅰ中:
用上述3LE31议定书试验另外的对照化合物3,4-二氢-6-羟基-4-氧代-N-苯基-5-嘧啶硫代甲酰胺(对照物T),这一实施例1化合物的硫化类似物在体内试验没有活性。它显示以下活性:
剂量(毫克/千克) T/C%
200 98
100 96
50 92
25 96
通过3 LE31试验系统,实施例1-4的全部化合物都表现出能重复的抗白血病活性,有必要加以进一步研究(T/C>125%),另一方面其对照化合物没有一个显示活性。
除了3 LE31试验之外,实施例3的化合物还根据国家癌症研究所3PS31议定书(腹膜内入P388白血病)和3MBG5(肾下包膜人类乳腺癌MX-1异种皮移植)进行试验如下:
实施例3的化合物对缓解腹腔内植入的P388白血病的抗白血病活性
根据国际癌症研究所试验议定书3PS31(癌症化疗报告第三部分第3卷第二期,1972年9月)对实施例3的试验化合物进行体内试验以测定其对腹腔内植入的P388白血病(美国病理杂志33卷3期,603页,1957)的疗效。每项试验包括在6只DBA/2小鼠中植入白血病细胞,每次实验用一种性别的动物,雄性小鼠体重最小为18克,雌性小鼠体重最小为17克,全部试验动物体重的变化范围在3克内。试验化合物在肿瘤植入一天之后,在0.1毫升剂量的稀释腹水液(每剂量106个细胞)中用腹腔内注射法给药,每日给药连续5天。
在30天的试验期内,每天称重试验动物并记录残存者。治疗动物与对照动物存活时间的比值(T/C)以百分率的形式求出。
以不同的剂量标准来进行上述试验。在3PS31试验系统中,初始T/C值必须至少等于或大于120%,才能说明试验化合物有中等活性。重复的T/C达到175%或更高,就认为具有明显的活性。实施例3的化合物显示下列活性;
剂量(毫克/千克) T/C% T/C%(重复)
400 - -
200 188 171
100 158 144
50 124 134
25 128 127
可见实施例3的化合物,在剂量低达25毫克/千克时也显示出抗白血病的活性(T/C%>120%)。
实施例3的化合物对缓解肾下包膜人类
乳腺癌MX-1异种皮移植中的比较试验
根据国家癌症研究所试验议定书3MBG5(癌症化疗报告第3部分第三卷第2期,1972年9月),将实施例3的试验化合物进行体内试验以测定其对肾下包膜人类乳腺癌(在1974年将经化疗的29岁妇女的原发性乳腺肿瘤进行外科移植)的作用。每次试验均涉及在无胸腺瑞士鼠或无胸腺随意饲养的小鼠的肾包膜下植入肿瘤碎片。每个试验组有6只小鼠,每个对照组有12只小鼠,每次实验用一种性别的动物。雄性小鼠体重最小为18克,雄性小鼠体重最小为17克,全部试验动物体重变化范围在4克之内。试验化合物在肿瘤植入一天之后,以腹腔注射给药,每四天重复1次,共注射3次。
在11天的试验期内,每天称重试验动物并记录死亡数。治疗动物与对照动物的平均肿瘤重量变化的比值以百分率(T/C)的形式求出,上述试验所用剂量不同。
业已测出初始T/C值应至少小于或等于20%,才能说明化合物的中等活性。重复的T/C值要小于或等于10%,认为具有显著活性。实施例3的化合物显示出下列活性:
剂量(毫克/千克) T/C% T/C%(重复)
800 - -
400 - 58
200 33 51
100 55 67
业已发现实施例3的化合物在3MBG5系统中没有活性。
综上所述,可以看到根据本发明提供的一类新型的取代的5-嘧啶甲酰胺,这些化合物能够缓解和/或抑制白血病的发展。很明显,可以对本发明的治疗上有活性的化合物的制备和应用的方法可以有多种变动。上面所包括的内容只应当作例证,而本发明的范围,则应根据所附权利要求书来理解。
Claims (12)
2、权利要求1的方法,其中4,6-二羟基-嘧啶或适当的4,6-二羟基-2-烷氧基-嘧啶与异氰酸苯酯或适当取代的异氰酸苯酯的摩尔比从2∶1到1∶2,反应在0到200℃的温度范围内进行。
3、权利要求1的方法,其中所述5-嘧啶甲酰胺的R3和R4都是氢。
4、权利要求1中所述通式的5-嘧啶甲酰胺的制备方法包括用阮内镍还原相应的2-硫代-5-嘧啶甲酰胺。
5、权利要求4中所述5-嘧啶甲酰胺的制备方法,其中R3或R4之一为氢时,另一为氟,该方法包括用阮内镍还原相应的N-(2-氟代苯基)或N-(4-氟代苯基)取代的2-硫代-5-嘧啶甲酰胺。
6、权利要求1中所述通式的5-嘧啶甲酰胺的制备方法包括用阮内镍还原相应的N-(2-氟代苯基)或N-(4-氟代苯基)取代的2-硫代-5-嘧啶甲酰胺。
7、权利要求1中所述通式的2-烷氧基-5-嘧啶甲酰胺的制备方法包括用氧-烷基假脲与适当取代的2-芳酰基氨基丙二酸二酯进行反应
8、上述权利要求1-4制备3,4-二氢-6-羟基-4-氧代-N-苯基-5-嘧啶甲酰胺的制备方法。
9、上述权利要求1-4制备3,4-二氢-6-羟基-2-甲氧基-4-氧代-N-苯基-5-嘧啶甲酰胺的方法。
10、上述权利要求4-6制备N-(2-氟代苯基)-3,4-二氢-6-羟基-4-氧代-5-嘧啶甲酰胺的方法。
11、上述权利要求4-6制备N-(4-氟代苯基)-3,4-二氢-6-羟基-4-氧代-5-嘧啶甲酰胺的方法。
12、一种制备药物组合物的方法,该方法包括用上述任一项权利要求制备的产物与药物学上可接受的实质上无毒的载体或赋形剂混合。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US06/725,736 US4636508A (en) | 1985-04-22 | 1985-04-22 | 5-pyrimidinecarboxyamides and treatment of leukemia therewith |
US725,736 | 1985-04-22 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN86102767A true CN86102767A (zh) | 1987-01-07 |
CN1014990B CN1014990B (zh) | 1991-12-04 |
Family
ID=24915762
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN86102767A Expired CN1014990B (zh) | 1985-04-22 | 1986-04-22 | 5-嘧啶甲酰胺类衍生物的制备方法 |
CN88103648A Pending CN1038450A (zh) | 1985-04-22 | 1988-06-11 | 取代的5-嘧啶甲酰胺类衍生物 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN88103648A Pending CN1038450A (zh) | 1985-04-22 | 1988-06-11 | 取代的5-嘧啶甲酰胺类衍生物 |
Country Status (21)
Country | Link |
---|---|
US (1) | US4636508A (zh) |
JP (1) | JPS6259264A (zh) |
CN (2) | CN1014990B (zh) |
AT (1) | AT391864B (zh) |
AU (3) | AU592559B2 (zh) |
BE (1) | BE904641A (zh) |
CA (1) | CA1274509A (zh) |
CH (1) | CH668970A5 (zh) |
DE (1) | DE3613447A1 (zh) |
DK (1) | DK182986A (zh) |
ES (3) | ES8800671A1 (zh) |
FR (1) | FR2580642B1 (zh) |
GB (1) | GB2174391B (zh) |
GR (1) | GR861024B (zh) |
IL (2) | IL78576A0 (zh) |
IT (1) | IT1214499B (zh) |
LU (1) | LU86403A1 (zh) |
NL (1) | NL8601023A (zh) |
NZ (1) | NZ215874A (zh) |
SE (1) | SE8601826L (zh) |
ZA (1) | ZA862630B (zh) |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4845217A (en) * | 1985-05-17 | 1989-07-04 | Uniroyal Chemical Ltd./Ltee | Purification of 5-pyrimidinecarboxamides |
US4920126A (en) * | 1988-05-10 | 1990-04-24 | Uniroyal Chemical Ltd/Uniroyal Chemical Ltee | Barbituric acid derivative and treatment of leukemia and tumors therewith |
FR2628741A1 (fr) * | 1988-07-14 | 1989-09-22 | Uniroyal Chemical Ltd | Nouveaux composes n-phenyl-5-pyrimidinecarboxamides et composition pharmaceutique les contenant utilisable pour induire la regression de la leucemie ou des tumeurs |
FR2628869A1 (zh) * | 1988-07-14 | 1989-09-22 | Uniroyal Chemical Ltd | |
EP0430885A3 (en) * | 1989-12-01 | 1991-11-06 | Ciba-Geigy Ag | Anthelmintical compounds |
WO2003035076A1 (en) * | 2001-10-26 | 2003-05-01 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa | Dihydroxypyrimidine carboxamide inhibitors of hiv integrase |
US9428466B2 (en) * | 2013-11-13 | 2016-08-30 | Raymond P. Warrell, Jr. | Methods for reducing uric acid levels using barbiturate derivatives |
US10093631B2 (en) * | 2014-02-14 | 2018-10-09 | Acquist Llc | Bifunctional compounds and use for reducing uric acid levels |
EP3247704A4 (en) | 2015-01-22 | 2018-10-03 | Acquist LLC | Bifunctional compounds and use for reducing uric acid levels |
TWI772309B (zh) | 2016-06-30 | 2022-08-01 | 美商艾克奎斯特有限責任公司 | 化合物及其於降低尿酸位準之用途(二) |
WO2018009615A1 (en) | 2016-07-06 | 2018-01-11 | Acquist Llc | Compounds and their use for reducing uric acid levels |
WO2018200571A1 (en) | 2017-04-25 | 2018-11-01 | Arbutus Biopharma Corporation | Substituted 2,3-dihydro-1h-indene analogs and methods using same |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE1670756A1 (de) * | 1966-10-05 | 1970-12-23 | Hoechst Ag | Verfahren zur Herstellung von 6-Amino-uracil-5-carbonamid-N-sulfonamiden |
DE2405733C2 (de) * | 1974-02-07 | 1984-12-13 | Bayer Ag, 5090 Leverkusen | Amidocarbonylthiobarbitursäurederivate und deren Salze, Verfahren zu ihrer Herstellung sowie ihre Verwendung zur Bekämpfung von Insekten, Milben und Pilzen |
CH614944A5 (en) * | 1974-04-16 | 1979-12-28 | Sandoz Ag | Process for the preparation of novel pyrimidine derivatives |
DE2719777A1 (de) * | 1976-05-06 | 1977-11-24 | Ciba Geigy Ag | Neue 5-phenylcarbamoyl-barbitursaeuren |
PL103086B1 (pl) * | 1976-05-06 | 1979-05-31 | Ciba Geigy Ag | Srodek owadobojczy |
US4283444A (en) * | 1978-09-12 | 1981-08-11 | Ciba-Geigy Corporation | Method of protecting keratinous material from attack by insects that feed on keratin by treatment with 5-phenylcarbamoylbarbituric acid compounds |
US4349552A (en) * | 1978-10-30 | 1982-09-14 | Fujisawa Pharmaceutical Company, Ltd. | 5-Fluorouracil derivatives, and their pharmaceutical compositions |
JPS5625166A (en) * | 1979-08-09 | 1981-03-10 | Banyu Pharmaceut Co Ltd | 5-fluorouracil derivative |
JPS5843960A (ja) * | 1981-09-10 | 1983-03-14 | Shoichiro Ozaki | 5−フルオロウラシル誘導体,その製造法および制ガン剤 |
DE3347795A1 (de) * | 1983-01-14 | 1985-08-01 | Ozaki, Shoichiro, Ehime | Neue 1-(n-substituierte carbamoyl)-5-fluorouracil-derivate und krebshemmende mittel, in denen sie als aktive bestandteile enthalten sind |
JPS6012322A (ja) * | 1983-07-01 | 1985-01-22 | Toyota Motor Corp | 四リンク型サスペンシヨン |
IL73840A (en) * | 1983-12-19 | 1988-11-15 | Uniroyal Chem Co Inc | 2-thio-5-(thio)carbamoyl barbituric acid derivatives,their preparation and pharmaceutical compositions containing them |
-
1985
- 1985-04-22 US US06/725,736 patent/US4636508A/en not_active Expired - Fee Related
-
1986
- 1986-04-08 ZA ZA862630A patent/ZA862630B/xx unknown
- 1986-04-16 GB GB08609244A patent/GB2174391B/en not_active Expired
- 1986-04-17 AT AT0101986A patent/AT391864B/de not_active IP Right Cessation
- 1986-04-18 NZ NZ215874A patent/NZ215874A/xx unknown
- 1986-04-18 GR GR861024A patent/GR861024B/el unknown
- 1986-04-18 IT IT8620153A patent/IT1214499B/it active
- 1986-04-18 CA CA000507040A patent/CA1274509A/en not_active Expired - Lifetime
- 1986-04-21 SE SE8601826A patent/SE8601826L/xx not_active Application Discontinuation
- 1986-04-21 DK DK182986A patent/DK182986A/da not_active Application Discontinuation
- 1986-04-21 CH CH1604/86A patent/CH668970A5/de not_active IP Right Cessation
- 1986-04-21 DE DE19863613447 patent/DE3613447A1/de active Granted
- 1986-04-21 FR FR8605715A patent/FR2580642B1/fr not_active Expired
- 1986-04-21 AU AU56418/86A patent/AU592559B2/en not_active Ceased
- 1986-04-21 BE BE0/216567A patent/BE904641A/fr not_active IP Right Cessation
- 1986-04-22 ES ES554245A patent/ES8800671A1/es not_active Expired
- 1986-04-22 IL IL78576A patent/IL78576A0/xx not_active IP Right Cessation
- 1986-04-22 NL NL8601023A patent/NL8601023A/nl not_active Application Discontinuation
- 1986-04-22 CN CN86102767A patent/CN1014990B/zh not_active Expired
- 1986-04-22 LU LU86403A patent/LU86403A1/fr unknown
- 1986-04-22 JP JP61093171A patent/JPS6259264A/ja active Pending
-
1987
- 1987-08-19 ES ES557683A patent/ES8801219A1/es not_active Expired
- 1987-08-19 ES ES557684A patent/ES8801220A1/es not_active Expired
-
1988
- 1988-06-11 CN CN88103648A patent/CN1038450A/zh active Pending
- 1988-06-12 IL IL8886711A patent/IL86711A0/xx unknown
- 1988-09-15 AU AU22195/88A patent/AU2219588A/en not_active Abandoned
- 1988-09-15 AU AU22196/88A patent/AU2219688A/en not_active Abandoned
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0001981B1 (de) | Neue 9-(Omega-heteroarylamino-alkylamino)-erythromycine, ihre Salze, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende Arzneimittel | |
EP0679656B1 (en) | Improvements in platinum complexes | |
CN86102767A (zh) | 5-嘧啶甲酰胺类衍生物的制备方法 | |
CN111448189A (zh) | 一种联芳基衍生物、其制备方法和在药学上的应用 | |
CN87103096A (zh) | N-(2′-氨基苯基)-苯甲酰胺衍生物其制备方法以及含它们的药物组合物 | |
EP2303848A2 (de) | Uracilderivate und deren verwendung | |
CN101045165A (zh) | 虾青素的羟丙基-β-环糊精的包合物及制备方法 | |
WO2012175046A1 (zh) | 水溶性铂配合物在制备防治肿瘤药物的用途 | |
WO2012175045A1 (zh) | 用于肿瘤治疗的含氟水溶性铂配合物及其制备方法 | |
JPS61171495A (ja) | 白金錯体類及びその製造方法 | |
CN1124278C (zh) | 铂配合物、其制备和治疗应用 | |
RU2141322C1 (ru) | Иммуномодулятор с антимикобактериальной активностью "изофон", способ его получения и применения | |
JPS62289591A (ja) | テトラヒドロ−3,4−フランジアミン−n,n’−白金錯体 | |
AT392469B (de) | Verfahren zur herstellung von neuen chinolinderivaten | |
DE3424107A1 (de) | Organogermaniumverbindung und diese als wirkstoff enthaltender opioidpeptidaseinhibitor | |
CN1068002C (zh) | 铂抗癌药物及合成 | |
CN1256331C (zh) | 杂多酸5-氟尿嘧啶盐类抗肿瘤药物及其合成方法 | |
EP0194571B1 (de) | Heterocyclische Disulfide, Verfahren zu ihrer Herstellung und pharmazeutische Mittel, die diese Verbindungen enthalten | |
CN1273446C (zh) | 一种抗生育化合物及其制备方法 | |
CN1780824A (zh) | 预防和治疗内毒素相关疾病和病症的组合物和方法 | |
RU2191015C2 (ru) | Динатриевая соль n-(6-метил-2,4-диоксо-1,2,3,4-тетрагидро-5h-пиримидинсульфон)-n'- изоникотиноилгидразида, проявляющая антимикробную и иммунотропную активность, и лекарственное средство на ее основе | |
JPH029855A (ja) | 置換ベンゼン誘導体、それらの製造方法及びそれらを含有する抗癌性組成物 | |
CN112300235B (zh) | 一种苯并咪唑衍生物bi321及其制备方法和应用 | |
WO1988003923A1 (en) | 9-substituted guanines | |
EA002153B1 (ru) | N,n'-(сульфонилди-1,4-фенилен)бис(n'',n''-диметилформамидин)-1,2,3,4-тетрагидро-6-метил-2,4-диоксо-5-пиримидинсульфонат, стимулирующий клеточный метаболизм и обладающий иммунотропной и антимикобактериальной активностью, и способ его получения |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C13 | Decision | ||
GR02 | Examined patent application | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C19 | Lapse of patent right due to non-payment of the annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |